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

【结 构 式】

【分子编号】65809

【品名】(S)-2-(Methylamino)-2-oxo-1-phenylethyl 4-methylbenzenesulfonate

【CA登记号】871224-68-9

【 分 子 式 】C16H17NO4S

【 分 子 量 】319.38132

【元素组成】C 60.17% H 5.37% N 4.39% O 20.04% S 10.04%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XII)

Condensation of 3,4-dimethoxyphenethylamine (I) with 4-(trifluoromethyl)hydrocinnamic acid (II) in refluxing toluene affords amide (III), which undergoes Bischler–Napieralski cyclization to the dihydroisoquinoline (IV) upon treatment with POCl3 in acetonitrile. Alternatively, intermediate (IV) is prepared by alkylation of 6,7-dimethoxy-2-methyl-3,4-dihydroisoquinoline (V) with 4-(trifluoromethyl)benzyl bromide (VI) in the presence of LDA (generated in situ from butyl lithium and diisopropylamine) in THF/hexane. Enantioselective transfer hydrogenation of (IV) using triethylammonium formate and Et3N in the presence of dichloro(p-cymene)ruthenium dimer and (R,R)-mesitylenesulfonyl-1,2-diphenylethanediamine (MstDPEN) furnishes the tetrahydroisoquinoline derivative (VII), which can be converted to almorexant by three alternative routes. a) Alkylation with methyl α-bromophenylacetate (VIII) in the presence of DIEA in refluxing THF/dioxane/toluene providing amino ester (IX) as a diastereomeric mixture, which is further hydrolyzed with NaOH in aqueous methanol at 60 °C to yield carboxylic acid (X). Finally, compound (X) is condensed with methylamine hydrochloride in the presence of EDC and HOBt in DMF followed by chromatographic separation of the diastereomers. Alternatively, almorexant is obtained by alkylation of tetrahydroisoquinoline (VII) with either: b) α-bromo-N-methylphenylacetamide (XI) or c) 2(S)-tosyloxy-N-methylphenylacetamide (XII) by means of DIEA in hot THF or butanone (1). Scheme 1.

1 Weller, T., Koberstein, R., Aissaoui, H., Clozel, M., Fischli, W. (Actelion Pharmaceuticals Ltd.). Substituted 1,2,3,4-tetrahydroisoquinoline derivatives. EP 1751111, JP 2007525531, US 2007191424, WO 2005118548.
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) 10098 2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine 120-20-7 C10H15NO2 详情 详情
(II) 65799 3-[4-(Trifluoromethyl)phenyl]propanoic acid 53473-36-2 C10H9F3O2 详情 详情
(III) 65800 N-[2-(3,4-Dimethoxyphenyl)ethyl]-3-[4-(trifluoromethyl)phenyl]propanamide 769172-66-9 C20H22F3NO3 详情 详情
(IV) 65801 1-(4-(Trifluoromethyl)Phenethyl)-6,7-Dimethoxy-3,4-Dihydroisoquinoline 324076-69-9 C20H20F3NO2 详情 详情
(V) 65802 6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinoline; 1-Methyl-6,7-dimethoxy-3,4-dihydroisoquinoline 4721-98-6 C12H15NO2 详情 详情
(VI) 65803 4-Trifluoromethylbenzyl bromide; 4-(Trifluoromethyl)benzyl bromide; 1-(Bromomethyl)-4-(trifluoromethyl)benzene 402-49-3 C8H6BrF3 详情 详情
(VII) 65804 6,7-Dimethoxy-1(S)-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,2,3,4-tetrahydroisoquinoline 769172-81-8 C20H22F3NO2 详情 详情
(VIII) 65805 Methyl alpha-bromophenylacetate; Methyl bromo(phenyl)acetate 3042-81-7 C9H9BrO2 详情 详情
(IX) 65806     C29H30F3NO4 详情 详情
(X) 65807     C28H28F3NO4 详情 详情
(XI) 65808 2-Bromo-N-Methyl-2-Phenyl-Acetamide 51685-62-2 C9H10BrNO 详情 详情
(XII) 65809 (S)-2-(Methylamino)-2-oxo-1-phenylethyl 4-methylbenzenesulfonate 871224-68-9 C16H17NO4S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XII)

The chiral intermediate (XII) is obtained by aminolysis of methyl (S)-(+)-mandelate (XV) with methylamine in MeOH to give 2(S)-hydroxy-N-methylphenylacetamide (XVI), which is treated with p-toluenesulfonyl chloride in the presence of DMAP and DIEA in CH2Cl2 (1). Scheme 3.

1 Weller, T., Koberstein, R., Aissaoui, H., Clozel, M., Fischli, W. (Actelion Pharmaceuticals Ltd.). Substituted 1,2,3,4-tetrahydroisoquinoline derivatives. EP 1751111, JP 2007525531, US 2007191424, WO 2005118548.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 65809 (S)-2-(Methylamino)-2-oxo-1-phenylethyl 4-methylbenzenesulfonate 871224-68-9 C16H17NO4S 详情 详情
(XV) 65811 (S)-(+)-Methyl mandelate; (+)-Methyl (S)-alpha-hydroxyphenylacetate 21210-43-5 C9H10O3 详情 详情
(XVI) 65812     C9H11NO2 详情 详情
Extended Information