Patent ID: 7544815

Claim:
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 (1) hydrogen (2) C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, (3) cyclopentenone, which is unsubstituted or substituted with halogen, hydroxyl or methyl, (4) —(CO)—C 1-6 alkyl, (5) —(CO)—NH 2 , (6) —(CO)—NHC 1-6 alkyl, and (7) —(CO)—N(C 1-6 alkyl)(C 1-6 alkyl); X is independently selected from the group consisting of: (1) hydrogen, (2) fluorine, and (3) methyl; 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 2 O and a second quenching with an aqueous inorganic acid to provide an enone of Formula (5) 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 2 R with a second reducing agent in an aprotic solvent to provide a triol of Formula (10) 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)