Patent ID: 7667049

Claim:
A method for producing a 3-cyclopropylaminomethyl-4-fluoropyrrolidine represented by the following chemical formula (IX): or a salt thereof, or an enantiomeric isomer thereof or a salt of the enantiomeric isomer thereof, comprising the steps of: asymmetrically hydrogenating, with a transitional metal catalyst, a 1-protected-4-oxo-3-pyrrolidine carboxylic acid ester derivative represented by the following chemical formula (I): (wherein R 1 is a protecting group for the amino group; and R 2 is a lower alkyl group) to obtain a 4-hydroxy-3-pyrrolidine carboxylic acid ester derivative of the following chemical formula (II): (wherein R 1 and R 2 are as defined above) or an enantiomeric isomer thereof; hydrolyzing the ester group of the compound of the chemical formula (II) to obtain a 4-hydroxy-3-pyrrolidine carboxylic acid represented by the following chemical formula (III): (wherein R 1 is as defined above) or an enantiomeric isomer thereof; condensing the compound of the chemical formula (III) with a cyclopropylamine represented by the following chemical formula (IV): to obtain an N-cyclopropyl-4-hydroxy-3-pyrrolidine carboxylic amide derivative represented by the following chemical formula (V): (wherein R 1 is as defined above) or an enantiomeric isomer thereof; reducing the amide group of the compound of the chemical formula (V) to obtain a 4-hydroxy-3-cyclopropylamino pyrrolidine derivative represented by the following chemical formula (VI): (wherein R 1 is as defined above) or an enantiomeric isomer thereof; protecting the amino group of the compound of the chemical formula (VI) to obtain a 4-hydroxy-3-cyclopropylamino pyrrolidine derivative represented by the following chemical formula (VII): (wherein R 1 is as defined above; and R 3 is a protecting group for the amino group and has the same definition as R 1 ) or an enantiomeric isomer thereof; fluorinating the hydroxyl group at the 4th position of the compound of the chemical formula (VII) to obtain a 3-cyclopropylaminomethyl-4-fluoropyrrolidine derivative represented by the following chemical formula (VIII): (wherein R 1 and R 3 are as defined above) or an enantiomeric isomer thereof; and removing the amino-protecting groups R 1 and R 3 of the compound of the chemical formula (VIII) to obtain the 3-cyclopropylaminomethyl-4-fluoropyrrolidine represented by the chemical formula (IX) or the salt thereof, or the enantiomeric isomer thereof or the salt of the enantiomeric isomer thereof.