1,1-dimethoxybutyl methyl ether; 1,1,1-trimethoxybutane -Drug Synthesis Database

【结构式】

【分子编号】16902

【品名】1,1-dimethoxybutyl methyl ether; 1,1,1-trimethoxybutane

【CA登记号】43083-12-1

【分子式】C₇H₁₆O₃

【分子量】148.20224

【元素组成】C 56.73% H 10.88% O 32.39%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

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

合成目标

【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：(II)

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

合成目标

【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

Extended Information