广东化工
廣東化工
엄동화공
GUANGDONG CHEMICAL INDUSTRY
2012年
8期
75-76,44
,共3页
张卫%陈年根%黄剑%翟锐锐%符乃光
張衛%陳年根%黃劍%翟銳銳%符迺光
장위%진년근%황검%적예예%부내광
盐酸洛哌丁胺%抗腹泻药物%合成
鹽痠洛哌丁胺%抗腹瀉藥物%閤成
염산락고정알%항복사약물%합성
loperamide hydrochloride%antidiarrhoea drug%synthesis
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。
目的:研究鹽痠洛哌丁胺、一種用于治療骨質疏鬆癥藥物的關鍵中間體的製備方法。方法:以2,2-二苯基-γ-丁內酯為起始原料,經開環、SN2取代、酰氯化、季銨化、縮閤和成鹽製得。結果:噹反應溫度為25℃,反應時間為24 h,開環和SN2取代的產率為81%。第二步反應,噹n(SOCl2):n(2,2-苯基-4-溴丁痠)=2:1、反應溫度為迴流時,HPLC顯示2,2-苯基-4-溴丁酰氯(4)的含量為97.25%。第三步反應,噹n(4):n(Na2CO3):n(二甲胺)的投料比為1.0:1.2:1.5,反應溫度為0~5℃,關鍵中間體二甲基-(四氫-3,3-二苯基-2-呋喃扠基)溴化銨(5)的產率由文獻報導的50%提高到68%。第四步洛哌丁胺遊離堿的製備,較好的投料比為n(7’):n(Na2CO3):n(羥基哌啶)=1.0:1.2:1.1,收率為85%。最後一步成鹽,在無水乙醇中調節pH為3左右,收率為89.6%。整箇閤成步驟(包括精製)的收率為34%,HPLC檢測純度達99.86%。其結構經IR、1H-NMR、13C-NMR和MS錶徵確認。結論:本製備方法剋服瞭文獻所報道的製備工藝的缺點,與現有技術相比,本髮明後處理更簡單,更適閤工業化生產。
목적:연구염산락고정알、일충용우치료골질소송증약물적관건중간체적제비방법。방법:이2,2-이분기-γ-정내지위기시원료,경개배、SN2취대、선록화、계안화、축합화성염제득。결과:당반응온도위25℃,반응시간위24 h,개배화SN2취대적산솔위81%。제이보반응,당n(SOCl2):n(2,2-분기-4-추정산)=2:1、반응온도위회류시,HPLC현시2,2-분기-4-추정선록(4)적함량위97.25%。제삼보반응,당n(4):n(Na2CO3):n(이갑알)적투료비위1.0:1.2:1.5,반응온도위0~5℃,관건중간체이갑기-(사경-3,3-이분기-2-부남차기)추화안(5)적산솔유문헌보도적50%제고도68%。제사보락고정알유리감적제비,교호적투료비위n(7’):n(Na2CO3):n(간기고정)=1.0:1.2:1.1,수솔위85%。최후일보성염,재무수을순중조절pH위3좌우,수솔위89.6%。정개합성보취(포괄정제)적수솔위34%,HPLC검측순도체99.86%。기결구경IR、1H-NMR、13C-NMR화MS표정학인。결론:본제비방법극복료문헌소보도적제비공예적결점,여현유기술상비,본발명후처리경간단,경괄합공업화생산。
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.