合成路线1

A new synthesis of fadrozole hydrochloride has been published: The oxidation of 4-(2-pyridyl)benzoic acid ethyl ester (I) with peracetic acid at 90 C gives the corresponding N-oxide (II), which by reaction with dimethyl sulfate and potassium cyanide yields 4-(6-cyano-2-pyridyl)benzoic acid ethyl ester (III). The hydrogenation of (III) with H2 over Pd/C in methanol affords 4-[6-(aminomethyl)-2-pyridyl]benzoic acid ethyl ester (IV), which is formylated with formic acid at 90 C, giving the formamido derivative (V). The cyclization of (V) by means of POCl3 in toluene at 90 C yields 4-(imidazo[1,5-a]pyridin-5-yl)benzoic acid ethyl ester (VI), which is hydrogenated with H2 over Pd/C in anhydrous ethanol containing HCl to afford 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzoic acid ethyl ester (VII). The hydrolysis of (VI) with NaOH in ethanol gives the corresponding acid (VIII), which by reaction with refluxing SOCl2 yields the acyl chloride (IX). The reaction of (IX) with dry ammonia in dichloromethane affords the 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzamide (X), which is finally treated with POCl3 in refluxing chloroform. The final product is obtained by treatment with dry HCl in ethylether.