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.