An efficient Fischer indole synthesis of avitriptan, a potent 5-HT1D receptor agonist
An efficient Fischer indole synthesis of avitriptan, a potent 5-HT1D receptor agonist
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DOI：
10.1021/jo971368q
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发表时间：
1997-12-26
影响因子：
3.6
通讯作者：
Reid, JG
中科院分区：
文献类型：
--
作者：
Brodfuehrer, PR;Chen, BC;Reid, JG
报道了抗偏头痛候选药物阿曲曲坦（1,BMS 180048）的高效合成。关键步骤是在肼6和5-氯戊醛20之间进行两相Fischer吲哚反应，得到易被酸催化降解的氯丙醇35。35依次与哌嗪26和4-氯-5-甲氧基嘧啶24偶联，总收率为40-45%。已知原料肼6,5 -氯戊醛20和4-氯-5-甲氧基嘧啶24的合成也取得了重大进展。
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.