合成路线1

The hydrolysis of N-(tert-butoxycarbonyl)-4(R)-(tert-butyldimethylsilyloxy)-L-proline methyl ester (I) with NaOH gives the corresponding protected amino acid (II), which is condensed with malonic acid monomethyl ester (II) by means of carbonyldiimidazole (CDI) in THF to afford the L-prolylacetate (IV). The reduction of (IV) with NaBH4 in refluxing THF-methanol gives (2S,4R)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-(1,3-dihydroxypropyl)pyrrolidine (V), which is acylated with tosyl chloride to the primary monotosylate (VI). The chromatographic separation of (VI) over SiO2 yields the [2S(1'R),4R]-enantiomer (VII), which by treatment first with methylamine followed by 4,6-dimethyl-2-(4-nitrobenzyloxycarbonylthio)pyrimidine (PNZ-Pym) affords the N-protected methylamino derivative (VIII). The mesylation of (VIII) with methanesulfonyl chloride followed by reaction with potassium thioacetate gives (2S,4S)-4-acetylthio-2-[1(R)-hydroxy-3-(4-nitrobenzyloxycarbonylamino) propyl]-1-(4-nitrobenzyl)pyrrolidine (IX), which is treated with NaOH in methanol-water to afford the corresponding thiol (X). The condensation of (X) with (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester (XI) by means of diisopropylethylamine in acetonitrile yields the protected compound (XII), which is finally hydrolyzed and deprotected by hydrogenation with H2 over Pd/C and treatment with HCl.