Improving Routes in API Manufacturing

Catalytic routes to producing atorvastatin and sitagliptin are recent advancements.
Jul 02, 2007


ILLUSTRATION: M. MCEVOY. PHOTOGRAPHY: PHOTOS.COM
Resolving a problem in the synthesis of an active pharmaceutical ingredient (API) or in scale-up is critical for the drug's commercial success. Several recent examples underscore the versatility of approaches to API manufacturing.

Catalytic routes

Pfizer, Inc.'s (New York) "Lipitor" (atorvastatin) is the pharmaceutical industry's top-selling drug, with 2006 sales of $13.6 billion, according to IMS Health (Fairfield, CT). A key intermediate in Lipitor is ethyl (R)-4-cyano-3-hydroxybutyrate, which can be produced through biocatalytic routes.

Dowpharma (Midland, MI) uses a nitrilase developed by Diversa Corporation (San Diego) for the asymmetric hydrolysis of 3-hydroxyglutaronitrile to make ethyl (R)-4-cyano-3-hydroxybutyric acid, which is then converted to ethyl (R)-4-cyano-3-hydroxybutyrate. The route to making ethyl (R)-4-cyano-3-hydroxybutyrate starts with epichlorohydrin, which is subjected to a cyanide reaction. This step is followed by an enzyme desymmetrization (100% theoretical yield) using a nitrilase engineered by Diversa to work at 3-M substrate concentration to give 99% conversion and 99% enantiomeric excess (1, 2).

A key part of the process is the scale-up of the production of the nitralase, which Dowpharma does via its "Pfenex" expression technology to give soluble, active enzyme in titers in excess of 25 g/L fermentation broth. The final step is a simple esterification (1, 2).

Codexis, Inc. (Redwood City, CA) also developed a biocatalytic process for making ethyl (R)-4-cyano-3-hydroxybutyrate. The process involves two enzymes that catalyze the enantioselective reduction of ethyl 4-chloroacetoacetate by glucose to form an enantiopure chlorohydrin. In the second step, a third evolved enzyme catalyzes the biocatalytic cyanation of the chlorohydrin to cyanohydrin under neutral conditions (2).


Figure 1: Merck & Co.'s Januvia (sitagliptin), a new molecular entity approved in 2006. (US FOOD AND DRUG ADMINISTRATION)
Merck & Co. Inc.'s (Whitehouse Station, NJ) "Januvia" (sitagliptin) (see Figure 1), a new molecular entity approved by the US Food and Drug Administration (Rockville, MD) in 2006 to treat Type 2 diabetes, is a chiral-β amino acid derivative. In collaboration with Solvias AG (Basel, Switzerland), Merck advanced an approach for the asymmetric catalytic hydrogenation of unprotected enamines to synthesize sitagliptin using a ferrocenyl ligand in a rhodium-based catalyst. This approach improved yield and reduced waste from the reaction (3).

Production for colesevelam


DSM's manufacturing facility in Linz, Austria. (DSM)
The production of colesevelam hydrochloride, the API in "WelChol," is an example of a successful scale-up for an API. DSM Pharma Chemicals, a business unit of DSM Pharmaceutical Products (Parsippany, NJ), is evaluating increasing production to meet increased demand for colesevelam, an oral polymeric, lipid-lowering agent. DSM produces colesevelam at its small-molecule manufacturing facility in Linz, Austria.