Doripenem synthesis

the hydroxyl proline is protected as the PNZ ester 32 first in 95% yield. The protected proline acid 32 was converted to the methyl ester with refluxing sulfuric acid in methanol followed by conversion of the alcohol to the mesylate 34 in 91% overall yield from 30. The mesylate ester was reduced with sodium borohydride to provide alcohol 35, which was converted without purification to thiol ester 36 by reacting with potassium thioacetate. Mitsunobu reaction of alcohol 36 with BOC-sulfonyl urea 38, which was prepared from chlorosulfonyl isocyanate with ammonia in tbutanol in 90% yield, provided the key thioacetate intermediate 39. Finally, protected doripenem 42 was prepared by coupling thiol 40, obtained by hyrolysis of thioacetate 39, with enolphosphate 41 in 88% yield. Deprotection of intermediate ester and carbamate protecting groups via hydrogenation gave the desired carbapenem VI, which was isolated after crystallization. Final form of the drug doripenem was prepared by sterilization, crystallization and granulation.