Clentiazem maleate, TA-3090, Logna
克仑硫卓马来酸盐 克仑硫卓 Chemical Name: (+)-(2S,3S)-3-Acetoxy-8-chloro-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one maleate
CAS No. 96128-92-6, 96125-53-0 (free base)
项目整合开发状态: Pre-Registered
项目研究机构: Tanabe Seiyaku (Originator), Aventis Pharma (Licensee)
合成路线:A new synthesis of TA-3090 has been published:The cyclization of 2-amino-5-chlorothiophenol (I) with trans-2,3-epoxy-3-(4-methoxyphenyl)propanoic acid methyl ester (II) by heating at 160 C gives cis-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,5-benzo thiazepin-4-one (III),which is submitted to optical resolution with (S)-1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl chloride.The (2S-cis)-isomer of (III) is then condensed with 2-(dimethylamino)ethyl chloride (IV) by means of K2CO3 in refluxing acetone - water,yielding (2S-cis)-8-chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphen yl-2,3,4,5-tetrahydro-1,5-benzothiazepin-4-one (V).Finally,this compound is acetylated with acetic anhydride in refluxing pyridine and converted into the maleate salt.
📌 参考资料/链接：
参考文献标题:Synthesis of halogen-substituted 1,5-benzothiazepine derivatives and their vasodilating and hypotensive activities
文献作者:Inoue,H.; Konda,M.; Hashiyama,T.; et al.
参考来源:J Med Chem 1991,34(2),675-87
📄 详细内容
合成路线:A new synthesis of racemic TA-3090 has been reported:The condensation of 5-chloro-2-nitrothiophenol (I) with 4-methoxybenzyl chloride (II) by means of sodium ethoxide in ethanol gives the thioether (III),which is reduced with SnCl2 in hot ethanol to afford 4-chloro-2-(4-methoxybenzylthio)aniline (IV).The acylation of (IV) with ethoxalyl chloride (V) by means of NaHCO3 in dichloromethane - water yields the oxamate (VI),which is condensed with 2-(dimethylamino)ethyl chloride (VII) by means of K2CO3 and 18-crown-6 in hot acetonitrile to afford the alkylated oxamate compound (VIII).The cyclization of (VIII) by means of lithium diisopropylamide in THF gives 8-chloro-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-1,5-benzothiaze pine-3,4(2H,5H)-dione (IX),which is reduced with NaBH4 in aqueous ethanol to cis-8-chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,5-benzothiazepin-4-one (X).Finally,this compound is acetylated in the usual manner.
参考文献标题:A new synthetic route to 1,5-benzothiazepines.Synthesis of derivatives of diltiazem
文献作者:Takeda,M.; Takamura,N.; Oh-ishi,T.; Harada,T.; Morimoto,M.; Inoue,H.; Nagasawa,M.
参考来源:Chem Pharm Bull 1992,40(8),1986
产品链接: CAS No. 96128-92-6›› 产品链接: CAS No.96125-53-0››