化学学报 ›› 1963, Vol. 29 ›› Issue (1): 28-36. 上一篇    下一篇

论文

降压药物的合成研究——Ⅰ.10-氨烷酰基和10-氨烷基吩噻嗪的制备

白东魯, 嵇汝运   

  1. 中国科学院药物研究所
  • 投稿日期:1962-05-30 发布日期:2013-06-03

SYNTHETIC STUDIES ON HYPOTENSIVE AGENTS Ⅰ. THE PREPARATION OF 10-AMINOACYL AND 10-AMINOALKYLPHENOTHIAZINES

BAI DONG-LU, KYI ZU-YOONG   

  1. Institute of Materia Medica, Academia Sinica
  • Received:1962-05-30 Published:2013-06-03

2-氯-10-氯烷酰基吩噻嗪或2-氯-10-(α-甲基丙烯酰基)吩噻嗪与氮七环、氮八环地应,生成相应的2-氯-10-氨烷酰基吩噻嗪(Ⅳ)。2-氯吩噻嗪与1-(β-氯乙基)氮八环在氨基钠存在下缩合,得2-氯-10-[β-(N-氮八环)乙基]吩噻嗪(Ⅴa);β-(10-吩噻嗪基)丙酸(Ⅵa)或β[10-(2-氯吩噻嗪基)]丙酸甲酯(Ⅵc)与氢化铝锂、氮八环或氮七环行氨解-还原反应,生成10-[γ-(N-氮八环)丙基]吩噻嗪(Ⅴb)及2-氯-10-[γ-(N-氮七环)丙基]吩噻嗪(Ⅴc)。当β-[10-(2-氯吩噻嗪基)]丙酸用五氯化磷处理时,分到10-氯-2,3-二氢3-酮-1H-吡啶并[3,2,1-kl]吩噻嗪(Ⅶa);后者与聚甲醛、氮七环盐酸盐反应,生成10-氯-2-(N-氮七环甲基)-2,3-二氢-3-酮-1H-吡啶并[3,2,1-kl]吩噻嗪(Ⅶd)盐酸盐。1-(β-氯丙酰基)氮七环(Ⅹ)用氢化铝锂还原时,得到1-正丙基氮七环(Ⅺ)。

Chlorpromazine (Ⅰ) produces depression of the central nervous system.It also exhibits weak adrenolytic and hypotensive effects.Hexahydro-l-azepinylpropionamidoxime (Ⅱ) and guanethidine (Ⅲ) were reported to have protracted antihypertensive properties with the capacity to block the transmission at peripheral adrenergic nerve terminals.The present work deals with the structural hybridization of chlorpromazine with hexahydro-1-azepinvl-nropionamidoxime and Quanethidine.The 2-chloro-l0-aminoacylphenothiazines(Ⅳ) were prepared by condensation of the appropriate 2-chloro-l0-haloacylphenothiazines or 2-chloro-l0-methacrylylphenothiazine and amines.2-Chlorophenothiazine was condensed with 1-(β-chloroethyl)heptamethy-lenimine in the presence of sodium amide,giving 2-chloro-10-[β-(N-heptamethylenimino) ethyl] phenothiazine (Va).β-[10-Phenothiazinyl) propionic acid (Ⅵa) and methyl β-(10-(2-chlorophenothiazinyl)] propionate (Ⅵc) reacted with hexamethylenimine or heptamethylenimine in the presence of lithium aluminium hydride in boiling tetrahydrofuran,forming the corresponding 10-(γ-aminopropyl)phenothiazines (Ⅴb,Ⅴc).We attempted to prepare β-[10-(2-chlorophenothiazinyl)] propionyl chloride,but only 10-chloro-2,3-dihydro-3-keto-lH-pyrido[3,2,1-k1]phenothiazine (Ⅶa) was obtained.Ⅶa was treated with paraformaldehyde and hexamethylenimine hydrochloride in isopropyl alcohol,giving the desired Mannich base (Ⅶd).The reduction of 1 (β-chloropropionyl) hexamethylenimine (Ⅹ) by means of lithium aluminium hydride yielded 1-propylhexamethylenimine (ⅩⅠ)