Process for Producing 3,4-Disubstituted Pyrrolidine Derivative and Production Intermediate Thereof

A method for producing an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine represented by the following chemical formula (IX):

• or an enantiomer thereof and/or a salt or a hydrate 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 general formula (I):
• (wherein R1 is a protecting group for amino group;
• and R2 is a lower alkyl group) to obtain an optically active 4-hydroxy-3-pyrrolidine carboxylic acid ester derivative of the following general formula (II):
• (wherein R1 and R2 are as defined above) or an enantiomer thereof;
• hydrolyzing the ester group of the compound of the general formula (II) to obtain an optically active 4-hydroxy-3-pyrrolidine carboxylic acid represented by the following general formula (III):
• (wherein R1 is as defined above) or an enantiomer thereof;
• condensing the compound of the general formula (III) with cyclopropylamine (IV):
• to obtain an optically active N-cyclopropyl-4-hydroxy-3-pyrrolidine carboxylic amide derivative represented by the following general formula (V):
• (wherein R1 is as defined above) or an enantiomer thereof;
• reducing the amide group of the compound of the general formula (V) to obtain an optically active 4-hydroxy-3-cyclopropylamino pyrrolidine derivative represented by the following general formula (VI):
• (wherein R1 is as defined above) or an enantiomer thereof;
• protecting the amino group of the compound of the general formula (VI) to obtain an optically active 4-hydroxy-3-cyclopropylamino pyrrolidine derivative represented by the following general formula (VII):
• (wherein R1 is as defined above;
• and R3 is also an protecting group for amino group and is the same definition as R1) or an enantiomer thereof;
• fluorinating the hydroxyl group at 4th position of the compound, of the general formula (VII) to obtain an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine derivative represented by the following general formula (VIII):
• (wherein R1 and R3 are as defined above) or an enantiomer thereof;
• and
• removing the amino-protecting groups R1 and R3 of the compound of the general formula (VIII) to obtain the desired compound.