Process for the preparation of chiral pyrollidine-2-yl- methanol derivatives

A process for the preparation of a chiral pyrollidine-2-yl-methanol derivative of formula I

• or a salt thereof, wherein
• R1 is aryl or heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of C1-4-alkyl, halo-C1-4-alkyl, C1-4-alkoxy and halogen,
• said process comprising
• a) transforming a pyrrolidine carboxylic acid derivative of formula II
• with an N,O-dialkylhydroxylamine of formula V
• R4ONHR3 V
• into the carbamoyl pyrrolidine derivative of formula III
• wherein R2 is an amino protecting group;
• and R3 and R4 are each independently C1-4-alkyl;
• b) reacting the carbamoyl pyrrolidine derivative of formula III with a Grignard reagent of the formula
• R1MgHal
• to form the aroyl pyrrolidine derivative of formula IV
• wherein
• R1 is aryl or heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of C1-4-alkyl, halo-C1-4-alkyl, C1-4-alkoxy and halogen;
• Hal is halogen;
• and
• R2 is an amino protecting group;
• and
• c) removing the amino protecting group R2 from the aroyl pyrrolidine derivative of formula IV, and subsequently hydrogenating the aroyl pyrrolidine derivative in the presence of a hydrogenation catalyst to form the chiral pyrollidine-2-yl-methanol derivative of formula I.