Ira Maude Synthesis

Iguratimod is a new kind of anti-inflammatory,which can be used in cure of arthritis.The target compound was synthesized from 4-chloro-3-nitroanisole as a starting material via seven steps including etherlation,reduction,methanesulfonylization,classical Gattermann-Koch reaction,acylation,hydrolysis,and cyclization.The synthetic route to T-614 is:4-chloro-3-nitroanisole(2) reacts with potassium phenolate in hot DMF and gives 4-phenoxy-3-nitroanisole(3),which is reduced to the corresponding 3-amino compound(4) by treatment with Fe and HC1.The reaction of(4) with mesyl chloride in pyridine gives the sulfonamide(5),which is acylated with 2-aminoacetonitrile and AlCl₃ in nitrobenzene/HCl and gives the 2-aminoacetophenone(6).Formylation of(6) at the NH₂ with acetic formic anhydride yields the formamide(7),which is demethylated with AICl₃ and Nal in acetonitrile affording the phenol(8).Finally,this compound(8) is cyclized with dimethylformamide dimethylacetal in CH₂Cl₂.This dissertation has studied the influence of several facts such as material ratio,reaction time to the yield,and discusses the mechanism of the reactions.An optimum reaction condition is obtained:the etherlation at 110℃for 5h with the mole ratio of 4-chloro-3-nitroanisole/phenol/potassium tert-butoxide being 0.25/0.35/0.42 obtains a yield of 82.5%;the reduction at 70℃for 1h with the ratio of(3)/Fe/4mol·L^-1 HCl being 4g/3g/1.2mL obtains a yield of 82.4%;the methanesulfonylization at 0℃-5℃for 1h with the ratio of(4)/mesyl chloride being 2.5g/1.8mL in pyridine 50mL obtains a yield of 93.0%. The total yield of Iguratimod(1) was 37.7%.