Development of the Commercial Route for the Manufacture of a 5-Lipoxygenase Inhibitor PF-04191834

Autor:	Gerald A. Weisenburger, Brian Patrick Chekal, Janice E. Sieser, Brian C. Vanderplas, David B. Damon, Michael St. Pierre, John G. Van Alsten, Carlos Mojica, Kyle R. Leeman, Danny Lafrance, Carrie Wager, Shu Yu, Rajappa Vaidyanathan, Gregory J. Withbroe, Karen Sutherland, Andrew S. Palm
Rok vydání:	2015
Předmět:	Reaction conditions Catalytic cycle Chemistry Commodity chemicals Yield (chemistry) Organic Chemistry 5-Lipoxygenase Inhibitor chemistry.chemical_element Nanotechnology Physical and Theoretical Chemistry Sulfur Combinatorial chemistry Reductive elimination
Zdroj:	Organic Process Research & Development. 19:1944-1953
ISSN:	1520-586X 1083-6160
DOI:	10.1021/op500412a
Popis:	A de novo three-step-one-pot process for the formation of PF-04191834 was developed. This methodology employed inexpensive, odorless, and readily available commodity chemical iso-octyl-3-mercaptopropionate as a sulfur source, which could be a general alternative to the popular TIPS-SH in the formation of diarylthioethers via Migita coupling. A kinetic study revealed that, at high temperature, reductive elimination could be the rate-limiting step in the catalytic cycle, which opens pathways for the generation of undesired impurities. By proper control of the reaction conditions, the desired API was synthesized in >70% crude yield and in 55% isolated yield after vigorous purifications. This process was successfully demonstrated on a 20 kg scale.
Databáze:	OpenAIRE
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