Publication details
CRYSTALLIZATION-INDUCED DIASTEREOMER TRANSFORMATION: A COST-EFFECTIVE ROUTE TO DIASTEREOSELECTIVELY PURE DRUGS – THE CASE OF APREPITANT
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| Year of publication | 2023 |
| Type | Appeared in Conference without Proceedings |
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| Description | The pharmaceutical industry produces a large amount of waste per 1 kg of active compound, which is much higher compared to other industries, resulting in more than 3 million tons of waste per year. The reason for it is that the preparation of active pharmaceutical ingredients (API) in most cases requires multi-step synthetic and purification processes. Very often these processes contain resolution techniques for the separation of homochiral organic molecules or the isolation of desired diastereomers. Most pharmaceutically active ingredients are known to be chiral, and one enantiomer or diastereomer is generally preferred over the racemic mixture.[1] Therefore, the implementation of novel cost-effective methods for the isolation of a single stereoisomer is highly desired in pharmaceutical production. One of the efficient methods for the isolation of single stereoisomers from the reaction mixture is called crystallization-induced stereoisomer transformations (CIST). CIST can, in principle, be divided into two main categories: crystallization-induced enantiomer transformations (CIET) and the much more common crystallization-induced diastereomer transformations (CIDT).[2,3] The use of crystallization-induced diastereomer transformations is presented on the industrial production of the drug aprepitant 1. Aprepitant 1 is an orally active human antagonist of neurokinin NK1 receptors, chemically known as 3-{[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-morpholin-4-yl]methyl}-4,5-dihydro-1H-1,2,4-triazol-5-one (Figure), developed by Merck, and marketed with a trading name of Emend, used for the prevention and treatment of acute and delayed nauzea and vomiting in adults related to anti-cancer chemotherapy. The aprepitant molecule contains three stereogenic centers, of which two are part of the morpholine skeleton. Several synthetic strategies have been developed for the preparation of aprepitant 1, [4-7] among which the synthesis starting from enantiopure (1R)-1-[3,5-bis(trifluoromethyl)-phenyl]ethan-1-ol was found to be efficient and scalable. Few methods of the synthesis (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethan-1-ol have been reported mainly from corresponding acetophenone. From them, we have selected the catalytic asymmetric transfer hydrogenation developed by Noyori [8,9] using (1S,2R)-cis-1-aminoindan-2-ol and dichloro(p-cymene)Ru(II)dimer as chiral ligand and metal source for reduction. As a safe and benign hydride source, propane-2-ol has been used as a stoichiometric reductant. The enantiopure alcohol was prepared with an average yield of 94 % and about 90 % e.e. The enrichment via recrystallization through DABCO inclusion complexes from n-heptane and subsequent DABCO removal led to a purity of alcohol of approximately 99 % e.e.[10] The overal yields from starting 1-[3,5-bis(trifluoromethyl)phenyl]ethan-1-one to (R)-alcohol was in the range of 67 – 76 %. The second building block racemic 4-benzyl-3-oxomorpholin-2-yl 2,2,2-trifluoroacetate 2 was prepared from N-benzylaminoethanol and aqueous glyoxylic acid followed by acylation with TFAA. Scheme. Trans-acetalization and crystallization-induced diastereomer transformation (CIDT) processes towards (R,R)-diastereomer 4. |