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【结 构 式】

【药物名称】Olmesartan medoxomil, CS-866DM, CS-866, Olmetec, Benicar, Benevas

【化学名称】4-(1-Hydroxy-1-methylethyl)-2-propyl-1-[2'-(1H-5-tetrazolyl)biphenyl-4-ylmethyl]imidazole-5-carboxylic acid 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl ester

【CA登记号】144689-63-4

【 分 子 式 】C29H30N6O6

【 分 子 量 】558.59905

【开发单位】Sankyo (Originator), Forest (Marketer), Pfizer (Marketer), Menarini (Comarketer), Nikken Chemicals (Comarketer), Sanwa (Comarketer), Kowa (Codevelopment)

【药理作用】CARDIOVASCULAR DRUGS, Diabetic Nephropathy, Agents for, ENDOCRINE DRUGS, Hypertension, Treatment of, Treatment of Diabetic Complications, Angiotensin AT1 Antagonists

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6

合成路线1

　

参考文献 中间体
【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2

　

参考文献 中间体
【1】 Hedvati L.Pilarsky G, Shenkar-Garcia N.2006. Process for preparing olmesartan medoxomil at pH higher than 2.5.US 20060148870
【2】 Hedvati L,Pilarsky G-2006. Prooess for the preparation of olmesartan medoxomiL. W0 2006029056（本专利属于Teva Pharmaceutical Industries Ltd.Israeli Teva Phumaceuticals Usa 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) 16906 diethyl 2-propyl-1H-imidazole-4,5-dicarboxylate C12H18N2O4 详情 详情
(II) 16907 ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate C12H20N2O3 详情 详情
(III) 15332 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile; 4'-bromomethyl-2-cyanobiphenyl 114772-54-2 C14H10BrN 详情 详情
(IV) 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
(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) 66557 1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid 144689-24-7 C24H26N6O3 详情 详情

合成路线3

　

参考文献 中间体
【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

合成路线4

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.

参考文献 中间体
【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5

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.

参考文献 中间体
【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

合成路线6

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.

参考文献 中间体
【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
Extended Information