| Fluoxetine hydrochloride is a kind of widely used non tricyclic antidepressants.It has been used for the treatment of various types of depressions in clinical such as depression,medical disease with depression,obsessive-compulsive disorder,panic disorder,etc.Fluoxetine hydrochloride which has been sold in the market is usually existed in the form of racemes.The development of optical activity fluoxetine hydrochlorid is of great significance,because pharmacokinetics and metabolism mechanisms of R-fluoxetine and S-fluoxetine are different.N-methyl-3-phenyl-3-hydroxy-propylamine is an important kind of intermediates of fluoxetine because of the superiority of diversity of raw materials and the high reaction yield.According the relative references,most of them synthesized N-methyl-3-phenyl-3-hydroxy-propylamine as the intermediate to research the synthesis of fluoxetine and analogues.In this paper,based on the previous studies,a high yield,economic,environment friendly,simple and suitable for industrial synthetic technology was designed.First,under the assistance of micromave,acetophenone reacted with methylamine hydrochloride and paraformaldehyde via Mannich reaction,yield of product N-methyl-3-phenyl-3-oxopropylamine was 72.2%,followed by the reduction reaction through borohydride,yield of product N-methyl-3-phenyl-3-hydroxy- propylamine was 87.5%.N-methyl-3-phenyl-3-hydroxylpropylamine was separated respectively by chiral agents S-(+)-mandelic acid and dibenoyl-L-tartaric acid which was synthesized in lab.Taked S-(+)-mandelic acid as chiral agents,yield of S-intermediates was 39.4%,yield of R-intermediates was 30.3%,recovered yield of chiral agents is 66.7%. Dibenoyl-L-tartaric acid was synthesized with L-tartaric acid and benzoyl chloride,yield was 83.1%.Taked dibenoyl-L-tartaric acid as chiral agents,yield of S-intermediates was 33.3%,yield of R-intermediates was 43.6%, recovered yield of chiral agents was 75.0%.N-methyl-3-phenyl-3-hydroxy-propylamine was used to synthesize fluoxetine and its analogues.Yield of N-Methy-3-(4-Trifluoromethylphenoxy)-3-phenyl-3- propylamine was 65.7%,yield of N-Methy-3-(2,4-Dinitrobenzeephenoxy)-3-phenyl -3-propyla-mine was 62.4%. |
