Synthesis

Scalable biocatalytic process for asymmetric reduction in the production of montelukast

Liang, Lalonde, Borup, Mitchell, Mundorff, Trinh, Kochrekar, Cherat, Pai.  Development of a Biocatalytic Process as an Alternative to the (−)-DIP-Cl-Mediated Asymmetric Reduction of a Key Intermediate of Montelukast. Org. Process Res. Dev. 2010, 14, 193-198. DOI: 10.1021/op900272d

This article from researchers at Codexis describes the development of a biocatalytic (i.e. enzyme-catalyzed) method for creating the lone stereocenter in the synthesis of montelukast sodium, aka Merck’s asthma drug Singulair. The original Merck process route includes an enantioselective ketone reduction using a boron reagent derived from alpha-pinene called (-)-DIP-Cl. The reaction works well: high yield, high enantioselectivity (although still requiring a recrystallization step to upgrade from ~95% to 99% ee), and (-)-DIP-Cl is made in one step from cheap starting materials. The downside is that at least 1.5 equivalents of (-)-DIP-Cl must be used, and the reagent is moisture sensitive and corrosive. Codexis, being in the enzyme business, decided to find an enzyme that would catalyze this same reaction. Continue reading

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