Improved Synthesis Research Of Intermediate Of Paroxetine

Paroxetine,which is a highly selective inhibitor of neuronal serotonin reuptake,is one of three major antidepressants,with good effect and less adverse effect.The dissertation mainly studied the improvement on the synthesis of the intermediate of the antidepressant agent paroxetine.This dissertation consists of two parts.The first chapter summarized the research progress of antidepressant drugs,introduced the research progress of paroxetine,summarized the synthetic route,analyze the advantages and disadvantages of these methods.The second chapter studied the improvement on the synthesis of paroxetine.The intermediate of paroxetine was synthesized from4-fluorobenzaldehyde through condensation,Michael addition and cycliazation reactions.4-?4-flurinatedphenyl?-3-hydroxymethyl-methyl-piperdine was synthesiszed from 4-?4-fluorophenyl?-3-ethoxy-1-methyl-piperidine)-2-dione by NaBH₄-MeOH-t-BuOH system.4-?4-flurinated-phenyl?-3-hydroxymethyl-1-methylpiperidine was split to obtain chiral in-termediates?-?-trans-4R-?4-fluorinatedphenyl?-3S-hydroxymethyl-1-me-ethylpiperidine.Investigated the reaction conditions such as related reagents,solvents,alkali,reaction temperature,feeding way,materials proportion and so on.Compared to the traditional craft,the improved process is higher in yield,lower in by-product and cost,easier to operate,and more suitable for industrial production.The third chapter introduces the asymmetric route and the overview of paroxetine.The chiral intermediate of paroxetine was synthesized from4-fluoride cinnamic aldehyde,L-proline potassium salt as catalyst and several factors were changed to investigate their effects on the reaction,i-ncluding the solvent,alkali and other factors.The diastereoisomers excess of 90.5%was gotten.The fourth chapter introduced the review of iminium catalysis firstly.Take the 4-fluoride cinnamic aldehyde as raw material,piperidine as catalyst for preparation of the intermediates,then investigated several factors:catalyst,the solvent,temperature and others.Lastly,82%yield of product was gotten.