ARS | Publication request: DEVELOPMENT OF AN EFFICIENT, SCALABLE, ALDOLASE-CATALYZED PROCESS FOR ENANTIOSELECTIVE SYNTHESIS OF STATIN INTERMEDIATES

Submitted to: Meeting Proceedings
Publication Type: Proceedings
Publication Acceptance Date: December 1, 2004
Publication Date: January 1, 2004
Citation: Greenberg, W.A., Varvak, A., Hanson, S.R., Wong, K., Huang, H., Chen, P., Burk, M.J. 2004. Development of an efficient, scalable, aldolase-catalyzed process for enantioselective synthesis of statin intermediates. #89158. 101(16):5788-5793.

Interpretive Summary: The manuscript reported a process for efficient production of key intermediates for cholesterol-lowering drugs such as Lipitor (atorvastatin) and Crestor (rosuvastatin). The process is an improvement of almost 400-fold in volumetric productivity relative to the published enzymatic reaction conditions. The process also allowed using much less catalyst (about10-fold) compared with published conditions as well. As a result, the new process converts the enzymatic product more efficiently to versatile intermediates applicable to preparation of atorvastatin and rosuvastatin. Economically, it could lower the production cost of atorvastatin and rosuvastatin.

Technical Abstract: A process is reported for efficient, enantioselective production of key intermediates for the common chiral side chain of statin-type cholesterol-lowering drugs such as Lipitor (atorvastatin) and Crestor (rosuvastatin). The process features a one-pot tandem aldol reaction catalyzed by a deoxyribose-5-phosphate aldolase (DERA) to form a 6-carbon intermediate with installation of two stereogenic centers from 2-carbon starting materials. An improvement of almost 400-fold in volumetric productivity relative to the published enzymatic reaction conditions has been achieved, resulting in a commercially attractive process that has been run on up to a 100-g scale in a single batch at a rate of 30.6 g/liter per h. Catalyst load has been improved by 10-fold as well, from 20 to 2.0 wt % DERA. These improvements were achieved by a combination of discovery from environmental DNA of DERAs with improved activity and reaction optimization to overcome substrate inhibition. The two stereogenic centers are set by DERA with enantiomeric excess at >99.9% and diastereomeric excess at 96.6%. In addition, down-stream chemical steps have been developed to convert the enzymatic product efficiently to versatile intermediates applicable to preparation of atorvastatin and rosuvastatin.