3-(4-oxocyclohexyl)-1H-indole-5-carbonitrile -Drug Synthesis Database

【结构式】

【分子编号】47079

【品名】3-(4-oxocyclohexyl)-1H-indole-5-carbonitrile

【CA登记号】

【分子式】C₁₅H₁₄N₂O

【分子量】238.28904

【元素组成】C 75.61% H 5.92% N 11.76% O 6.71%

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：(V)

Condensation of 3-methoxyphenethylamine (I) with methyl chloroformate in the presence of Et3N gave carbamate (II). This was cyclized to the isoquinolinone (III) by treatment with polyphosphoric acid at 140 C. Reduction of lactam (III) with LiAlH4 provided the tetrahydroisoquinoline (IV). Reductive condensation of (IV) with 4-(5-cyano-3-indolyl)cyclohexanone (V) employing sodium triacetoxyborohydride furnished the corresponding 1,4-disubstituted cyclohexane as a cis/trans mixture from which the desired cis-isomer was isolated by column chromatography.

参考文献中间体

合成目标

【1】 Meagher, K.L.; Mewshaw, R.E. (American Home Products Corp.); Tetrahydroisoquinolinyl-indole derivs. for the treatment of depression. WO 0064886 .

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)	37185	2-(3-methoxyphenyl)-1-ethanamine; 3-methoxyphenethylamine	2039-67-0	C₉H₁₃NO	详情	详情
(II)	47076	methyl 3-methoxyphenethylcarbamate		C₁₁H₁₅NO₃	详情	详情
(III)	47077	6-methoxy-3,4-dihydro-1(2H)-isoquinolinone		C₁₀H₁₁NO₂	详情	详情
(IV)	47078	methyl 1,2,3,4-tetrahydro-6-isoquinolinyl ether; 6-methoxy-1,2,3,4-tetrahydroisoquinoline		C₁₀H₁₃NO	详情	详情
(V)	47079	3-(4-oxocyclohexyl)-1H-indole-5-carbonitrile		C₁₅H₁₄N₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

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3

该中间体在本合成路线中的序号：(V)

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

合成路线4

该中间体在本合成路线中的序号：(V)

Acylation of 3-methoxyphenethyl amine (VI) with methyl chloroformate gave the corresponding carbamate (VII). Intramolecular cyclization of (VII) with hot polyphosphoric acid produced a mixture of isomeric isoquinolinones (VIII) and (IX) from which the desired 6-methoxy isomer (IX) was isolated by column chromatography. Reduction of (IX) with LiAlH4 furnished the tetrahydro isoquinoline (X). Then reductive alkylation of amine (X) with ketone (V) in the presence of NaBH(OAc)3 produced the corresponding cyclohexyl amine as a mixture of cis/trans isomers. The title trans compound was obtained from the reaction mixture by chromatographic separation.

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.; Mewshaw, R.E. (American Home Products Corp.); Tetrahydroisoquinolinyl-indole derivs. for the treatment of depression. WO 0064886 .

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)	37185	2-(3-methoxyphenyl)-1-ethanamine; 3-methoxyphenethylamine	2039-67-0	C₉H₁₃NO	详情	详情
(VII)	47076	methyl 3-methoxyphenethylcarbamate		C₁₁H₁₅NO₃	详情	详情
(VIII)	52503	8-(methyloxy)-3,4-dihydro-1(2H)-isoquinolinone		C₁₀H₁₁NO₂	详情	详情
(IX)	47077	6-methoxy-3,4-dihydro-1(2H)-isoquinolinone		C₁₀H₁₁NO₂	详情	详情
(X)	47078	methyl 1,2,3,4-tetrahydro-6-isoquinolinyl ether; 6-methoxy-1,2,3,4-tetrahydroisoquinoline		C₁₀H₁₃NO	详情	详情

Extended Information