【结 构 式】 |
【分子编号】16912 【品名】(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 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 【CA登记号】 |
【 分 子 式 】C48H44N6O6 【 分 子 量 】800.9142 【元素组成】C 71.98% H 5.54% N 10.49% O 11.99% |
合成路线1
该中间体在本合成路线中的序号:(XI)The cyclization of trimethyl orthobutyrate (I) with (Z)-2,3-diaminobutenedinitrile (II) gives 2-propylimidazole-4,5-dicarbonitrile (III), which is hydrolyzed with 6N HCl to the corresponding dicarboxylic acid (IV). The esterification of (IV) with ethanol/dry HCl yields the diethyl ester (V), which is treated with methylmagnesium iodide in ethyl ether/dichloromethane affording 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (VI). The condensation of (VI) with 5-[4'-(bromomethyl)biphenyl-2-yl]-1-(triphenylmethyl)tetrazole (VII) by means of potassium tert-butoxide in dimethylacetamide (DMA) (1) or sodium hydride in DMF (2) gives 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-[1-(triphenylmethyl)-5-tetrazolyl]biphenyl-4-ylmethyl]imidazole-5-carboxylic acid ethyl ester (VIII), which is hydrolyzed with LiOH in dioxane/water to the corresponding free acid (IX). The esterification of (IX) with the chloromethyldioxole (X) by means of K2CO3 in DMA gives the desired ester (XI), which is finally deprotected with aqueous acetic acid.
【1】 Graul, A.; Leeson, P.; Castañer, J.; CS-866. Drugs Fut 1997, 22, 11, 1205. |
【2】 Yanagisawa, H.; Shimoji, Y.; Fujimoto, K.; Kanazaki, T.; Anemiya, Y.; Koike, H.; Sada, T. (Sankyo Co., Ltd.); Angiotensin II antagonist 1-biphenylmethylimidazole cpds. and their therapeutic use. EP 0503785; EP 0545912; JP 1993078328; US 5616599 . |
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) | 16902 | 1,1-dimethoxybutyl methyl ether; 1,1,1-trimethoxybutane | 43083-12-1 | C7H16O3 | 详情 | 详情 |
(II) | 16903 | (Z)-2,3-diamino-2-butenedinitrile;diaminomaleonitrile | 1187-42-4 | C4H4N4 | 详情 | 详情 |
(III) | 16904 | 2-propyl-1H-imidazole-4,5-dicarbonitrile | C8H8N4 | 详情 | 详情 | |
(IV) | 16905 | 2-propyl-1H-imidazole-4,5-dicarboxylic acid | C8H10N2O4 | 详情 | 详情 | |
(V) | 16906 | diethyl 2-propyl-1H-imidazole-4,5-dicarboxylate | C12H18N2O4 | 详情 | 详情 | |
(VI) | 16907 | ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate | C12H20N2O3 | 详情 | 详情 | |
(VII) | 15538 | 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-trityl-2H-1,2,3,4-tetraazole | 124750-51-2 | C33H25BrN4 | 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 | |
(IX) | 16910 | 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-carboxylic acid | C43H40N6O3 | 详情 | 详情 | |
(X) | 16911 | 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one | C5H5ClO3 | 详情 | 详情 | |
(XI) | 16912 | (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 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 | C48H44N6O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XI)2) The hydrolysis of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (VI) with LiOH in water gives the corresponding free acid (XII), which is esterified with the chloromethyldioxole (X) by means of diisopropylethylamine (DIEA) yielding the expected ester (XIII). Finally, this compound is condensed with 5-[4-'(bromomethyl)biphenyl-2-yl]-1-(triphenylmethyl)tetrazole (VII) by means of potassium carbonate in DMA to afford the protected CS-866 (XI) already obtained.
【1】 Graul, A.; Leeson, P.; Castañer, J.; CS-866. Drugs Fut 1997, 22, 11, 1205. |
【2】 Yanagisawa, H.; Shimoji, Y.; Fujimoto, K.; Kanazaki, T.; Anemiya, Y.; Koike, H.; Sada, T. (Sankyo Co., Ltd.); Angiotensin II antagonist 1-biphenylmethylimidazole cpds. and their therapeutic use. EP 0503785; EP 0545912; JP 1993078328; US 5616599 . |
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 | |
(VII) | 15538 | 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-trityl-2H-1,2,3,4-tetraazole | 124750-51-2 | C33H25BrN4 | 详情 | 详情 |
(X) | 16911 | 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one | C5H5ClO3 | 详情 | 详情 | |
(XI) | 16912 | (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 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 | C48H44N6O6 | 详情 | 详情 | |
(XII) | 16913 | 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid | C10H16N2O3 | 详情 | 详情 | |
(XIII) | 16914 | (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate | C15H20N2O6 | 详情 | 详情 |