The condensation of 6-fluoro-2-methylindole (I) with beta-chloropropionitrile (II) by means of ethylmagnesium iodide (that forms the magnesium salt of (I)) in refluxing ether gives 3-(6-fluoro-2-methyl-3-indolyl)propionitrite (III), which is hydrolyzed with KOH in refluxing water yielding 3-(6-fluoro-2-methyl-3-indolyl)propionic acid (IV) (1). The condensation of (IV) with 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (V) by means of ethyl chloroformate and triethylamine in refluxing THF affords 1-[3-(6-fluoro-2-methyl-3-indolyl)propionyl]-4-hydroxy-4-(3-trifluromethylphenyl)piperidine (VI), which is reduced with LiAlH4 in refluxing THF giving 1-[3-(6-fluoro-2-methyl-3-indolyl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (VII). The ozonolysis of (VII) in HOAc affords 1-[3-(2-acetamido-4-fluorobenzoyl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (VIII), which is finally hydrolyzed with concentrated HCl in refluxing EtOH
Sulfenylation of the Grignard reagent derived from ethyl 5-chloroindole-2-carboxylate (I) with S-phenyl benzenethiosulfonate affords the 3-phenylsulfanyl indole (II). This is then alkylated with 4-chlorobenzyl chloride (III) in the presence of potassium hexamethyldisilazide to yield the N-benzyl indole derivative (IV). Finally, hydrolysis of ethyl ester (IV) by means of potassium trimethylsilanolate under anhydrous conditions produces the target carboxylic acid (1,2).
The reaction of 4-fluoro-2-nitrobenzoic acid (IX) with refluxing SOCl2 gives the corresponding acyl chloride (X), which is then condensed with alpha-acetyl-gamma-butyrolactone (XI) by means of Mg(OEt)2 in toluene yielding alpha-acetyl-alpha-(4-fluoro-2-nitrobenzoyl)-gamma-butyrolactone (XII). The hydrolysis of (XII) with HCl affords alpha-(4-fluoro-2-nitrobenzoyl)-gamma-butyrolactone (XIII), which by treatment with HBr (d, 1.48) at 85 C is converted into gamma-bromo-4-fluoro-2-nitrobutyrophenone (XIV). The ketalization of (XIV) with ethyleneglycol and ethylenesulfite by means of p-toluenesulfonic acid in refluxing toluene yields the corresponding ketal (XV), which is condensed with the piperidine (V) by means of K2CO3 in hot methyl isobutylketone giving 4-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidino]-1-(4-fluoro-2-nitrophenyl)-1,1-ethylenedioxy-n-butane (XVI). The hydrolysis of (XVI) HCl in refluxing isopropanol affords gamma-[hydroxy-4-(3-trifluoromethylphenyl)piperidino]-4-fluoro-2-nitrobutyrophenone (XVII), which is finally reduced with H2 over Pd/C in MeOH The direct condensation of butyrophenone (XIV) with piperidine (V) by means of K2CO3 as before gives the already obtained butyrophenone (XVII).