AN EFFICIENT FISCHER INDOLE SYNTHESIS OF AVITRIPTAN, A POTENT 5-HT1D RECEPTOR AGONIST

An efficient synthesis of the antimigraine drug candidate avitriptan ( 1, BMS 180048) is reported. The key step is a two-phase Fischer indoli zation reaction between hydrazine 6 and 5-chlorovaleraldehyde, 20, to give the chloropropylindole 35, which is susceptible to acid-catalyzed degradation under the reaction conditions required for its formation. Sequential coupling of 35 with piperazine, 26, and 4-chloro-5-methoxy pyrimidine, 24, gives the title compound in 40-45% overall yield. Sign ificant improvements in the syntheses of the known starting materials, hydrazine 6, 5-chlorovaleraldehyde, 20, and 4-chloro-5-methoxypyrimid ine, 24, were also achieved.