合成路线1

The reaction of 3-fluoro-4-methylbenzoic acid (I) with malonic acid monoethyl ester potassium salt (II) by means of CDI and MgCl2 in THF gives 3-(3-fluoro-4-methylphenyl)-3-oxopropionic acid ethyl ester (III), which can alternatively be obtained by condensation of 3'-fluoro-4'-methylacetophenone (IV) with diethyl carbonate (V) by means of NaH in THF. The condensation of ketoester (III) with 5-(2-nitrovinyl)-2,3-dihydrobenzofuran (VI) (obtained by condensation of 2,3-dihydrobenzofuran-5-carbaldehyde (VII) with nitromethane (VIII) by means of NH4OAc in hot acetic acid) yields the adduct (IX), which is reductively cyclized by hydrogenation with H2 over Raney-Ni in acetic acid, followed by a treatment with TFA to afford the pyrrolidine (X) as a mixture of isomers. The isomerization of (X) with DBU in refluxing toluene provides (rac)-(trans,trans)-pyrrolidine derivative (XI), which is hydrolyzed with NaOH and protected with Boc2O to give the racemic carboxylic acid (XII), which is suitable for optical resolution. The optical resolution of (XII) is performed with (R)-(+)-alpha-methylbenzylamine and the resulting chiral acid is esterified with HCl and ethanol, yielding the (R,R,S)-esterified precursor (XIII). The condensation of (XIII) with 2-bromo-N,N-dibutylacetamide (XIV) by means of DIEA in acetonitrile affords the chiral pyrrolidine-carboxylate (XV), which is finally hydrolyzed with NaOH to provide the target carboxylic acid.