Patent ID: 7544815
Filing Date: 2009-06-09
Classification: C07D

Abstract:
1. A process of making hydroisoindoline tachykinin receptor antagonists of Formula (I) and pharmaceutically acceptable salts thereof, wherein R1 is selected from the group consisting of X is independently selected from the group consisting of: comprising: Step (a) reacting a phenyl acetic acid of Formula (2) with SOCl 2 in an aprotic solvent optionally in the presence of a first catalyst to provide a compound of Formula (3) Step (b) reacting the compound of Formula (3) with NHMeOMe in the presence of an aqueous inorganic base to provide a Weinreb amide of Formula (4) Step (c) reacting the Weinreb amid of Formula 4 with a suitable Grignard reagent in an second aprotic solvent followed by a first quenching with Ac Step (d) reacting the enone of Formula (5) with a silane reagent in a third aprotic solvent and an organic base to provide a diene of Formula (6) Step (e) reacting a diene of Formula (6) with a fumarate of Formula (7) wherein R is (−)-menthyl and a Lewis acid in a non-polar solvent to provide a compound of Formula (8) Step (f) hydrolyzing a compound of Formula (8) with suitable hydrolysis reagents in an organic polar solvent to provide a compound of Formula (9) Step (g) reducing the ketone functionality of the compound of Formula (9) with a first reducing agent, followed by reduction of CO Step (h) reacting the triol of Formula (10) with an alkylsulfonyl chloride in the presence of an organic base to provide a compound of Formula (11) wherein R 2 is methyl, ethyl or propyl, Step (i) reacting the compound of Formula (11) with compound of Formula (12) in the presence of an acid catalyst in an aprotic solvent to produce a compound of Formula (13)  Step (j) cyclizing the compound of Formula (13) with allylamine in a polar solvent to provide a compound of Formula (14)  Step (k) reacting the compound of Formula (14) with third catalyst followed by addition of acid to provide a compound of Formula (15) as an acid salt; Step (l) reacting the acid salt of the compound of Formula (15) with a functionalizing reagent in a polar solvent to provide the compound of Formula (I)