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).
Condensation of the intermediate pyrrolidine (XII) with the fluoronaphthyridine (XIX) provided adduct (XX). Simultaneous cleavage of the ketal and N-Boc groups under acidic conditions gave (XXI). The keto group of (XXI) was finally converted to the title O-methyloxime by treatment with O-methylhydroxylamine in pyridine.
In a similar procedure, ester (IV) was reduced to the corresponding alcohol (XIII) using LiAlH4. After conversion of (XIII) to the corresponding mesylate (XIV), displacement by NaN3 provided azide (XV). Reduction of (XV) to the primary amine (XVI) was effected by treatment with PPh3 in moist acetonitrile. Resolution of the racemic amine (XVI) was achieved by acylation with N-tosyl-L-proline (IX) followed by chromatographic separation. The desired isomer (XVII) was hydrolyzed with KOH in isopropanol, and the resultant amine was further protected as the N-Boc derivative (XVIII). Catalytic hydrogenolysis of (XVIII) then provided the target pyrrolidine (XII).