Figure 2 ALL Figures Courtesy of US Food and Drug Administration
|
Merck & Co.'s (Whitehouse Station, NJ) sitagliptin is a chiral-β amino-acid derivative (see Figure 2). 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 (7).
Specifically, Merck discovered that hydrogenation of unprotected enamines using rhodium salts of a ferrocenyl-based ligand
as the catalyst produces β-amino acid derivatives of high optical purity and yield. Merck applied the method in the final
synthetic step. The dehydro precursor to sitagliptin used in the asymmetric hydrogenation is prepared in a one-pot procedure.
Following hydrogenation, Merck recovers and recycles over 95% of the rhodium. The reactive amino group of sitagliptin is only
revealed in the final step, and therefore there is no need for protecting groups. The new synthesis has only three steps,
increasing the overall yield by nearly 50%, and reducing the amount of waste by 80% (7). Asymmetric hydroformylation is another approach in producing single-enantiomer compounds. Hydroformylation can produce synthetically
useful aldehydes in atom economical transformations using readily available alkenes, dihydrogen, and carbon monoxide, but
generally, enantioselective hydroformylation has not been well developed. The development of new chiral ligands to produce
catalysts with high activity and selectivity, however, is changing this situation (8). A case in point is work being done at the University of Wisconsin at Madison. Several years ago, Professor Clark Landis and his research group began a collaboration with Dowpharma (Midland, MI) to apply 3,4-diazaphospholane ligands to the problem of enantioselective hydroformylation. These compounds
are easily synthesized by the condensation of primary phosphines with azines. With bisphospholane ligands, rapid hydroformylation
of substrates such as styrene, allyl cyanide, and vinyl acetate is effected with high enantiomeric excess (89%, 90%, and 97%,
respectively), high branch:linear ratios (20:1, 6:1, and 50:1, respectively) at rates similar to commodity scale, nonenantioselective
hydroformylation. These results showing excellent selectivity have rekindled interest in the application of similar phosphine
and phosphite ligands, many of which were developed for application in enantioselective hydrogenation, to asymmetric hydroformylation,
including asymmetric hydroformylation of vinyl arenes. References 1. P.L. Bonate et al.,"Discovery and Development of Clofarabine: A Nucleoside Analog for Treating Cancer," Nat. Rev. Drug Discov. 5 (10), 855–863 (2006). 2. W.L. Bauta et al., "A New Process for Antineoplastic Agent Clofarabine," Org. Process Res. Dev. 8 (6) 889–896 (2004). 3. "Lipoxin Analogs With Improved Performance," Chem. & Eng. News 85 (46), 45 (2007). 4 P. Guiry et al., "Aromatic Lipoxin A4 and Lipoxin B4 Analogues Display Potent Biological Activities," J. Med. Chem. 50 (24), 5894–5902 (2007). 5. Q. Chen et al., "Enzymatic Total Synthesis of Enterocin Polyketides," Nat. Chem. Biol. 3 (9), 557–558 (2007). 6. I.C. Lennon, N.B. Johnson, and P. Moran, "Manufacture of Asymmetric Catalysts" Pharm. Technol. 31 Pharmaceutical Ingredients suppl., s6–s13 (2007). 7. P. Van Arnum, "Optimizing Strategies for API Synthesis and Formulation Development," Pharm. Technol. 30 (11), 44–48 (2006). 8 P. Van Arnum, "Advances in Asymmetric Synthesis," Pharm. Technol. 31 (9), 58–65 (2007).
|
Speed, Resolution, Reproducibility, Flexibility, Durability: Unmatched in sample throughput & data precision, Shimadzu's Prominence Ultrafast LC (UFLC) delivers data without compromise. Learn more.
Processing & Packaging Online Auction - November 24th, 2009 - 9-4 ET
DJS Enterprises - Since 1991 buying and selling high quality, reasonably priced New, Used and Reconditioned Process and Packaging Equipment for the Pharmaceutical, Vitamin, Food and Confectionery Industries.
Buy new and used pharmaceutical equipment, used process equipment and laboratory equipment at LabX. Auctions, classifieds, and post FREE wanted ads to locate equipment.
Swagelok® DR series valve design saves space, minimizes entrapment, extends diaphragm life. See how.
Applying E-Commerce to Support Discovery and Development of Medicines: Key Lessons and Learnings Tuesday, December 15 @ 11:00 a.m. ET
Million Dollar Biotech & Pharmaceutical Equipment Online Auctions