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【结 构 式】 
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【药物名称】Almorexant, ACT-078573 【化学名称】(2R)-[6,7-Dimethoxy-1(S)-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,2,3,4-tetrahydroisoquinolin-2-yl]-N-methyl-2-phenylacetamide 【CA登记号】871224-64-5, 871224-62-3 (racemate), 913358-93-7 (hydrochloride) 【 分 子 式 】C29H31F3N2O3 【 分 子 量 】512.5632 |
【开发单位】Actelion Pharmaceuticals, Ltd. (CH); being developed in collaboration with GlaxoSmithKline. 【药理作用】Dual orexin OX1/OX2 antagonist, Treatment of sleep disorders. |
合成路线1
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
The bromo amide intermediate (XI) is prepared by condensation of phenylacetyl chloride (XIII) with N-methylhydroxylamine hydrochloride in the presence of Et3N in CH2Cl2 to produce the Weinreb amide (XIV), which is then acylated with methanesulfonyl chloride and Et3N followed by ultrasound-promoted rearrangement of the N-sulfonyloxy amide intermediate in the presence of DIEA and LiBr in acetonitrile (1). Scheme 2.
| 【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 |
|---|---|---|---|---|---|---|
| (XI) | 65808 | 2-Bromo-N-Methyl-2-Phenyl-Acetamide | 51685-62-2 | C9H10BrNO | 详情 | 详情 |
| (XIII) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (XIV) | 65810 | N-Methylphenylacetohydroxamic Acid; N-Hydroxy-N-Methyl-2-Phenyl-Acetamide; N-Hydroxy-N-Methyl-2-Phenyl-Ethanamide | 72229-75-5 | C9H11NO2 | 详情 | 详情 |
合成路线3
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. |