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【结 构 式】

【分子编号】32925

【品名】1-(2-methoxy-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid

【CA登记号】

【 分 子 式 】C14H15NO4

【 分 子 量 】261.27744

【元素组成】C 64.36% H 5.79% N 5.36% O 24.49%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XVII)

A further route to benzyl ester (X) is shown in the next scheme: Protection of 2,4,6-trimethylaniline (XI) with Boc2O gave carbamate (XII). Condensation of (XII) with diethyl oxalate in the presence of sec-butyllithium produced the intermediate ketoester (XIII), which was deprotected and cyclized under acidic conditions to yield indole (V). Hydrolysis, followed by alkylation with benzyl bromide as above provided the corresponding benzyl ester (X). An alternative and more direct procedure consisted in the condensation of protected aniline (XII) with dibenzyl oxalate, and then cyclization upon treatment with trifluoroacetic acid. The intermediate indole (X) was N-alkylated with tert-butyl bromoacetate and NaH to give the indole diester (XIV). Subsequent deprotection of the benzyl ester group by hydrogenation over Pd/C gave rise to diacid mono tert-butyl ester (XV). Optionally, the analogous methyl ester (XVII) was prepared by alkylation of indole (X) with methyl bromoacetate, followed by benzyl group hydrogenolysis.

1 Brodin, R.; Boigegrain, R.; Molimard, J.-C.; Bignon, E.; Olliero, D. (Sanofi-Synthelabo ); Carboxamidothiazole derivs., preparation, pharmaceutical compsns. containing them. EP 1017693; FR 2768737; FR 2777887; WO 9915525 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
40591 benzyl 2-(benzyloxy)-2-oxoacetate C16H14O4 详情 详情
(V) 32914 ethyl 5,7-dimethyl-1H-indole-2-carboxylate C13H15NO2 详情 详情
(X) 32919 benzyl 5,7-dimethyl-1H-indole-2-carboxylate C18H17NO2 详情 详情
(XI) 28804 2,4,6-trimethylaniline 88-05-1 C9H13N 详情 详情
(XII) 32920 tert-butyl mesitylcarbamate C14H21NO2 详情 详情
(XIII) 32921 ethyl 3-[2-[(tert-butoxycarbonyl)amino]-3,5-dimethylphenyl]-2-oxopropanoate C18H25NO5 详情 详情
(XIV) 32922 benzyl 1-[2-(tert-butoxy)-2-oxoethyl]-5,7-dimethyl-1H-indole-2-carboxylate C24H27NO4 详情 详情
(XV) 32923 1-[2-(tert-butoxy)-2-oxoethyl]-5,7-dimethyl-1H-indole-2-carboxylic acid C17H21NO4 详情 详情
(XVI) 32924 benzyl 1-(2-methoxy-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylate C21H21NO4 详情 详情
(XVII) 32925 1-(2-methoxy-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid C14H15NO4 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XVII)

4-Cyclohexylbutyric acid (XVIII) was converted to the corresponding acid chloride (XIX) with SOCl2. Subsequent Friedel-Crafts condensation with 2,5-dimethoxychlorobenzene (XX) yielded ketone (XXI). After bromination of (XXI) in CH2Cl2, the resulting bromoketone (XXII) was condensed with thiourea (XXIII), providing aminothiazole (XXIV). This amine was coupled with indole acid (XV) by means of BOP to give amide (XXV). The title compound was then obtained by deprotection of the tert-butyl ester with trifluoroacetic acid. In a related alternative procedure, coupling of aminothiazole (XXIV) with indole acid (XVII) gave amide (XXVI). The methyl ester was then deprotected by hydrolysis with K2CO3 in aqueous butanol.

1 Brodin, R.; Boigegrain, R.; Molimard, J.-C.; Bignon, E.; Olliero, D. (Sanofi-Synthelabo ); Carboxamidothiazole derivs., preparation, pharmaceutical compsns. containing them. EP 1017693; FR 2768737; FR 2777887; WO 9915525 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 32923 1-[2-(tert-butoxy)-2-oxoethyl]-5,7-dimethyl-1H-indole-2-carboxylic acid C17H21NO4 详情 详情
(XVII) 32925 1-(2-methoxy-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid C14H15NO4 详情 详情
(XVIII) 32926 4-cyclohexylbutyric acid 4441-63-8 C10H18O2 详情 详情
(XIX) 32927 4-cyclohexylbutanoyl chloride C10H17ClO 详情 详情
(XX) 32928 2-chloro-1,4-dimethoxybenzene; 2-chloro-4-methoxyphenyl methyl ether 2100-42-7 C8H9ClO2 详情 详情
(XXI) 32929 1-(4-chloro-2,5-dimethoxyphenyl)-4-cyclohexyl-1-butanone C18H25ClO3 详情 详情
(XXII) 32930 2-bromo-1-(4-chloro-2,5-dimethoxyphenyl)-4-cyclohexyl-1-butanone C18H24BrClO3 详情 详情
(XXIII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(XXIV) 32931 4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-amine; 4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-ylamine C19H25ClN2O2S 详情 详情
(XXV) 32932 tert-butyl 2-[2-([[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]amino]carbonyl)-5,7-dimethyl-1H-indol-1-yl]acetate C36H44ClN3O5S 详情 详情
(XXVI) 32933 methyl 2-[2-([[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]amino]carbonyl)-5,7-dimethyl-1H-indol-1-yl]acetate C33H38ClN3O5S 详情 详情
Extended Information