Study On The Synthesis Of Racemic Famoxadone

In this paper, the synthesis of racemic famoxadone and related intermediates including4-bromo-diphenyl ether, ethyl2-(4-phenoxyphenyl)lactate were studied. The traditional reaction route was improved and the use of Grignard reaction and toxic phosgene was avoided. Significant results are obtained.Reaction of diphenyl ether with NaBr/NaBrO3gave4-bromo-diphenyl ether. With optimization of the parameters, the yield of the product was increased. In the presence of catalytic amount of NH4NO3, reaction of diphenyl ether with NBS gave4-bromo-diphenyl ether in98%yield. A possible reaction mechanism was proposed.According to the literature, the synthesis of2-(4-phenoxy-phenyl)ethyl lactate was studied. The Grignard reagent of4-bromo-diphenyl ether was synthesized in THF. Nucleophilic addition of the resulted Grignard reagent to ethyl pyruvate gave ethyl2-(4-phenoxyphenyl)lactate. Through optimizing the reaction parameters, the overall yield was59%, compared with the literature value of52%.One pot reaction of diphenyl ether with ethyl pyruvate in the presence of AlCl3gave ethyl2-(4-phenoxyphenyl)lactate, too. With optimization of the parameters, such as the feeding ratio, solvent, the type of catalysts and reaction temperature, the yield of product was remarkably improved.Cyclization of2-(4-phenoxyphenyl)lactate with CDI and phenylhydrazine gave racemic famoxadone. The reaction parameters such as the amounts of CDI, phenylhydrazine, acetic acid and solvents were optimized. The overall yield was89%, compared with the patents value of80%.Synthesis of racemic famoxadone using triphosgene as carbonylation agent was also studied and69%yield was obtained under optimized conditions. Compared with phosgene, triphosgene is low toxic and is easy to operate, which is beneficial for industrial production.