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Design of Experiments Helps Increase Yield of Pharmaceutical Intermediate from 70% to 88%

Shanghai Biopharmaleader Co.,Ltd | Updated: Feb 28, 2017

Researchers at Codexis Laboratories Singapore performed a full-factorial designed experiment with 20 runs to determine the impact of four independent variables on product selectivity during a silylation reaction. The experiment revealed that the optimal combination of factors increased the selectivity of the reaction to 97% for silylation on oxygen with less than 2% each for the undesirable alternatives. Codexis researchers adjusted the factors to increase the concentration for improved throughput, resulting in a process that delivered 95% selectivity along with an 88% yield.

A joint research program between Codexis and a leading pharmaceutical manufacturer addressed the production of an O-silylazetidinone, a key intermediate for the synthesis of many beta-lactam antibiotics including ertapenem, meropenem and doripenem, through the silyation of a hydroxyazetidinone. The output of the original process consisted of 70% the desired product where the silyl group is on oxygen. The output also included 11% of an isometric byproduct where the silyl group is on nitrogen and 17% of a third option where the silyl group is on both oxygen and nitrogen (i.e. bis-silylation). 

Codexis develops and commercializes processes to active pharmaceutical ingredients (APIs) and pharmaceutical intermediates using its proprietary biocatalytic processes. The overwhelming majority of APIs have at least one chiral center. Increased regulatory requirements for improved product purity have led to growing demand for stereochemically pure intermediates. Using proprietary biocatalysts, Codexis manufactures virtually 100% chirally pure intermediates and APIs. These are often manufactured directly at high purity, compared to low purity materials that must be isolated after being produced by traditional chemical processes.

Codexis has developed an efficient and selective process for dynamic ketone reduction of  a ketotester to produce a diastereomeric hydroxyketone. Conversion of the diastereomeric alcohol into the O-silylazetidinone requires additional challenging steps including the silyation of the hydroxyazetidinone.  The previous pilot plant process involved treatment of a slurry of hydroxyazetidione in toluene at 25-30oC with imidazole and then feeding in a solution of tert-butyldimethylsilyl chloride (TBSCI) in toluene. After workup and crystallization, this provided the desired product in yields of about 70%. 

A team of Codexis researchers including Steve Collier and Rob Wilson, set about scaling down the current process in the laboratory, addressing the selectivity and yield issues and transferring the process back to the pilot plant in as short a time as possible. The conventional approach to optimizing the factors would have been to run a series of experiments while varying a single factor, sometimes called the one-factor-at-a-time (OFAT) approach. The problem with this approach is that it does not detect interactions between factors or second order effects.


Shanghai Biopharmaleader Co.,Ltd is a young and innovative company specializing in the design and synthesis of organic compounds for pharmaceutical, medicinal chemistry, biotechnology, drug discovery industries and world's top universities.

We specialize in complex, multi-stage custom synthesis and process research. We are capable of supplying mg to multiple-ton quantities of key pharmaceutical intermediates and Bioactive Molecules, pre-clinical and high-throughput screening compounds, analogues, building blocks.

More information on Pharmaceutical Intermediate   http://www.biopharmaleader.net/pharmaceutical-intermediate/


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