合成路线:Condensation of the anion resulting from 2-fluoro-4-methylpyridine (I) and LDA with N-methoxy-N-methyl-3-trifluoromethylbenzamide (II) afforded ketone (III).Subsequent alpha-oximination of (III) with tert-butyl nitrite and HCl provided the required E-oxime (IV) as the major isomer.Cyclization of (IV) with N-(benzyloxycarbonyl)piperidine-4-carboxaldehyde (V) and ammonium acetate in refluxing AcOH afforded hydroxyimidazole (VI).Further reduction of (VI) to imidazole (VII) was carried out with titanium trichloride.Methylation of the imidazole ring of (VII) by treatment with N,N-dimethylformamide dimethylacetal in boiling toluene gave rise to a mixture of both N-methylated imidazoles,from which the desired compound (VIII) was isolated by column chromatography as the minor isomer.Nucleophilic displacement of the fluoropyridine of (VIII) by (S)-alpha-methylbenzylamine (IX) at 150 C gave the corresponding aminopyridine derivative (X).The N-benzyloxycarbonyl protecting group was finally removed by catalytic hydrogenation over Pd/C.
合成路线:In a modified procedure,displacement of fluoropyridine (VII) by (S)-alpha-methylbenzylamine (IX) afforded aminopyridine derivative (XI).This was then alkylated with iodomethane and Cs2CO3 to provide the required N-methyl imidazole (X) as the major isomer,which was finally deprotected by catalytic hydrogenation over Pd/C.
参考文献标题:Design and synthesis of potent,selective,and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase
文献作者:Liverton,N.J.; Butcher,J.W.; Claiborne,C.F.; Claremon,D.A.; Libby,B.E.; Nguyen,K.T.; Pitzenberger,S.M.; Selnick,H.G.; Smith,G.R.; Tebben,A.; Vacca,J.P.; Varga,S.L.; Agarwal,L.; Dancheck,K.; Forsyth,A.J.; Fletcher,D.S.; et al.
参考来源:J Med Chem 1999,42(12),2180
合成路线:Keto oxime (IV) was converted to the syn amino alcohol (XII) by palladium-catalyzed hydrogenation.Subsequent N-methylation of (XII) to give (XIV) was then achieved via formylation of the primary amine to formamide (XIII) in refluxing ethyl formate,followed by borane reduction.Acylation of the secondary amine (XIV) with N-(benzyloxycarbonyl)piperidine-4-carbonyl chloride (XV) provided amide (XVI).After Swern oxidation of the alcohol group of (XVI),the keto amide (XVII) was cyclized to the desired imidazole (VIII) in boiling ammonium formate.
参考文献标题:An efficient synthesis of tetrasubstituted imidazoles from N-(2-oxo)-amides
文献作者:Claiborne,C.F.; et al.
参考来源:Tetrahedron Lett 1998,39(49),8939
产品链接: CAS No. 189442-43-1››