|
【结 构 式】 
|
【分子编号】32923 【品名】1-[2-(tert-butoxy)-2-oxoethyl]-5,7-dimethyl-1H-indole-2-carboxylic acid 【CA登记号】 |
【 分 子 式 】C17H21NO4 【 分 子 量 】303.35808 【元素组成】C 67.31% H 6.98% N 4.62% O 21.1% |
合成路线1
该中间体在本合成路线中的序号：(XV)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：(XV)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 |