摘要
目的:研究盐酸洛哌丁胺、一种用于治疗骨质疏松症药物的关键中间体的制备方法。方法:以2,2-二苯基-γ-丁内酯为起始原料,经开环、SN2取代、酰氯化、季铵化、缩合和成盐制得。结果:当反应温度为25℃,反应时间为24 h,开环和SN2取代的产率为81%。第二步反应,当n(SOCl2):n(2,2-苯基-4-溴丁酸)=2:1、反应温度为回流时,HPLC显示2,2-苯基-4-溴丁酰氯(4)的含量为97.25%。第三步反应,当n(4):n(Na2CO3):n(二甲胺)的投料比为1.0:1.2:1.5,反应温度为0～5℃,关键中间体二甲基-(四氢-3,3-二苯基-2-呋喃叉基)溴化铵(5)的产率由文献报导的50%提高到68%。第四步洛哌丁胺游离碱的制备,较好的投料比为n(7’):n(Na2CO3):n(羟基哌啶)=1.0:1.2:1.1,收率为85%。最后一步成盐,在无水乙醇中调节pH为3左右,收率为89.6%。整个合成步骤(包括精制)的收率为34%,HPLC检测纯度达99.86%。其结构经IR、1H-NMR、13C-NMR和MS表征确认。结论:本制备方法克服了文献所报道的制备工艺的缺点,与现有技术相比,本发明后处理更简单,更适合工业化生产。
Objective： To study the preparation of the synthetic process of loperamide hydrochlo-ride,a drug which was widely used in the treatment of acute diarrhoea with low side effect.Methods： Loperamide hydrochloride was synthesized from 2,2-diphenyl-4-hydroxybutyric acid-γ-lactone as raw matercial via ring-opening、SN2 substitution、acidylation、quaterisation、Conden-sation and salifying.Results： In the first step,when the reaction time was 24 h and temperature was 25 ℃,the yield was 81%.In the second step,when the molr ratio of n（SOCl2）：n（3）=2：1 and temperature was reflux,the content of 4-bromo-2,2-diphenylbutyroyl chloride（4） was 97.25 %.And the key intermediate dimethyl（tetrahydro-3,3-diphenyl-2-furylidene）ammonium bromide（5） was obtained with the yield increased from 50%（literature reported） to 68% when the molr ratio of n（4）： n（Na2CO3）： dimethylamine=1.0：1.2：1.5 and temperature was 0～5 ℃。When the molr ratio of n（5）： n（4-p-chlorophenyl-4-piperidinol）： n（Na2CO3）=1.0： 1.2： 1.1,loperamide（6） was obtained with yield of 85%.After simple salification,the target compound 1 was synthesized from（6） with the yield of 89.6 %.The overall yield was 34% and its structure was characterized by IR,1H-NMR,13C-NMR and MS spectra.Conclusion： Some drawbacks in the literature was improved and the method was easy for synthesis and suitable for industrial manufacturing.
出处
《广东化工》
CAS
2012年第8期75-76,44,共3页
Guangdong Chemical Industry
关键词
盐酸洛哌丁胺
抗腹泻药物
合成
loperamide hydrochloride
antidiarrhoea drug
synthesis
