Olmesartan hydrate, DE-092, CS-088, -Drug Synthesis Database

【结构式】

【药物名称】Olmesartan hydrate, DE-092, CS-088

【化学名称】4-(1-Hydroxy-1-methylethyl)-2-propyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazole-5-carboxylic acid monohydrate

【CA登记号】144689-24-7(anhydrous)

【分子式】C₂₄H₂₈N₆O₄

【分子量】464.52856

【开发单位】Sankyo (Originator), Santen (Licensee)

【药理作用】Antiglaucoma Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Angiotensin AT1 Antagonists

合成路线1 合成路线2

合成路线1

Condensation of diaminomaleonitrile (I) with trimethyl orthobutyrate (II) produced the imino ether (III), which was further cyclized to imidazole (IV) upon heating in xylene. Acid hydrolysis of the imidazole dinitrile (IV) led to diacid (V), and subsequent Fischer esterification with ethanolic HCl provided diester (VI). Regioselective addition of methylmagnesium bromide to diester (VI) furnished the imidazole carbinol (VII). Alkylation of imidazole (VII) with the biphenyl bromide (VIII) furnished the (biphenylylmethyl)imidazole (IX). Then, removal of the trityl protecting group of (IX) under acidic conditions, followed by alkaline ester hydrolysis gave rise to the title compound.

参考文献中间体

【1】 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)	16903	(Z)-2,3-diamino-2-butenedinitrile;diaminomaleonitrile	1187-42-4	C₄H₄N₄	详情	详情
(II)	16902	1,1-dimethoxybutyl methyl ether; 1,1,1-trimethoxybutane	43083-12-1	C₇H₁₆O₃	详情	详情
(III)	56321	methyl N-[(Z)-2-amino-1,2-dicyanoethenyl]butanimidoate		C₉H₁₂N₄O	详情	详情
(IV)	16904	2-propyl-1H-imidazole-4,5-dicarbonitrile		C₈H₈N₄	详情	详情
(V)	16905	2-propyl-1H-imidazole-4,5-dicarboxylic acid		C₈H₁₀N₂O₄	详情	详情
(VI)	16906	diethyl 2-propyl-1H-imidazole-4,5-dicarboxylate		C₁₂H₁₈N₂O₄	详情	详情
(VII)	16907	ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate		C₁₂H₂₀N₂O₃	详情	详情
(VIII)	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
(IX)	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

合成路线2

In a further patented method, the biphenylyl nitrile (X) was converted to tetrazole (XI) by dipolar cycloaddition with sodium azide in the presence of triethylammonium chloride. Subsequent basic hydrolysis of the ethyl ester function of (XI) yielded the corresponding carboxylic acid.

参考文献中间体

【1】 Koguro, K.; Oga, T.; Tokunaga, N.; Mitsui, S.; Orita, R. (Tokyo Kasei Kogyo Co., Ltd.); Process for preparation of 5-substd. tetrazoles. EP 0796852 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	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
(XI)	56322	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