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Development of a Commercial Process To Prepare AMG 232 Using a Green Ozonolysis–Pinnick Tandem Transformation

2018; American Chemical Society; Volume: 84; Issue: 8 Linguagem: Inglês

10.1021/acs.joc.8b02390

1520-6904

Brian M. Cochran, Michael T. Corbett, Tiffany L. Correll, Yuan‐Qing Fang, Tawnya G. Flick, Siân C. Jones, Maria Victoria Silva Elipe, Austin G. Smith, John L. Tucker, Filisaty Vounatsos, Greg Wells, David L. Yeung, Shawn D. Walker, Matthew M. Bio, Seb Caille,

Chemical Reactions and Isotopes

A robust process to manufacture AMG 232 was developed to deliver drug substance of high purity. Highlights of the commercial process development efforts include the following: (i) use of a novel bench-stable Vilsmeier reagent, methoxymethylene-N,N-dimethyliminium methyl sulfate, for selective in situ activation of a primary alcohol intermediate; (ii) use of a new crystalline and stable isopropyl calcium sulfinate reagent ensuring robust preparation of a sulfone intermediate; (iii) development of a safe ozonolysis process conducted in an aqueous solvent mixture in either batch or continuous manufacturing mode; and (iv) control of the drug substance purity by crystallization of a salt rejecting impurities effectively. The new process was demonstrated to afford the drug substance (99.9 LC area %) in 49.8% overall yield from starting material DLAC (1).