Almotriptan has been obtained by several related ways: 1) The hydrolysis of 4-chlorobutyraldehyde dimethylacetal (I) with HCl gives the corresponding aldehyde (II), which is condensed with 4-(1-pyrrolidinylsulfonylmethyl)phenylhydrazine (III) by means of HCl in methanol/water, giving 3-(2-aminoethyl)-5-(1-pyrrolidinylsulfonylmethyl)-1H-indole (IV). Finally, this compound is methylated with formaldehyde and NaBH4 in methanol. 2) The direct condensation of 4-chlorobutyraldehyde dimethylacetal (I) with 4-(1-pyrrolidinylsulfonylmethyl)phenylhydrazine (III) by means of HCl in water also yields intermediate 3-(2-aminoethyl)-5-(1-pyrrolidinylsulfonylmethyl)-1H-indole (IV). 3) The decarboxylation of 3-[2-(dimethylamino)ethyl]-5-(1-pyrrolidinylsulfonylmethyl)-1H-indole-2-carboxylic acid (V) catalyzed by means of Cu2O in quinoline at 190 C also gives almotriptan.
4) The intermediate 4-(1-pyrrolidinylsulfonylmethyl)phenylhydrazine (III) can be obtained as follows: The condensation of pyrrolidine (VI) with 1-(4-nitrobenzylsulfonyl)chloride (VII) in dichloromethane gives the expected sulfonamide (VIII), which is reduced with H2 over RaNi in DMF, yielding 4-(1-pyrrolidinylsulfonylmethyl)aniline (IX). The diazotation of (IX) with NaNO2/HCl affords the corresponding diazo compound (X), which is finally reduced to the target intermediate (III) with SnCl2/HCl.