2-(3-methoxyphenyl)-1-ethanamine; 3-methoxyphenethylamine -Drug Synthesis Database

【结构式】

【分子编号】37185

【品名】2-(3-methoxyphenyl)-1-ethanamine; 3-methoxyphenethylamine

【CA登记号】2039-67-0

【分子式】C₉H₁₃NO

【分子量】151.20836

【元素组成】C 71.49% H 8.67% N 9.26% O 10.58%

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)

The reaction of 3-methoxyphenylethylamine (I) with phenylethyl bromide (II) in refluxing triethylamine gives 3-methoxy-N-(phenylethyl)phenylethylamine (III), which is alkylated with 1-iodopropane by means of K2CO3 in refluxing acetone yielding 3-methoxy-N-propyl-N-(phenylethyl)phenylethylamine (IV). Finally, this compound is demethylated by treatment with refluxing aqueous 48% HBr and formation of the HCl salt with hydrochloric acid.

参考文献中间体

合成目标

【1】 Nedelec, L.; et al.; Synthesis of study of the dopaminergic activity of di(phenylethyl)amine derivatives. Eur J Med Chem - Chim Ther 1978, 13, 6, 553-556.
【2】 Serradell, M.N.; Castañer, J.; Blancafort, P.; Owen, R.T.; RU-24213. Drugs Fut 1981, 6, 4, 237.

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)	20730	1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide	103-63-9	C₈H₉Br	详情	详情
(III)	37186	N-(3-methoxyphenethyl)-N-phenethylamine; 2-(3-methoxyphenyl)-N-phenethyl-1-ethanamine		C₁₇H₂₁NO	详情	详情
(IV)	28758	1-iodopropane	107-08-4	C₃H₇I	详情	详情
(V)	37187	N-(3-methoxyphenethyl)-N-phenethyl-N-propylamine; N-(3-methoxyphenethyl)-N-phenethyl-1-propanamine		C₂₀H₂₇NO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

3-Methoxyphenethylamine (I) was converted into formamide (II) upon refluxing in ethyl formate. Subsequent cyclization of (II) in hot polyphosphoric acid produced the dihydroisoquinoline (III). This was subjected to a tandem Mannich-Michael condensations by refluxing in methyl vinyl ketone (IV) to yield the benzoquinolizinone system (V). The desired (S)-enantiomer (VI) was then isolated by crystallization of the diastereoisomeric salts with (-)-di-p-toluoyl-L-tartaric acid in EtOAc. Condensation of (VI) with methylamine in the presence of TiCl4, followed by reduction of the intermediate imine with NaBH4 provided amine (VII). This was finally converted to the target sulfonamide by treatment with methanesulfonyl chloride and Et3N.

参考文献中间体

合成目标

【1】 Yamamoto, O.; Shirouchi, Y. (Nippon Shinyaku Co., Ltd.); Benzoquinolizine derivs. and medicinal compsns.. EP 0897923; WO 9740046 .

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)	41118	3-methoxyphenethylformamide		C₁₀H₁₃NO₂	详情	详情
(III)	41119	6-methoxy-3,4-dihydroisoquinoline; 3,4-dihydro-6-isoquinolinyl methyl ether		C₁₀H₁₁NO	详情	详情
(IV)	30324	3-buten-2-one; methyl vinyl ketone	78-94-4	C₄H₆O	详情	详情
(V)	41120	9-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one		C₁₄H₁₇NO₂	详情	详情
(VI)	41121	(11bS)-9-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one		C₁₄H₁₇NO₂	详情	详情
(VII)	41122	(2R,11bS)-9-methoxy-N-methyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-amine; N-[(2R,11bS)-9-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-N-methylamine		C₁₅H₂₂N₂O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

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4

该中间体在本合成路线中的序号：(VI)

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