Improved Synthesis Of The Active Pharmaceutical Ingredient 2-[Diphenylmethyl] Sulphinyl] Acetamide (Modafinil)

[Diphenylmethyl]sulphinyl]acetamide?Modafinil?is a central nervous system stimulant drug that was discovered and developed by the French company Lafon.It has wakefulness promoting properties and is used primarily for the treatment of narcolepsy.Modafinil was marketed in 1992 in France,1998 in the US,and 2017 in China.The mechanism of action of Modafinil on the CNS is not clear,its stimulant properties are similar to the other sympathomimetic agent amphetamine and methylphenidate,but the pharmacological profile is novel from the sympathomimetic amines and is unknown.Modafinil does not bind with receptors of histamine,norepinephrine,serotonin and dopamine,but it does bind with dopamine transporter with low affinity.Apart from its clinical application for the treatment of narcolepsy,obstructive sleep apnea,and shift work disorder,Modafinil has other wide applications.Modafinil had been used in military operations to be given to combative military personnel to counter sleep deprivation and fatigue.Modafinil is also a cognitive enhancer that improves human memory and performance that was used for non-medical purposes.Modafinil has other broad applications in off-label medication.Reported syntheses of Modafinil can be categorized into two different synthetic sequences.One sequence started with benzhydrol and thiourea to install the thiol group,and then used chloroacetic acid to get the key intermediate diphenylmethylthioacetic acid,which was converted to acid chloride and went through ammonolysis to give the diphenylmethylthioacetamide.Further controlled oxidation with hydrogen peroxide converts thiol to sulfinyl to produce diphenylmethylsulfinylacetamide?Modafinil?.An alternative sequence for Modafinil started with benzhydrol and mercaptoacetic acid under acid catalysis to give the diphenylmethylthioacetic acid,which was then converted to Modafinil.This research had looked at the two Modafinil route and examined the reaction conditions in terms of reagents,ratios,temperature and catalysts,and have tried to use alternative reagents that are not previously used for Modafinil synthesis,but has economic and environmental advantages.It also optimized the reduction of benzophenone to benzhydrol with borohydride reagents,and looked at hydrogenation method with novel palladium containing perovskites as catalysts.Five palladium containing perovskites were prepared,La_1.00Fe_0.95Pd_0.05O₃,La_1.00Fe_0.90Pd_0.10O₃,La_1.00Co_0.95Pd_0.05O₃,La_1.00Cu_0.95Pd_0.05O₃,La_1.00Al_0.95Pd_0.05O₃.They were tested as catalysts for hydrogenation of benzophenone,which gave good yield and selectivity,with La_1.00Cu_0.95Pd_0.05O₃ giving 98%yield of benzhydrol,and have potentials for recycling use.Thereactionofbenzhydrolwithmercaptoaceticacidfor diphenylmethylthioacetic acid was optimized with regard to the use of toluene as solvent and the use of trifluoroacetic acid catalyst with less than 0.5 equivalent amount.For the oxidation of diphenylmethylthioacetamide to Modafinil with hydrogen peroxide,styrene series acidic cation exchange resin was used instead of the sulfuric acid,and the use of sodium tungsten oxide dehydrate was also examined as catalyst for the hydrogen peroxide oxidation.Potassium peroxymonosulphate?Oxone?was used as an alternative oxidizing agent to hydrogen peroxide to give comparable yield with efficient operation.Through this investigation,it was discovered that the over oxidized sulfonyl by-product diphenylmethylsulfonylacetamide can be converted in situ to bnezhdrol,which was not reported in previous literature.In summary,in this work the synthesis of Modafinil was investigated from an industrial perspective.The collected results provide information on the reaction parameters which would be useful for further process development for Modafinil manufacturing.