Neurokinin intermediate

Evidences for intermediate conformational states have also been observed in other receptors. Time-resolved peptide-binding studies on the neurokinin receptor revealed that an agonist peptide binds with biphasic... 

A series of cyclobutane derivatives that possess neurokinin-1 (NK1) receptor antagonist activity has been reported.4S These compounds could not be prepared utilizing the classical Strecker reaction conditions, as the intermediate a-aminonitrile 105 could not be hydrolyzed. Thus, ketone 104 was exposed to the Bucherer-Bergs reaction conditions to produce the corresponding hydantoins 106 and 107. The related a-amino acids, 108 and 109, respectively, could be generated by hydrolysis. 

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 27.11). In this reaction, quite high iy -diastereo-selectivity was obtained. The electron-withdrawing imine-protecting Boc-group is important for the reactivity. The Mannich adduct 66 was transformed into a key intermediate alcohol 67 for synthesis of a potent neurokinin substance P antagonist, (-b)-CP-99,994 68. °... 

A third example of drug synthesis consists in the preparation of the human neurokinin receptor antagonist h-NKl 156. An chiral intermediate toward its synthesis is prepared by kinetic resolution of a 2-aryl-cyclopentenol derivative 157 in chloroform with the usual Pd(II) with (—)-sparteine 132 obtaining very high selectivity up to 82.7, which is a really impressive result, with conversion of 50.8% and ee of 94.7% of the product 158 (Scheme 34.41). 

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... 

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