Intermediate Of Penem Synthetic Technology Research

In this study work, we have synthesised the key intermediate of penem, includingbiapenem and meropenem.The side chain of biapenem,methyl-7-oxo-1-azabicyclo [3.2.0]-hept-2-en-3-yl]thio-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium inner salt, was synthesized fromhydrazine via condensation, allylation, deprotection of ketimine, bromination, cyclization,thioacetylation, methanolysis, oxidation, defomylation,cyclization and reduction over11steps, and purity is98.0%. All procedures of preparation were smoothly without operationproblem. All regent and solvent purchased from commercial source were inexpensive,convenient and available. The process was suitable for scale-up and manufacture.Trans-4-Hydroxy-L-proline was treated with P-nitrobenzyl chloroformate to giveN-protected4-hydroxyproline, carboxylic acid was transformed into amide by activationwith isopropyl chloroformate followed by reaction with the dimethylamine hydrochloricacid salt.The hydroxyl group was mesylated with methanesulfonyl chloride andtriethylamine to give mesylate.Treatment of the mesylate with potassium thioacetate gavethioacetate which was hydrolyzed to give the target molecule.Meropenem’s side chain,nitrobenzyloxycarbonyl)-1-pyrrolidine;(2S-cis)-2-[(Dimethylamino)carbonyl]-4-mercapto-1-pyrrolidinecarboxylic acid (4-nitrophenyl) methyl ester, was obtainedfrom multi-steps, over yield of5steps is41.6%. The product was detected by IR, NMRand HPLC with purity of99.0%.