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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Development of an efficient, scalable, aldolase-catalyzed process for enantioselective synthesis of statin intermediates
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Development of an efficient, scalable, aldolase-catalyzed process for enantioselective synthesis of statin intermediates

机译：开发高效，可扩展，醛缩酶催化的他汀类药物中间体对映选择性合成方法

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摘要

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 stereo-genic 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, downstream chemical steps have been developed to convert the enzymatic product efficiently to versatile intermediates applicable to preparation of atorvastatin and rosuvastatin.
机译：据报道，有一种方法可以有效，对映选择性地生产他汀类降胆固醇药物的通用手性侧链的关键中间体，如立普妥（阿托伐他汀）和克瑞斯托（罗舒伐他汀）。该方法的特点是由一脱氧核糖-5-磷酸醛缩酶（DERA）催化一锅串联醛醇缩合反应，形成6-碳中间体，并由2-碳起始原料安装两个立体中心。相对于已发表的酶促反应条件，已实现了近400倍的容积生产率提高，从而产生了具有商业吸引力的工艺，该工艺已以30.6 g / kg的速率在单批中以100 g的规模运行每小时升催化剂负载也从20到2.0 wt％DERA改善了10倍。这些改进是通过结合从DERAs的环境DNA中发现具有改善的活性和克服底物抑制的反应优化来实现的。 DERA设定了两个立体异构中心，对映体过量> 99.9％，非对映体过量96.6％。另外，已经开发出下游化学步骤以将酶产物有效地转化为适用于制备阿托伐他汀和罗苏伐他汀的通用中间体。

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