methyl 4-(3,5-dimethoxyphenyl)-1H-imidazole-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】22765

【品名】methyl 4-(3,5-dimethoxyphenyl)-1H-imidazole-2-carboxylate

【CA登记号】

【分子式】C₁₃H₁₄N₂O₄

【分子量】262.26524

【元素组成】C 59.54% H 5.38% N 10.68% O 24.4%

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：(XIV)

In a further procedure, 3,5-dimethoxybenzoic acid (X) was converted to the acetophenone (XI) using methyllithium. Treatment of (XI) with phenyltrimethylammonium tribromide provided the dibromoacetophenone (XII) which, upon reaction with morpholine at 55 C, followed by hydrolysis with aqueous HCl, gave the phenylglyoxal (VIII). Alternatively, (VIII) was prepared directly by treating acetophenone (XI) with DMSO and HBr or by oxidation with SeO2. Condensation of the phenylglyoxal (VIII) with methyl glyoxylate hemiacetal (XIII) and ammonium acetate produced the phenylimidazole (XIV), which was protected as the tetrahydrofuranyl derivative (XVI) with dihydrofuran and catalytic p-TsOH. Reduction of the protected imidazole ester (XVI) with LiBH4 provided alcohol (XVII), and then reaction of (XVII) with trichloroacetonitrile in the presence of DBU furnished the acetimidate (XVIII). Finally, the target compound was obtained by reaction of ascomycin (I) with trichloroacetimidate (XVIII) in the presence of fluoboric acid etherate, followed by hydrolytic deprotection.

参考文献中间体

合成目标

【1】 Mathre, D.J.; Sohar, P.; Shuman, R.F.; Song, Z. (Merck & Co., Inc.); Process for the preparation of imidazolyl macrolide immunosuppressants. JP 1999512096; US 5777105; WO 9708182 .

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)	14951	(1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-ethyl-1,14-dihydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetron		C₄₃H₆₉NO₁₂	详情	详情
(VIII)	22759	1-(3,5-dimethoxyphenyl)-2,2-dihydroxy-1-ethanone		C₁₀H₁₂O₅	详情	详情
(X)	22761	3,5-dimethoxybenzoic acid	1132-21-4	C₉H₁₀O₄	详情	详情
(XI)	22762	1-(3,5-dimethoxyphenyl)-1-ethanone	39151-19-4	C₁₀H₁₂O₃	详情	详情
(XII)	22763	2,2-dibromo-1-(3,5-dimethoxyphenyl)-1-ethanone		C₁₀H₁₀Br₂O₃	详情	详情
(XIII)	22764	methyl 2-hydroxy-2-methoxyacetate	19757-97-2	C₄H₈O₄	详情	详情
(XIV)	22765	methyl 4-(3,5-dimethoxyphenyl)-1H-imidazole-2-carboxylate		C₁₃H₁₄N₂O₄	详情	详情
(XV)	22766	2,3-dihydrofuran	1191-99-7	C₄H₆O	详情	详情
(XVI)	22767	methyl 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole-2-carboxylate		C₁₇H₂₀N₂O₅	详情	详情
(XVI)	22768	[4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methanol		C₁₆H₂₀N₂O₄	详情	详情
(XVIII)	22769	[4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methyl 2,2,2-trichloroethanimidoate		C₁₈H₂₀Cl₃N₃O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The cyclization of 2-(3,5-dimethoxyphenyl)glyoxal monohydrate (I) with methyl glyoxylate hemiacetal (II) and ammonium acetate in acetonitrile gives the imidazole derivative (III), which is protected with dihydrofuran (IV) and TsOH, yielding compound (V). The reduction of the ester group of (V) with LiBH4 affords the carbinol (VI), which is esterified with trichloroacetonitrile (VII) to provide the trichloroacetimidate (VIII). The condensation of (VIII) with ascomycin (IX) by means of CF3SO3H in N,N-dimethylpivalamide gives the adduct (X), which is finally deprotected with hot aqueous CF3SO3H.

参考文献中间体

合成目标

【1】 Song, Z.; et al.; Highly chemoselective trichloroacetimidate-mediated alkylation of ascomycin: A convergent, practical synthesis of the immunosuppressant L-733,725. J Org Chem 1999, 64, 6, 1859.

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)	22759	1-(3,5-dimethoxyphenyl)-2,2-dihydroxy-1-ethanone		C₁₀H₁₂O₅	详情	详情
(II)	22764	methyl 2-hydroxy-2-methoxyacetate	19757-97-2	C₄H₈O₄	详情	详情
(III)	22765	methyl 4-(3,5-dimethoxyphenyl)-1H-imidazole-2-carboxylate		C₁₃H₁₄N₂O₄	详情	详情
(IV)	22766	2,3-dihydrofuran	1191-99-7	C₄H₆O	详情	详情
(V)	22767	methyl 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole-2-carboxylate		C₁₇H₂₀N₂O₅	详情	详情
(VI)	22768	[4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methanol		C₁₆H₂₀N₂O₄	详情	详情
(VII)	42279	2,2,2-trichloroacetonitrile; Trichloromethylcyanide	545-06-2	C₂Cl₃N	详情	详情
(VIII)	22769	[4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methyl 2,2,2-trichloroethanimidoate		C₁₈H₂₀Cl₃N₃O₄	详情	详情
(IX)	14951	(1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-ethyl-1,14-dihydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetron		C₄₃H₆₉NO₁₂	详情	详情
(X)	42280	(1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-12-[(E)-2-((1R,3R,4R)-4-[[4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methoxy]-3-methoxycyclohexyl)-1-methylethenyl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,2		C₅₉H₈₇N₃O₁₅	详情	详情

Extended Information