Making API Synthesis Greener - Pharmaceutical Technology

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Making API Synthesis Greener
The authors explain chemical transformations that are achievable through certain biocatalytic routes.


Pharmaceutical Technology
Volume 36, Issue 9, pp. s12-s15


Plant focus: High-potency manufacturing and sustainability at Pfizer
Innovation was achieved by delivering a green process that was scalable, derived from readily available feedstocks, and used off-the-shelf selectAZyme enzymes. From retrosynthetic analysis, it was shown that the registered starting material could be made from feedstocks that would not have any long-term supply issues and could be sourced readily from India and China. Having the proposed route on paper, the next step was to synthesize the key intermediates and begin enzyme screening.


Table I: Comparison of process conditions and efficiencies for a selected synthesis when made from a chemical route and a biocatalytic route.
The project involved an early-stage bioresolution that resulted in a carboxylic acid product with > 96% enantiomeric excess (ee). From this point, a bioreduction step introduced another chiral center. Key to this enzyme screening was to find a carbonyl reductase (CRED) enzyme that was able to stereospecifically reduce the ketone of the desired enantiomer feedstock and not the undesired (2% ee) enantiomer from the bioresolution step. The CRED identified resulted in a stereospecific reduction and subsequent biopolish of the diastereomeric mixture. The remaining undesired ketone was easily removed using conventional work-up at the next step. The process ran from start to finish using two solvent combinations. Having developed the process, all stereoisomers (seven different products) were synthesized readily from other key selectAZyme enzymes, so analytical development could be undertaken to determine the fate of these potential impurities. The summarized advantages of the green enzyme process are shown in Table I.

It is clear from the example described herein that biocatalysis offers an attractive approach for a synthesis, which can result in greener processes and lower API costs. Advances in evolution technologies and metagenomic programs help to further enhance biocatalysis as a tool in chemical syntheses. Biocatalysis is a maturing technology and aids in the supply and delivery of chiral intermediates, fine chemicals, and APIs.

Tom Moody, PhD,* is head of biocatalysis and isotope chemistry, and Gareth Brown, PhD, is biocatalysis senior chemist, both at Almac, Stranmillis Road, Belfast, Northern Ireland, BT95AG,

*To whom correspondence should be addressed.


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