3- Benzazepines synthesis

Tetrahydro-l-benzazepin-2-ones are formed from a-tetralone by Beckmann or related reactions (CHEC 5.16.4.1.1). Classical ring closures (of the Friedel-Crafts, Dieckmann, etc. types) can also be applied to benzazepine synthesis (74AHC(17)45). 

The dinitration route from benzazepine to varenicline was high yielding, direct, and sufficiently safe for commercial operation. These characteristics defined the process chemistry objective to enable a benzazepine synthesis for manufacturing. The preferred process route to varenicline evolved with dedicated research, however, as described below. 

Classical ring closures (of the FriedelCrafts, Dieckmann, etc., types) can be applied to benzazepine synthesis <1974AHC(17)45>. Particularly useful are approaches to benzazepines based on transition metal-catalyzed cyclizations , as illustrated by the synthesis of 1-benzazepine derivative 149 in high yield by Ru-catalyzed ring-closing metathesis with Grubbs I catalyst (Scheme 87) <2005JOC1545>. 

Dibenzazepines and other tricyclic azepines, general review 84HC(43,1)1. Heteroazepines, cyclization and cycloaddition reactions of 81H(15)1569. 5//-Isoindolo[l,2-h 3]benzazepines, synthesis and biological activity of ... 

A novel route to the rhoeadines starts with the readily available immonium salt 13 which was subjected to Schotten-Baumann conditions the aldehyde 15 was formed in 91% yield via the intermediate A-benzoylated pseudobase 14. Intramolecular aldol condensation of the aldehyde was induced by a strong base, thus generating the lactonic rhoeadine amide 16 in 56% yield. This short series of transformations represents a new benzazepine synthesis. 

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