The Synthesis Of Allyl 3-[(2S,4S)-4-(Acetylthio)-1- (Diisopropoxyphosphoryl) Pyrrolidine-2-carboxamino] Benzoate As Intermediate Of Ertapenem

Carbapenem antibiotics are new β-lactam antibiotics developed in 1970s. Ertapenem, a carbapenem antibiotic developed by Merck, was approval by FDA in the United States in 2002. It has a good effect on the treatment of infections, such as, adult infection caused by severe sensitive strains, complicated intra-abdominal infections, skin and soft tissue infections, pneumonia, complicated urinary tract infections, pyelonephritis, and acute pelvic inflammatory disease. The compound is also stable against dehydropeptidase-I (DHP-I) and does not require combination therapy with the enzyme inhibitor cilastatin. Once daily dose is expected to be sufficient for treatment.The first chapter reviews the progress in domestic and abroad in the synthesis of ertapenem. At present, the strategy for the synthesis of these compounds via (3R,4R)-3-[(R)-l-tert-butyl dimethyl silicone ethyl]-4-acetoxy-2-azetidinone (4-AA) as a key intermediates developed by Merck is widely used. They introduct the side chain at the position 2 with [(2S,4S)-4-(acetyl-thiol)-pyrrole- 2- carbamoyl] benzoic acid into the carbapenem nucleus 6-MAP derives from 4-AA in order to obtain the target compound.In the chapter 2, we design the route to synthesise allyl 3-[(2S,4S)-4-(acetylthio)-1-(diisopropoxyphosphoryl) pyrrolidine-2-carboxamino] benzoate from trans-4-hydroxy-L-proline and nitrobenzoic acid in six steps base on the literatures. The compound 5,6 and 7 are new compounds.In this paper, we take the cheap diisopropyl phosphoryl (DIPP) instead of the common tert-butoxycarbonyl (Boc) as amino protecting groups. We use methanesulfonyl chloride to activate the carboxyl, and then form amino amide in order to simplify the reaction steps. Both the target products and the intermediates were confirmed by IR, NMR and mass spectrometry. The rotation of the chiral compounds were measured.