Neurokinin receptor antagonist, synthesis

SCHEME 34.41. Asymmetric secondary alcohol oxidation kinetic resolution step in the synthesis of human neurokinin receptor antagonist h-NKl 156. 

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). 

To obtain neurokinin-1 (NKi) receptor antagonists. Cooper and co-workers [410] synthesized a series of variously substituted indoles by means of a Fischer indole synthesis on a solid phase. Thus, EUman resin [411], based on Kenner s safety-catch Hnker [318], was first reacted with 4-(4-chlorobenzoyl)butyric acid affording (598) and then treated with differently substituted phenyUiydrazines, affording the required indoles (599). These compounds were then cleaved from the resin using bromoacetonitrile, and subsequently coupled in solution with the desired amines under standard conditions (600) (Scheme 125). 

A recent publication described a short enantioselective synthesis of (+)-L-733,060, a selective and potent nonpeptide neurokinin substance P receptor antagonist. The key chirality-inducing step involved a Shi epoxidation of homoallylic carboxylate 89. Subsequent intramolecular reductive cyclization of azidolactone constructed the piperidine ring. 

Apart from linear unfunctionahzed nitroalkanes, various other prochiral nitro-aUcanes bearing aryl, alcohol, ether, and ester groups also participate effectively in reactions promoted by 25, producing sy -P-nitroamines in good yields and high enantiomeric excesses [32]. The utihty of this methodology was demonstrated by the synthesis of the neurokinin-1 receptor antagonist CP-99,994 (Scheme 29.14). 

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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