ethyl 5,7-dimethyl-1H-indole-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】32914

【品名】ethyl 5,7-dimethyl-1H-indole-2-carboxylate

【CA登记号】

【分子式】C₁₃H₁₅NO₂

【分子量】217.26764

【元素组成】C 71.87% H 6.96% N 6.45% O 14.73%

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：(V)

The intermediate benzyl 5,7-dimethylindole-2-carboxylate (X) was prepared by several procedures. Diazotization of 2,4-dimethylaniline (I), followed by Japp-Klingemann condensation of the diazonium salt (II) with ethyl 2-methyl-3-oxobutyrate (III) furnished hydrazone (IV). Subsequent Fischer indole synthesis in formic acid at 75 C provided ethyl 5,7-dimethylindole-2-carboxylate (V). An alternative route to indole (V) involved condensation of 3,5-dimethylbenzaldehyde (VI) with ethyl azidoacetate (VII) in ethanolic NaOEt, followed by thermal cyclization of the resulting azidocinnamate ester (VIII). Basic hydrolysis of ethyl ester (V) gave carboxylic acid (IX), which was converted to the benzyl ester (X) upon treatment with benzyl bromide and DBU.

参考文献中间体

合成目标

【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
	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(I)	32911	2,4-dimethylaniline; 2,4-dimethylphenylamine	95-68-1	C₈H₁₁N	详情	详情
(II)	32912	2,4-dimethylbenzenediazonium		C₈H₉N₂	详情	详情
(III)	10362	ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate	609-14-3	C₇H₁₂O₃	详情	详情
(IV)	32913	ethyl 2-[(Z)-2-(2,4-dimethylphenyl)hydrazono]propanoate		C₁₃H₁₈N₂O₂	详情	详情
(V)	32914	ethyl 5,7-dimethyl-1H-indole-2-carboxylate		C₁₃H₁₅NO₂	详情	详情
(VI)	32915	3,5-dimethylbenzaldehyde	5779-95-3	C₉H₁₀O	详情	详情
(VII)	32916	ethyl 2-azidoacetate	637-81-0	C₄H₇N₃O₂	详情	详情
(VIII)	32917	ethyl (Z)-2-azido-3-(3,5-dimethylphenyl)-2-propenoate		C₁₃H₁₅N₃O₂	详情	详情
(IX)	32918	5,7-dimethyl-1H-indole-2-carboxylic acid		C₁₁H₁₁NO₂	详情	详情
(X)	32919	benzyl 5,7-dimethyl-1H-indole-2-carboxylate		C₁₈H₁₇NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

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.

参考文献中间体

合成目标

【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

Extended Information