合成路线1

The starting 3-fluorothiophenol (I) is obtained either from 3-fluoro-1-bromobenzene (II) by reaction with Mg and a following treatment with S, or from 3-fluoroaniline (III) by the Leuckart method via 3-fluorobenzenediazonium xanthate and 3-fluorophenyl xanthate. Two different ways were described for obtaining the acid (VI): 1) Reaction of (I) with 5-chloro-2-iodobenzoic acid (A) in a boiling aqueous KOH solution in the presence of Cu, which leads to the acid (IV). This is transformed in three steps (reduction with sodium dihydrodibis(2-methoxyethoxy)aluminate, followed by reaction with SOCl2 in pyridine, and final reaction with NaCN in boiling aqueous ethanol) to the nitrile (V), which is hydrolyzed with a boiling solution of KOH in aqueous ethanol. 2) Reaction of (I) with 2,5-dichloro acetophenone (B) in dimethylformamide at 150 C in the presence of Cu. The resulting ketone (VII) is proceased by the Kindler's modification of the Willgerodt reaction: treatment with S in boiling morpholine (C) gives the thiomorpholide (VIII), which is hydrolyzed either with a boiling ethanolic KOH solution or with a refluxing mixture of dilute H2SO4 and acetic acid. The acid (VI), obtained by both routes, is cyclized with polyphosphoric acid at 150 C to the ketone (IX), which is reduced with sodium borohydride in aqueous ethanol to the alcohol (X). Treatment with HCl in benzene in the presence of CaCl2 affords the reactive chloride (XI), which can be converted to the final product (XIV) by two methods: (b) substitution reaction of (XI) with 1-(ethoxycarbonyl)piperazine (D), followed by alkaline hydrolysis of the carbamate (XII) and addition of the secondary amine (XIII) to acrylamide in tert-butyl alcohol in the presence of benzyltriethylammonium hydroxide. (a) substitution reaction with 3-(1-piperazinyl)propionamide (E) in boiling chloroform gives directly (XIV);