合成路线1

Friedel-Crafts acylation of 2-fluorotoluene (I) with succinic anhydride (II) in the presence of AlCl3 afforded 4-(4-fluoro-3-methylphenyl)-4-oxobutanoic acid (III). Ketone (III) reduction by hydrogenation over Pd/C furnished the arylbutyric acid (IV), which was esterified to (V) by means of SOCl2 in MeOH. Subsequent aromatic ring nitration of (V) yielded (VI). After basic hydrolysis of the methyl ester of (VI), the arylbutyric acid (VII) was subjected to intramolecular cyclization in hot polyphosphoric acid producing tetralone (VIII). Reduction of the keto group of (VIII) with NaBH4, followed by dehydration of the resultant alcohol (IX) under acidic conditions, gave rise to the dihydronaphthalene (X). Hydrogenation of the olefin double bond of (X) and simultaneous nitro group reduction in the presence of PtO2 produced the amino tetralin (XI). The amino group of (XI) was further protected as the acetamide (XII) employing Ac2O and Et3N. Regioselective benzylic oxidation of (XII) with KMnO4 gave tetralone (XIII). Functionalization of the alpha position of (XIII) to ketone was achieved employing n-butyl nitrite and potassium tert-butoxide. The resulting keto oxime (XIV) was then reduced with zinc in the presence of Ac2O, yielding acetamide (XV). Both amide functions of (XV) were hydrolyzed under acidic conditions to give diamine (XVI). The aliphatic amine of (XVI) was then selectively acylated with ethyl trifluoroacetate to produce the trifluoroacetamide (XVII).