Scaling Up API Syntheses - Pharmaceutical Technology

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Scaling Up API Syntheses
Approaches centre on ways to optimise process conditions and operability.


Pharmaceutical Technology Europe
Volume 24, Issue 8

Approaches centre on ways to optimise process conditions and operability.


Patricia Van Arnum
Process chemists face the challenge of developing cost-effective and efficient commercial manufacturing routes for APIs. They encounter the challenges of increasing product yield, achieving greater stereoselectivity and regioselectivity, and improving process conditions, such as temperature and pressure, all in a means to produce a high-quality pharmaceutical compound in a safe manner A variety of tools may be used in this effort, including the application of green-chemistry approaches, such as biocatalysis, solvent replacement and continuous-flow chemistry, to help achieve more efficient chemical transformations under improved reaction conditions.

Biocatalytic route to simvastatin

In June 2012, Codexis, a company specialising in biocatalysis, and Yi Tang, professor in the Department of Chemical and Biomolecular Engineering at the University of California at Los Angeles (UCLA) (US), were awarded the "2012 Greener Synthetic Pathways Award" as part of the US Environmental Protection Agency's (EPA) Presidential Green Chemistry Challenge Awards for developing a biocatalytic route for making simvastatin, the active ingredient in Merck & Co.'s anticholesterol drug Zocor, which is now off patent (1). Codexis and Tang won the award this year after having made prior submissions of the new process in 2010 and 2011 (2–4).

For the simvastatin route, Codexis licensed technology from Tang. The previous synthetic routes to simvastatin involved converting lovastatin into simvastatin by adding a methyl group that required protecting and then deprotecting other functionalities in the lovastatin molecule in a multistep synthesis. In the first route, lovastatin was hydrolysed to the triol, monacolin J, followed by protection with selective silylation, esterification with dimethyl butyryl chloride and deprotection. The second route involved protecting the carboxylic acid and alcohol functionalities, methylating the C2' carbon with methyl iodide and deprotecting the product. These routes were inefficient because they produced less than 70% overall yield and were mass-intensive due to protection and deprotection (1–4).

The route developed by Tang and his group circumvented protection and deprotection and resulted in greater atom economy, reduced waste and overall less hazardous reaction conditions. First, they cloned LovD, a natural acyltransferase produced by Aspergillus terreus that is involved in synthesising lovastatin and that can accept nonnatural acyl donors. Recognising that LovD might be a type of simvastatin synthase and a starting point for creating a new biocatalytic process, they evolved the enzyme toward commercial utility (1–5). Codexis licensed Tang's technology, engineered the enzyme further and optimised the simvastatin manufacture.

The biocatalyst LovD selectively transferred the 2-methylbutyryl side chain to the C8 alcohol of monacolin J sodium or ammonium salt. The acyl donor, dimethylbutyryl-S-methylmercaptopropionate (DMB-SMMP), is efficient for the LovD-catalysed reaction, is safer than traditional alternatives and is prepared in a single step from inexpensive precursors, according to the awards summary report (1). Codexis licensed this process from UCLA and subsequently optimised the enzyme and the chemical process for commercial manufacture. Codexis carried out nine iterations of in vitro evolution, creating 216 libraries and screening 61,779 variants to develop a LovD variant with improved activity, in-process stability and tolerance to product inhibition (1). The approximately 1000-fold improved enzyme and the new process pushed the reaction to completion at high substrate loading and minimised the amounts of acyl donor and of solvents for extraction and product separation. In the new route, lovastatin is hydrolysed and converted to the water-soluble ammonium salt of monacolin J. (1–5).

As specified in the Presidential Green Chemistry Challenge Awards summary report, the genetically evolved variant of LovD acyltransferase from E. coli uses DMB-SMMP as the acyl donor to make the water-insoluble ammonium salt of simvastatin. The only coproduct of simvastatin synthesis is methyl 3-mercaptopropionic acid, which is recycled. The final yield of simvastatin ammonium salt is more than 97% at a loading of 75 g/L of monacolin J. It avoids the use of several hazardous chemicals including tert-butyl dimethyl silane chloride, methyl iodide and n-butyl lithium. More than 10 metric tons of simvastatin have been manufactured using this new process (1).


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