【结 构 式】 |
【分子编号】16915 【品名】4'-methyl[1,1'-biphenyl]-2-carboxylic acid 【CA登记号】7148-03-0 |
【 分 子 式 】C14H12O2 【 分 子 量 】212.24808 【元素组成】C 79.23% H 5.7% O 15.08% |
合成路线1
该中间体在本合成路线中的序号:(XIV)3) The amidation of 4'-methylbiphenyl-2-carboxylic acid (XIV) with tert-butylamine by means of oxalyl chloride in dichloromethane gives the corresponding tert-butylamide (XV), which is brominated with N-bromosuccinimide (NBS) and benzoyl peroxide in CCl4 yielding 4'-(bromomethyl)-N-(tert-butyl)biphenyl-2-carboxamide (XVI). The condensation of (XVI) with 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (VI) by means of potassium tert-butoxide in DMA affords 1-[2'-(N-tert-butylcarbamoyl)biphenyl-4-ylmethyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (XVII), which by reaction with oxalyl chloride in dichloromethane is converted into 1-(2'-cyanobiphenyl-4-ylmethyl)-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (XVIII). The cyclization of (XVIII) with tributyltin azide in toluene gives 4-(1-hydroxy-1-methylethyl)-2-propyl 1-[2'-(5-tetrazolyl)biphenyl-4-ylmethyl]imidazole-5-carboxylic acid ethyl ester (XIX), which is finally tritiated with trityl chloride in pyridine to afford 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-[1-(triphenylmethyl)-5-tetrazolyl]biphenyl-4-ylmethyl]imidazole-5-carboxylic acid ethyl ester (VIII), already obtained.
【1】 Mizuno, M.; Sada, T.; Ikeda, M.; Fukuda, N.; Miyamoto, M.; Yanagisawa, H.; Koike, H.; Pharmacology of CS-866, a novel nonpeptide angiotensin II receptor antagonist. Eur J Pharmacol 1992, 285, 181-188. |
【2】 Graul, A.; Leeson, P.; Castañer, J.; CS-866. Drugs Fut 1997, 22, 11, 1205. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VI) | 16907 | ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate | C12H20N2O3 | 详情 | 详情 | |
(VIII) | 16909 | ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylate | C45H44N6O3 | 详情 | 详情 | |
(XIV) | 16915 | 4'-methyl[1,1'-biphenyl]-2-carboxylic acid | 7148-03-0 | C14H12O2 | 详情 | 详情 |
(XV) | 16916 | N-(tert-butyl)-4'-methyl[1,1'-biphenyl]-2-carboxamide | C18H21NO | 详情 | 详情 | |
(XVI) | 16917 | 4'-(bromomethyl)-N-(tert-butyl)[1,1'-biphenyl]-2-carboxamide | C18H20BrNO | 详情 | 详情 | |
(XVII) | 16918 | ethyl 1-([2'-[(tert-butylamino)carbonyl][1,1'-biphenyl]-4-yl]methyl)-4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate | C30H39N3O4 | 详情 | 详情 | |
(XVIII) | 16919 | ethyl 1-[(2'-cyano[1,1'-biphenyl]-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate | C26H29N3O3 | 详情 | 详情 | |
(XIX) | 16920 | ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylate | C26H30N6O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(III)2-Methoxybenzoic acid (I) was protected as the oxazoline (II). Further coupling with tolylmagnesium bromide, followed by acid hydrolysis of the oxazoline provided the intermediate biphenyl carboxylic acid (III).
【1】 Hosogai, N.; Tanaka, H.; Tomita, M.; Ohkawa, T.; Hemmi, K.; Setoi, H.; Zenkoh, O.; Synthesis and characterization of orally active nonpeptide vasopressin V2 receptor antagonists. Chem Pharm Bull 1999, 47, 4, 501. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
35657 | bromo(4-methylphenyl)magnesium | 4294-57-9 | C7H7BrMg | 详情 | 详情 | |
(I) | 13926 | 2-Methoxybenzoic acid; o-Methoxybenzoic Acid | 579-75-9 | C8H8O3 | 详情 | 详情 |
(II) | 13927 | 2-(2-Methoxyphenyl)-4,4-dimethyl-2-oxazoline; 2-(2-Methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole; 2-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl methyl ether | 57598-33-1 | C12H15NO2 | 详情 | 详情 |
(III) | 16915 | 4'-methyl[1,1'-biphenyl]-2-carboxylic acid | 7148-03-0 | C14H12O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(III)Condensation of benzodiazepinone (IV) with 4-nitrobenzoyl chloride (V) afforded amide (VI), which was alkylated with ethyl bromoacetate in the presence of NaH to give (VII). The nitro group of (VII) was reduced to aniline (VIII) using Fe and AcOH. Subsequent coupling of (VIII) with the acid chloride generated from biphenyl carboxylic acid (III) and oxalyl chloride produced the corresponding amide (IX). The ester group of (IX) was then hydrolyzed with NaOH, and the resulting carboxylic acid (X) was finally condensed with N-methylpiperazine (XI) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole as the coupling reagents.
【1】 Hosogai, N.; Tanaka, H.; Tomita, M.; Ohkawa, T.; Hemmi, K.; Setoi, H.; Zenkoh, O.; Synthesis and characterization of orally active nonpeptide vasopressin V2 receptor antagonists. Chem Pharm Bull 1999, 47, 4, 501. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 | |
(III) | 16915 | 4'-methyl[1,1'-biphenyl]-2-carboxylic acid | 7148-03-0 | C14H12O2 | 详情 | 详情 |
(IV) | 18498 | 1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one | C9H10N2O | 详情 | 详情 | |
(V) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
(VI) | 27975 | 5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one | C16H13N3O4 | 详情 | 详情 | |
(VII) | 27976 | ethyl 2-[5-(4-nitrobenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetate | C20H19N3O6 | 详情 | 详情 | |
(VIII) | 27977 | ethyl 2-[5-(4-aminobenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetate | C20H21N3O4 | 详情 | 详情 | |
(IX) | 27978 | ethyl 2-[5-(4-[[(4'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]benzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetate | C34H31N3O5 | 详情 | 详情 | |
(X) | 27979 | 2-[5-(4-[[(4'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]benzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetic acid | C32H27N3O5 | 详情 | 详情 | |
(XI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |