NOVEL STEREOSELECTIVE SYNTHESES OF THE FUSED BENZAZEPINE DOPAMINE D-1ANTAGONIST HYDRO-7-METHY-5H-BENZO[D]NAPHTH[2,1-B]AZEPIN-12-OL (SCH-39166) - 1 - AZIRIDINIUM SALT BASED SYNTHESES

Several novel enantioselective syntheses of the dopamine D-1 antagonis t (6aS,13bR)-11-chloro-6,6a,7,8,9,13b-hexahydro-7- methyl-5H-benzo[d]n aphth[2,1-b]azepin-12-ol (2) are described in which the key intermedia te was 1-(2,2 yl)-1-methyl-1a,2,3,7b-tetrahydro-1H-naphth[1,2-b] aziri dinium salt (20), The latter species was prepared either from thoxyeth yl)-1a,2,3,7b-tetrahydro-]H-naphth[1,2-b]- azirine (18) by methylation or from the tertiary amino alcohols 2-dimethoxyethyl)methylamino]-1,2 ,3,4-tetrahydro-2 -naphthalenol (23) or 2,2-dimethoxyethyl)methylamino ]-1,2,3,4-tetrahydro -1-naphthalenol (24) by tosylation and in situ ri ng closure. Regioselective trapping of 20 with Grignard reagent (4-chl oro-3-methoxyphenyl)magnesium bromide (10) then afforded the transamin e ro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-1,2,3,4 -tetrahydro-N-met hyl-2-naphth-alenamine (22), which was cyclized to give a,7,8,9,13b-he xahydro-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 novo synthesis from L-homophenylalani ne, and a classical salt resolution sequence, were developed for the p reparation of the key intermediates in chiral form.