KR100209299B1 - New amine ring compounds - Google Patents
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- KR100209299B1 KR100209299B1 KR1019950056837A KR19950056837A KR100209299B1 KR 100209299 B1 KR100209299 B1 KR 100209299B1 KR 1019950056837 A KR1019950056837 A KR 1019950056837A KR 19950056837 A KR19950056837 A KR 19950056837A KR 100209299 B1 KR100209299 B1 KR 100209299B1
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- -1 amine ring compounds Chemical class 0.000 title claims abstract description 11
- 230000003287 optical effect Effects 0.000 claims abstract description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims abstract description 3
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 3
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 13
- 230000000845 anti-microbial effect Effects 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 5
- 239000004599 antimicrobial Substances 0.000 abstract description 4
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- PAJPWUMXBYXFCZ-UHFFFAOYSA-N 1-aminocyclopropanecarboxylic acid Chemical compound OC(=O)C1(N)CC1 PAJPWUMXBYXFCZ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 229940072132 quinolone antibacterials Drugs 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- GGIKHRPRPONWLF-UHFFFAOYSA-N 1-amino-2-ethylcyclopropane-1-carboxylic acid hydrochloride Chemical compound [Cl-].CCC1CC1([NH3+])C(O)=O GGIKHRPRPONWLF-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical class NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000012448 Lithium borohydride Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- OBMKZINZPBARIK-UHFFFAOYSA-N (1-aminocyclopropyl)methanol Chemical compound OCC1(N)CC1 OBMKZINZPBARIK-UHFFFAOYSA-N 0.000 description 1
- LVUQCTGSDJLWCE-UHFFFAOYSA-N 1-benzylpyrrolidin-2-one Chemical compound O=C1CCCN1CC1=CC=CC=C1 LVUQCTGSDJLWCE-UHFFFAOYSA-N 0.000 description 1
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- QWUVLSOOERJFLZ-UHFFFAOYSA-N benzyl N-(1-ethylcyclopropyl)carbamate Chemical compound C(C)C1(CC1)NC(=O)OCC1=CC=CC=C1 QWUVLSOOERJFLZ-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 229960002549 enoxacin Drugs 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- SBMSLRMNBSMKQC-UHFFFAOYSA-N pyrrolidin-1-amine Chemical compound NN1CCCC1 SBMSLRMNBSMKQC-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
본 발명은 다음 일반식 (Ⅰ)로 표시되며 3번 위치의 비대칭탄소로 생성되는 광학 이성질체를 포함하는 아민고리 화합물 및 그 산부가염을 제공한다.The present invention provides an amine ring compound and an acid addition salt thereof, which are represented by the following general formula (I) and contain an optical isomer produced by asymmetric carbon at position 3.
상기식중에서 X는 할로겐 원자, -OR1, 또는 -SR2이고(여기서 R1, R2는 서로 같거나 다르며 각각 수소원자 또는 탄소수 1-3개의 저급알킬리를 나타낸다.), n은 1 또는 2의 정수이다.Wherein X is a halogen atom, -OR 1 , or -SR 2 (wherein R 1 , R 2 are the same as or different from each other and each represents a hydrogen atom or lower alkylli having 1-3 carbon atoms), and n is 1 or Is an integer of 2.
본 발명에 따른 상기 일반식 (Ⅰ)의 새로운 아민고리 화합물은 항균활성을 갖는 각종 퀴놀론 유도체 화합물 제조시 도입기로 이용되는 원료화합물인 중간체로서 매우 유용하며 이러한 본 발명의 새로운 화합물을 모핵에 도입한 퀴놀론 항균제는 뛰어난 항균활성을 나타낸다.The new amine ring compound of the general formula (I) according to the present invention is very useful as an intermediate which is a raw material used as an introduction material in the preparation of various quinolone derivative compounds having antibacterial activity, and the quinolone having introduced the new compound of the present invention into the mother nucleus. Antimicrobial agents show excellent antimicrobial activity.
Description
본 발명은 다음 일반식 (Ⅰ)로 표시되는 새로운 아민 고리화합물 및 그 산부가염에 관한 것이다.The present invention relates to novel amine cyclic compounds represented by the following general formula (I) and acid addition salts thereof.
상기식 중에서 Ⅹ는 할로겐 원자, (여기서 R1, R2는 서로 같거나 다르며 각각 수소원자 또는 탄소수 1-3개의 저급알킬리를 나타낸다.), n은 1 또는 2의 정수이다.In the above formula, Ⅹ is a halogen atom (wherein R 1 and R 2 are the same as or different from each other and each represent a hydrogen atom or lower alkyl group having 1 to 3 carbon atoms), and n is an integer of 1 or 2.
일반식 (Ⅰ)로 표시되는 화합물은 3번 위치의 비대칭 탄소로 인한 광학적 이성질체를 포함한다. 따라서 이 명세서에 있어서 모든 광학 이성질체 및 그들의 혼합물은 편리상 단일구조식으로 표기한다.The compound represented by general formula (I) includes the optical isomer due to the asymmetric carbon at position 3. Accordingly, all optical isomers and mixtures thereof in the present specification are conveniently expressed as monostructure.
일반적으로 퀴놀론 카르복실산 항균제는 뛰어난 항균력과 광범위한 항균활성화합물로서 이미 널리 사용되로 있으며 그 대표적인 예로서 노플록사신, 에녹사신, 시플록사신 및 오플록사신 등이 현재 시판중에 있다.In general, the quinolone carboxylic acid antimicrobial agent is already widely used as an excellent antibacterial activity and a wide range of antimicrobial active compounds, and representative examples thereof are nofloxacin, enoxacin, cifloxacin and oploxacin.
그러나 이들 항균제의 경우 그람음성균에 대해서는 탁월한 항균력을 보여주지만 그람양성균에 대해서는 그 항균력이 현저히 떨어지고 또한 내성균 발현으로 인하여 새로운 항균제 개발이 요구되어져 왔다.However, these antimicrobial agents show excellent antimicrobial activity against gram-negative bacteria, but the antimicrobial activity against gram-positive bacteria has decreased significantly, and development of new antimicrobial agents has been required due to the expression of resistant bacteria.
이에 본 발명자들은 상술한 바와 같은 퀴놀론계 항균제의 단점을 보완하기 위해 기존의 퀴놀론 모핵의 C-7위치에 새로운 도입기를 찾아내려는 연구 결과 본 발명을 완성하게 되었다.Therefore, the present inventors have completed the present invention as a result of finding a new introducer at the C-7 position of the existing quinolone mother nucleus in order to compensate for the disadvantage of the quinolone antibacterial agent as described above.
따라서 본 발명은 퀴놀론계 항균화합물에 도입되는 매우 유용한 중간체인 상기 일반식(Ⅰ)의 새로운 아민고리 화하바물을 제공하는 데 그 목적이 있다.It is therefore an object of the present invention to provide a new amine ring hawaba of the general formula (I), which is a very useful intermediate to be introduced into a quinolone antibacterial compound.
이러한 본 발명의 새로운 상기 일반식(Ⅰ)의 화합물의 제조 방법을 살펴보면 다음의 반응식과 같이 공지의 화합물(Ⅱ)를 출발물질로 한다.Looking at the preparation method of the new compound of the general formula (I) of the present invention, known compound (II) is used as a starting material as shown in the following reaction scheme.
상기식에서 X와 n은 전술한 바와 같다.Wherein X and n are as described above.
화합물(Ⅱ)와 상기 일반식(Ⅲ)으로 표시되는 시클로프로필아민 유도체를 소디움시아노보로 하이드라이드와 같은 환원성 시약 존재하에 축합반응시켜 화합물(Ⅳ)를 제조한 다음 이것을 팔라듐 존재하에 수소 가압반응을 통하여 탈벤질화 반응을 시켜 상기 구조식 (Ⅰ)의 화합물을 얻을 수 있다.Compound (II) and the cyclopropylamine derivative represented by the above general formula (III) are condensed in the presence of a reducing reagent such as sodium cyanoborohydride to prepare compound (IV), which is then subjected to hydrogen pressurization in the presence of palladium. Debenzylation can be carried out to obtain the compound of formula (I).
상기 일반식(Ⅲ)으로 표시되는 시클로프로필아민 유도체는 공지의 출발물인 1-아미노시클로프로판카르복실산으로부터 다음의 반응과정을 거쳐 제조할 수 있다.(J. Med. Chem. 29, 1840(1986))The cyclopropylamine derivative represented by the general formula (III) can be prepared from the known starting 1-aminocyclopropanecarboxylic acid through the following reaction process. (J. Med. Chem. 29, 1840 (1986) ))
상기식에서 X는 앞에서 정의한 바와 같다.X is as defined above.
이와 같이 본 발명에 따라 제조된 상기 일반식(Ⅰ)의 새로운 아민고리 화합물은 항균활성을 갖는 각종 퀴놀론 유도체 화합물 제조시 도입기로 이용되는 원료화합물인 중간체로서 매우 유용하며 이러한 본 발명의 새로운 화합물을 모핵에 도입한 퀴놀론 항균제는 뛰어난 항균활성을 나타낸다.As described above, the new amine ring compound of the general formula (I) prepared according to the present invention is very useful as an intermediate which is a raw material used as an introducer in the preparation of various quinolone derivative compounds having antimicrobial activity. The quinolone antibacterial agent introduced into the exhibits excellent antimicrobial activity.
이하, 본 발명을 실시예로써 상세히 설명하지만 본 발명이 이들 실시예에 한정되는 것은 아니다.Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these Examples.
[실시예 1]Example 1
[1-아미노-1-히드록시케틸-시클로프로판의 제조(화합물 Ⅲ)][Production of 1-amino-1-hydroxyketyl-cyclopropane (Compound III)]
1-아미노시클로프로판카르복실산 10.2g을 에탄올 300㎖에 현탁시키고 얼음물로 냉각한 후 티오닐클로라이드 22㎖를 천천히 넣어주었다. 적가가 끝난 후 환류하에서 약 2시간 반응시켰다. 반응물을 농축 후 물로 녹이고 에틸아세테이트로 씻어 준 후 물층을 농축하여 에틸-1-아미노-시클로프로판카르복실산 염산염 16.7g을 얻었다.10.2 g of 1-aminocyclopropanecarboxylic acid was suspended in 300 ml of ethanol, cooled with ice water, and 22 ml of thionyl chloride was slowly added thereto. After the addition was completed, the reaction was performed at reflux for about 2 hours. The reaction product was concentrated, dissolved in water, washed with ethyl acetate, and the water layer was concentrated to obtain 16.7 g of ethyl-1-amino-cyclopropanecarboxylic acid hydrochloride.
이렇게 얻어진 에틸-1-아미노-시클로프로판카르복실산 염산염 33g을 포타슘 바이카보네이트 99g과 물 100㎖, 에틸아세테이트 100㎖의 혼합용매에 분산시킨 후 벤질클로로포메이트 36㎖를 천천히 넣어주었다. 반응 혼합물을 실온에서 하룻밤 반응시킨 후 에틸아세테이트로 희석하고 1N 염산수용액으로 2회, 소디움 바이카보네이트 용액으로 1회, 소금물로 2회 씻어준 후 건조하여 에틸-1-[(벤질옥시카보닐)아미노]-시클로프로판 47.6g를 얻었다.33 g of ethyl-1-amino-cyclopropanecarboxylic acid hydrochloride thus obtained was dispersed in a mixed solvent of 99 g of potassium bicarbonate, 100 ml of water and 100 ml of ethyl acetate, and then 36 ml of benzylchloroformate was slowly added thereto. The reaction mixture was allowed to react overnight at room temperature, diluted with ethyl acetate, washed twice with 1N aqueous hydrochloric acid solution, once with sodium bicarbonate solution, twice with brine, and then dried with ethyl-1-[(benzyloxycarbonyl) amino 47.6 g of] -cyclopropane were obtained.
이렇게 얻어진 에틸--[(벤질옥시카보닐)아미노]-시클로프로판 45.8g를 건조한 테트라히드로퓨란 500㎖에 녹이고 리튬보로하이드라이드(2M 테트라히드로퓨란 용액)174㎖를 주사기로 천천히 넣어주었다. 반응혼합물을 실온에서 하룻밤 반응시킨후 에테르로 희석하고 50% 초산을 천천히 넣어주면서 과량의 리튬보로하이드라이드를 분해하였다. 물로 희석 후 소디움 바이카보네이트 용액으로 3회, 소금물로 2회 씻어준 후 건조하여 29.7g의 1-벤질옥시카보닐-1-(2-히드록시메틸)시클로프로판을 얻었다.45.8 g of ethyl-[(benzyloxycarbonyl) amino] -cyclopropane thus obtained was dissolved in 500 ml of dry tetrahydrofuran and 174 ml of lithium borohydride (2M tetrahydrofuran solution) was slowly added into a syringe. The reaction mixture was allowed to react overnight at room temperature, diluted with ether, and slowly added 50% acetic acid to decompose excess lithium borohydride. After dilution with water, the mixture was washed three times with sodium bicarbonate solution and twice with brine and dried to obtain 29.7 g of 1-benzyloxycarbonyl-1- (2-hydroxymethyl) cyclopropane.
이렇게 얻어진 1-벤질옥시카보닐-1-(2-히드록시메틸)시클로프로판 20g을 메탄올 200㎖에 녹이고 10% 팔라듐 2g을 가한 후 30psi의 수소압력을 가하며 상온에서 3시간 동안 교반하였다. 반응후 남은 팔라듐을 여과하여 여과액을 농축시켜 목적화합물3.2g을 얻었다.20 g of 1-benzyloxycarbonyl-1- (2-hydroxymethyl) cyclopropane thus obtained was dissolved in 200 ml of methanol, 2 g of 10% palladium was added, and a hydrogen pressure of 30 psi was added thereto, followed by stirring at room temperature for 3 hours. The remaining palladium was filtered and the filtrate was concentrated to give 3.2 g of the target compound.
1H-NMR(CDCl3,ppm) : 1.0-1.5(d,4H) 4.1(s,2H) 7.0-7.6(bs,2H) 1 H-NMR (CDCl 3 , ppm): 1.0-1.5 (d, 4H) 4.1 (s, 2H) 7.0-7.6 (bs, 2H)
[실시예 2]Example 2
[1-벤질-3-(1-히드록시메틸시클로프로필)아미노 필롤리딘의 제조(화합물 Ⅳ)][Preparation of 1-benzyl-3- (1-hydroxymethylcyclopropyl) amino pyrrolidine (Compound IV)]
메탄올 30㎖에 N-벤질피롤리디논 1.6㎖(10mmol)과 1-아미노-1-히드록시메틸시클로프로판 1.2㎖를 가하고 실온에서 15분간 교반하였다. 여기에 소디움시아노보로하이드라이드 240㎎을 가한 후 실온에서 3시간 교반한 후 용매를 감압농축하여 제거하였다. 잔사를 칼럼크로마토그래피에 의해 분리하여 목적화합물 1.6g(70%)를 얻었다.1.6 ml (10 mmol) of N-benzylpyrrolidinone and 1.2 ml of 1-amino-1-hydroxymethylcyclopropane were added to 30 ml of methanol, and the mixture was stirred at room temperature for 15 minutes. 240 mg of sodium cyanoborohydride was added thereto, followed by stirring at room temperature for 3 hours, and then the solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain 1.6 g (70%) of the title compound.
1H-NMR(CDCl3,ppm) : 1.2(m,4H) 1.61-2.36(m,3H) 2.81-3.82(m,4H) 4.0-4.15(m,3H) 5.0-5.2(m,2H) 7.2-7.4(m,5H) 1 H-NMR (CDCl 3 , ppm): 1.2 (m, 4H) 1.61-2.36 (m, 3H) 2.81-3.82 (m, 4H) 4.0-4.15 (m, 3H) 5.0-5.2 (m, 2H) 7.2 -7.4 (m, 5H)
[실시예 3]Example 3
[3-(1-히드록시메틸시클로프로필)아미노 피롤리딘의 제조(화합물 Ⅰ)][Preparation of 3- (1-hydroxymethylcyclopropyl) amino pyrrolidine (Compound I)]
1-벤질-3-(1-히드록시메틸시클로프로필)아미노 피롤리딘 2.4g(11mmol)을 무수 에탄올 20㎖에 가하고 교반하면서 10% Pd-C 0.2g을 가하였다. 수소로 60psi의 한압을 가하고 600℃에서 6시간 동안 반응 다음 여과하고 농축하여 목적화합물 0.8g을 얻었다.(수율 50%)2.4 g (11 mmol) of 1-benzyl-3- (1-hydroxymethylcyclopropyl) amino pyrrolidine was added to 20 ml of anhydrous ethanol and 0.2 g of 10% Pd-C was added with stirring. 60 psi of hydrogen was added, the reaction was carried out at 600 ° C. for 6 hours, filtered and concentrated to obtain 0.8 g of the target compound (yield 50%).
1H-NMR(CDCl3,ppm) : 1.2(m,4H) 1.61-2.36(m,3H) 2.81-3.82(m,4H) 4.0-4.15(m,3H) 1 H-NMR (CDCl 3 , ppm): 1.2 (m, 4H) 1.61-2.36 (m, 3H) 2.81-3.82 (m, 4H) 4.0-4.15 (m, 3H)
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