合成路线1

Alkylation of ethyl 1-benzyloxycarbonyl-3-oxopyrrolidine-4-carboxylate (I) with iodomethane and K2CO3 produced the 4-methylpyrrolidine (II). The keto group of (III) was then protected as the corresponding ketal (IV) with 2,2-dimethyl-1,3-propanodiol (III). Replacement of the benzyloxycarbonyl protecting group of (IV) with a benzyl group (V) was accomplished by catalytic hydrogenolysis, followed by alkylation of the resulting pyrrolidine with benzyl chloride. The ester group of (V) was then reduced to the primary alcohol (VI) using LiAlH4. After conversion of alcohol (VI) to the corresponding mesylate, displacement with NaN3 provided the alkyl azide (VII). This was reduced to the primary amine (VIII) by catalytic hydrogenation over Raney-Ni. Resolution of the racemic amine (VIII) was carried out via acylation with N-tosyl-L-proline (IX), followed by chromatographic separation of the diastereomeric amides. Base-promoted hydrolysis of the chiral auxiliary from the desired diastereoisomer (X) provided the (R)-amine, which was further protected as the N-Boc derivative (XI). The N-benzyl group of (XI) was then removed by catalytic hydrogenolysis over Pd/C to yield the target pyrrrolidine (XII).