As contract manufacturers and pharmaceutical companies gather later this month for Informex in New Orleans, discussions of
approaches for the synthesis of active pharmaceutical ingredients (APIs) and intermediates will invariably ensue. A review
of several sources, including contract manufacturers, academicians, and recent literature reveals several interesting approaches
in API synthesis.
PHOTOS.COM/M.MCEVOY, Structures courtesy of US FOOD AND DRUG ADMINISTRATION
Nucleoside analogs have provided a rich structural class for the design of novel anticancer and antiviral drugs. "Leustatin"
(cladribine) by Ortho Biotech and "Fludara" (fludarabine phosphate), developed by Berlex Oncology and now owned by Bayer Healthcare (Leverkusen, Germany), are two members of that class that were evaluated as potential anticancer agents. "While these were
exciting discoveries, there was some initial concern in the discovery community that the glycosidic bond of those agents might
prove too labile for ultimate utility in the clinic," explains Stephen Munk, president and CEO of Ash Stevens (Detroit, MI). Ash Stevens is the contract manufacturer of fludarabine phosphate, the API in Fludara. While both of these agents were subsequently approved
as drugs by various regulatory agencies, including the USFood and Drug Administration, that concern led scientists at the
Southern Research Institute in Birmingham, Alabama, to consider analogs that would retain activity while affording a chemical
structure with a glycosidic bond with enhanced stability, says Munk. Those studies led to the discovery by Secrist and Montgomery
of a nucleoside analog now known as clofarabine (1).
Clofarabine (see Figure 1) is the API in "Clolar," an anticancer therapy developed by Ilex Oncology (San Antonio, TX). Ilex
was acquired by Genyzme (Cambridge, MA) in December 2004. Clolar was approved by FDA in 2004 as a treatment for children with refractory or relapsed acute lymphoblastic leukemia.
Figure 1 ALL Figures Courtesy of US Food and Drug Administration
Clofarabine is a second-generation adenosine-related antimetabolite. The original synthesis of clofarabine involved chromatography
and was not adequately cost-effective or scalable. The task for improving the synthesis was to develop a new process that
would avoid chromatography, produce a drug substance of high purity, and improve the cost-effectiveness of the manufacturing
Workers at Ilex Oncology (now part of Genyzme) and Ash Stevens developed a very efficient process that proved quite scalable (2). That process involved preparing a suitably
protected bromosugar and coupling with chloroadenine in the presence of potassium tert-butoxide to afford protected clofarabine that had excellent anomeric purity following crystallization, explains Munk. Subsequent
deprotection and further crystallization afforded clofarabine drug substance with minimal α-anomer as an impurity. "The process
proved scaleable and avoided chromatographic purification steps, which can be very costly at plant scale," says Munk. Ash
Stevens successfully commercialized the process.
Early this year, the Centre for Synthesis and Chemical Biology in Ireland reported progress in synthesizing novel lipoxin-based molecules that may be used as anti-inflammatory agents.
The Centre for Synthesis and Chemical Biology is a collaboration in the chemical sciences between University College Dublin (UCD), Trinity College Dublin (TCD), and the
Royal College of Surgeons in Ireland (RCSI). The UCD center forms part of the UCD Conway Institute of Biomolecular and Biomedical
Lipoxins were first isolated in the 1980s. These molecules appear at the site of inflammation, leading researchers to believe
that they are involved in the process and thus may have potential therapeutic applications. Some of the beneficial action
ascribed to aspirin is now believed to be due to the formation of lipoxins. Both Lipoxin A4 and Lipoxin B4 have been detected
in a variety of inflammatory conditions.
"Lipoxins have been shown to promote phagocytosis of the neutrophils," said Pat Guiry, professor of organic chemistry at the
UCD School of Chemistry and Chemical Biology, in an April 2007 press release. Reducing the number of neutrophils reduces the
inflammation. "However the therapeutic potential of lipoxins is limited by reactions with enzymes in our bodies which break