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【结 构 式】 
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【分子编号】22767 【品名】methyl 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole-2-carboxylate 【CA登记号】 |
【 分 子 式 】C17H20N2O5 【 分 子 量 】332.35628 【元素组成】C 61.44% H 6.07% N 8.43% O 24.07% |
合成路线1
该中间体在本合成路线中的序号：(XVI)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.
| 【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：(V)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.
| 【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 |
合成路线3
该中间体在本合成路线中的序号：(VII)The cyclization of 2-(3,5-dimethoxyphenyl)glyoxal monohydrate (I) with methyl glyoxylic acid (II) and ammonium acetate in acetonitrile gives the aryl imidazole (III), which is protected with dihydrofuran (IV) and Ts-OH, yielding compound (V). The regioselective lithiation of (V) with n-BuLi, followed by reaction with labeled 14CO2 provides the carboxylic acid (VI), which is esterified with MeI and CaO in DMSO to furnish the methyl ester (VII). The reduction of the ester group of (VII) with LiBH4 affords the carbinol (VIII), which is esterified with trichloroacetonitrile (IX) to provide the trichloroacetimidate (X).
| 【1】 Egan, M.A.M.; et al.; Carbon-14 labeling of a potential new immunoregulant agent. J Label Compd Radiopharm 2000, 43, 11, 1095. |
| 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) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (III) | 42281 | 4-(3,5-dimethoxyphenyl)-1H-imidazole; 3-(1H-imidazol-4-yl)-5-methoxyphenyl methyl ether | C11H12N2O2 | 详情 | 详情 | |
| (IV) | 22766 | 2,3-dihydrofuran | 1191-99-7 | C4H6O | 详情 | 详情 |
| (V) | 42282 | 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole; 3-methoxy-5-(1-tetrahydro-2-furanyl-1H-imidazol-4-yl)phenyl methyl ether | C15H18N2O3 | 详情 | 详情 | |
| (VI) | 42283 | lithium 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole-2-carboxylate | C16H17LiN2O5 | 详情 | 详情 | |
| (VI) | 45345 | lithium 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole-2-carboxylate | C16H17LiN2O5 | 详情 | 详情 | |
| (VII) | 22767 | methyl 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole-2-carboxylate | C17H20N2O5 | 详情 | 详情 | |
| (VII) | 45346 | methyl 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole-2-carboxylate | C17H20N2O5 | 详情 | 详情 | |
| (VIII) | 22768 | [4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methanol | C16H20N2O4 | 详情 | 详情 | |
| (VIII) | 45347 | [4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methanol | C16H20N2O4 | 详情 | 详情 | |
| (IX) | 42279 | 2,2,2-trichloroacetonitrile; Trichloromethylcyanide | 545-06-2 | C2Cl3N | 详情 | 详情 |
| (X) | 22769 | [4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methyl 2,2,2-trichloroethanimidoate | C18H20Cl3N3O4 | 详情 | 详情 |