J. Org. Chem. 1997, 62, 9192-9202
An Efficient Fischer Indole Synthesis of Avitriptan, a Potent 5-HT1D Receptor Agonist
Paul R. Brodfuehrer,* Bang-Chi Chen, Thomas R. Sattelberg, Sr., Patrick R. Smith, Jayachandra P. Reddy, Derron R. Stark, Sandra L. Quinlan, and J. Gregory Reid
Process Exploration Labs-I, Technical Operations Division, Bristol-Myers Squibb Company, P.O. Box 4755,Syracuse, New York 13221-4755
John K. Thottathil and Shaopeng Wang*
Chemical Process Research, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, P.O. Box 191, New Brunswick, New Jersey 08903-0191
Received July 24, 1997X
An efficient synthesis of the antimigraine drug candidate avitriptan (1, BMS 180048) is reported. The key step is a two-phase Fischer indolization reactionbetween 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 startingmaterials, hydrazine 6, 5-chlorovaleraldehyde, 20, and 4-chloro-5-methoxypyrimidine, 24, were also achieved. Introduction Among the many biologically active indoles, serotonin (5-hydroxytriptamine, 5-HT) is known to exhibit antimigraine activity, and numerous serotonin-like compounds are currently under investigation as 5-HT1D receptor agonists for the treatment of migraine headache. Sumatriptan, 2, is thefirst of these to be commercialized,1 and several others, including MK 0462, 3,2 L-695,894, 4,3 and avitriptan (1, BMS 180048), are under development. Avitriptan has been shown to exhibit similar 5-HT1D agonist activity to sumatriptan in cerebral arteries in a number of animal models,4 but did not elicit a response in 5-HT2 receptors in either porcine coronary artery or rat thoracic aorta,5indicating that it may be a more selective vasoconstrictor than sumatriptan. These results make it an attractive candidate for development as an antimigraine drug.
substituted aniline A, a five-carbon chain B to complete construction of the indole ring and form the three-carbon linkage to C, the piperazinylpyrimidine. There are a number of different options for putting these subunitstogether, some of which are demonstrated in the known literature syntheses of this compound. The indole portion of avitriptan has been prepared by a zinc chloride-catalyzed Fischer indolization of hydrazine 6 with dihydropyran, 7, to give the hydroxypropylindole 8 (Scheme 2);6 by a more convergent route in which the B and C subunits were combined to form diethyl acetal 10 and then reacted with 6 in aFischer indolization to give 1 directly (Scheme 3);7 and by a palladium-catalyzed heteroannulation reaction of iodoaniline 12 with silyl(5) Sarbin, N. S.; Gylys, J. A.; Iben, L. G.; Mahle, C. D.; Izzarelli, E. M.; Parker, E. M.; Noonan, J. W.; Williams, A. D.; Smith, D. W.; Hamel, E.; Yocca, F. D. FASB J. Abstr. 1995, 9, A347. (6) Smith, D. W.; Yocca, F. D.; Yevich, J. P.; Mattson, R. J.; Williams,A.; Ruediger, E. H. U.S. Patent 5,300,506, 1994. (7) Remuzon, P.; Dussy, C.; Jacquet, J. P.; Soumeillant, M.; Bouzard, D. Tetrahedron Lett. 1995, 6227.
A retrosynthetic analysis of 1 (Scheme 1) shows that it consists of three basic subunits; an appropriately
X Abstract published in Advance ACS Abstracts, December 1, 1997. (1) Hopkins, S. J. Drugs Today 1992, 28, 155. (2) MK-0462 Drugs Future1995, 20(7), 676-679. (3) Chen, C.-Y.; Senanayake, C. H.; Bill, T. J.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. R. J. Org. Chem. 1994, 59, 3738. (4) (a) Saxena, P. R.; De Vries, P.; Wang, W.; Heilegers, J. P. C.; VanDenBrink, A. M.; Bax, W. A.; Yocca, F. D. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1997, 355, 295. (b) Wiener, H. L.; Thlody, G. P.; Yocca, F. D. FASB J. Abstr. 1995, 9, A347....