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【结 构 式】

【分子编号】16910

【品名】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

【CA登记号】

【 分 子 式 】C43H40N6O3

【 分 子 量 】688.82924

【元素组成】C 74.98% H 5.85% N 12.2% O 6.97%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(IX)

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:(VI)

 

1 Sebastian S,Gade SR, Mallepalli SR, et aL 2007. Process for preparation of olmesartan medoxomiL. W0 2007047838.(本专利属于Dr Reddy's Laboratories Ltd, India; Dr Reddy's Laboratories, Inc)
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) 16905 2-propyl-1H-imidazole-4,5-dicarboxylic acid C8H10N2O4 详情 详情
(II) 16906 diethyl 2-propyl-1H-imidazole-4,5-dicarboxylate C12H18N2O4 详情 详情
(III) 66559 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1H-tetrazole   C14H11BrN4 详情 详情
(IV) 66556 dimethyl 1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-propyl-1H-imidazole-4,5-dicarboxylate   C24H24N6O4 详情 详情
(V) 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
(VI) 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
(VII) 16911 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one C5H5ClO3 详情 详情

合成路线3

该中间体在本合成路线中的序号:(VII)

 

1 Yu XH, Tang J,Wen XM,et aL 2005.Synthesis of a novel angiotensin Ⅱreceptor anugonist olmesartan medoxomiL. 华东理工大学学报,自然科学版.31: 189~192(本文作者来自于School of Chemistry and Pharmaceutics.East China UIuversity of Science and Technology,Shanghai,Peop Rep China)
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) 66558 (2S,3R)-2,3-dihydroxysuccinic acid 87-69-4 C4H6O6 详情 详情
(II) 16905 2-propyl-1H-imidazole-4,5-dicarboxylic acid C8H10N2O4 详情 详情
(III) 16906 diethyl 2-propyl-1H-imidazole-4,5-dicarboxylate C12H18N2O4 详情 详情
(IV) 16907 ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate C12H20N2O3 详情 详情
(V) 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
(VI) 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
(VII) 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
(VIII) 16911 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one C5H5ClO3 详情 详情
Extended Information