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【结 构 式】 
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【药物名称】YM-31472 【化学名称】2-Butyl-4-(3,N-dimethyl-2-butenamido)-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazole-5-carboxylic acid 1-(ethoxycarbonyloxy)ethyl ester 【CA登记号】149586-24-3 【 分 子 式 】C33H39N7O6 【 分 子 量 】629.72208 |
【开发单位】Yamanouchi (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Angiotensin AT1 Antagonists |
合成路线1
The reaction of ethyl valerimidate hydrochloride (I) with cyanamide in ethanol yielded cyanoimidate (II), which was converted into the cyanoimidoylglycine (IV) on treatment with glycine ethyl ester (III) and triethylamine. Alkylation of (IV) with the biphenyl derivative (V) in the presence of 1 mole of NaH in DMF gave the intermediate cyanoamidine (VI), which, by further addition of half an equivalent of sodium hydride was cyclized to the imidazole (VII). Acylation of (VII) with 3,3-dimethylacryloyl chloride (VIII) in cold pyridine yielded amide (IX), and then N-alkylation with iodomethane and sodium hydride in DMF provided (X). Acidic treatment with acetic acid in refluxing ethanol removed the trityl group to give (XI).
| 【1】 Okazaki, T.; et al.; Studies on nonpeptide angiotensin II receptor antagonists. IV. Synthesis and biological evaluation of 4-acrylamide-1H-imidazole derivatives. Chem Pharm Bull 1998, 46, 6, 973. |
| 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) | 15120 | ethyl pentanimidoate | C7H15NO | 详情 | 详情 | |
| (II) | 17804 | ethyl N-cyanopentanimidoate | C8H14N2O | 详情 | 详情 | |
| (III) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (IV) | 17806 | ethyl 2-(pentanimidoylamino)acetate | C10H17N3O2 | 详情 | 详情 | |
| (V) | 65045 | 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1-trityl-1H-1,2,3,4-tetraazole | C33H25BrN4 | 详情 | 详情 | |
| (VI) | 17808 | ethyl 2-(pentanimidoyl[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)acetate | C43H41N7O2 | 详情 | 详情 | |
| (VII) | 17809 | ethyl 4-amino-2-butyl-1-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylate | C43H41N7O2 | 详情 | 详情 | |
| (VIII) | 17810 | 3-methyl-2-butenoyl chloride; 3,3-Dimethylacryloyl chloride | 3350-78-5 | C5H7ClO | 详情 | 详情 |
| (IX) | 17811 | ethyl 2-butyl-4-[(3-methyl-2-butenoyl)amino]-1-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylate | C48H47N7O3 | 详情 | 详情 | |
| (X) | 17812 | ethyl 2-butyl-4-[methyl(3-methyl-2-butenoyl)amino]-1-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylate | C49H49N7O3 | 详情 | 详情 | |
| (XI) | 17813 | ethyl 2-butyl-4-[methyl(3-methyl-2-butenoyl)amino]-1-[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylate | C30H35N7O3 | 详情 | 详情 |
合成路线2
The alkaline hydrolysis of the ester group of (XI) yielded acid (XII). Tetrazole ring was then protected by alkylation with trityl chloride to the trityl derivative (XIII), which was then converted to the potassium salt (XIV) with ethanolic KOH. Alkylation of the potassium salt with 1-iodoethyl ethyl carbonate (XV) in acetone provided the acetaldehyde acylal (XVI), and final deprotection of trityl group with ethanolic acetic acid furnished the target compound (1).
| 【1】 Okazaki, T.; et al.; Studies on nonpeptide angiotensin II receptor antagonists. IV. Synthesis and biological evaluation of 4-acrylamide-1H-imidazole derivatives. Chem Pharm Bull 1998, 46, 6, 973. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 17813 | ethyl 2-butyl-4-[methyl(3-methyl-2-butenoyl)amino]-1-[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylate | C30H35N7O3 | 详情 | 详情 | |
| (XII) | 17814 | 2-butyl-4-[methyl(3-methyl-2-butenoyl)amino]-1-[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylic acid | C28H31N7O3 | 详情 | 详情 | |
| (XIII) | 17815 | 2-butyl-4-[methyl(3-methyl-2-butenoyl)amino]-1-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylic acid | C47H45N7O3 | 详情 | 详情 | |
| (XIV) | 17816 | 2-Butyl-4-[N-methyl-N-(3-methyl-2-butenoyl)amino]-1-[2'-[1-(tribenzyl)-1H-tetrazol-5-yl]biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylic acid potassium salt | C47H44KN7O3 | 详情 | 详情 | |
| (XV) | 17817 | ethyl 1-iodoethyl carbonate | C5H9IO3 | 详情 | 详情 | |
| (XVI) | 17818 | 1-[(ethoxycarbonyl)oxy]ethyl 2-butyl-4-[methyl(3-methyl-2-butenoyl)amino]-1-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylate | C52H53N7O6 | 详情 | 详情 |