CN108341778B - A kind of synthetic method of phenanthridine compound - Google Patents
A kind of synthetic method of phenanthridine compound Download PDFInfo
- Publication number
- CN108341778B CN108341778B CN201710053228.0A CN201710053228A CN108341778B CN 108341778 B CN108341778 B CN 108341778B CN 201710053228 A CN201710053228 A CN 201710053228A CN 108341778 B CN108341778 B CN 108341778B
- Authority
- CN
- China
- Prior art keywords
- phenanthridine
- compound
- benzamide
- reaction
- synthetic method
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 phenanthridine compound Chemical class 0.000 title claims abstract description 52
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthrridine Natural products C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 title claims abstract 16
- 238000010189 synthetic method Methods 0.000 title claims description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000002243 precursor Substances 0.000 claims abstract description 28
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000001301 oxygen Substances 0.000 claims abstract description 22
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- KLYCPFXDDDMZNQ-UHFFFAOYSA-N Benzyne Chemical compound C1=CC#CC=C1 KLYCPFXDDDMZNQ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000654 additive Substances 0.000 claims abstract description 9
- 230000000996 additive effect Effects 0.000 claims abstract description 9
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 6
- 230000009471 action Effects 0.000 claims abstract description 5
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 63
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 35
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- PCRAJOWHMTYSKR-UHFFFAOYSA-N iodobenzene;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.IC1=CC=CC=C1 PCRAJOWHMTYSKR-UHFFFAOYSA-N 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 3
- UMGHKWHNASPCND-UHFFFAOYSA-L copper diacetate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].CC([O-])=O.CC([O-])=O UMGHKWHNASPCND-UHFFFAOYSA-L 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims description 2
- 239000011698 potassium fluoride Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims 4
- 150000005053 phenanthridines Chemical class 0.000 claims 3
- 125000003107 substituted aryl group Chemical group 0.000 claims 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims 1
- 238000000605 extraction Methods 0.000 claims 1
- 238000005292 vacuum distillation Methods 0.000 claims 1
- 239000010949 copper Substances 0.000 abstract description 22
- RZFVLEJOHSLEFR-UHFFFAOYSA-N phenanthridone Chemical class C1=CC=C2C(O)=NC3=CC=CC=C3C2=C1 RZFVLEJOHSLEFR-UHFFFAOYSA-N 0.000 abstract description 18
- NVOXRHIABFKYOT-UHFFFAOYSA-N Crinasiadine Chemical compound C1=C2C(=O)NC3=CC=CC=C3C2=CC2=C1OCO2 NVOXRHIABFKYOT-UHFFFAOYSA-N 0.000 abstract description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 6
- 229930014626 natural product Natural products 0.000 abstract description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052802 copper Inorganic materials 0.000 abstract description 4
- 239000000758 substrate Substances 0.000 abstract description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 229910052763 palladium Inorganic materials 0.000 abstract description 3
- 229910052707 ruthenium Inorganic materials 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 241000234270 Amaryllidaceae Species 0.000 abstract description 2
- 229930013930 alkaloid Natural products 0.000 abstract description 2
- 150000002739 metals Chemical class 0.000 abstract description 2
- 229910052703 rhodium Inorganic materials 0.000 abstract description 2
- 239000010948 rhodium Substances 0.000 abstract description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 64
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 239000013078 crystal Substances 0.000 description 20
- 238000010438 heat treatment Methods 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 19
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- 238000001816 cooling Methods 0.000 description 18
- 238000007789 sealing Methods 0.000 description 18
- 238000010926 purge Methods 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- WREVVZMUNPAPOV-UHFFFAOYSA-N 8-aminoquinoline Chemical compound C1=CN=C2C(N)=CC=CC2=C1 WREVVZMUNPAPOV-UHFFFAOYSA-N 0.000 description 3
- RNKGUYMQALAAEY-UHFFFAOYSA-N 9-methyl-5h-phenanthridin-6-one Chemical compound C1=CC=C2NC(=O)C3=CC=C(C)C=C3C2=C1 RNKGUYMQALAAEY-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 239000005749 Copper compound Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001880 copper compounds Chemical class 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JVLYNPZHBKOAFC-UHFFFAOYSA-N (8-aminoquinolin-2-yl)-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C2=NC3=C(C=CC=C3N)C=C2 JVLYNPZHBKOAFC-UHFFFAOYSA-N 0.000 description 1
- OTRKQWNXRBPMIM-UHFFFAOYSA-N (8-aminoquinolin-2-yl)-(3-methoxyphenyl)methanone Chemical compound COC1=CC=CC(=C1)C(=O)C2=NC3=C(C=CC=C3N)C=C2 OTRKQWNXRBPMIM-UHFFFAOYSA-N 0.000 description 1
- KNNMJWFZDCZEDD-UHFFFAOYSA-N (8-aminoquinolin-2-yl)-(3-methylphenyl)methanone Chemical compound CC1=CC(=CC=C1)C(=O)C2=NC3=C(C=CC=C3N)C=C2 KNNMJWFZDCZEDD-UHFFFAOYSA-N 0.000 description 1
- NBRVADVARQIDJC-UHFFFAOYSA-N (8-aminoquinolin-2-yl)-(4-methylphenyl)methanone Chemical compound CC1=CC=C(C=C1)C(=O)C2=NC3=C(C=CC=C3N)C=C2 NBRVADVARQIDJC-UHFFFAOYSA-N 0.000 description 1
- OPFGXNCJSFTULV-UHFFFAOYSA-N (8-aminoquinolin-2-yl)-(4-nitrophenyl)methanone Chemical compound C1=CC2=C(C(=C1)N)N=C(C=C2)C(=O)C3=CC=C(C=C3)[N+](=O)[O-] OPFGXNCJSFTULV-UHFFFAOYSA-N 0.000 description 1
- GTKIGDZXPDCIKR-UHFFFAOYSA-N 2-phenylbenzamide Chemical class NC(=O)C1=CC=CC=C1C1=CC=CC=C1 GTKIGDZXPDCIKR-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 238000010499 C–H functionalization reaction Methods 0.000 description 1
- 238000004252 FT/ICR mass spectrometry Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical group C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 208000015606 cardiovascular system disease Diseases 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 150000004053 quinones Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/10—Aza-phenanthrenes
- C07D221/12—Phenanthridines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及一种菲啶酮类化合物的合成方法，该方法是将具有导向基团的苯甲酰胺与苯炔前体，在催化剂、无机碱、添加剂、溶剂以及氧气的共同作用下，进行碳‑氢键和氮‑氢键活化环化反应，生成菲啶酮类化合物核心骨架，再脱除导向基团，即合成菲啶酮类化合物。与现有技术相比，本发明方法采用廉价易得和环境友好的铜催化剂，反应过程避免使用稀有金属，例如，钌、铑、钯等催化剂，底物具有多样性，反应条件比较温和，可重复性好，采用本发明方法可以合成Phenaglydon、Crinasiadine等菲啶酮类天然产物，为菲啶酮类化合物的合成以及对石蒜科生物碱天然产物的合成提供了新的思路，具有很好的应用前景。The invention relates to a method for synthesizing a phenanthridine compound. The method comprises the steps of combining a benzamide with a guiding group and a benzyne precursor under the combined action of a catalyst, an inorganic base, an additive, a solvent and oxygen to form a carbon -Hydrogen bond and nitrogen-hydrogen bond activate the cyclization reaction to generate the core skeleton of the phenanthridine compound, and then remove the guiding group to synthesize the phenanthridine compound. Compared with the prior art, the method of the present invention adopts a cheap, readily available and environmentally friendly copper catalyst, and the reaction process avoids the use of rare metals, such as ruthenium, rhodium, palladium and other catalysts, the substrates are diverse, the reaction conditions are relatively mild, and the Good repeatability, the method of the invention can be used to synthesize phenanthridine natural products such as Phanalydon and Crinasiadine, which provides a new idea for the synthesis of phenanthridone compounds and the synthesis of the natural products of Amaryllidaceae alkaloids, and has good performance. application prospects.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and relates to a synthesis method of phenanthridinone compounds.
Background
The phenanthridinone alkaloid is widely existed in nature, and as a high-activity natural product, a plurality of molecules and derivatives thereof show good physiological activity in the aspects of cardiovascular system diseases, cancer resistance, antibiosis, antivirus and the like. Therefore, the development of new synthetic methods of the phenanthridinone alkaloid and derivative compounds thereof is always a hot content of organic synthetic chemistry and has wide market prospect.
In the traditional synthetic method, the adopted starting raw materials have complex synthetic steps, the yield of the synthetic route is low, the raw materials are expensive and not easy to obtain, and the variety of the synthetic products is limited. For example, the chinese patent application No. 201210566411.8 discloses a method for preparing 6(5H) -phenanthridinone derivatives by copper compound catalysis, namely, in air or a closed environment, the copper compound catalyzes 2-phenylbenzamide derivatives to perform N-arylation reaction under ligand coordination to generate 6(5H) -phenanthridinone derivatives. The Chinese patent with application number 201310195297.7 discloses a preparation method of phenanthridinone derivatives, which comprises the following steps: the catalyst is added,Adding an oxidant and a 2-aminobiaryl compound into an organic solvent, reacting for a period of time in a carbon monoxide atmosphere with one atmosphere, and performing post-treatment after the reaction is finished to obtain a phenanthridinone derivative; the catalyst is a divalent palladium catalyst. Chinese patent application No. 201510269511.8 discloses a synthesis method of phenanthridinone compounds, which comprises adding ortho-halogen aromatic amine and aryl methanol (or aromatic amine and ortho-halogen aryl methanol), ruthenium catalyst, palladium salt, nitrogen heterocyclic imidazole salt and alkali into organic solvent, adding N-halogen aromatic amine and aryl methanol into organic solvent, and reacting under reduced pressure to obtain phenanthridinone compounds2Heating under the protection of gas, and carrying out hydrogen transfer reaction and carbon-hydrogen bond activation reaction to generate the phenanthridinone compound in one step. The method provided by the invention avoids using carbon monoxide gas and noble metal catalysts, and has the advantages of mild reaction conditions, wide substrate applicability and better economy.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a method for synthesizing the phenanthridinone compound, which has the advantages of mild reaction conditions, easiness in operation, good controllability, good repeatability, cheap and easily-obtained raw materials, basically no toxicity, wide substrate application range and good economy.
The purpose of the invention can be realized by the following technical scheme:
a synthesis method of phenanthridinone compounds is characterized in that benzamide with a guide group and a benzyne precursor are subjected to carbon-hydrogen bond and nitrogen-hydrogen bond activation cyclization reaction under the combined action of a catalyst, inorganic base, an additive, a solvent and oxygen to generate a phenanthridinone compound core skeleton, and then the guide group is removed to synthesize the phenanthridinone compounds;
the benzamide with the guiding group has a chemical structural formula as follows:
the chemical structural formula of the benzyne precursor is as follows:
the phenanthridineThe chemical structural formula of the core skeleton of the ketone compound is as follows:
the chemical structural formula of the phenanthridinone compound is as follows:
wherein R is1Selected from H, alkyl, branched alkyl, cycloalkyl, aryl containing substituent, heterocyclic radical containing substituent, halogen substituent, nitro or cyano;
R2selected from H, alkyl, branched alkyl, cycloalkyl, aryl containing substituent, heterocyclic radical containing substituent or halogen substituent;
R3selected from 8-aminoquinolyl, 5-chloro-8-aminoquinolyl or 5-methoxy-8-aminoquinolyl.
A synthesis method of phenanthridinone compounds specifically comprises the following steps:
step (1): under the action of a catalyst, an additive and an organic solvent A, adding a certain amount of inorganic base into a benzyne precursor and benzamide with a guide group, carrying out carbon-hydrogen bond and nitrogen-hydrogen bond activated cyclization reaction in an oxygen atmosphere, and then carrying out reduced pressure distillation and column chromatography purification to prepare a phenanthridinone compound core framework;
step (2): and (2) reacting the phenanthridinone compound core skeleton prepared in the step (1) with boron tribromide in tetrahydrofuran at room temperature for 12-20h, dissolving the phenanthridinone compound core skeleton with a solvent B, reacting the dissolved phenanthridinone compound core skeleton with iodobenzene trifluoroacetate at 0 ℃ for 2-3h, and then extracting, distilling under reduced pressure and purifying by column chromatography to obtain the phenanthridinone compound.
The catalyst in the step (1) comprises one of copper acetate or copper acetate pentahydrate, the additive comprises one of tetrabutylammonium bromide or tetrabutylammonium iodide, and the inorganic base comprises one of cesium fluoride or potassium fluoride.
The organic solvent A in the step (1) comprises one or more of N, N-dimethylformamide, acetonitrile, toluene or tetrahydrofuran, and the solvent B in the step (2) is formed by mixing acetonitrile, tetrahydrofuran and water.
The molar ratio of the phenylalkyne precursor to the benzamide with the guiding group in the step (1) is 1: 0.5-5.
As a preferable technical scheme, the molar ratio of the phenylalkyne precursor to the benzamide with the guiding group in the step (1) is 1: 1.8-2.5.
The molar ratio of the catalyst in the step (1) to the benzamide with the guiding group is 0.5-2.5: 1.
As a preferable technical scheme, the molar ratio of the catalyst in the step (1) to the benzamide with the guiding group is 1-2: 1.
The molar ratio of the additive in the step (1) to the benzamide with the guide group is 0.2-1.5: 1.
As a preferable technical scheme, the molar ratio of the additive in the step (1) to the benzamide with the guide group is 0.5-1: 1.
The molar ratio of the inorganic base to the benzamide with the guiding group in the step (1) is 0.5-2: 1.
As a preferable technical scheme, the molar ratio of the inorganic base in the step (1) to the benzamide with the guiding group is 1.2-1.5: 1.
The temperature of the cyclization reaction in the step (1) is 40-120 ℃, and the reaction time is 4-24 h.
The synthetic route of the method is as follows:
the method adopts the design idea that cheap and easily-obtained benzamide and benzyne precursors are used as raw materials, a carbon-carbon/carbon-nitrogen bond is constructed in one step through novel carbon-hydrogen/nitrogen-hydrogen bond activation reaction under the action of a guide group and a copper catalyst, so that the phenanthridinone compound core skeleton is efficiently synthesized, then the phenanthridinone compound core skeleton is reacted with boron tribromide to convert the 5-methoxy group of quinoline into hydroxyl, then the hydroxyl is reacted with iodobenzene trifluoroacetate, and the quinoline is subjected to reactionAnd converting the quinoline into quinones for removing the guide groups to synthesize the phenanthridinone compound. A directing group R3The quinoline N in the compound can be complexed with metal copper, and simultaneously forms an N, N-bidentate ligand with N in the amide.
The benzamide with the guide group in the invention is synthesized in the laboratory: prepared by reacting acyl chloride or carboxylic acid with amine. Adding triethylamine and benzoyl chloride into a dichloromethane solution of 8-aminoquinoline at 0 ℃, and stirring for 12 hours at room temperature; or adding thionyl chloride and a catalytic amount of N, N-dimethylformamide into a dichloromethane solution of benzoic acid, refluxing for 5h at 55 ℃, distilling under reduced pressure to remove the solvent, redissolving the crude product, adding 8-aminoquinoline and triethylamine at 0 ℃, and stirring for 12h at room temperature. After the reaction is completed, quenching with saturated sodium bicarbonate, extracting with dichloromethane, washing the organic phase with water and saturated saline solution respectively, drying, distilling under reduced pressure, and purifying by column chromatography to obtain the benzamide with the guide group.
Compared with the prior art, the invention has the following characteristics:
1) the method adopts a cheap and easily-obtained copper catalyst which is environment-friendly, and rare metals such as ruthenium, rhodium and palladium catalysts are avoided in the reaction process;
2) the method has diversified substrates, and can synthesize phenanthridinone compounds with various substituents;
3) the method has the advantages of simple process steps, easy operation, mild reaction conditions and good repeatability;
4) the method can be used for synthesizing phenanthridinone natural products such as Phenaglydon, Crinasiadine and the like, provides a new thought for synthesizing phenanthridinone compounds and natural products of amaryllidaceae alkaloids, and has good application prospect.
Detailed Description
The invention is further illustrated by the following examples, which are intended only for a better understanding of the contents of the invention. Therefore, the scope of protection of the patent is not limited to these embodiments.
In the present embodiment, the hydrogen nuclear magnetic resonance spectrum of the compound (b) ((b))1H NMR) by Bruker AVANCE III HD 400; mass Spectrometry (ESI-MS) was determined by SolariX-70 FT-MS; all reagents used were commercially available reagents.
The synthesis method can prepare the phenanthridinone compound skeleton structure (Q ═ 8-aminoquinoline) shown in the formula:
example 1: preparation of Compound intermediate (I-1)
0.2mmol of 2-methyl-benzoyl-8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.07mmol of Cu (OAc)2Adding 0.24mmol of cesium fluoride, 0.1mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide and 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12h, cooling to room temperature, distilling under reduced pressure, and purifying to obtain the colorless crystal compound (I-1) with the yield of 37%.
The compound (I-1) is:
1HNMR(CDCl3,400MHz,ppm):δ8.80(dd,J＝4.2,1.7Hz,1H),8.33-8.26(m,3H),8.04-8.00(m,1H),7.77-7.73(m,2H),7.66(t,J＝7.8Hz,1H),7.44-7.41(m,1H),7.40(d,J＝7.4Hz,1H),7.21(td,J＝7.2,1.4Hz,1H),7.14(td,J＝8.5,1.6Hz,1H),6.37(dd,J＝8.2,1.0Hz,1H),2.91(s,3H)；13CNMR(CDCl3,100MHz,ppm)δ162.97,151.54,144.84,143.34,139.77,136.80,136.49,136.15,132.03,131.89,130.85,130.02,129.33,129.05,127.04,124.61,123.56,122.28,122.08,120.32,119.42,116.61,24.69；HRMS:calculated for C23H17N2O[M+H+]:337.1335；found:337.1333.
example 2: preparation of Compound intermediate (I-2)
0.2mmol of 3-methyl-benzoyl-8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.07mmol of Cu (OAc)20.24mmol of cesium fluoride, 0.1mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide, 1mL of MeCNPurging with oxygen in a bottle, sealing, heating to 80 deg.C, reacting for 12h, cooling to room temperature, distilling under reduced pressure, and purifying to obtain colorless crystal compound (I-2) with yield of 57%.
The compound (I-2) is:
1HNMR(CDCl3,400MHz,ppm):δ8.78(dd,J＝4.2,1.7Hz,1H),8.37(s,1H),8.31-8.25(m,3H),8.02(dd,J＝7.0,2.7Hz,1H),7.77-7.72(m,2H),7.63(dd,J＝8.3,1.7Hz,1H),7.42-7.39(m,1H),7.23(td,J＝8.4,2.3Hz,1H),7.15(td,J＝8.4,1.5Hz,1H),6.47(dd,J＝8.3,1.0Hz,1H),2.52(s,3H)；13CNMR(CDCl3,100MHz,ppm)δ162.20,151.50,144.76,139.36,138.22,136.43,134.21,132.11,130.72,129.94,129.47,129.00,128.66,126.90,126.02,122.96,122.52,122.03,119.41,116.95,21.53；HRMS:calculated for C23H17N2O[M+H+]:337.1335；found:337.1334.
example 3: preparation of Compound intermediate (I-3)
0.2mmol of 4-methyl-benzoyl-8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.07mmol of Cu (OAc)2Adding 0.24mmol of cesium fluoride, 0.1mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide and 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12 hours, cooling to room temperature, distilling under reduced pressure, and purifying to obtain the colorless crystal compound (I-3) with the yield of 70%.
The compound (I-3) is:
1HNMR(CDCl3,400MHz,ppm):δ8.78(dd,J＝4.2,1.7,1H),8.46(d,J＝8.1 Hz,1H),8.33(dd,J＝7.9,1.4Hz,1H),8.26(dd,J＝8.3,1.7Hz,1H),8.17(s,1H),8.02(dd,J＝7.2,2.5Hz,1H),7.78-7.72(m,2H),7.44-7.40(m,2H),7.25-7.21(m,1H),7.19-7.15(m,1H),6.47(dd,J＝8.2,1.0Hz,1H),2.60(s,3H)；13CNMR(CDCl3,100MHz,ppm)δ162.18,151.54,144.84,143.36,139.88,136.42,134.58,130.78,129.94,129.51,129.46,129.29,129.02,126.91,123.95,123.15,122.45,122.07,122.03,119.27,117.03,22.39；HRMS:calculated for C23H17N2O[M+H+]:337.1335；found:337.1334.
example 4: preparation of Compound intermediate (I-4)
0.2mmol of 3-methoxy-benzoyl-8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.07mmol of Cu (OAc)2Adding 0.24mmol of cesium fluoride, 0.1mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide and 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12 hours, cooling to room temperature, distilling under reduced pressure, and purifying to obtain the colorless crystal compound (I-4) with the yield of 73%.
The compound (I-4) is:
1HNMR(CDCl3,400MHz,ppm):δ8.79(dd,J＝4.2,1.7Hz,1H),8.30-8.23(m,3H),8.04-8.01(m,2H),7.78-7.72(m,2H),7.42-7.39(m,2H),7.25-7.20(m,1H),7.15-7.11(m,1H),6.48(dd,J＝8.3,1.0Hz,1H),3.93(s,3H)；13CNMR(CDCl3,100MHz,ppm)δ161.93,159.70,151.55,144.75,138.69,136.42,130.61,129.91,129.50,128.16,128.09,127.42,126.87,123.84,122.70,122.64,122.03,119.41,116.93,109.63,55.73；HRMS:calculated for C23H17N2O2[M+H+]:353.1284；found:353.1282.
example 5: preparation of Compound intermediate (I-5)
0.2mmol of 3-trifluoromethyl-benzoyl-8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.4mmol of Cu (OAc)2Adding 0.24mmol of cesium fluoride, 0.1mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide and 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12 hours, cooling to room temperature, distilling under reduced pressure, and purifying to obtain the colorless crystal compound (I-5) with the yield of 67%.
The compound (I-5) is:
1HNMR(CDCl3,400MHz,ppm):δ8.86(s,1H),8.79(dd,J＝4.2,1.7Hz,1H),8.49(d,J＝8.6Hz,1H),8.35(dd,J＝7.9,1.9Hz,1H),8.30(dd,J＝8.4,1.7Hz,1H),8.09-8.04(m,1H),8.02(dd,J＝8.6,1.9Hz,1H),7.80-7.75(m,2H),7.46-7.43(m,1H),7.32-7.24(m,2H),6.53(dd,J＝7.9,1.1Hz,1H)；13CNMR(CDCl3,100MHz,ppm)δ161.25,151.64,144.49,140.28,137.38,136.55,135.73,130.57,130.48,130.18,129.99,129.85,129.03,129.00,126.94,126.22,125.36,123.77,123.01,122.99,122.65,122.22,118.19,117.30；HRMS:calculated for C23H14F3N2O[M+H+]:391.1053；found:391.1049.
example 6: preparation of Compound intermediate (I-6)
0.2mmol of 3-bromo-benzoyl-8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.07mmol of Cu (OAc)2Adding 0.24mmol of cesium fluoride, 0.1mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide and 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12 hours, cooling to room temperature, distilling under reduced pressure, and purifying to obtain the colorless crystal compound (I-6), wherein the yield is 85%.
The compound (I-6) is:
1HNMR(CDCl3,400MHz,ppm):δ8.79(dd,J＝4.2,1.7Hz,1H),8.70(d,J＝2.2Hz,1H),8.30-8.28(m,2H),8.25(d,J＝8.8Hz,1H),8.08-8.03(m,1H),7.92(dd,J＝8.7,2.2Hz,1H),7.77-7.76(m,2H),7.46-7.43(m,1H),7.29-7.19(m,2H),6.49(dd,J＝8.1,1.0Hz,1H)；13CNMR(CDCl3,100MHz,ppm)δ160.94,151.61,144.54,139.61,136.54,136.01,135.92,133.44,131.93,130.64,129.99,129.75,129.63,127.63,126.95,123.95,123.18,122.89,122.26,122.19,118.61,117.20；HRMS:calculated for C22H14BrN2O[M+H+]:401.0284；found:401.0280.
example 7: preparation of Compound intermediate (I-7)
0.2mmol of 4-tert-butyl-benzoyl-8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.07mmol of Cu (OAc)2Adding 0.24mmol of cesium fluoride, 0.1mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide and 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12 hours, cooling to room temperature, distilling under reduced pressure, and purifying to obtain the colorless crystal compound (I-7) with the yield of 83%.
The compound (I-7) is:
1HNMR(CDCl3,400MHz,ppm):δ8.76(dd,J＝4.2,1.7Hz,1H),8.50(d,J＝8.4Hz,1H),8.38(t,J＝4.0,1.7Hz,2H),8.26(dd,J＝8.4,1.7Hz,1H),8.02(dd,J＝7.1,2.6Hz,1H),7.78-7.72(m,2H),7.68(dd,J＝8.4,1.8Hz,1H),7.42-7.39(m,1H),7.27-7.23(m,1H),7.19-7.15(m,1H),6.48(dd,J＝8.3,1.0Hz,1H),1.49(s,9H)；13CNMR(CDCl3,100MHz,ppm)δ162.06,156.24,151.44,144.70,139.81,136.37,136.29,134.17,130.73,129.87,129.41,129.02,128.91,126.84,126.00,123.83,122.99,122.38,121.98,119.52,118.13,117.00,35.60,31.59；HRMS:calculated forC26H23N2O[M+H+]:379.1805；found:379.1803.
example 8: preparation of Compound intermediate (I-8)
0.2mmol of 4-nitro-benzoyl-8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.07mmol of Cu (OAc)2Adding 0.24mmol of cesium fluoride, 0.1mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide and 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12 hours, cooling to room temperature, distilling under reduced pressure, and purifying to obtain the colorless crystal compound (I-8), wherein the yield is 40%.
The compound (I-8) is:
1HNMR(CDCl3,400MHz,ppm):δ9.24(d,J＝2.1Hz,1H),8.79(dd,J＝4.2,1.6Hz,1H),8.74(d,J＝8.7Hz,1H),8.42-8.36(m,2H),8.31(dd,J＝8.3,1.6Hz,1H),8.10-8.06(m,1H),7.81-7.76(m,2H),7.48-7.45(m,1H),7.35(td,J＝7.3,1.2Hz,1H),7.29(td,J＝8.4,1.6Hz,1H),6.54(dd,J＝8.2,1.0Hz,1H)；13CNMR(CDCl3,100MHz,ppm)δ160.70,151.71,150.84,144.36,140.20,136.61,135.81, 135.53,131.40,130.76,130.50,130.10,130.00,126.97,123.68,123.37,122.32,121.78,118.09,117.94,117.43；HRMS:calculated for C22H14N3O3[M+H+]:368.1030；found:368.1027.
example 9: preparation of Compound intermediate (I-9)
0.2mmol of 4-iodo-benzoyl-8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.07mmol of Cu (OAc)2Adding 0.24mmol of cesium fluoride, 0.1mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide and 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12h, cooling to room temperature, distilling under reduced pressure, and purifying to obtain the colorless crystal compound (I-9) with the yield of 80%.
The compound (I-9) is:
1HNMR(CDCl3,400MHz,ppm):δ8.79(dd,J＝4.2,1.7Hz,1H),8.75(d,J＝1.5Hz,1H),8.29-8.24(m,3H),8.07-8.02(m,1H),7.92(dd,J＝8.4,1.6Hz,1H),7.76(s,1H),7.75(d,J＝1.5Hz,1H),7.45-7.42(m,1H),7.28-7.19(m,2H),6.48(dd,J＝8.1,1.1Hz,1H)；13CNMR(CDCl3,100MHz,ppm)δ161.81,151.62,144.58,139.97,137.09,136.51,136.13,135.96,131.37,130.83,130.64,129.96,129.88,129.71,126.94,125.40,123.29,122.86,122.17,117.88,117.19,101.07；HRMS:calculated for C22H14IN2O[M+H+]:449.0145；found:449.0141.
example 10: preparation of Compound intermediate (I-10)
0.2mmol of 3,4, 5-trifluorobenzoyl-8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.07mmol of Cu (OAc)20.24mmol of cesium fluoride, 0.2mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide,Adding 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12h, cooling to room temperature, carrying out reduced pressure distillation, and purifying to obtain the colorless crystal compound (I-10), wherein the yield is 45%.
The compound (I-10) is:
1HNMR(CDCl3,400MHz,ppm):δ8.78(dd,J＝4.2,1.7Hz,1H),8.70(dt,J＝8.2,1.8Hz,1H),8.31-8.24(m,2H),8.09-8.04(m,1H),7.79-7.75(m,2H),7.47-7.44(m,1H),7.32-7.23(m,2H),6.53(dd,J＝8.2,1.2Hz,1H)；13CNMR(CDCl3,100MHz,ppm)δ159.74,151.70,144.34,139.34,136.57,135.67,130.49,130.01,129.93,127.37,127.14,126.95,123.41,122.43,122.30,121.66,117.17,116.11,112.60,112.56,112.41,112.37；HRMS:calculated for C22H12F3N2O[M+H+]:377.0896；found:377.0894.
example 11: preparation of Compound intermediate (I-11)
0.2mmol of 3, 4-dimethoxy-benzoyl-8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.07mmol of Cu (OAc)2Adding 0.24mmol of cesium fluoride, 0.1mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide and 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12 hours, cooling to room temperature, distilling under reduced pressure, and purifying to obtain the colorless crystal compound (I-11) with the yield of 92%.
The compound (I-11) is:
1HNMR(CDCl3,400MHz,ppm):δ8.80(dd,J＝4.2,1.7Hz,1H),8.28(dd,J＝8.3,1.7Hz,1H),8.21(dd,J＝8.1,1.1Hz,1H),8.06-8.01(m,1H),7.98(s,1H),7.78-7.73(m,2H),7.71(s,1H),7.44-7.41(m,1H),7.26-7.22(m,1H),7.16(td,J＝8.4,1.4Hz,1H),6.50(dd,J＝8.3,1.0Hz,1H),4.13(s,3H),4.01(s,3H)；13C NMR(CDCl3,100MHz,ppm)δ161.71,153.76,151.56,149.99,144.84,139.22,136.45,130.72,129.91,129.48,129.42,128.32,126.88,122.64,122.43,122.02,120.13,119.19,117.05,109.49,56.34,56.25；HRMS:calculated for C24H19N2O3[M+H+]:383.1390；found:383.1388.
example 12: preparation of Compound intermediate (I-12)
0.2mmol of 2-naphthoyl-8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.4mmol of Cu (OAc)2Adding 0.24mmol of cesium fluoride, 0.2mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide and 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12 hours, cooling to room temperature, distilling under reduced pressure, and purifying to obtain the colorless crystal compound (I-12) with the yield of 73%.
The compound (I-12) is:
1HNMR(CDCl3,400MHz,ppm):δ9.15(s,1H),8.99(d,J＝6.4Hz,2H),8.79(dd,J＝4.1,1.7Hz,1H),8.33(dd,J＝8.3,1.6Hz,1H),8.14-8.80(m,3H),7.99(d,J＝8.07Hz,1H),7.88(dd,J＝7.2,1.5Hz,1H),7.83(t,J＝8.0Hz,1H),7.70-7.66(m,1H),7.61-7.57(m,1H),7.46-7.41(m,2H),7.40-7.36(m,2H),6.80(s,1H)；13CNMR(CDCl3,100MHz,ppm)δ162.42,151.62,144.83,138.30,136.61,136.56,135.63,133.56,132.71,130.93,130.86,130.54,130.11,129.64,129.52,128.64,128.30,128.10,127.21,127.08,126.90,126.84,125.05,124.33,122.96,122.13,121.50,120.54,113.30；HRMS:calculated for C30H19N2O[M+H+]:423.1492；found:423.1489.
example 13: preparation of Compound intermediate (I-13)
0.2mmol of 3, 4-methylenedioxybenzoyl-8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.07mmol of Cu (OAc)2Adding 0.24mmol of cesium fluoride, 0.1mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide and 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12 hours, cooling to room temperature, distilling under reduced pressure, and purifying to obtain the colorless crystal compound (I-13) with the yield of 95%.
The compound (I-13) is:
1HNMR(CDCl3,400MHz,ppm):δ8.82(dd,J＝4.2,1.7Hz,1H),8.28(dd,J＝8.3,1.7Hz,1H),8.23(s,1H),8.22(d,J＝9.3Hz,1H),8.03(dd,J＝7.8,1.9Hz,1H),7.80-7.74(m,2H),7.45-7.42(m,1H),7.08(d,J＝8.4Hz,1H),6.30(dd,J＝4.3,1.4Hz,2H),5.93(s,1H),3.97(s,3H),3.40(s,3H)；13CNMR(CDCl3,100MHz,ppm)δ161.59,151.66,150.99,150.10,144.91,144.68,142.25,136.54,136.48,134.77,130.78,129.88,129.57,126.87,125.03,122.10,120.38,119.87,110.09,109.72,108.53,102.13,100.12,56.47,55.68,31.09；HRMS:calculated for C25H19N2O5[M+H+]:427.1288；found:427.1286.
example 14: preparation of Compound intermediate (I-14)
0.2mmol of 3, 4-dimethoxy-benzoyl-8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.07mmol of Cu (OAc)2Adding 0.24mmol of cesium fluoride, 0.1mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide and 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12 hours, cooling to room temperature, distilling under reduced pressure, and purifying to obtain the colorless crystal compound (I-14), wherein the yield is 95%.
The compound (I-14) is:
1HNMR(CDCl3,400MHz,ppm):δ8.83(dd,J＝4.2,1.7Hz,1H),8.28(dd,J＝8.4,1.7Hz,1H),8.03(dd,J＝7.9,1.8Hz,1H),7.96(s,1H),7.80-7.73(m,2H),7.56(s,1H),7.51(s,1H),7.45-7.41(m,1H),5.99(s,1H),4.13(s,3H),4.00(s,6H),3.42(s,3H)；13CNMR(CDCl3,100MHz,ppm)δ161.65,153.75,151.66,150.18,149.26,145.45,144.74,136.60,136.48,134.24,130.69,129.84,129.57,129.48,126.81,122.06,119.17,111.98,109.55,105.33,102.53,100.60,56.84,56.36,56.21,55.78；HRMS:calculated for C26H23N2O5[M+H+]:443.1601；found:443.1599.
example 15: preparation of Compound intermediate (I-15)
0.2mmol of 3, 4-methylenedioxybenzoyl-8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.07mmol of Cu (OAc)2Adding 0.24mmol of cesium fluoride, 0.1mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide and 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12 hours, cooling to room temperature, distilling under reduced pressure, and purifying to obtain the colorless crystal compound (I-15) with the yield of 49%.
The compound (I-15) is:
1HNMR(CDCl3,400MHz,ppm):δ8.82(dd,J＝4.2,1.7Hz,1H),8.28(dd,J＝8.4,1.7Hz,1H),8.05-8.01(m,1H),7.88(s,1H),7.77-7.73(m,2H),7.53(d,J＝6.1Hz,2H),7.45-7.42(m,1H),6.13(s,2H),5.96(s,1H),5.92(dd,J＝13.5,1.3Hz,2H)；13CNMR(CDCl3,100MHz,ppm)δ161.40,152.68,151.69,148.61,147.90,144.65,144.11,136.65,136.52,135.22,131.81,130.67,130.00,129.63,126.96,122.13,121.86,120.61,113.25,107.29,102.03,101.69,101.66,100.48,98.04；HRMS:calculated for C24H15N2O5[M+H+]:411.0975；found:411.0973.
example 16: preparation of Compound intermediate (I-16)
0.2mmol of 3, 4-dimethoxy-benzoyl-8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.07mmol of Cu (OAc)2Adding 0.24mmol of cesium fluoride, 0.2mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide and 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12 hours, cooling to room temperature, distilling under reduced pressure, and purifying to obtain the colorless crystal compound (I-16), wherein the yield is 95%.
The compound (I-16) is:
1HNMR(CDCl3,400MHz,ppm):δ8.81(dd,J＝4.2,1.6Hz,1H),8.31(dd,J＝8.3,1.6Hz,1H),8.10-8.05(m,1H),7.98-7.93(m,2H),7.79-7.75(m,2H),7.50-7.45(m,2H),6.30(dd,J＝12.1,7.2Hz,1H),4.14(s,3H),4.01(s,3H)；13C NMR(CDCl3,100MHz,ppm)δ161.55,154.00,151.76,150.30,144.46,136.62,135.90,130.64,130.05,130.00,128.13,126.96,124.61,122.28,119.90,110.84,110.66,109.58,106.09,105.86,103.03,56.46,56.34；HRMS:calculated for C24H17F2N2O3[M+H+]:419.1202；found:419.1199.
example 17: preparation of Phenaglydon
0.2mmol of 4-methyl-benzoyl- (5-methoxy) -8-quinolinamine, 0.4mmol of the benzyne precursor, 0.07mmol of Cu (OAc)2Adding 0.24mmol of cesium fluoride, 0.1mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide and 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12 hours, cooling to room temperature, distilling under reduced pressure, and purifying to obtain the colorless crystal compound (I), wherein the yield is 91%.
Then 0.15mmol of compound (I) and 0.8mmol of 1M boron tribromide were dissolved in tetrahydrofuran and reacted at room temperature for 16 hours. The colorless crystal compound (II) is obtained by adding 2.3mmol of iodobenzene trifluoroacetate into acetonitrile/tetrahydrofuran/water (volume ratio) which is 6:2:5 as a solvent, reacting for 2h at 0 ℃, extracting, distilling under reduced pressure and purifying, wherein the yield is 62%.
Compound (I) is:
1HNMR(CDCl3,400MHz,ppm):δ8.77(dd,J＝4.2,1.8Hz,1H),8.66(dd,J＝8.5,1.8Hz,1H),8.46(d,J＝8.1Hz,1H),8.32(dd,J＝7.9,1.6Hz,1H),8.16(s,1H),7.65(d,J＝8.2Hz,1H),7.42(dd,J＝8.1,1.0Hz,1H),7.40-7.37(m,1H),7.22(td,J＝7.2,1.3Hz,1H),7.18(td,J＝8.3,1.7Hz,1H),7.03(d,J＝8.2Hz,1H),6.56(dd,J＝8.1,1.1Hz,1H),4.10(s,3H),2.60(s,3H)；13CNMR(CDCl3,100MHz,ppm)δ162.41,155.99,151.69,145.20,143.24,140.17,134.54,131.33,130.61,129.43,129.32,128.65,123.99,123.08,122.35,122.19,122.01,121.04,119.28,117.17,104.38,56.15,22.39；HRMS:calculated for C24H19N2O2[M+H+]:367.1441；found:367.1440.
compound (II) is:
phenaglydon as known compound, relevant data and references are given here:1HNMR(CDCl3,400MHz,ppm):δ10.34(s,1H),8.48(d,J＝8.0Hz,1H),8.22(d,J＝8.0Hz,1H),8.10(s,1H),7.46(dd,J＝12.0,7.6Hz,2H),7.34-7.26(m,2H),2.60(s,3H).Ref：Rajeshkumar,V.,Lee,T.-H.&Chuang,S.-C.Palladium-catalyzed oxidative insertion of carbon monoxide to N-sulfonyl-2-aminobiaryls through C–H bond activation:access to bioactive phenanthridinone derivatives in one pot.Org.Lett.15,1468-1471(2013).
example 18: preparation of Crinasiadine
0.2mmol of 3, 4-methylenedioxy-benzoyl- (5-methoxy) -8-quinolinamine, 0.4mmol of a phenylalkyne precursor, 0.07mmol of Cu (OAc)2Adding 0.24mmol of cesium fluoride, 0.1mmol of tetrabutylammonium iodide, 1mL of N, N-dimethylformamide and 1mL of MeCN into a reaction bottle, purging with oxygen, sealing, heating to 80 ℃ for reaction for 12 hours, cooling to room temperature, distilling under reduced pressure, and purifying to obtain the colorless crystal compound (I), wherein the yield is 46%.
Then 0.15mmol of compound (I) and 0.8mmol of 1M boron tribromide were dissolved in tetrahydrofuran and reacted at room temperature for 16 hours. The colorless crystal compound (II) is obtained by adding 2.3mmol of iodobenzene trifluoroacetate into acetonitrile/tetrahydrofuran/water (volume ratio) which is 6:2:5 as a solvent, reacting for 2h at 0 ℃, extracting, distilling under reduced pressure and purifying, wherein the yield is 55%.
Compound (I) is:
1HNMR(CDCl3,400MHz,ppm):δ8.78(dd,J＝4.2,1.7Hz,1H),8.67(dd,J＝8.5,1.8Hz,1H),8.14(dd,J＝8.0,1.4,1H),7.93(s,1H),7.73(s,1H),7.65(d,J＝8.2,1H),7.41-7.38(m,1H),7.24-7.20(m,1H),7.18-7.14(m,1H),7.03(d,J＝8.2Hz,1H),6.56(dd,J＝8.2,1.1Hz,1H),6.15(s,2H),4.11(s,3H)；13CNMR(CDCl3,100MHz,ppm)δ161.70,156.03,152.56,151.75,148.48,145.16,139.40,131.52,131.36,130.57,128.61,128.51,122.85,122.40,122.20,121.90,121.09,119.24,117.15,107.47,104.37,102.08,100.85；HRMS:calculated for C24H17N2O4[M+H+]:397.1183；found:397.1184.
compound (II) is:
crinasiadine is known as a compound, relevant data and references are given here:1HNMR(CDCl3,400MHz,ppm):δ9.14(s,1H),8.01(d,J＝8.4Hz,1H),7.73(d,J＝8.4Hz,1H),7.15–7.36(m,3H),7.06(d,J＝8.1Hz,1H),6.22(s,2Η).Ref：Rajeshkumar,V.,Lee,T.-H.&Chuang,S.-C.Palladium-catalyzed oxidative insertion of carbon monoxide to N-sulfonyl-2-aminobiaryls through C–H bond activation:access to bioactive phenanthridinone derivatives in one pot.Org.Lett.15,1468-1471(2013).
the embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (8)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710053228.0A CN108341778B (en) | 2017-01-22 | 2017-01-22 | A kind of synthetic method of phenanthridine compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710053228.0A CN108341778B (en) | 2017-01-22 | 2017-01-22 | A kind of synthetic method of phenanthridine compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108341778A CN108341778A (en) | 2018-07-31 |
| CN108341778B true CN108341778B (en) | 2021-07-09 |
Family
ID=62961911
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710053228.0A Active CN108341778B (en) | 2017-01-22 | 2017-01-22 | A kind of synthetic method of phenanthridine compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108341778B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108794572B (en) * | 2017-04-27 | 2021-10-15 | 上海交通大学 | A kind of natural product Lucentamycin A total synthesis method |
| CN110857286B (en) * | 2018-08-23 | 2022-12-09 | 上海交通大学 | A kind of preparation method of small molecule yNA with biological activity |
| CN109705060B (en) * | 2019-01-16 | 2023-04-14 | 华东理工大学 | A kind of preparation method of N-(2-morpholino-5-trifluoromethylphenyl)-2-(3-methylphenoxy)propionamide |
| CN111393322B (en) * | 2020-03-24 | 2023-03-17 | 石河子大学 | Cyclization synthesis method of naphthalocyanide and derivative thereof |
| CN116554100A (en) * | 2023-02-22 | 2023-08-08 | 江苏师范大学 | A kind of palladium catalyzed method for synthesizing phenanthridinone compound |
-
2017
- 2017-01-22 CN CN201710053228.0A patent/CN108341778B/en active Active
Non-Patent Citations (3)
| Title |
|---|
| Copper-Catalyzed Intramolecular Benzylic C-H Amination for the Synthesis of Isoindolinones;Chiaki Yamamoto et al.,;《J. Org. Chem.》;20160809;第81卷;第7678页第Scheme 6，第7683页倒数第2段 * |
| Palladium-catalyzed cyclization of benzamides with arynes: application to the synthesis of phenaglydon and N-methylcrinasiadine;Sandeep Pimparkar et al.,;《Chem. Commun.》;20140818;第50卷;第12117页Scheme 1和第12118页左栏反应式 * |
| Strain-Promoted Oxidative Annulation of Arynes and Cyclooctynes with Benzamides: Palladium-Catalyzed C-H/N-H Activation for the Synthesis of N‑Heterocycles;Xianglong Peng et al.,;《Org. Lett.》;20141002;第16卷;第5355页表2，实验部分第4倒数第1段和第5页第1段 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108341778A (en) | 2018-07-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108341778B (en) | A kind of synthetic method of phenanthridine compound | |
| CN112354564B (en) | A supported copper catalyst for the preparation of substituted amine compounds and bisphenol F | |
| CN108864164B (en) | A kind of synthetic method of primary amine-directed 2-alkynyl indole compounds | |
| CN105646382A (en) | Preparation method of 1,3,5-trisubstituted 1,2,4-triazole compound | |
| CN113461629A (en) | Preparation method of 5-hydroxymethyl-oxazolidine-2-ketone compound | |
| CN116023359B (en) | Synthesis method of aminothiophene compound and aminothiophene compound | |
| CN110028451B (en) | Preparation method of fully-substituted pyrazole derivative | |
| CN103980201B (en) | A kind of preparation method of the full substituted pyrazolecarboxylic containing sulfuryl | |
| CN108675999B (en) | A method for preparing 8-(9-sulfoxide-10-dihydrophenanthrene) quinoline compounds catalyzed by copper acetate | |
| CN103044383B (en) | Method for preparing Penicillide racemate natural product | |
| CN114031556B (en) | Synthetic method for preparing 5-amino-N-aryl-3-arylpyrazole compound by green one-pot method | |
| CN113511986B (en) | Preparation method of aryl acetonitrile derivative | |
| CN113004215B (en) | A kind of synthetic method of 2,4,5-tri-substituted oxazole compounds | |
| CN111662290B (en) | A kind of benzoindolizine compound and its synthetic method | |
| CN103551193A (en) | N2 substituted 1,2,3-triazole ligand/Cu(I) composite catalyst, as well as synthesis and applications thereof | |
| CN108440438B (en) | Method for constructing 2, 4-diaryl oxazole by acetophenone compounds, ammonium persulfate and dimethyl sulfoxide | |
| CN108383779B (en) | Preparation method of 3 '-aryl-2, 2' -bipyridine-6-formamide derivative | |
| CN110526866B (en) | Synthesis method of 2-quinolinone compounds | |
| CN113072470A (en) | N-acetonitrile bis-benzenesulfonylimine derivative and preparation method and application thereof | |
| CN105418691A (en) | Method for preparing bis-ferrocenyl pyridine derivative in supercritical carbon dioxide | |
| CN113004248A (en) | Method for synthesizing carbazole compound by catalyzing hydrocarbon amination reaction with cobalt | |
| CN109912640A (en) | A kind of preparation method of 2-pyrrolidone compounds | |
| CN109970596B (en) | Method for preparing 1, 1-diiodo olefin derivative through N-propynamide trifunctional reaction | |
| CN112552235B (en) | A kind of synthetic method of 2,3-diacylquinoline compounds | |
| CN103113297A (en) | 8-aryl-1-naphthylamide compound and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |