CN108341778B - Synthetic method of phenanthridinone compound - Google Patents
Synthetic method of phenanthridinone compound Download PDFInfo
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- 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
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- C07—ORGANIC CHEMISTRY
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- 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
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- C07—ORGANIC CHEMISTRY
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- 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
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Abstract
The invention relates to a synthesis method of phenanthridinone compounds, which comprises the steps of carrying out carbon-hydrogen bond and nitrogen-hydrogen bond activation cyclization reaction on benzamide with a guide group and a phenylalkyne precursor under the combined action of a catalyst, inorganic base, an additive, a solvent and oxygen to generate a phenanthridinone compound core skeleton, and then removing the guide group to synthesize the phenanthridinone compounds. Compared with the prior art, the method adopts a cheap and easily-obtained copper catalyst which is environment-friendly, rare metals such as ruthenium, rhodium, palladium and the like are avoided in the reaction process, the substrates have diversity, the reaction conditions are mild, the repeatability is good, the method can be used for synthesizing phenanthridinone natural products such as Phenaglydon, Crinasiadine and the like, a new idea is provided for the synthesis of phenanthridinone compounds and the synthesis of lycopodium alkaloid natural products, and the application prospect is good.
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)
1. A synthesis method of phenanthridinone compounds is characterized by comprising 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): 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 benzamide with the guiding group has a chemical structural formula as follows:
the chemical structural formula of the benzyne precursor is as follows:
the chemical structural formula of the phenanthridinone compound core skeleton is as follows:
the chemical structural formula of the phenanthridinone compound is as follows:
wherein R is1Selected from H, alkyl, cycloalkyl, aryl containing substituent, heterocyclic radical containing substituent, halogen, nitro or cyano;
R2selected from H, alkyl, cycloalkyl, aryl containing substituent, heterocyclic radical containing substituent or halogen;
R3selected from 8-quinolyl, 5-chloro-8-quinolyl and 5-methoxy-8-quinolyl;
the catalyst in the step (1) is one of copper acetate or copper acetate pentahydrate, the additive is one of tetrabutylammonium bromide or tetrabutylammonium iodide, and the inorganic base is one of cesium fluoride or potassium fluoride.
2. The method for synthesizing phenanthridinone compounds according to claim 1, wherein the organic solvent A in step (1) comprises one or more of N, N-dimethylformamide, acetonitrile, toluene or tetrahydrofuran, and the solvent B in step (2) is formed by mixing acetonitrile, tetrahydrofuran and water.
3. The method for synthesizing phenanthridinone compounds according to claim 1, wherein the molar ratio of the benzyne precursor in step (1) to the benzamide having the directing group is 1: 0.5-5.
4. The method for synthesizing phenanthridinone compounds according to claim 1, wherein the molar ratio of the catalyst in step (1) to the benzamide having the directing group is 0.5-2.5: 1.
5. The method for synthesizing phenanthridinone compounds according to claim 1, wherein the molar ratio of the additive in step (1) to the benzamide having a directing group is 0.2-1.5: 1.
6. The method for synthesizing phenanthridinone compounds according to claim 1, wherein the molar ratio of the inorganic base in step (1) to the benzamide having a directing group is 0.5-2: 1.
7. The method for synthesizing phenanthridinone compounds according to claim 1, wherein the temperature of the cyclization reaction in step (1) is 40-120 ℃, and the reaction time is 4-24 hours.
8. The method for synthesizing phenanthridinone compounds according to claim 1, wherein the synthetic route of the method is as follows:
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| 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 * |
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