KR102682154B1 - Aggregation induced emission compound and composition for cell imaging using the same - Google Patents
Aggregation induced emission compound and composition for cell imaging using the same Download PDFInfo
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- KR102682154B1 KR102682154B1 KR1020200126356A KR20200126356A KR102682154B1 KR 102682154 B1 KR102682154 B1 KR 102682154B1 KR 1020200126356 A KR1020200126356 A KR 1020200126356A KR 20200126356 A KR20200126356 A KR 20200126356A KR 102682154 B1 KR102682154 B1 KR 102682154B1
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- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- KTMKRRPZPWUYKK-UHFFFAOYSA-N methylboronic acid Chemical compound CB(O)O KTMKRRPZPWUYKK-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000013365 molecular weight analysis method Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 1
- 239000012855 volatile organic compound Substances 0.000 description 1
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Abstract
본 발명은 응집유도발광용 화합물 및 이를 이용한 세포이미징용 조성물에 관한 것으로, 보다 상세하게는 인돌리진 분자 골격체를 기반으로 하는 응집유도발광용 화합물, 상기 응집유도발광용 화합물 및 미토콘드리아 타겟물질이 결합된 미토콘드리아 타겟용 복합체, 및 이를 이용한 세포이미징용 조성물에 관한 것이다.
본 발명에서는 분자의 특정 위치에 전자밀도의 변화를 통해 모든 색의 발광파장을 낼 수 있는 체계적인 구조를 가진 인돌리진 골격체를 기반으로 하는 신규한 응집유도발광 물질을 합성하였으며, 이들을 미토콘드리아 타겟용 물질과 결합하여 사용할 경우, 세포의 미토콘드리아에 염색되어 별도의 세척과정 없이 효과적으로 세포 이미징이 가능함을 확인하였다. 따라서, 본 발명의 신규한 응집유도발광 물질은 다양한 세포 이미징에 유용하게 활용할 수 있다.The present invention relates to a compound for aggregation-induced luminescence and a composition for cell imaging using the same, and more specifically, to a compound for aggregation-induced luminescence based on an indolizine molecular framework, where the compound for aggregation-induced luminescence and a mitochondrial target material are combined. It relates to a complex for targeting mitochondria and a composition for cell imaging using the same.
In the present invention, we synthesized a novel aggregation-induced luminescent material based on the indolizine skeleton, which has a systematic structure that can emit light emitting wavelengths of all colors through changes in electron density at specific positions of the molecule, and used them as mitochondria-targeting materials. When used in combination with , it was confirmed that effective cell imaging is possible without a separate washing process by staining the mitochondria of cells. Therefore, the novel aggregation-induced luminescent material of the present invention can be usefully used for various cell imaging.
Description
본 발명은 응집유도발광용 화합물 및 이를 이용한 세포이미징용 조성물에 관한 것으로, 보다 상세하게는 인돌리진 분자 골격체를 기반으로 하는 응집유도발광용 화합물, 상기 응집유도발광용 화합물 및 미토콘드리아 타겟물질이 결합된 미토콘드리아 타겟용 복합체, 및 이를 이용한 세포이미징용 조성물에 관한 것이다.The present invention relates to a compound for aggregation-induced luminescence and a composition for cell imaging using the same, and more specifically, to a compound for aggregation-induced luminescence based on an indolizine molecular framework, where the compound for aggregation-induced luminescence and a mitochondrial target material are combined. It relates to a complex for targeting mitochondria and a composition for cell imaging using the same.
형광 현상은 현대 과학과 의약 기술에 있어서 필수적인 빛을 기반으로 하는 과학 기술이다. 그러나 대부분의 전형적인 형광체는 응집에 의한 소거(Aggregation caused quenching=ACQ) 현상을 나타내므로, 이런 ACQ 효과에 의해 실용적인 응용에 방해가 되는 문제점이 있다.Fluorescence phenomenon is a light-based scientific technology that is essential in modern science and medical technology. However, since most typical phosphors exhibit aggregation caused quenching (ACQ), there is a problem that the ACQ effect hinders practical application.
최근, 몇가지 형광물질들에서 응집 유도 발광(Aggregation induced emission = AIE) 현상을 보이는 AIEgen이라 불리우는 물질들이 발견되었으며, 이들 AIEgen은 응집이 되어 고체상태가 되면 강한 형광을 보이는 특성을 나타내었다. 이런 독특한 메커니즘에 의해, AIEgen은 전형적인 형광물질이 갖는 ACQ 현상의 단점을 극복할 수 있으므로, 형광 물질로 신규 AIEgen의 발견이 큰 각광을 받게 되었다. AIEgen 물질을 이용하여 세포이미징 및 실시간 관찰에 적용하는 연구가 많이 이루어지고 있으며, 나아가, 항암제 등의 약물 치료에도 적용하는 방법이 연구되고 있다 (대한민국 등록특허 제10-1830579호, 대한민국공개특허 제10-2018-0102443호).Recently, several fluorescent substances called AIEgen, which exhibit aggregation induced emission (AIE) phenomenon, were discovered, and these AIEgens exhibited strong fluorescence when aggregated and in a solid state. Through this unique mechanism, AIEgen can overcome the shortcomings of the ACQ phenomenon of typical fluorescent materials, so the discovery of new AIEgen as a fluorescent material has received great attention. A lot of research is being done on applying AIEgen materials to cell imaging and real-time observation, and furthermore, methods of applying them to drug treatment such as anticancer drugs are being studied (Korea Registered Patent No. 10-1830579, Korea Published Patent No. 10) -2018-0102443).
이에, 본 발명에서는 보다 효과적인 응집 유도 발광 물질을 개발하기 위해 예의 노력하였으며, 인돌리진 골격체를 기반으로 새로운 응집유도 발광 물질을 합성하였으며, 이를 갤럭시 플로어(GalaxyFluor; GxF, 이하, "GxF" 또는 "GxF 물질"로 표기함)로 명명하였다. GxF는 분자의 특정 위치에 전자밀도의 변화를 통해 모든 색의 발광파장을 낼 수 있는 체계적인 구조가 되도록 제조한 것으로, 본 발명에서는 결정구조 분석, 컴퓨터 계산 및 용매 의존 발색 현상등의 연구를 통해 GxF 구조 내에서 분자 내 전하 이동과 분자 내 회전 제한을 통한 상승 효과를 제안하였다. Accordingly, in the present invention, we made diligent efforts to develop a more effective aggregation-inducing luminescent material, and synthesized a new aggregation-inducing luminescent material based on the indolizine skeleton, which was called Galaxy Fluor (GxF), hereinafter referred to as "GxF" or " It was named “GxF material”). GxF is manufactured to have a systematic structure that can emit light wavelengths of all colors through changes in electron density at specific positions of the molecule. In the present invention, GxF was developed through research on crystal structure analysis, computer calculations, and solvent-dependent color development. A synergistic effect was proposed through intramolecular charge transfer and intramolecular rotation restriction within the structure.
또한, 총 75종의 GxF 화합물 중에서 응집유도 발광 물질에 적합한 화합물 4종을 선별하였으며, 이들을 미토콘드리아 타겟용 물질과 결합하여 사용할 경우, 세포의 미토콘드리아에 염색되어 별도의 세척과정 없이 효과적으로 세포 이미징이 가능함을 확인하고, 발명을 완성하였다.In addition, among a total of 75 types of GxF compounds, 4 types of compounds suitable for aggregation-inducing luminescent materials were selected, and when these are used in combination with mitochondrial targeting materials, they stain the mitochondria of cells, enabling effective cell imaging without a separate washing process. Confirmed, the invention was completed.
본 발명의 목적은 응집유도발광용 화합물을 제공하는 데 있다.The purpose of the present invention is to provide a compound for aggregation-induced luminescence.
본 발명의 다른 목적은 미토콘드리아 타겟을 위한 미토콘드리아 타겟물질-응집유도발광용 화합물 복합체 및 이를 이용한 세포이미징용 조성물을 제공하는 데 있다.Another object of the present invention is to provide a mitochondrial target material-aggregation-induced luminescence compound complex for targeting mitochondria and a composition for cell imaging using the same.
상술한 목적을 달성하기 위해, To achieve the above-mentioned purpose,
본 발명은 하기 화학식 1로 표시되는 응집유도발광용 화합물을 제공한다.The present invention provides a compound for aggregation-induced luminescence represented by the following formula (1).
[화학식 1][Formula 1]
상기 화학식 1에서, In Formula 1,
R1은 수소; 니트릴기; 할로겐; 니트로기; C1-C6의 알콕시기; C6-C20의 아릴기; C5-C20의 시클로헤테로고리기; 보론기; 아자이드기; NR4R5(여기에서, R4 및 R5는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임), 니트릴, C1-C6의 알콕시, 할로겐, 보론기, 하이드록시기 또는 CH2NR4R5 (여기에서, R4 및 R5는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임)로 치환된 C6-C20의 아릴기; C1-C8의 직쇄 또는 측쇄 알킬기; C2-C8의 알케닐기; C2-C8의 알키닐기; C3-C8의 시클로알킬기; 또는 C4-C20의 헤테로아릴기이고,R 1 is hydrogen; Nitrile group; halogen; nitro group; C 1 -C 6 alkoxy group; C 6 -C 20 aryl group; C 5 -C 20 cycloheterocyclic group; boron group; Azide group; NR 4 R 5 (where R 4 and R 5 are each independently hydrogen, a C 1 -C 10 alkyl group, a C 6 -C 20 aryl group, or a C 4 -C 20 heteroaryl group), nitrile, C 1 -C 6 alkoxy, halogen, boron group, hydroxy group or CH 2 NR 4 R 5 (where R 4 and R 5 are each independently hydrogen, C 1 -C 10 alkyl group, C 6 -C 20 a C 6 -C 20 aryl group substituted with an aryl group or a C 4 -C 20 heteroaryl group; C 1 -C 8 straight or branched alkyl group; C 2 -C 8 alkenyl group; C 2 -C 8 alkynyl group; C 3 -C 8 cycloalkyl group; or a C 4 -C 20 heteroaryl group,
R2는 수소; C1-C8의 직쇄 또는 측쇄 알킬기; C2-C8의 알케닐기; C2-C8의 알키닐기; C3-C8의 시클로알킬기; 하이드록시기; C1-C6의 알콕시기; 폴리에틸렌글라이콜기; 니트릴기; 니트로기; 카르복실기; 설포닐기; 아자이드기; 메탄설포닐기; 말레이미드기; 터셔리-부틸디메틸실릴기(TBS)로 보호된 알콜; 또는 NR6R7(여기에서, R6 및 R7는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임)이고,R 2 is hydrogen; C 1 -C 8 straight or branched alkyl group; C 2 -C 8 alkenyl group; C 2 -C 8 alkynyl group; C 3 -C 8 cycloalkyl group; hydroxyl group; C 1 -C 6 alkoxy group; polyethylene glycol group; Nitrile group; nitro group; Carboxyl group; Sulfonyl group; Azide group; methanesulfonyl group; maleimide group; Alcohol protected with tertiary-butyldimethylsilyl group (TBS); or NR 6 R 7 (where R 6 and R 7 are each independently hydrogen, a C 1 -C 10 alkyl group, a C 6 -C 20 aryl group, or a C 4 -C 20 heteroaryl group),
R3는 수소; 할로겐; 니트릴기; 보론기; 하이드록시기; COY(여기에서 Y는 수소, C1-C8의 직쇄 또는 측쇄 알킬기, C2-C8의 알케닐기, C2-C8의 알키닐기, C3-C8의 시클로알킬기, 또는 NR8R9(여기에서, R8 및 R9는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임]); C1-C6의 알콕시기; C6-C20의 아릴기; 또는 NR10R11(여기에서, R10 및 R11는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임), 니트릴 또는 할로겐으로 치환된 C6-C20의 아릴기이다.R 3 is hydrogen; halogen; Nitrile group; boron group; hydroxyl group; COY (where Y is hydrogen, C 1 -C 8 straight or branched alkyl group, C 2 -C 8 alkenyl group, C 2 -C 8 alkynyl group, C 3 -C 8 cycloalkyl group, or NR 8 R 9 (where R 8 and R 9 are each independently hydrogen, a C 1 -C 10 alkyl group, a C 6 -C 20 aryl group, or a C 4 -C 20 heteroaryl group]); an alkoxy group of C 6 -C 20 or NR 10 R 11 (where R 10 and R 11 are each independently hydrogen, a C 1 -C 10 alkyl group, or a C 6 -C 20 aryl group; It is a C 4 -C 20 heteroaryl group), and a C 6 -C 20 aryl group substituted with nitrile or halogen.
본 발명의 바람직한 일실시예에 있어서, 상기 R1은 수소; 트리플루오로메틸기(Trifluoromethyl); 아세틸기; 메톡시기; 또는 다이메틸아민기이고, 상기 R2는 메틸; 트리플루오로메틸페닐기; 페닐기; 메톡시페닐기; 또는 다이에틸아민페닐기이며, 상기 R3는 수소; 트리플루오로메틸기(Trifluoromethyl); 또는 아세틸기일 수 있다. In a preferred embodiment of the present invention, R 1 is hydrogen; Trifluoromethyl; Acetyl group; methoxy group; or a dimethylamine group, and R 2 is methyl; trifluoromethylphenyl group; phenyl group; methoxyphenyl group; or a diethylamine phenyl group, and R 3 is hydrogen; Trifluoromethyl; Or it may be an acetyl group.
본 발명의 바람직한 다른 일실시예에 있어서, 상기 화학식 1은 하기 화학식 1-1 내지 화학식 1-75로 구성된 군에서 선택된 1종 이상으로 표시될 수 있다. In another preferred embodiment of the present invention, Formula 1 may be represented by one or more members selected from the group consisting of the following Formulas 1-1 to 1-75.
[화학식 1-1][Formula 1-1]
[화학식 1-2][Formula 1-2]
[화학식 1-3][Formula 1-3]
[화학식 1-4][Formula 1-4]
[화학식 1-5][Formula 1-5]
[화학식 1-6][Formula 1-6]
[화학식 1-7][Formula 1-7]
[화학식 1-8][Formula 1-8]
[화학식 1-9][Formula 1-9]
[화학식 1-10][Formula 1-10]
[화학식 1-11][Formula 1-11]
[화학식 1-12][Formula 1-12]
[화학식 1-13][Formula 1-13]
[화학식 1-14][Formula 1-14]
[화학식 1-15][Formula 1-15]
[화학식 1-16][Formula 1-16]
[화학식 1-17][Formula 1-17]
[화학식 1-18][Formula 1-18]
[화학식 1-19][Formula 1-19]
[화학식 1-20][Formula 1-20]
[화학식 1-21][Formula 1-21]
[화학식 1-22][Formula 1-22]
[화학식 1-23][Formula 1-23]
[화학식 1-24][Formula 1-24]
[화학식 1-25][Formula 1-25]
[화학식 1-26][Formula 1-26]
[화학식 1-27][Formula 1-27]
[화학식 1-28][Formula 1-28]
[화학식 1-29][Formula 1-29]
[화학식 1-30][Formula 1-30]
[화학식 1-31][Formula 1-31]
[화학식 1-32][Formula 1-32]
[화학식 1-33][Formula 1-33]
[화학식 1-34][Formula 1-34]
[화학식 1-35][Formula 1-35]
[화학식 1-36][Formula 1-36]
[화학식 1-37][Formula 1-37]
[화학식 1-38][Formula 1-38]
[화학식 1-39][Formula 1-39]
[화학식 1-40][Formula 1-40]
[화학식 1-41][Formula 1-41]
[화학식 1-42][Formula 1-42]
[화학식 1-43][Formula 1-43]
[화학식 1-44][Formula 1-44]
[화학식 1-45][Formula 1-45]
[화학식 1-46][Formula 1-46]
[화학식 1-47][Formula 1-47]
[화학식 1-48][Formula 1-48]
[화학식 1-49][Formula 1-49]
[화학식 1-50][Formula 1-50]
[화학식 1-51][Formula 1-51]
[화학식 1-52][Formula 1-52]
[화학식 1-53][Formula 1-53]
[화학식 1-54][Formula 1-54]
[화학식 1-55][Formula 1-55]
[화학식 1-56][Formula 1-56]
[화학식 1-57][Formula 1-57]
[화학식 1-58][Formula 1-58]
[화학식 1-59][Formula 1-59]
[화학식 1-60][Formula 1-60]
[화학식 1-61][Formula 1-61]
[화학식 1-62][Formula 1-62]
[화학식 1-63][Formula 1-63]
[화학식 1-64][Formula 1-64]
[화학식 1-65][Formula 1-65]
[화학식 1-66][Formula 1-66]
[화학식 1-67][Formula 1-67]
[화학식 1-68][Formula 1-68]
[화학식 1-69][Formula 1-69]
[화학식 1-70][Formula 1-70]
[화학식 1-71][Formula 1-71]
[화학식 1-72][Formula 1-72]
[화학식 1-73][Formula 1-73]
[화학식 1-74][Formula 1-74]
[화학식 1-75][Formula 1-75]
본 발명의 바람직한 또 다른 일실시예에 있어서, 상기 화학식 1은 바람직하게 상기 화학식 1-1, 화학식 1-3, 화학식 1-5 및 화학식 1-11로 구성된 군에서 선택된 1종 이상으로 표시될 수 있다. In another preferred embodiment of the present invention, Formula 1 may preferably be represented by one or more selected from the group consisting of Formula 1-1, Formula 1-3, Formula 1-5, and Formula 1-11. there is.
본 발명의 바람직한 또 다른 일실시예에 있어서, 상기 응집유도발광용 화합물은 화학식 1-1로 표시되는 화합물 ＞ 화학식 1-11로 표시되는 화합물 ＞ 화학식 1-5로 표시되는 화합물 ＞ 화학식 1-3으로 표시되는 화합물 순으로 형광 증가율이 높을 수 있다. In another preferred embodiment of the present invention, the compound for aggregation-induced luminescence is a compound represented by Formula 1-1 > a compound represented by Formula 1-11 > a compound represented by Formula 1-5 > Formula 1-3 The fluorescence increase rate may be higher in the order of compounds indicated by .
또한, 본 발명은 (a) 화학식 A의 화합물 및 화학식 B의 화합물을 반응시켜, 화학식 C의 화합물을 제조하는 단계; In addition, the present invention includes the steps of (a) reacting a compound of Formula A and a compound of Formula B to prepare a compound of Formula C;
(b) 상기 화학식 C의 화합물과 에틸아크릴레이트(ethyl acrylate), 아세트산나트륨(sodium acetate) 및 구리아세트산 모노수화물(Copper(II) Acetate monohydrate)을 반응시켜 화학식 D의 화합물을 제조하는 단계;(b) preparing a compound of Formula D by reacting the compound of Formula C with ethyl acrylate, sodium acetate, and copper(II) Acetate monohydrate;
(c) 상기 화학식 D의 화합물 및 NBS(N-Bromosuccinimide)를 반응시켜 화학식 E의 화합물을 제조하는 단계; 및 (c) reacting the compound of Formula D with N-Bromosuccinimide (NBS) to prepare a compound of Formula E; and
(d) 상기 화학식 E의 화합물 및 화학식 F의 화합물을 반응시켜 화학식 1의 화합물을 제조하는 단계를 포함하며, 하기 반응식 1로 표시되는 화학식 1의 응집유도발광용 화합물의 제조방법을 제공한다:(d) preparing a compound of Formula 1 by reacting the compound of Formula E and the compound of Formula F, and providing a method for producing a compound for aggregation-induced luminescence of Formula 1, represented by the following Scheme 1:
[반응식 1][Scheme 1]
상기 R1은 수소; 트리플루오로메틸기(Trifluoromethyl); 아세틸기; 메톡시기; 또는 다이메틸아민기이고, 상기 R2는 메틸; 트리플루오로메틸페닐기; 페닐기; 메톡시페닐기; 또는 다이에틸아민페닐기이며, 상기 R3는 수소; 트리플루오로메틸기(Trifluoromethyl); 또는 아세틸기이다.R 1 is hydrogen; Trifluoromethyl; Acetyl group; methoxy group; or a dimethylamine group, and R 2 is methyl; trifluoromethylphenyl group; phenyl group; methoxyphenyl group; or a diethylamine phenyl group, and R 3 is hydrogen; Trifluoromethyl; Or it is an acetyl group.
상술한 다른 목적을 달성하기 위해, To achieve the other purposes described above,
본 발명은 상기 응집유도발광용 화합물 및 미토콘드리아 타겟물질이 결합된 미토콘드리아 타겟용 복합체를 제공한다.The present invention provides a mitochondrial targeting complex in which the aggregation-induced luminescence compound and the mitochondrial targeting material are combined.
본 발명의 바람직한 일실시예에 있어서, 상기 미토콘드리아 타겟물질은 TPP(triphenylphosphonium), 로다민(rhodamine), 로다민 19(rhodamine 19), 로다민 123(rhodamine 123), 실리콘 로다민-Me(Siliconrhodamien-Me), JC-1 (5,5,6,6-Tetrachloro-1,1,3,3-tetraethylbenzimidazolylcarbocyanine iodide) 및 MPP(N-methyl-4-phenylpyridinium)로 구성된 군에서 선택된 하나의 친유성 양이온(Lipophilic cation); TOM(translocase of the outer membrane) 및 TIM(translocase of the inner membrane)를 표적으로 하는 미토콘드리아 표적 신호 펩티드(Mitochondrial targeting signal peptide; MTS); DQA(Delocalized lipophilic cations, such as dequalinium); 페닐설포닐프록산(phenylsulfonylfuroxan); 구아니딘(guanidine); 사이클릭 구아니딘(cyclic guanidine); 또는 F-16(4-[(1E)-2-(1H-indol-3-yl)ethenyl]-1-methyl-pyridinium iodide)일 수 있다.In a preferred embodiment of the present invention, the mitochondrial target material is TPP (triphenylphosphonium), rhodamine, rhodamine 19, rhodamine 123, and silicon rhodamien-Me (Siliconrhodamien-Me). Me), one lipophilic cation ( Lipophilic cation); Mitochondrial targeting signal peptide (MTS) targeting the translocase of the outer membrane (TOM) and the translocase of the inner membrane (TIM); Delocalized lipophilic cations, such as dequalinium (DQA); phenylsulfonylfuroxan; guanidine; cyclic guanidine; Or it may be F-16 (4-[(1E)-2-(1H-indol-3-yl)ethenyl]-1-methyl-pyridinium iodide).
또한, 본 발명은 상기 응집유도발광용 화합물 및 미토콘드리아 타겟물질이 결합된 미토콘드리아 타겟용 복합체를 포함하는 세포이미징용 조성물을 제공한다.In addition, the present invention provides a composition for cell imaging comprising a mitochondrial targeting complex in which the aggregation-induced luminescence compound and the mitochondrial targeting material are combined.
또한, 본 발명은 상기 응집유도발광용 화합물 및 미토콘드리아 타겟물질이 결합된 미토콘드리아 타겟용 복합체를 포함하는 세포이미징용 키트를 제공한다.In addition, the present invention provides a kit for cell imaging comprising a mitochondrial targeting complex in which the aggregation-induced luminescence compound and the mitochondrial targeting material are combined.
또한, 본 발명은 상기 응집유도발광용 화합물 및 미토콘드리아 타겟물질이 결합된 미토콘드리아 타겟용 복합체를 세포와 접촉시키는 단계를 포함하는 세포 이미징 방법을 제공한다.In addition, the present invention provides a cell imaging method including the step of contacting a mitochondrial targeting complex, in which the aggregation-induced luminescence compound and the mitochondrial targeting material are bound, with a cell.
본 발명에서는 분자의 특정 위치에 전자밀도의 변화를 통해 모든 색의 발광파장을 낼 수 있는 체계적인 구조를 가진 인돌리진 골격체를 기반으로 하는 신규한 응집유도발광 물질을 합성하였으며, 이들을 미토콘드리아 타겟용 물질과 결합하여 사용할 경우, 살아있는 세포의 미토콘드리아에 염색되어 별도의 세척과정 없이 효과적으로 세포 이미징이 가능함을 확인하였다. 따라서, 본 발명의 신규한 응집유도발광 물질은 다양한 세포 이미징에 유용하게 활용할 수 있다.In the present invention, we synthesized a novel aggregation-induced luminescent material based on the indolizine skeleton, which has a systematic structure that can emit light emitting wavelengths of all colors through changes in electron density at specific positions of the molecule, and used them as mitochondria-targeting materials. When used in combination with , it was confirmed that effective cell imaging is possible without a separate washing process by staining the mitochondria of living cells. Therefore, the novel aggregation-induced luminescent material of the present invention can be usefully used for various cell imaging.
도 1은 본 발명의 신규한 응집유도발광용 화합물인 GxF의 화학적 구조와 호모(HOMO) 및 루모(LUMO)의 모양을 나타낸 모식도이다.
도 2는 GxF 1, GxF 3, GxF 5 및 GxF 11의 화학적 구조와 호모(HOMO) 및 루모(LUMO)의 모양을 나타낸 모식도이다.
도 3은 본 발명의 응집유도발광용 화합물의 제조방법을 나타낸 모식도이다.
도 4는 전 가시광선 영역에 걸친 발광 파장을 보이는 형광 화합물의 특징을 나타낸 도면이다.
도 5는 본 발명의 응집유도발광용 화합물의 응집유도발광현상을 유도한 결과이다. (a) GxF 화합물의 화학적 핵심 골격 구조, (b) 고체 상태에서 GxF 11(파란색), GxF 1(녹색), GxF 3(주황색) 및 GxF 5(빨간색)의 방출 스펙트럼, (c) 용액(THF, 바이알) 및 고체 필름의 주변 광(위) 및 365nm UV 광(아래)하에서 화합물 GxF 11, GxF 1, GxF 3 및 GxF 5 (왼쪽에서 오른쪽으로) 사진, 및 (d) 물 분획(0-90 %)이 다른 THF/물 혼합 용매(20 μM)에서 GxF 11, GxF 1, GxF 3 및 GxF 5 (왼쪽에서 오른쪽으로) 용액의 방출 스펙트럼이다.
도 6은 THF / 물 혼합물에서 GxF 11(a, b), GxF 1(c, d), GxF 3(e, f) 및 GxF 5(g, h) 용액의 응집에 따른 동적광산란(DLS) 신호(a,c,e,g) 및 형광 방출 스펙트럼(b,d,f,h)을 확인한 결과이다.
도 7은 GxF 1 및 GxF 63의 x-선 회절 분석법을 이용한 단분자 구조분석(A) 및 결정구조 분석(B) 결과이다.
도 8은 본 발명의 응집유도발광용 화합물의 THF / Hexane 비율에 따른 용매의존 발색 현상의 변화를 확인한 결과이다.
도 9는 본 발명의 응집유도발광용 화합물의 용매에 따른 형광 강도의 변화를 확인한 결과이다.
도 10은 TPP-GxF 복합체의 제조방법을 나타낸 모식도이다.
도 11은 TPP-GxF 복합체를 세포에 처리한 후, 별도의 세척 과정 없이 세포를 관찰한 형광 이미징 사진이다.
도 12는 TPP-GxF 복합체를 세포에 처리하였을 때와 미토콘드리아 내 발현시킨 형광 단백질의 위치를 확인한 데이터이다.
도 13은 TPP-GxF 복합체를 세포에 처리한 후, 별도의 세척 과정 없이 시간의 흐름에 따라 세포를 관찰한 형광 이미징 사진이다.
도 14는 농도에 따른 TPP-GxF 복합체를 세포에 처리한 후, 별도의 세척 과정 없이 세포 내 미토콘드리아 염색 이미지를 확인한 사진이다.Figure 1 is a schematic diagram showing the chemical structure of GxF, a novel compound for aggregation-induced luminescence of the present invention, and the shapes of HOMO and LUMO.
Figure 2 is a schematic diagram showing the chemical structures of GxF 1, GxF 3, GxF 5 and GxF 11 and the shapes of HOMO and LUMO.
Figure 3 is a schematic diagram showing a method for producing the compound for aggregation-induced luminescence of the present invention.
Figure 4 is a diagram showing the characteristics of a fluorescent compound that exhibits an emission wavelength spanning the entire visible light range.
Figure 5 shows the results of inducing the aggregation-induced luminescence phenomenon of the compound for aggregation-induced luminescence of the present invention. (a) Chemical core framework structure of the GxF compound, (b) emission spectra of GxF 11 (blue), GxF 1 (green), GxF 3 (orange), and GxF 5 (red) in the solid state, (c) solution (THF) , vial) and (d) photographs of compounds GxF 11, GxF 1, GxF 3, and GxF 5 (from left to right) under ambient light (top) and 365 nm UV light (bottom) of solid films, and (d) water fraction (0-90 %) are the emission spectra of solutions of GxF 11, GxF 1, GxF 3 and GxF 5 (from left to right) in different THF/water mixed solvents (20 μM).
Figure 6 shows dynamic light scattering (DLS) signals resulting from aggregation of GxF 11 (a, b), GxF 1 (c, d), GxF 3 (e, f) and GxF 5 (g, h) solutions in THF / water mixture. (a, c, e, g) and fluorescence emission spectra (b, d, f, h).
Figure 7 shows the results of single molecule structural analysis (A) and crystal structure analysis (B) using x-ray diffraction analysis of GxF 1 and GxF 63.
Figure 8 shows the results of confirming the change in solvent-dependent color development according to the THF / Hexane ratio of the compound for aggregation-induced luminescence of the present invention.
Figure 9 shows the results of confirming the change in fluorescence intensity of the compound for aggregation-induced luminescence according to the solvent of the present invention.
Figure 10 is a schematic diagram showing the manufacturing method of the TPP-GxF complex.
Figure 11 is a fluorescence imaging photograph of cells observed without a separate washing process after treating the cells with the TPP-GxF complex.
Figure 12 shows data confirming the location of the fluorescent protein expressed in the mitochondria when cells were treated with the TPP-GxF complex.
Figure 13 is a fluorescence imaging photograph of cells observed over time without a separate washing process after treating the cells with the TPP-GxF complex.
Figure 14 is a photograph showing intracellular mitochondrial staining images without a separate washing process after treating cells with TPP-GxF complexes at different concentrations.
이하 본 발명을 상세하게 설명한다. Hereinafter, the present invention will be described in detail.
응집유도발광용 화합물Compound for aggregation-induced luminescence
본 발명은 하기 화학식 1로 표시되는 응집유도발광용 화합물을 제공한다.The present invention provides a compound for aggregation-induced luminescence represented by the following formula (1).
[화학식 1][Formula 1]
상기 화학식 1에서, In Formula 1,
R1은 수소; 니트릴기; 할로겐; 니트로기; C1-C6의 알콕시기; C6-C20의 아릴기; C5-C20의 시클로헤테로고리기; 보론기; 아자이드기; NR4R5(여기에서, R4 및 R5는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임), 니트릴, C1-C6의 알콕시, 할로겐, 보론기, 하이드록시기 또는 CH2NR4R5 (여기에서, R4 및 R5는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임)로 치환된 C6-C20의 아릴기; C1-C8의 직쇄 또는 측쇄 알킬기; C2-C8의 알케닐기; C2-C8의 알키닐기; C3-C8의 시클로알킬기; 또는 C4-C20의 헤테로아릴기이고,R 1 is hydrogen; Nitrile group; halogen; nitro group; C 1 -C 6 alkoxy group; C 6 -C 20 aryl group; C 5 -C 20 cycloheterocyclic group; boron group; Azide group; NR 4 R 5 (where R 4 and R 5 are each independently hydrogen, a C 1 -C 10 alkyl group, a C 6 -C 20 aryl group, or a C 4 -C 20 heteroaryl group), nitrile, C 1 -C 6 alkoxy, halogen, boron group, hydroxy group or CH 2 NR 4 R 5 (where R 4 and R 5 are each independently hydrogen, C 1 -C 10 alkyl group, C 6 -C 20 a C 6 -C 20 aryl group substituted with an aryl group or a C 4 -C 20 heteroaryl group; C 1 -C 8 straight or branched alkyl group; C 2 -C 8 alkenyl group; C 2 -C 8 alkynyl group; C 3 -C 8 cycloalkyl group; or a C 4 -C 20 heteroaryl group,
R2는 수소; C1-C8의 직쇄 또는 측쇄 알킬기; C2-C8의 알케닐기; C2-C8의 알키닐기; C3-C8의 시클로알킬기; 하이드록시기; C1-C6의 알콕시기; 폴리에틸렌글라이콜기; 니트릴기; 니트로기; 카르복실기; 설포닐기; 아자이드기; 메탄설포닐기; 말레이미드기; 터셔리-부틸디메틸실릴기(TBS)로 보호된 알콜; 또는 NR6R7(여기에서, R6 및 R7는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임)이고,R 2 is hydrogen; C 1 -C 8 straight or branched alkyl group; C 2 -C 8 alkenyl group; C 2 -C 8 alkynyl group; C 3 -C 8 cycloalkyl group; hydroxyl group; Alkoxy group of C 1 -C 6 ; polyethylene glycol group; Nitrile group; nitro group; Carboxyl group; Sulfonyl group; Azide group; methanesulfonyl group; maleimide group; Alcohol protected with tertiary-butyldimethylsilyl group (TBS); or NR 6 R 7 (where R 6 and R 7 are each independently hydrogen, a C 1 -C 10 alkyl group, a C 6 -C 20 aryl group, or a C 4 -C 20 heteroaryl group),
R3는 수소; 할로겐; 니트릴기; 보론기; 하이드록시기; COY(여기에서 Y는 수소, C1-C8의 직쇄 또는 측쇄 알킬기, C2-C8의 알케닐기, C2-C8의 알키닐기, C3-C8의 시클로알킬기, 또는 NR8R9(여기에서, R8 및 R9는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임]); C1-C6의 알콕시기; C6-C20의 아릴기; 또는 NR10R11(여기에서, R10 및 R11는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임), 니트릴 또는 할로겐으로 치환된 C6-C20의 아릴기이다.R 3 is hydrogen; halogen; Nitrile group; boron group; hydroxyl group; COY (where Y is hydrogen, C 1 -C 8 straight or branched alkyl group, C 2 -C 8 alkenyl group, C 2 -C 8 alkynyl group, C 3 -C 8 cycloalkyl group, or NR 8 R 9 (where R 8 and R 9 are each independently hydrogen, a C 1 -C 10 alkyl group, a C 6 -C 20 aryl group, or a C 4 -C 20 heteroaryl group]); an alkoxy group of C 6 -C 20 or NR 10 R 11 (where R 10 and R 11 are each independently hydrogen, a C 1 -C 10 alkyl group, or a C 6 -C 20 aryl group; It is a C 4 -C 20 heteroaryl group), and a C 6 -C 20 aryl group substituted with nitrile or halogen.
본 발명의 바람직한 일실시예에 있어서, 상기 R1은 수소; 트리플루오로메틸기(Trifluoromethyl); 아세틸기; 메톡시기; 또는 다이메틸아민기이고, 상기 R2는 메틸; 트리플루오로메틸페닐기; 페닐기; 메톡시페닐기; 또는 다이에틸아민페닐기이며, 상기 R3는 수소; 트리플루오로메틸기(Trifluoromethyl); 또는 아세틸기일 수 있다. In a preferred embodiment of the present invention, R 1 is hydrogen; Trifluoromethyl; Acetyl group; methoxy group; or a dimethylamine group, and R 2 is methyl; trifluoromethylphenyl group; phenyl group; methoxyphenyl group; or a diethylamine phenyl group, and R 3 is hydrogen; Trifluoromethyl; Or it may be an acetyl group.
바람직하게, 상기 화학식 1은 하기 화학식 1-1 내지 화학식 1-75으로 구성된 군에서 선택된 1종 이상으로 표시될 수 있다. Preferably, Formula 1 may be represented by one or more members selected from the group consisting of the following Formulas 1-1 to 1-75.
[화학식 1-1][Formula 1-1]
[화학식 1-2][Formula 1-2]
[화학식 1-3][Formula 1-3]
[화학식 1-4][Formula 1-4]
[화학식 1-5][Formula 1-5]
[화학식 1-6][Formula 1-6]
[화학식 1-7][Formula 1-7]
[화학식 1-8][Formula 1-8]
[화학식 1-9][Formula 1-9]
[화학식 1-10][Formula 1-10]
[화학식 1-11][Formula 1-11]
[화학식 1-12][Formula 1-12]
[화학식 1-13][Formula 1-13]
[화학식 1-14][Formula 1-14]
[화학식 1-15][Formula 1-15]
[화학식 1-16][Formula 1-16]
[화학식 1-17][Formula 1-17]
[화학식 1-18][Formula 1-18]
[화학식 1-19][Formula 1-19]
[화학식 1-20][Formula 1-20]
[화학식 1-21][Formula 1-21]
[화학식 1-22][Formula 1-22]
[화학식 1-23][Formula 1-23]
[화학식 1-24][Formula 1-24]
[화학식 1-25][Formula 1-25]
[화학식 1-26][Formula 1-26]
[화학식 1-27][Formula 1-27]
[화학식 1-28][Formula 1-28]
[화학식 1-29][Formula 1-29]
[화학식 1-30][Formula 1-30]
[화학식 1-31][Formula 1-31]
[화학식 1-32][Formula 1-32]
[화학식 1-33][Formula 1-33]
[화학식 1-34][Formula 1-34]
[화학식 1-35][Formula 1-35]
[화학식 1-36][Formula 1-36]
[화학식 1-37][Formula 1-37]
[화학식 1-38][Formula 1-38]
[화학식 1-39][Formula 1-39]
[화학식 1-40][Formula 1-40]
[화학식 1-41][Formula 1-41]
[화학식 1-42][Formula 1-42]
[화학식 1-43][Formula 1-43]
[화학식 1-44][Formula 1-44]
[화학식 1-45][Formula 1-45]
[화학식 1-46][Formula 1-46]
[화학식 1-47][Formula 1-47]
[화학식 1-48][Formula 1-48]
[화학식 1-49][Formula 1-49]
[화학식 1-50][Formula 1-50]
[화학식 1-51][Formula 1-51]
[화학식 1-52][Formula 1-52]
[화학식 1-53][Formula 1-53]
[화학식 1-54][Formula 1-54]
[화학식 1-55][Formula 1-55]
[화학식 1-56][Formula 1-56]
[화학식 1-57][Formula 1-57]
[화학식 1-58][Formula 1-58]
[화학식 1-59][Formula 1-59]
[화학식 1-60][Formula 1-60]
[화학식 1-61][Formula 1-61]
[화학식 1-62][Formula 1-62]
[화학식 1-63][Formula 1-63]
[화학식 1-64][Formula 1-64]
[화학식 1-65][Formula 1-65]
[화학식 1-66][Formula 1-66]
[화학식 1-67][Formula 1-67]
[화학식 1-68][Formula 1-68]
[화학식 1-69][Formula 1-69]
[화학식 1-70][Formula 1-70]
[화학식 1-71][Formula 1-71]
[화학식 1-72][Formula 1-72]
[화학식 1-73][Formula 1-73]
[화학식 1-74][Formula 1-74]
[화학식 1-75][Formula 1-75]
더 바람직하게, 상기 화학식 1은 상기 화학식 1-1, 화학식 1-3, 화학식 1-5 및 화학식 1-11로 구성된 군에서 선택된 1종 이상으로 표시될 수 있다. More preferably, Formula 1 may be represented by one or more members selected from the group consisting of Formula 1-1, Formula 1-3, Formula 1-5, and Formula 1-11.
본 발명의 구체적인 일구현예에서는, 보다 효과적인 응집유도발광 물질을 합성하기 위해, 인돌리진 골격체 기반의 신규한 응집유도발광 물질을 합성하였으며, 이를 갤럭시 플로어(GalaxyFluor; GxF, 이하, "GxF" 또는 "GxF 물질"로 표기함)로 명명하였다. 양자계산 결과 GxF 물질의 경우 HOMO와 LUMO lobe의 구획화가 명확히 일어나고 있음을 확인하여 분자내 전하이동(Intramolecular Charge Transfer: ICT) 형상을 유도할 수 있음을 검증하였다 (도 2 및 도 3).In a specific embodiment of the present invention, in order to synthesize a more effective aggregation-induced luminescence material, a novel aggregation-induced luminescence material based on the indolizine skeleton was synthesized, which was called Galaxy Fluor (GxF, hereinafter referred to as "GxF" or It was named "GxF material"). As a result of quantum calculations, it was confirmed that compartmentalization of the HOMO and LUMO lobes was clearly occurring in the case of the GxF material, verifying that an intramolecular charge transfer (ICT) shape could be induced (Figures 2 and 3).
또한, GxF 화합물들의 응집유도발광 현상을 관찰한 결과, GxF 1의 경우 119.5배, GxF 3의 경우 18.3배, GxF 5의 경우 28.8배 및 GxF 11의 경우 41.3배로 형광이 증가한 것으로 확인되었다 (도 5d). In addition, as a result of observing the aggregation-induced luminescence phenomenon of GxF compounds, it was confirmed that fluorescence increased 119.5 times for GxF 1, 18.3 times for GxF 3, 28.8 times for GxF 5, and 41.3 times for GxF 11 (Figure 5d ).
따라서, 상기 GxF 화합물의 AIE(Aggregation induced emission)에 대한 우선 순위는 화학식 1-1로 표시되는 화합물(GxF 1) ＞ 화학식 1-11로 표시되는 화합물(GxF 11) ＞ 화학식 1-5로 표시되는 화합물(GxF 5) ＞ 화학식 1-3으로 표시되는 화합물(GxF 3)이다. 이러한 우선순위가 나오는 원리는 분자 회전(rotation)이 잘 일어나는 치환기가 R1 ＞ R3 ＞ R2 순으로 AIE 형상을 더 잘 유도하기 때문으로, R1기에 트리플루오로메틸기(Trifluoromethyl; CF3)가 위치한 GxF 1 및 GxF 11가 GxF 3 및 GxF 5에 비해 AIE에 대한 우선순위가 높게 나타났으며, R1기에 다이메틸아민기(dimethylamino; DMA)가 위치한 GxF 5가 R1기에 수소(H)가 위치한 GxF 3에 비해 AIE에 대한 우선순위가 높게 나타났다.Therefore, the priority for Aggregation induced emission (AIE) of the GxF compound is: Compound represented by Formula 1-1 (GxF 1) > Compound represented by Formula 1-11 (GxF 11) > Compound represented by Formula 1-5 Compound (GxF 5) > It is a compound (GxF 3) represented by Chemical Formula 1-3. The principle of this priority is that substituents that undergo molecular rotation are better at inducing the AIE shape in the order of R 1 > R 3 > R 2 , and the trifluoromethyl group (CF 3 ) in the R 1 group GxF 1 and GxF 11, where is located, showed higher priority for AIE than GxF 3 and GxF 5, and GxF 5, where dimethylamino (DMA) is located at R 1 group, has hydrogen (H) at R 1 group. The priority for AIE was higher than that of GxF 3, where is located.
본 발명의 구체적인 다른 일구현예에서, 수용액 조건에서(THF/Water mixture 1:9) GxF 화합물의 응집형상 및 광물리적 특성을 동적광산란광도계(Dynamic light scattering: DLS) 장비를 이용하여 측정한 결과, GxF 화합물은 응집이 유도되고 그 크기가 2~500 nm 정도되는 것을 확인하였다 (도 6 및 표 2).In another specific embodiment of the present invention, the aggregate shape and photophysical properties of the GxF compound were measured in aqueous solution conditions (THF/Water mixture 1:9) using a dynamic light scattering (DLS) equipment, It was confirmed that the GxF compound induced aggregation and its size was about 2 to 500 nm (Figure 6 and Table 2).
본 발명의 구체적인 또 다른 일구현예에서, THF/Hexane 비율에 따른 용매의존 발색 현상의 변화를 관찰한 결과, Hexane 비율이 높을 수록 형광 강도가 증가하였으며(도 8), 용매 종류에 따른 형광 강도의 변화를 확인한 결과, Hexane을 용매로 사용하는 경우 다른 용매에 비해 형광 강도가 현저하게 높은 것을 확인하였다 (도 9).In another specific embodiment of the present invention, as a result of observing the change in solvent-dependent color development according to the THF/Hexane ratio, the fluorescence intensity increased as the Hexane ratio increased (FIG. 8), and the fluorescence intensity depending on the type of solvent As a result of checking the change, it was confirmed that when hexane was used as a solvent, the fluorescence intensity was significantly higher than that of other solvents (Figure 9).
본 발명은 다른 관점에서, (a) 화학식 A의 화합물 및 화학식 B의 화합물을 반응시켜, 화학식 C의 화합물을 제조하는 단계; In another aspect, the present invention provides a method comprising: (a) reacting a compound of Formula A and a compound of Formula B to prepare a compound of Formula C;
(b) 상기 화학식 C의 화합물과 에틸아크릴레이트(ethyl acrylate), 아세트산나트륨(sodium acetate) 및 구리아세트산 모노수화물(Copper(II) Acetate monohydrate)을 반응시켜 화학식 D의 화합물을 제조하는 단계;(b) preparing a compound of Formula D by reacting the compound of Formula C with ethyl acrylate, sodium acetate, and copper(II) Acetate monohydrate;
(c) 상기 화학식 D의 화합물 및 NBS(N-Bromosuccinimide)를 반응시켜 화학식 E의 화합물을 제조하는 단계; 및 (c) reacting the compound of Formula D with N-Bromosuccinimide (NBS) to prepare a compound of Formula E; and
(d) 상기 화학식 E의 화합물 및 화학식 F의 화합물을 반응시켜 화학식 1의 화합물을 제조하는 단계를 포함하며, 하기 반응식 1로 표시되는 화학식 1의 응집유도발광용 화합물의 제조방법에 관한 것이다.(d) preparing a compound of Formula 1 by reacting the compound of Formula E and the compound of Formula F, and relates to a method for producing a compound for aggregation-induced luminescence of Formula 1, which is represented by Scheme 1 below.
[반응식 1][Scheme 1]
상기 반응식 1에서 R1은 수소; 트리플루오로메틸기(Trifluoromethyl); 아세틸기; 메톡시기; 또는 다이메틸아민기이고, 상기 R2는 메틸; 트리플루오로메틸페닐기; 페닐기; 메톡시페닐기; 또는 다이에틸아민페닐기이며, 상기 R3는 수소; 트리플루오로메틸기(Trifluoromethyl); 또는 아세틸기일 수 있다. In Scheme 1, R 1 is hydrogen; Trifluoromethyl; Acetyl group; methoxy group; or a dimethylamine group, and R 2 is methyl; trifluoromethylphenyl group; phenyl group; methoxyphenyl group; or a diethylamine phenyl group, and R 3 is hydrogen; Trifluoromethyl; Or it may be an acetyl group.
구체적으로, 도 3에 나타난 방법으로 본 발명의 응집유도발광용 화합물인 GxF 물질을 합성할 수 있으며, 보다 구체적으로 본 발명에 따른 응집유도발광용 화합물의 제조방법을 단계별로 상세히 설명하면 다음과 같다. Specifically, the GxF material, which is a compound for aggregation-induced luminescence according to the present invention, can be synthesized by the method shown in Figure 3. More specifically, the method for producing the compound for aggregation-induced luminescence according to the present invention is described in detail step by step as follows. .
a) 단계: 피리딘 물질의 아실화Step a): Acylation of pyridine material
본 단계에서는 화합물 B를 알킬 할라이드를 이용하여 아실화 한다. In this step, compound B is acylated using an alkyl halide.
상기의 아실화는 당업계에서 알려진 통상의 방법을 이용하여 제한 없이 수행될 수 있는데, 바람직하게는 상기 알킬 할라이드로서 화합물 B는 R2 치환기를 함유하는 2-브로모-1-[4-(트리플루오로메틸)페닐]에탄-1-온(2-bromo-1-[4-(trifluoromethyl)-phenyl]ethane-1-one), 클로로아세톤(chloroacetone), 2-브로모아세토페논(2-bromoacetophenone), 2-브로모4-메톡시아세토페논(2-bromo-4-methoxyacetophenone), 2-브로모-4'-(다이에틸아미노_아세토-페논(2-Bromo-4'-(diethylamino)aceto-phenone)등과 같은 친전자성 모이어티(electrophilic moiety)를 함유하는 것을 사용하고 R3 치환기를 갖는 피리딘을 사용한다. The above acylation can be carried out without limitation using a common method known in the art. Preferably, Compound B as the alkyl halide is 2-bromo-1-[4-(tri-containing R 2 substituent). Fluoromethyl)phenyl]ethane-1-one (2-bromo-1-[4-(trifluoromethyl)-phenyl]ethane-1-one), chloroacetone, 2-bromoacetophenone ), 2-bromo-4-methoxyacetophenone, 2-Bromo-4'-(diethylamino_aceto-phenone (2-Bromo-4'-(diethylamino)aceto) Use one containing an electrophilic moiety such as -phenone) and use pyridine with an R 3 substituent.
구체적으로 알킬할라이드와 피리딘의 유기혼합물 용액을, 적정 온도(20℃ 내지 100℃)에서 1 ~ 24시간 동안 교반하여 피리딘 염 화합물을 산출한다. 이때, 상기 반응을 보내는데 있어 사용되는 유기용매는 통상의 유기용매를 사용할 수 있으며, 알킬할라이드 및 피리딘 화합물의 구체적인 종류에 따라 당업자가 적절히 결정할 수 있다. Specifically, a solution of an organic mixture of alkyl halide and pyridine is stirred at an appropriate temperature (20°C to 100°C) for 1 to 24 hours to produce a pyridine salt compound. At this time, the organic solvent used in carrying out the above reaction can be a common organic solvent, and can be appropriately determined by a person skilled in the art depending on the specific type of alkyl halide and pyridine compound.
b) 단계: 1,3-디폴라 고리화 반응Step b): 1,3-dipolar cyclization reaction
a) 단계에서 얻어진 아실화된 화학식 c로 표현되는 화합물을 에틸아크릴레이트(ethyl acrylate), 아세트산나트륨(sodium acetate) 및 구리아세트산 모노수화물(Copper(II) Acetate monohydrate)을 반응시켜 화학식D 로 표현되는 화합물을 얻는 단계이다. The acylated compound represented by formula c obtained in step a) is reacted with ethyl acrylate, sodium acetate, and copper(II) Acetate monohydrate to obtain formula D. This is the step of obtaining the compound.
구체적으로, 상기 a) 단계에서 얻어진 아실화된 화합물 유기혼합물 용액을, 적정 온도 (50℃ 내지 120℃)에서 1 ~ 24시간 동안 교반한뒤, 통상의 추출, 건조, 여과, 농축 및 정제 과정을 거쳐 화학식 D로 표현되는 화합물을 산출한다. 이때, 상기 반응을 보내는데 있어 사용되는 유기용매는 통상의 유기용매를 사용할 수 있으며, 화합물의 구체적인 종류에 따라 당업자가 적절히 결정할 수 있다. Specifically, the acylated compound organic mixture solution obtained in step a) was stirred at an appropriate temperature (50°C to 120°C) for 1 to 24 hours, and then subjected to the usual extraction, drying, filtration, concentration and purification processes. This yields a compound represented by formula D. At this time, the organic solvent used in carrying out the above reaction can be a common organic solvent, and can be appropriately determined by a person skilled in the art depending on the specific type of compound.
c)단계: Br 치환기 도입 단계 Step c): Br substituent introduction step
화학식 D로 표현되는 화합물을 비누화 반응(Saponification)과 브롬화 (Bromination) 반응을 거쳐 화학식 E로 표현되는 화합물을 얻는 단계이다.This is the step of obtaining a compound represented by Formula E through saponification and bromination of the compound represented by Formula D.
상기의 반응은 당업계에서 알려진 통상의 방법을 이용하여 제한 없이 수행될 수 있는데, 바람직하게는 먼저 상기 화학식 D로 표현되는 화합물을 유기용매에 용해 시키고 수산화리튬(Lithium hydroxide), 수산화칼륨(Potassium hydroxide), 수산화 나트륨(sodium hydroxide)과 같은 강염기를 첨가 하고 생성된 유기혼합물 용액을 적정 온도(50℃ 내지 120℃)에서 1 ~ 24시간 동안 교반한뒤, 통상의 추출, 건조, 여과, 농축 및 정제 과정을 거쳐 중간 물질을 얻어 낸다. 이후 중간 물질을 적절한 유기용매에 녹이고 이후 NBS(N-Bromosuccinimide)를 처리한후 생성된 유기혼합물 용액을 적정 온도 (50℃ 내지 120℃)에서 1 ~ 24시간 동안 교반한뒤, 통상의 추출, 건조, 여과, 농축 및 정제 과정을 거쳐 화학식 E로 표현되는 화합물을 산출한다. 이때, 상기 반응을 보내는데 있어 사용되는 유기용매는 통상의 유기용매를 사용할 수 있으며, 화합물의 구체적인 종류에 따라 당업자가 적절히 결정할 수 있다. The above reaction can be performed without limitation using conventional methods known in the art. Preferably, the compound represented by Formula D is first dissolved in an organic solvent and then dissolved in lithium hydroxide or potassium hydroxide. ), a strong base such as sodium hydroxide is added, the resulting organic mixture solution is stirred at an appropriate temperature (50℃ to 120℃) for 1 to 24 hours, and then subjected to conventional extraction, drying, filtration, concentration and purification. Through this process, intermediate materials are obtained. Afterwards, the intermediate material is dissolved in an appropriate organic solvent and then treated with NBS (N-Bromosuccinimide). The resulting organic mixture solution is stirred at an appropriate temperature (50°C to 120°C) for 1 to 24 hours, followed by normal extraction and drying. , filtration, concentration, and purification processes yield the compound represented by formula E. At this time, the organic solvent used in carrying out the above reaction can be a common organic solvent, and can be appropriately determined by a person skilled in the art depending on the specific type of compound.
d) 단계: Suzuki coupling 단계Step d): Suzuki coupling step
화학식 E로 표현되는 화합물을 화학식 F로 표현되는 화합물과 Pd 촉매를 사용하여 반응 시켜 본 발명의 형광 화합물을 얻는 단계이다. This is the step of obtaining the fluorescent compound of the present invention by reacting the compound represented by formula E with the compound represented by formula F using a Pd catalyst.
상기의 반응은 당업계에서 알려진 통상의 방법을 이용하여 제한 없이 수행될 수 있는데, 먼저 상기 R1 치환기를 포함하는 화학식 F로 표현되는 화합물은 특별히 제한되지 않으며, 바람직하게는 경우 트리플루오로페닐 보론산(triflulorophenyl boronic acid), 4-아세틸페닐 보론산(4-acetylphenyl boronic acid), 페닐 보론산(phenyl boronic acid), 4-메톡시페닐 보론산(4-methoxyphenyl boronic acid), 4-(다이메틸아미노)페닐 보론산(4-(dimethylamino)phenyl boronic acid)을 사용할 수 있다. 상기의 반응은, 통상의 유기용매 내에서 R1 치환기를 갖는 화학식 F로 표현되는 화합물과 c) 단계에서 얻어진 화학식 E로 표현되는 화합물을 Pd(PPh3)4과 Sodium carbonate와 혼합하고, 생성된 유기혼합물 용액을 적정 온도 (50℃ 내지 120℃)에서 1 ~ 24시간 동안 교반한뒤, 통상의 추출, 건조, 여과, 농축 및 정제 과정을 거쳐 본 발명의 응집유도발광용 화합물을 얻어 낸다. 이때, 상기 반응을 보내는데 있어 사용되는 유기용매는 통상의 유기용매를 사용할 수 있으며, 화합물의 구체적인 종류에 따라 당업자가 적절히 결정할 수 있다. The above reaction can be performed without limitation using conventional methods known in the art. First, the compound represented by formula F containing the R1 substituent is not particularly limited, and preferably trifluorophenyl boronic acid. (triflulorophenyl boronic acid), 4-acetylphenyl boronic acid, phenyl boronic acid, 4-methoxyphenyl boronic acid, 4-(dimethylamino )Phenyl boronic acid (4-(dimethylamino)phenyl boronic acid) can be used. In the above reaction, the compound represented by the formula F having a R 1 substituent and the compound represented by the formula E obtained in step c) are mixed with Pd(PPh 3 ) 4 and sodium carbonate in a common organic solvent, and the resulting The organic mixture solution is stirred at an appropriate temperature (50°C to 120°C) for 1 to 24 hours, and then the compound for aggregation-induced luminescence of the present invention is obtained through conventional extraction, drying, filtration, concentration and purification processes. At this time, the organic solvent used in carrying out the above reaction can be a common organic solvent, and can be appropriately determined by a person skilled in the art depending on the specific type of compound.
미토콘드리아 타겟물질-응집유도발광용 화합물 복합체Mitochondrial target material-compound complex for aggregation-induced luminescence
본 발명은 또 다른 관점에서, 미토콘드리아 타겟을 위한 미토콘드리아 타겟물질-응집유도발광용 화합물 복합체에 관한 것이다.From another perspective, the present invention relates to a mitochondrial target material-aggregation-induced luminescence compound complex for targeting mitochondria.
상기 미토콘드리아 타겟물질은 미토콘드리아를 타겟하면서, 말단에 -COOH를 가지는 물질을 제한 없이 사용할 수 있으며, 바람직하게는 TPP(triphenylphosphonium), 로다민(rhodamine), 로다민 19(rhodamine 19), 로다민 123(rhodamine 123), 실리콘 로다민-Me(Siliconrhodamien-Me), JC-1 (5,5,6,6-Tetrachloro-1,1,3,3-tetraethylbenzimidazolylcarbocyanine iodide) 및 MPP(N-methyl-4-phenylpyridinium)로 구성된 군에서 선택된 하나의 친유성 양이온(Lipophilic cation); TOM(translocase of the outer membrane) 및 TIM(translocase of the inner membrane)를 표적으로 하는 미토콘드리아 표적 신호 펩티드(Mitochondrial targeting signal peptide; MTS); DQA(Delocalized lipophilic cations, such as dequalinium); 페닐설포닐프록산(phenylsulfonylfuroxan); 구아니딘(guanidine); 사이클릭 구아니딘(cyclic guanidine); 또는 F-16(4-[(1E)-2-(1H-indol-3-yl)ethenyl]-1-methyl-pyridinium iodide)일 수 있다.The mitochondrial target material targets mitochondria and can be used without limitation as a material having -COOH at the end, preferably TPP (triphenylphosphonium), rhodamine, rhodamine 19, rhodamine 123 ( rhodamine 123), Siliconrhodamien-Me, JC-1 (5,5,6,6-Tetrachloro-1,1,3,3-tetraethylbenzimidazolylcarbocyanine iodide) and MPP (N-methyl-4-phenylpyridinium) ) One lipophilic cation selected from the group consisting of; Mitochondrial targeting signal peptide (MTS) targeting the translocase of the outer membrane (TOM) and the translocase of the inner membrane (TIM); Delocalized lipophilic cations, such as dequalinium (DQA); phenylsulfonylfuroxan; guanidine; cyclic guanidine; Or it may be F-16 (4-[(1E)-2-(1H-indol-3-yl)ethenyl]-1-methyl-pyridinium iodide).
본 발명의 구체적인 일구현예에서는 미토콘드리아 타겟 물질로 TPP을 이용하였으며, 도 10에 나타난 방법을 이용하여 TPP-GxF 복합체를 제조하였다. In a specific embodiment of the present invention, TPP was used as a mitochondrial target material, and the TPP-GxF complex was prepared using the method shown in Figure 10.
세포 이미징cell imaging
본 발명은 또 다른 관점에서, 상기 미토콘드리아 타겟을 위한 미토콘드리아 타겟물질-응집유도발광용 화합물 복합체를 포함하는 세포이미징용 조성물에 관한 것이다. From another perspective, the present invention relates to a composition for cell imaging comprising a mitochondrial target material-aggregation-induced luminescence compound complex for the mitochondrial target.
상기 미토콘드리아 타겟물질 및 응집유도발광용 화합물에 대한 구체적 내용은 상술한 바와 같으며, 본 발명의 구체적인 일구현예에서 제조한 TPP-GxF 복합체를 이용하여 세포 이미징을 수행하였다.The details of the mitochondrial target material and the compound for aggregation-induced luminescence are as described above, and cell imaging was performed using the TPP-GxF complex prepared in a specific embodiment of the present invention.
세포에 TPP-GxF 복합체를 처리한 후, 별도의 세척과정 없이 형광정도를 관찰한 결과, 미토콘드리아 내 발현물질인 Mito-YFP와 마찬가지로 TPP-GxF 복합체가 세포 내 미토콘드리아에 염색되는 것을 확인하였으며, Mito-YFP 및 TPP-GxF 복합체의 형광이 동일한 위치에서 관찰되는 것을 확인하였다 (도 11 및 도 12).After treating the cells with the TPP-GxF complex, the fluorescence level was observed without a separate washing process. As a result, it was confirmed that the TPP-GxF complex stained the mitochondria within the cell, similar to Mito-YFP, which is expressed in the mitochondria, and Mito- It was confirmed that the fluorescence of YFP and TPP-GxF complex was observed at the same location (Figures 11 and 12).
또한, 시간의 흐름에 따른 형광 정도를 관찰한 결과, TPP-GxF 복합체는 세포에 처리 1분 후에 형광이 관찰되는 것을 확인하였으며(도 13), 농도에 따른 TPP-GxF 복합체를 세포에 처리한 결과, TPP-GxF 복합체는 낮은 농도 뿐만 아니라, 높은 농도에서도 높은 형광을 보이는 것을 확인하였다 (도 14). In addition, as a result of observing the level of fluorescence over time, it was confirmed that fluorescence of the TPP-GxF complex was observed 1 minute after treatment on the cells (Figure 13), and the results of treating the cells with the TPP-GxF complex according to concentration , it was confirmed that the TPP-GxF complex showed high fluorescence not only at low concentrations but also at high concentrations (Figure 14).
대부분의 형광체들은 낮은 농도 혹은 액체 상태에서 강한 형광 상태를 보이나, 높은 농도 혹은 고체 상태에서는 약한 형광을 보이는 반면, TPP-GxF 복합체는 농도 및 고체 응집 정도에 대한 제한 없이 강한 형광 상태를 보일 뿐만 아니라, 별도의 세척과정 없이도 빠른 시간 내 세포를 관찰할 수 있는 것을 확인하였다.Most fluorescent substances show strong fluorescence at low concentrations or in the liquid state, but show weak fluorescence at high concentrations or in the solid state, whereas the TPP-GxF complex not only shows strong fluorescence without restrictions on concentration and degree of solid aggregation, It was confirmed that cells could be observed quickly without any additional washing process.
본 발명은 또 다른 관점에서, 상기 미토콘드리아 타겟을 위한 미토콘드리아 타겟물질-응집유도발광용 화합물 복합체를 포함하는 세포이미징용 키트에 관한 것이다.From another perspective, the present invention relates to a kit for cell imaging comprising a mitochondrial target material-aggregation-induced luminescence compound complex for the mitochondrial target.
상기 키트는 미토콘드리아 타겟물질-응집유도발광용 화합물 복합체 이외에도 세포 염색을 위한 완충액, 세포 고정을 위한 물질, 세포 고정 또는 배양용 디쉬/슬라이드 등을 추가로 포함할 수 있으나, 이에 한정되는 것은 아니다.In addition to the mitochondrial target material-aggregation-induced luminescence compound complex, the kit may additionally include, but is not limited to, a buffer for cell staining, materials for cell fixation, and dishes/slides for cell fixation or culture.
본 발명은 또 다른 관점에서, 상기 미토콘드리아 타겟을 위한 미토콘드리아 타겟물질-응집유도발광용 화합물 복합체를 세포와 접촉시키는 단계를 포함하는 세포 이미징 방법에 관한 것이다.From another perspective, the present invention relates to a cell imaging method including the step of contacting a mitochondrial target material-aggregation-induced luminescence compound complex for the mitochondrial target with a cell.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다.Hereinafter, the present invention will be described in more detail through examples.
이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.These examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as limited by these examples.
인돌리진 기반 신규 형광 물질 합성Synthesis of new fluorescent substances based on indolizine
본 발명에서는 휘발성 유기 화합물을 실시간 모니터링하기 위해 인돌리진 골격체 기반의 신규한 형광 물질을 합성하였다. In the present invention, a novel fluorescent material based on an indolizine framework was synthesized for real-time monitoring of volatile organic compounds.
구체적으로, 반응식 1 및 도 3에 나타난 방법으로 신규 형광 물질인 갤럭시 플로어(GalaxyFluor; GxF)를 합성하였으며, 화학식 1의 형광 화합물이 하기와 같은 치환기를 가지도록 각각 조합하여 최종 75종의 신규한 GxF 물질을 합성하였다:Specifically, Galaxy Fluor (GxF), a new fluorescent material, was synthesized using the method shown in Scheme 1 and Figure 3, and the fluorescent compounds of Formula 1 were each combined to have the substituents as follows, resulting in a final 75 types of new GxF. The material was synthesized:
R1: 수소(-H), 트리플루오로메틸기(Trifluoromethyl; -CF3), 아세틸기(-COCH3), 메톡시기(-OCH3), 다이메틸아민이기(Dimethylamine; DMA; -N(CH3)2)R 1 : Hydrogen (-H), trifluoromethyl (-CF 3 ), acetyl group (-COCH 3 ), methoxy group (-OCH 3 ), dimethylamine (DMA; -N(CH) 3 ) 2 )
R2: 메틸(-CH3), 트리플루오로메틸페닐기(Trifluoromethylphenyl; -CF3Ph), 페닐기(-Ph), 메톡시페닐기(OCH3Ph), 다이에틸아민페닐기(Diethylaminephenyl; -N(C2H5)2Ph)R 2 : Methyl (-CH 3 ), Trifluoromethylphenyl (-CF 3 Ph), phenyl (-Ph), methoxyphenyl (OCH 3 Ph), diethylaminephenyl (-N(C) 2 H 5 ) 2 Ph)
R3: 수소(-H), 트리플루오로메틸기(Trifluoromethyl; -CF3), 아세틸기(-COCH3).R 3 : Hydrogen (-H), trifluoromethyl (-CF 3 ), acetyl group (-COCH 3 ).
1H 및 13C NMR 스펙트럼은 JEOL ECZ-600R (JEOL Ltd, Japan)를 사용하여 기록되었으며, 화학적 이동(chemical shift)은 내부 테트라메틸실란 표준의 ppm의 낮은 장(downfield) 범위를 측정하였다. 1 H and 13 C NMR spectra were recorded using a JEOL ECZ-600R (JEOL Ltd, Japan), and chemical shifts were measured downfield in the ppm low field range of the internal tetramethylsilane standard.
다중도(multiplicity)는 다음과 같이 표시하였다: s(singlet); d(doublet); t(triplet); q(quartet); m(multiplet); dd(doublet of doublet); ddd(doublet of doublet of doublet); dt(doublet of triplet); td(triplet of doublet); brs(broad singlet).Multiplicity is expressed as follows: s(singlet); d(double); t(triplet); q(quartet); m(multiplet); dd(doublet of doublet); ddd(doublet of doublet of doublet); dt(doublet of triplet); td(triplet of doublet); brs (broad singlet).
커플링 상수는 Hz로 기록하였다. 질량 분석(routine mass analyses)은 역상컬럼(C-18, 50Х2.1mm, 5㎛)이 구비된 LC/MS 시스템과 전자 분무 이온화(ESI) 또는 대기압 화학 이온화(APCI)를 이용한 광다이오드 분석 탐지기 상에서 수행되었다.Coupling constants were reported in Hz. Routine mass analyzes were performed on an LC/MS system equipped with a reversed-phase column (C-18, 50Х2.1 mm, 5 μm) and a photodiode analytical detector using electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). carried out.
화합물의 분자량 분석은 고분해능 질량분석기(LRMS; high-resolution mass spectrometry)에 의해 확인하였다. LRMS 분석은 LCMS-2020 (Shimadzu, Japan) 를 사용하여 수행하였다.The molecular weight analysis of the compound was confirmed by high-resolution mass spectrometry (LRMS). LRMS analysis was performed using LCMS-2020 (Shimadzu, Japan).
합성한 75종의 GxF 물질 각각의 합성 방법은 다음과 같다:The synthesis methods for each of the 75 synthesized GxF materials are as follows:
<GxF 1 ~ 5><GxF 1 ~ 5>
IA-E : 하기 반응식 2와 같이 합성하였으며, 구체적으로, 4(트리플루오로메틸)피리딘(4-(trifluoromethyl)pyridine, 637 μL, 5.50 mmol) 및 2-브로모-1-[4-(4(트리플루오로메틸)-페닐]에탄-1-온(2-bromo-1-[4-(trifluoromethyl)-phenyl]ethane-1-one, 1.54 g, 5.70 mmol)이 포함된 디메틸포름아미드(dimethylformamide; DMF, 10.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(ethyl acrylate, 293 μL, 2.75 mmol), 구리(II) 아세테이트 모노하이드레이트(copper(II) acetate monohydrate, 1.64 g, 8.25 mmol) 및 소듐 아세테이트(sodium acetate, 1.35 g, 16.5 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 구리아세테이트(copper acetate)를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(silica-gel flash column chromatography, EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IA-E(518 mg, 1.20 mmol, 43.8% 수율)를 수득 하였다. IA-E : Synthesized according to Scheme 2 below, specifically, 4-(trifluoromethyl)pyridine (4-(trifluoromethyl)pyridine, 637 μL, 5.50 mmol) and 2-bromo-1-[4-(4(trifluoromethyl) Dimethylformamide (DMF) containing 2-bromo-1-[4-(trifluoromethyl)-phenyl]ethane-1-one, 1.54 g, 5.70 mmol) 10.0 mL) was stirred at 100°C overnight, then ethyl acrylate (293 μL, 2.75 mmol), copper(II) acetate monohydrate (copper(II) acetate monohydrate, 1.64 g, 8.25 mmol) and sodium Acetate (sodium acetate, 1.35 g, 16.5 mmol) was added and stirred at 100°C for 16 hours. After TLC confirmed that the reaction was complete, copper acetate was removed by filtration through a Celite pad. The resulting filtrate was concentrated under vacuum. The resulting crude product was extracted three times with DCM, dried over anhydrous Na 2 SO 4 and concentrated. was purified by silica-gel flash column chromatography (1 to 15% hexane containing EtOAc) to obtain compound IA-E (518 mg, 1.20 mmol, 43.8% yield) as a yellow solid. .
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 10.0 (d, J = 7.2 Hz, 1H), 8.70 (s, 1H), 7.91 (d, J = 7.6 Hz 2H), 7.82 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.2 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H); 13C NMR(100 MHz, CDCl3), δ 184.0, 162.8, 141.9, 137.7, 133.3, 132.6, 129.3, 128.9, 125.3, 124.7, 124.0, 122.6, 122.0, 121.2, 117.1, 110.9, 108.9, 60.6, 14.4. 1 H NMR (400 MHz, CDCl 3 ) δ 10.0 (d, J = 7.2 Hz, 1H), 8.70 (s, 1H), 7.91 (d, J = 7.6 Hz 2H), 7.82 (s, 1H), 7.79 ( d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.2 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 184.0, 162.8, 141.9, 137.7, 133.3, 132.6, 129.3, 128.9, 125.3, 124.7, 124.0, 122.6, 122.0, 121.2, .1, 110.9, 108.9, 60.6, 14.4.
IA-B : IA-E(517.9 mg, 1.206 mmol)가 포함된 메탄올(10 mL)에 KOH (5386 mg, 96.00 mmol)를 첨가한 후, 실온에서 하룻밤 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 갈색고체의 화합물 IA-A를 수득하였다. IA-B : KOH (5386 mg, 96.00 mmol) was added to methanol (10 mL) containing IA-E (517.9 mg, 1.206 mmol), and then stirred at room temperature overnight. The reaction mixture was acidified by adding 6N HCl, and the resulting solid was collected through filtration, washed with water, and dried in a drying oven to obtain Compound IA-A as a brown solid.
수득한 화합물 IA-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IA-A이 포함된 DMF (10.0 mL)에 소듐 바이카보네이트(sodium bicarbonate, 302.4 mg, 3.600 mmol)를 첨가하고 및 NBS(320.3 mg, 1.800 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - EA 12%)로 정제하여 황색 고체의 화합물 IA-B(434.1 mg, 0.99 mmol, 82.9% 수율)를 수득 하였다.The obtained compound IA-A was used in the next step without further purification. Sodium bicarbonate (302.4 mg, 3.600 mmol) was added to DMF (10.0 mL) containing IA-A, and NBS (320.3 mg) , 1.800 mmol) was added in portions at 0°C. The reaction mixture was stirred at room temperature for 12 hours, then the resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8 - EA 12%) to obtain compound IA-B (434.1 mg, 0.99 mmol, 82.9% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 95.5 (d, J = 7.2 Hz, 1H), 7.90 (s, 2H), 7.87 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.40 (s, 1H), 7.13 (d, J = 7.2 Hz, 1H); 13C NMR(100 MHz, NNN) δ 183.1, 142.4, 135.0, 133.1, 129.2, 127.6, 126.6, 125.6, 125.5, 124.4, 123.0, 121.7, 115.4, 110.4, 93.0; LRMS (ESI) m/z calcd for C17H8BrF6NO [M+Na]+ : 435.0, found : 436.3. 1 H NMR (400 MHz, CDCl 3 ) δ 95.5 (d, J = 7.2 Hz, 1H), 7.90 (s, 2H), 7.87 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.40 (s, 1H), 7.13 (d, J = 7.2 Hz, 1H); 13 C NMR (100 MHz, NNN) δ 183.1, 142.4, 135.0, 133.1, 129.2, 127.6, 126.6, 125.6, 125.5, 124.4, 123.0, 121.7, 115.4, 110.4, 93.0; LRMS (ESI) m/z calcd for C 17 H 8 BrF 6 NO [M+Na] + : 435.0, found : 436.3.
[반응식 2][Scheme 2]
화합물 GxF 1 : Compound GxF 1 :
IA-B(50.4 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(4-triflulorophenyl boronic acid, 88.0 mg, 0.46 mmol), 테트라키스(트리페닐 포스핀)팔라듐(Tetrakis(triphenyl phosphine)palladium, 231 mg, 20.0 mol%) 및 소듐 카보네이트(Sodium carbonate, 49.0 mg, 0.46 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-1로 표시되는 황색 고체의 화합물 GxF 1(50.0 mg, 0.09 mmol, 86.7% 수율)을 수득 하였다.4-triflulorophenyl boronic acid (88.0 mg, 0.46 mmol) and tetrakis in a solution containing IA-B (50.4 mg, 0.11 mmol) mixed with DMF and water at a ratio of 2:1. Tetrakis(triphenyl phosphine)palladium (231 mg, 20.0 mol%) and sodium carbonate (49.0 mg, 0.46 mmol) were added, and then stirred at 100°C for 12 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 1 (50.0 mg, 0.09 mmol, 86.7%) as a yellow solid represented by the following formula 1-1. yield) was obtained.
[화학식 1-1][Formula 1-1]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 10.6 (d, J = 7.6 Hz, 1H), 8.11 (s, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.18 (d, J = 7.4 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 183.9, 142.9, 137.1, 134.4, 133.4, 133.1, 129.5, 129.2, 128.3, 127.3, 127.0, 126.2, 126.0, 125.6, 125.1, 124.5, 123.2, 122.8, 122.4, 121.8, 119.2, 115.3, 110.4; LRMS (ESI) m/z calcd for C24H12F9NO [M+Na]+ : 501.1, found : 502.1. 1 H NMR (400 MHz, CDCl 3 ) δ 10.6 (d, J = 7.6 Hz, 1H), 8.11 (s, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.8 Hz) , 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.18 (d, J = 7.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.9, 142.9, 137.1, 134.4, 133.4, 133.1, 129.5, 129.2, 128.3, 127.3, 127.0, 126.2, 126.0, 125.6, 125. 1, 124.5, 123.2, 122.8, 122.4, 121.8 , 119.2, 115.3, 110.4; LRMS (ESI) m/z calcd for C 24 H 12 F 9 NO [M+Na] + : 501.1, found : 502.1.
화합물 GxF 2 : Compound GxF 2 :
IA-B(50.2 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(4-acetylphenyl boronic acid , 75.0 mg, 0.46 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(49.0 mg, 0.46 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-2로 표시되는 황색 고체의 화합물 GxF 2(48.4 mg, 0.10 mmol, 88.5% 수율)을 수득 하였다.4-acetylphenyl boronic acid (75.0 mg, 0.46 mmol) and tetrakis (tri) were added to a solution containing IA-B (50.2 mg, 0.11 mmol) and DMF and water mixed 2:1. Phenylphosphine)palladium (231 mg, 20.0 mol%) and sodium carbonate (49.0 mg, 0.46 mmol) were added, and then stirred at 100°C for 12 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to produce compound GxF 2 (48.4 mg, 0.10 mmol, 88.5%) as a yellow solid represented by the following formula 1-2. yield) was obtained.
[화학식 1-2][Formula 1-2]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 10.0 (d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 8.07 (d, J = 6.8 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 6.8 Hz, 2H), 7.54 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 197.2, 183.9, 142.9, 138.2, 135.8, 134.4, 133.0, 129.5, 129.3, 129.2, 128.0, 127.3, 126.9, 125.9, 125.6, 124.5, 123.3, 122.4, 121.8, 119.4, 115.5, 115.4, 110.4, 26.9; LRMS (ESI) m/z calcd for C25H15F6NO2 [M+Na]+ : 475.1, found : 476.2. 1 H NMR (400 MHz, CDCl 3 ) δ 10.0 (d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 8.07 (d, J = 6.8 Hz, 2H), 7.95 (d, J = 8.4 Hz) , 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 6.8 Hz, 2H), 7.54 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.2, 183.9, 142.9, 138.2, 135.8, 134.4, 133.0, 129.5, 129.3, 129.2, 128.0, 127.3, 126.9, 125.9, 125. 6, 124.5, 123.3, 122.4, 121.8, 119.4 , 115.5, 115.4, 110.4, 26.9; LRMS (ESI) m/z calcd for C 25 H 15 F 6 NO 2 [M+Na] + : 475.1, found : 476.2.
화합물 GxF 3 : Compound GxF 3 :
IA-B(51.2 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(phenyl boronic acid, 57.0 mg, 0.46 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(49.0 mg, 0.46 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-3으로 표시되는 황색 고체의 화합물 GxF 3(48.7 mg, 0.11 mmol, 96.0% 수율)을 수득 하였다.Phenyl boronic acid (57.0 mg, 0.46 mmol) and tetrakis(triphenylphosphine)palladium in a solution containing IA-B (51.2 mg, 0.11 mmol) mixed with DMF and water at a ratio of 2:1. (231 mg, 20.0 mol%) and sodium carbonate (49.0 mg, 0.46 mmol) were added, and then stirred at 100°C for 12 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 3 (48.7 mg, 0.11 mmol, 96.0%) as a yellow solid represented by the following formula 1-3. yield) was obtained.
[화학식 1-3][Formula 1-3]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 10.04 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.55 (s, 1H), 7.53 (d, J = 3.6 Hz, 2H), 7.49 (d, J = 3.2 Hz, 2H), 7.39 (d, J = 7.2 Hz, 1H) 7.13 (dd, J = 7.4 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 183.7, 143.1, 134.4, 133.3, 133.2, 132.9, 129.3, 129.2, 128.1, 127.5, 126.6, 125.8, 125.5, 125.4, 125.1, 124.7, 122.9, 122.0, 120.9, 115.7, 110.1. 1 H NMR (400 MHz, CDCl 3 ) δ 10.04 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz) , 2H), 7.55 (s, 1H), 7.53 (d, J = 3.6 Hz, 2H), 7.49 (d, J = 3.2 Hz, 2H), 7.39 (d, J = 7.2 Hz, 1H) 7.13 (dd, J = 7.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.7, 143.1, 134.4, 133.3, 133.2, 132.9, 129.3, 129.2, 128.1, 127.5, 126.6, 125.8, 125.5, 125.4, 125. 1, 124.7, 122.9, 122.0, 120.9, 115.7 , 110.1.
화합물 GxF 4 : Compound GxF 4 :
IA-B(51.0 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(4-methoxyphenyl boronic acid, 71.0 mg, 0.46 mmol), 테트라키스(트리페닐 포스핀)팔라듐(Tetrakis(triphenyl phosphine)palladium, 231 mg, 20.0 mol%) 및 소듐 카보네이트(Sodium carbonate, 49.0 mg, 0.46 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-4로 표시되는 황색 고체의 화합물 GxF 4(51.4 mg, 0.11 mmol, 94.8% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (71.0 mg, 0.46 mmol) and tetrakis( Tetrakis(triphenyl phosphine)palladium (231 mg, 20.0 mol%) and sodium carbonate (49.0 mg, 0.46 mmol) were added, and then stirred at 100°C for 12 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to obtain compound GxF 4 (51.4 mg, 0.11 mmol, 94.8%) as a yellow solid represented by the following formula 1-4. yield) was obtained.
[화학식 1-4][Formula 1-4]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 10.02 (d, J = 6.8 Hz, 1H), 8.08 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.46 (s, 1H), 7.42 (d, J = 5.0 Hz, 2H), 7.10 (d, J = 7.4 Hz, 1H), 7.02 (d, J = 4.6 Hz, 2H), 3.86 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 183.5, 159.0, 143.1, 134.4, 133.0, 132.7, 129.2, 127.6, 126.3, 125.9, 125.6, 125.5, 125.4, 125.4, 125.1, 125.6, 122.7, 122.4, 121.9, 120.7, 115.7, 114.6, 114.1, 109.9; LRMS (ESI) m/z calcd C24H15F6NO2 for [M+Na]+ : 463.1, found : 464.1. 1 H NMR (400 MHz, CDCl 3 ) δ 10.02 (d, J = 6.8 Hz, 1H), 8.08 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz) , 2H), 7.46 (s, 1H), 7.42 (d, J = 5.0 Hz, 2H), 7.10 (d, J = 7.4 Hz, 1H), 7.02 (d, J = 4.6 Hz, 2H), 3.86 (s) , 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.5, 159.0, 143.1, 134.4, 133.0, 132.7, 129.2, 127.6, 126.3, 125.9, 125.6, 125.5, 125.4, 125.4, 125. 1, 125.6, 122.7, 122.4, 121.9, 120.7 , 115.7, 114.6, 114.1, 109.9; LRMS (ESI) m/z calcd C 24 H 15 F 6 NO 2 for [M+Na] + : 463.1, found : 464.1.
화합물 GxF 5 : Compound GxF 5 :
IA-B(51.4 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(4-(dimethylamino)phenyl boronic acid, 78.0 mg, 0.47 mmol), 테트라키스(트리페닐 포스핀)팔라듐(Tetrakis(triphenyl phosphine)palladium, 231 mg, 20.0 mol%) 및 소듐 카보네이트(Sodium carbonate, 50mg, 0.47 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-5로 표시되는 주황색 고체의 화합물 GxF 5(51.5 mg, 0.10 mmol, 91.6% 수율)을 수득 하였다.4-(dimethylamino)phenyl boronic acid (78.0 mg, 0.47 mg) in a solution containing IA-B (51.4 mg, 0.11 mmol) mixed with DMF and water at a ratio of 2:1. mmol), Tetrakis(triphenyl phosphine)palladium (231 mg, 20.0 mol%), and sodium carbonate (50 mg, 0.47 mmol) were added, and then incubated at 100°C for 12 hours. It was stirred. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to obtain compound GxF 5 (51.5 mg, 0.10 mmol, 91.6%) as an orange solid represented by the following formula 1-5. yield) was obtained.
[화학식 1-5][Formula 1-5]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 10.01 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 7.94 (d, J = 8 Hz, 2H), 7.78 (d, J = 8 Hz, 2H), 7.41 (d, J = 5.0 Hz, 2H), 7.40 (s, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 7.6 Hz, 2H), 3.02 (d, J = 6.4 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 183.4, 149.8, 143.3, 134.3, 132.9, 132.6, 129.2, 129.1, 128.8, 125.9, 125.7, 125.5, 125.1, 124.7, 122.6, 122.4, 122.0, 121.5, 121.4, 121.0, 116.0, 115.9, 112.9, 109.7, 40.6; LRMS (ESI) m/z calcd for C25H18F6N2O[M+Na]+ : 476.1, found : 476.2. 1 H NMR (400 MHz, CDCl 3 ) δ 10.01 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 7.94 (d, J = 8 Hz, 2H), 7.78 (d, J = 8 Hz) , 2H), 7.41 (d, J = 5.0 Hz, 2H), 7.40 (s, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 7.6 Hz, 2H), 3.02 (d) , J = 6.4 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.4, 149.8, 143.3, 134.3, 132.9, 132.6, 129.2, 129.1, 128.8, 125.9, 125.7, 125.5, 125.1, 124.7, 122. 6, 122.4, 122.0, 121.5, 121.4, 121.0 , 116.0, 115.9, 112.9, 109.7, 40.6; LRMS (ESI) m/z calcd for C 25 H 18 F 6 N 2 O[M+Na] + : 476.1, found : 476.2.
<GxF 6 ~ 10><GxF 6 ~ 10>
IB-E : 하기 반응식 3과 같이 합성하였으며, 구체적으로, 4(트리플루오로메틸)피리딘(695 μL, 6.00 mmol) 및 클로로아세톤(chloroacetone,501 μL, 6.30 mmol)이 포함된 DMF(10.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(320 μL, 3 mmol), 구리(II) 아세테이트 모노하이드레이트(1.79 g, 9.00 mmol) 및 소듐 아세테이트(1476.5 mg, 18 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IB-E(659.5 mg, 2.2 mmol, 73.4% 수율)를 수득 하였다. IB-E : Synthesized according to Scheme 3 below. Specifically, DMF (10.0 mL) containing 4(trifluoromethyl)pyridine (695 μL, 6.00 mmol) and chloroacetone (501 μL, 6.30 mmol) was incubated at 100°C. After stirring overnight, ethyl acrylate (320 μL, 3 mmol), copper (II) acetate monohydrate (1.79 g, 9.00 mmol), and sodium acetate (1476.5 mg, 18 mmol) were added and incubated at 100°C for 16 hours. It was stirred for a while. After confirming that the reaction was complete by TLC, copper acetate was removed by filtration through a Celite pad, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (1 to 15% hexane containing EtOAc) to obtain compound IB-E (659.5 mg, 2.2 mmol, 73.4% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.96 (d, J = 7.2 Hz, 1H), 8.66 (t, J = 1.2Hz, 1H), 8.06 (s, 1H), 7.15 (dd, J = 2 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 2.63(s, 3H), 1.45 (t, J = 7.0 Hz, 3H); 13C NMR(400 MHz, CDCl3) δ 188.0, 163.1, 136.7, 129.1, 128.3, 128.0, 127.6, 127.3, 126.9, 126.0, 124.2, 123.4, 121.5, 118.8, 116.9, 116.8, 110.5, 110.4, 108.1, 60.6, 27.5, 14.5; LRMS (ESI) m/z calcd for C14H12F3NO3 [M+Na]+ : 299.1, found : 300.1. 1H NMR (400 MHz, CDCl 3 ), δ 9.96 (d, J = 7.2 Hz, 1H), 8.66 (t, J = 1.2Hz, 1H), 8.06 (s, 1H), 7.15 (dd, J = 2 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 2.63(s, 3H), 1.45 (t, J = 7.0 Hz, 3H); 13 C NMR (400 MHz, CDCl 3 ) δ 188.0, 163.1, 136.7, 129.1, 128.3, 128.0, 127.6, 127.3, 126.9, 126.0, 124.2, 123.4, 121.5, 118.8, 116. 9, 116.8, 110.5, 110.4, 108.1, 60.6 , 27.5, 14.5; LRMS (ESI) m/z calcd for C 14 H 12 F 3 NO 3 [M+Na] + : 299.1, found : 300.1.
IB-B : IB-E(0.66 g, 2.20 mmol)가 포함된 메탄올(10 mL)에 KOH (5386 mg, 96.00 mmol)를 첨가한 후, 실온에서 4시간 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 갈색고체의 화합물 IB-A를 수득하였다. IB-B : KOH (5386 mg, 96.00 mmol) was added to methanol (10 mL) containing IB-E (0.66 g, 2.20 mmol), and then stirred at room temperature for 4 hours. The reaction mixture was acidified by adding 6N HCl, and the resulting solid was collected through filtration, washed with water, and dried in a drying oven to obtain compound IB-A as a brown solid.
수득한 화합물 IB-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IB-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(554 mg, 6.60 mmol)를 첨가하고 및 NBS(587 mg, 3.30 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - EA 12%)로 정제하여 황색 고체의 화합물 IB-B(588 mg, 1.92 mmol, 100% 수율)를 수득 하였다.The obtained compound IB-A was used in the next step without further purification. Sodium bicarbonate (554 mg, 6.60 mmol) was added to DMF (10.0 mL) containing IB-A and NBS (587 mg, 3.30 mmol) ) was added in portions at 0°C. The reaction mixture was stirred at room temperature for 12 hours, then the resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8 - EA 12%) to obtain compound IB-B (588 mg, 1.92 mmol, 100% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.88 (d, J = 7.2 Hz, 1H), 7.85 (s, 1H), 7.60 (s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 2.59 (s, 1H); 13C NMR(100 MHz, CDCl3) δ 204.4, 186.9, 133.6, 128.7, 124.9, 123.5, 121.7, 115.2, 109.7, 92.0, 27.5. 1 H NMR (400 MHz, CDCl 3 ) δ 9.88 (d, J = 7.2 Hz, 1H), 7.85 (s, 1H), 7.60 (s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 2.59 (s, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 204.4, 186.9, 133.6, 128.7, 124.9, 123.5, 121.7, 115.2, 109.7, 92.0, 27.5.
[반응식 3][Scheme 3]
화합물 GxF 6 : Compound GxF 6 :
IB-B(74.6 mg, 0.24 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리풀로로페닐 보론산(103 mg, 0.97 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(49.0 mg, 0.46 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-6으로 표시되는 황색 고체의 화합물 GxF 6(75.9 mg, 0.2 mmol, 85% 수율)을 수득 하였다.4-tripulorophenyl boronic acid (103 mg, 0.97 mmol) and tetrakis(triphenyl phosphine) were added to a solution containing IB-B (74.6 mg, 0.24 mmol) mixed with DMF and water at a ratio of 2:1. ) Palladium (231 mg, 20.0 mol%) and sodium carbonate (49.0 mg, 0.46 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 6 (75.9 mg, 0.2 mmol, 85%) as a yellow solid represented by the following formula 1-6. yield) was obtained.
[화학식 1-6][Formula 1-6]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.95 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.71 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.03 (dd, J = 7.6 Hz, 1H), 2.65 (s, 1H); 13C NMR(100 MHz, CDCl3) δ 187.6, 137.4, 133.0, 129.2, 129.0, 128.1, 126.1, 125.7, 125.5, 124.6, 123.8, 123.1, 122.8, 121.9, 118.2, 115.1, 109.7, 27.8; LRMS (ESI) m/z calcd for C18H11F6NO [M+Na]+ : 371.1, found : 372.1. 1 H NMR (400 MHz, CDCl 3 ) δ 9.95 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.71 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.03 (dd, J = 7.6 Hz, 1H), 2.65 (s, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 187.6, 137.4, 133.0, 129.2, 129.0, 128.1, 126.1, 125.7, 125.5, 124.6, 123.8, 123.1, 122.8, 121.9, 2, 115.1, 109.7, 27.8; LRMS (ESI) m/z calcd for C 18 H 11 F 6 NO [M+Na] + : 371.1, found : 372.1.
화합물 GxF 7 : Compound GxF 7 :
IB-B(52.4 mg, 0.22 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(144 mg, 0.88 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(93.0 mg, 0.88 mmol)를 첨가한 후, 100℃에서 17시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-7로 표시되는 황색 고체의 화합물 GxF 7(56.4 mg, 0.16 mmol, 74.2% 수율)을 수득 하였다.4-acetylphenyl boronic acid (144 mg, 0.88 mmol), tetrakis(triphenylphosphine)palladium ( 231 mg, 20.0 mol%) and sodium carbonate (93.0 mg, 0.88 mmol) were added, and then stirred at 100°C for 17 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to produce compound GxF 7 (56.4 mg, 0.16 mmol, 74.2%) as a yellow solid represented by the following formula 1-7. yield) was obtained.
[화학식 1-7][Formula 1-7]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.91 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 2.63 (s, 3H), 2.61 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 197.4, 187.9, 144.4, 138.8, 136.7, 135.8, 133.3, 129.5, 128.0, 127.6, 124.9, 124.1, 123.4, 122.1, 118.7, 115.5, 109.9, 28.1, 27.1; LRMS (ESI) m/z calcd for C19H14F3NO2 [M+Na]+ : 345.1, found : 346.1. 1 H NMR (400 MHz, CDCl 3 ) δ 9.91 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.72 (s , 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 2.63 (s, 3H), 2.61 (s , 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.4, 187.9, 144.4, 138.8, 136.7, 135.8, 133.3, 129.5, 128.0, 127.6, 124.9, 124.1, 123.4, 122.1, 118. 7, 115.5, 109.9, 28.1, 27.1; LRMS (ESI) m/z calcd for C 19 H 14 F 3 NO 2 [M+Na] + : 345.1, found : 346.1.
화합물 GxF 8 : Compound GxF 8 :
IB-B(73.8 mg, 0.24 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(117 mg, 0.96 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(102mg, 0.96 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-8로 표시되는 황색 고체의 화합물 GxF 8(79.8 mg, 0.26 mmol, 100% 수율)을 수득 하였다.Phenylboronic acid (117 mg, 0.96 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 20.0 mol%) and sodium carbonate (102 mg, 0.96 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 8 (79.8 mg, 0.26 mmol, 100%) as a yellow solid represented by the following formula 1-8. yield) was obtained.
[화학식 1-8][Formula 1-8]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.94 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.07 (dd, J = 7.2 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 3.90 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 184.2, 162.6, 137.5, 133.3, 132.1, 131.2, 129.2, 128.1, 126.1, 126.0, 125.8, 125.1, 123.7, 118.2, 113.7, 109.5, 55.6. 1 H NMR (400 MHz, CDCl 3 ) δ 9.94 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.4 Hz) , 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.07 (dd, J = 7.2 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 3.90 (s) , 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.2, 162.6, 137.5, 133.3, 132.1, 131.2, 129.2, 128.1, 126.1, 126.0, 125.8, 125.1, 123.7, 118.2, 7, 109.5, 55.6.
화합물 GxF 9 : Compound GxF 9 :
IB-B(52.1 mg, 0.22 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(133 mg, 0.87 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트((92.7 mg, 0.87 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-9로 표시되는 황색 고체의 화합물 GxF 9(547.2 mg, 0.14 mmol, 64% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (133 mg, 0.87 mmol) and tetrakis(triphenylphosphine)palladium were added to a solution containing IB-B (52.1 mg, 0.22 mmol) mixed with DMF and water at a ratio of 2:1. (231 mg, 20.0 mol%) and sodium carbonate ((92.7 mg, 0.87 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was washed with DCM. Extracted three times were combined, dried over anhydrous Na 2 SO 4 and concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%). Thus, compound GxF 9 (547.2 mg, 0.14 mmol, 64% yield) as a yellow solid represented by the following Chemical Formula 1-9 was obtained.
[화학식 1-9][Formula 1-9]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.89 (d, J = 7.2 Hz, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 7.2 Hz, 1H), 3.87 (s, 3H), 2.62 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 187.4, 158.8, 132.8, 129.1, 128.8, 126.0, 125.0, 124.8, 124.6, 123.3, 122.7, 122.1, 119.8, 115.5, 114.5, 109.2, 55.5, 27.7; LRMS (ESI) m/z calcd for C18H14F3NO2 [M+Na]+ : 333.11, found : 334.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.89 (d, J = 7.2 Hz, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 7.2 Hz, 1H), 3.87 (s, 3H), 2.62 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 187.4, 158.8, 132.8, 129.1, 128.8, 126.0, 125.0, 124.8, 124.6, 123.3, 122.7, 122.1, 119.8, 115.5, 114. 5, 109.2, 55.5, 27.7; LRMS (ESI) m/z calcd for C 18 H 14 F 3 NO 2 [M+Na] + : 333.11, found : 334.2.
화합물 GxF 10 : Compound GxF 10 :
IB-B(77.8 mg, 0.25 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(167 mg, 1.01 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(108 mg, 1.01 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-10로 표시되는 황색 고체의 화합물 GxF 10(85.3 mg, 0.25 mmol, 100% 수율)을 수득 하였다.4-(dimethylamino)phenyl boronic acid (167 mg, 1.01 mmol) and tetrakis (triphenyl phosphatase) were added to a solution containing IB-B (77.8 mg, 0.25 mmol) mixed with DMF and water at a ratio of 2:1. Finn) Palladium (231 mg, 20.0 mol%) and sodium carbonate (108 mg, 1.01 mmol) were added, and then stirred at 100°C for 12 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 10 (85.3 mg, 0.25 mmol, 100%) as a yellow solid represented by the following formula 1-10. yield) was obtained.
[화학식 1-10][Formula 1-10]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.88 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.57 (s, 1H), 7.41 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 3.01 (s, 6H), 2.62 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 186.9, 149.3, 132.4, 128.3, 124.5, 124.1, 123.8, 122.9, 121.9, 121.8, 121.1, 121.0, 120.1, 115.4, 112.5, 108.6, 40.2, 27.3; LRMS (ESI) m/z calcd for C19H17F3N2O [M+Na]+ : 346.1, found : 347.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.88 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.57 (s, 1H), 7.41 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 3.01 (s, 6H), 2.62 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.9, 149.3, 132.4, 128.3, 124.5, 124.1, 123.8, 122.9, 121.9, 121.8, 121.1, 121.0, 120.1, 115.4, 112. 5, 108.6, 40.2, 27.3; LRMS (ESI) m/z calcd for C 19 H 17 F 3 N 2 O [M+Na] + : 346.1, found : 347.2.
<GxF 11 ~ 15><GxF 11 ~ 15>
IC-E : 하기 반응식 4와 같이 합성하였으며, 구체적으로, 4(트리플루오로메틸)피리딘(348 μL, 3.00 mmol) 및 2-브로모아세토페논(2-bromoacetophenone; 627 mg, 3.15 mmol)이 포함된 DMF(7.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(160 μL, 0.50 mmol), 구리(II) 아세테이트 모노하이드레이트(898 mg, 1.50 mmol) 및 소듐 아세테이트(738 mg, 9.00 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IC-E(481.9 mg, 1.3 mmol, 88.9% 수율)를 수득 하였다. IC-E : Synthesized according to Scheme 4 below, specifically, DMF (DMF) containing 4(trifluoromethyl)pyridine (348 μL, 3.00 mmol) and 2-bromoacetophenone (2-bromoacetophenone; 627 mg, 3.15 mmol) 7.0 mL) was stirred at 100°C overnight, then ethyl acrylate (160 μL, 0.50 mmol), copper(II) acetate monohydrate (898 mg, 1.50 mmol), and sodium acetate (738 mg, 9.00 mmol) were added. and stirred at 100°C for 16 hours. After confirming that the reaction was complete by TLC, copper acetate was removed by filtration through a Celite pad, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (1 to 15% hexane containing EtOAc) to obtain compound IC-E (481.9 mg, 1.3 mmol, 88.9% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.88 (d, J = 7.6 Hz, 1H), 8.59 (s, 1H), 7.78 (s, 1H), 7.74 (d, J = 6.8 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.10 (dd, J = 7.4 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H); 13C NMR(100 MHz, CDCl3) δ 185.3, 163.0, 138.8, 137.2, 131.7, 129.2, 128.8, 128.5, 128.3, 128.2, 128.0, 124.2, 123.2, 121.5, 117.0, 110.4, 108.5, 60.5, 14.5; LRMS (ESI) m/z calcd for C19H14F3NO [M+Na]+ : 361.1, found : 362.1. 1 H NMR (400 MHz, CDCl 3 ) δ 9.88 (d, J = 7.6 Hz, 1H), 8.59 (s, 1H), 7.78 (s, 1H), 7.74 (d, J = 6.8 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.10 (dd, J = 7.4 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.37 (t , J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 185.3, 163.0, 138.8, 137.2, 131.7, 129.2, 128.8, 128.5, 128.3, 128.2, 128.0, 124.2, 123.2, 121.5, 117. 0, 110.4, 108.5, 60.5, 14.5; LRMS (ESI) m/z calcd for C 19 H 14 F 3 NO [M+Na] + : 361.1, found : 362.1.
IC-B : IC-E(481.9 mg, 1.3 mmol)가 포함된 메탄올(10 mL)에 KOH (519mg, 10.0 mmol)를 첨가한 후, 실온에서 4시간 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 흰색고체의 화합물 IC-A를 수득하였다. IC-B : KOH (519 mg, 10.0 mmol) was added to methanol (10 mL) containing IC-E (481.9 mg, 1.3 mmol), and then stirred at room temperature for 4 hours. The reaction mixture was acidified by adding 6N HCl, and the resulting solid was collected through filtration, washed with water, and dried in a drying oven to obtain Compound IC-A as a white solid.
수득한 화합물 IC-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IC-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(162.4 mg, 1.9 mmol)를 첨가하고 및 NBS(172.0 mg, 0.9 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - EA 12%)로 정제하여 황색 고체의 화합물 IC-B(219.2 mg, 0.595 mmol, 99.2% 수율)를 수득 하였다.The obtained compound IC-A was used in the next step without further purification. Sodium bicarbonate (162.4 mg, 1.9 mmol) was added to DMF (10.0 mL) containing IC-A and NBS (172.0 mg, 0.9 mmol) ) was added in portions at 0°C. The reaction mixture was stirred at room temperature for 12 hours, then the resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8 - EA 12%) to obtain compound IC-B (219.2 mg, 0.595 mmol, 99.2% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.96 (d, J = 7.6 Hz, 1H), 7.90 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.46 (s, 1H), 7.09 (d, J = 7.6 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 185.4, 139.1, 134.2, 131.7, 128.9, 128.8, 128.3, 127.4, 126.1, 125.7, 124.4, 123.2, 121.7, 115.1, 109.8, 92.3; LRMS (ESI) m/z calcd for C16H9BrF3NO [M+Na]+ : 367.0, found : 368.0. 1 H NMR (400 MHz, CDCl 3 ) δ 9.96 (d, J = 7.6 Hz, 1H), 7.90 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.59 (t, J = 7.4 Hz) , 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.46 (s, 1H), 7.09 (d, J = 7.6 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 185.4, 139.1, 134.2, 131.7, 128.9, 128.8, 128.3, 127.4, 126.1, 125.7, 124.4, 123.2, 121.7, 115.1, 109. 8, 92.3; LRMS (ESI) m/z calcd for C 16 H 9 BrF 3 NO [M+Na] + : 367.0, found : 368.0.
[반응식 4][Scheme 4]
화합물 GxF 11 : Compound GxF 11 :
IC-B(51.2 mg, 0.14 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(106 mg, 0.55 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(59.0 mg, 0.55 mmol)를 첨가한 후, 100℃에서 5시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-11로 표시되는 황색 고체의 화합물 GxF 11(54.0 mg, 0.12 mmol, 89.0% 수율)을 수득 하였다.IC-B (51.2 mg, 0.14 mmol), 4-trifluorophenyl boronic acid (106 mg, 0.55 mmol), tetrakis(triphenyl phosphine) in a 2:1 mixture of DMF and water. Palladium (231 mg, 20.0 mol%) and sodium carbonate (59.0 mg, 0.55 mmol) were added, and then stirred at 100°C for 5 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 11 (54.0 mg, 0.12 mmol, 89.0%) as a yellow solid represented by the following formula 1-11. yield) was obtained.
[화학식 1-11][Formula 1-11]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 10.05 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 7.85 (dd, J = 8.2 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.60 (t, J = 6.8 Hz, 1H), 7.57 (s, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 7.4 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 185.5, 139.8, 137.5, 133.9, 131.8, 129.5, 129.1, 128.6, 128.3, 126.4, 126.2, 126.2, 126.0, 125.8, 123.8, 118.7, 115.3, 110.0, 110.0, 47.1, 34.7; LRMS (ESI) m/z calcd for C23H13F6NO [M+Na]+ : 433.1, found : 434.3. 1 H NMR (400 MHz, CDCl 3 ) δ 10.05 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 7.85 (dd, J = 8.2 Hz, 2H), 7.74 (d, J = 8.0 Hz) , 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.60 (t, J = 6.8 Hz, 1H), 7.57 (s, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.14 (d , J = 7.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 185.5, 139.8, 137.5, 133.9, 131.8, 129.5, 129.1, 128.6, 128.3, 126.4, 126.2, 126.2, 126.0, 125.8, 123. 8, 118.7, 115.3, 110.0, 110.0, 47.1 , 34.7; LRMS (ESI) m/z calcd for C 23 H 13 F 6 NO [M+Na] + : 433.1, found : 434.3.
화합물 GxF 12 : Compound GxF 12 :
IC-B(36.9 mg, 0.1 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(65.6 mg, 0.4 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(42.4 mg, 0.4 mmol)를 첨가한 후, 100℃에서 6시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-12로 표시되는 황색 고체의 화합물 GxF 12(38.1 mg, 0.09 mmol, 93.5% 수율)을 수득 하였다.4-acetylphenyl boronic acid (65.6 mg, 0.4 mmol), tetrakis(triphenyl phosphine)palladium ( 231 mg, 20.0 mol%) and sodium carbonate (42.4 mg, 0.4 mmol) were added, and then stirred at 100°C for 6 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to produce compound GxF 12 (38.1 mg, 0.09 mmol, 93.5%) as a yellow solid represented by the following formula 1-12. yield) was obtained.
[화학식 1-12][Formula 1-12]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 10.03 (d, J = 7.2 Hz, 1H), 8.13 (s,1H), 8.06 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.59 (s, 1H), 7.52 (d, J = 7.4 Hz, 3H), 7.12 (dd, J = 7.2 Hz, 1H), 2.65 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 197.5, 185.6, 139.9, 138.8, 135.8, 134.1, 132.0, 129.7, 129.5, 129.3, 128.7, 128.1, 126.8, 126.5, 126.1, 124.9, 123.9, 122.2, 119.1, 115.6, 115.6, 110.1, 110.2, 27.1; LRMS (ESI) m/z calcd for C24H16F3NO2 [M+Na]+ : 407.1, found : 408.1. 1 H NMR (400 MHz, CDCl 3 ) δ 10.03 (d, J = 7.2 Hz, 1H), 8.13 (s,1H), 8.06 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz) , 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.59 (s, 1H), 7.52 (d, J = 7.4 Hz, 3H), 7.12 (dd, J = 7.2 Hz, 1H), 2.65 (s) , 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.5, 185.6, 139.9, 138.8, 135.8, 134.1, 132.0, 129.7, 129.5, 129.3, 128.7, 128.1, 126.8, 126.5, 126. 1, 124.9, 123.9, 122.2, 119.1, 115.6 , 115.6, 110.1, 110.2, 27.1; LRMS (ESI) m/z calcd for C 24 H 16 F 3 NO 2 [M+Na] + : 407.1, found : 408.1.
화합물 GxF 13 : Compound GxF 13 :
IC-B(40.5 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(53.7 mg, 0.44 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(46.6mg, 0.44 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-13으로 표시되는 황색 고체의 화합물 GxF 13(79.8 mg, 0.10 mmol, 94.5% 수율)을 수득 하였다.Phenylboronic acid (53.7 mg, 0.44 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 20.0 mol%) and sodium carbonate (46.6 mg, 0.44 mmol) were added, and then stirred at 100°C for 12 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 13 (79.8 mg, 0.10 mmol, 94.5%) as a yellow solid represented by the following formula 1-13. yield) was obtained.
[화학식 1-13][Formula 1-13]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 10.04 (d, J = 7.2 Hz, 1H), 8.12 (s, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7.58 (d, J = 6.0 Hz, 1H), 7.52 (m, 7H), 7.38 (d, J = 7.6 Hz, 1H), 7.10 (dd, J = 7.6 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 185.3, 140.0, 133.8, 133.7, 131.5, 129.2, 129.1, 129.1, 128.4, 128.1, 127.3, 126.0, 125.8, 125.7, 123.4, 122.1, 120.4, 115.7, 115.6, 109.6, 47.0, 34.6; LRMS (ESI) m/z calcd for C22H14F3NO [M+Na]+ : 365.1, found : 366.1. 1 H NMR (400 MHz, CDCl 3 ) δ 10.04 (d, J = 7.2 Hz, 1H), 8.12 (s, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7.58 (d, J = 6.0 Hz) , 1H), 7.52 (m, 7H), 7.38 (d, J = 7.6 Hz, 1H), 7.10 (dd, J = 7.6 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 185.3, 140.0, 133.8, 133.7, 131.5, 129.2, 129.1, 129.1, 128.4, 128.1, 127.3, 126.0, 125.8, 125.7, 123. 4, 122.1, 120.4, 115.7, 115.6, 109.6 , 47.0, 34.6; LRMS (ESI) m/z calcd for C 22 H 14 F 3 NO [M+Na] + : 365.1, found : 366.1.
화합물 GxF 14 : Compound GxF 14 :
IC-B(47.9 mg, 0.13 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(79.0 mg, 0.52 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(55.1 mg, 0.52 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-14로 표시되는 황색 고체의 화합물 GxF 14(57.6 mg, 0.14 mmol, 100% 수율)을 수득 하였다.IC-B (47.9 mg, 0.13 mmol), 4-methoxyphenyl boronic acid (79.0 mg, 0.52 mmol), tetrakis(triphenylphosphine)palladium in a 2:1 mixture of DMF and water. (231 mg, 20.0 mol%) and sodium carbonate (55.1 mg, 0.52 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 14 (57.6 mg, 0.14 mmol, 100%) as a yellow solid represented by the following formula 1-14. yield) was obtained.
[화학식 1-14][Formula 1-14]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 10.02 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 7.85 (d, J = 6.8 Hz, 2H), 7.58 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.48 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.07 (dd, J = 7.2 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 185.1, 158.8, 139.9, 133,6, 131.4, 129.2, 129.0(2), 128.3, 125.9, 125.6, 125.5, 125.4, 125.2, 123.1, 120.1, 115.6, 115.5, 114.5, 109.4, 109.3, 55.5; LRMS (ESI) m/z calcd for C23H16F3NO2 [M+Na]+ : 395.1, found : 396.1. 1H NMR (400 MHz, CDCl 3 ), δ 10.02 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 7.85 (d, J = 6.8 Hz, 2H), 7.58 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.48 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.07 (dd, J = 7.2 Hz, 1H), 7.02 ( d, J = 8.8 Hz, 2H), 3.86 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 185.1, 158.8, 139.9, 133,6, 131.4, 129.2, 129.0(2), 128.3, 125.9, 125.6, 125.5, 125.4, 125.2, 123.1, 1 20.1, 115.6, 115.5, 114.5, 109.4, 109.3, 55.5; LRMS (ESI) m/z calcd for C 23 H 16 F 3 NO 2 [M+Na] + : 395.1, found : 396.1.
화합물 GxF 15 : Compound GxF 15 :
IC-B(39.5 mg, 0.10 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(45.5 mg, 0.43 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(108 mg, 1.01 mmol)를 첨가한 후, 100℃에서 19시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-15로 표시되는 황색 고체의 화합물 GxF 15(43.5 mg, 0.10 mmol, 99.7% 수율)을 수득 하였다.4-(dimethylamino)phenyl boronic acid (45.5 mg, 0.43 mmol) and tetrakis (triphenyl phosphatase) were added to a solution containing IC-B (39.5 mg, 0.10 mmol) mixed 2:1 with DMF and water. Finn) Palladium (231 mg, 20.0 mol%) and sodium carbonate (108 mg, 1.01 mmol) were added, and then stirred at 100°C for 19 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 15 (43.5 mg, 0.10 mmol, 99.7%) as a yellow solid represented by the following formula 1-15. yield) was obtained.
[화학식 1-15][Formula 1-15]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 10.02 (d, J = 7.2 Hz, 1H), 8.11 (s, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.57 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.05 (dd, J = 7.4 Hz, 1H), 6.87 (d, J = 8.0 Hz, 2H), 3.02 (s, 6H); 13C NMR(100 MHz, CDCl3) δ 185.2, 166.7, 149.8, 140.3, 133.8, 131.5, 129.2, 129.0, 128.4, 127.3, 125.8, 125.4, 125.1, 125.0, 123.2, 122.3, 121.0, 116.1, 116.0, 113.2, 109.4, 47.1, 41.0, 34.7; LRMS (ESI) m/z calcd for C24H19F3N2O [M+Na]+ : 408.1, found : 409.2. 1 H NMR (400 MHz, CDCl 3 ) δ 10.02 (d, J = 7.2 Hz, 1H), 8.11 (s, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.57 (d, J = 7.2 Hz) , 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.05 (dd, J = 7.4 Hz, 1H), 6.87 (d , J = 8.0 Hz, 2H), 3.02 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 185.2, 166.7, 149.8, 140.3, 133.8, 131.5, 129.2, 129.0, 128.4, 127.3, 125.8, 125.4, 125.1, 125.0, 123. 2, 122.3, 121.0, 116.1, 116.0, 113.2 , 109.4, 47.1, 41.0, 34.7; LRMS (ESI) m/z calcd for C 24 H 19 F 3 N 2 O [M+Na] + : 408.1, found : 409.2.
<GxF 16 ~ 20><GxF 16 ~ 20>
ID-E : 하기 반응식 5와 같이 합성하였으며, 구체적으로, 4(트리플루오로메틸)피리딘(695 μL, 6.00 mmol) 및 2-브로모-4-메톡시아세토페논(2-bromo-4-methoxyacetophenone, 1.44 g, 6.30 mmol)이 포함된 DMF(10.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(320 μL, 3.00 mmol), 구리(II) 아세테이트 모노하이드레이트(1.79 g, 9.00 mmol) 및 소듐 아세테이트(1.47 g, 18.0 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 ID-E(1.02 g, 2.63 mmol, 87.6% 수율)를 수득 하였다. ID-E : Synthesized according to Scheme 5 below, specifically, 4(trifluoromethyl)pyridine (695 μL, 6.00 mmol) and 2-bromo-4-methoxyacetophenone (1.44 g) , 6.30 mmol) was stirred at 100°C overnight, and then ethyl acrylate (320 μL, 3.00 mmol), copper(II) acetate monohydrate (1.79 g, 9.00 mmol), and sodium acetate. (1.47 g, 18.0 mmol) was added and stirred at 100°C for 16 hours. After confirming that the reaction was complete by TLC, copper acetate was removed by filtration through a Celite pad, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (1 to 15% hexane containing EtOAc) to obtain compound ID-E (1.02 g, 2.63 mmol, 87.6% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.93 (d, J = 7.2 Hz, 1H), 8.69 (s, 1H), 7.89 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 7.4Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 4.41 (d, J = 7.2 Hz, 2H), 3.92 (s, 3H), 1.42 (d, J = 6.6 Hz, 3H); 13C NMR(100 MHz, CDCl3) δ 184.1, 163.2, 162.7, 137.0, 131.3, 131.1, 129.2, 127.9, 127.8, 127.6, 124.3, 123.3, 121.6, 121.3, 116.9, 113.6, 110.1, 108.2, 60.5, 55.4, 14.5; LRMS (ESI) m/z calcd for C20H16F3NO4 [M+Na]+ : 391.1, found : 392.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.93 (d, J = 7.2 Hz, 1H), 8.69 (s, 1H), 7.89 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 7.4 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 4.41 (d, J = 7.2 Hz, 2H), 3.92 (s, 3H), 1.42 (d, J = 6.6 Hz , 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.1, 163.2, 162.7, 137.0, 131.3, 131.1, 129.2, 127.9, 127.8, 127.6, 124.3, 123.3, 121.6, 121.3, 9, 113.6, 110.1, 108.2, 60.5, 55.4 , 14.5; LRMS (ESI) m/z calcd for C 20 H 16 F 3 NO 4 [M+Na] + : 391.1, found : 392.2.
ID-B : ID-E(1.02 g, 2.62 mmol)가 포함된 메탄올(18 mL)에 KOH(5.91 g, 105 mmol)를 첨가한 후, 실온에서 4시간 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 흰색고체의 화합물 ID-A를 수득하였다. ID-B : KOH (5.91 g, 105 mmol) was added to methanol (18 mL) containing ID-E (1.02 g, 2.62 mmol), and then stirred at room temperature for 4 hours. The reaction mixture was acidified by adding 6N HCl, and the resulting solid was collected through filtration, washed with water, and dried in a drying oven to obtain Compound ID-A as a white solid.
수득한 화합물 ID-A는 추가 정제없이 바로 다음 단계에 사용하였으며, ID-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(660 mg, 7.86 mmol)를 첨가하고 및 NBS(699 mg, 3.93 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - EA 12%)로 정제하여 황색 고체의 화합물 ID-B(0.93 g, 2.36 mmol, 90.0% 수율)를 수득 하였다.The obtained compound ID-A was used in the next step without further purification. Sodium bicarbonate (660 mg, 7.86 mmol) was added to DMF (10.0 mL) containing ID-A and NBS (699 mg, 3.93 mmol). ) was added in portions at 0°C. The reaction mixture was stirred at room temperature for 12 hours, then the resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8 - EA 12%) to obtain compound ID-B (0.93 g, 2.36 mmol, 90.0% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.88 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.46 (s, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 183.3, 162.5, 133.8, 131.5, 131.1, 128.8, 126.7, 125.6, 125.3. 124.4, 123.3, 121.7, 121.3, 115.1, 109.4, 62.0, 55.5. 1 H NMR (400 MHz, CDCl 3 ) δ 9.88 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.46 (s, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.3, 162.5, 133.8, 131.5, 131.1, 128.8, 126.7, 125.6, 125.3. 124.4, 123.3, 121.7, 121.3, 115.1, 109.4, 62.0, 55.5.
[반응식 5][Scheme 5]
화합물 GxF 16 : Compound GxF 16 :
ID-B(1.05 g, 0.26 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(202 mg, 1.06 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(112 mg, 1.06 mmol)를 첨가한 후, 100℃에서 5시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-16으로 표시되는 황색 고체의 화합물 GxF 16(90.2 mg, 0.19 mmol, 73.4% 수율)을 수득 하였다.ID-B (1.05 g, 0.26 mmol), 4-trifluorophenyl boronic acid (202 mg, 1.06 mmol), and tetrakis(triphenyl phosphine) in a 2:1 mixture of DMF and water. Palladium (231 mg, 20.0 mol%) and sodium carbonate (112 mg, 1.06 mmol) were added, and then stirred at 100°C for 5 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 16 (90.2 mg, 0.19 mmol, 73.4%) as a yellow solid represented by the following formula 1-16. yield) was obtained.
[화학식 1-16][Formula 1-16]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.91 (d, J = 7.2 Hz, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 7.51 (m, 6H), 7.37 (t, J = 7.2 Hz, 1H), 2.63 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 187.4, 133.6, 132.8, 129.0, 128.8, 127.9, 127.1, 125.2, 124.9, 124.7, 123.4, 122.9, 122.0, 119.9, 115.4, 115.4, 109.3, 109.2, 27.7. 1 H NMR (400 MHz, CDCl 3 ) δ 9.91 (d, J = 7.2 Hz, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 7.51 (m, 6H), 7.37 (t, J = 7.2 Hz, 1H), 2.63 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 187.4, 133.6, 132.8, 129.0, 128.8, 127.9, 127.1, 125.2, 124.9, 124.7, 123.4, 122.9, 122.0, 119.9, 4, 115.4, 109.3, 109.2, 27.7.
화합물 GxF 17 : Compound GxF 17 :
ID-B(94.3 mg, 0.23 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(155 mg, 0.94 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(100 mg, 0.94 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-17로 표시되는 황색 고체의 화합물 GxF 17(118 mg, 0.27 mmol, 100% 수율)을 수득 하였다.4-acetylphenyl boronic acid (155 mg, 0.94 mmol), tetrakis(triphenylphosphine)palladium ( 231 mg, 20.0 mol%) and sodium carbonate (100 mg, 0.94 mmol) were added, and then stirred at 100°C for 9 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to produce compound GxF 17 (118 mg, 0.27 mmol, 100%) as a yellow solid represented by the following formula 1-17. yield) was obtained.
[화학식 1-17][Formula 1-17]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.96 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 8.07 (t, J = 8.2 Hz, 3H), 7.88 (d, J = 9.2 Hz, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.09 (dd, J = 7.4 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 3.91 (s, 3H), 2.66 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 197.0, 183.8, 162.4, 143.8, 138.4, 136.2, 135.2, 133.0, 131.8, 131.1, 129.0, 128.7, 127.5, 127.1, 125.4, 124.9, 124.5, 123.6, 121.8, 118.3, 115.1, 113.5, 109.2, 55.4, 26.6; LRMS (ESI) m/z calcd for C25H18F3NO3[M+Na]+ : 437.1, found : 438.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.96 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 8.07 (t, J = 8.2 Hz, 3H), 7.88 (d, J = 9.2 Hz) , 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.09 (dd, J = 7.4 Hz, 1H), 7.03 (d , J = 8.8 Hz, 1H), 3.91 (s, 3H), 2.66 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.0, 183.8, 162.4, 143.8, 138.4, 136.2, 135.2, 133.0, 131.8, 131.1, 129.0, 128.7, 127.5, 127.1, 125. 4, 124.9, 124.5, 123.6, 121.8, 118.3 , 115.1, 113.5, 109.2, 55.4, 26.6; LRMS (ESI) m/z calcd for C 25 H 18 F 3 NO 3 [M+Na] + : 437.1, found : 438.2.
화합물 GxF 18 : Compound GxF 18 :
ID-B(94.0 mg, 0.23 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(115 mg, 0.94 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(100 mg, 0.94 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-18로 표시되는 황색 고체의 화합물 GxF 18(97.6 mg, 0.24 mmol, 100% 수율)을 수득 하였다.Phenylboronic acid (115 mg, 0.94 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 20.0 mol%) and sodium carbonate (100 mg, 0.94 mmol) were added, and then stirred at 100°C for 12 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 18 (97.6 mg, 0.24 mmol, 100%) as a yellow solid represented by the following formula 1-18. yield) was obtained.
[화학식 1-18][Formula 1-18]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.95 (d, J = 7.6 Hz, 1H), 8.11 (s,1H), 7.88 (d, J = 8.8 Hz, 2H), 7.56(m, 3H), 7.49 (t, J = 7.8 Hz, 2H), 7.38 (q, J = 7.6 Hz, 1H), 7.06 (dd, J = 7.8 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 3.91 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 184.5, 162.7, 134.1, 133.6, 132.7, 131.6, 129.4, 129.3, 128.4, 127.5, 125.8, 125.5, 125.4, 125.1, 123.7, 122.4, 120.3, 115.9, 115.8, 114.0, 109.6, 109.5, 55.9; LRMS (ESI) m/z calcd for C23H16F3NO2 [M+Na]+ : 395.1, found : 396.1. 1 H NMR (400 MHz, CDCl 3 ) δ 9.95 (d, J = 7.6 Hz, 1H), 8.11 (s, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.56 (m, 3H), 7.49 (t, J = 7.8 Hz, 2H), 7.38 (q, J = 7.6 Hz, 1H), 7.06 (dd, J = 7.8 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 3.91 (s) , 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.5, 162.7, 134.1, 133.6, 132.7, 131.6, 129.4, 129.3, 128.4, 127.5, 125.8, 125.5, 125.4, 125.1, 123. 7, 122.4, 120.3, 115.9, 115.8, 114.0 , 109.6, 109.5, 55.9; LRMS (ESI) m/z calcd for C 23 H 16 F 3 NO 2 [M+Na] + : 395.1, found : 396.1.
화합물 GxF 19 : Compound GxF 19 :
ID-B(120 mg, 0.30 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(182 mg, 1.20 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(127 mg, 1.20 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-19로 표시되는 황색 고체의 화합물 GxF 19(125.6 mg, 0.29 mmol, 98.4% 수율)을 수득 하였다.ID-B (120 mg, 0.30 mmol), 4-methoxyphenyl boronic acid (182 mg, 1.20 mmol), and tetrakis(triphenylphosphine)palladium in a 2:1 mixture of DMF and water. (231 mg, 20.0 mol%) and sodium carbonate (127 mg, 1.20 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 19 (125.6 mg, 0.29 mmol, 98.4%) as a yellow solid represented by the following formula 1-19. yield) was obtained.
[화학식 1-19][Formula 1-19]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.93 (d, J = 7.6 Hz, 1H), 8.05 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.49 (s, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 6.4 Hz, 3H), 7.01 (d, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.87 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 183.8, 162.2, 158.7, 133.0, 132.2, 131.1, 129.0, 128.8, 126.0, 124.9, 124.8, 124.7, 124.6, 123.1, 122.1, 119.7, 115.4, 115.4, 114.4, 113.5, 108.8, 108.9, 55.4, 55.3; LRMS (ESI) m/z calcd for C24H18F3NO3[M+Na]+ : 425.1, found : 426.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.93 (d, J = 7.6 Hz, 1H), 8.05 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.49 (s, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 6.4 Hz, 3H), 7.01 (d, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.87 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.8, 162.2, 158.7, 133.0, 132.2, 131.1, 129.0, 128.8, 126.0, 124.9, 124.8, 124.7, 124.6, 123.1, 122. 1, 119.7, 115.4, 115.4, 114.4, 113.5 , 108.8, 108.9, 55.4, 55.3; LRMS (ESI) m/z calcd for C 24 H 18 F 3 NO 3 [M+Na] + : 425.1, found : 426.2.
화합물 GxF 20 : Compound GxF 20 :
ID-B(1.32 mg, 0.33 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(220 mg, 1.33 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(141 mg, 1.33 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-20으로 표시되는 황색 고체의 화합물 GxF 20(151 mg, 0.34 mmol, 100% 수율)을 수득 하였다.4-(dimethylamino)phenyl boronic acid (220 mg, 1.33 mmol), tetrakis (triphenyl phosphatase), and tetrakis(triphenyl phosphatase) were added to a solution containing ID-B (1.32 mg, 0.33 mmol) mixed 2:1 with DMF and water. Finn) Palladium (231 mg, 20.0 mol%) and sodium carbonate (141 mg, 1.33 mmol) were added, and then stirred at 100°C for 9 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 20 (151 mg, 0.34 mmol, 100%) as a yellow solid represented by the following formula 1-20. yield) was obtained.
[화학식 1-20][Formula 1-20]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.92 (d, J = 7.6 Hz, 1H), 8.08 (s,1H), 7.87 (d, J = 7.6 Hz, 2H), 7.48 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 3H), 6.85 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 3.01 (s, 6H); 13C NMR(100 MHz, CDCl3) δ 183.8, 162.1, 149.5, 133.0, 132.4, 131.1, 128.7, 128.6, 127.5, 124.8, 124.5, 124.4, 124.2, 123.8, 123.0, 122.1, 121.4, 120.5, 119.4, 115.7, 113.4, 112.7, 108.7, 55.4, 40.5; LRMS (ESI) m/z calcd for C25H21F3N2O2 [M+Na]+ : 438.2, found : 439.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.92 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.48 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 3H), 6.85 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 3.01 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.8, 162.1, 149.5, 133.0, 132.4, 131.1, 128.7, 128.6, 127.5, 124.8, 124.5, 124.4, 124.2, 123.8, 123. 0, 122.1, 121.4, 120.5, 119.4, 115.7 , 113.4, 112.7, 108.7, 55.4, 40.5; LRMS (ESI) m/z calcd for C 25 H 21 F 3 N 2 O 2 [M+Na] + : 438.2, found : 439.2.
<GxF 21 ~ 25><GxF 21 ~ 25>
IE-E : 하기 반응식 6과 같이 합성하였으며, 구체적으로, 4(트리플루오로메틸)피리딘(695 μL, 6.00 mmol) 및 2-브로모-4'-(다이에틸아미노)아세토페논(2-Bromo-4’-(diethylamino)aceto-phenone, 1.70 mL, 6.30 mmol)이 포함된 DMF(6.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(320 μL, 3.00 mmol), 구리(II) 아세테이트 모노하이드레이트(1.79 g, 9.00 mmol) 및 소듐 아세테이트(1.47 g, 18.0 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IE-E(1.12 g, 2.60 mmol, 86.9% 수율)를 수득 하였다. IE-E : Synthesized according to Scheme 6 below, specifically, 4(trifluoromethyl)pyridine (695 μL, 6.00 mmol) and 2-bromo-4'-(diethylamino)acetophenone (2-Bromo-4') DMF (6.0 mL) containing -(diethylamino)aceto-phenone, 1.70 mL, 6.30 mmol) was stirred at 100°C overnight, then ethyl acrylate (320 μL, 3.00 mmol) and copper(II) acetate monohydrate. (1.79 g, 9.00 mmol) and sodium acetate (1.47 g, 18.0 mmol) were added and stirred at 100°C for 16 hours. After confirming that the reaction was complete by TLC, copper acetate was removed by filtration through a Celite pad, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (1 to 15% hexane containing EtOAc) to obtain compound IE-E (1.12 g, 2.60 mmol, 86.9% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.83 (d, J = 8.0 Hz, 1H), 8.66 (s, 1H), 7.91 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 5.4 Hz, 2H), 4.41 (q, J = 6.9, 2H), 3.46 (q, J = 6.6 Hz, 4H), 1.43 (t, J = 5.2, 3H), 1.25 (d, J = 5.5 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 182.8, 163.1, 150.4, 136.1, 131.4, 128.9, 126.7, 126.4, 126.1, 124.6, 124.3, 123.6, 121.6, 116.5(2), 109.8, 109.1, 109.2, 107.4, 60.0, 44.2, 14.3, 12.3; LRMS (ESI) m/z calcd for C23H23F3N2O3[M+Na]+ : 432.2, found : 433.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.83 (d, J = 8.0 Hz, 1H), 8.66 (s, 1H), 7.91 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 5.4 Hz, 2H), 4.41 (q, J = 6.9, 2H), 3.46 (q, J = 6.6 Hz, 4H), 1.43 (t, J = 5.2, 3H), 1.25 (d, J = 5.5 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 182.8, 163.1, 150.4, 136.1, 131.4, 128.9, 126.7, 126.4, 126.1, 124.6, 124.3, 123.6, 121.6, 116.5(2), 1 09.8, 109.1, 109.2, 107.4, 60.0, 44.2, 14.3, 12.3; LRMS (ESI) m/z calcd for C 23 H 23 F 3 N 2 O 3 [M+Na] + : 432.2, found : 433.2.
IE-B : IE-E(1.12 g, 2.60 mmol)가 포함된 메탄올(10 mL)에 KOH(5.85 g, 104 mmol)를 첨가한 후, 실온에서 4시간 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 흰색고체의 화합물 IE-A를 수득하였다. IE-B : KOH (5.85 g, 104 mmol) was added to methanol (10 mL) containing IE-E (1.12 g, 2.60 mmol), and then stirred at room temperature for 4 hours. The reaction mixture was acidified by adding 6N HCl, and the resulting solid was collected through filtration, washed with water, and dried in a drying oven to obtain compound IE-A as a white solid.
수득한 화합물 IE-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IE-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(655 mg, 7.80 mmol)를 첨가하고 및 NBS(694 mg, 3.90 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - EA 12%)로 정제하여 황색 고체의 화합물 IE-B(829 mg, 1.88 mmol, 72.6% 수율)를 수득 하였다.The obtained compound IE-A was used in the next step without further purification. Sodium bicarbonate (655 mg, 7.80 mmol) was added to DMF (10.0 mL) containing IE-A and NBS (694 mg, 3.90 mmol) ) was added in portions at 0°C. The reaction mixture was stirred at room temperature for 12 hours, then the resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8 - EA 12%) to obtain compound IE-B (829 mg, 1.88 mmol, 72.6% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.83 (d, J = 8.0 Hz, 1H), 8.66 (s, 1H), 7.91 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 5.4 Hz, 2H), 4.41 (q, J = 6.9, 2H), 3.46 (q, J = 6.6 Hz, 4H), 1.43 (t, J = 5.2, 3H), 1.25 (d, J = 5.5 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 182.0, 152.9, 135.2, 134.2, 133.9, 129.0, 128.8, 126.9, 126.0, 125.7, 124.6, 123.2, 122.3, 121.9, 120.1, 115.3, 92.5, 46.5, 12.8, 12.7. 1H NMR (400 MHz, CDCl 3 ), δ 9.83 (d, J = 8.0 Hz, 1H), 8.66 (s, 1H), 7.91 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 5.4 Hz, 2H), 4.41 (q, J = 6.9, 2H), 3.46 (q, J = 6.6 Hz, 4H), 1.43 (t , J = 5.2, 3H), 1.25 (d, J = 5.5 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 182.0, 152.9, 135.2, 134.2, 133.9, 129.0, 128.8, 126.9, 126.0, 125.7, 124.6, 123.2, 122.3, 121.9, 120. 1, 115.3, 92.5, 46.5, 12.8, 12.7 .
[반응식 6][Scheme 6]
화합물 GxF 21 : Compound GxF 21 :
IE-B(54.0 mg, 0.12 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(94.4 mg, 0.49 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(52.7 mg, 0.49 mmol)를 첨가한 후, 100℃에서 5시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-21로 표시되는 황색 고체의 화합물 GxF 21(43.1 mg, 0.08 mmol, 68.8% 수율)을 수득 하였다.IE-B (54.0 mg, 0.12 mmol), 4-trifluorophenyl boronic acid (94.4 mg, 0.49 mmol), tetrakis(triphenyl phosphine) in a 2:1 mixture of DMF and water. Palladium (231 mg, 20.0 mol%) and sodium carbonate (52.7 mg, 0.49 mmol) were added, and then stirred at 100°C for 5 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 21 (43.1 mg, 0.08 mmol, 68.8%) as a yellow solid represented by the following formula 1-21. yield) was obtained.
[화학식 1-21][Formula 1-21]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.95 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 7.83 (dd, J = 8.6 Hz, 1H), 7.76 (s, 1H), 7.74 (d, J = 5.6 Hz, 1H), 7.67 (m, 5H), 7.64 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 6.6 Hz, 1H), 3.00 (q, J = 6.9 Hz, 4H), 0.98 (t, J = 7.0 Hz, 6H); 13C NMR δ 184.3, 152.6, 145.1, 137.7, 133.6, 133.5, 133.2, 132.5, 130.1, 129.4, 129.3, 129.0(2), 128.3, 126.3, 126.2(2), 125.7, 125.6, 125.5, 125.1, 124.0, 120.0, 118.4, 46.0, 12.4; LRMS (ESI) m/z calcd for C27H22F6N2O[M+Na]+ : 504.2, found 505.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.95 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 7.83 (dd, J = 8.6 Hz, 1H), 7.76 (s, 1H), 7.74 (d, J = 5.6 Hz, 1H), 7.67 (m, 5H), 7.64 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 6.6 Hz, 1H), 3.00 (q, J = 6.9 Hz, 4H), 0.98 (t, J = 7.0 Hz, 6H); 13 C NMR δ 184.3, 152.6, 145.1, 137.7, 133.6, 133.5, 133.2, 132.5, 130.1, 129.4, 129.3, 129.0(2), 128.3, 126.3, 126.2(2), .7, 125.6, 125.5, 125.1, 124.0, 120.0, 118.4, 46.0, 12.4; LRMS (ESI) m/z calcd for C 27 H 22 F 6 N 2 O[M+Na] + : 504.2, found 505.2.
화합물 GxF 22 : Compound GxF 22 :
IE-B(49.7 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(74.2 mg, 0.45 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(48.0 mg, 0.45 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-22로 표시되는 황색 고체의 화합물 GxF 22(9.70 mg, 0.02 mmol, 18% 수율)을 수득 하였다.4-acetylphenyl boronic acid (74.2 mg, 0.45 mmol), tetrakis(triphenylphosphine)palladium ( 231 mg, 20.0 mol%) and sodium carbonate (48.0 mg, 0.45 mmol) were added, and then stirred at 100°C for 9 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to produce compound GxF 22 (9.70 mg, 0.02 mmol, 18%) as a yellow solid represented by the following formula 1-22. yield) was obtained.
[화학식 1-22][Formula 1-22]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.95 (d, J = 7.6 Hz, 1H), 8.12(s, 1H), 8.08(d, J = 8.4 Hz, 2H), 7.91(d, J = 2.0 Hz, 1H), 7.30(m, 2H), 7.67(d, J = 8.8 Hz, 2H), 7.63(s, 1H), 7.00(m, 2H), 3.29(q, J = 7.0 Hz, 4H), 2.66(s, 3H), 1.14(t, J = 7.2 Hz, 6H); 13C NMR δ 197.2, 183.1, 151.4, 138.6, 135.6, 133.6, 133.3, 132.1, 129.2, 128.7, 128.2, 127.9, 125.2, 121.5, 118.8, 46.1, 29.9, 26.9, 12.7; LRMS (ESI) m/z calcd for C28H25F3N2O2[M+Na]+ : 478.2, found 479.3. 1 H NMR (400 MHz, CDCl 3 ), δ 9.95 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 2.0 Hz, 1H), 7.30(m, 2H), 7.67(d, J = 8.8 Hz, 2H), 7.63(s, 1H), 7.00(m, 2H), 3.29(q, J = 7.0 Hz, 4H), 2.66(s, 3H), 1.14(t, J = 7.2 Hz, 6H); 13 C NMR δ 197.2, 183.1, 151.4, 138.6, 135.6, 133.6, 133.3, 132.1, 129.2, 128.7, 128.2, 127.9, 125.2, 121.5, 118.8, 46.1, 29. 9, 26.9, 12.7; LRMS (ESI) m/z calcd for C 28 H 25 F 3 N 2 O 2 [M+Na] + : 478.2, found 479.3.
화합물 GxF 23 : Compound GxF 23 :
IE-B(50.0 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(55.0 mg, 0.45 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(49.0 mg, 0.45 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-23으로 표시되는 황색 고체의 화합물 GxF 23(39.9 mg, 0.09 mmol, 80.1% 수율)을 수득 하였다.Phenylboronic acid (55.0 mg, 0.45 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 20.0 mol%) and sodium carbonate (49.0 mg, 0.45 mmol) were added, and then stirred at 100°C for 9 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 23 (39.9 mg, 0.09 mmol, 80.1%) as a yellow solid represented by the following formula 1-23. yield) was obtained.
[화학식 1-23][Formula 1-23]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.96 (d, J = 7.2 Hz, 1H), 8.11 (s,1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.59 (t, J = 7.6 Hz, 3H), 7.50 (t, J = 6.8 Hz, 1H), 7.40 (m, 2H), 7.32 (d, J = 6.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 3.03 (q, J = 6.5 Hz, 4H), 1.01 (t, J = 6.6 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 184.7, 152.6, 141.7, 135.1, 134.2, 133.6, 133.5, 132.5, 129.7, 129.4, 129.3, 128.8, 128.7, 128.4, 127.4, 127.1, 125.3, 125.2, 124.0, 120.2, 119.8, 115.9, 109.4, 46.1, 12.6; LRMS (ESI) m/z calcd for C26H23F3N2O[M+Na]+ : 436.2, found 437.2. 1H NMR (400 MHz, CDCl 3 ), δ 9.96 (d, J = 7.2 Hz, 1H), 8.11 (s,1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.59 (t, J = 7.6 Hz, 3H), 7.50 (t, J = 6.8 Hz, 1H), 7.40 (m, 2H), 7.32 (d, J = 6.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 3.03 (q, J = 6.5 Hz, 4H), 1.01 (t, J = 6.6 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.7, 152.6, 141.7, 135.1, 134.2, 133.6, 133.5, 132.5, 129.7, 129.4, 129.3, 128.8, 128.7, 128.4, 127. 4, 127.1, 125.3, 125.2, 124.0, 120.2 , 119.8, 115.9, 109.4, 46.1, 12.6; LRMS (ESI) m/z calcd for C 26 H 23 F 3 N 2 O[M+Na] + : 436.2, found 437.2.
화합물 GxF 24 : Compound GxF 24 :
IE-B(53.7 mg, 0.12 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(74.0 mg, 0.48 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(52.0 mg, 0.48 mmol)를 첨가한 후, 100℃에서 10시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-24로 표시되는 황색 고체의 화합물 GxF 24(44.8 mg, 0.09 mmol, 78.7% 수율)을 수득 하였다.IE-B (53.7 mg, 0.12 mmol), 4-methoxyphenyl boronic acid (74.0 mg, 0.48 mmol), tetrakis(triphenylphosphine)palladium in a 2:1 mixture of DMF and water. (231 mg, 20.0 mol%) and sodium carbonate (52.0 mg, 0.48 mmol) were added, and then stirred at 100°C for 10 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 24 (44.8 mg, 0.09 mmol, 78.7%) as a yellow solid represented by the following formula 1-24. yield) was obtained.
[화학식 1-24][Formula 1-24]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.84 (d, J = 7.6 Hz, 1H), 8.02 (s, 1H), 7.86 (d, J = 9.2 Hz, 2H), 7.54 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.96 (dd, J = 7.6 Hz, 1H), 6.71 (d, J = 9.2 Hz, 2H), 3.87 (s, 3H), 3.45 (q, J = 6.9 Hz, 4H), 1.23 (t, J = 7.2 Hz, 6H).; 13C NMR(100 MHz, CDCl3) δ 184.0, 152.0, 141.0, 134.4, 133.6, 133.0, 132.8, 131.9, 129.0, 128.7, 128.2, 128.1, 127.8, 126.8, 126.5, 124.9, 124.7, 124.5, 123.3, 121.8, 119.6, 119.1, 115.2, 108.8, 45.4, 29.6, 12.0. 1 H NMR (400 MHz, CDCl 3 ), δ 9.84 (d, J = 7.6 Hz, 1H), 8.02 (s, 1H), 7.86 (d, J = 9.2 Hz, 2H), 7.54 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.96 (dd, J = 7.6 Hz, 1H), 6.71 (d, J = 9.2 Hz, 2H), 3.87 ( s, 3H), 3.45 (q, J = 6.9 Hz, 4H), 1.23 (t, J = 7.2 Hz, 6H).; 13 C NMR (100 MHz, CDCl 3 ) δ 184.0, 152.0, 141.0, 134.4, 133.6, 133.0, 132.8, 131.9, 129.0, 128.7, 128.2, 128.1, 127.8, 126.8, 126. 5, 124.9, 124.7, 124.5, 123.3, 121.8 , 119.6, 119.1, 115.2, 108.8, 45.4, 29.6, 12.0.
화합물 GxF 25 : Compound GxF 25 :
IE-B(57.5 mg, 0.13 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(88.0 mg, 0.52 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(55.5 mg, 0.52 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-25로 표시되는 황색 고체의 화합물 GxF 25(43.1 mg, 0.08 mmol, 72.4% 수율)을 수득 하였다.4-(dimethylamino)phenyl boronic acid (88.0 mg, 0.52 mmol) and tetrakis (triphenyl phosphatase) were added to a solution containing IE-B (57.5 mg, 0.13 mmol) mixed with DMF and water at a ratio of 2:1. Finn) Palladium (231 mg, 20.0 mol%) and sodium carbonate (55.5 mg, 0.52 mmol) were added, and then stirred at 100°C for 12 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 25 (43.1 mg, 0.08 mmol, 72.4%) as a yellow solid represented by the following formula 1-25. yield) was obtained.
[화학식 1-25][Formula 1-25]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.95 (d, J = 7.2 Hz, 1H), 8.10 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.61 (s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.00 (dd, J = 7.4 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 3.07 (q, J = 7.1 Hz, 4H), 3.03 (s, 3H), 3.00 (s, 3H), 1.01 (d, J = 7.2 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 184.2, 151.8, 149.3, 149.0, 134.6, 132.7, 132.2, 129.0, 128.8, 128.6, 128.5, 128.1, 124.6, 124.2, 124.1, 123.8, 123.2, 121.9, 121.5, 120.1, 119.2, 115.5, 112.6, 112.1, 108.4, 45.1, 40.4, 11.9; LRMS (ESI) m/z calcd for C28H28F3N3O [M+Na]+ : 479.2, found 480.4. 1 H NMR (400 MHz, CDCl 3 ), δ 9.95 (d, J = 7.2 Hz, 1H), 8.10 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 8.6) Hz, 1H), 7.61 (s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.00 ( dd, J = 7.4 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 3.07 (q, J = 7.1 Hz, 4H), 3.03 (s, 3H), 3.00 (s, 3H), 1.01 (d, J = 7.2 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.2, 151.8, 149.3, 149.0, 134.6, 132.7, 132.2, 129.0, 128.8, 128.6, 128.5, 128.1, 124.6, 124.2, 124. 1, 123.8, 123.2, 121.9, 121.5, 120.1 , 119.2, 115.5, 112.6, 112.1, 108.4, 45.1, 40.4, 11.9; LRMS (ESI) m/z calcd for C 28 H 28 F 3 N 3 O [M+Na] + : 479.2, found 480.4.
<GxF 26 ~ 30><GxF 26 ~ 30>
IF-E : 하기 반응식 7과 같이 합성하였으며, 구체적으로, 4-아세틸피리딘(4-Acetylpyridine, 394.6 μL, 3.567 mmol) 및 2-브로모-4’-(트리플루오로메틸)아세토페논(2-Bromo-4’-(trifluoromethyl)acetophenone, 1.0 g, 3.8 mmol)이 포함된 DMF(12.0 mL)을 80℃에서 4시간 동안 교반한 다음, 에틸아크릴레이트(193.6 μl, 1.79 mmol), 구리(II) 아세테이트 모노하이드레이트(2.14 g, 10.7 mmol) 및 소듐 아세테이트(1.17 g, 14.3 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 황색 고체의 화합물 IF-E(556.5 mg, 77.3% 수율)를 수득 하였다. IF-E : Synthesized according to Scheme 7 below, specifically, 4-Acetylpyridine (394.6 μL, 3.567 mmol) and 2-Bromo-4'-(trifluoromethyl)acetophenone (2-Bromo-4) DMF (12.0 mL) containing '-(trifluoromethyl)acetophenone, 1.0 g, 3.8 mmol) was stirred at 80°C for 4 hours, then ethyl acrylate (193.6 μl, 1.79 mmol) and copper(II) acetate monohydrate. (2.14 g, 10.7 mmol) and sodium acetate (1.17 g, 14.3 mmol) were added and stirred at 100°C for 16 hours. After confirming that the reaction was complete by TLC, copper acetate was removed by filtration through a Celite pad, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound IF-E (556.5 mg, 77.3% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.87 (dd, J = 7.2, 1.2 Hz, 1H), 8.96 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.79 (m, 3H), 7.61 (dd, J = 7.4, 2.4 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H); 13C NMR(100 MHz, CDCl3) 195.6, 184.4, 163.5, 142.5, 138.8, 134.8,133.7, 133.3, 129.4, 129.1, 128.9, 125.8, 125.7 (2), 125.2, 123.4, 122.5, 121.6, 121.1, 113.1, 109.9 60.9, 26.6, 14.9; LRMS (ESI) m/z calcd for C21H16F3NO4 [M+Na]+ : 403.1, found : 404.2. 1H NMR (400 MHz, CDCl 3 ), δ 9.87 (dd, J = 7.2, 1.2 Hz, 1H), 8.96 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.79 (m, 3H) ), 7.61 (dd, J = 7.4, 2.4 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) 195.6, 184.4, 163.5, 142.5, 138.8, 134.8,133.7, 133.3, 129.4, 129.1, 128.9, 125.8, 125.7 (2), 125.2, 4, 122.5, 121.6, 121.1, 113.1 , 109.9 60.9, 26.6, 14.9; LRMS (ESI) m/z calcd for C 21 H 16 F 3 NO 4 [M+Na] + : 403.1, found : 404.2.
IF-B : IF-E(556.5 mg, 1.379 mmol)가 포함된 메탄올(5 mL)에 KOH(2.21 g, 55.2 mmol)를 첨가한 후, 실온에서 하룻밤 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 갈색고체의 화합물 IF-A를 수득하였다. IF-B : KOH (2.21 g, 55.2 mmol) was added to methanol (5 mL) containing IF-E (556.5 mg, 1.379 mmol), and then stirred at room temperature overnight. The reaction mixture was acidified by adding 6N HCl, and the resulting solid was collected through filtration, washed with water, and dried in a drying oven to obtain compound IF-A as a brown solid.
수득한 화합물 IF-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IF-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(350.3 mg, 4.170 mmol)를 첨가하고 및 NBS(259.6 mg, 1.459 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 황색 고체의 화합물 IF-B(358.6 mg, 63.4%수율)를 수득 하였다.The obtained compound IF-A was used in the next step without further purification. Sodium bicarbonate (350.3 mg, 4.170 mmol) was added to DMF (10.0 mL) containing IF-A and NBS (259.6 mg, 1.459 mmol) ) was added in portions at 0°C. The reaction mixture was stirred at room temperature for 12 hours, then the resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound IF-B (358.6 mg, 63.4% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.87 (d, J = 7.4 Hz, 1H), 8.18 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.53 (dd, J = 7.4, 2 Hz, 1H), 7.39 (s, 1H), 2.72 (s, 3H); 13C NMR(100 MHz, CDCl3) 195.2, 183.3, 142.7, 135.8, 133.5, 133.2, 132.8, 129.3, 128.5, 127.6, 125.7(2), 125.2, 123.5, 122.5, 119.2, 112.5, 94.5, 26.7; LRMS (ESI) m/z calcd for C18H11BrF3NO2 [M+Na]+ : 409.0, found : 410.0. 1H NMR (400 MHz, CDCl 3 ), δ 9.87 (d, J = 7.4 Hz, 1H), 8.18 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.53 (dd, J = 7.4, 2 Hz, 1H), 7.39 (s, 1H), 2.72 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) 195.2, 183.3, 142.7, 135.8, 133.5, 133.2, 132.8, 129.3, 128.5, 127.6, 125.7(2), 125.2, 123.5, 122.5, .2, 112.5, 94.5, 26.7; LRMS (ESI) m/z calcd for C 18 H 11 BrF 3 NO 2 [M+Na] + : 409.0, found : 410.0.
[반응식 7][Scheme 7]
화합물 GxF 26 : Compound GxF 26 :
IF-B(30.0 mg, 0.063 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(35.9 mg, 0.189 mmol), 테트라키스(트리페닐 포스핀)팔라듐(15.0 mg, 0.013 mmol) 및 소듐 카보네이트(33.6 mg, 0.315 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-26으로 표시되는 황색 고체의 화합물 GxF 26(28.6 mg, 95.4% 수율)을 수득 하였다.IF-B (30.0 mg, 0.063 mmol), 4-trifluorophenyl boronic acid (35.9 mg, 0.189 mmol), tetrakis(triphenyl phosphine) in a solution containing DMF and water mixed at a ratio of 10:1. Palladium (15.0 mg, 0.013 mmol) and sodium carbonate (33.6 mg, 0.315 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 26 (28.6 mg, 95.4% yield) as a yellow solid represented by the following formula 1-26. Obtained.
[화학식 1-26][Formula 1-26]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.97(d, J = 7.4 Hz, 1H), 8.42(s, 1H), 7.95(d, J = 8 Hz, 2H), 7.78(dd, J = 19 Hz, 4 H), 7.95(d, J= 8 Hz, 2H), 7.55(dd, J = 7.2 Hz, 1H), 7.49(s, 1H), 2.67(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.3, 184.0,143.1,137.4, 135.3, 133.5, 133.1, 129.7, 129.4, 129.3, 128.7, 128.5, 126.3, 126.3, 125.8, 125.7, 125.7, 125.2, 123.7, 122.9, 122.5, 120.5, 119.1, 112.6, 26.8; LRMS (ESI) m/z calcd for C25H15F6NO2 [M+Na]+ : 375.1, found : 376.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.97 (d, J = 7.4 Hz, 1H), 8.42 (s, 1H), 7.95 (d, J = 8 Hz, 2H), 7.78 (dd, J = 19 Hz, 4 H), 7.95 (d, J = 8 Hz, 2H), 7.55 (dd, J = 7.2 Hz, 1H), 7.49 (s, 1H), 2.67 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.3, 184.0,143.1,137.4, 135.3, 133.5, 133.1, 129.7, 129.4, 129.3, 128.7, 128.5, 126.3, 126.3, , 125.7, 125.7, 125.2, 123.7, 122.9, 122.5, 120.5, 119.1, 112.6, 26.8; LRMS (ESI) m/z calcd for C 25 H 15 F 6 NO 2 [M+Na] + : 375.1, found : 376.1.
화합물 GxF 27 : Compound GxF 27 :
IF-B(30.0 mg, 0.063 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(31.0 mg, 0.189 mmol), 테트라키스(트리페닐 포스핀)팔라듐(15.0 mg, 0.013 mmol) 및 소듐 카보네이트(33.6 mg, 0.315 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-27로 표시되는 황색 고체의 화합물 GxF 27(27.3 mg, 96.3% 수율)을 수득 하였다.4-acetylphenyl boronic acid (31.0 mg, 0.189 mmol), tetrakis(triphenylphosphine)palladium ( 15.0 mg, 0.013 mmol) and sodium carbonate (33.6 mg, 0.315 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 27 (27.3 mg, 96.3% yield) as a yellow solid represented by the following formula 1-27. Obtained.
[화학식 1-27][Formula 1-27]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ9.97(d, J = 7.2 Hz, 1H), 8.46(s, 1H), 8.08(d, J = 8.4 Hz, 2H), 7.96(d, J = 8.4 Hz, 2H), 7.90(d, J = 8.4 Hz, 1H), 7.80(d, J = 8.4 Hz, 2H), 7.67(d, J = 6.6 Hz, 2H), 7.55(dd, J = 7.4 Hz, 2 Hz, 1H), 7.51 (s, 1H), 6.90(d, J = 8.4 Hz, 1H), 2.68(s, 3H), 2.66(s, 3H); 13C NMR(100 MHz, CDCl3), δ 197.4, 195.4, 185.5, 140.0, 138.9, 135.7, 134.8, 132.6, 131.8, 129.4,129.2, 128.6, 128.1, 125.8, 124.3, 120.4,119.3, 112.2, 27.0, 26.7.; LRMS (ESI) m/z calcd for C26H18F3NO3 [M+Na]+ : 449.1, found :450.0. 1 H NMR (400 MHz, CDCl 3 ), δ 9.97 (d, J = 7.2 Hz, 1H), 8.46 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.90(d, J = 8.4 Hz, 1H), 7.80(d, J = 8.4 Hz, 2H), 7.67(d, J = 6.6 Hz, 2H), 7.55(dd, J = 7.4 Hz, 2 Hz, 1H), 7.51 (s, 1H), 6.90(d, J = 8.4 Hz, 1H), 2.68(s, 3H), 2.66(s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 197.4, 195.4, 185.5, 140.0, 138.9, 135.7, 134.8, 132.6, 131.8, 129.4, 129.2, 128.6, 128.1, 125.8, 124. 3, 120.4,119.3, 112.2, 27.0, 26.7.; LRMS (ESI) m/z calcd for C 26 H 18 F 3 NO 3 [M+Na] + : 449.1, found : 450.0.
화합물 GxF 28 : Compound GxF 28 :
IF-B(30.0 mg, 0.063 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(23.0 mg, 0.189 mmol), 테트라키스(트리페닐 포스핀)팔라듐(15.0 mg, 0.013 mmol) 및 소듐 카보네이트(33.6 mg, 0.315 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-28으로 표시되는 황색 고체의 화합물 GxF 28(23.6 mg, 91.9% 수율)을 수득 하였다.IF-B (30.0 mg, 0.063 mmol), 4-acetylphenyl boronic acid (23.0 mg, 0.189 mmol), tetrakis(triphenylphosphine)palladium ( 15.0 mg, 0.013 mmol) and sodium carbonate (33.6 mg, 0.315 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 28 (23.6 mg, 91.9% yield) as a yellow solid represented by the following formula 1-28. Obtained.
[화학식 1-28][Formula 1-28]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.94(d, J = 8 Hz, 1H), 8.41(s, 1H), 7.86(d, J = 6.8 Hz, 2H), 7.72(dd, J = 23 Hz, 8 Hz, 4H), 7.62(t, J = 5.2, 2 Hz, 1H), 7.54(m, 4H), 2.67(s, 3H); 13C NMR(100 MHz, CDCl3), 195.4, 185.5, 140.0, 137.8, 134.7, 132.6, 131.8, 129.5, 129.2, 128.6, 128.4, 126.3, 126.2, 125.8, 124.2, 120.1, 119.1, 112.2, 26.7; LRMS (ESI) LRMS (ESI) m/z calcd for C24H16F3NO2 [M+Na]+ : 407.1, found : 408.2. 1 H NMR (400 MHz, CDCl 3) , δ 9.94 (d, J = 8 Hz, 1H), 8.41 (s, 1H), 7.86 (d, J = 6.8 Hz, 2H), 7.72 (dd, J = 23 Hz, 8 Hz, 4H), 7.62 (t, J = 5.2, 2 Hz, 1H), 7.54 (m, 4H), 2.67 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), 195.4, 185.5, 140.0, 137.8, 134.7, 132.6, 131.8, 129.5, 129.2, 128.6, 128.4, 126.3, 126.2, 125.8, , 120.1, 119.1, 112.2, 26.7; LRMS (ESI) LRMS (ESI) m/z calcd for C 24 H 16 F 3 NO 2 [M+Na] + : 407.1, found : 408.2.
화합물 GxF 29 : Compound GxF 29 :
IF-B(30.0 mg, 0.063 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(28.7 mg, 0.189 mmol), 테트라키스(트리페닐 포스핀)팔라듐(15.0 mg, 0.013 mmol) 및 소듐 카보네이트(33.6 mg, 0.315 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-29로 표시되는 황색 고체의 화합물 GxF 29(25.4 mg, 92.2% 수율)을 수득 하였다.IF-B (30.0 mg, 0.063 mmol), 4-methoxyphenyl boronic acid (28.7 mg, 0.189 mmol), and tetrakis(triphenylphosphine)palladium were added to a solution containing DMF and water mixed at a ratio of 10:1. (15.0 mg, 0.013 mmol) and sodium carbonate (33.6 mg, 0.315 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 29 (25.4 mg, 92.2% yield) as a yellow solid represented by the following formula 1-29. Obtained.
[화학식 1-29][Formula 1-29]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.92(d, J = 7.4 Hz, 1H), 8.39(s, 1H), 7.94(d, J = 8 Hz, 2H), 7.78(d, J = 8.4 Hz, 2H), 7.49(m, 3H), 7.38(s, 1H), 7.04(d, J = 8.8Hz, 1H), 3.88(s, 3H), 2.66(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.5, 183.7, 159.2, 143.4, 135.2, 133.2, 132.9, 132.4, 129.5, 129.4, 128.5, 126.1, 125.6, 125.5, 125.4, 125.3, 123.3, 122.6, 122.3,119.8,116.2, 115.0, 114.8, 112.2, 56.1, 55.7, 30.1, 26.7; LRMS (ESI) m/z calcd for C25H18F3NO3 [M+Na]+ : 437.1, found : 438.2. 1 H NMR (400 MHz, CDCl 3) , δ 9.92 (d, J = 7.4 Hz, 1H), 8.39 (s, 1H), 7.94 (d, J = 8 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.49(m, 3H), 7.38(s, 1H), 7.04(d, J = 8.8Hz, 1H), 3.88(s, 3H), 2.66(s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.5, 183.7, 159.2, 143.4, 135.2, 133.2, 132.9, 132.4, 129.5, 129.4, 128.5, 126.1, 125.6, 125.5, .4, 125.3, 123.3, 122.6, 122.3, 119.8,116.2, 115.0, 114.8, 112.2, 56.1, 55.7, 30.1, 26.7; LRMS (ESI) m/z calcd for C 25 H 18 F 3 NO 3 [M+Na] + : 437.1, found : 438.2.
화합물 GxF 30 : Compound GxF 30 :
IF-B(30.0 mg, 0.063 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(31.2 mg, 0.189 mmol), 테트라키스(트리페닐 포스핀)팔라듐(15.0 mg, 0.013 mmol) 및 소듐 카보네이트(33.6 mg, 0.315 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-30으로 표시되는 주황색 고체의 화합물 GxF 30(26.5 mg, 93.5% 수율)을 수득 하였다.IF-B (30.0 mg, 0.063 mmol), 4-(dimethylamino)phenyl boronic acid (31.2 mg, 0.189 mmol), and tetrakis (triphenyl phosphatase) were added to a solution containing DMF and water mixed at a ratio of 10:1. Pin) Palladium (15.0 mg, 0.013 mmol) and sodium carbonate (33.6 mg, 0.315 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 30 (26.5 mg, 93.5% yield) as an orange solid represented by the following formula 1-30. Obtained.
[화학식 1-30][Formula 1-30]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) , δ 9.91(d, J = 7.6 Hz, 1H), 8.43(s, 1H), 7.95(d, J = 8 Hz, 2H), 7.78(d, J = 8 Hz, 2H), 7.46(m, 3H), 7.36(s, 1H), 6.85(d, J = 8 Hz, 2H), 3.03(s, 6H), 2.65(s, 3H); 13C NMR(100 MHz, CDCl3) , δ 195.5, 183.6, 150.0, 143.6, 135.2, 133.1, 132.8, 132.1, 129.4, 129.1, 128.4, 125.5, 125.5, 125.3, 125.0, 123.3, 123.1, 122.6, 121.5, 120.2, 113.1, 112.0, 40.9, 30.1, 26.6; LRMS (ESI) m/z calcd for C26H21N2O2 [M+Na]+ : 450.2, found : 451.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.91 (d, J = 7.6 Hz, 1H), 8.43 (s, 1H), 7.95 (d, J = 8 Hz, 2H), 7.78 (d, J = 8 Hz, 2H), 7.46(m, 3H), 7.36(s, 1H), 6.85(d, J = 8 Hz, 2H), 3.03(s, 6H), 2.65(s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.5, 183.6, 150.0, 143.6, 135.2, 133.1, 132.8, 132.1, 129.4, 129.1, 128.4, 125.5, 125.5, 125.3, 12 5.0, 123.3, 123.1, 122.6, 121.5, 120.2, 113.1, 112.0, 40.9, 30.1, 26.6; LRMS (ESI) m/z calcd for C 26 H 21 N 2 O 2 [M+Na]+ : 450.2, found : 451.2.
<GxF 31 ~ 35><GxF 31 ~ 35>
IG-E : 하기 반응식 8과 같이 합성하였으며, 구체적으로, 4-아세틸피리딘(158.1 μL, 1.431 mmol) 및 2-클로로아세톤(2-chloroacetone, 120.7 μL, 1.5 mmol)이 포함된 DMF(12.0 mL)을 80℃에서 4시간 동안 교반한 다음, 에틸아크릴레이트(77.5 μl, 0.715 mmol), 구리(II) 아세테이트 모노하이드레이트(856.5 mg, 4.29 mmol) 및 소듐 아세테이트(469.2 mg, 5.72 mmol)를 첨가하여 100℃에서 5시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 황색 고체의 화합물 IG-E(166.7 mg, 85.3% 수율)를 수득 하였다. IG-E : Synthesized as shown in Scheme 8 below. Specifically, DMF (12.0 mL) containing 4-acetylpyridine (158.1 μL, 1.431 mmol) and 2-chloroacetone (120.7 μL, 1.5 mmol) was incubated at 80°C. After stirring for 4 hours, ethyl acrylate (77.5 μl, 0.715 mmol), copper (II) acetate monohydrate (856.5 mg, 4.29 mmol), and sodium acetate (469.2 mg, 5.72 mmol) were added and incubated at 100°C for 5 hours. Stirred for an hour. After confirming that the reaction was complete by TLC, copper acetate was removed by filtration through a Celite pad, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound IG-E (166.7 mg, 85.3% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.85(d, J = 6.8 Hz, 1H), 8.80(s, 1H), 7.44(d, J = 7.4 Hz, 1H), 4.39(q, J = 14.2 Hz, 2H), 2.62(s, 3H), 2.58(s, 3H), 1.43(t, J = 7.6Hz, 3H); 13C NMR(100 MHz, CDCl3), δ 185.4, 159.1, 140.2, 134.6, 131.8, 131.6, 129.5, 129.2, 128.5, 128.3, 126.4, 125.4, 123.8, 121.8, 121.6, 119.9, 114.8, 111.7, 55.7, 26.7; LRMS (ESI) m/z calcd for C15H15NO4 [M+Na]+ : 273.3, found : 274.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.85 (d, J = 6.8 Hz, 1H), 8.80(s, 1H), 7.44(d, J = 7.4 Hz, 1H), 4.39(q, J = 14.2 Hz, 2H), 2.62(s, 3H), 2.58(s, 3H) , 1.43(t, J = 7.6Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 185.4, 159.1, 140.2, 134.6, 131.8, 131.6, 129.5, 129.2, 128.5, 128.3, 126.4, 125.4, 123.8, 121.8, .6, 119.9, 114.8, 111.7, 55.7, 26.7 ; LRMS (ESI) m/z calcd for C 15 H 15 NO 4 [M+Na] + : 273.3, found : 274.1.
IG-B : IG-E(166.7 mg, 0.610 mmol)가 포함된 메탄올(5 mL)에 KOH(1.37 g, 24.4 mmol)를 첨가한 후, 실온에서 하룻밤 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 갈색고체의 화합물 IG-A를 수득하였다. IG-B : KOH (1.37 g, 24.4 mmol) was added to methanol (5 mL) containing IG-E (166.7 mg, 0.610 mmol), and then stirred at room temperature overnight. The reaction mixture was acidified by adding 6N HCl, and the resulting solid was collected through filtration, washed with water, and dried in a drying oven to obtain compound IG-A as a brown solid.
수득한 화합물 IG-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IG-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(51.2 mg, 1.83 mmol)를 첨가하고 및 NBS(108.5 mg, 0.64 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 황색 고체의 화합물 IG-B(135.5 mg, 79.3% 수율)를 수득 하였다.The obtained compound IG-A was used in the next step without further purification. Sodium bicarbonate (51.2 mg, 1.83 mmol) was added to DMF (10.0 mL) containing IG-A and NBS (108.5 mg, 0.64 mmol) ) was added in portions at 0°C. The reaction mixture was stirred at room temperature for 12 hours, then the resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound IG-B (135.5 mg, 79.3% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.65(d, J = 7.4 Hz, 1H), 8.00(s, 1H),7.49(s, 1H), 7.32(d, 7.4Hz), 2.63(s, 3H), 2.53(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.2, 187.1, 134.4, 131.7, 128.0, 124.8, 124.1, 119.1, 111.8, 93.6, 27.9, 26.6; LRMS (ESI) m/z calcd for C12H10BrNO2 [M+Na]+ : 280.1, found : 280.0. 1 H NMR (400 MHz, CDCl 3 ), δ 9.65 ( d, J = 7.4 Hz, 1H), 8.00(s, 1H),7.49(s, 1H), 7.32(d, 7.4Hz), 2.63(s, 3H), 2.53(s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.2, 187.1, 134.4, 131.7, 128.0, 124.8, 124.1, 119.1, 111.8, 93.6, 27.9, 26.6; LRMS (ESI) m/z calcd for C 12 H 10 BrNO 2 [M+Na] + : 280.1, found : 280.0.
[반응식 8][Scheme 8]
화합물 GxF 31 : Compound GxF 31 :
IG-B(25.0 mg, 0.089 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(50.71 mg, 0.27 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.58 mg, 0.018 mmol) 및 소듐 카보네이트(47.13 mg, 0.45 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-31으로 표시되는 황색 고체의 화합물 GxF 31(29.9 mg, 97.2% 수율)을 수득 하였다.4-trifluorophenyl boronic acid (50.71 mg, 0.27 mmol) and tetrakis (triphenyl phosphine) in a solution containing IG-B (25.0 mg, 0.089 mmol) mixed with DMF and water at a ratio of 10:1. Palladium (20.58 mg, 0.018 mmol) and sodium carbonate (47.13 mg, 0.45 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 31 (29.9 mg, 97.2% yield) as a yellow solid represented by the following formula 1-31. Obtained.
[화학식 1-31][Formula 1-31]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.86(d, J = 7.6 Hz, 1H), 8.36(s, 1H), 7.74(dd, J = 8.4, 24.6 Hz, 5H), 7.43(d, J = 8 Hz, 1H), 2.66(s, 3H), 2.64(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.5, 187.9, 156.9, 137.8, 134.0, 132.1, 129.5, 129.1, 128.4, 126.3, 126.3, 125.7, 124.4, 123.1, 123.0, 119.8, 119.1, 112.1, 28.1, 26.7; LRMS (ESI) m/z calcd for C19H14F3NO2 [M+Na]+ : 345.3, found : 346.1. 1 H NMR (400 MHz, CDCl 3) , δ 9.86 (d, J = 7.6 Hz, 1H), 8.36 (s, 1H), 7.74 (dd, J = 8.4, 24.6 Hz, 5H), 7.43 (d, J = 8 Hz, 1H), 2.66(s, 3H), 2.64(s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.5, 187.9, 156.9, 137.8, 134.0, 132.1, 129.5, 129.1, 128.4, 126.3, 126.3, 125.7, 124.4, 123.1, .0, 119.8, 119.1, 112.1, 28.1, 26.7; LRMS (ESI) m/z calcd for C 19 H 14 F 3 NO 2 [M+Na] + : 345.3, found : 346.1.
화합물 GxF 32 : Compound GxF 32 :
IG-B(25.0 mg, 0.089 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(43.78 mg, 0.27 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.58 mg, 0.018 mmol) 및 소듐 카보네이트(47.13 mg, 0.45 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-32로 표시되는 황색 고체의 화합물 GxF 32(27.6 mg, 97.2% 수율)을 수득 하였다.4-acetylphenyl boronic acid (43.78 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium ( 20.58 mg, 0.018 mmol) and sodium carbonate (47.13 mg, 0.45 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 32 (27.6 mg, 97.2% yield) as a yellow solid represented by the following formula 1-32. Obtained.
[화학식 1-32][Formula 1-32]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) , δ 9.86(d, J = 7.4 Hz, 1H), 8.39(s, 1H), 8.10(d, J = 6.6 Hz, 2H), 7.70(d, J = 5.2Hz, 2H), 7.69(s, 1H), 7.42(dd, J = 2 Hz, 7.2 Hz, 1H), 2.67(s, 3H), 2.66(s, 3H), 2.64(s, 3H); 13C NMR(100 MHz, CDCl3) , δ 197.5, 195.5, 187.9, 139.0, 135.7, 134.1, 132.1, 129.4, 128.5, 128.1, 124.4, 123.1, 120.1, 119.3,112.1, 28.1, 27.1, 26.7; LRMS (ESI) m/z calcd for C20H17NO3 [M+Na]+ : 319.4, found : 320.1. 1 H NMR (400 MHz, CDCl 3) , δ 9.86 (d, J = 7.4 Hz, 1H), 8.39 (s, 1H), 8.10 (d, J = 6.6 Hz, 2H), 7.70 (d, J = 5.2 Hz, 2H), 7.69(s, 1H), 7.42(dd, J = 2 Hz, 7.2 Hz, 1H), 2.67(s, 3H), 2.66(s, 3H), 2.64(s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 197.5, 195.5, 187.9, 139.0, 135.7, 134.1, 132.1, 129.4, 128.5, 128.1, 124.4, 123.1, 120.1, .1, 28.1, 27.1, 26.7; LRMS (ESI) m/z calcd for C 20 H 17 NO 3 [M+Na]+ : 319.4, found : 320.1.
화합물 GxF 33 : Compound GxF 33 :
IG-B(25.0 mg, 0.089 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 페닐 보론산(32.56 mg, 0.27 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.58 mg, 0.018 mmol) 및 소듐 카보네이트(47.13 mg, 0.45 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-33으로 표시되는 황색 고체의 화합물 GxF 33(23.5 mg, 95.4% 수율)을 수득 하였다.Phenylboronic acid (32.56 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium (20.58 mg, 0.018 mmol) and sodium carbonate (47.13 mg, 0.45 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 33 (23.5 mg, 95.4% yield) as a yellow solid represented by the following formula 1-33. Obtained.
[화학식 1-33][Formula 1-33]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.81(d, J = 7.4 Hz, 1H), 8.37(s, 1H), 7.64(s, 1H), 7.59(d, J = 7.4 Hz, 2H), 7.51(t, J = 7.2 Hz, 2H), 7.40(t, J = 7.2 Hz, 2H), 2.64(s, 3H), 2.61(s, 3H); 13C NMR(100 MHz, CDCl3) , δ 195.6, 187.8, 134.1, 133.9, 131.6, 129.3, 128.3, 128.2, 127.4, 124.1, 122.9, 121.7, 119.8, 111.7, 28.1, 26.7; LRMS (ESI) m/z calcd for C18H15NO2 [M+Na]+ : 277.3, found : 278.3. 1 H NMR (400 MHz, CDCl 3 ), δ 9.81 (d, J = 7.4 Hz, 1H), 8.37 (s, 1H), 7.64 (s, 1H), 7.59 (d, J = 7.4 Hz, 2H), 7.51(t, J = 7.2 Hz, 2H), 7.40(t, J = 7.2 Hz, 2H), 2.64(s, 3H), 2.61(s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.6, 187.8, 134.1, 133.9, 131.6, 129.3, 128.3, 128.2, 127.4, 124.1, 122.9, 121.7, 119.8, 111.7, 28 .1, 26.7; LRMS (ESI) m/z calcd for C 18 H 15 NO 2 [M+Na] + : 277.3, found : 278.3.
화합물 GxF 34 : Compound GxF 34 :
IG-B(25.0 mg, 0.089 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(40.57 mg, 0.27 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.58 mg, 0.018 mmol) 및 소듐 카보네이트(47.13 mg, 0.45 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-34로 표시되는 황색 고체의 화합물 GxF 34(26.5 mg, 96.9% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (40.57 mg, 0.27 mmol) and tetrakis(triphenylphosphine)palladium in a solution containing IG-B (25.0 mg, 0.089 mmol) mixed with DMF and water at a ratio of 10:1. (20.58 mg, 0.018 mmol) and sodium carbonate (47.13 mg, 0.45 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 34 (26.5 mg, 96.9% yield) as a yellow solid represented by the following formula 1-34. Obtained.
[화학식 1-34][Formula 1-34]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.78(d, J = 7.4 Hz, 1H), 8.31(s, 1H), 7.57(s, 1H), 7.49(d, J = 6.6 Hz, 2H), 7.35(dd, J = 2 H, 7.4 Hz, 1H), 7.05(s, 1H), 7.03(s, 1H),3.88(s, 3H), 2.62(s, 3H), 2.60(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.6, 187.7, 159.1, 133.8, 131.3, 129.4, 128.1, 126.5, 124.0, 122.6, 121.6, 119.9, 114.8, 111.5, 55.7, 28.0, 26.6; LRMS (ESI) m/z calcd for C19H17NO3 [M+Na]+ : 307.4, found : 308.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.78 (d, J = 7.4 Hz, 1H), 8.31 (s, 1H), 7.57 (s, 1H), 7.49 (d, J = 6.6 Hz, 2H), 7.35(dd, J = 2 H, 7.4 Hz, 1H), 7.05(s, 1H), 7.03(s, 1H), 3.88(s, 3H), 2.62(s, 3H), 2.60(s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.6, 187.7, 159.1, 133.8, 131.3, 129.4, 128.1, 126.5, 124.0, 122.6, 121.6, 119.9, 114.8, 111.5, 7, 28.0, 26.6; LRMS (ESI) m/z calcd for C 19 H 17 NO 3 [M+Na] + : 307.4, found : 308.1.
화합물 GxF 35 : Compound GxF 35 :
IG-B(25.0 mg, 0.089 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(44.06 mg, 0.27 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.58 mg, 0.018 mmol) 및 소듐 카보네이트(47.13 mg, 0.45 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-35로 표시되는 황색 고체의 화합물 GxF 35(26.9 mg, 94.8% 수율)을 수득 하였다.4-(dimethylamino)phenyl boronic acid (44.06 mg, 0.27 mmol) and tetrakis(triphenyl phosphatase) were added to a solution containing IG-B (25.0 mg, 0.089 mmol) mixed with DMF and water at a ratio of 10:1. Pin) Palladium (20.58 mg, 0.018 mmol) and sodium carbonate (47.13 mg, 0.45 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 35 (26.9 mg, 94.8% yield) as a yellow solid represented by the following formula 1-35. Obtained.
[화학식 1-35][Formula 1-35]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.78(d, J = 6.8 Hz), 8.36(s, 1H), 7.56(s, 1H), 7.47(dd, J = 2.4, 9.2 Hz, 2H), 7.36(dd, J = 2, 2Hz, 1H), 6.87(d, J = 8.8 Hz), 3.03(s, 6H), 2.63(s, 3H), 2.60(s, 3H); 13C NMR(100 MHz, CDCl3) , δ 195.7, 187.7, 149.9, 33.8, 131.0, 129.1, 128.0, 124.0, 122.4, 122.3, 122.0, 121.6(2), 120.3, 113.2, 111.4, 111.2, 40.9, 28.1, 26.6; LRMS (ESI) m/z calcd for C20H17NO3 [M+Na]+ : 320.2, found : 321.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.78 (d, J = 6.8 Hz), 8.36 (s, 1H), 7.56 (s, 1H), 7.47 (dd, J = 2.4, 9.2 Hz, 2H), 7.36 (dd, J = 2, 2 Hz, 1H), 6.87 (d, J = 8.8 Hz), 3.03 (s, 6H), 2.63 (s, 3H), 2.60 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.7, 187.7, 149.9, 33.8, 131.0, 129.1, 128.0, 124.0, 122.4, 122.3, 122.0, 121.6(2), 120.3, 113.2, 111.4, 111.2, 40.9, 28.1 , 26.6; LRMS (ESI) m/z calcd for C 20 H 17 NO 3 [M+Na] + : 320.2, found : 321.2.
<GxF 36 ~ 40><GxF 36 ~ 40>
IH-E : 하기 반응식 9와 같이 합성하였으며, 구체적으로, 4-아세틸피리딘(105.9 μL, 0.957 mmol) 및 2-브로모아세토페논(2-bromoacetophenone, 200.0 mg, 1.01 mmol)이 포함된 DMF(4.0 mL)을 80℃에서 5시간 동안 교반한 다음, 에틸아크릴레이트(51.8 μl, 0.479 mmol), 구리(II) 아세테이트 모노하이드레이트(573.2 mg, 2.87 mmol) 및 소듐 아세테이트(314.0 mg, 3.83 mmol)를 첨가하여 100℃에서 5시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 황색 고체의 화합물 IH-E(556.5 mg, 77.3% 수율)를 수득 하였다. IH-E : Synthesized according to Scheme 9 below, specifically, DMF (4.0 mL) containing 4-acetylpyridine (105.9 μL, 0.957 mmol) and 2-bromoacetophenone (200.0 mg, 1.01 mmol) After stirring at 80°C for 5 hours, ethyl acrylate (51.8 μl, 0.479 mmol), copper(II) acetate monohydrate (573.2 mg, 2.87 mmol), and sodium acetate (314.0 mg, 3.83 mmol) were added and the mixture was stirred at 100°C. It was stirred for 5 hours. After confirming that the reaction was complete by TLC, copper acetate was removed by filtration through a Celite pad, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound IH-E (556.5 mg, 77.3% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ9.83 (dd, J = 7.2, 0.8 Hz, 1H), 8.90(s, 1H), 7.80(m, 3H), 7.54(m, 4H) 4.38(q, 2H), 2.69(s, 3H); 13C NMR(100 MHz, CDCl3) 195.7, 163.7, 139.4, 138.3, 134.3, 132.1, 129.2, 128.9, 128.9, 128.9,121.1, 60.8, 26.6, 14.9; LRMS (ESI) m/z calcd for C20H17NO4 [M+Na]+ : 335.1 ,found : 336.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.83 (dd, J = 7.2, 0.8 Hz, 1H), 8.90 (s, 1H), 7.80 (m, 3H), 7.54 (m, 4H) 4.38 (q, 2H) ), 2.69(s, 3H); 13 C NMR (100 MHz, CDCl 3 ) 195.7, 163.7, 139.4, 138.3, 134.3, 132.1, 129.2, 128.9, 128.9, 128.9,121.1, 60.8, 26.6, 14.9; LRMS (ESI) m/z calcd for C 20 H 17 NO 4 [M+Na] + : 335.1 ,found : 336.2.
IH-B : IH-E(200.0 mg, 0.60 mmol)가 포함된 메탄올(4 mL)에 KOH(336.8 mg, 6.0 mmol)를 첨가한 후, 실온에서 하룻밤 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 갈색고체의 화합물 IH-A를 수득하였다. IH-B : KOH (336.8 mg, 6.0 mmol) was added to methanol (4 mL) containing IH-E (200.0 mg, 0.60 mmol), and then stirred at room temperature overnight. The reaction mixture was acidified by adding 6N HCl, and the resulting solid was collected through filtration, washed with water, and dried in a drying oven to obtain compound IH-A as a brown solid.
수득한 화합물 IH-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IH-A이 포함된 DMF(2.0 mL)에 소듐 바이카보네이트(131.1 mg, 1.56 mmol)를 첨가하고 및 NBS(97.9 mg, 0.55 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 황색 고체의 화합물 IH-B(135.2 mg, 76.3% 수율)를 수득 하였다.The obtained compound IH-A was used in the next step without further purification. Sodium bicarbonate (131.1 mg, 1.56 mmol) was added to DMF (2.0 mL) containing IH-A and NBS (97.9 mg, 0.55 mmol) ) was added in portions at 0°C. The reaction mixture was stirred at room temperature for 12 hours, then the resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound IH-B (135.2 mg, 76.3% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.85(d, J = 7.4 Hz, 1H), 8.17(s, 1H), 7.8(d, J = 7.6 Hz, 2H), 7.52(m,5H), 2.71(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.3, 184.8, 139.5, 135.2, 132.2, 131.9, 129.1, 128.6, 128.3, 127.5, 123.9, 119.2, 112.0, 94.1, 26.7; LRMS (ESI) m/z calcd for C17H12BrNO2 [M+Na]+ : 341.0, found : x. 1 H NMR (400 MHz, CDCl 3 ), δ 9.85 (d, J = 7.4 Hz, 1H), 8.17 (s, 1H), 7.8 (d, J = 7.6 Hz, 2H), 7.52 (m, 5H), 2.71(s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.3, 184.8, 139.5, 135.2, 132.2, 131.9, 129.1, 128.6, 128.3, 127.5, 123.9, 119.2, 112.0, 94.1, ; LRMS (ESI) m/z calcd for C 17 H 12 BrNO 2 [M+Na] + : 341.0, found : x.
[반응식 9][Scheme 9]
화합물 GxF 36 : Compound GxF 36 :
IH-B(30.0 mg, 0.088 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(49.95 mg, 0.26 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.28 mg, 0.018 mmol) 및 소듐 카보네이트(46.4 mg, 0.44 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 40%)로 정제하여 하기 화학식 1-36으로 표시되는 황색 고체의 화합물 GxF 36(33.8 mg, 94.3% 수율)을 수득 하였다.4-trifluorophenyl boronic acid (49.95 mg, 0.26 mmol) and tetrakis (triphenyl phosphine) in a solution containing IH-B (30.0 mg, 0.088 mmol) mixed with DMF and water at a ratio of 10:1. Palladium (20.28 mg, 0.018 mmol) and sodium carbonate (46.4 mg, 0.44 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 40%) to obtain compound GxF 36 (33.8 mg, 94.3% yield) as a yellow solid represented by the following formula 1-36. Obtained.
[화학식 1-36][Formula 1-36]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) δ 9.92(d, J = 7.6 Hz, 1H), 8.09(s, 1H), 7.85(dd, J = 8.2 Hz, 2H), 7.74(d, J = 8.0 Hz, 2H), 7.66(d, J = 8.0 Hz, 2H), 7.60(t, J = 6.8 Hz, 1H), 7.57(s, 1H), 7.54(d, J = 7.6 Hz, 2H), 7.14(d, J = 7.4 Hz, 1H); 13C NMR(100 MHz, CDCl3) 185.5, 139.9, 137.5, 133.1, 131.8, 129.5, 129.8, 128.2, 128.3, 126.4, 126.7, 126.2, 126.1, 125.4, 123.8, 118., 115.7, 110.0, 110.0, 47.1, 34.4; LRMS (ESI) m/z calcd for C24H16F3NO2 [M+Na]+ : 407.1, found : 408.1. 1 H NMR (400 MHz, CDCl 3 ) δ 9.92 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 7.85 (dd, J = 8.2 Hz, 2H), 7.74 (d, J = 8.0 Hz) , 2H), 7.66(d, J = 8.0 Hz, 2H), 7.60(t, J = 6.8 Hz, 1H), 7.57(s, 1H), 7.54(d, J = 7.6 Hz, 2H), 7.14(d , J = 7.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) 185.5, 139.9, 137.5, 133.1, 131.8, 129.5, 129.8, 128.2, 128.3, 126.4, 126.7, 126.2, 126.1, 125.4, 118., 115.7, 110.0, 110.0, 47.1 , 34.4; LRMS (ESI) m/z calcd for C 24 H 16 F 3 NO 2 [M+Na] + : 407.1, found : 408.1.
화합물 GxF 37 : Compound GxF 37 :
IH-B(30.0 mg, 0.088 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(343.12 mg, 0.26 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.28 mg, 0.018 mmol) 및 소듐 카보네이트(46.4 mg, 0.44 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-37로 표시되는 황색 고체의 화합물 GxF 37(32.1 mg, 95.6% 수율)을 수득 하였다.4-acetylphenyl boronic acid (343.12 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium ( 20.28 mg, 0.018 mmol) and sodium carbonate (46.4 mg, 0.44 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 37 (32.1 mg, 95.6% yield) as a yellow solid represented by the following formula 1-37. Obtained.
[화학식 1-37][Formula 1-37]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.92(d, J = 8 Hz, 1H), 8.44(s, 1H), 8.07(d, J = 7.2 Hz, 2H), 7.85(d, J = 7.6 Hz, 2H), 7.54(m, 5 H), 2.66(s, 3H), 2.65(s, 3H); 13C NMR(100 MHz, CDCl3), δ 197.4, 195.4, 185.5, 140.0, 138.9, 135.7, 134.8, 132.6, 131.8, 129.4,129.2, 128.6, 128.1, 125.8, 124.3, 120.4,119.3, 112.2, 27.0, 26.7.; LRMS (ESI) m/z calcd for C25H19NO3 [M+Na]+ : 381.1, found : 382.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.92 (d, J = 8 Hz, 1H), 8.44 (s, 1H), 8.07 (d, J = 7.2 Hz, 2H), 7.85 (d, J = 7.6 Hz, 2H), 7.54(m, 5 H), 2.66(s, 3H), 2.65(s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 197.4, 195.4, 185.5, 140.0, 138.9, 135.7, 134.8, 132.6, 131.8, 129.4, 129.2, 128.6, 128.1, 125.8, 124. 3, 120.4,119.3, 112.2, 27.0, 26.7.; LRMS (ESI) m/z calcd for C 25 H 19 NO 3 [M+Na] + : 381.1, found : 382.2.
화합물 GxF 38 : Compound GxF 38 :
IH-B(30.0 mg, 0.088 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 메틸 보론산(32.07 mg, 0.26 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.28 mg, 0.018 mmol) 및 소듐 카보네이트(46.4 mg, 0.44 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-38으로 표시되는 황색 고체의 화합물 GxF 38(28.5 mg, 95.4% 수율)을 수득 하였다.Methyl boronic acid (32.07 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (20.28 mg, 0.018 mmol) and sodium carbonate (46.4 mg, 0.44 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 38 (28.5 mg, 95.4% yield) as a yellow solid represented by the following formula 1-38. Obtained.
[화학식 1-38][Formula 1-38]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.92(d, J = 7.6 Hz, 1H), 8.43(s, 1H), 7.86(d, J = 6.4 Hz, 2H), 7.58(m, 3H), 7.50(m, J= 30.4 Hz, 7H),7.38(t, J = 7.2 Hz, 1H), 2.65(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.6, 185.5, 140.2, 134.7, 134.1, 132.1, 131.7, 129.3, 129.2, 128.5, 128.3, 125.7, 119.8, 111.8; LRMS (ESI) m/z calcd for C23H17NO2 [M+Na]+ : 339.1, found : 340.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.92 (d, J = 7.6 Hz, 1H), 8.43 (s, 1H), 7.86 (d, J = 6.4 Hz, 2H), 7.58 (m, 3H), 7.50 (m, J = 30.4 Hz, 7H), 7.38 (t, J = 7.2 Hz, 1H), 2.65 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.6, 185.5, 140.2, 134.7, 134.1, 132.1, 131.7, 129.3, 129.2, 128.5, 128.3, 125.7, 119.8, 111.8; LRMS (ESI) m/z calcd for C 23 H 17 NO 2 [M+Na]+ : 339.1, found : 340.2.
화합물 GxF 39 : Compound GxF 39 :
IH-B(30.0 mg, 0.088 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(4-methoxyphenyl boronic acid, 39.97 mg, 0.26 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.28 mg, 0.018 mmol) 및 소듐 카보네이트(46.4 mg, 0.44 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-39로 표시되는 황색 고체의 화합물 GxF 39(30.1 mg, 92.7% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (39.97 mg, 0.26 mmol) and tetrakis( Triphenyl phosphine)palladium (20.28 mg, 0.018 mmol) and sodium carbonate (46.4 mg, 0.44 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 39 (30.1 mg, 92.7% yield) as a yellow solid represented by the following formula 1-39. Obtained.
[화학식 1-39][Formula 1-39]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) 9.89(d,e J = 8 Hz, 1H), 8.36(s, 1H), 7.84(d, 8.2 Hz, 2H), 7.51(m,7H), 7.03(d, 7Hz, 2H), 3.87(s, 3H), 2.65(s, 3H); 13C NMR(100 MHz, CDCl3) 195.6, 185.4, 159.1, 140.2, 134.6, 131.8, 131.6, 129.5, 129.2, 128.5, 128.3, 126.4, 125.4, 123.8, 121.8, 121.6, 119.9, 114.8, 111.7, 55.7, 26.7; LRMS (ESI) m/z calcd for C24H19NO3 [M+Na]+ :369.1, found : 370.2. 1H NMR (400 MHz, CDCl 3 ) 9.89(d,e J = 8 Hz, 1H), 8.36(s, 1H), 7.84(d, 8.2 Hz, 2H), 7.51(m,7H), 7.03(d , 7Hz, 2H), 3.87(s, 3H), 2.65(s, 3H); 13 C NMR (100 MHz, CDCl 3 ) 195.6, 185.4, 159.1, 140.2, 134.6, 131.8, 131.6, 129.5, 129.2, 128.5, 128.3, 126.4, 125.4, 123.8, 121.6, 119.9, 114.8, 111.7, 55.7, 26.7; LRMS (ESI) m/z calcd for C 24 H 19 NO 3 [M+Na]+ :369.1, found : 370.2.
화합물 GxF 40 : Compound GxF 40 :
IH-B(30.0 mg, 0.088 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 페닐(다이메틸아미노)페닐 보론산(phenyl (dimethylamino)phenylboronic acid, 43.40 mg, 0.26 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.28 mg, 0.018 mmol) 및 소듐 카보네이트(46.4 mg, 0.44 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-40으로 표시되는 주황색 고체의 화합물 GxF 40(32.9 mg, 94.9% 수율)을 수득 하였다.Phenyl (dimethylamino)phenylboronic acid (43.40 mg, 0.26 mmol) in a solution containing IH-B (30.0 mg, 0.088 mmol) mixed with DMF and water at a ratio of 10:1. Tetrakis(triphenylphosphine)palladium (20.28 mg, 0.018 mmol) and sodium carbonate (46.4 mg, 0.44 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 40 (32.9 mg, 94.9% yield) as an orange solid represented by the following formula 1-40. Obtained.
[화학식 1-40][Formula 1-40]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.89(d, J = 7.4 Hz, 1H), 8.41(s, 1H), 7.86(d, J = 8.2 Hz, 2H), 7.51(m, 8H), 6.85(d, J = 7.8 Hz, 2H), 3.02(s, 6H), 2.65(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.6, 185.3, 149.9, 140.4, 134.5, 131.5, 131.5, 129.3, 129.1, 128.5, 128.2, 125.0, 123.8, 122.6, 121.9, 120.3, 113.1, 111.5, 53.8, 40.9, 26.6; LRMS (ESI) m/z calcd for C25H22N2O2 [M+Na]+ : 382.2, found : 383.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.89 (d, J = 7.4 Hz, 1H), 8.41 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.51 (m, 8H), 6.85(d, J = 7.8 Hz, 2H), 3.02(s, 6H), 2.65(s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.6, 185.3, 149.9, 140.4, 134.5, 131.5, 131.5, 129.3, 129.1, 128.5, 128.2, 125.0, 123.8, 122.6, .9, 120.3, 113.1, 111.5, 53.8, 40.9, 26.6; LRMS (ESI) m/z calcd for C 25 H 22 N 2 O 2 [M+Na]+ : 382.2, found : 383.2.
<GxF 41 ~ 45><GxF 41 ~ 45>
II-E : 하기 반응식 10과 같이 합성하였으며, 구체적으로, 4-아세틸피리딘(585.2 μL, 5.29 mmol) 및 2-브로모아세토페논(1.5 g, 5.6 mmol)이 포함된 DMF(17.6 mL)을 80℃에서 5시간 동안 교반한 다음, 에틸아크릴레이트(286.6 μl, 2.65 mmol), 구리(II) 아세테이트 모노하이드레이트(3.17 g, 15.87 mmol) 및 소듐 아세테이트(1.74 g, 21.16 mmol)를 첨가하여 100℃에서 5시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 황색 고체의 화합물 II-E(709.8 mg, 73.3% 수율)를 수득 하였다. II-E : Synthesized as shown in Scheme 10 below. Specifically, DMF (17.6 mL) containing 4-acetylpyridine (585.2 μL, 5.29 mmol) and 2-bromoacetophenone (1.5 g, 5.6 mmol) was reacted at 80°C for 5 days. After stirring for an hour, ethyl acrylate (286.6 μl, 2.65 mmol), copper (II) acetate monohydrate (3.17 g, 15.87 mmol) and sodium acetate (1.74 g, 21.16 mmol) were added and incubated at 100°C for 5 hours. It was stirred. After confirming that the reaction was complete by TLC, copper acetate was removed by filtration through a Celite pad, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain Compound II-E (709.8 mg, 73.3% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) 9.62 (dd J = 7.4, 0.4 Hz, 1H), 8.76 (s, 1H), 7.74(dd, J = 6.6, 2 Hz, 2 H), 7.69 (s, 1H), 7.39 (dd, J = 7.4, 2 Hz, 1H), 6.92(dd, J = 6.8, 2 Hz, 2H), 4.33(q, J = 7.2 Hz, 2H), 3.82(s,3H), 2.61(s, 3H), 1.362(t, J = 7.2 Hz, 3H); 13C NMR(100 MHz, CDCl3) 195.6, 184.3, 163.4, 162.8, 137.6, 133.7, 131.9, 131.4, 128.4, 127.5, 123.2, 120.9, 113. 8, 112.5, 109.1, 60.6, 55.6, 26.4, 14.8; LRMS (ESI) m/z calcd for C21H19NO4 [M+Na]+ : 365.1 ,found :366.2. 1 H NMR (400 MHz, CDCl 3 ) 9.62 (dd J = 7.4, 0.4 Hz, 1H), 8.76 (s, 1H), 7.74 (dd, J = 6.6, 2 Hz, 2 H), 7.69 (s, 1H) ), 7.39 (dd, J = 7.4, 2 Hz, 1H), 6.92(dd, J = 6.8, 2 Hz, 2H), 4.33(q, J = 7.2 Hz, 2H), 3.82(s,3H), 2.61 (s, 3H), 1.362(t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) 195.6, 184.3, 163.4, 162.8, 137.6, 133.7, 131.9, 131.4, 128.4, 127.5, 123.2, 120.9, 113.8, 112.5, , 60.6, 55.6, 26.4, 14.8; LRMS (ESI) m/z calcd for C 21 H 19 NO 4 [M+Na]+ : 365.1 ,found :366.2.
II-B : II-E(709.8 mg, 1.94 mmol)가 포함된 메탄올(19 mL)에 KOH(3.1 g, 77.6 mmol)를 첨가한 후, 실온에서 하룻밤 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 갈색고체의 화합물 II-A를 수득하였다. II-B : KOH (3.1 g, 77.6 mmol) was added to methanol (19 mL) containing II-E (709.8 mg, 1.94 mmol), and then stirred at room temperature overnight. The reaction mixture was acidified by adding 6N HCl, and the resulting solid was collected through filtration, washed with water, and dried in a drying oven to obtain Compound II-A as a brown solid.
수득한 화합물 II-A는 추가 정제없이 바로 다음 단계에 사용하였으며, II-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(478.9 mg, 5.7 mmol)를 첨가하고 및 NBS(354.9 mg, 2.0 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 황색 고체의 화합물 II-B(462.0 mg, 72.1% 수율)를 수득 하였다.The obtained compound II-A was used in the next step without further purification. Sodium bicarbonate (478.9 mg, 5.7 mmol) was added to DMF (10.0 mL) containing II-A and NBS (354.9 mg, 2.0 mmol) ) was added in portions at 0°C. The reaction mixture was stirred at room temperature for 12 hours, then the resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain Compound II-B (462.0 mg, 72.1% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) 9.73(d, J = 7.2Hz,1 H), 8.12(s, 1H), 7.81(d, J = 8.8 Hz, 2H), 7.42 (m, 1H), 6.99(d, 2H), 3.88(s, 3H), 2.68(s, 3H); 13C NMR(100 MHz, CDCl3)195.3, 183.7, 162.8, 134.8, 132.0, 131.9, 131.4, 128.1, 126.9, 124.0, 119.3, 113.9, 111.7, 93.9, 55.8, 26.6; LRMS (ESI) m/z calcd for C18H14NO4 [M+Na]+ : 372. 2 ,found : 372.1. 1 H NMR (400 MHz, CDCl 3 ) 9.73 (d, J = 7.2 Hz, 1 H), 8.12 (s, 1 H), 7.81 (d, J = 8.8 Hz, 2 H), 7.42 (m, 1 H), 6.99 (d, 2H), 3.88(s, 3H), 2.68(s, 3H); 13 C NMR (100 MHz, CDCl 3 )195.3, 183.7, 162.8, 134.8, 132.0, 131.9, 131.4, 128.1, 126.9, 124.0, 119.3, 113.9, 111.7, 93.9, 55.8, 26 .6; LRMS (ESI) m/z calcd for C 18 H 14 NO 4 [M+Na]+ : 372. 2 ,found : 372.1.
[반응식 10][Scheme 10]
화합물 GxF 41 : Compound GxF 41 :
II-B(30.0 mg, 0.081 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-트리플로로페닐 보론산(46.2 mg, 0.243 mmol), 테트라키스(트리페닐 포스핀)팔라듐(18.7 mg, 0.016 mmol) 및 소듐 카보네이트(42.9 mg, 0.405 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 40%)로 정제하여 하기 화학식 1-41로 표시되는 황색 고체의 화합물 GxF 41(34.4 mg, 97.2% 수율)을 수득 하였다.In a solution (1.1 mL) containing II-B (30.0 mg, 0.081 mmol) mixed with DMF and water at a ratio of 10:1, 4-trifluorophenyl boronic acid (46.2 mg, 0.243 mmol) and tetrakis Phenylphosphine)palladium (18.7 mg, 0.016 mmol) and sodium carbonate (42.9 mg, 0.405 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 40%) to obtain compound GxF 41 (34.4 mg, 97.2% yield) as a yellow solid represented by the following formula 1-41. Obtained.
[화학식 1-41][Formula 1-41]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3) 9.84 (d, J = 7.4 Hz, 1H), 8.39(s, 1H), 7.88(d, J = 6.8Hz, 2H), 7.72(q, J = 1.2 Hz, 4H), 7.54(s, 1H), 7.45(dd, J = 7.2, 2 Hz, 2H), 3.90(s, 3H), 2.66(s, 3H); 13C NMR(100 MHz, CDCl3) 195.6, 184.5, 162.8, 137.9, 134.3, 132.8, 132.4, 132.2, 131.5, 129.4, 129.0, 128.4, 126.3, 126.2, 125.7, 125.3, 124.3, 123.0, 122.5, 119.9, 119.3, 115.8, 114.0, 111.9; LRMS (ESI) m/z calcd for C25H18F3NO3 [M+Na]+ :437.1, found : 438.2. 1 H NMR (400 MHz, CDCl 3 ) 9.84 (d, J = 7.4 Hz, 1H), 8.39 (s, 1H), 7.88 (d, J = 6.8 Hz, 2H), 7.72 (q, J = 1.2 Hz, 4H), 7.54(s, 1H), 7.45(dd, J = 7.2, 2 Hz, 2H), 3.90(s, 3H), 2.66(s, 3H); 13 C NMR (100 MHz, CDCl 3 ) 195.6, 184.5, 162.8, 137.9, 134.3, 132.8, 132.4, 132.2, 131.5, 129.4, 129.0, 128.4, 126.3, 126.2, 125.3, 124.3, 123.0, 122.5, 119.9, 119.3, 115.8, 114.0, 111.9; LRMS (ESI) m/z calcd for C 25 H 18 F 3 NO 3 [M+Na]+ :437.1, found : 438.2.
화합물 GxF 42 : Compound GxF 42 :
II-B(30.0 mg, 0.081 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-아세틸페닐 보론산(39.8 mg, 0.243 mmol), 테트라키스(트리페닐 포스핀)팔라듐(18.7 mg, 0.016 mmol) 및 소듐 카보네이트(42.9 mg, 0.405 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-42로 표시되는 황색 고체의 화합물 GxF 42(32.5 mg, 97.5% 수율)을 수득 하였다.A solution (1.1 mL) containing II-B (30.0 mg, 0.081 mmol) mixed with DMF and water at a ratio of 10:1 was added with 4-acetylphenyl boronic acid (39.8 mg, 0.243 mmol) and tetrakis (triphenyl phosphatase). Pin) Palladium (18.7 mg, 0.016 mmol) and sodium carbonate (42.9 mg, 0.405 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 42 (32.5 mg, 97.5% yield) as a yellow solid represented by the following formula 1-42. Obtained.
[화학식 1-42][Formula 1-42]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.84(d, J = 7.2 Hz, 1H), 8.4(s, 1H), 8.07(d, J = 8 Hz, 2H), 7.88(dd, J = 7, 2Hz, 2 H), 7.68(d, J = 8.4 Hz, 2H), 7.56(s, 1H) 7.45 (dd, J = 7.4, 2 Hz), 3.90(s, 3H), 2.65(s, 3H); 13C NMR(100 MHz, CDCl3), δ 197.4, 195.5, 184.5, 162.8, 139.1, 135.6, 134.3, 132.4, 132.3, 131.5, 129.4, 128.4, 128.1, 125.2, 124.4, 120.1, 119.4, 114.0, 111.9, 55.8, 30.1, 27.0, 26.7; LRMS (ESI) m/z calcd for C26H21NO4 [M+Na]+ :411.5, found : 412.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.84 (d, J = 7.2 Hz, 1H), 8.4 (s, 1H), 8.07 (d, J = 8 Hz, 2H), 7.88 (dd, J = 7 , 2Hz, 2 H), 7.68(d, J = 8.4 Hz, 2H), 7.56(s, 1H) 7.45 (dd, J = 7.4, 2 Hz), 3.90(s, 3H), 2.65(s, 3H) ; 13 C NMR (100 MHz, CDCl 3 ), δ 197.4, 195.5, 184.5, 162.8, 139.1, 135.6, 134.3, 132.4, 132.3, 131.5, 129.4, 128.4, 128.1, 125.2, .4, 120.1, 119.4, 114.0, 111.9, 55.8, 30.1, 27.0, 26.7; LRMS (ESI) m/z calcd for C 26 H 21 NO 4 [M+Na]+ :411.5, found : 412.2.
화합물 GxF 43 : Compound GxF 43 :
II-B(30.0 mg, 0.081 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 벤젠 보론산(benzene boronic acid, 29.6 mg, 0.243 mmol), 테트라키스(트리페닐 포스핀)팔라듐(18.7 mg, 0.016 mmol) 및 소듐 카보네이트(42.9 mg, 0.405 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-43으로 표시되는 황색 고체의 화합물 GxF 43(28.9 mg, 96.6% 수율)을 수득 하였다.Benzene boronic acid (29.6 mg, 0.243 mmol) and tetrakis (triphenyl Phosphine) palladium (18.7 mg, 0.016 mmol) and sodium carbonate (42.9 mg, 0.405 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 43 (28.9 mg, 96.6% yield) as a yellow solid represented by the following formula 1-43. Obtained.
[화학식 1-43][Formula 1-43]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.84(d, J = 7.2, 0.8 Hz, 1 H), 8.42(s, 1H), 7.89(dd, J = 7.6, 2Hz, 2H), 7.58(d, J = 1.2 Hz, 2H), 7.51(m, 3H), 7.43(dd, J = 7.6, 2 Hz, 1H), 7.35(t, J = 7.2 Hz, 1H), 7.13(s, 2H), 7.01(d, J = 6.8 Hz, 2H), 3.9 (s, 3H), 2.64(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.63, 184.4, 162.6, 134.2(2),132.7, 131.8, 131.5, 129.3, 129.3, 128.2, 127.4, 125.1, 124.1,121.7,121.6,113.9, 111.5, 55.8, 30.1, 26.7; LRMS (ESI) m/z calcd for C26H21NO4 [M+Na]+ :369.1, found : 370.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.84 (d, J = 7.2, 0.8 Hz, 1 H), 8.42 (s, 1H), 7.89 (dd, J = 7.6, 2 Hz, 2H), 7.58 (d , J = 1.2 Hz, 2H), 7.51(m, 3H), 7.43(dd, J = 7.6, 2 Hz, 1H), 7.35(t, J = 7.2 Hz, 1H), 7.13(s, 2H), 7.01 (d, J = 6.8 Hz, 2H), 3.9 (s, 3H), 2.64(s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.63, 184.4, 162.6, 134.2(2), 132.7, 131.8, 131.5, 129.3, 129.3, 128.2, 127.4, 125.1, 124.1, 121.7, 12 1.6,113.9, 111.5, 55.8 , 30.1, 26.7; LRMS (ESI) m/z calcd for C 26 H 21 NO 4 [M+Na]+ :369.1, found : 370.2.
화합물 GxF 44 : Compound GxF 44 :
II-B(30.0 mg, 0.081 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-메톡시페닐 보론산(36.9 mg, 0.243 mmol), 테트라키스(트리페닐 포스핀)팔라듐(18.7 mg, 0.016 mmol) 및 소듐 카보네이트(42.9 mg, 0.405 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-44로 표시되는 황색 고체의 화합물 GxF 44(30.4 mg, 94.0% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (36.9 mg, 0.243 mmol), tetrakis (triphenyl Phosphine) palladium (18.7 mg, 0.016 mmol) and sodium carbonate (42.9 mg, 0.405 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 44 (30.4 mg, 94.0% yield) as a yellow solid represented by the following formula 1-44. Obtained.
[화학식 1-44][Formula 1-44]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.80(d, J = 7.2 Hz, 1H), 8.36(s, 1H), 7.87(d, J = 7 Hz, 2 H), 7.49(d, J = 6.6 Hz, 2H), 7.45(s, 1H), 7.40(dd, J = 7.2, 2 Hz, 1H), 7.02(m, 4H), 3.90(s, 3H), 3.87(s, 3H), 2.63(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.6, 184.4, 162.6, 159.0, 134.2, 132.7, 131.5, 129.5, 128.1, 126.6, 124.8, 124.0, 121.6, 119.9, 114.8, 113.8, 111.4, 55.8, 55.7, 26.6 LRMS (ESI) m/z calcd for C25H21NO4 [M+Na]+ :399.2, found : 400.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.80 (d, J = 7.2 Hz, 1H), 8.36 (s, 1H), 7.87 (d, J = 7 Hz, 2 H), 7.49 (d, J = 6.6 Hz, 2H), 7.45(s, 1H), 7.40(dd, J = 7.2, 2 Hz, 1H), 7.02(m, 4H), 3.90(s, 3H), 3.87(s, 3H), 2.63( s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.6, 184.4, 162.6, 159.0, 134.2, 132.7, 131.5, 129.5, 128.1, 126.6, 124.8, 124.0, 121.6, 119.9, .8, 113.8, 111.4, 55.8, 55.7, 26.6 LRMS (ESI) m/z calcd for C 25 H 21 NO 4 [M+Na]+ :399.2, found : 400.2.
화합물 GxF 45 : Compound GxF 45 :
II-B(30.0 mg, 0.081 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-다이메틸아미노페닐 보론산(40.0 mg, 0.24 mmol), 테트라키스(트리페닐 포스핀)팔라듐(18.7 mg, 0.016 mmol) 및 소듐 카보네이트(42.9 mg, 0.405 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-45로 표시되는 황색 고체의 화합물 GxF 45(31.2 mg, 93.3% 수율)을 수득 하였다.In a solution (1.1 mL) containing II-B (30.0 mg, 0.081 mmol) mixed with DMF and water at a ratio of 10:1, 4-dimethylaminophenyl boronic acid (40.0 mg, 0.24 mmol) and tetrakis (tri Phenylphosphine)palladium (18.7 mg, 0.016 mmol) and sodium carbonate (42.9 mg, 0.405 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 45 (31.2 mg, 93.3% yield) as a yellow solid represented by the following formula 1-45. Obtained.
[화학식 1-45][Formula 1-45]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.80(d, J = 7.2 Hz, 1H), 8.40(s, 1H), 7.88(d, J = 2.8 Hz, 2H), 7.46(m, 3H), 7.40 (dd, J = 7.4, 2 Hz, 1H), 7.00(d, J = 6.6 Hz, 2H), 6.86(d, J = 6.8 Hz, 2H), 3.90(s, 3H), 3.02(s, 6H), 2.63(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.7, 184.4, 162.5, 149.9, 134.1, 132.9, 131.5, 131.2, 129.1, 128.0, 124.5, 124.0, 122.4, 122.1, 120.4, 113.8, 113.2, 111.2, 55.8, 40.9, 26; LRMS (ESI) m/z calcd for C26H24N2O3 [M+Na]+ :412.2, found : 413.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.80 (d, J = 7.2 Hz, 1H), 8.40 (s, 1H), 7.88 (d, J = 2.8 Hz, 2H), 7.46 (m, 3H), 7.40 (dd, J = 7.4, 2 Hz, 1H), 7.00(d, J = 6.6 Hz, 2H), 6.86(d, J = 6.8 Hz, 2H), 3.90(s, 3H), 3.02(s, 6H) ), 2.63(s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.7, 184.4, 162.5, 149.9, 134.1, 132.9, 131.5, 131.2, 129.1, 128.0, 124.5, 124.0, 122.4, 122.1, .4, 113.8, 113.2, 111.2, 55.8, 40.9, 26; LRMS (ESI) m/z calcd for C 26 H 24 N 2 O 3 [M+Na]+ :412.2, found : 413.2.
<GxF 46 ~ 50><GxF 46 ~ 50>
IJ-E : 하기 반응식 11과 같이 합성하였으며, 구체적으로, 4-아세틸피리딘(194.9 μL, 1.76 mm) 및 2-브로모-4'-다이에틸아미노아세토페논(500 mg, 1.85 mmol)이 포함된 DMF(6.0 mL)을 80℃에서 5시간 동안 교반한 다음, 에틸아크릴레이트(88.1 μl, 0.88 mmol), 구리(II) 아세테이트 모노하이드레이트(1.05 g, 5.28 mmol) 및 소듐 아세테이트(577.5 mg, 7.04 mmol)를 첨가하여 100℃에서 5시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 황색 고체의 화합물 IJ-E(295.6 mg, 82.7% 수율)를 수득 하였다. IJ-E : Synthesized according to Scheme 11 below, specifically, DMF (6.0%) containing 4-acetylpyridine (194.9 μL, 1.76 mm) and 2-bromo-4'-diethylaminoacetophenone (500 mg, 1.85 mmol) mL) was stirred at 80°C for 5 hours, then ethyl acrylate (88.1 μl, 0.88 mmol), copper (II) acetate monohydrate (1.05 g, 5.28 mmol), and sodium acetate (577.5 mg, 7.04 mmol) were added. and stirred at 100°C for 5 hours. After confirming that the reaction was complete by TLC, copper acetate was removed by filtration through a Celite pad, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound IJ-E (295.6 mg, 82.7% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.66(d, J = 7.6 Hz, 1H), 8.89(s, 1H), 7.8(m, 3H), 7.46(dd, J = 7.6Hz, 2Hz, 1H), 6.69(d, J = 7 Hz, 2H), 4.39(q, J = 7.2Hz, 2H), 3.43(q, J = 7.2 Hz, 4H), 2.68(s, 3H), 1.42(t, J = 7.2 Hz, 3H), 1.21(t, J = 7.2Hz, 6H); 13C NMR(100 MHz, CDCl3), δ 195.9, 183.9, 164.1, 151.0, 137.5, 133.3, 132.3, 132.2, 128.5, 127.1, 125.4, 124.7, 121.6, 121.3, 111.7, 110.5, 108.8, 60.6, 44.9, 26.5, 14.9, 13.0; LRMS (ESI) m/z calcd for C24H26N2O4 [M+Na]+ : 406.2, found : 407.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.66 (d, J = 7.6 Hz, 1H), 8.89 (s, 1H), 7.8 (m, 3H), 7.46 (dd, J = 7.6 Hz, 2 Hz, 1H ), 6.69(d, J = 7 Hz, 2H), 4.39(q, J = 7.2Hz, 2H), 3.43(q, J = 7.2 Hz, 4H), 2.68(s, 3H), 1.42(t, J = 7.2 Hz, 3H), 1.21(t, J = 7.2Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.9, 183.9, 164.1, 151.0, 137.5, 133.3, 132.3, 132.2, 128.5, 127.1, 125.4, 124.7, 121.6, 121.3, .7, 110.5, 108.8, 60.6, 44.9, 26.5, 14.9, 13.0; LRMS (ESI) m/z calcd for C 24 H 26 N 2 O 4 [M+Na]+ : 406.2, found : 407.2.
IJ-B : IJ-E(295.6 mg, 0.73 mmol)가 포함된 메탄올(16 mL)에 KOH(1.63 g, 29.2 mmol)를 첨가한 후, 실온에서 하룻밤 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 갈색고체의 화합물 IJ-A를 수득하였다. IJ-B : KOH (1.63 g, 29.2 mmol) was added to methanol (16 mL) containing IJ-E (295.6 mg, 0.73 mmol), and then stirred at room temperature overnight. The reaction mixture was acidified by adding 6N HCl, and the resulting solid was collected through filtration, washed with water, and dried in a drying oven to obtain compound IJ-A as a brown solid.
수득한 화합물 IJ-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IJ-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(306.6 mg, 3.65 mmol)를 첨가하고 및 NBS(136.4 mg, 0.77 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 황색 고체의 화합물 IJ-B(241.0 mg, 80.1% 수율)를 수득 하였다.The obtained compound IJ-A was used in the next step without further purification. Sodium bicarbonate (306.6 mg, 3.65 mmol) was added to DMF (10.0 mL) containing IJ-A and NBS (136.4 mg, 0.77 mmol) ) was added in portions at 0°C. The reaction mixture was stirred at room temperature for 12 hours, then the resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound IJ-B (241.0 mg, 80.1% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.61(d, J = 7.2 Hz, 1H), 8.06(s, 1H), 7.77(d, J = 8.8 Hz, 2H), 7.42(s, 1H), 7.32(dd, J = 2 Hz, 7.4 Hz), 6.66(d, J = 8.8 Hz, 2H), 3.42(q, 7.2 Hz, 4H), 2.64(s, 3H), 1.21(t, J = 7.2 Hz, 6H); 13C NMR(100 MHz, CDCl3), δ 195.4, 183.1, 150.9, 133.9, 132.1, 131.0, 127.8, 125.9, 125.6, 124.6, 119.4, 111.0, 110.5, 93.4, 77.7, 77.4, 77.1, 44.9, 26.6, 13.0; LRMS (ESI) m/z calcd for C21H21BrN2O2 [M+Na]+ : 412.08 ,found : x. 1 H NMR (400 MHz, CDCl 3 ), δ 9.61 (d, J = 7.2 Hz, 1H), 8.06 (s, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.42 (s, 1H), 7.32(dd, J = 2 Hz, 7.4 Hz), 6.66(d, J = 8.8 Hz, 2H), 3.42(q, 7.2 Hz, 4H), 2.64(s, 3H), 1.21(t, J = 7.2 Hz) , 6H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.4, 183.1, 150.9, 133.9, 132.1, 131.0, 127.8, 125.9, 125.6, 124.6, 119.4, 111.0, 110.5, 93.4, , 77.4, 77.1, 44.9, 26.6, 13.0; LRMS (ESI) m/z calcd for C21H21BrN2O2 [M+Na]+: 412.08,found: x.
[반응식 11][Scheme 11]
화합물 GxF 46 : Compound GxF 46 :
IJ-B(20.0 mg, 0.048 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-트리플로로페닐 보론산(27.3 mg, 0.14 mmol), 테트라키스(트리페닐 포스핀)팔라듐(11.1 mg, 0.01 mmol) 및 소듐 카보네이트(25.4 mg, 0.24 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 40%)로 정제하여 하기 화학식 1-46으로 표시되는 황색 고체의 화합물 GxF 46(22.2 mg, 96.6% 수율)을 수득 하였다.In a solution (1.1 mL) containing IJ-B (20.0 mg, 0.048 mmol) mixed with DMF and water at a ratio of 10:1, 4-trifluorophenyl boronic acid (27.3 mg, 0.14 mmol) and tetrakis (tri Phenylphosphine)palladium (11.1 mg, 0.01 mmol) and sodium carbonate (25.4 mg, 0.24 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 40%) to obtain compound GxF 46 (22.2 mg, 96.6% yield) as a yellow solid represented by the following formula 1-46. Obtained.
[화학식 1-46][Formula 1-46]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.75(d, J = 7.7 Hz, 1H), 8.39(s,1H), 7.88(d, 7.2 Hz, 2H), 7.73(q, J = 8.8 Hz, 5.2 Hz, 4H), 7.59(s, 1H), 7.40(dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.72(d, J = 9.2 Hz, 2H), 3.46(q, J = 7.2 Hz, 4H), 2.65(s, 3H), 1.24(t, J = 7.2 Hz, 6H); 13C NMR(100 MHz, CDCl3), δ 195.6, 183.9, 150.9, 138.3, 133.5, 132.2, 131.5, 128.3, 128.2, 126.2, 126.0, 125.0, 124.3, 119.5, 119.4, 111.3, 110.5, 44.9, 26.7, 13.0; LRMS (ESI) m/z calcd for C28H25F3N2O2 [M+Na]+ : 478.2, found : x. 1 H NMR (400 MHz, CDCl 3 ), δ 9.75 (d, J = 7.7 Hz, 1H), 8.39 (s, 1H), 7.88 (d, 7.2 Hz, 2H), 7.73 (q, J = 8.8 Hz, 5.2 Hz, 4H), 7.59(s, 1H), 7.40(dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.72(d, J = 9.2 Hz, 2H), 3.46(q, J = 7.2 Hz, 4H) ), 2.65(s, 3H), 1.24(t, J = 7.2 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.6, 183.9, 150.9, 138.3, 133.5, 132.2, 131.5, 128.3, 128.2, 126.2, 126.0, 125.0, 124.3, 119.5, .4, 111.3, 110.5, 44.9, 26.7, 13.0; LRMS (ESI) m/z calcd for C 28 H 25 F 3 N 2 O 2 [M+Na]+ : 478.2, found : x.
화합물 GxF 47 : Compound GxF 47 :
IJ-B(20.0 mg, 0.048 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-아세틸페닐 보론산(323.6 mg, 0.14 mmol), 테트라키스(트리페닐 포스핀)팔라듐(11.1 mg, 0.01 mmol) 및 소듐 카보네이트(25.4 mg, 0.24 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-47로 표시되는 황색 고체의 화합물 GxF 47(20.5 mg, 94.5% 수율)을 수득 하였다.In a solution (1.1 mL) containing IJ-B (20.0 mg, 0.048 mmol) mixed with DMF and water at a ratio of 10:1, 4-acetylphenyl boronic acid (323.6 mg, 0.14 mmol) and tetrakis (triphenyl phosphatase) were added. After adding palladium (11.1 mg, 0.01 mmol) and sodium carbonate (25.4 mg, 0.24 mmol), the mixture was stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 47 (20.5 mg, 94.5% yield) as a yellow solid represented by the following formula 1-47. Obtained.
[화학식 1-47][Formula 1-47]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.74(d, J= 7.4Hz, 1H), 8.43(s, 1H), 8.08(d, J = 6.4 Hz, 2H), 7.87(d, J = 7.2Hz, 2H), 7.70(d, J = 6.8 Hz, 2H), 7.61(s, 1H), 7.39(dd, J = 7.8 Hz, 1H), 6.72(d, J = 7.2Hz, 2H), 3.46(q, J = 7.2Hz, 4H), 2.67(s, 3H), 2.65(s, 3H), 1.24(t, J = 7.2Hz, 6H); 13C NMR(100 MHz, CDCl3), δ 197.5, 195.6, 183.9, 150.9, 139.5, 135.4, 133.6, 132.2, 131.5, 129.4, 128.2, 128.0, 126.0, 125.1, 124.3, 119.7, 119.6, 111.3, 110.6,44.9, 27.0, 26.7, 13.0; LRMS (ESI) m/z calcd for C29H28N2O3 [M+Na]+ : 452.1, found : x. 1 H NMR (400 MHz, CDCl 3 ), δ 9.74 (d, J = 7.4 Hz, 1H), 8.43 (s, 1H), 8.08 (d, J = 6.4 Hz, 2H), 7.87 (d, J = 7.2 Hz, 2H), 7.70(d, J = 6.8 Hz, 2H), 7.61(s, 1H), 7.39(dd, J = 7.8 Hz, 1H), 6.72(d, J = 7.2Hz, 2H), 3.46( q, J = 7.2Hz, 4H), 2.67(s, 3H), 2.65(s, 3H), 1.24(t, J = 7.2Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ), δ 197.5, 195.6, 183.9, 150.9, 139.5, 135.4, 133.6, 132.2, 131.5, 129.4, 128.2, 128.0, 126.0, 125.1, .3, 119.7, 119.6, 111.3, 110.6, 44.9, 27.0, 26.7, 13.0; LRMS (ESI) m/z calcd for C 29 H 28 N 2 O 3 [M+Na] + : 452.1, found : x.
화합물 GxF 48 : Compound GxF 48 :
IJ-B(20.0 mg, 0.048 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-벤젠 보론산(23.8 mg, 0.14 mmol),테트라키스(트리페닐 포스핀)팔라듐(11.1 mg, 0.01 mmol) 및 소듐 카보네이트(17.6 mg, 0.24 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-48로 표시되는 황색 고체의 화합물 GxF 48(18.2 mg, 92.2% 수율)을 수득 하였다.4-benzene boronic acid (23.8 mg, 0.14 mmol) and tetrakis(triphenyl phosphine) were added to a solution (1.1 mL) containing IJ-B (20.0 mg, 0.048 mmol) mixed with DMF and water at a ratio of 10:1. ) Palladium (11.1 mg, 0.01 mmol) and sodium carbonate (17.6 mg, 0.24 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 48 (18.2 mg, 92.2% yield) as a yellow solid represented by the following formula 1-48. Obtained.
[화학식 1-48][Formula 1-48]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.73(d, J = 7.4Hz, 1H), 8.41(s, 1H), 7.88(d, J = 8Hz, 2H), 7.60(d, J = 8.2 Hz, 2H), 7.57(s, 1H), 7.52(t, J = 7.2Hz, 2H), 7.37(m, 2H), 6.71(d, J = 9.2Hz, 2H), 3.45(q, J = 6.8Hz, 4H), 2.63(s, 3H), 1.24(t, J = 7.2Hz, 6H); 13C NMR(100 MHz, CDCl3), δ 195.7, 184.0, 150.8, 134.6, 133.4, 132.1, 131.0 129.2, 128.3, 128.0, 127.1, 126.3, 124.7, 1242.3, 121.3, 120.0, 110.9, 110.5, 44.9, 26.6, 13.0; LRMS (ESI) m/z calcd for C27H26N2O2 [M+Na]+ : 410.2, found : x. 1 H NMR (400 MHz, CDCl 3 ), δ 9.73 (d, J = 7.4 Hz, 1H), 8.41 (s, 1H), 7.88 (d, J = 8 Hz, 2H), 7.60 (d, J = 8.2 Hz) , 2H), 7.57(s, 1H), 7.52(t, J = 7.2Hz, 2H), 7.37(m, 2H), 6.71(d, J = 9.2Hz, 2H), 3.45(q, J = 6.8Hz) , 4H), 2.63(s, 3H), 1.24(t, J = 7.2Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.7, 184.0, 150.8, 134.6, 133.4, 132.1, 131.0 129.2, 128.3, 128.0, 127.1, 126.3, 124.7, 1242.3, .3, 120.0, 110.9, 110.5, 44.9, 26.6 , 13.0; LRMS (ESI) m/z calcd for C 27 H 26 N 2 O 2 [M+Na]+ : 410.2, found : x.
화합물 GxF 49 : Compound GxF 49 :
IJ-B(20.0 mg, 0.048 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-메톡시페닐 보론산(21.9 mg, 0.14 mmol), 테트라키스(트리페닐 포스핀)팔라듐(11.1 mg, 0.01 mmol) 및 소듐 카보네이트(25.4 mg, 0.24 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-49로 표시되는 황색 고체의 화합물 GxF 49(19.7 mg, 93.4% 수율)을 수득 하였다.In a solution (1.1 mL) containing IJ-B (20.0 mg, 0.048 mmol) mixed with DMF and water at a ratio of 10:1, 4-methoxyphenyl boronic acid (21.9 mg, 0.14 mmol) and tetrakis Phosphine) palladium (11.1 mg, 0.01 mmol) and sodium carbonate (25.4 mg, 0.24 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to obtain compound GxF 49 (19.7 mg, 93.4% yield) as a yellow solid represented by the following formula 1-49. Obtained.
[화학식 1-49][Formula 1-49]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.72(d, J = 7.8 Hz, 1H), 8.36(s, 1H), 7.87(d, J = 7.2 Hz, 2H), 7.52(d, J = 6.6Hz, 3H), 7.35(dd, J = 1.6 Hz, 7.6 Hz, 1H), 7.04(d, J = 6.6 Hz, 2H), 6.71(d, J = 8.8 Hz, 2H), 3.88(s, 3H), 3.45(q, J = 8 Hz, 4H), 2.63(s, 3H), 1.23(t, J = 7.2Hz, 6H); 13C NMR(100 MHz, CDCl3), δ 195.7, 183.9, 158.9, 150.7, 133.3, 132.1, 130.7, 129.5, 127.9, 127.0, 126.4, 124.6, 124.0, 121.2, 120.1, 114.7, 110.8, 110.5, 55.7, 44.9, 26.6, 13.0; LRMS (ESI) m/z calcd for C28H28N2O3 [M+Na]+ : 440.2, found : x. 1 H NMR (400 MHz, CDCl 3 ), δ 9.72 (d, J = 7.8 Hz, 1H), 8.36 (s, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.52 (d, J = 6.6) Hz, 3H), 7.35(dd, J = 1.6 Hz, 7.6 Hz, 1H), 7.04(d, J = 6.6 Hz, 2H), 6.71(d, J = 8.8 Hz, 2H), 3.88(s, 3H) , 3.45(q, J = 8 Hz, 4H), 2.63(s, 3H), 1.23(t, J = 7.2Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.7, 183.9, 158.9, 150.7, 133.3, 132.1, 130.7, 129.5, 127.9, 127.0, 126.4, 124.6, 124.0, 121.2, .1, 114.7, 110.8, 110.5, 55.7, 44.9, 26.6, 13.0; LRMS (ESI) m/z calcd for C 28 H 28 N 2 O 3 [M+Na]+ : 440.2, found : x.
화합물 GxF 50 : Compound GxF 50 :
IJ-B(20.0 mg, 0.048 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-다이메틸아미노페닐 보론산(23.8 mg, 0.14 mmol), 테트라키스(트리페닐 포스핀)팔라듐(11.1 mg, 0.01 mmol) 및 소듐 카보네이트(25.4 mg, 0.24 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-50으로 표시되는 황색 고체의 화합물 GxF 50(20.2 mg, 93.0% 수율)을 수득 하였다.In a solution (1.1 mL) containing IJ-B (20.0 mg, 0.048 mmol) mixed with DMF and water at a ratio of 10:1, 4-dimethylaminophenyl boronic acid (23.8 mg, 0.14 mmol) and tetrakis (tri Phenylphosphine)palladium (11.1 mg, 0.01 mmol) and sodium carbonate (25.4 mg, 0.24 mmol) were added, and then stirred at 100°C for 8 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to produce compound GxF 50 (20.2 mg, 93.0% yield) as a yellow solid represented by the following formula 1-50. Obtained.
[화학식 1-50][Formula 1-50]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.70(d, J = 7.2 Hz, 1H), 8.39(s, 1H), 7.87(d, J = 9.2 Hz, 2H), 7.49(d, J = 8.6Hz, 3H), 7.34(dd, 2.0Hz, 7.6Hz, 1H), 6.87(d, J = 8.8Hz, 2H), 6.70(d, J = 8.8 Hz, 2H), 3.45(q, J = 7.6Hz, 4H), 3.03(s, 6H), 2.62(s, 3H), 1.24(t, J = 6.8Hz, 6H); 13C NMR(100 MHz, CDCl3), δ 195.8, 183.0, 150.7, 149.8, 133.3, 132.2, 130.4, 129.1, 127.8, 126.4, 124.6, 123.8, 122.5, 122.0, 120.6, 113.2, 110.6, 110.5, 44.9, 41.0, 26.5, 13.0; LRMS (ESI) m/z calcd for C29H31N3O2 [M+Na]+ : 453.2, found : x. 1 H NMR (400 MHz, CDCl 3 ), δ 9.70 (d, J = 7.2 Hz, 1H), 8.39 (s, 1H), 7.87 (d, J = 9.2 Hz, 2H), 7.49 (d, J = 8.6) Hz, 3H), 7.34(dd, 2.0Hz, 7.6Hz, 1H), 6.87(d, J = 8.8Hz, 2H), 6.70(d, J = 8.8 Hz, 2H), 3.45(q, J = 7.6Hz) , 4H), 3.03(s, 6H), 2.62(s, 3H), 1.24(t, J = 6.8Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.8, 183.0, 150.7, 149.8, 133.3, 132.2, 130.4, 129.1, 127.8, 126.4, 124.6, 123.8, 122.5, 122.0, .6, 113.2, 110.6, 110.5, 44.9, 41.0, 26.5, 13.0; LRMS (ESI) m/z calcd for C 29 H 31 N 3 O 2 [M+Na]+ : 453.2, found : x.
<GxF 51 ~ 55><GxF 51 ~ 55>
IK-E : 하기 반응식 12와 같이 합성하였으며, 구체적으로, 피리딘(pyridine, 564 μL, 7 mmol) 및 2-브로모-1-[4-(4(트리플루오로메틸)-페닐]에탄-1-온(1.96 mL, 7.35 mmol)이 포함된 DMF(15.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(372 μL, 3.50 mmol), 구리(II) 아세테이트 모노하이드레이트(2.09 g, 10.5 mmol) 및 소듐 아세테이트(1.72 g, 21.0 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IK-E(906 mg, 2.50 mmol, 71.6% 수율)를 수득 하였다. IK-E : Synthesized according to Scheme 12 below, specifically, pyridine (564 μL, 7 mmol) and 2-bromo-1-[4-(4(trifluoromethyl)-phenyl]ethan-1-one ( DMF (15.0 mL) containing 1.96 mL, 7.35 mmol) was stirred at 100°C overnight, then ethyl acrylate (372 μL, 3.50 mmol), copper(II) acetate monohydrate (2.09 g, 10.5 mmol), and Sodium acetate (1.72 g, 21.0 mmol) was added and stirred at 100°C for 16 hours. After TLC confirmed that the reaction was complete, copper acetate was removed by filtration through a Celite pad, and the resulting filtrate was vacuumed. The resulting crude product was washed with water, extracted three times with DCM, dried over anhydrous Na 2 SO 4 and concentrated on a silica-gel flash column. The product was purified by chromatography (1 to 15% hexane containing EtOAc) to obtain compound IK-E (906 mg, 2.50 mmol, 71.6% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.98(d, J = 6.8 Hz, 1H), 8.42(d, J = 9.2 Hz, 1H), 7.91(d, J = 8.0 Hz, 2H), 7.78(d, J = 8.4 Hz, 2H), 7.76(s, 1H), 7.50(t, J = 8.0 Hz, 1H), 7.14(d, J = 6.2 Hz, 1H), 4.38(q, J = 7.1 Hz, 2H), 1.40(t, J = 7.1 Hz, 3H); 13C NMR(100 MHz, CDCl3) δ 183.6, 163.6, 142.9, 140.0, 132.9, 132.6, 129.1, 129.9, 128.9, 128.1, 125.3(3), 125.0, 122.3, 121.9, 121.4, 119.5, 115.6, 106.8, 60.3, 14.7; LRMS (ESI) m/z calcd for C19H14F3NO3 [M+Na]+ : 361.1, found : 362.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.98 (d, J = 6.8 Hz, 1H), 8.42 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.78 ( d, J = 8.4 Hz, 2H), 7.76(s, 1H), 7.50(t, J = 8.0 Hz, 1H), 7.14(d, J = 6.2 Hz, 1H), 4.38(q, J = 7.1 Hz, 2H), 1.40(t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.6, 163.6, 142.9, 140.0, 132.9, 132.6, 129.1, 129.9, 128.9, 128.1, 125.3(3), 125.0, 122.3, 121.9, 1 21.4, 119.5, 115.6, 106.8, 60.3, 14.7; LRMS (ESI) m/z calcd for C 19 H 14 F 3 NO 3 [M+Na] + : 361.1, found : 362.1.
IK-B : IK-E(632 mg, 2.50 mmol)가 포함된 메탄올(20 mL)에 KOH(8.44 g, 150 mmol)를 첨가한 후, 실온에서 4시간 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 흰색고체의 화합물 IK-A를 수득하였다. IK-B : KOH (8.44 g, 150 mmol) was added to methanol (20 mL) containing IK-E (632 mg, 2.50 mmol), and then stirred at room temperature for 4 hours. The reaction mixture was acidified by adding 6N HCl, and the resulting solid was collected through filtration, washed with water, and dried in a drying oven to obtain Compound IK-A as a white solid.
수득한 화합물 IK-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IK-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(630 mg, 7.50 mmol)를 첨가하고 및 NBS(667 mg, 3.75 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - EA 12%)로 정제하여 황색 고체의 화합물 IK-B(664 mg, 1.80 mmol, 72.1% 수율)를 수득 하였다.The obtained compound IK-A was used in the next step without further purification. Sodium bicarbonate (630 mg, 7.50 mmol) was added to DMF (10.0 mL) containing IK-A and NBS (667 mg, 3.75 mmol) ) was added in portions at 0°C. The reaction mixture was stirred at room temperature for 12 hours, then the resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8 - EA 12%) to obtain compound IK-B (664 mg, 1.80 mmol, 72.1% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.96 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 9.2 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.32 (s, 1H), 7.05 (t, J = 7.0 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 181.4, 142.9, 136.6, 132.4, 128.8, 128.3, 126.5, 125.4, 125.0, 124.9, 122.2, 121.3, 116.7, 114.6, 89.9;LRMS (ESI) m/z calcd for C16H9BrF3NO[M+Na]+ : 367.0, found : 368.0. 1 H NMR (400 MHz, CDCl 3 ), δ 9.96 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.64 ( d, J = 9.2 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.32 (s, 1H), 7.05 (t, J = 7.0 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 181.4, 142.9, 136.6, 132.4, 128.8, 128.3, 126.5, 125.4, 125.0, 124.9, 122.2, 121.3, 116.7, 114.6, ;LRMS (ESI) m/z calcd for C 16 H 9 BrF 3 NO[M+Na] + : 367.0, found : 368.0.
[반응식 12][Scheme 12]
화합물 GxF 51 : Compound GxF 51 :
IK-B(59.0 mg, 0.16 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(122 mg, 0.64 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(68.0 mg, 0.64 mmol)를 첨가한 후, 100℃에서 1시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-51으로 표시되는 황색 고체의 화합물 GxF 51(62.1 mg, 0.14 mmol, 89.5% 수율)을 수득 하였다.4-trifluorophenyl boronic acid (122 mg, 0.64 mmol) and tetrakis(triphenyl phosphine) in a solution containing IK-B (59.0 mg, 0.16 mmol) mixed with DMF and water at a ratio of 2:1. Palladium (231 mg, 20.0 mol%) and sodium carbonate (68.0 mg, 0.64 mmol) were added, and then stirred at 100°C for 1 hour. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 51 (62.1 mg, 0.14 mmol, 89.5%) as a yellow solid represented by the following formula 1-51. yield) was obtained.
[화학식 1-51][Formula 1-51]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 10.05 (d, J = 6.8 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.68 (q, J = 8.0 Hz, 5H), 7.43 (s, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.08 (t, J = 6.2 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 182.8, 143.6, 138.0, 136.7, 132.7, 132.4, 129.2, 129.0, 128.7, 128.4, 127.8, 126.2, 125.8, 125.8, 125.5, 125.4, 125.3(2), 122.1, 117.3, 116.4, 114.9. 1 H NMR (400 MHz, CDCl 3 ), δ 10.05 (d, J = 6.8 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.78 ( d, J = 8.4 Hz, 2H), 7.68 (q, J = 8.0 Hz, 5H), 7.43 (s, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.08 (t, J = 6.2 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 182.8, 143.6, 138.0, 136.7, 132.7, 132.4, 129.2, 129.0, 128.7, 128.4, 127.8, 126.2, 125.8, 125.8, 125. 5, 125.4, 125.3(2), 122.1, 117.3, 116.4, 114.9.
화합물 GxF 52 : Compound GxF 52 :
IK-B(58.6 mg, 0.16 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(104 mg, 0.64 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(67.5 mg, 0.64 mmol)를 첨가한 후, 100℃에서 7시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-52로 표시되는 황색 고체의 화합물 GxF 52(58.4 mg, 0.14 mmol, 89.5% 수율)을 수득 하였다.4-acetylphenyl boronic acid (104 mg, 0.64 mmol), tetrakis(triphenylphosphine)palladium ( 231 mg, 20.0 mol%) and sodium carbonate (67.5 mg, 0.64 mmol) were added, and then stirred at 100°C for 7 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to produce compound GxF 52 (58.4 mg, 0.14 mmol, 89.5%) as a yellow solid represented by the following formula 1-52. yield) was obtained.
[화학식 1-52][Formula 1-52]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 10.03 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 9.2 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.34 (s, 1H), 7.27 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 8.8 Hz, 3H), 3.86 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 182.3, 158.5, 144.0, 136.8, 132.4, 132.0, 129.0(2), 126.6, 125.3, 125.2(2), 125.1(2), 124.9, 122.5, 121.5, 118.0, 117.6, 114.5, 114.3, 55.4. 1 H NMR (400 MHz, CDCl 3 ), δ 10.03 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 9.2 Hz, 1H), 7.77 ( d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.34 (s, 1H), 7.27 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 8.8 Hz, 3H), 3.86 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 182.3, 158.5, 144.0, 136.8, 132.4, 132.0, 129.0(2), 126.6, 125.3, 125.2(2), 125.1(2), 124.9, 122.5, 12 1.5, 118.0, 117.6, 114.5, 114.3, 55.4.
화합물 GxF 53 : Compound GxF 53 :
IK-B(53.0 mg, 0.14 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(71.2 mg, 0.57 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(61.0 mg, 0.57 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-53으로 표시되는 황색 고체의 화합물 GxF 53(53.1 mg, 0.14 mmol, 100% 수율)을 수득 하였다.Phenylboronic acid (71.2 mg, 0.57 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 20.0 mol%) and sodium carbonate (61.0 mg, 0.57 mmol) were added, and then stirred at 100°C for 9 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 53 (53.1 mg, 0.14 mmol, 100%) as a yellow solid represented by the following formula 1-53. yield) was obtained.
[화학식 1-53][Formula 1-53]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 10.04 (d, J = 6.8 Hz, 1H), 7.92 (t, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H), 7.45 (t, J = 7.8 Hz, 2H), 7.39 (s, 1H), 7.32 (m, 3H), 6.97 (t, J = 6.6 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 182.5, 143.9, 136.8, 134.2, 132.5, 132.1, 129.1, 129.0, 128.9, 127.8, 126.7, 125.6, 125.3, 125.2, 122.5, 121.7, 118.2, 117.6, 114.6; LRMS (ESI) m/z calcd for C22H14F3NO[M+Na]+ : 365.1, found : 366.1. 1 H NMR (400 MHz, CDCl 3 ), δ 10.04 (d, J = 6.8 Hz, 1H), 7.92 (t, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.55 ( d, J = 7.6 Hz, 2H), 7.45 (t, J = 7.8 Hz, 2H), 7.39 (s, 1H), 7.32 (m, 3H), 6.97 (t, J = 6.6 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 182.5, 143.9, 136.8, 134.2, 132.5, 132.1, 129.1, 129.0, 128.9, 127.8, 126.7, 125.6, 125.3, 125.2, 122. 5, 121.7, 118.2, 117.6, 114.6; LRMS (ESI) m/z calcd for C 22 H 14 F 3 NO[M+Na] + : 365.1, found : 366.1.
화합물 GxF 54 : Compound GxF 54 :
IK-B(56.2 mg, 0.15 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(92.8 mg, 0.61 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(64.7 mg, 0.61 mmol)를 첨가한 후, 100℃에서 10시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-54로 표시되는 황색 고체의 화합물 GxF 54(65.9 mg, 0.16 mmol, 100% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (92.8 mg, 0.61 mmol) and tetrakis(triphenylphosphine)palladium were added to a solution containing IK-B (56.2 mg, 0.15 mmol) mixed with DMF and water at a ratio of 2:1. (231 mg, 20.0 mol%) and sodium carbonate (64.7 mg, 0.61 mmol) were added, and then stirred at 100°C for 10 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 54 (65.9 mg, 0.16 mmol, 100%) as a yellow solid represented by the following formula 1-54. yield) was obtained.
[화학식 1-54][Formula 1-54]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.99 (d, J = 7.2 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.42 (s,1H), 7.32 (t, J = 8.0 Hz, 1H), 7.01 (t, J = 6.8 Hz, 1H), 2.60 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 197.1, 182.6, 144.0, 143.5, 139.1, 136.7, 136.3, 135.0, 132.6, 132.2, 129.1, 128.9, 128.8, 127.4, 127.2, 126.2, 125.2, 122.4, 122.1, 117.4, 116.6, 114.9, 26.7; LRMS (ESI) m/z calcd for [M+Na]+ : 395.1, found : 396.4. 1 H NMR (400 MHz, CDCl 3 ), δ 9.99 (d, J = 7.2 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.73 ( d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.42 (s, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.01 (t, J = 6.8 Hz, 1H), 2.60 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.1, 182.6, 144.0, 143.5, 139.1, 136.7, 136.3, 135.0, 132.6, 132.2, 129.1, 128.9, 128.8, 127.4, 127. 2, 126.2, 125.2, 122.4, 122.1, 117.4 , 116.6, 114.9, 26.7; LRMS (ESI) m/z calcd for [M+Na] + : 395.1, found : 396.4.
화합물 GxF 55 : Compound GxF 55 :
IK-B(60.6 mg, 0.16 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(108.6 mg, 0.66 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(69.7 mg, 0.66 mmol)를 첨가한 후, 100℃에서 11시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-55로 표시되는 황색 고체의 화합물 GxF 55(59.5 mg, 0.14 mmol, 91% 수율)을 수득 하였다.4-(dimethylamino)phenyl boronic acid (108.6 mg, 0.66 mmol) and tetrakis (triphenyl phosphatase) were added to a solution containing IK-B (60.6 mg, 0.16 mmol) mixed with DMF and water at a ratio of 2:1. Finn) Palladium (231 mg, 20.0 mol%) and sodium carbonate (69.7 mg, 0.66 mmol) were added, and then stirred at 100°C for 11 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 55 (59.5 mg, 0.14 mmol, 91%) as a yellow solid represented by the following formula 1-55. yield) was obtained.
[화학식 1-55][Formula 1-55]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 10.03 (d, J = 6.8 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.31 (s, 1H), 7.27 (t, J = 7.2 Hz, 1H), 6.95 (t, J = 6.9 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 2.98 (s, 6H); 13C NMR(100 MHz, CDCl3) δ 181.7, 149.1,143.8, 136.5, 131.9, 131.6, 128.8, 128.6, 128.3, 124.9, 124.8, 124.7, 124.3, 122.2, 121.8, 121.1, 118.4, 117.5, 114.1, 112.5, 40.3; LRMS (ESI) m/z calcd for C24H19F3N2O [M+Na]+ : 408.1, found : 409.2. 1 H NMR (400 MHz, CDCl 3 ), δ 10.03 (d, J = 6.8 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.75 ( d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.31 (s, 1H), 7.27 (t, J = 7.2 Hz, 1H), 6.95 (t, J = 6.9 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 2.98 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 181.7, 149.1,143.8, 136.5, 131.9, 131.6, 128.8, 128.6, 128.3, 124.9, 124.8, 124.7, 124.3, 122.2, , 121.1, 118.4, 117.5, 114.1, 112.5 , 40.3; LRMS (ESI) m/z calcd for C 24 H 19 F 3 N 2 O [M+Na] + : 408.1, found : 409.2.
<GxF 56 ~ 60><GxF 56 ~ 60>
IL-E : 하기 반응식 13과 같이 합성하였으며, 구체적으로, 피리딘(564 μL, 7.00 mmol) 및 클로로아세톤(chloroacetone, 585 μL, 7.35 mmol)이 포함된 DMF(15.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(373 μL, 3.50 mmol), 구리(II) 아세테이트 모노하이드레이트(2.09 g, 10.5 mmol) 및 소듐 아세테이트(1.72 g, 21.0 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IL-E(633 mg, 2.73 mmol, 85.0% 수율)를 수득 하였다. IL-E : Synthesized as shown in Scheme 13 below. Specifically, DMF (15.0 mL) containing pyridine (564 μL, 7.00 mmol) and chloroacetone (585 μL, 7.35 mmol) was stirred at 100°C overnight, Ethyl acrylate (373 μL, 3.50 mmol), copper (II) acetate monohydrate (2.09 g, 10.5 mmol), and sodium acetate (1.72 g, 21.0 mmol) were added and stirred at 100°C for 16 hours. After confirming that the reaction was complete by TLC, copper acetate was removed by filtration through a Celite pad, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (1 to 15% hexane containing EtOAc) to obtain compound IL-E (633 mg, 2.73 mmol, 85.0% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.88 (d, J = 6.4 Hz, 1H), 8.34(d, J = 5.0 Hz, 1H), 7.99(s, 1H), 7.38(q, J = 9.3 Hz, 1H), 6.95(t, J = 7.0 Hz, 1H), 4.39(q, J = 7.1 Hz, 2H), 2.60(s, 3H), 1.43(t, J = 7.2 Hz, 3H); 13C NMR(100 MHz, CDCl3) δ 187.6, 164.0, 139.2, 129.1, 127.2, 126.2, 122.7, 119.4, 115.2, 105.8, 60.3, 27.6, 14.9 ; LRMS (ESI) m/z calcd for C13H13NO3 [M+Na]+ : 231.1, found : 232.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.88 (d, J = 6.4 Hz, 1H), 8.34 (d, J = 5.0 Hz, 1H), 7.99 (s, 1H), 7.38 (q, J = 9.3) Hz, 1H), 6.95(t, J = 7.0 Hz, 1H), 4.39(q, J = 7.1 Hz, 2H), 2.60(s, 3H), 1.43(t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 187.6, 164.0, 139.2, 129.1, 127.2, 126.2, 122.7, 119.4, 115.2, 105.8, 60.3, 27.6, 14.9; LRMS (ESI) m/z calcd for C 13 H 13 NO 3 [M+Na] + : 231.1, found : 232.1.
IL-B : IL-E(633 mg, 2.73 mmol)가 포함된 메탄올(20 mL)에 KOH(6.14 g, 109 mmol)를 첨가한 후, 실온에서 4시간 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 흰색고체의 화합물 IL-A를 수득하였다. IL-B : KOH (6.14 g, 109 mmol) was added to methanol (20 mL) containing IL-E (633 mg, 2.73 mmol), and then stirred at room temperature for 4 hours. The reaction mixture was acidified by adding 6N HCl, and the resulting solid was collected through filtration, washed with water, and dried in a drying oven to obtain compound IL-A as a white solid.
수득한 화합물 IL-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IL-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(688 mg, 8.19 mmol)를 첨가하고 및 NBS(2.18 g, 12.3 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - EA 12%)로 정제하여 황색 고체의 화합물 IL-B(477 mg, 2.0 mmol, 73.4% 수율)를 수득 하였다.The obtained compound IL-A was used in the next step without further purification. Sodium bicarbonate (688 mg, 8.19 mmol) was added to DMF (10.0 mL) containing IL-A and NBS (2.18 g, 12.3 mmol) ) was added in portions at 0°C. The reaction mixture was stirred at room temperature for 12 hours, then the resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8 - EA 12%) to obtain compound IL-B (477 mg, 2.0 mmol, 73.4% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.83 (d, J = 6.8 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.51 (s, 1H), 7.22 (q, J = 7.8 Hz, 1H), 6.91 (t, J = 6.4 Hz, 1H), 2.54 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 185.5, 135.4, 127.9, 124.0, 123.8, 121.9, 116.5, 113.9, 88.5, 27.1; LRMS (ESI) m/z calcd for C10H8BrNO[M+Na]+ : 237.0, found :238.0. 1 H NMR (400 MHz, CDCl 3 ), δ 9.83 (d, J = 6.8 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.51 (s, 1H), 7.22 (q, J = 7.8 Hz, 1H), 6.91 (t, J = 6.4 Hz, 1H), 2.54 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 185.5, 135.4, 127.9, 124.0, 123.8, 121.9, 116.5, 113.9, 88.5, 27.1; LRMS (ESI) m/z calcd for C 10 H 8 BrNO[M+Na] + : 237.0, found :238.0.
[반응식 13][Scheme 13]
화합물 GxF 56 : Compound GxF 56 :
IL-B(21.7 mg, 0.09 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(69.0 mg, 0.36 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(39.0 mg, 0.36 mmol)를 첨가한 후, 100℃에서 10시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-56으로 표시되는 황색 고체의 화합물 GxF 56(24.4 mg, 0.08 mmol, 89.3% 수율)을 수득 하였다.IL-B (21.7 mg, 0.09 mmol), 4-trifluorophenyl boronic acid (69.0 mg, 0.36 mmol), and tetrakis(triphenyl phosphine) in a 2:1 mixture of DMF and water. Palladium (231 mg, 20.0 mol%) and sodium carbonate (39.0 mg, 0.36 mmol) were added, and then stirred at 100°C for 10 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 56 (24.4 mg, 0.08 mmol, 89.3%) as a yellow solid represented by the following formula 1-56. yield) was obtained.
[화학식 1-56][Formula 1-56]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.93 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 9.2 Hz, 2H), 7.69 (d, J = 4.4 Hz, 2H), 7.65 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.24 (dd, J = 10.0 Hz, 1H), 6.95 (t, J = 7.0 Hz, 1H), 2.62 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 186.8, 138.4, 135.7, 129.0, 128.1, 127.8, 125.8, 125.8, 125.6, 125.1, 122.8, 122.6, 117.1, 115.5(2), 114.4, 27.5; LRMS (ESI) m/z calcd for C17H12F3NO [M+Na]+ : 303.1, found : 304.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.93 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 9.2 Hz, 2H), 7.69 (d, J = 4.4 Hz, 2H), 7.65 ( s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.24 (dd, J = 10.0 Hz, 1H), 6.95 (t, J = 7.0 Hz, 1H), 2.62 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.8, 138.4, 135.7, 129.0, 128.1, 127.8, 125.8, 125.8, 125.6, 125.1, 122.8, 122.6, 117.1, 115.5(2), 1 14.4, 27.5; LRMS (ESI) m/z calcd for C 17 H 12 F 3 NO [M+Na] + : 303.1, found : 304.1.
화합물 GxF 57 : Compound GxF 57 :
IL-B(25.8 mg, 0.10 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(71.0 mg, 0.43mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(46.0 mg, 0.43 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-57로 표시되는 황색 고체의 화합물 GxF 57(19.0 mg, 0.06 mmol, 63.4% 수율)을 수득 하였다.4-acetylphenyl boronic acid (71.0 mg, 0.43 mmol), tetrakis(triphenyl phosphine)palladium ( 231 mg, 20.0 mol%) and sodium carbonate (46.0 mg, 0.43 mmol) were added, and then stirred at 100°C for 12 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to produce compound GxF 57 (19.0 mg, 0.06 mmol, 63.4%) as a yellow solid represented by the following formula 1-57. yield) was obtained.
[화학식 1-57][Formula 1-57]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.91 (d, J = 6.8 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.66 (d, J = 3.6 Hz, 2H), 7.23 (dd, J = 7.8 Hz, 1H), 6.93 (t, J = 6.9 Hz, 1H), 2.63 (s, 3H), 2.61 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 197.5, 186.9, 139.9, 135.7, 134.9, 129.1, 127.6, 127.5, 125.3, 122.9, 122.8, 117.5, 115.7, 114.5, 27.7, 27.0; LRMS (ESI) m/z calcd for C18H15NO2 [M+Na]+ : 277. 1, found : 278.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.91 (d, J = 6.8 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.8 Hz, 1H), 7.68 ( s, 1H), 7.66 (d, J = 3.6 Hz, 2H), 7.23 (dd, J = 7.8 Hz, 1H), 6.93 (t, J = 6.9 Hz, 1H), 2.63 (s, 3H), 2.61 ( s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.5, 186.9, 139.9, 135.7, 134.9, 129.1, 127.6, 127.5, 125.3, 122.9, 122.8, 117.5, 115.7, 114.5, , 27.0; LRMS (ESI) m/z calcd for C 18 H 15 NO 2 [M+Na] + : 277. 1, found : 278.1.
화합물 GxF 58 : Compound GxF 58 :
IL-B(54.4 mg, 0.23 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(111 mg, 0.91 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(97.0 mg, 0.91 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-58로 표시되는 황색 고체의 화합물 GxF 58(66.8 mg, 0.28 mmol, 100% 수율)을 수득 하였다.Phenylboronic acid (111 mg, 0.91 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 231 mg, 20.0 mol%) and sodium carbonate (97.0 mg, 0.91 mmol) were added, and then stirred at 100°C for 9 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 58 (66.8 mg, 0.28 mmol, 100%) as a yellow solid represented by the following formula 1-58. yield) was obtained.
[화학식 1-58][Formula 1-58]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.91 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 7.58 (d, J = 7.2 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.90 (t, J = 6.8 Hz, 1H), 2.60 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 186.2, 135.2, 134.4, 128.5, 128.4, 127.6, 126.2, 124.0, 122.2, 122.0, 117.2, 116.7, 113.7, 27.2; LRMS (ESI) m/z calcd for C16H13NO [M+Na]+ : 235.1, found : 236.1. 1H NMR (400 MHz, CDCl 3 ), δ 9.91 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 7.58 (d, J = 7.2 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.90 (t, J = 6.8 Hz, 1H), 2.60 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.2, 135.2, 134.4, 128.5, 128.4, 127.6, 126.2, 124.0, 122.2, 122.0, 117.2, 116.7, 113.7, 27.2; LRMS (ESI) m/z calcd for C 16 H 13 NO [M+Na] + : 235.1, found : 236.1.
화합물 GxF 59 : Compound GxF 59 :
IL-B(20.3 mg, 0.08 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(52.0 mg, 0.34 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(36.0 mg, 0.34 mmol)를 첨가한 후, 100℃에서 13시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-59로 표시되는 황색 고체의 화합물 GxF 59(13.3 mg, 0.05 mmol, 62.6% 수율)을 수득 하였다.IL-B (20.3 mg, 0.08 mmol), 4-methoxyphenyl boronic acid (52.0 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium in a 2:1 mixture of DMF and water. (231 mg, 20.0 mol%) and sodium carbonate (36.0 mg, 0.34 mmol) were added, and then stirred at 100°C for 13 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 59 (13.3 mg, 0.05 mmol, 62.6%) as a yellow solid represented by the following formula 1-59. yield) was obtained.
[화학식 1-59][Formula 1-59]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.90 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 6.8 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.16 (t, J = 7.7 Hz, 1H), 7.01 (t, J = 6.8 Hz, 2H), 6.88 (t, J = 6.8 Hz, 1H), 3.87 (s, 3H), 2.60 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 186.4, 158.3, 135.5, 129.0, 128.7, 127.2, 124.0, 122.2, 117.5, 116.8, 114.3, 113.9, 55.5, 27.5; LRMS (ESI) m/z calcd for C17H15NO2[M+Na]+ : 265.1, found : 266.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.90 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 6.8 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.16 (t, J = 7.7 Hz, 1H), 7.01 (t, J = 6.8 Hz, 2H), 6.88 (t, J = 6.8 Hz, 1H), 3.87 (s, 3H), 2.60 ( s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.4, 158.3, 135.5, 129.0, 128.7, 127.2, 124.0, 122.2, 117.5, 116.8, 114.3, 113.9, 55.5, 27.5; LRMS (ESI) m/z calcd for C 17 H 15 NO 2 [M+Na] + : 265.1, found : 266.1.
화합물 GxF 60 : Compound GxF 60 :
IL-B(27.5 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(76.0 mg, 0.46 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(49.0 mg, 0.46 mmol)를 첨가한 후, 100℃에서 11시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-60으로 표시되는 황색 고체의 화합물 GxF 60(12.5 mg, 0.04 mmol, 40.8% 수율)을 수득 하였다.4-(dimethylamino)phenyl boronic acid (76.0 mg, 0.46 mmol) and tetrakis (triphenyl phosphatase) were added to a 2:1 solution containing IL-B (27.5 mg, 0.11 mmol) and DMF and water. Finn) Palladium (231 mg, 20.0 mol%) and sodium carbonate (49.0 mg, 0.46 mmol) were added, and then stirred at 100°C for 11 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 60 (12.5 mg, 0.04 mmol, 40.8%) as a yellow solid represented by the following formula 1-60. yield) was obtained.
[화학식 1-60][Formula 1-60]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.89 (d, J = 6.4 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.46 (d, J = 7.2 Hz, 2H), 7.13 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 6.8 Hz, 3H), 3.00 (s, 6H), 2.59 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 186.2, 149.3, 135.5, 128.7, 123.7, 122.8, 122.0, 121.9, 117.7, 117.5, 113.8, 113.0, 40.8, 27.5; LRMS (ESI) m/z calcd for C18H18N2O [M+Na]+ : 278.1, found : 279.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.89 (d, J = 6.4 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.46 (d, J = 7.2 Hz, 2H), 7.13 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 6.8 Hz, 3H), 3.00 (s, 6H), 2.59 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.2, 149.3, 135.5, 128.7, 123.7, 122.8, 122.0, 121.9, 117.7, 117.5, 113.8, 113.0, 40.8, 27.5; LRMS (ESI) m/z calcd for C 18 H 18 N 2 O [M+Na] + : 278.1, found : 279.2.
<GxF 61 ~ 65><GxF 61 ~ 65>
IM-E : 하기 반응식 14와 같이 합성하였으며, 구체적으로, 피리딘(564 μL, 7.00 mmol) 및 브로모아세토페논(1.46 g, 7.35 mmol)이 포함된 DMF(15.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(373 μL, 3.50 mmol), 구리(II) 아세테이트 모노하이드레이트(2.09 g, 10.5 mmol) 및 소듐 아세테이트(1.72 g, 21.0 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IM-E(616 mg, 2.10 mmol, 60% 수율)를 수득 하였다. IM-E : Synthesized as shown in Scheme 14 below. Specifically, DMF (15.0 mL) containing pyridine (564 μL, 7.00 mmol) and bromoacetophenone (1.46 g, 7.35 mmol) was stirred at 100°C overnight, Ethyl acrylate (373 μL, 3.50 mmol), copper (II) acetate monohydrate (2.09 g, 10.5 mmol), and sodium acetate (1.72 g, 21.0 mmol) were added and stirred at 100°C for 16 hours. After confirming that the reaction was complete by TLC, copper acetate was removed by filtration through a Celite pad, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (1 to 15% hexane containing EtOAc) to obtain compound IM-E (616 mg, 2.10 mmol, 60% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.83(d, J = 7.2 Hz, 1H), 8.25(d, J = 9.0 Hz, 1H), 7.73(d, J = 7.2 Hz, 2H), 7.71(s, 1H), 7.46(d, J = 7.2 Hz, 1H), 7.40(t, J = 7.2 Hz, 2H), 7.29(t, J = 8.0 Hz, 1H), 6.93(t, J = 7.0 Hz, 1H), 4.29(q, J = 7.0 Hz, 2H), 1.31(t, J = 7.0 Hz, 3H); 13C NMR(100 MHz, CDCl3) δ 184.8, 163.4, 139.5, 139.3, 131.1, 128.7, 128.6, 128.4, 128.0, 127.2, 122.1, 121.2, 119.0, 114.9, 105.9, 59.9, 14.5; LRMS (ESI) m/z calcd for C18H15NO3 [M+Na]+ : 293.1, found : 294.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.83 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 7.2 Hz, 2H), 7.71 ( s, 1H), 7.46(d, J = 7.2 Hz, 1H), 7.40(t, J = 7.2 Hz, 2H), 7.29(t, J = 8.0 Hz, 1H), 6.93(t, J = 7.0 Hz, 1H), 4.29(q, J = 7.0 Hz, 2H), 1.31(t, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.8, 163.4, 139.5, 139.3, 131.1, 128.7, 128.6, 128.4, 128.0, 127.2, 122.1, 121.2, 119.0, 114.9, 9, 59.9, 14.5; LRMS (ESI) m/z calcd for C 18 H 15 NO 3 [M+Na] + : 293.1, found : 294.2.
IM-B : IM-E(616 mg, 2.10 mmol)가 포함된 메탄올(20 mL)에 KOH(7.06 g, 126 mmol)를 첨가한 후, 실온에서 4시간 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 흰색고체의 화합물 IM-A를 수득하였다. IM-B : KOH (7.06 g, 126 mmol) was added to methanol (20 mL) containing IM-E (616 mg, 2.10 mmol), and then stirred at room temperature for 4 hours. The reaction mixture was acidified by adding 6N HCl, and the resulting solid was collected through filtration, washed with water, and dried in a drying oven to obtain compound IM-A as a white solid.
수득한 화합물 IM-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IM-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(529 mg, 6.30 mmol)를 첨가하고 및 NBS(561 mg, 3.15 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - EA 12%)로 정제하여 황색 고체의 화합물 IM-B(590 mg, 1.96 mmol, 93.6% 수율)를 수득 하였다.The obtained compound IM-A was used in the next step without further purification. Sodium bicarbonate (529 mg, 6.30 mmol) was added to DMF (10.0 mL) containing IM-A and NBS (561 mg, 3.15 mmol). ) was added in portions at 0°C. The reaction mixture was stirred at room temperature for 12 hours, then the resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8 - EA 12%) to obtain compound IM-B (590 mg, 1.96 mmol, 93.6% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 10.04 (d, J = 6.8 Hz, 1H), 7.78 (d, J = 6.4 Hz, 2H), 7.61 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.50 (d, J =7.6 Hz, 2H), 7.37 (s, 1H), 7.30 (m, 1H), 6.98 (t, J = 7.0 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 184.0, 140.3, 136.9, 131.3, 129.0, 128.8, 128.5, 127.2, 125.4, 122.3, 117.3, 114.8, 89.9, 47.1, 34.8; LRMS (ESI) m/z calcd for C15H10BrNO [M+Na]+ : 299.0, found : 300.0. 1 H NMR (400 MHz, CDCl 3 ), δ 10.04 (d, J = 6.8 Hz, 1H), 7.78 (d, J = 6.4 Hz, 2H), 7.61 (d, J = 8.8 Hz, 1H), 7.54 ( d, J = 7.6 Hz, 1H), 7.50 (d, J =7.6 Hz, 2H), 7.37 (s, 1H), 7.30 (m, 1H), 6.98 (t, J = 7.0 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.0, 140.3, 136.9, 131.3, 129.0, 128.8, 128.5, 127.2, 125.4, 122.3, 117.3, 114.8, 89.9, 47.1, 34.8; LRMS (ESI) m/z calcd for C 15 H 10 BrNO [M+Na] + : 299.0, found : 300.0.
[반응식 14][Scheme 14]
화합물 GxF 61 : Compound GxF 61 :
IM-B(59.4 mg, 0.19 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(150 mg, 0.79 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(84.0 mg, 0.79 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-61로 표시되는 황색 고체의 화합물 GxF 61(33.9 mg, 0.09 mmol, 46.8% 수율)을 수득 하였다.IM-B (59.4 mg, 0.19 mmol), 4-trifluorophenyl boronic acid (150 mg, 0.79 mmol), and tetrakis(triphenyl phosphine) in a 2:1 mixture of DMF and water. Palladium (231 mg, 20.0 mol%) and sodium carbonate (84.0 mg, 0.79 mmol) were added, and then stirred at 100°C for 9 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 61 (33.9 mg, 0.09 mmol, 46.8%) as a yellow solid represented by the following formula 1-61. yield) was obtained.
[화학식 1-61][Formula 1-61]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 10.04 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.84 (m, J = 6.8 Hz, 2H), 7.67 (m, J = 2.4 Hz,4H), 7.56 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.49 (s, 1H), 7.31 (m, J = 7.9 Hz, 1H), 6.96 (m, J = 6.9 Hz, 1H); 13C NMR(400 MHz, CDCl3) δ 184.5, 140.4, 138.3, 136.1, 131.0, 129.0, 128.8, 128.7, 128.4, 128.2, 128.0, 127.7, 125.7, 125.7, 125.7, 125.6, 125.4, 122.9, 122.4, 117.1, 115.8, 114.4; LRMS (ESI) m/z calcd for C22H14F3NO [M+Na]+ : 365.1, found : 366.1. 1 H NMR (400 MHz, CDCl 3 ), δ 10.04 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.84 (m, J = 6.8 Hz, 2H), 7.67 ( m, J = 2.4 Hz, 4H), 7.56 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.49 (s, 1H), 7.31 (m, J = 7.9 Hz, 1H), 6.96 (m, J = 6.9 Hz, 1H); 13 C NMR (400 MHz, CDCl 3 ) δ 184.5, 140.4, 138.3, 136.1, 131.0, 129.0, 128.8, 128.7, 128.4, 128.2, 128.0, 127.7, 125.7, 125.7, 125. 7, 125.6, 125.4, 122.9, 122.4, 117.1 , 115.8, 114.4; LRMS (ESI) m/z calcd for C 22 H 14 F 3 NO [M+Na] + : 365.1, found : 366.1.
화합물 GxF 62 : Compound GxF 62 :
IM-B(55.5 mg, 0.18 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(121 mg, 0.74 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(78.7 mg, 0.74 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-62로 표시되는 황색 고체의 화합물 GxF 62(50.0 mg, 0.14 mmol, 79.2% 수율)을 수득 하였다.4-acetylphenyl boronic acid (121 mg, 0.74 mmol), tetrakis(triphenylphosphine)palladium ( 231 mg, 20.0 mol%) and sodium carbonate (78.7 mg, 0.74 mmol) were added, and then stirred at 100°C for 12 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to produce compound GxF 62 (50.0 mg, 0.14 mmol, 79.2%) as a yellow solid represented by the following formula 1-62. yield) was obtained.
[화학식 1-62][Formula 1-62]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 10.02 (d, J = 6.8 Hz, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.89 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 6.8 Hz, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 7.2 Hz, 1H), 7.53 (s, 1H), 7.51 (s, 1H), 7.29 (t, J = 7.0 Hz, 1H), 7.00 (t, J = 6.6 Hz, 1H), 2.63 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 197.0, 184.3, 143.9, 140.3, 139.4, 136.2, 136.1, 134.6, 130.9, 128.9, 128.8, 128.7, 128.1, 127.2, 127.1, 125.6, 125.3, 122.4, 117.2, 115.9, 114.4, 26.7, 26.6; LRMS (ESI) m/z calcd for C23H17NO2 [M+Na]+ : 339.1, found :340.2. 1 H NMR (400 MHz, CDCl 3 ), δ 10.02 (d, J = 6.8 Hz, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.89 (d, J = 8.8 Hz, 1H), 7.84 ( d, J = 6.8 Hz, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 7.2 Hz, 1H), 7.53 (s, 1H), 7.51 (s, 1H), 7.29 (t, J = 7.0 Hz, 1H), 7.00 (t, J = 6.6 Hz, 1H), 2.63 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.0, 184.3, 143.9, 140.3, 139.4, 136.2, 136.1, 134.6, 130.9, 128.9, 128.8, 128.7, 128.1, 127.2, 127. 1, 125.6, 125.3, 122.4, 117.2, 115.9 , 114.4, 26.7, 26.6; LRMS (ESI) m/z calcd for C 23 H 17 NO 2 [M+Na] + : 339.1, found : 340.2.
화합물 GxF 63 : Compound GxF 63 :
IM-B(61.5 mg, 0.21 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(100 mg, 0.82 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(87.0 mg, 0.82 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-63으로 표시되는 황색 고체의 화합물 GxF 63(56.2 mg, 0.18 mmol, 89.9% 수율)을 수득 하였다.Phenylboronic acid (100 mg, 0.82 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 20.0 mol%) and sodium carbonate (87.0 mg, 0.82 mmol) were added, and then stirred at 100°C for 9 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 63 (56.2 mg, 0.18 mmol, 89.9%) as a yellow solid represented by the following formula 1-63. yield) was obtained.
[화학식 1-63][Formula 1-63]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 10.04 (d, J = 6.8 Hz, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.84 (d, J = 6.8 Hz, 2H), 7.19 (m, 7H), 7.31 (t, J = 7.4 Hz, 1H), 7.27 (dd, J = 6.6 Hz, 1H), 7.25 (dd, J = 6.6 Hz, 1H), 6.94 (t, J = 6.6 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 183.9, 140.3, 135.9, 134.2, 130.4, 128.5, 128.4, 127.8, 127.5, 126.1, 125.0, 124.6, 121.8, 117.2, 117.1, 113.8; LRMS (ESI) m/z calcd for C21H15NO [M+Na]+ : 297.1, found : 298.1. 1 H NMR (400 MHz, CDCl 3 ), δ 10.04 (d, J = 6.8 Hz, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.84 (d, J = 6.8 Hz, 2H), 7.19 ( m, 7H), 7.31 (t, J = 7.4 Hz, 1H), 7.27 (dd, J = 6.6 Hz, 1H), 7.25 (dd, J = 6.6 Hz, 1H), 6.94 (t, J = 6.6 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.9, 140.3, 135.9, 134.2, 130.4, 128.5, 128.4, 127.8, 127.5, 126.1, 125.0, 124.6, 121.8, 117.2, 1, 113.8; LRMS (ESI) m/z calcd for C 21 H 15 NO [M+Na] + : 297.1, found : 298.1.
화합물 GxF 64 : Compound GxF 64 :
IM-B(62.0 mg, 0.21 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(129 mg, 0.83 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(88.0 mg, 0.83 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-64로 표시되는 황색 고체의 화합물 GxF 64(51.4 mg, 0.15 mmol, 74.7% 수율)을 수득 하였다.IM-B (62.0 mg, 0.21 mmol), 4-methoxyphenyl boronic acid (129 mg, 0.83 mmol), and tetrakis(triphenylphosphine)palladium in a 2:1 mixture of DMF and water. (231 mg, 20.0 mol%) and sodium carbonate (88.0 mg, 0.83 mmol) were added, and then stirred at 100°C for 9 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 64 (51.4 mg, 0.15 mmol, 74.7%) as a yellow solid represented by the following formula 1-64. yield) was obtained.
[화학식 1-64][Formula 1-64]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 10.03 (d, J = 6.8 Hz, 1H), 7.84 (s, 1H), 7.82 (m, 2H), 7.53 (d, J = 6.8 Hz, 1H), 7.50 (s, 1H), 7.48 (m, 4H), 7.40 (s, 1H), 7.23 (m, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 184.1, 158.3, 140.7, 136.2, 130.7, 128.9, 128.8, 128.8, 128.1, 127.0, 125.0, 124.7, 121.9, 121.3, 117.5, 117.4, 114.2, 114.0, 55.4; LRMS (ESI) m/z calcd for C22H17NO2 [M+Na]+ : 327.1, found : 328.1. 1 H NMR (400 MHz, CDCl 3 ), δ 10.03 (d, J = 6.8 Hz, 1H), 7.84 (s, 1H), 7.82 (m, 2H), 7.53 (d, J = 6.8 Hz, 1H), 7.50 (s, 1H), 7.48 (m, 4H), 7.40 (s, 1H), 7.23 (m, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.1, 158.3, 140.7, 136.2, 130.7, 128.9, 128.8, 128.8, 128.1, 127.0, 125.0, 124.7, 121.9, 121.3, 117. 5, 117.4, 114.2, 114.0, 55.4; LRMS (ESI) m/z calcd for C 22 H 17 NO 2 [M+Na] + : 327.1, found : 328.1.
화합물 GxF 65 : Compound GxF 65 :
IM-B(27.5 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(149 mg, 0.90 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(95.7 mg, 0.90 mmol)를 첨가한 후, 100℃에서 11시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-65로 표시되는 황색 고체의 화합물 GxF 65(67.0 mg, 0.19 mmol, 87% 수율)을 수득 하였다.4-(dimethylamino)phenyl boronic acid (149 mg, 0.90 mmol) and tetrakis (triphenyl phosphatase) were added to a solution containing IM-B (27.5 mg, 0.11 mmol) and DMF and water mixed 2:1. Finn) Palladium (231 mg, 20.0 mol%) and sodium carbonate (95.7 mg, 0.90 mmol) were added, and then stirred at 100°C for 11 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 65 (67.0 mg, 0.19 mmol, 87%) as a yellow solid represented by the following formula 1-65. yield) was obtained.
[화학식 1-65][Formula 1-65]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 10.02 (d, J = 7.6 Hz, 1H), 7.87 (s, 1H), 7.84 (d, J = 6.4 Hz, 2H), 7.53 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.39 (s, 1H), 7.21 (m, 1H), 6.92 (t, J = 7.0 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 2.99 (s, 6H); 13C NMR(100 MHz, CDCl3) δ 183.9, 149.3, 140.9, 136.2, 130.6, 128.8, 128.7, 128.6, 128.0, 124.7, 124.3, 122.5, 121.8, 121.3, 118.1, 117.7, 113.9, 112.8, 40.7; LRMS (ESI) m/z calcd for C23H20N2O [M+Na]+ : 340.2, found : 341.2. 1H NMR (400 MHz, CDCl 3 ), δ 10.02 (d, J = 7.6 Hz, 1H), 7.87 (s, 1H), 7.84 (d, J = 6.4 Hz, 2H), 7.53 (d, J = 7.6) Hz, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.39 (s, 1H), 7.21 (m, 1H), 6.92 (t, J = 7.0 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 2.99 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.9, 149.3, 140.9, 136.2, 130.6, 128.8, 128.7, 128.6, 128.0, 124.7, 124.3, 122.5, 121.8, 121.3, 1, 117.7, 113.9, 112.8, 40.7; LRMS (ESI) m/z calcd for C 23 H 20 N 2 O [M+Na] + : 340.2, found : 341.2.
<GxF 66 ~ 70><GxF 66 ~ 70>
IN-E : 하기 반응식 15와 같이 합성하였으며, 구체적으로, 피리딘(483 μL, 6.00 mmol) 및 2-브로모-4-메톡시아세토페논(1.44 g, 6.30 mmol)이 포함된 DMF(10.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(320 μL, 3.00 mmol), 구리(II) 아세테이트 모노하이드레이트(1.79 g, 9.00 mmol) 및 소듐 아세테이트(1.47 g, 18.0 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IN-E(467 mg, 1.44 mmol, 48.2%수율)를 수득 하였다. IN-E : Synthesized according to Scheme 15 below. Specifically, DMF (10.0 mL) containing pyridine (483 μL, 6.00 mmol) and 2-bromo-4-methoxyacetophenone (1.44 g, 6.30 mmol) was incubated at 100°C. After stirring overnight, ethyl acrylate (320 μL, 3.00 mmol), copper (II) acetate monohydrate (1.79 g, 9.00 mmol), and sodium acetate (1.47 g, 18.0 mmol) were added and incubated at 100°C for 16 hours. It was stirred for a while. After confirming that the reaction was complete by TLC, copper acetate was removed by filtration through a Celite pad, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (1 to 15% hexane containing EtOAc) to obtain compound IN-E (467 mg, 1.44 mmol, 48.2% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.90(d, J = 6.8 Hz, 1H), 8.38(d, J = 8.8 Hz, 1H), 7.85(s, 1H), 7.83(d, J = 3.2 Hz, 2H), 7.42(q, J = 9.0 Hz, 1H), 6.97(t, J = 7.0 Hz, 1H), 7.01(d, J = 8.8 Hz, 2H), 4.38(q, J = 7.1 Hz, 2H), 3.90(s, 3H), 1.40(t, J = 7.0 Hz, 3H); 13C NMR(100 MHz, CDCl3) δ 183.6, 163.6, 162.2, 139.2, 132.1, 131.0, 128.7, 127.6, 127.0, 122.3, 121.6, 119.0, 114.7, 113.5, 105.7, 60.0, 55.4, 14.7; LRMS (ESI) m/z calcd for C19H17NO4 [M+Na]+ : 323.1, found : 324.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.90 (d, J = 6.8 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 7.85 (s, 1H), 7.83 (d, J = 3.2 Hz, 2H), 7.42(q, J = 9.0 Hz, 1H), 6.97(t, J = 7.0 Hz, 1H), 7.01(d, J = 8.8 Hz, 2H), 4.38(q, J = 7.1 Hz, 2H), 3.90(s, 3H), 1.40(t, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.6, 163.6, 162.2, 139.2, 132.1, 131.0, 128.7, 127.6, 127.0, 122.3, 121.6, 119.0, 114.7, 113.5, 7, 60.0, 55.4, 14.7; LRMS (ESI) m/z calcd for C 19 H 17 NO 4 [M+Na] + : 323.1, found : 324.2.
IN-B : IN-E(467 mg, 1.44 mmol)가 포함된 메탄올(10 mL)에 KOH(4.84 g, 86.4 mmol)를 첨가한 후, 실온에서 14시간 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 흰색고체의 화합물 IN-A를 수득하였다. IN-B : KOH (4.84 g, 86.4 mmol) was added to methanol (10 mL) containing IN-E (467 mg, 1.44 mmol), and then stirred at room temperature for 14 hours. The reaction mixture was acidified by adding 6N HCl, and the resulting solid was collected through filtration, washed with water, and dried in a drying oven to obtain compound IN-A as a white solid.
수득한 화합물 IN-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IN-A이 포함된 DMF(5.0 mL)에 소듐 바이카보네이트(363 mg, 4.32 mmol)를 첨가하고 및 NBS(384 mg, 2.16 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - EA 12%)로 정제하여 황색 고체의 화합물 IN-B(350 mg, 1.06 mmol, 73.6% 수율)를 수득 하였다.The obtained compound IN-A was used in the next step without further purification. Sodium bicarbonate (363 mg, 4.32 mmol) was added to DMF (5.0 mL) containing IN-A and NBS (384 mg, 2.16 mmol). ) was added in portions at 0°C. The reaction mixture was stirred at room temperature for 12 hours, then the resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8 - EA 12%) to obtain compound IN-B (350 mg, 1.06 mmol, 73.6% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.83 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 1H), 7.34 (s, 1H), 7.18 (q, J = 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.89 (t, J = 6.8 Hz, 1H), 3.84 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 184.0, 164.1, 162.2, 139.3, 132.0, 130.9, 128.7, 127.9, 127.1, 122.3, 119.1, 114.8, 113.4, 105.3, 55.4, 51.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.83 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 1H), 7.34 ( s, 1H), 7.18 (q, J = 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.89 (t, J = 6.8 Hz, 1H), 3.84 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.0, 164.1, 162.2, 139.3, 132.0, 130.9, 128.7, 127.9, 127.1, 122.3, 119.1, 114.8, 113.4, 105.3, , 51.2.
[반응식 15][Scheme 15]
화합물 GxF 66 : Compound GxF 66 :
IN-B(50.2 mg, 0.15 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(115 mg, 0.60 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(64.4 mg, 0.60 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-66으로 표시되는 황색 고체의 화합물 GxF 66(48.2 mg, 0.12 mmol, 80.2% 수율)을 수득 하였다.IN-B (50.2 mg, 0.15 mmol), 4-trifluorophenyl boronic acid (115 mg, 0.60 mmol), and tetrakis(triphenyl phosphine) in a 2:1 mixed solution of DMF and water. Palladium (231 mg, 20.0 mol%) and sodium carbonate (64.4 mg, 0.60 mmol) were added, and then stirred at 100°C for 12 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 66 (48.2 mg, 0.12 mmol, 80.2%) as a yellow solid represented by the following formula 1-66. yield) was obtained.
[화학식 1-66][Formula 1-66]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.96 (d, J = 6.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 3H), 7.68 (s, 3H), 7.51 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 3H); 13C NMR(100 MHz, CDCl3) δ 183.8, 162.1, 138.4, 136.1, 132.8, 131.1, 129.0, 128.4, 128.1, 127.8, 126.9, 125.8(2), 125.6, 125.4, 125.1, 122.6, 117.2, 115.7, 115.6, 114.4, 113.6, 55.6; LRMS (ESI) m/z calcd for C23H16F3NO2 [M+Na]+ : 395.1, found : 396.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.96 (d, J = 6.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 3H), 7.68 (s, 3H), 7.51 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.8, 162.1, 138.4, 136.1, 132.8, 131.1, 129.0, 128.4, 128.1, 127.8, 126.9, 125.8(2), 125.6, 125.4, 1 25.1, 122.6, 117.2, 115.7, 115.6, 114.4, 113.6, 55.6; LRMS (ESI) m/z calcd for C 23 H 16 F 3 NO 2 [M+Na] + : 395.1, found : 396.1.
화합물 GxF 67 : Compound GxF 67 :
IN-B(21 mg, 0.06 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(42 mg, 0.25 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(27 mg, 0.25 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-67로 표시되는 황색 고체의 화합물 GxF 67(22.6 mg, 0.06 mmol, 97.1% 수율)을 수득 하였다.IN-B (21 mg, 0.06 mmol), 4-acetylphenyl boronic acid (42 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium ( 231 mg, 20.0 mol%) and sodium carbonate (27 mg, 0.25 mmol) were added, and then stirred at 100°C for 12 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to produce compound GxF 67 (22.6 mg, 0.06 mmol, 97.1%) as a yellow solid represented by the following formula 1-67. yield) was obtained.
[화학식 1-67][Formula 1-67]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.96 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 9.2 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.54 (s, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 3.90 (s, 3H), 2.64 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 197.1, 183.4, 161.8, 139.4, 135.7, 134.4, 132.5, 130.7, 128.7, 127.1, 125.1, 124.7, 122.4, 177.0, 115.5, 114.0, 113.3, 55.3, 26.4; LRMS (ESI) m/z calcd for C24H19NO3 [M+Na]+ : 369.1, found :370.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.96 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 9.2 Hz, 2H), 7.86 ( d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.54 (s, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 3.90 (s, 3H), 2.64 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.1, 183.4, 161.8, 139.4, 135.7, 134.4, 132.5, 130.7, 128.7, 127.1, 125.1, 124.7, 122.4, 177.0, 115. 5, 114.0, 113.3, 55.3, 26.4; LRMS (ESI) m/z calcd for C 24 H 19 NO 3 [M+Na] + : 369.1, found : 370.2.
화합물 GxF 68 : Compound GxF 68 :
IN-B(20.0 mg, 0.06 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(29.0 mg, 0.24 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(26.0 mg, 0.24 mmol)를 첨가한 후, 100℃에서 13시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-68로 표시되는 황색 고체의 화합물 GxF 68(21.8 mg, 0.06 mmol, 100% 수율)을 수득 하였다.Phenyl boronic acid (29.0 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 20.0 mol%) and sodium carbonate (26.0 mg, 0.24 mmol) were added, and then stirred at 100°C for 13 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 68 (21.8 mg, 0.06 mmol, 100%) as a yellow solid represented by the following formula 1-68. yield) was obtained.
[화학식 1-68][Formula 1-68]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.97 (d, J = 6.8 Hz, 1H), 7.87 (d, J = 6.4 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.49 (s, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.0 (d, J = 8.4 Hz, 2H), 6.92 (t, J = 6.9 Hz, 1H), 6.89 (t, J = 6.8 Hz, 1H), 3.89 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 183.5, 161.9, 136.0, 134.7, 133.2, 131.0, 128.8, 127.9, 126.4, 126.6, 124.9, 124.6, 123.9, 122.2, 118.6, 117.5, 117.3, 115.4, 114.0, 113.5, 102.3, 55.6; LRMS (ESI) m/z calcd for C22H17NO2 [M+Na]+ : 327.1, found :328.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.97 (d, J = 6.8 Hz, 1H), 7.87 (d, J = 6.4 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.49 ( s, 1 H), 7.44 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.0 (d, J = 8.4 Hz) , 2H), 6.92 (t, J = 6.9 Hz, 1H), 6.89 (t, J = 6.8 Hz, 1H), 3.89 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.5, 161.9, 136.0, 134.7, 133.2, 131.0, 128.8, 127.9, 126.4, 126.6, 124.9, 124.6, 123.9, 122.2, 118. 6, 117.5, 117.3, 115.4, 114.0, 113.5 , 102.3, 55.6; LRMS (ESI) m/z calcd for C 22 H 17 NO 2 [M+Na] + : 327.1, found : 328.2.
화합물 GxF 69 : Compound GxF 69 :
IN-B(20.8 mg, 0.06 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(38.0 mg, 0.25 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(26.7 mg, 0.25 mmol)를 첨가한 후, 100℃에서 13시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-69로 표시되는 황색 고체의 화합물 GxF 69(22.6 mg, 0.06 mmol, 100% 수율)을 수득 하였다.IN-B (20.8 mg, 0.06 mmol), 4-methoxyphenyl boronic acid (38.0 mg, 0.25 mmol), and tetrakis(triphenylphosphine)palladium in a 2:1 mixture of DMF and water. (231 mg, 20.0 mol%) and sodium carbonate (26.7 mg, 0.25 mmol) were added, and then stirred at 100°C for 13 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 69 (22.6 mg, 0.06 mmol, 100%) as a yellow solid represented by the following formula 1-69. yield) was obtained.
[화학식 1-69][Formula 1-69]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.96 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.42 (s, 1H), 7.19 (m, J = 8.2 Hz, 1H), 6.99 (dd, J = 8.8 Hz, 4H), 6.93 (t, J = 6.8 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 183.7, 162.1, 158.6, 136.2, 133.6, 131.3, 129.3, 129.1, 127.5, 124.9, 124.7, 122.4, 117.8, 117.4, 114.6, 114.2, 113.8, 55.9, 55.8; LRMS (ESI) m/z calcd for C23H19NO3 [M+Na]+ : 357.14, found : 358.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.96 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 7.6 Hz, 1H), 7.48 ( d, J = 8.8 Hz, 2H), 7.42 (s, 1H), 7.19 (m, J = 8.2 Hz, 1H), 6.99 (dd, J = 8.8 Hz, 4H), 6.93 (t, J = 6.8 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.7, 162.1, 158.6, 136.2, 133.6, 131.3, 129.3, 129.1, 127.5, 124.9, 124.7, 122.4, 117.8, 117.4, 114. 6, 114.2, 113.8, 55.9, 55.8; LRMS (ESI) m/z calcd for C 23 H 19 NO 3 [M+Na] + : 357.14, found : 358.1.
화합물 GxF 70 : Compound GxF 70 :
IN-B(20.0 mg, 0.06 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(40.0 mg, 0.24 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(26.0 mg, 0.24 mmol)를 첨가한 후, 100℃에서 13시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-70으로 표시되는 황색 고체의 화합물 GxF 70(23.8 mg, 0.06 mmol, 100% 수율)을 수득 하였다.IN-B (20.0 mg, 0.06 mmol), 4-(dimethylamino)phenyl boronic acid (40.0 mg, 0.24 mmol), and tetrakis (triphenyl phosphatase) were added to a solution containing DMF and water mixed 2:1. Finn) Palladium (231 mg, 20.0 mol%) and sodium carbonate (26.0 mg, 0.24 mmol) were added, and then stirred at 100°C for 13 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 70 (23.8 mg, 0.06 mmol, 100%) as a yellow solid represented by the following formula 1-70. yield) was obtained.
[화학식 1-70][Formula 1-70]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.96 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.83 (s,1H), 7.44 (d, J = 6.8 Hz, 2H), 7.41 (s, 1H), 7.17 (dd, J = 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.90 (t, J = 6.9 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H), 2.99 (s, 6H); 13C NMR(100 MHz, CDCl3) δ 183.3, 161.8, 149.3, 136.0, 133.5, 131.1, 128.7(2), 124.4, 124.0, 122.9, 117.8, 113.8, 113.5, 113.0, 55.6, 40.9; LRMS (ESI) m/z calcd for C24H22N2O2 [M+Na]+ : 370.2, found : 371.2. 1H NMR (400 MHz, CDCl 3 ), δ 9.96 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.83 (s,1H), 7.44 (d, J = 6.8 Hz, 2H), 7.41 (s, 1H), 7.17 (dd, J = 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.90 (t, J = 6.9 Hz, 1H), 6.83 ( d, J = 8.8 Hz, 2H), 3.89 (s, 3H), 2.99 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.3, 161.8, 149.3, 136.0, 133.5, 131.1, 128.7(2), 124.4, 124.0, 122.9, 117.8, 113.8, 113.5, 113.0, 5 5.6, 40.9; LRMS (ESI) m/z calcd for C 24 H 22 N 2 O 2 [M+Na] + : 370.2, found : 371.2.
<GxF 71 ~ 75><GxF 71 ~ 75>
IO-E : 하기 반응식 16과 같이 합성하였으며, 구체적으로, 피리딘(695 μL, 6.00 mmol) 및 2-브로모-4'-(다이에틸아미노)아세토페논(1.70 mL, 6.3 mmol)이 포함된 DMF(10.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(320 μL, 3.00 mmol), 구리(II) 아세테이트 모노하이드레이트(1.79 g, 9.00 mmol) 및 소듐 아세테이트(1.47 g, 18.0 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IO-E(273 mg, 0.75 mmol, 25.0% 수율)를 수득 하였다. IO-E : Synthesized according to Scheme 16 below, specifically, DMF (10.0 mL) containing pyridine (695 μL, 6.00 mmol) and 2-bromo-4'-(diethylamino)acetophenone (1.70 mL, 6.3 mmol) ) was stirred at 100°C overnight, and then ethyl acrylate (320 μL, 3.00 mmol), copper (II) acetate monohydrate (1.79 g, 9.00 mmol), and sodium acetate (1.47 g, 18.0 mmol) were added to 100 μL, 3.00 mmol). It was stirred at ℃ for 16 hours. After confirming that the reaction was complete by TLC, copper acetate was removed by filtration through a Celite pad, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (1 to 15% hexane containing EtOAc) to obtain compound IO-E (273 mg, 0.75 mmol, 25.0% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.94 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.86 (s,2H), 7.34 (m, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 9.2 Hz, 2H), 4.41 (q, J = 7.2 Hz, 2H), 3.43 (q, J = 7.1 Hz, 4H), 1.43 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.2 Hz, 6H).; 13C NMR(100 MHz, CDCl3) δ 186.8, 156.2, 136.0, 134.4, 129.4, 128.8, 127.8, 126.5, 124.8, 124.4, 124.1, 123.0, 122.1, 120.0, 118.5, 117.5, 117.4, 115.4, 114.3, 113.9, 102.5, 27.1, 27.9; LRMS (ESI) m/z calcd for C22H24N2O3 [M+Na]+ : 364.2, found : 365.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.94 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.86 ( s,2H), 7.34 (m, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 9.2 Hz, 2H), 4.41 (q, J = 7.2 Hz, 2H), 3.43 ( q, J = 7.1 Hz, 4H), 1.43 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.2 Hz, 6H).; 13 C NMR (100 MHz, CDCl 3 ) δ 186.8, 156.2, 136.0, 134.4, 129.4, 128.8, 127.8, 126.5, 124.8, 124.4, 124.1, 123.0, 122.1, 120.0, 118. 5, 117.5, 117.4, 115.4, 114.3, 113.9 , 102.5, 27.1, 27.9; LRMS (ESI) m/z calcd for C 22 H 24 N 2 O 3 [M+Na] + : 364.2, found : 365.2.
IO-B : IO-E(273 mg, 0.74 mmol)가 포함된 메탄올(10 mL)에 KOH(4.20 g, 74.9 mmol)를 첨가한 후, 실온에서 하룻밤 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 흰색고체의 화합물 IO-A를 수득하였다. IO-B : KOH (4.20 g, 74.9 mmol) was added to methanol (10 mL) containing IO-E (273 mg, 0.74 mmol), and then stirred at room temperature overnight. The reaction mixture was acidified by adding 6N HCl, and the resulting solid was collected through filtration, washed with water, and dried in a drying oven to obtain compound IO-A as a white solid.
수득한 화합물 IO-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IO-A이 포함된 DMF(5.0 mL)에 소듐 바이카보네이트(189 mg, 2.24 mmol)를 첨가하고 및 NBS(200 mg, 1.12 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - EA 12%)로 정제하여 황색 고체의 화합물 IO-B(187 mg, 0.50 mmol, 67.3% 수율)를 수득 하였다.The obtained compound IO-A was used in the next step without further purification. Sodium bicarbonate (189 mg, 2.24 mmol) was added to DMF (5.0 mL) containing IO-A and NBS (200 mg, 1.12 mmol) ) was added in portions at 0°C. The reaction mixture was stirred at room temperature for 12 hours, then the resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8 - EA 12%) to obtain compound IO-B (187 mg, 0.50 mmol, 67.3% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.88 (d, J = 7.2 Hz, 1H), 8.03 (s, 1H), 7.83(s, 1H), 7.69 (dd, J = 8.2 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.41 (s, 1H), 7.28 (m, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.98 (t, J = 7.0 Hz, 1H), 3.25 (q, J = 6.9 Hz, 4H), 1.10 (t, J = 7.0 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 181.4, 152.2, 136.6, 135.2, 134.9, 128.6, 126.5, 125.1, 122.6, 122.0, 121.9, 120.5, 117.2, 114.6, 89.7, 46.6, 46.43, 12.8, 12.7. 1 H NMR (400 MHz, CDCl 3 ), δ 9.88 (d, J = 7.2 Hz, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 7.69 (dd, J = 8.2 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.41 (s, 1H), 7.28 (m, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.98 (t, J = 7.0 Hz, 1H), 3.25 (q, J = 6.9 Hz, 4H), 1.10 (t, J = 7.0 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 181.4, 152.2, 136.6, 135.2, 134.9, 128.6, 126.5, 125.1, 122.6, 122.0, 121.9, 120.5, 117.2, 114.6, , 46.6, 46.43, 12.8, 12.7.
[반응식 16][Scheme 16]
화합물 GxF 71 : Compound GxF 71 :
IO-B(24 mg, 0.06 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(49.0 mg, 0.25 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(27.0 mg, 0.25mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-71로 표시되는 황색 고체의 화합물 GxF 71(19.0 mg, 0.04 mmol, 72.5% 수율)을 수득 하였다.4-trifluorophenyl boronic acid (49.0 mg, 0.25 mmol) and tetrakis(triphenyl phosphine) in a solution containing IO-B (24 mg, 0.06 mmol) mixed with DMF and water at a ratio of 2:1. Palladium (231 mg, 20.0 mol%) and sodium carbonate (27.0 mg, 0.25 mmol) were added, and then stirred at 100°C for 12 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 71 (19.0 mg, 0.04 mmol, 72.5%) as a yellow solid represented by the following formula 1-71. yield) was obtained.
[화학식 1-71][Formula 1-71]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.97 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.70 (m, 6H), 7.58 (s, 1H), 7.26 (m, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.98 (m, 1H), 2.99 (q, J = 7.0 Hz, 4H), 0.98 (t, J = 7.2 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 183.9, 152.2, 136.3, 134.0, 133.7, 133.1, 130.1, 129.3(2), 129.2, 128.2(2), 126.1(2), 125.7,125.6(2), 123.0, 120.3, 117.5, 115.9, 114.6, 46.2, 30.2, 12.5; LRMS (ESI) m/z calcd for C26H23F3N2O [M+Na]+ : 436.2, found : 437.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.97 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.70 ( m, 6H), 7.58 (s, 1H), 7.26 (m, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.98 (m, 1H), 2.99 (q, J = 7.0 Hz, 4H), 0.98 (t, J = 7.2 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.9, 152.2, 136.3, 134.0, 133.7, 133.1, 130.1, 129.3(2), 129.2, 128.2(2), 126.1(2), 125.7,125.6(2), 123.0 , 120.3, 117.5, 115.9, 114.6, 46.2, 30.2, 12.5; LRMS (ESI) m/z calcd for C 26 H 23 F 3 N 2 O [M+Na] + : 436.2, found : 437.2.
화합물 GxF 72 : Compound GxF 72 :
IO-B(30.0 mg, 0.08 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(53.0 mg, 0.32 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(34.0 mg, 0.32 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - EA 40%)로 정제하여 하기 화학식 1-72로 표시되는 황색 고체의 화합물 GxF 72(18.9 mg, 0.04 mmol, 57.5% 수율)을 수득 하였다.4-acetylphenyl boronic acid (53.0 mg, 0.32 mmol), tetrakis(triphenylphosphine)palladium ( 231 mg, 20.0 mol%) and sodium carbonate (34.0 mg, 0.32 mmol) were added, and then stirred at 100°C for 12 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5 - EA 40%) to produce compound GxF 72 (18.9 mg, 0.04 mmol, 57.5%) as a yellow solid represented by the following formula 1-72. yield) was obtained.
[화학식 1-72][Formula 1-72]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.95 (d, J = 6.8 Hz, 1H), 8.05 (d, J = 7.2 Hz, 3H), 7.90 (s, 1H), 7.71 (d, J = 8.4 Hz, 3H), 7.67 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.30 (m, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.00 (m, 1H), 3.27 (q, J = 7.0 Hz, 4H), 2.65 (s, 3H), 1.13 (t, J = 7.0 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 197.1, 182.1, 150.4, 143.9, 139.3, 136.1, 135.9, 134.5, 134.1, 131.5, 128.7, 128.6, 128.4, 127.7, 127.1, 125.3, 124.6, 122.1, 121.4, 117.1, 115.7, 114.1, 45.8, 29.6, 26.6, 12.3; LRMS (ESI) m/z calcd for C27H26N2O2 [M+Na]+ : 410.2, found :411.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.95 (d, J = 6.8 Hz, 1H), 8.05 (d, J = 7.2 Hz, 3H), 7.90 (s, 1H), 7.71 (d, J = 8.4 Hz, 3H), 7.67 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.30 (m, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.00 (m, 1H), 3.27 (q, J = 7.0 Hz, 4H), 2.65 (s, 3H), 1.13 (t, J = 7.0 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.1, 182.1, 150.4, 143.9, 139.3, 136.1, 135.9, 134.5, 134.1, 131.5, 128.7, 128.6, 128.4, 127.7, 127. 1, 125.3, 124.6, 122.1, 121.4, 117.1 , 115.7, 114.1, 45.8, 29.6, 26.6, 12.3; LRMS (ESI) m/z calcd for C 27 H 26 N 2 O 2 [M+Na] + : 410.2, found : 411.2.
화합물 GxF 73 : Compound GxF 73 :
IO-B(30.0 mg, 0.08 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(39.4 mg, 0.32 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(34.0 mg, 0.32 mmol)를 첨가한 후, 100℃에서 13시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-73으로 표시되는 황색 고체의 화합물 GxF 73(22.2 mg, 0.06 mmol, 75.3% 수율)을 수득 하였다.Phenylboronic acid (39.4 mg, 0.32 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 20.0 mol%) and sodium carbonate (34.0 mg, 0.32 mmol) were added, and then stirred at 100°C for 13 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 73 (22.2 mg, 0.06 mmol, 75.3%) as a yellow solid represented by the following formula 1-73. yield) was obtained.
[화학식 1-73][Formula 1-73]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.98 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.59 (m, 3H), 7.46 (m, 2H), 7.38 (m, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.20 (m, 1H), 7.12 (dd, J = 8.2 Hz, 1H), 6.94 (d, J = 7.0 Hz, 1H), 3.01 (q, J = 4.4 Hz, 4H), 0.97 (t, J = 7.0 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 183.5, 151.4, 141.1, 135.6, 134.6, 133.0, 132.7, 128.8, 128.5, 128.3, 128.0, 127.6, 126.4, 126.1, 124.5, 124.1, 122.1, 121.1, 119.3, 117.2, 116.8, 113.6, 45.9, 45.5, 12.0; LRMS (ESI) m/z calcd for C25H24N2O [M+Na]+ : 368.2, found : 369.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.98 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.59 ( m, 3H), 7.46 (m, 2H), 7.38 (m, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.20 (m, 1H), 7.12 (dd, J = 8.2 Hz, 1H), 6.94 (d, J = 7.0 Hz, 1H), 3.01 (q, J = 4.4 Hz, 4H), 0.97 (t, J = 7.0 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.5, 151.4, 141.1, 135.6, 134.6, 133.0, 132.7, 128.8, 128.5, 128.3, 128.0, 127.6, 126.4, 126.1, 124. 5, 124.1, 122.1, 121.1, 119.3, 117.2 , 116.8, 113.6, 45.9, 45.5, 12.0; LRMS (ESI) m/z calcd for C 25 H 24 N 2 O [M+Na] + : 368.2, found : 369.2.
화합물 GxF 74 : Compound GxF 74 :
IO-B(39.5 mg, 0.10 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(65.0 mg, 0.42 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(45.0 mg, 0.42 mmol)를 첨가한 후, 100℃에서 13시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-74로 표시되는 황색 고체의 화합물 GxF 74(42.5 mg, 0.10 mmol, 100% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (65.0 mg, 0.42 mmol) and tetrakis(triphenylphosphine)palladium in a solution containing IO-B (39.5 mg, 0.10 mmol) mixed with DMF and water at a ratio of 2:1. (231 mg, 20.0 mol%) and sodium carbonate (45.0 mg, 0.42 mmol) were added, and then stirred at 100°C for 13 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 74 (42.5 mg, 0.10 mmol, 100%) as a yellow solid represented by the following formula 1-74. yield) was obtained.
[화학식 1-74][Formula 1-74]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.95 (d, J = 6.8 Hz, 1H), 7.89 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.44 (s, 1H), 7.22 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 6.8 Hz, 2H), 6.96 (t, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.26 (q, J = 7.1 Hz, 4H), 0.96 (t, J = 7.2 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 182.2, 158.4, 150.4, 136.3, 135.0, 131.8, 129.7, 129.1, 128.9, 128.0, 127.1, 124.7, 124.6, 121.8(2), 117.6, 117.4, 114.4, 114.1, 113.7, 55.5, 46.7, 45.7, 29.9, 12.6; LRMS (ESI) m/z calcd for C26H26N2O2 [M+Na]+ : 398.2, found : 399.4. 1H NMR (400 MHz, CDCl 3 ), δ 9.95 (d, J = 6.8 Hz, 1H), 7.89 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.44 (s, 1H), 7.22 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 6.8 Hz, 2H), 6.96 (t, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.26 (q, J = 7.1 Hz, 4H), 0.96 (t, J = 7.2 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 182.2, 158.4, 150.4, 136.3, 135.0, 131.8, 129.7, 129.1, 128.9, 128.0, 127.1, 124.7, 124.6, 121.8(2), 1 17.6, 117.4, 114.4, 114.1, 113.7, 55.5, 46.7, 45.7, 29.9, 12.6; LRMS (ESI) m/z calcd for C 26 H 26 N 2 O 2 [M+Na] + : 398.2, found : 399.4.
화합물 GxF 75 : Compound GxF 75 :
IO-B(73.0 mg, 0.16 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(109 mg, 0.66 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(70.0 mg, 0.66 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - EA 25%)로 정제하여 하기 화학식 1-75로 표시되는 황색 고체의 화합물 GxF 75(257.8 mg, 0.14 mmol, 84.6% 수율)을 수득 하였다.4-(dimethylamino)phenyl boronic acid (109 mg, 0.66 mmol) and tetrakis (triphenyl phosphatase) were added to a solution containing IO-B (73.0 mg, 0.16 mmol) mixed with DMF and water at a ratio of 2:1. Finn) Palladium (231 mg, 20.0 mol%) and sodium carbonate (70.0 mg, 0.66 mmol) were added, and then stirred at 100°C for 12 hours. After confirming that the reaction was complete by TLC, it was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4 - EA 25%) to produce compound GxF 75 (257.8 mg, 0.14 mmol, 84.6%) as a yellow solid represented by the following formula 1-75. yield) was obtained.
[화학식 1-75][Formula 1-75]
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR(400 MHz, CDCl3), δ 9.95 (d, J = 6.8 Hz, 1H), 7.89 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 8.4 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.43 (s, 1H), 7.20 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 6.8 Hz, 1H), 6.84 (d, J = 6.8 Hz, 2H), 3.26 (q, J = 7.1 Hz, 4H), 3.00 (s, 6H), 1.12 (t, J = 7.0 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 197.5, 197.2, 183.5, 151.8, 146.4, 139.7, 135.9, 135.4, 134.7, 133.6, 133.1, 132.7, 129.7, 129.0, 128.9, 128.7, 128.5, 127.4, 125.3, 124.7, 122.7, 119.8, 117.3, 115.7, 114.2, 45.8, 26.8, 12.2; LRMS (ESI) m/z calcd for C27H29N3O [M+Na]+ : 411.2, found : 412.3. 1H NMR (400 MHz, CDCl 3 ), δ 9.95 (d, J = 6.8 Hz, 1H), 7.89 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 8.4 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.43 (s, 1H), 7.20 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 6.8 Hz, 1H), 6.84 (d, J = 6.8 Hz, 2H), 3.26 (q, J = 7.1 Hz, 4H), 3.00 (s, 6H), 1.12 ( t, J = 7.0 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.5, 197.2, 183.5, 151.8, 146.4, 139.7, 135.9, 135.4, 134.7, 133.6, 133.1, 132.7, 129.7, 129.0, 128. 9, 128.7, 128.5, 127.4, 125.3, 124.7 , 122.7, 119.8, 117.3, 115.7, 114.2, 45.8, 26.8, 12.2; LRMS (ESI) m/z calcd for C 27 H 29 N 3 O [M+Na] + : 411.2, found : 412.3.
75종의 GxF 물질들의 광물리학적 특성 확인Confirmation of photophysical properties of 75 types of GxF materials
본 발명에서는 상기 실시예 1에서 합성한 75종의 GxF 물질들에 대한 광물리학적 특성을 관찰하였다. In the present invention, the 75 types synthesized in Example 1 above Photophysical properties of GxF materials were observed.
최종 형광 화합물의 UV 흡수는 UV-VISIBLE 스펙트로포토미터(JASCO V-670, JASCO, INC. 일본)를 이용하여 측정하였으며, 여기 형광 발광파장은 JASCO 형광 스펙트로포토미터(JASCO FP-8200, JASCO, INC. 일본)를 이용하여 측정하였다. 양자 수득률(absolute quantum yield)은 Absolute PL 양자 수득률 측정 시스템(QE-2000, Otsuka Electronics, Japan)에 의해 측정하였다.The UV absorption of the final fluorescent compound was measured using a UV-VISIBLE spectrophotometer (JASCO V-670, JASCO, INC. Japan), and the excitation fluorescence emission wavelength was measured using a JASCO fluorescence spectrophotometer (JASCO FP-8200, JASCO, INC. was measured using . Japan). Quantum yield (absolute quantum yield) was measured by the Absolute PL quantum yield measurement system (QE-2000, Otsuka Electronics, Japan).
(T: Trifluoromethyl, A: Acetyl, H: Hydrogen, TP:4-trifluoromethylphenyl, C: Methyl, MP: 4-methoxyphenyl, DEP: 4-Diethylaminophenyl, M: Methoxy, DM: dimethylamino, L: solution state, S: solid state, λA: Absorption maxima, λE: Emission maxima, ε: extinction coefficient (x104) in solution state, Φ: quantum yield (%) in solution state, H: HOMO energy level (ev), L: LUMO energy level (ev), gap: energy gap between LUMO 및 HOMO (ev))(T: Trifluoromethyl, A: Acetyl, H: Hydrogen, T P :4-trifluoromethylphenyl, C: Methyl, M P : 4-methoxyphenyl, DE P : 4-Diethylaminophenyl, M: Methoxy, DM: dimethylamino, L: solution state , S: solid state, λ A : Absorption maxima, λ E : Emission maxima, ε: extinction coefficient (x10 4 ) in solution state, Φ: quantum yield (%) in solution state, H: HOMO energy level (ev), L: LUMO energy level (ev), gap: energy gap between LUMO and HOMO ( ev))
상기 표 1에 나타난 바와 같이, GxF 물질들은 발광파장이 416 nm에서 620 nm에 이르는 전 가시광선 영역을 아우르는 것을 확인하였고, 특히 도 5에 나타난 바와 같이 고체상 형광현상을 (solid state fluorescence) 나타낼 수 있다는 것을 확인하였다.As shown in Table 1 above, GxF materials were confirmed to have an emission wavelength spanning the entire visible light range from 416 nm to 620 nm, and in particular, as shown in Figure 5, they can exhibit solid state fluorescence. confirmed.
또한, GxF 물질 중, GxF 1, GxF 3, GxF 5 및 GxF 11 화합물들의 고체상태 형광 현상을 관찰한 결과, 도 5b 및 도 5c에 나타난 바와 같이, GxF 화합물들은 응집발광유도 현상을 나타낼수 있는 것을 확인하였으며, GxF 1의 경우 119.5배, GxF 3의 경우 18.3배, GxF 5의 경우 28.8배 및 GxF 11의 경우 41.3배로 형광이 증가한 것으로 확인되었다 (도 5d). In addition, as a result of observing the solid-state fluorescence phenomenon of GxF 1, GxF 3, GxF 5, and GxF 11 compounds among GxF materials, as shown in FIGS. 5b and 5c, it was found that GxF compounds can exhibit a coherent luminescence induction phenomenon. It was confirmed that the fluorescence increased 119.5 times for GxF 1, 18.3 times for GxF 3, 28.8 times for GxF 5, and 41.3 times for GxF 11 (Figure 5d).
또한, 수용액 조건에서(THF/Water mixture 1:9) GxF 화합물의 응집형상 및 광물리적 특성을 동적광산란광도계(Dynamic light scattering: DLS) 장비를 이용하여 측정한 결과, GxF 1, GxF 3, GxF 5 및 GxF 11은 응집이 유도되고 그 크기가 2 ~ 500 nm 정도되는 것을 확인하였다 (도 6 및 표 2).In addition, the aggregate shape and photophysical properties of the GxF compound were measured in aqueous solution conditions (THF/Water mixture 1:9) using a dynamic light scattering (DLS) equipment, and the results were GxF 1, GxF 3, and GxF 5. and GxF 11, it was confirmed that aggregation was induced and the size was about 2 to 500 nm (Figure 6 and Table 2).
나아가, GxF 1 및 GxF 63 물질에 대한 x-선 회절 분석법을 이용한 단분자 구조분석(A) 및 결정구조 분석(B)을 수행하였으며(도 7), 분석결과는 하기 표 3에 나타내었다.Furthermore, single molecule structural analysis (A) and crystal structure analysis (B) using x-ray diffraction analysis were performed on GxF 1 and GxF 63 materials (FIG. 7), and the analysis results are shown in Table 3 below.
GxF 1 및 GxF 63의 단결정 구조는 10 ㎖의 메탄올(methanol)과 디클로로메탄(dichloromethane)(3:7의 부피비)에 녹아 있는 용액을 35℃ 오븐에서 이틀동안 건조시키는 slow evaporation 방법을 사용하여 수득하였다. 용매가 모두 증발하고 나서 얻어진 결정은 걸러서 수득하고 이를 헥산(hexane)으로 세척하였다 (G. M. Shleldrick, Acta Cryst. 2015, C71, 3-8).The single crystal structures of GxF 1 and GxF 63 were obtained using a slow evaporation method in which a solution dissolved in 10 ml of methanol and dichloromethane (volume ratio of 3:7) was dried in an oven at 35°C for two days. . After all the solvents had evaporated, the obtained crystals were filtered and washed with hexane (GM Shleldrick, Acta Cryst . 2015, C71, 3-8).
용매 비율 및 종류에 따른 형광 강도 변화 관찰Observe changes in fluorescence intensity depending on solvent ratio and type
본 발명에서는 GxF 화합물에 대해 용매 비율 및 종류에 따른 형광 강도 변화를 관찰하였다. In the present invention, changes in fluorescence intensity of the GxF compound were observed depending on the solvent ratio and type.
구체적으로, 테트라하이드로퓨란(THF)/헥산(Hexane) 비율에 따른 발색 현상 변화 및 헥산(Hexane), 테트라하이드로퓨란(THF), 아세토니트릴(Acetonitrile; ACN) 및 DMSO과 같이 용매 종류에 따른 형광 강도 변화를 확인하였다. Specifically, the change in color development according to the tetrahydrofuran (THF)/hexane ratio and the fluorescence intensity according to the type of solvent such as hexane, tetrahydrofuran (THF), acetonitrile (ACN), and DMSO. Changes were confirmed.
형광발광 파장 및 강도 변화는 JASCO FP-8200 분광형광계(spectrofluorometer)를 사용하여 측정하였고, 절대발광효율은 QE-2000 (Otsuka Electronics)를 사용하였으며, UV-Vis 흡광파장은 JASCO V-670 분광형광계를 사용하여 관측하였다. 모든 실험은 1x1 cm 석영큐벳을 사용하였다. 각 물질들은 테트라하이드로퓨란(THF), 아세토니트릴(Acetonitrile; ACN) 및 DMSO 혹은 서로다른 헥산 비율을 지니는 테트라하이드로퓨란(THF)/헥산(Hexane) 혼합액에 20 uM의 농도로 녹여 측정되었다. 테트라하이드로퓨란(THF)/헥산(Hexane) 비율에 따른 발색 현상 변화 관찰을 위하여 헥산의 비율은 부피비를 기준으로 0%에서 100% 까지 10% 단위로 증가시켜 가며 관측하였다.Fluorescent emission wavelength and intensity changes were measured using a JASCO FP-8200 spectrofluorometer, absolute luminous efficiency was measured using a QE-2000 (Otsuka Electronics), and UV-Vis absorption wavelength was measured using a JASCO V-670 spectrofluorometer. It was observed using All experiments used 1x1 cm quartz cuvettes. Each substance was measured by dissolving it in tetrahydrofuran (THF), acetonitrile (ACN), DMSO, or tetrahydrofuran (THF)/hexane mixtures with different hexane ratios at a concentration of 20 uM. To observe changes in color development according to the tetrahydrofuran (THF)/hexane ratio, the ratio of hexane was observed by increasing it in 10% increments from 0% to 100% based on the volume ratio.
THF/Hexane 비율에 따른 용매의존 발색 현상의 변화를 관찰한 결과, Hexane 비율이 높을 수록 형광 강도가 증가하였으며(도 8), 용매 종류에 따른 형광 강도의 변화를 확인한 결과, Hexane을 용매로 사용하는 경우 다른 용매에 비해 형광세기가 현저하게 높은 것을 확인하였다 (도 9).As a result of observing the change in solvent-dependent color development according to the THF/Hexane ratio, the fluorescence intensity increased as the Hexane ratio increased (Figure 8). As a result of confirming the change in fluorescence intensity according to the type of solvent, it was found that hexane was used as a solvent. In this case, it was confirmed that the fluorescence intensity was significantly higher than that of other solvents (Figure 9).
미토콘드리아 타겟물질-GxF 물질 복합체 제조Manufacture of mitochondrial target material-GxF material complex
본 발명에서는 미토콘드리아 타겟을 위한 미토콘드리아 타겟물질-GxF 물질 복합체를 제조하였으며, 미토콘드리아 타겟물질로 TPP를 사용하였다. In the present invention, a mitochondrial target material-GxF material complex was prepared for mitochondrial targeting, and TPP was used as the mitochondrial target material.
<TPP-GxF><TPP-GxF>
TPP-GxF는 도 10의 방법으로 합성하였으며, 구체적인 방법은 하기와 같다.TPP-GxF was synthesized by the method shown in Figure 10, and the specific method is as follows.
화합물 1: 실시예 1에서 합성한 IM-B(200.0 mg, 0.7 mmol)이 포함된 DMF 및 H2O 혼합액(v:v = 10:1)에 4-메톡시카르보닐보론산(4-methoxycarbonyl boronic acid, 359.7 mg, 2.0 mmol), 테트라키스(트리페닐포스핀)팔라듐(tetrakis(triphenylphosphine)palladium, 154.1 mg, 0.13 mmol) 및 소듐나트륨(sodium carbonate, 352.8 mg, 3.33 mmol)을 첨가한 다음, 반응혼합물은 아르곤 조건으로 100℃에서 8시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 다음, 반응 혼합물을 진공에서 농축하고 조생성물을 DCM 및 물로 분산시킨 후, 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA:Hexane = 1:9 - EA 20%)로 정제하여 황색 고체의 화합물 1(155.2 mg, 65.6 %수율)을 수득 하였다. Compound 1 : 4-methoxycarbonylboronic acid (4-methoxycarbonyl) was added to a mixture of DMF and H 2 O (v:v = 10:1) containing IM-B (200.0 mg, 0.7 mmol) synthesized in Example 1. boronic acid, 359.7 mg, 2.0 mmol), tetrakis(triphenylphosphine)palladium (154.1 mg, 0.13 mmol), and sodium carbonate (352.8 mg, 3.33 mmol) were added, The reaction mixture was stirred at 100°C for 8 hours under argon conditions. After confirming that the reaction was complete by TLC, the reaction mixture was concentrated in vacuo, the crude product was dispersed with DCM and water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA:Hexane = 1:9 - EA 20%) to obtain Compound 1 (155.2 mg, 65.6% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR (600 MHz, CDCl3) δ 10.05 (td, J = 4.2 Hz, 1.2 Hz, 1H), 8.11 (td, J = 5.1 Hz, 1.8 Hz, 2H), 7.93 (td, J = 5.1 Hz, 1.2 Hz, 1H), 7.86 -7.84 (m, 2H), 7.65 (dt, J = 5.1 Hz, 1.8 Hz, 2H), 7.58 (tt, J = 7.2 Hz, 1.8 Hz, 1H), 7.31 (td, J = 6.0 Hz, 3H), 7.35- 7.32 (m, 1H), 7.05 (td, J = 6.9 Hz, 1.8 Hz, 1H), 3.95 (s, 3H); 13C NMR (150 MHz, CDCl3), δ 184.2, 140.3, 136.9, 131.2, 128.9(2), 128.8(3), 127.2, 125.3, 117.3(3), 114.6, 89.7; LRMS (ESI) m/z calcd for C23H18NO3 [M+H]+ : 356.12, found : 356.07. 1 H NMR (600 MHz, CDCl 3 ) δ 10.05 (td, J = 4.2 Hz, 1.2 Hz, 1H), 8.11 (td, J = 5.1 Hz, 1.8 Hz, 2H), 7.93 (td, J = 5.1 Hz, 1.2 Hz, 1H), 7.86 -7.84 (m, 2H), 7.65 (dt, J = 5.1 Hz, 1.8 Hz, 2H), 7.58 (tt, J = 7.2 Hz, 1.8 Hz, 1H), 7.31 (td, J = 6.0 Hz, 3H), 7.35-7.32 (m, 1H), 7.05 (td, J = 6.9 Hz, 1.8 Hz, 1H), 3.95 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ), δ 184.2, 140.3, 136.9, 131.2, 128.9(2), 128.8(3), 127.2, 125.3, 117.3(3), 114.6, 89.7; LRMS (ESI) m/z calcd for C 23 H 18 NO 3 [M+H] + : 356.12, found : 356.07.
화합물 2: 화합물 1(20 mg, 56 μmol) 및 수산화칼륨(potassium hydroxide, 94.7 mg, 1.7 mmol)을 1.0mL의 메탄올에 녹인 후, 환류조건에서 5시간 동안 교반하였다. TLC로 반응이 완료되었음을 확인한 후, 반응 혼합물을 실온으로 냉각시키고 6N HCL을 혼합물에 천천히 첨가하였다. 생성된 침전물을 여과로 수득하고 물로 세척한 다음, 조생성물인 화합물 2를 추가 정제 없이 다음 반응에 사용하였다. Compound 2 : Compound 1 (20 mg, 56 μmol) and potassium hydroxide (94.7 mg, 1.7 mmol) were dissolved in 1.0 mL of methanol and stirred for 5 hours under reflux conditions. After confirming that the reaction was complete by TLC, the reaction mixture was cooled to room temperature and 6N HCL was slowly added to the mixture. The resulting precipitate was obtained by filtration and washed with water, and then the crude product, Compound 2, was used in the next reaction without further purification.
화합물 3: 화합물 2(145.3 mg, 0.43 mmol)가 포함된 DMF에 TEA (118.7 μL, 0.85 mmol)를 첨가하고 생성된 혼합물을 주위온도(ambient temperature)에서 30분 동안 교반하였다. 상기 반응 혼합물에 N-(tertbutoxycarbonyl)-1,2-diaminoethane(100.2 μL, 0.64 mmol) 및 PyBOP(443.1mg, 0.85 mmol)를 첨가하고, 혼합물을 주위온도에서 교반하였다. TLC로 반응이 완료되었음을 확인한 다음, 생성된 조생성물을 물로 세척하고, 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA:Hexane = 9:1 - EA 90%)로 정제하여 황색 고체의 화합물 3(131.5 mg, 63.2 % 수율)을 수득 하였다. Compound 3 : TEA (118.7 μL, 0.85 mmol) was added to DMF containing Compound 2 (145.3 mg, 0.43 mmol), and the resulting mixture was stirred at ambient temperature for 30 minutes. N-(tertbutoxycarbonyl)-1,2-diaminoethane (100.2 μL, 0.64 mmol) and PyBOP (443.1 mg, 0.85 mmol) were added to the reaction mixture, and the mixture was stirred at ambient temperature. After confirming that the reaction was complete by TLC, the resulting crude product was washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA:Hexane = 9:1 - EA 90%) to obtain Compound 3 (131.5 mg, 63.2% yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR (600 MHz, CDCl3) δ 10.01 (d, J = 12.0 Hz, 1H), 7.88 (d, J = 12.0 Hz 3H), 7.86 (d, J = 6.0 Hz, 1H), 7.82 (d, J = 6.0 Hz, 2H), 7.58 (d, J = 6.0 Hz, 2H), 7.55 (t, J = 6.0 Hz, 2H), 7.49 (t, J = 6.0 Hz, 1H), 7.47 (s, 1H), 7.31 (brs, 1H), 7.27 (t, J = 6.0 Hz, 1H), 7.00 (t, J = 6.0 Hz, 1H), 5.09 (s, 1H), 3.57 (q, J = 6.0 Hz, 2H), 3.42 (q, J = 6.0 Hz, 2H), 3.63 (s, 9H); 13C NMR (150 MHz, CDCl3), δ 184.8, 171.3, 167.5, 140.7, 138.0, 136.5, 131.2, 129.2, 129.0, 128.4, 127.8, 127.7, 122.6, 117.5, 116.5, 114.6, 80.0, 42.3, 40.1, 28.5(2), 28.4(2), 21.1, 14.3; LRMS (ESI) m/z calcd for C29H30N3O4 [M+H]+ : 484.22, found : 484.15. 1H NMR (600 MHz, CDCl 3 ) δ 10.01 (d, J = 12.0 Hz, 1H), 7.88 (d, J = 12.0 Hz 3H), 7.86 (d, J = 6.0 Hz, 1H), 7.82 (d, J = 6.0 Hz, 2H), 7.58 (d, J = 6.0 Hz, 2H), 7.55 (t, J = 6.0 Hz, 2H), 7.49 (t, J = 6.0 Hz, 1H), 7.47 (s, 1H) , 7.31 (brs, 1H), 7.27 (t, J = 6.0 Hz, 1H), 7.00 (t, J = 6.0 Hz, 1H), 5.09 (s, 1H), 3.57 (q, J = 6.0 Hz, 2H) , 3.42 (q, J = 6.0 Hz, 2H), 3.63 (s, 9H); 13 C NMR (150 MHz, CDCl 3 ), δ 184.8, 171.3, 167.5, 140.7, 138.0, 136.5, 131.2, 129.2, 129.0, 128.4, 127.8, 127.7, 122.6, 117.5, .5, 114.6, 80.0, 42.3, 40.1, 28.5(2), 28.4(2), 21.1, 14.3; LRMS (ESI) m/z calcd for C 29 H 30 N 3 O 4 [M+H] + : 484.22, found : 484.15.
화합물 4: 화합물 3(231.4 mg, 0.48 mmol)이 포함된 DCM에 1,4-디옥산(1,4-dioxane)이 포함된 4 M HCl 4 mL 을 첨가한 다음, 생성된 반응 혼합물을 주위온도에서 1시간 동안 교반하였다. 용매를 감압하에 증발시킨 후, 조생성물인 화합물 3를 추가 정제 없이 다음 반응에 사용하였다. Compound 4 : Add 4 mL of 4 M HCl containing 1,4-dioxane to DCM containing Compound 3 (231.4 mg, 0.48 mmol), then cool the resulting reaction mixture to ambient temperature. It was stirred for 1 hour. After the solvent was evaporated under reduced pressure, the crude product, Compound 3, was used in the next reaction without further purification.
TPP-GxF: (5-카르복시펜틸)트리페닐 포스핀 브로마이드((5-carboxypentyl)triphenyl phosphine bromide, 10.4 mg, 0.02 mmol) 및 DIPEA(14.4 μL, 0.08 mmol) 가 포함된 DMF (200 μL)에 화합물 4(10.0 mg, 0.02 mmol) 및 PyBOP(21.5 mg, 0.04 mmol)를 첨가한 다음, 반응 혼합물을 주위온도에서 교반시켰다. TLC로 반응이 완료되었음을 확인한 후, 반응 혼합물을 실리카-겔 플래쉬 컬럼 크로마토그래피(Water:ACN = 0 ~ 100 %)로 정제하여 황색 고체의 TPP-GxF(2.3 mg, 14.7 % 수율)를 수득 하였다. TPP-GxF : Compound in DMF (200 μL) containing (5-carboxypentyl)triphenyl phosphine bromide (10.4 mg, 0.02 mmol) and DIPEA (14.4 μL, 0.08 mmol) 4 (10.0 mg, 0.02 mmol) and PyBOP (21.5 mg, 0.04 mmol) were added and the reaction mixture was stirred at ambient temperature. After confirming that the reaction was complete by TLC, the reaction mixture was purified by silica-gel flash column chromatography (Water:ACN = 0 ~ 100 %) to obtain TPP-GxF (2.3 mg, 14.7 % yield) as a yellow solid.
NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.
1H NMR (600 MHz, CDCl3) δ 9.98 (d, J = 6.0 Hz, 1H),7.93 - 7.89 (m, 3H), 7.81 - 7.75 (m, 6H), 7.66 - 7.60 (m, 15H), 7.42 (t, J = 6.0 Hz, 1H), 7.37 (s, 1H), 7.15 (t, J = 12.0 Hz, 1H), 3.53 (t, J = 6.0 Hz, 2H), 3.44 (t, J = 6.0 Hz, 2H), 3.32 - 3.31 (quin, 6H), 3.18 - 3.13 (m, 2H); 13C NMR (150 MHz, CDCl3), δ 184.9, 175.0 (2), 168.6 (2), 162.4, 162.2, 161.9, 140.4, 137.8 136.7, 134.9 (5), 134.8, 133.5 (2), 133.4 (3), 133.3 (3), 133.2, 132.0, 130.2, 130.1, 130.0 (5), 128.7, 128.2 (2), 127.8 (3), 127.3 (2), 127.2 (3), 118.7, 118.1 (2), 117.7, 116.3 (2), 115.8, 63.2, 38.7 (3), 37.4, 35.2, 29.0; LRMS (ESI) m/z calcd for C48H46N3O3P+ [M+H]+ : 743.32, found : 743.23. 1 H NMR (600 MHz, CDCl 3 ) δ 9.98 (d, J = 6.0 Hz, 1H), 7.93 - 7.89 (m, 3H), 7.81 - 7.75 (m, 6H), 7.66 - 7.60 (m, 15H), 7.42 (t, J = 6.0 Hz, 1H), 7.37 (s, 1H), 7.15 (t, J = 12.0 Hz, 1H), 3.53 (t, J = 6.0 Hz, 2H), 3.44 (t, J = 6.0 Hz, 2H), 3.32 - 3.31 (quin, 6H), 3.18 - 3.13 (m, 2H); 13 C NMR (150 MHz, CDCl 3 ), δ 184.9, 175.0 (2), 168.6 (2), 162.4, 162.2, 161.9, 140.4, 137.8 136.7, 134.9 (5), 134.8, 133.5 (2), 133.4 ( 3 ), 133.3 (3), 133.2, 132.0, 130.2, 130.1, 130.0 (5), 128.7, 128.2 (2), 127.8 (3), 127.3 (2), 127.2 (3), 118.7, 118.1 (2), 117.7 , 116.3 (2), 115.8, 63.2, 38.7 (3), 37.4, 35.2, 29.0; LRMS (ESI) m/z calcd for C 48 H 46 N 3 O 3 P + [M+H] + : 743.32, found : 743.23.
TPP-GxF 복합체를 이용한 세포 이미징Cell imaging using TPP-GxF complex
본 발명에서는 상기 실시예 4에서 제조한 TPP-GxF 복합체가 살아있는 세포 내 미토콘드리아를 타겟으로 하여 응집유도발광 현상이 일어나는지 확인하였다. In the present invention, it was confirmed whether the TPP-GxF complex prepared in Example 4 targets mitochondria in living cells and causes aggregation-induced luminescence.
먼저, 미토콘드리아 표적 황색 형광 단백질인 Mito-YFP를 안정적으로 과발현하는 세포(Human Chang Liver cell)를 10% FBS, 1% NEAA, 및 25.0 μg/mL G418이 포함된 DMEM 배지에서 37℃, 5% CO2 조건으로 배양하였다. 배양된 세포는 TrypLE™Express(GIBCO)를 이용하여 수확한 다음, 신선한 배양 배지에 현탁시켰으며, 1 × 104 개 세포를 공초점 디쉬(SPL)에 접종하고 48시간 동안 배양하였다. First, cells (Human Chang Liver cells) stably overexpressing Mito-YFP, a mitochondria-targeting yellow fluorescent protein, were cultured in DMEM medium containing 10% FBS, 1% NEAA, and 25.0 μg/mL G418 at 37°C and 5% CO. Cultured under 2 conditions. Cultured cells were harvested using TrypLE™Express (GIBCO), then suspended in fresh culture medium, and 1 × 10 4 cells were inoculated into a confocal dish (SPL) and cultured for 48 hours.
세포내 미토콘드리아 염색을 위해 다양한 농도의 TPP-GxF를 첨가하였으며, 별도의 세척과정 없이 도립형광현미경(inverted fluorescence microscope, DMi8, LEICA)을 이용하여 세포를 관찰하였다. To stain intracellular mitochondria, various concentrations of TPP-GxF were added, and cells were observed using an inverted fluorescence microscope (DMi8, LEICA) without a separate washing process.
DAPI channel은 325 ~ 375 nm exciter 및 435 ~ 485 nm emitter 조건으로, DAPI channel is under the conditions of 325 ~ 375 nm exciter and 435 ~ 485 nm emitter.
GxF channel은 460 ~ 500 nm exciter 및 512 ~ 542 nm emitter 조건으로,GxF channel is under the conditions of 460 ~ 500 nm exciter and 512 ~ 542 nm emitter,
YFP channel은 541 ~ 551 nm exciter 및 565 ~ 605 nm emitter 조건으로 관찰하였으며, ImageJ(National Institutes of Health) 소프트웨어로 이미지를 분석하였다.The YFP channel was observed under 541 ~ 551 nm exciter and 565 ~ 605 nm emitter conditions, and images were analyzed using ImageJ (National Institutes of Health) software.
세포에 TPP-GxF 복합체를 처리한 후, 별도의 세척과정 없이 형광정도를 관찰한 결과, 미토콘드리아 내 발현물질인 Mito-YFP와 마찬가지로 TPP-GxF 복합체가 세포 내 미토콘드리아에 염색되는 것을 확인하였으며, Mito-YFP 및 TPP-GxF 복합체의 형광이 동일한 위치에서 관찰되는 것을 확인하였다 (도 11 및 도 12).After treating the cells with the TPP-GxF complex, the fluorescence level was observed without a separate washing process. As a result, it was confirmed that the TPP-GxF complex stained the mitochondria within the cell, similar to Mito-YFP, which is expressed in the mitochondria, and Mito- It was confirmed that the fluorescence of YFP and TPP-GxF complex was observed at the same location (Figures 11 and 12).
또한, 시간의 흐름에 따른 형광 정도를 관찰한 결과, TPP-GxF 복합체는 세포에 처리 1분 후에 형광이 관찰되는 것을 확인하였으며(도 13), 농도에 따른 TPP-GxF 복합체를 세포에 처리한 결과, TPP-GxF 복합체는 낮은 농도 뿐만 아니라, 높은 농도에서도 높은 형광을 보이는 것을 확인하였다 (도 14). In addition, as a result of observing the level of fluorescence over time, it was confirmed that fluorescence of the TPP-GxF complex was observed 1 minute after treatment on the cells (Figure 13), and the results of treating the cells with the TPP-GxF complex according to concentration , it was confirmed that the TPP-GxF complex showed high fluorescence not only at low concentrations but also at high concentrations (Figure 14).
Claims (10)
[화학식 1]
상기 화학식 1에서,
상기 R1은 수소; 트리플루오로메틸기(Trifluoromethyl); 아세틸기; 메톡시기; 또는 다이메틸아민기이고, 상기 R2는 메틸; 트리플루오로메틸페 닐기; 페닐기; 메톡시페닐기; 또는 다이에틸아민페닐기이며, 상기 R3는 수소; 트리 플루오로메틸기(Trifluoromethyl); 또는 아세틸기이다.
A composition for aggregation-induced luminescence comprising a compound represented by the following formula (1):
[Formula 1]
In Formula 1,
R 1 is hydrogen; Trifluoromethyl; Acetyl group; methoxy group; or a dimethylamine group, and R 2 is methyl; trifluoromethylphenyl group; phenyl group; methoxyphenyl group; or a diethylamine phenyl group, and R 3 is hydrogen; Trifluoromethyl; Or it is an acetyl group.
[화학식 1-1]
[화학식 1-3]
[화학식 1-5]
[화학식 1-11]
.
The composition for aggregation-induced luminescence according to claim 1, wherein the compound is represented by at least one selected from the group consisting of Formula 1-1, Formula 1-3, Formula 1-5, and Formula 1-11:
[Formula 1-1]
[Formula 1-3]
[Formula 1-5]
[Formula 1-11]
.
The method of claim 2, wherein the compound has a high fluorescence increase rate in the following order: compound represented by Formula 1-1 > compound represented by Formula 1-11 > compound represented by Formula 1-5 > compound represented by Formula 1-3. A composition for aggregation-induced luminescence, characterized in that:
A mitochondrial targeting complex in which the compound of the aggregation-induced luminescence composition of any one of claims 1 to 3 and a mitochondrial targeting material are combined.
The method of claim 4, wherein the mitochondrial target material is triphenylphosphonium (TPP), rhodamine, rhodamine 19, rhodamine 123, siliconrhodamien-Me, JC -1 (5,5,6,6-Tetrachloro-1,1,3,3-tetraethylbenzimidazolylcarbocyanine iodide) and one lipophilic cation selected from the group consisting of MPP (N-methyl -4-phenylpyridinium); Mitochondrial targeting signal peptide (MTS) targeting the translocase of the outer membrane (TOM) and the translocase of the inner membrane (TIM); Delocalized lipophilic cations, such as dequalinium (DQA); phenylsulfonylfuroxan; guanidine; cyclic guanidine; or F-16 (4-[(1E)-2-(1H-indol-3-yl)ethenyl]-1-methyl-pyridinium iodide).
A composition for cell imaging comprising the mitochondrial targeting complex according to claim 4.
The method of claim 6, wherein the mitochondrial target material is triphenylphosphonium (TPP), rhodamine, rhodamine 19, rhodamine 123, silicon rhodamien-Me, One lipophilic cation (Lipophilic cation) selected from the group consisting of JC-1 (5,5,6,6-Tetrachloro-1,1,3,3-tetraethylb enzimidazolylcarbocyanine iodide) and MPP (N-methyl-4-phenylpyrid inium). cation); Mitochondrial targeting signal peptide (MTS) targeting the translocase of the outer membrane (TOM) and the translocase of the inner membrane (TIM); Delocalized lipophilic cations, such as dequalinium (DQA); phenylsulfonylfuroxan; guanidine; cyclic guanidine; Or a composition for cell imaging, characterized in that it is F-16 (4-[(1E)-2-(1H-indol-3-yl)ethenyl]-1-me thyl-pyridinium iodide).
A kit for cell imaging comprising the mitochondrial targeting complex according to claim 4.
A cell imaging method comprising the step of contacting the mitochondrial targeting complex according to claim 4 with a cell.
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