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【结 构 式】

【分子编号】20951

【品名】2-nitrobenzoic acid;o-Nitrobenzoic acid

【CA登记号】552-16-9

【 分 子 式 】C7H5NO4

【 分 子 量 】167.12104

【元素组成】C 50.31% H 3.02% N 8.38% O 38.29%

与该中间体有关的原料药合成路线共 6 条

合成路线1

该中间体在本合成路线中的序号:(I)

The reaction of 3-nitrobenzoic acid (I) with refluxing SOCl2 gives the corresponding acyl chloride (II), which by reaction with methylamine in chloroform is converted to the methylamide (III). The reduction of (III) with H2 over RaNi in methanol yields the 3-amino-N-methylbenzamide (IV), which is finally condensed with 2-chloro-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide (V) by means of NaI and CaCO3 in hot DMF.

1 Miki, T.; Asano, M.; Hosokami, T. (Daiichi Seiyaku Co.; Ltd.); Aminobenzamide derivatives. EP 0185368 .
2 Prous, J.; Castaner, J.; DQ-2511. Drugs Fut 1989, 14, 7, 620.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 20951 2-nitrobenzoic acid;o-Nitrobenzoic acid 552-16-9 C7H5NO4 详情 详情
(II) 21099 o-nitrobenzoyl chloride; 2-nitrobenzoyl chloride 610-14-0 C7H4ClNO3 详情 详情
(III) 20953 N-methyl-2-nitrobenzamide C8H8N2O3 详情 详情
(IV) 20954 2-amino-N-methylbenzamide 4141-08-6 C8H10N2O 详情 详情
(V) 20955 2-chloro-N-(3,4-dimethoxyphenethyl)acetamide C12H16ClNO3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(I)

This compound can be prepared by two related ways: 1) The reaction of 2-nitrobenzoic acid (I) with PCl5 at 50 C gives the corresponding acyl chloride (II), which by a Friedel-Craft's condensation with benzene and AlCl3 yields 2-nitrobenzophenone (III). The reduction of (III) with H2 over Pd/C in ethanol affords 2-aminobenzophenone (IV), which is acylated with acetic anhydride sodium acetate to give 2-acetamidobenzophenone (V). The cyclization of (V) by means of sodium methoxide in refluxing ethanol yields 4-phenylquinoline-2(1H)-one (VI), which by reaction with SOCl2-DMF in hot CHCl3 is converted to 2-chloro-4-phenylquinoline (VII). Finally, this compound is condensed with N-ethylpiperazine (VIII) at 130 C. 2) Quinoline (VII) is condensed with piperazine (IX) as before to give 4-phenyl-2-(1-piperazinyl)quinoline (X), which is finally alkylated with ethyl iodide and sodium carbonate in refluxing butanone.

1 Uno, H.; Nagai, Y.; Karasawa, T.; Furukawa, K. (Dainippon Pharm. Co.; Ltd.); 2-(4-Ethyl-1-piperazinyl)-4-phenylquinoline and its salts with acids, process for their preparation and their use as antidepressant agents. DE 2912414 .
2 Uno, H.; Nagai, Y.; Hino, K.; Kawashima, K.; Oka, M.; Matsumoto, J.; A novel class of antiulcer agents. 4-Phenyl-2-(1-piperazinyl)quinolines. Chem Pharm Bull 1989, 37, 1, 110.
3 Prous, J.; Castaner, J.; AD-2646. Drugs Fut 1989, 14, 8, 735.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 20951 2-nitrobenzoic acid;o-Nitrobenzoic acid 552-16-9 C7H5NO4 详情 详情
(II) 21099 o-nitrobenzoyl chloride; 2-nitrobenzoyl chloride 610-14-0 C7H4ClNO3 详情 详情
(III) 21100 (2-nitrophenyl)(phenyl)methanone 2243-79-0 C13H9NO3 详情 详情
(IV) 21101 (2-aminophenyl)(phenyl)methanone; 2-Aminobenzophenone 2835-77-0 C13H11NO 详情 详情
(V) 21102 N-(2-benzoylphenyl)acetamide 85-99-4 C15H13NO2 详情 详情
(VI) 21103 4-phenyl-2(1H)-quinolinone C15H11NO 详情 详情
(VII) 21104 2-chloro-4-phenylquinoline C15H10ClN 详情 详情
(VIII) 14213 N-Ethylpiperazine; 1-Ethylpiperazine 5308-25-8 C6H14N2 详情 详情
(IX) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(X) 21107 4-phenyl-2-(1-piperazinyl)quinoline C19H19N3 详情 详情

合成路线3

该中间体在本合成路线中的序号:(I)

The reaction of 2-nitrobenzoic acid with SOCl2 gives the acyl chloride (II), which is condensed with D-proline (III) by means of TEA in dichloromethane yielding the acyl proline (IV). The reductive cyclization of (IV) with H2 over Pd/C in methanol affords the pyrrolobenzodiazepinedione (V). The selective reduction of the C-11 lactam group of (V) with NaBH4 and TFA in glyme gave the pyrrolobenzodiazepinone (VI), which is finally coupled with 4-[(2-phenylbenzoyl)amino]benzoyl chloride (VII) furnishing the title compound.

1 Naito, A.; Ohtake, Y.; Hasegawa, H.; et al.; Novel vasopressin V2 receptor-selective antagonists, pyrrolo[2,1-a]quinoxaline and pyrrolo[2,1-c][1,4]benzodiazepine derivatives. Bioorg Med Chem 1999, 7, 6, 1247.
2 Matsukawa, H.; Toyofuku, H.; Naito, A.; Ohtake, Y.; Saito, Y.; Naito, K. (Wakamoto Pharmaceutical Co., Ltd.); Biphenyl derivs. and medicinal compsns.. EP 0987266; WO 9843976 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 20951 2-nitrobenzoic acid;o-Nitrobenzoic acid 552-16-9 C7H5NO4 详情 详情
(II) 21099 o-nitrobenzoyl chloride; 2-nitrobenzoyl chloride 610-14-0 C7H4ClNO3 详情 详情
(III) 29552 methyl (2S)-2-pyrrolidinecarboxylate 2133-40-6 C6H11NO2 详情 详情
(IV) 36812 methyl (2S)-1-(2-nitrobenzoyl)-2-pyrrolidinecarboxylate C13H14N2O5 详情 详情
(V) 36813 (11aS)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione C12H12N2O2 详情 详情
(VI) 36814 (11aS)-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine C12H16N2 详情 详情
(VII) 36810 4-[([1,1'-biphenyl]-2-ylcarbonyl)amino]benzoyl chloride C20H14ClNO2 详情 详情
(VIII) 29797 2H-3,1-benzoxazine-2,4(1H)-dione;Isatoic anhydride;4H-3,1-Benzoxazine-2,4(1H)-dione;1,2-Dihydro-4H-3,1-benzoxazine-2,4-dione;1H-benzo[d][1,3]oxazine-2,4-dione 118-48-9 C8H5NO3 详情 详情

合成路线4

该中间体在本合成路线中的序号:(I)

The reaction of 2-nitrobenzoic acid with SOCl2 gives the acyl chloride (II), which is condensed with D-proline (III) by means of TEA in dichloromethane yielding the acyl proline (IV). The reductive cyclization of (IV) with H2 over Pd/C in methanol affords the pyrrolobenzodiazepinedione (V). The reduction of both lactam groups of (V) with LiAlH4 gave the pyrrolobenzodiazepine (VI), which is finally coupled with 4-[(2-phenylbenzoyl)amino]-benzoyl chloride (VII) furnishing the title compound.

1 Naito, A.; Ohtake, Y.; Hasegawa, H.; et al.; Novel vasopressin V2 receptor-selective antagonists, pyrrolo[2,1-a]quinoxaline and pyrrolo[2,1-c][1,4]benzodiazepine derivatives. Bioorg Med Chem 1999, 7, 6, 1247.
2 Matsukawa, H.; Toyofuku, H.; Naito, A.; Ohtake, Y.; Saito, Y.; Naito, K. (Wakamoto Pharmaceutical Co., Ltd.); Biphenyl derivs. and medicinal compsns.. EP 0987266; WO 9843976 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 20951 2-nitrobenzoic acid;o-Nitrobenzoic acid 552-16-9 C7H5NO4 详情 详情
(II) 21099 o-nitrobenzoyl chloride; 2-nitrobenzoyl chloride 610-14-0 C7H4ClNO3 详情 详情
(III) 36811 methyl (2R)-2-pyrrolidinecarboxylate C6H11NO2 详情 详情
(IV) 36807 methyl (2R)-1-(2-nitrobenzoyl)-2-pyrrolidinecarboxylate C13H14N2O5 详情 详情
(V) 36808 (11aR)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione C12H12N2O2 详情 详情
(VI) 36809 (11aR)-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine C12H16N2 详情 详情
(VII) 36810 4-[([1,1'-biphenyl]-2-ylcarbonyl)amino]benzoyl chloride C20H14ClNO2 详情 详情
(VIII) 29797 2H-3,1-benzoxazine-2,4(1H)-dione;Isatoic anhydride;4H-3,1-Benzoxazine-2,4(1H)-dione;1,2-Dihydro-4H-3,1-benzoxazine-2,4-dione;1H-benzo[d][1,3]oxazine-2,4-dione 118-48-9 C8H5NO3 详情 详情

合成路线5

该中间体在本合成路线中的序号:(I)

 

1 Moran HW. 1981. 2-Amino-3-[hydroxy (phenyl)-methyl] phenylacetic acids, esters and amides. FR 2470671
2 Walsh DA.1981. 2-Amino-3-benzoyl-phenylacetamiDErivatives, pharmaceutical compositions containing them and process for their preparation. DE 3035688(本专利为Wyeth consumerhealthcare所有)
3 Walsh DA. 1990. Antiinflammatory agents.4.Syntheses and biological evaluation of potential prodrugs of 2-amino-3-benzoylbenzeneacetic acid and 2-amincr3-(4-chlorobenzoyl) benzeneacetic acid. J Med Chem,33 (8): 2296~2304
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 20951 2-nitrobenzoic acid;o-Nitrobenzoic acid 552-16-9 C7H5NO4 详情 详情
(II) 21099 o-nitrobenzoyl chloride; 2-nitrobenzoyl chloride 610-14-0 C7H4ClNO3 详情 详情
(III) 21100 (2-nitrophenyl)(phenyl)methanone 2243-79-0 C13H9NO3 详情 详情
(IV) 21101 (2-aminophenyl)(phenyl)methanone; 2-Aminobenzophenone 2835-77-0 C13H11NO 详情 详情
(V) 66542 Acetamide,2-(methylthio)-;(Methylthio)acetamide;2-(Methylthio)acetamide 22551-24-2 C3H7NOS 详情 详情
(VI) 66543 2-Amino-3-benzoyl-alpha-(methylthio)benzeneacetamide;2-amino-3-benzoly-a-methylthio-phenylacetamide;2-Amino-3-benzoyl-alpha-(methylthio)benzeneacetamide 78281-61-5 C16H16N2O2S 详情 详情

合成路线6

该中间体在本合成路线中的序号:(I)

 

1 Prats Palacin J,Valles Plana JM.Process for the preparation of ambroxol:ES,Patent 544,291,1984.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 20951 2-nitrobenzoic acid;o-Nitrobenzoic acid 552-16-9 C7H5NO4 详情 详情
(II) 69565 trans-4-aminocyclohexyl acetate C8H15NO2 详情 详情
(III) 69566 trans-4-(2-nitrobenzamido)cyclohexyl acetate C15H18N2O5 详情 详情
(IV) 40342 4-[(2-aminobenzyl)amino]cyclohexanol C13H20N2O 详情 详情
Extended Information