Main > SURGERY > 3. PostOperative Nausea & Vomitting > Treatment with AntiEmetics > Aprepitant > Co.: USA. M. (Brand Cap./Patents) > Green Synthesis Description

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Aprepitant has a morpholine core with two substituents attached to adjacent ring carbons and a third substituent attached to the morpholine ring nitrogen. "Overall, the molecule contains three chiral centers in close proximity to one another as part of a beta-amino acetal arrangement, making it a challenging synthetic target. The new synthesis assembles aprepitant in only three steps by merging four compound fragments of comparable size and complexity. To begin, enantiopure trifluoromethylated phenylethanol is coupled to a racemic morpholine precursor. The desired isomer of the resulting intermediate crystallizes out of solution, leaving behind an undesired isomer. But rather than separating and discarding the unwanted isomer, the chemists control the reaction conditions to achieve a "crystallization-induced asymmetric transformation," converting the unwanted isomer completely to the desired isomer. In the additional two steps, a fluorophenyl group is stereoselectively attached to the morpholine ring and a triazolinone side chain is added to the ring. The streamlined route doubles the overall yield to 76% and significantly reduces operating costs and the environmental impact. Besides eliminating several hazardous reactants, the synthesis has reduced both the amount of water used and the amount of reagents and solvents needed by 80%. Relative to the initial synthetic route, 340,000 L of waste has been eliminated per metric ton of aprepitant produced, an 85% reduction. Because the new synthesis was implemented during the first year of aprepitant production, the benefits will be realized over nearly the entire product lifetime.




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