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.
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).