合成路线:The partial reduction of 4-methylanisole (I) with sodium in liquid ammonia/THF/ethanol gives the enol ether (II),which is condensed with 2-chloro-6-fluoroaniline (III) by means of TiCl4 in chlorobenzene/THF to yield the imine (IV),which,without isolation,is aromatized with I2 in AcOH/THF to provide N-(2-chloro-6-fluorophenyl)-N-(4-methylphenyl)amine (V).The acylation of (V) with 2-chloroacetyl chloride (VI) at 90 C affords the 2-chloroacetamide (VII),which is cyclized by means of AlCl3 by heating at 160?C to afford 1-(2-chloro-6-fluorophenyl)-5-methylindolin-2-one (VIII).Finally,this compound is hydrolyzed with NaOH in refluxing ethanol/water and acidified with 1N HCl.Alternatively,the intermediate N-(2-chloro-6-fluorophenyl)-N-(4-methylphenyl)amine (V) can also be obtained by condensation of 2-chloro-N-(4-methylphenyl)acetamide (IX) with 2-chloro-6-fluorophenol (X) by means of K2CO3 in isopropanol to yield 2-(2-chloro-6-fluorophenoxy)-N-(4-methylphenyl)acetamide (XI),which is treated with MeONa in methanol to obtain the target secondary amine (V).
参考文献标题:Process for phenylacetic acid derivs.
文献作者:Xu,D.; Allmendinger,T.; Acemoglu,M.; Calienni,J.V.; Cercus,J.; Loiseleur,O.; Sedelmeier,G.(Novartis AG; Novartis-Erfindungen VmbH)
参考来源:WO 0123346
合成路线:The partial reduction of 4-methylanisole (I) with sodium in liquid ammonia/THF/ethanol gives the enol ether (II),which is condensed with 2-chloro-6-fluoroaniline (III) by means of TiCl4 in chlorobenzene/THF to yield the imine (IV),which,without isolation,is aromatized with I2 in AcOH/THF to provide N-(2-chloro-6-fluorophenyl)-N-(4-methylphenyl)amine (V).The acylation of (V) with 2-chloroacetyl chloride (VI) at 90 C affords the 2-chloroacetamide (VII),which is cyclized by means of AlCl3 by heating at 160?C to afford 1-(2-chloro-6-fluorophenyl)-5-methylindolin-2-one (VIII).Finally,this compound is hydrolyzed with NaOH in refluxing ethanol/water and acidified with 1N HCl.Alternatively,the intermediate N-(2-chloro-6-fluorophenyl)-N-(4-methylphenyl)amine (V) can also be obtained by condensation of 2-chloro-N-(4-methylphenyl)acetamide (IX) with 2-chloro-6-fluorophenol (X) by means of K2CO3 in isopropanol to yield 2-(2-chloro-6-fluorophenoxy)-N-(4-methylphenyl)acetamide (XI),which is treated with MeONa in methanol to obtain the target secondary amine (V).
合成路线:The reduction of 2-iodo-5-methylbenzoic acid (I) with BH3/THF in THF gives 2-iodo-5-methylbenzyl alcohol (II),which is treated with refluxing 48% HBr to yield the benzyl bromide (III).Reaction of (III) with NaCN in ethanol/water afford the phenylacetonitrile (IV),which is hydrolyzed with NaOH in refluxing EtOH/water to provide the phenylacetic acid (V).Reaction of (V) with SOCl2 in refluxing dichloromethane gives the corresponding acyl chloride (VI),which is treated with dimethylamine in diethyl ether/THF to yield 2-(2-iodo-5-methylphenyl)-N,N-dimethylacetamide (VII).Condensation of (VII) with 2-chloro-6-fluoroaniline (VIII) by means of Cu powder,Cu2I2 and K2CO3 in refluxing xylene affords 2-[2-(2-chloro-6-fluorophenylamino)-5-methylphenyl]-N,N-dimethylacetamide (IX),which is finally hydrolyzed with NaOH in refluxing butanol/water.
参考文献标题:Lumiracoxib
文献作者:Bay閟,M.; Silvestre,J.S.; Sorbera,L.A.; Castar,J.
参考来源:Drugs Fut 2002,27(8),740
产品链接: CAS No. 220991-20-8››