Pfizer synthesis

Scheme 11.52 Pfizer synthesis of SEM-protected 2,4-dichloro-7//-p5Trolo[2,3-d]-pyrimidine-5-carbonitrile.

In the first chapter, N. M. Ahmad and J. J. Li (Pfizer, Ann Arbor, USA) discuss the use of palladium in quinoline synthesis, thus filling an important gap in a recent monograph on the uses of palladium catalysis in heterocyclic synthesis authored by the same group. This is followed by an account of pyrimidine-pyridine interconversions by H. C. van der Plas (Wageningen University, The Netherlands) the immense variety of heterocyclic chemistry is illustrated by the large number of diverse strategies for such transformations. 

A summary of the industrial-scale process development for the nitrilase-catalyzed [93] route to ethyl (/ )-4-cyano-3-hydroxy-butyrate, an intermediate in the synthesis of Atorvastatin (Pfizer Lipitor) from epichlorohydrin via 3-hydroxyglutaronitrile (3-HGN) was recently reported (Figure 8.15) [94], The reaction conditions were further optimized to operate at 3 m (330 gL ) substrate, pH 7.5 and 27 °C. Under these conditions, 100% conversion and product ee of 99% was obtained in 16 h reaction time with a crude enzyme loading of 6% (based on total protein, 0.1 U mg-1). It is noted that at pH < 6.0 the reaction stalled at <50% conversion and at alkaline pH a slowing in reaction rate was observed. Since the starting material is of low cost and the nitrilase can be effectively expressed in the Pfenex (Pseudomonas) expression system at low cost, introduction of the critical stereogenic center... 

Workers at Pfizer report a total synthesis of ( )-cytisine via the intramolecular cyclization of 2-methoxypyridine 26 <00OL4201>. 

A similar problem was noted by researchers from Pfizer and Dowpharma in their synthesis of (S)-3-aminomethyl-5-methylhexanoic acid (Pregabalin, 5) via the enantioselective hydrogenation of an acrylonitrile-type substrate 3 (Scheme 44.6) [41]. 

Corey, E. J. Bakshi, R. K. Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551. Elias 1. Corey (1928—) was bom in Metbuen, Massacbusetts. After earning bis Pb.D. at MET from John Sbeeban at age 22, be began bis independent academic career at tbe University of Illinois in 1950 and moved to Harvard University in 1959. Corey won tbe Nobel Prize in Chemistry in 1990 for development of novel methods for the synthesis of complex natural compounds and retrosynthetic analysis. He is still carrying out active research at Harvard. Prof. Corey has been a consultant to Pfizer for more than 50 years. 

There are five basic sources of pharmaceuticals. By dollar value of products, fermentation is probably the most important, whereas by tonnage, chemical synthesis is dominant. Fermentation is used for antibiotics such as penicillins and tetracyclines. Chemical synthesis provides drugs such as the psychotropics and antihistamines. Animal extracts provide hormones. Biological sources lead to vaccines and serums. Vegetable extracts provide steroids and alkaloids. The top ten pharmaceutical companies in order of revenues are the following Merck, Pfizer, Bristol-Myers Squibb, Johnson ... 

The first enantioselective synthesis of pregabalin (2) was developed by Yuen and co-workers at Pfizer using Evans chiral oxazolidinone chemistry (Yuen et al., 1994). 

Kissel, Ramsden, and other researchers at Pfizer and Chirotech jointly published a novel chiral synthesis of pregabalin (2) in 2003 based on asymmetric hydrogenation (Burk et al., 2001, 2003). Their synthesis started with the condensation of isobutyralde-hyde with acrylonitrile under Baylis-Hillman conditions to give allylic alcohol 65. This alcohol was activated as the carbonate 66 and subjected to palladium-catalyzed car-bonylation conditions to give cyanoester 67. The ester 67 was hydrolyzed and converted to... 

Schnur and colleagues at Pfizer " " prepared a wide variety of 2,4-oxazoli-dinediones that have been evaluated as hypoglycemic agents and as aldose reductase inhibitors (Tables 6.8, Fig. 6.17 6.9, Fig. 6.18 Fig. 6.19). Several approaches were evaluated including a trimethylsilylcyanide-mediated synthesis of cyanohydrins that were then converted to the corresponding imidates in situ followed by cyclization and work-up. This methodology has been successfully... 

From an industrial viewpoint there are several drivers that need to be satisfied before a catalyst can be successfully implemented in production plants. Technically there have been various challenges to be met including the synthesis of the requisite ligands, catalyst sensitivity to the environment in which it is applied, reproducibility in product enantiomeric excess (ee) and yield, feasibility in the use of commercial solvents and IP issues around freedom to operate . All these issues have been factors that have influenced commercial exploitation. An example of how one or more of these factors can decide the selection of a catalyst system was described by Hawkins,where Pfizer s selection of the Degussa DEGUPHOS catalyst system over the technically superior DUPHOS system in the synthesis of a Candoxatiil intermediate (shown in Figure 1.1) was decided by royalty payments and freedom to operate issues. 

TRICHICKENFOOTPHOS Figure 1.7 Pfizer -amino acid synthesis. 

Despite the fact that solvent effects on enzyme enantioselectivity appear to resist our efforts to rationalize their outcome using commonly accepted solvent descriptors, the effects are certainly there. An impressive example is provided in a report on the successful resolution of ds/trans-( 1 R,5 R)-bicyclo[3.2.0]hept-6-ylidene-acetate ethyl esters, intermediates in the synthesis of GABA (y-aminobutyric acid) analogs, by the Pfizer Bio transformations and Global R D groups (Scheme 2.2) [136]. From a screening protocol, CaLB was identified as a reactive catalyst for the hydrolysis of the racemic mixture of / //-os lor enantiomers with approximately equal activity for the ds- and tmns-isomers and a rather modest (E = 2.7) preference for the /Z-(lR,5R)-enantiomers. Application of medium engineering resulted in a phenomenal increase in the enantioselectivity (addition of 40% acetone, E > 200), while the ds- and trans-isomers were still converted at an almost equal rate. 

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