Practical Synthesis of a Neuropeptide Y Antagonist via Stereoselective Addition to a Ketene

The synthesis of neuropeptide Y antagonist 1, currently under clinical investigation for the treatment
of obesity, is described. The convergent synthesis from trans-spirolactone carboxylic acid intermediate 2a and aminopyrazole 3 is predicated on a stereoselective route to the former. The coupling
reaction of ethyl 4-oxocyclohexanecarboxylate (10a) with lithiated isonicotinamide 11 was
investigated in detail, but even optimized conditions only provided a 45:55 ratio of trans:cis isomers
(12a:12b). While selective crystallization schemes were developed to isolate the thermodynamically
less stable trans isomer 2a, improved stereocontrol was subsequentially achieved by the application
of ketene chemistry. The ketene formation and quench was investigated under a variety of conditions
aimed at maximizing the trans:cis ratio. Reacting a mixture of carboxylic acids 2a and 2b with
POCl3 in THF, followed by concomitant addition of tert-butyl alcohol in the presence of TMEDA at
35 °C provided a 4:1 ratio of trans:cis tert-butyl esters (18a:18b) via in situ ketene formation. Ester
hydrolysis, followed by selective crystallization of undesired 2b as the HCl salt, led to isolation of
2a in 47% overall yield. Aminopyrazole intermediate 3 was synthesized via the condensation reaction
of 2-fluorophenylhydrazine hydrochloride (4a) with acrylonitrile derivative 5 in 65−70% yield.
Coupling of advanced intermediates 2a and 3b via activation with thionyl chloride gave a 92%
yield of 1.