Research On The Synthesis Of Venlafaxine Hydrochloride

Venlafaxine hydrochloride is an antidepressant drug developed by Wyeth’s company.In this dissertation,based on the literature,cyclohexanone and p-methoxyphenylacetonitrile were used as the starting material,through condensation reaction,reduction reaction,methylation reaction and purification process,the final product of venlafaxine hydrochloride was obtained.Moreover,the synthetic process of venlafaxine hydrochloride was optimized and the pilot production was verified.It laid a foundation for the industrialized production of venlafaxine hydrochloride.Through the test-batch experiments,the reaction condition was determined as follows:in condensation,cyclohexanone and p-methoxyphenylacetonitrile(p-MPA)were used as starting materials,with water used as reaction solvent,sodium hydroxide used as catalyst,and tetrabutylammonium bromide used as phase transfer catalyst.The intermediate(1-hydroxycyclohexyl)-p-methoxyphenylacetonitrile(code:VLFX01)was synthesized by condensation.The condensation temperature was 10～30 ℃,cyclohexanone/p-MPA(kg/kg)= 0.6-1.3,tetrabutylammonium bromide/p-MPA(kg/kg)=0.02～0.05,sodium hydroxide/p-MPA(kg/kg)= 0.03-0.10,water/p-MPA(kg/kg)＝0.5～1.5.Reduction reaction condition was determined as follows:ethanol-ammonia water as solvent and Raney nickel as catalyst,the intermediate VLFX01 was reduced and salted to obtain 1-[(1R,S)-2-amino-l-(4-methoxyphenyl)ethyl]-cyclohexanol hydrochloride(code:VLFX02).Detailed process parameters were as follows:reaction temperature is 30～50 ℃,Raney/VLFX01(kg/kg)= 0.05～0.30.Methylation process condition was as follows:in the presence of formaldehyde and formic acid,with water as solvent,via reductive amination reaction,the amino group in the structure of intermediate VLFX was converted to dimethylamino group,and the crude product of venlafaxine hydrochloride(code:VLFX03)was obtained.Detailed process parameters were as follows:reaction temperature was 90～100 ℃,formaldehyde/VLFX02(kg/kg)= 0.8～1.2,formic acid/VLFX02(kg/kg)=0.5～5.0,water/VLFX02(kg/kg)=10-16.Purification process conditions:the crude Venlafaxine hydrochloride was purified in the mixture of ethanol/ethyl acetate to give the final product(code:VLFX).Detailed process parameters were as follows:ethanol/VLFX03(kg/kg)= 1.2～3.0,ethyl acetate/VLFX03(kg/kg)= 1.0-3.0,activated carbon/VLFX03(kg/kg)= 0.01～0.10,dissolution temperature was 70-80 ℃,the decolorization time was 0.5～1.0h,the crystallization temperature was 0-5 ℃,and the crystallization time was 6-10h.On the basis of results of test batches,the synthetic process of venlafaxine hydrochloride was validated in pilot-scale.The results were consistent with expectations,and the reliability of the process was verified.The structures of key intermediates and final product were confirmed by 1D-NMR including 1H-NMR,13C-NMR and DEPT135 and 2D-NMR including H-H COSY,HSQC,HMBC and NOSEY.