title: Practical synthesis of a neuropeptide Y antagonist via stereoselective addition to a ketene.
abstract: [Reaction: see text]. 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 degrees 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.
authors.affiliation: Process Research, Process R&D, Laboratories for Technology Development, Banyu Pharmaceutical Co., Ltd., 9-1 Kamimutsuna 3-chome, Okazaki, Aichi 444-0858 Japan. takehiko_iida@merck.com
authors.forename: Takehiko
authors.initials: T
authors.lastname: Iida
authors.forename: Hiroki
authors.initials: H
authors.lastname: Satoh
authors.forename: Kenji
authors.initials: K
authors.lastname: Maeda
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Asakawa
authors.forename: Naotaka
authors.initials: N
authors.lastname: Sawada
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Wada
authors.forename: Chie
authors.initials: C
authors.lastname: Kadowaki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Itoh
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Mase
authors.forename: Steven A
authors.initials: SA
authors.lastname: Weissman
authors.forename: Dave
authors.initials: D
authors.lastname: Tschaen
authors.forename: Shane
authors.initials: S
authors.lastname: Krska
authors.forename: R P
authors.initials: RP
authors.lastname: Volante
mesh_terms: D001965:Bromides / Q000494:pharmacology; D005030:Ethylenes / Q000737:chemistry*; D007659:Ketones / Q000737:chemistry*; D018020:Lithium Compounds / Q000494:pharmacology; D015394:Molecular Structure; D009478:Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D001965:Bromides; D005030:Ethylenes; D007659:Ketones; D018020:Lithium Compounds; D009478:Neuropeptide Y; C040949:lithium bromide; C008223:ketene