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【结 构 式】 
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【分子编号】16136 【品名】N-Methyl-1,2-phenylenediamine; N(1)-methyl-1,2-benzenediamine; N-(2-aminophenyl)-N-methylamine 【CA登记号】4760-34-3 |
【 分 子 式 】C7H10N2 【 分 子 量 】122.16988 【元素组成】C 68.82% H 8.25% N 22.93% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The acylation of 4-amino-3-methylbenzoic acid methyl ester (I) with butyryl chloride (II) in hot chlorobenzene gives the corresponding amide (III), which is nitrated with HNO3/H2SO4 yielding 4-butyramido-3-methyl-5-nitrobenzoic acid methyl ester (IV). The hydrogenation of (IV) with H2 over Pd/C in methanol affords the expected amino compound (V), which is cyclized in refluxing acetic acid to 2-propyl-4-methylbenzimidazole-6-carboxylic acid methyl ester (VI). The hydrolysis of (VI) with NaOH in refluxing methanol/water affords the corresponding free acid (VII), which is cyclized with N-methyl-o-phenylenediamine (VIII) by means of polyphosphoric acid (PPA) at 150 C, giving 4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazole (IX). The condensation of (IX) with 4'-(bromomethyl)biphenyl-4-carboxylic acid tert-butyl ester (X) by means of potassium tert-butoxide in DMSO yields the tert-butyl ester (XI), which is finally hydrolyzed with trifluoroacetic acid.
| 【1】 Merlos, M.; Casas, A.; Castaner, J.; Telmisartan. Drugs Fut 1997, 22, 10, 1112. |
| 【2】 Hauel, N.; Narr, B.; Ries, U.; Van Meel, J.; Wienen, W.; Entzeroth, M. (Dr. Karl Thomae GmbH); Benzimidazoles, medicaments containing them and process for their preparation. DE 4103492; DE 4117121; EP 0502314; EP 0543263; JP 1992346978 . |
| 【3】 Ries, U.J.; Mihm, G.; Narr, B.; Hasselbach, K.M.; Wittneben, H.; Entzeroth, M.; van Meel, J.C.A.; Wienen, W.; Hauel, N.H.; 6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: Synthesis, biological activity, and structure-activity relationships. J Med Chem 1993, 36, 25, 4040-51. |
| 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) | 16129 | methyl 4-amino-3-methylbenzoate | C9H11NO2 | 详情 | 详情 | |
| (II) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 16131 | methyl 4-(butyrylamino)-3-methylbenzoate | C13H17NO3 | 详情 | 详情 | |
| (IV) | 16132 | methyl 4-(butyrylamino)-3-methyl-5-nitrobenzoate | C13H16N2O5 | 详情 | 详情 | |
| (V) | 16133 | methyl 3-amino-4-(butyrylamino)-5-methylbenzoate | C13H18N2O3 | 详情 | 详情 | |
| (VI) | 16134 | methyl 4-methyl-2-propyl-1H-benzimidazole-6-carboxylate | C13H16N2O2 | 详情 | 详情 | |
| (VII) | 16135 | 4-methyl-2-propyl-1H-benzimidazole-6-carboxylic acid | C12H14N2O2 | 详情 | 详情 | |
| (VIII) | 16136 | N-Methyl-1,2-phenylenediamine; N(1)-methyl-1,2-benzenediamine; N-(2-aminophenyl)-N-methylamine | 4760-34-3 | C7H10N2 | 详情 | 详情 |
| (IX) | 16137 | 4-Methyl-6-(1-methylbenzaimidazol-2-yl)-2-propyl-1H-benzimidazole | C19H20N4 | 详情 | 详情 | |
| (X) | 16138 | tert-butyl 4'-(bromomethyl)[1,1'-biphenyl]-2-carboxylate | 114772-40-6 | C18H19BrO2 | 详情 | 详情 |
| (XI) | 16139 | 4'-[4-Methyl-6-(1-methylbenzaimidazol-2-yl)-2-propylbenzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid tert-butyl ester | C37H38N4O2 | 详情 | 详情 |