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A six-step practical synthesis of (6aS,13bR)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5H-benzo[d]naphtho-[2,1-b]azepin-12-ol, a selective D1 dopamine receptor, is developed starting from (1S,2S)-phenyl-2-amino-1,3-propanediol. An acid-promoted stereo-and regioselective cyclization of the benzazepine ring was established. Three double reactions in which two functional groups are transformed in a single step were developed. These include the double hydrolysis, the double reduction, and the cyclization and demethylation. The use of practical and economical reagents reduced the cost significantly.

Several novel enantioselective syntheses of the dopamine D 1 antagonist (6aS,13bR)-11-chloro-6,6a,7,8,9,13b-hexahydro-7methyl-5H-benzo[d]naphth[2,1-b]azepin-12-ol (2) are described in which the key intermediate was 1-(2,2-dimethoxyethyl)-1methyl-1a,2,3,7b-tetrahydro-1H-naphth[1,2-b]aziridinium salt (20). The latter species was prepared either from 1-(2,2dimethoxyethyl)-1a,2,3,7b-tetrahydro-1H-naphth[1,2-b]azirine (18) by methylation or from the tertiary amino alcohols 1-[(2,2-dimethoxyethyl)methylamino]-1,2,3,4-tetrahydro-2naphthalenol (23) or 2-[(2,2-dimethoxyethyl)methylamino]-1,2,3,4-tetrahydro-1-naphthalenol (24) by tosylation and in situ ring closure. Regioselective trapping of 20 with Grignard reagent (4-chloro-3-methoxyphenyl)magnesium bromide (10) then afforded the trans amine 1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-N-methyl-2-naphthalenamine (22), which was cyclized to give 11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-12-methoxy-5H-benzo[d]naphth[2,1-b]azepine (9), a known precursor of 2. Several enantioselective syntheses, including a Jacobsen epoxidation route, a de noWo synthesis from L-homophenylalanine, and a classical salt resolution sequence, were developed for the preparation of the key intermediates in chiral form.