【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% |
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 |