Synthesis of a Naphthyridone p38 MAP Kinase Inhibitor

Abstract

Compound 1 is a p38 MAP kinase inhibitor potentially useful for the treatment of rheumatoid arthritis and psoriasis. A novel six-step synthesis suitable for large-scale preparation was developed in support of a drug development program at Merck Research Laboratories. The key steps include a tandem Heck-lactamization, N-oxidation, and a highly chemoselective Grignard addition of 4-(N-tert-butylpiperidinyl)magnesium chloride to a naphthyridone N-oxide. The N-oxide exerted complete chemoselectivity via chelation in directing the Grignard addition to the alpha position as opposed to 1,4-addition on the ene-lactam. The dihydropyridyl adduct was in situ aromatized with isobutylchloroformate followed by heating in pyridine. Syntheses of Grignard precursor, N-tert-butyl-4-chloro-piperidine, were accomplished via transamination with a quaternary ammonium piperidone or via addition of methylmagnesium chloride to an iminium ion. Utilizing this chemistry, multi-kilogram preparation of compound 1 was successfully demonstrated.

Development of a Potential Manufacturing Route to PF-00610355: A Novel Inhaled β2-Adrenoreceptor Agonist

“…In particular, salmeterol is prepared from a protected chiral ethanolamine fragment and an electrophile (Scheme , route a) and both formoterol and indacaterol from the reaction between an epoxide and a fully elaborated amine (Scheme , route b). In the case of 8 , the former route was considered less likely to succeed due to the challenge of introducing the quaternary carbon adjacent to the secondary amine, and priority was given to exploration of the latter strategy, focusing on the well-precedented epoxide or halohydrin routes shown in Scheme …”

Applications of and alternatives to π-electron-deficient azine organometallics in metal catalyzed cross-coupling reactions

“…Fu ¨rstner and co-workers have described an iron catalyzed Kumada coupling of 3-pyridyl Grignard reagents with heterocyclic aryl chlorides (eqn (10)). 44 This provides an interesting alternative to the use of the more expensive Hiyama coupling.…”

“…The use of 3-or 4-silyl pyridines in Hiyama cross-couplings is scarce. A rare example, using 3-(6methoxypyridyl) triethylammonium bis (catechol) silicate (10), was recently reported by Seganish and DeShong. 45 The silicate is prepared from the corresponding pyridyl siloxane by treatment with catechol and triethylamine.…”

“…This motif is also found in seretonin receptor agonists 9 and MAP kinase inhibitors. 10 Many P,N ligands are based on arylazine frameworks such as QUINAP. 11 When considering the synthesis of one of these compounds, the development of palladium catalyzed cross-coupling methods has had the greatest impact.…”

Direct arylation of N-heterocycles enabled by photoredox catalysis

“…As representative structural motifs, N-heterobiaryls exist in many natural products, bioactive molecules, agrochemicals and ligands (Scheme 1a). [1][2][3][4][5][6][7][8][9][10][11] For instance, 2-arylpyridines are a key constitutive structure of photocatalysts, in which their substitutions can productively adjust the redox potentials of the photocatalysts. 3,12,13 In addition, 2-(pyridin-2-yl)phenols showed broad applications in luminescent materials as N,O-bidentate ligands.…”