Improved Process For The Synthesis Of Apremilast

In this paper, the pathogenesis of psoriasis and the research progress of the anti-psoriasis drugs were introduced. On the basis of literature research about the syntheses of the apremilast, in this work amination route was selected to synthesize the apremilast by the reaction of intermediates I(S- 1-(3- ethoxy- 4- methoxy phenyl)- 2- methyl sulfonyl ethylamine) with intermediates II(3- acetyl amino phthalic anhydride), and finally the refined process of the crude apremilast was improved. Using iso vanillin as starting material, 3-ethoxy-4-methoxy benzaldehyde was obtained by the O-alkylation; the condensation of 3-ethoxy-4-methoxy benzaldehyde with hydroxylamine hydrochloride provided 3-ethoxy-4 methoxybenzonitrile, which reacted with dimethyl sulfoxide in presence of n-butyllithium to give dimethyl sulfoxide mono-lithium salt. The mono-lithium salt was added into 3-ethoxy-4-methoxy benzaldehyde to obtain the racemic intermediate Ⅰ, and then key intermediate S-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl –ethylamine was prepared by chemical separation method The intermediate II(3- acetyl amino phthalic anhydride) was obtained by N-acetylation of 3-aminophthalic acid which was reduced by starting material 3-nitrophthalic acid. The reaction conditions of the above two key intermediates were optimized, and stable process parameters such as solvent, weight ratio, reaction temperature, reaction time and catalyst were established. This process of the apremilast simplified the operation steps and improved the yield, has made the beneficial exploration for industrialized production. This work was made a beneficial exploration for industrialized process of apremilast...