Novel Stereoselective Syntheses of the Fused Benzazepine Dopamine D₁ Antagonist (6aS,13bR)-11-Chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5H- benzo[d]naphth[2,1-b]azepin-12-ol (Sch 39166):  1. Aziridinium Salt Based Syntheses

Abstract

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.

Novel Stereoselective Syntheses of the Fused Benzazepine Dopamine D1 Antagonist (6aS,13bR)-11-Chloro-6,6a,7,8,9,13b-hexahydro-7-methyl- 5H-benzo[d]naphth[2,1-b]azepin-12-ol (Sch 39166): 2. l-Homophenylalanine-Based Syntheses

“…This concludes a formal total synthesis of 1 since 2 has been previously converted to 1 . However, to confirm the stereochemical integrity, 2 (prepared from 6 ) was converted to O -methyl 20 , whose enantiomeric excess was shown to be 95% ee by chiral HPLC (see Scheme ).…”

“…In the preceding paper we described several enantioselective syntheses based on a chiral aziridinium salt approach to the novel, selective, dopamine D 1 receptor antagonist Sch 39166 ( 1 ), whose pharmacological profile makes it an important commercial synthetic target . In this paper, we describe a number of alternative stereoselective syntheses of 1 starting from the readily available synthon (+)- l -homophenylalanine ( 6 )…”

Boron Reagents in Process Chemistry: Excellent Tools for Selective Reductions

“…The use of alkylamine boranes such as TBAB for reductive amination is very advantageous when the reaction is carried out in acidic media. Draper and co-workers effectively used TBAB to reduce enamine intermediates for the synthesis of a dopamine D1 antagonist (Sch 39166) . Substituted tetralone 167 was condensed with an amine to the enamine and reduced in situ with TBAB to a 9:1 mixture of cis / trans isomers 168 (Scheme ).…”

Synthesis, Structural Characterization and Biological Evaluation of N‐Protected Cyclopropylethylcarbamates as Potential Histone Deacetylase Inhibitor

“…Compounds 7 and 9 were treated with LiOH in tetrahydrofuran (THF)/H 2 O at −78 to 0 °C for 20 min to yield primary alcohols 8 and 10 , which were readily subjected to acetylation with acetyl chloride in dichloromethane to generate N‐protected acetates 11 and 12 in 54% and 50%, two step yields, respectively. Finally, N‐protected acetate ( 11) was deprotected with 4 m aqueous HCl solution in 1,4‐dioxane at 0 °C to give amine·HCl salt ( 13) in 85% yield (14), while removal of Cbz group by using hydrogenation reaction of 12 was unsuccessful giving decomposed products. In order to investigate optimal reaction condition for generation of terminal alcohol 8 from bromide 7 , compound 8 was treated with various bases, such as LiOH, NaOH, KOH and Ba(OH) 2 in THF/H 2 O as cosolvent system.…”