(S)-噻吗洛尔半水合物的合成及表征

Synthesis and Characterization of(S)-Timolol Hemihydrate

为了开发β受体阻断剂新药(S)-噻吗洛尔半水合物,采用3-吗啉-4-氯-1,2,5-噻二唑为起始原料,经水解反应得到中间体1(3-吗啉-4-羟基-1,2,5-噻二唑)。中间体1与R-环氧氯丙烷发生醚化反应,经后处理及重结晶得到中间体2{(R)-4-[4-(环氧乙烷-2-基甲氧基)-1,2,5-噻二唑-3-基]吗啉}。中间体2经胺化反应、马来酸成盐及重结晶得到(S)-马来酸噻吗洛尔。(S)-马来酸噻吗洛尔经游离、纯水转晶得到符合药典标准的(S)-噻吗洛尔半水合物,总收率14.05%且e.e.值为99.66%。最终成品经IR、1 H-NMR、13C-NMR、MS、TGA、DSC表征,并优化各步反应条件。结果表明:以三乙胺为醚化反应缚酸剂75℃反应最佳;以乙醇为胺化反应溶剂46℃反应16 h最佳;S-噻吗洛尔的转晶拆分以水作溶剂,比传统不对称合成工艺安全稳定,操作简单,适合工业化生产。

To develop theβ-blocker new drug(S)-timolol hemihydrate,3-morpholine-4-chloro-1,2,5-thiadiazole was used as the starting material,followed by the hydrolysis to obtain intermediate 1(3-morpholine-4-hydroxy-1,2,5-thiadiazole).Intermediate 1 and R-epichlorohydrin underwent a etherification reaction,after treatment and recrystallization to obtain intermediate 2{(R)-4-[4-(ethylene oxide-2-ylmethoxy)-1,2,5-thiadiazol-3-yl]morpholine}.Intermediate 2 underwent a amination reaction,maleic acid salt formation and recrystallization to obtain(S)-Timolol maleate.(S)-Timolol maleate was crystallized by free and pure water to obtain(S)-Timolol Hemihydrate in compliance with Pharmacopoeia standards,with a total yield of 14.05%and an e.e.value of 99.66%.The final product was characterized by infrared spectroscopy,1H-nuclear magnetic resonance spectroscopy,13C-nuclear mgnetic resonance spectroscopy,mass spectroscopy,thermogravimetric analysis,differential scanning calorimetry.The reaction conditions of each step were also optimized.The results show that using triethylamine as the acid binding agent for the etherification reaction at 75℃is the best;using ethanol as the amination reaction solvent at 46℃for 16 h is the best reaction.The symmetrical synthesis process with water as the solvent for S-timolol's crystal resolution is safe,stable and simple to operate,and is suitable for the industrial production.