Study On New Process Development Of Dapoxetine Intermediate

The male premature ejaculation is getting more and more attention in recent years;however,so far there is no systematic explanation for its cause.Dapoxetine is a more commonly used drug for premature ejaculation.It is a selective serotonin reuptake inhibitor which was originally used for the treatment of depression.Due to its side effects such as delayed ejaculation in sexual aspect,dapoxetine became the gospel of patients with premature ejaculation.According to relevant medical clinical trial data,dapoxetine is effective in treating premature ejaculation,which is well tolerated with few side effects,and has a very broad market prospect.In this thesis a comprehensive review of the existing synthetic process of dapoxetine intermediate is provided.Comparing of the advantages and disadvantages of the existing synthetic processes at home and abroad,a new synthetic process suitable for industrial production was provided.The original process,started with benzaldehyde,malonic acid and ammonium acetate as raw materials,applied a six-step process including Knoevenagel reaction,ammonium methylation,esterification,Li Al H₄reduction,etherification and chemical resolution.After re-designing the process,a new process,starts with benzaldehyde,malonic acid and ammonium acetate as raw materials,applies a five-step process including Knoevenagel reaction,ammonium methylation,Li Al H₄reduction,chemical resolution and etherification to prepare each intermediate and the target product dapoxetine.Meanwhile,in order to optimize the yield of each intermediate and the dapoxetine,the subject studied and verified the reaction material feed ratio and feed order for Knoevenagel reaction,ammonium methylation,Li Al H₄reduction,chemical resolution and etherification reaction in great detail.The optimal reaction conditions for the preparation of 3-amino-3-phenyl-propionic acid are:using ethanol as the reaction solvent,the molar feeding ratio of benzaldehyde,malonic acid and ammonium acetate is 1:1:2,the reaction temperature is,the reaction time is 10 h and the final yield is 50.2%.The optimal reaction conditions for the preparation of 3-N,N-dimethylammonium-3-phenylpropionic acid are:formic acid is used as the reaction solvent and3-amino-3-phenylpropionic acid is first placed in an ice water bath.Slowly put in formaldehyde,the molar feed ratio of formaldehyde to 3-amino-3-phenylpropionic acid is 4:1,the reaction temperature is,the reaction time is 10.2 h and the final yield is 48.2%.The optimal reaction conditions for the preparation of 3-N,N-dimethylammonium-3-phenylpropanol are:reduction of 3-N,N-dimethylamm-onium-3-phenylpropionic acid using Li Al H₄as a reducing agent in an ice water bath.The molar ratio of the 3-N,N-dimethylammonium-3-phenylpropionic acid to Li Al H₄is 1:2.5 and the final yield is 85.2%.The optimal reaction conditions for the preparation of S-3-N,N-dimethylammonium-3-phenylpropanol are:ethanol as the reaction solvent,succinic acid as the chiral resolution reagent,ethanol and 3-N,N-dimethylammonium-3-phenylpropanol is 5:1 and the final yield is 35%.The optimal reaction conditions for the preparation of dapoxetine are:anhydrous tetrahydrofuran as the reaction solvent,the molar ratio of potassium t-butoxide to S-3-N,N-dimethylammonium-3-phenylpropanol is 4:1 At that time,the reaction was performed at an oil bath temperature offor 1 h and then1-fluoronaphthalene was added,followed by a reaction at an oil bath temperature offor 6.1 h and the final yield was 72.23%.The synthetic process has the advantages of simple operation,cheap and easy-to-obtain raw materials,mild and easy-to-control reaction conditions,low toxicity.And most importantly the chirality issue was solved.