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.
ILLUSTRATION: M. MCEVOY. PHOTOGRAPHY: PHOTOS.COM
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
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).
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
Figure 1: Merck & Co.'s Januvia (sitagliptin), a new molecular entity approved in 2006. (US FOOD AND DRUG ADMINISTRATION)
Production for colesevelam
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.
DSM's manufacturing facility in Linz, Austria. (DSM)