【结 构 式】 |
【分子编号】45741 【品名】ethyl 5-(1-piperazinyl)-1-benzofuran-2-carboxylate 【CA登记号】 |
【 分 子 式 】C15H18N2O3 【 分 子 量 】274.3196 【元素组成】C 65.68% H 6.61% N 10.21% O 17.5% |
合成路线1
该中间体在本合成路线中的序号:(XI)Vilazodone can be prepared by two related ways: 1) The condensation of indole-5-carbonitrile (I) with 4-chlorobutyryl chloride (II) gives 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile (III), which is reduced with diborane, yielding 3-(4-chlorobutyl)-1H-indole-5-carbonitrile (IV). Reaction of compound (IV) with 5-(1-piperazinyl)benzofuran-2-carboxylic acid (V) affords the expected 1,4-disubstituted piperazine (VI). Finally, the carboxy group of (VI) is converted into the target carboxamide by reaction with 2-chloro-1-methylpyridinium methanesulfonate (CMPM) and ammonia gas. 5-(1-Piperazinyl)benzofuran-2-carboxylic acid (V) is obtained by cyclization of 5-aminobenzofuran-2-carboxylic acid (VII) with bis(2-chloroethyl)amine (VIII). 2) The hydrogenation of 5-nitrobenzofuran-2-carboxylic acid ethyl ester (IX) with H2 and Raney nickel in MeOH gives the corresponding 5-aminobenzofuran compound (X), which is cyclized with bis(2-chloroethyl)amine (VIII) in dichloromethane to afford 5-(1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester (XI). Reaction of compound (XI) with di-tert-butyl dicarbonate in THF provides the protected amine compound 5-[4-(tert-butoxycarbonyl)-1-piperazinyl]benzofuran-2-carboxylic acid ethyl ester (XII), which first is reacted with formamide and sodium alkoxide in N-methylpyrrolidone to provide the corresponding amide (XIII) and then is deprotected by treatment with HCl/MeOH to give 5-(1-piperazinyl)benzofuran-2-carboxamide (XIV). Finally, amide (XIV) is condensed with 3-(4-chlorobutyl)-1H-indole-5-carbonitrile (IV).
【1】 Rabasseda, X.; Sorbera, L.A.; Silvestre, J.S.; Castaner, J.; Vilazodone Hydrochloride. Drugs Fut 2001, 26, 3, 247. |
【2】 Bottcher, H.; Greiner, H.; Seyfried, C.; Bartoszyk, G. (Merck Patent GmbH); Indole derivs.. DE 4101686; EP 0496222; JP 1992334366; US 5418237 . |
【3】 Bottcher, H.; Seyfried, C.; Bartoszyk, G.; Greiner, H. (Merck Patent GmbH); Piperidine and piperazine derivs. which affect the CNS. CA 2133152; DE 4333254; EP 0648767; US 5532241 . |
【4】 Bathe, A.; Helfert, B.; Bottcher, H.; Schuster, K. (Merck Patent GmbH); 5-Amino-benzofuran-2-carboxylic acid derivs.. CA 2174494; DE 19514567; EP 0738722; JP 1996291161; US 5723614 . |
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) | 31341 | 5-Cyanoindole; Indole-5-carbonitrile; 1H-Indole-5-carbonitrile | 15861-24-2 | C9H6N2 | 详情 | 详情 |
(II) | 11265 | 4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride | 4635-59-0 | C4H6Cl2O | 详情 | 详情 |
(III) | 45735 | 3-(4-chlorobutanoyl)-1H-indole-5-carbonitrile | C13H11ClN2O | 详情 | 详情 | |
(IV) | 45736 | 3-(4-chlorobutyl)-1H-indole-5-carbonitrile | C13H13ClN2 | 详情 | 详情 | |
(V) | 45737 | 5-(1-piperazinyl)-1-benzofuran-2-carboxylic acid | C13H14N2O3 | 详情 | 详情 | |
(VI) | 45738 | 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-1-benzofuran-2-carboxylic acid | C26H26N4O3 | 详情 | 详情 | |
(VII) | 45739 | 5-amino-1-benzofuran-2-carboxylic acid | C9H7NO3 | 详情 | 详情 | |
(VIII) | 21583 | 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine | 821-48-7 | C4H9Cl2N | 详情 | 详情 |
(IX) | 42308 | ethyl 5-nitro-1-benzofuran-2-carboxylate | 69404-00-8 | C11H9NO5 | 详情 | 详情 |
(X) | 45740 | ethyl 5-amino-1-benzofuran-2-carboxylate | C11H11NO3 | 详情 | 详情 | |
(XI) | 45741 | ethyl 5-(1-piperazinyl)-1-benzofuran-2-carboxylate | C15H18N2O3 | 详情 | 详情 | |
(XII) | 45742 | tert-butyl 4-[2-(ethoxycarbonyl)-1-benzofuran-5-yl]-1-piperazinecarboxylate | C20H26N2O5 | 详情 | 详情 | |
(XIII) | 45743 | tert-butyl 4-[2-(aminocarbonyl)-1-benzofuran-5-yl]-1-piperazinecarboxylate | C18H23N3O4 | 详情 | 详情 | |
(XIV) | 45744 | 5-(1-piperazinyl)-1-benzofuran-2-carboxamide | C13H15N3O2 | 详情 | 详情 |