• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【分子编号】13954

【品名】(3S)Decahydro-3-isoquinolinecarboxylic acid

【CA登记号】

【 分 子 式 】C10H17NO2

【 分 子 量 】183.25052

【元素组成】C 65.54% H 9.35% N 7.64% O 17.46%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(III)

The synthesis of Ro-31-8959/003 (X) was carried out as follows: Condensation of L-phenylalanine (I) with formaldehyde in concentrated hydrochloric acid gave the tetrahydroisoquinoline (II), which was hydrogenated in 90% acetic acid over rhodium on carbon to yield the decahydroisoquinoline (III) as a mixture of diastereoisomers. Treatment of (III) with benzyl chloroformate in aqueous sodium hydroxide solution gave a mixture of N-protected amino acids which was separated by fractional crystallization of the cyclohexylamine salts to give the (S,S,S)-isomer. Reaction with dicyclohexylcarbodiimide and N-hydroxysuccinimide in dimethoxyethane, followed by treatment of the activated ester with tert-butylamine in dichloromethane and subsequent hydrogenolysis of the benzyloxycarbonyl protecting group gave the decahydroisoquinoline (IV). In the other branch of the synthesis L-phenylalanine was treated with benzyl chloroformate in aqueous sodium hydroxide solution to give the N-protected amino acid. This was converted to the corresponding mixed anhydride with isobutyl chloroformate and N-ethylmorpholine in tetrahydrofuran and immediately reacted with diazomethane in diethyl ether to give the diazomethyl ketone (V). Treatment of (V) with ethereal hydrogen chloride gave the chloromethyl ketone (VI), which on reduction with sodium borohydride in aqueous tetrahydrofuran gave a mixture of diastereoisomeric chlorohydrins. Solvent extraction with boiling n-hexane followed by recrystallization of the less soluble isomer from isopropanol gave pure chlorohydrin (VII), which on treatment with ethanolic potassium hydroxide gave the epoxide (VIII). Condensation of (VIII) with (IV) in ethanol gave the hydroxyethylamine (IX). Hydrogenolysis of (IX) was followed by condensation with N-benzyloxycarbonyl-L-asparagine in tetrahydrofuran in the presence of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide. Hydrogenolysis in ethanol over palladium on charcoal, followed by condensation with quinoline-2-carboxylic acid in tetrahydrofuran in the presence of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, gave the free base, Ro-31-8959/000. Treatment with methanesulfonic acid in aqueous ethanol then afforded the mesylate salt (X), Ro-31-8959/003.

1 Martin, J.A.; Ro-31-8959/003. Drugs Fut 1991, 16, 3, 210.
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) 13952 (S)-(-)-Phenylalanine; L-Phenylalanine 63-91-2 C9H11NO2 详情 详情
(II) 13953 (3S)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid; (S)-(-)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid 74163-81-8 C10H11NO2 详情 详情
(III) 13954 (3S)Decahydro-3-isoquinolinecarboxylic acid C10H17NO2 详情 详情
(IV) 13955 (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide C14H26N2O 详情 详情
(V) 13956 (3S)-1-Imino-4-phenyl-3-[[(2-phenylacetyl)oxy]amino]-2-butanone C18H18N2O3 详情 详情
(VI) 13957 (3S)-1-Chloro-4-phenyl-3-[[(2-phenylacetyl)oxy]amino]-2-butanone C18H18ClNO3 详情 详情
(VII) 13958 (2S,3S)-1-Chloro-4-phenyl-3-[[(2-phenylacetyl)oxy]amino]-2-butanol C18H20ClNO3 详情 详情
(VIII) 13959 N-[(1S)-1-[(2S)Oxiranyl]-2-phenylethyl]-N-[(2-phenylacetyl)oxy]amine; (1S)-1-[(2S)Oxiranyl]-2-phenyl-N-[(2-phenylacetyl)oxy]-1-ethanamine C18H19NO3 详情 详情
(IX) 13960 (3S,4aS,8aS)-N-(tert-Butyl)-2-((2R,3S)-2-hydroxy-4-phenyl-3-[[(2-phenylacetyl)oxy]amino]butyl)decahydro-3-isoquinolinecarboxamide C32H45N3O4 详情 详情
Extended Information