Aprepitant synthesis

Both enantiomers of l-[3,5-bis(trifluoromethyl)phenyl]ethan-2-ol are of importance in the pharmaceutical industry, and so considerable effort has been expended in their asymmetric synthesis. The (7 )-enantiomer is a building block for aprepitant, a neurokinin-1 (NK-1) antagonist used for the treatment of chemotherapy-induced nausea (Figure 1.11). ... 

The initial synthesis of aprepitant (1), which relies on a Tebbe olefination and reduction to install a methyl group on the benzyl ether side chain, is shown in Scheme 3.8,19 The initial steps are from a literature-precedented synthesis of p-fluorophenyl glycine based on conversion of chiral oxazolidinone 33 to azide 34. Formation of morpholinone intermediate 36 proceeds via benzylation and reaction with 1,2-dibromoethane. 

After the identification of aprepitant as a clinical candidate, Merck invested considerable process research toward an improved synthesis of aprepitant, which culminated in the elegant manufacturing process shown in Scheme 6.21,22 The key step relies on displacement of a trifluoroacetate from intermediate 48 by the optically active alcohol intermediate 49. The synthesis of 49 was accomplished via an oxazaborolidine-catalyzed borane reduction of the corresponding acetophenone. Although the displacement resulted in an almost equal mixture of the two diastereomers 50 and 51, the desired diastereomer 50 could be recovered in high yield by base-catalyzed equilibration of the mixture and crystallization. Addition of p-fluorophenyl magnesium bromide followed by hydrogenolysis afforded the key intermediate 40, which can be readily converted to 1 as detailed in the previous synthesis. 

Merck has also developed fosaprepitant (21), a phosphate prodrug of aprepitant with improved solubility and the synthesis is detailed in Scheme 8. It is based on phosphorylation with a ben2yl-protected reagent to give 62 followed by debenzylation and formation of the 7V-methyl-/)-glucamine salt.9... 

A neurokinin inhibitor whose strueture differs markedly from aprepitant (200) incorporates a substituted tetrazole ring. The synthesis of the tetrazole-containing moiety of vofopitant (241) start by acylation of substituted aniline 231 with trifluoroaeetyl ehloride to afford the amide (232). Reaction of that under Mitsonobu eonditions leads to the enol chloride (233). Treatment of 233 with sodium azide probablty starts with addition-elimination of azide ion this undergoes internal 1,3-cycloaddition to form the tetrazole ring. Catalytie hydrogenation then removes the benzyl... 

The intermediate lactol was to be subjected to a diastereoselective acetalization with (/ )-3,5-bistrifluoromethylphenyl ethanol. In order to probe this diastereoselective coupling, a variety of chiral iV-R lactols 76 was desired. In addition, since the ultimate success to aprepitant via this route depended on crystalline intermediates, numerous A -substituted lactols 76 needed to be prepared in order to investigate the crystalline properties of downstream intermediates. Accordingly, a versatile procedure to access a variety of A-substituted morpholine-2,3-diones 75 and 2-hydroxymorpholin-3-ones 76 was required. This was accomplished by the condensation of amino alcohols 74 with diethyl oxalate to afford diones 75, which could be selectively reduced to the corresponding lactols 76 (Scheme 22). A host of these substrates were synthesized however, none offered any significant advantage over the simple A-Bn lactol 69. Thus, the objective became the development of a concise synthesis for this substrate. 

A Redesigned, Efficient Synthesis of Aprepitant, the Active Ingredient in Emend A New Therapy for Chemotherapy-Induced Emesis... 

Greener Synthesis of Aprepitant, a Therapy for Chemotherapy-Induced Discomforts... 

Aprepitant, which has two heterocyclic rings and three stereogenic centers, is a challenging synthetic target. Merck s first-generation commercial synthesis required six synthetic steps, and was based on the discovery synthesis. The raw material and environmental costs of this route, however, along with operational safety issues compelled Merck to discover, develop, and implement a completely new route to aprepitant. 

The alternative synthetic pathway for the synthesis of aprepitant is an example of minimizing environmental impact while greatly reducing production costs. Because Merck implemented the new synthesis... 

For more examples of synthetic approaches that have reduced the use of ammonia, see also the case studies describing catalytic dehydrogenation of diethanolamine, HCN-free synthesis of the amino acids, and HCN-free synthesis of the specialty chemical, sarcosinate, all listed under the section on hydrogen cyanide, and the case study describing synthesis of the drug aprepitant. 

Both enantiomers of 3,5-bis-trifluoromethylphenylethanol 11 are used as key intermediates in the stereoselective S5mthesis of NK-1 receptor antagonists. The (R)-isomer is a key building block in the synthesis of the Merck drug aprepitant... 

R)-l-[3,5-Bis(trifluoromethyl)phenyl]ethanol (Scheme 57.6) is a valuable intermediate in the synthesis of the orally active NKi receptor antagonist aprepitant (an antiemetic... 

Transfer hydrogenation has also been applied by scientists at Merck to the synthesis of alcohol 44, a key intermediate on route to aprepitant, an NK-1 receptor antagonist used for the treatment of chemotherapy... 

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