Merck synthesis neurokinin-1 receptor antagonist

Neurokinin-1 receptor antagonists such as 120 (Scheme 2.19) have been identified as potential antiinflammatory agents by researchers at Merck Research Laboratories. To access the tra 5-3,4-disubstituted 8-lactone 119, a key intermediate in the synthesis of 120, an asymmetric conjugate addition strategy was developed. As depicted in Scheme 2.19, reaction of the lithium enolate derived from the amide 115 with enoate 116 afforded... 

SCHEME 2.19. Merck synthesis of neurokinin-1 (NKi) receptor antagonist 120. 

Researchers at Merck utilised the Jacobsen epoxidation as the key stereodefining step in their synthesis of a variety of substituted piperidines which were screened as neurokinin-1 receptor antagonists (Scheme 14.55). Lee et al, effectively epoxidised cis styrene derivative 141 to prepare the key intermediate (142) in good yield and 94% ee. Utilising 142, the authors prepared piperidine 143, which was further elaborated to the final targets (144 and 145). Formation of 143 proceeds by a 5-exo cyclisation of 142 followed by ring-expansion to furnish the piperidine ring systems. This process... 

Pseudoephedrine was used as a chiral auxiliary in Merck s synthesis of neurokinin-1 (NKj receptor antagonists 226. NKi receptor antagonists have been shown to prevent acute delayed chemotherapy-induced nausea and vomiting. The enolate of (f ,f )-pseudoephedrine amide 222 was formed by reaction with LiHMDS in the presence of TMEDA, and subsequent reaction with ot,p-unsaturated ester afforded the desired product 224 in 56% yield with the required diastereoisomer as the major product. Following reduction of the ester functionality, the chiral auxiliary was removed via acid induced cyclisation to afford lactone 225. This was transformed into NKi receptor antagonist 226 in eight steps (Scheme 14.77). 

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See also in sourсe #XX -- [ ]

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