【结 构 式】 |
【药物名称】 【化学名称】1(R)-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3(S)-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexanecarbonitrile 【CA登记号】162101-90-8 (cis-isomer) 【 分 子 式 】C22H27N3O3 【 分 子 量 】381.47879 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Asthma Therapy, Bronchodilators, RESPIRATORY DRUGS, Phosphodiesterase IV Inhibitors |
合成路线1
The reaction of 5-cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxocyclohexanecarboxylic acid methyl ester (I) with trifluoromethanesulfonic anhydride gives the enol triflate (II), which is desulfonated with triphenylphosphine, palladium acetate and formic acid yielding 5-cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)-1-clohexene-1-carboxylic acid methyl ester (III). The hydrogenation of the double bond of (III) with H2 over Pd/C in methanol affords the cis carboxylic ester (IV), which is hydrolyzed with KOH in in methanol to provide the free carboxylic acid (V). The reaction of (V) with isobutyl chloroformate and then with NH4OH gives the corresponding amide (VI), which is finally cyclized with N,N-dimethylacetamide dimethylacetal (VII) by heating at 110 C to obtain target compound as a racemate.
【1】 Board, M.; Newsholme, E.A. (Isis Pharmaceuticals, Inc.); Use of glucokinase inhibitors for the manufacture of a medicament for treating tumours. WO 9503809 . |
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) | 16515 | methyl 5-cyano-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-oxocyclohexanecarboxylate | C21H25NO5 | 详情 | 详情 | |
(II) | 26690 | methyl 5-cyano-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-[[(trifluoromethyl)sulfonyl]oxy]-1-cyclohexene-1-carboxylate | C22H24F3NO7S | 详情 | 详情 | |
(III) | 26691 | methyl 5-cyano-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-cyclohexene-1-carboxylate | C21H25NO4 | 详情 | 详情 | |
(IV) | 26692 | methyl (1S,3R)-3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylate | C21H27NO4 | 详情 | 详情 | |
(V) | 26693 | (1S,3R)-3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylic acid | C20H25NO4 | 详情 | 详情 | |
(VI) | 26694 | (1S,3R)-3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxamide | C20H26N2O3 | 详情 | 详情 | |
(VII) | 22915 | 1,1-dimethoxy-N,N-dimethyl-1-ethanamine;N,N-dimethylacetamide dimethylacetal; N-(1,1-dimethoxyethyl)-N,N-dimethylamine | 18871-66-4 | C6H15NO2 | 详情 | 详情 |