5-Cyanoindole; Indole-5-carbonitrile; 1H-Indole-5-carbonitrile -Drug Synthesis Database

【结构式】

【分子编号】31341

【品名】5-Cyanoindole; Indole-5-carbonitrile; 1H-Indole-5-carbonitrile

【CA登记号】15861-24-2

【分子式】C₉H₆N₂

【分子量】142.16012

【元素组成】C 76.04% H 4.25% N 19.71%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(I)

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).

参考文献中间体

合成目标

【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

合成路线2

该中间体在本合成路线中的序号：(I)

The alkylation of 5-cyanoindole (I) with methyl bromoacetate (II) in the presence of NaH in DMF provided the indolylacetate ester (III), which was hydrolyzed to the corresponding carboxylic acid (IV) with methanolic KOH. Coupling of (IV) with 4-benzylpiperidine (V) employing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-HCl (EDC) afforded amide (VI). Pinner reaction of (VI) with methanolic HCl produced imidate (VII), which was finally treated with ammonium carbonate in MeOH to yield the target amidine

参考文献中间体

合成目标

【1】 Duffy, D.E.; Dominguez, C.; Han, Q.; et al.; Design and synthesis of potent and selective 5,6-fused heterocyclic thrombin inhibitors. Bioorg Med Chem Lett 1999, 9, 7, 925.
【2】 Dominguez, C.; Han, Q.; Duffy, D.E.; Park, J.M.; Quan, M.L.; Rossi, K.A.; Wexler, R.R. (DuPont Pharmaceuticals Co.); Amidinoindoles, amidinoazoles, and analogs thereof as inhibitors of factor Xa and of thrombin. EP 0960102; WO 9801428 .

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)	12309	methyl 2-bromoacetate; methyl bromoacetate	96-32-2	C₃H₅BrO₂	详情	详情
(III)	31342	methyl 2-(5-cyano-1H-indol-1-yl)acetate		C₁₂H₁₀N₂O₂	详情	详情
(IV)	31343	2-(5-cyano-1H-indol-1-yl)acetic acid		C₁₁H₈N₂O₂	详情	详情
(V)	26225	4-benzylpiperidine	31252-42-3	C₁₂H₁₇N	详情	详情
(VI)	31344	1-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-1H-indole-5-carbonitrile		C₂₃H₂₃N₃O	详情	详情
(VII)	31345	methyl 1-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-1H-indole-5-carboximidoate		C₂₄H₂₇N₃O₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

The intermediate 4-(5-cyano-1H-indol-3-yl)cyclohexanone (V) has been obtained as follows: The condensation of 1H-indole-5-carbonitrile (VI) with cyclohexanone monoethyleneketal (VII) by means of KOH in refluxing methanol gives the cyclohexenone ethyleneketal (VIII), which is reduced with H2 over Pd/C in ethanol to yield 4-(5-cyano-1H-indol-3-yl)cyclohexanone ethyleneketal (IX). Finally, this compound is hydrolyzed to the target intermediate (V) with HCl in THF.

参考文献中间体

合成目标

【1】 Meagher, K.L.; et al.; Studies towards the next generation of antidepressants. Part 1: Indolylcyclohexylamines as potent serotonin reuptake inhibitors. Bioorg Med Chem Lett 2001, 11, 14, 1885.
【2】 Meagher, K.L.; Smith, D.L.; Scerni, R.; Shi, X.; Albuthawa, S.; Andree, T.H.; Mewshaw, R.E.; Schechter, L.E.; Evrard, D.A.; Indolylcyclohexylamines as potent serotonin reuptake inhibitors. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 108.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	47079	3-(4-oxocyclohexyl)-1H-indole-5-carbonitrile		C₁₅H₁₄N₂O	详情	详情
(VI)	31341	5-Cyanoindole; Indole-5-carbonitrile; 1H-Indole-5-carbonitrile	15861-24-2	C₉H₆N₂	详情	详情
(VII)	11377	1,4-Dioxaspiro[4.5]decan-8-one	4746-97-8	C₈H₁₂O₃	详情	详情
(VIII)	52018	3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-indole-5-carbonitrile		C₁₇H₁₆N₂O₂	详情	详情
(IX)	52019	3-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-indole-5-carbonitrile		C₁₇H₁₈N₂O₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

Base-catalyzed condensation of 5-cyanoindole (I) with 1,4-cyclohexanedione mono-ethylene ketal (II) furnished the cyclohexenyl indole (III), which was further hydrogenated in the presence of Pd/C to the cyclohexyl analogue (IV). Subsequent hydrolysis of the ethylene ketal function of (IV) gave ketone (V).

参考文献中间体

合成目标

【1】 Meagher, K.L.; et al.; Studies towards the next generation of antidepressants. Part 1: Indolylcyclohexylamines as potent serotonin reuptake inhibitors. Bioorg Med Chem Lett 2001, 11, 14, 1885.

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)	11377	1,4-Dioxaspiro[4.5]decan-8-one	4746-97-8	C₈H₁₂O₃	详情	详情
(III)	52018	3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-indole-5-carbonitrile		C₁₇H₁₆N₂O₂	详情	详情
(IV)	52019	3-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-indole-5-carbonitrile		C₁₇H₁₈N₂O₂	详情	详情
(V)	47079	3-(4-oxocyclohexyl)-1H-indole-5-carbonitrile		C₁₅H₁₄N₂O	详情	详情

Extended Information