Industrial processes carbapenems

Carbapenem antibiotics (29) can be manufactured from intermediates obtained by Ru(BINAP)-catalyzed reduction of a-substituted P-keto esters by a dynamic kinetic resolution (Scheme 12.8). 4-Acetoxy azetidinone (30) is prepared by a regioselective RuCl3-catalyzed acetoxylation reaction of 31 with peracetic acid 46 This process has been successful in the industrial preparation of the azetidinone 30 in a scale of 120 tons per year.47 The current process has changed ligands to 3,5-Xyl-BINAP (3c), and 31 is obtained in 98% ee and >94% de (substrate-to-catalyst ratio, or S/C ratio = 1,000).23... 

A convenient biocatalytic process has been developed using a novel whole-cell biocatalyst for the preparation of (R)-l,3-butanediol (BDO) by stereo-specific oxidoreduction on an industrial scale. (R)-l,3-BDO is an important chiral synthon for the synthesis of various optically active compounds, such as azetidinone derivatives, which are used to prepare penem and carbapenem antibiotics for industrial usage. 

A powerful application of this technology has been demonstrated by the conversion of racemic p-ketoesters to a single stereoisomer via asymmetric reduction combined with dynamic kinetic resolution. Cationic ruthenium complexes were employed in the conversion of 28 to 29, a key intermediate in the synthesis of carbapenem antibiotics (Scheme 14.10). Increased steric bulk on the aryl groups was required to give high diastereoselectivity as well as enantioselectivity, and this process was used for industrial production on a scale of 100 metric tonnes per year. 

Catalytic asymmetric hydrogenation processes have been at the forefiont of practical applicadons. Following the classical Monsanto s L-DOPA production using DiPAMP-Rh catalyst, BINAP-Ru catalysts have been used in the industrial synthesis of a P-lactam key intermediate to carbapenem antibiofics (Takasago InL Carp.), 1,2-ptopanedioi (SO tons ear),... 

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