Unfolding Catalytic Routes to APIs - Pharmaceutical Technology

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Unfolding Catalytic Routes to APIs
Chemocatalytic and biocatalytic routes show promise for more efficient syntheses of select active ingredients.

Pharmaceutical Technology

Biocatalysis in API synthesis

In addition to chemocatalysis, biocatalysis is used to synthesize APIs or intermediates. Historically, pharmaceutical companies have been reluctant to use biocatalysts because naturally occurring biocatalysts have not been viable economically for commercial production. This situation, however, is changing as biocatalysts may be engineered to address some of the drawbacks of conventional chemistry. Enzyme-catalyzed reactions can exhibit higher enantioselectivity, regioselectivity, substrate specificity, and stability, and therefore require mild conditions (i.e., ambient pressures and temperatures) to react while achieving higher reaction efficiency and product yields.

Biocatalysis is part of the toolbox of major pharmaceutical companies and fine-chemical producers, such as DSM (Heerlen, the Netherlands), Evonik (Düsseldorf, Germany), Dowpharma (Midland, MI), Kaneka (Osaka, Japan), Lonza (Basel, Switzerland), and PCAS (Longjumeau, France). It has also generated companies and researchers to specialize in biocatalysis.

A case in point is Codexis (Redwood City, CA). In April 2008, Codexis filed a Form S-1 with the US Securities and Exchange Commission for an initial public offering for $100 million. Codexis has carved out a niche in biocatalysis, including biocatalysis for pharmaceutical applications. The company was founded in 2002 as a wholly owned subsidiary of Maxygen (Redwood City, CA). Codexis added to its toolbox in pharmaceutical manufacture with the acquisitions of Jülich Fine Chemicals in 2005 and BioCatalytics in 2007. Codexis's pharmaceutical customers have included Arch Pharmalabs (Hyderabad, India), Bristol-Myers Squibb (New York), Dr. Reddy's Laboratories (Hyderabad), Merck & Co., Pfizer (New York), Ranbaxy Laboratories (Gurgaon, India), Schering-Plough (Kenilworth, NJ), and Teva Pharmaceutical (Jerusalem).

As an example of its work in pharmaceuticals, Codexis developed four enzymes and reduced the cost of two intermediates for producing atorvastatin, the API in Pfizer's "Lipitor." It supplies Pfizer with one of these intermediates and generic atorvastatin manufacturers with the other intermediate, according to the company's S-1 filing.

The key advanced chiral intermediate in atorvastatin is tert-butyl (4R, 6R)-6-cyanomethyl-2, 2-dimethyl-1,3-dioxane-4-acetate (ATS-8 or TBIN). Pfizer's traditional ATS-8 process uses a sodium borohydride (NaBH4) reduction of the corresponding (5R)-hydroxy-3-ketoester (ATS-6 or HK) under cryogenic conditions to give, after quenching, the (3R, 5R)-dihydroxyester (ATS-7 or diol). The ATS-6 is first converted in situ to a diastereodirecting boron chelate by treating diethylmethoxyborane that is reacted with NaBH4 below 85 °C to promote diastereoselectivity. After the reaction, the borane reagent is regenerated and recovered by repeated methanol quenches and vacuum distillations. Several percent of the undesired (3S)-diastereomer is formed. Subsequently, the ATS-7 diol, an oil, is protected as its acetonide, ATS-8. ATS-8's diastereopurity is upgraded by crystallization with concomitant product loss (2).

To improve the synthesis, Codexis developed a biocatalytic route. The process involves reducing ATS-6 to stereopure ATS-7. It uses a ketoreductase biocatalyst specifically evolved to reduce ATS-6 with perfect diastereoselectivity under green reaction conditions (300 g/L in water at ambient temperature and pressure) with a previously evolved glucose dehydrogenase biocatalyst that returns the oxidized cofactor nicotinamide adenine dinucleotide phosphate (NADP+) to its reduced state (NADPH). This process eliminates the use of boron reagents, reduces solvent use by 85%, decreases waste by 60%, and increases the yield of ATS-7 with greater stereopurity. Codexis's biocatalytic process is used commercially to supply ATS-8 to generic atorvastatin manufacturers (2).


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