1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile -Drug Synthesis Database

【结构式】

【分子编号】33026

【品名】1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile

【CA登记号】

【分子式】C₁₀H₁₀N₂

【分子量】158.20288

【元素组成】C 75.92% H 6.37% N 17.71%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(IV)

Tetrahydroisoquinoline (II) was prepared by intramolecular cyclization of N-trifluoroacetyl 4-bromophenethylamine (I) with paraformaldehyde in acetic/ sulfuric acid. Displacement of the bromine atom of (II) with CuCN in boiling N-methyl-2-pyrrolidinone produced nitrile (III). The trifluoroacetyl group og (III) was then removed by means of K2CO3 in aqueous methanol, yielding the intermediate isoquinoline (IV).

参考文献中间体

合成目标

【1】 Stokker, G.E.; Preparation of 1,2,3,4-tetrahydroisoquinolines lacking electron donating groups - an intramolecular cyclization complementary to the Pictet-Spengler reaction. Tetrahedron Lett 1996, 37, 31, 5453.
【2】 Branch, C.L.; Stemp, G.; Johnson, C.N. (SmithKline Beecham plc); Tetrahydroisoquinoline derivs. as modulators of dopamine D3 receptors. EP 0983244; WO 9850364 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	33023	N-(4-bromophenethyl)-2,2,2-trifluoroacetamide	C₁₀H₉BrF₃NO	详情	详情
(II)	33024	1-[7-bromo-3,4-dihydro-2(1H)-isoquinolinyl]-2,2,2-trifluoro-1-ethanone	C₁₁H₉BrF₃NO	详情	详情
(III)	33025	2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile	C₁₂H₉F₃N₂O	详情	详情
(IV)	33026	1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile	C₁₀H₁₀N₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Swern oxidation of hydroxy ketal (V) led to aldehyde (VI), which was reductively condensed with tetrahydroquinoline (IV) in the presence of sodium triacetoxyborohydride to produce the N-alkylated quinoline (VII). Acid hydrolysis of the ethylene ketal of (VII) afforded the corresponding ketone (VIII). Subsequent reductive amination of (VIII) with ammonium acetate in the presence of sodium borohydride furnished the primary amine (IXa-b) as a mixture of cis and trans isomers. Coupling of (IXa-b) with indole-2-carboxylic acid (X) employing EDC and HOBt yielded the corresponding amide as a mixture of geometric isomers. The target trans isomer was finally isolated by chromatography on silica gel.

参考文献中间体

合成目标

【1】 Branch, C.L.; Stemp, G.; Johnson, C.N. (SmithKline Beecham plc); Tetrahydroisoquinoline derivs. as modulators of dopamine D3 receptors. EP 0983244; WO 9850364 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IXa)	33031	2-[2-(4-aminocyclohexyl)ethyl]-1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile		C₁₈H₂₅N₃	详情	详情
(IXb)	33032	2-[2-(4-aminocyclohexyl)ethyl]-1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile		C₁₈H₂₅N₃	详情	详情
(IV)	33026	1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile		C₁₀H₁₀N₂	详情	详情
(V)	33027	2-(1,4-dioxaspiro[4.5]dec-8-yl)-1-ethanol		C₁₀H₁₈O₃	详情	详情
(VI)	33028	2-(1,4-dioxaspiro[4.5]dec-8-yl)acetaldehyde		C₁₀H₁₆O₃	详情	详情
(VII)	33029	2-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]-1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile		C₂₀H₂₆N₂O₂	详情	详情
(VIII)	33030	2-[2-(4-oxocyclohexyl)ethyl]-1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile		C₁₈H₂₂N₂O	详情	详情
(X)	25226	1H-Indole-2-carboxylic acid; Indole-2-carboxylic acid	1477-50-5	C₉H₇NO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

An alternative procedure started from trans-4-aminocyclohexylacetic acid hydrogen sulfate (XI), which was esterified with methanol and sulfuric acid to give aminoester (XII). Protection of the amino group of (XII) as the tert-butyl carbamate (XIII), followed by ester reduction with DIBAL gave rise to aldehyde (XIV). Reductive condensation of (XIV) with tetrahydroisoquinoline (IV) provided (XV). The Boc group of (XV) was then cleaved with trifluoroacetic acid to furnish the trans amine (XVI). This was finally converted to the target compound by coupling with indole-2-carboxylic acid (X) as above.

参考文献中间体

合成目标

【1】 Stokker, G.E.; Preparation of 1,2,3,4-tetrahydroisoquinolines lacking electron donating groups - an intramolecular cyclization complementary to the Pictet-Spengler reaction. Tetrahedron Lett 1996, 37, 31, 5453.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	33026	1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile		C₁₀H₁₀N₂	详情	详情
(X)	25226	1H-Indole-2-carboxylic acid; Indole-2-carboxylic acid	1477-50-5	C₉H₇NO₂	详情	详情
(XI)	33033	2-(4-aminocyclohexyl)acetic acid		C₈H₁₅NO₂	详情	详情
(XII)	33034	methyl 2-(4-aminocyclohexyl)acetate		C₉H₁₇NO₂	详情	详情
(XIII)	33035	methyl 2-[4-[(tert-butoxycarbonyl)amino]cyclohexyl]acetate		C₁₄H₂₅NO₄	详情	详情
(XIV)	33036	tert-butyl 4-(2-oxoethyl)cyclohexylcarbamate		C₁₃H₂₃NO₃	详情	详情
(XV)	33037	tert-butyl 4-[2-[7-cyano-3,4-dihydro-2(1H)-isoquinolinyl]ethyl]cyclohexylcarbamate		C₂₃H₃₃N₃O₂	详情	详情
(XVI)	33038	2-[2-(4-aminocyclohexyl)ethyl]-1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile		C₁₈H₂₅N₃	详情	详情

Extended Information