An Efficient Fischer Indole Synthesis of Avitriptan, a Potent 5-HT1D Receptor Agonist
The Journal of Organic Chemistry1997Vol. 62(26), pp. 9192–9202
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Paul R. Brodfuehrer, Bang‐Chi Chen, Thomas R. Sattelberg, Patrick Smith, Jayachandra P. Reddy, Derron R. Stark, Sandra L. Quinlan, J. G. REID, John K. Thottathil, Shaopeng Wang
Abstract
An efficient synthesis of the antimigraine drug candidate avitriptan (1, BMS 180048) is reported. The key step is a two-phase Fischer indolization 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-methoxypyrimidine, 24, gives the title compound in 40−45% overall yield. Significant improvements in the syntheses of the known starting materials, hydrazine 6, 5-chlorovaleraldehyde, 20, and 4-chloro-5-methoxypyrimidine, 24, were also achieved.
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