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CN1169799C - 噻唑烷的制备方法 - Google Patents

噻唑烷的制备方法 Download PDF

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CN1169799C
CN1169799C CNB008087253A CN00808725A CN1169799C CN 1169799 C CN1169799 C CN 1169799C CN B008087253 A CNB008087253 A CN B008087253A CN 00808725 A CN00808725 A CN 00808725A CN 1169799 C CN1169799 C CN 1169799C
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reaction
solvent
process according
ammonia
thiazolidine
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��˹-�ڶ���ϣ��������
汉斯-乌尔里希·德穆特
3
苏珊·科鲁伯
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

制备噻唑烷碱及其盐的方法，其特征在于，使式(I)的六亚甲基四胺与式(II)的半胱胺或其盐反应其中X(-)代表酸基，并优选为卤离子或硫酸根。

Description

噻唑烷的制备方法
本发明涉及制备噻唑烷碱及其盐的方法，该方法简单而且在技术上易于操作。
噻唑烷可用作合成氨基酰基-和肽基-thiazolidides的中间产物，后者作为酶抑制剂具有诊断和治疗价值(H.-U.DEMUTH，J.EnzymeInhibition 3，249(1990))。
因为氨基酰基thiazolidides特别适合于调节哺乳动物的血糖水平，成本低而且可工业应用的制备这些化合物以及它们的母体化合物的方法在医药、制药和经济方面都是令人感兴趣的(参见DE 19 616 486)。
已知噻唑烷和噻唑烷衍生物可如下制得：在水溶液中使醛与硫酸氨基乙酯或者氨基乙基卤及硫化钠回流，其中输入过量的能量，时间为几个小时。产率约为理论值的60％(参见US 4 584 407)。
本发明的目的是提供一种制备噻唑烷碱或其盐的方法，其中不需要输入过量的能量。
本发明现提供制备噻唑烷碱及其盐的方法，其特征在于，使式(I)的六亚甲基四胺
与式(II)的半胱胺或其盐反应
Figure C0080872500051
其中X(-)代表酸残基，并优选为卤离子或者硫酸根。
非常令人惊奇地发现，上述方法以非常高的纯度和产率形成游离碱噻唑烷及其盐，而且在反应期间不需要施加过量的热量。这使得本发明的方法具有成本和技术上的优势，特别是作为制备噻唑烷的工业方法(参见EP 0 054 409)。
在本发明中，反应例如在极性溶剂中进行，如醇。优选的溶剂是甲醇和/或乙醇。
本发明的方法在工业制备噻唑烷时还具有经济和技术方面的优势，六亚甲基四胺可作为噻唑烷副产物的药物用途，这是因为其是药物学上可以接受的：许多年来，已使用该物质作为尿消毒剂和食品防腐剂(参见Mutschler，Arzneimittelwirkungen，第572页以及随后页，Stuttgart：Wissenschaftliche Verlagsges.(1986))。
优选的是，使用氨作为初始物和/或在反应期间添加。通过这种方法，可在单个步骤中进行至游离碱的合成(参见S.Ratner，H.T.Clarke，J.Am.Chem.Soc.59，200-206(1937))，使得可省略复杂而且昂贵的额外反应步骤。
本发明的方法可设计成用于实验室和商业规模，例如如下进行：一次性或者分批将六亚甲基四胺添加在优选半胱胺盐的甲醇溶液中，该半胱胺盐可为固体形式或者溶解在溶剂中。在室温下搅拌该混合物几个小时，或者在约30-35℃的温度下搅拌。如果需要，所述添加步骤可按照相反的顺序进行。
本发明的方法并不需要象其他方法那样在惰性气体环境中进行(参见EP 0 695 744)。
根据本发明的方法制得的噻唑烷可用作制备药物活性物质的起始物。以下将参考实施例来描述本发明。
实施例
在30-35℃将1.358kg(12mol)作为起始物的半胱胺盐酸盐溶解在1.8L甲醇中形成溶液，然后在30-35℃的反应温度下分两批添加291.59g(2.08mol)六亚甲基四胺。在添加第一批六亚甲基四胺后，观察到明显的放热反应(约45℃)，并形成紫色，然后冷却反应混合物。开始形成氯化铵粗沉淀物。当放热反应停止(约1.5小时)后，添加第二批六亚甲基四胺。在反应物中添加氨至饱和，然后添加700ml的叔丁基甲基醚。
定量沉淀的氯化铵可作为反应进程的指示剂。真空过滤氯化铵，并用反应溶液洗涤滤饼。在溶液中加入30ml的氨基乙基乙醇胺作为Sumpfbildner。蒸馏纯制噻唑烷，bp：60-70℃，8-10mbar。得到非常纯的物质，产率为88-93％。
1H MR(200MHz，D2O)δ(ppm)＝2.80-2.83(t，3J＝6.45Hz，2H，NCH2CH2)，3.04-3.19(t，3J＝6.45Hz，2H，CH2CH2S)，4.05(s，2H，NCH2S)13C NMR(100.5MHz，DMSO-d6)δ(ppm)＝30.69(s，NCH2CH2)，47.31(s，CH2CH2S)，47.95(s，NCH2S)
MS(MALDI-TOF)89(M+H)
EA：C3H7NS  理论：C＝40.44％  实测：C＝40.27％
                       H＝7.91％         H＝8.02％
                       N＝15.72％        N＝15.90％
                       S＝35.91％        S＝35.73％

Claims (13)

1、制备噻唑烷及其盐的方法，其特征在于，使式(I)的六亚甲基四胺
Figure C008087250002C1
与式(II)的半胱胺或其盐反应
其中X(-)代表酸残基。
2、如权利要求1所述的方法，其特征在于X(-)是卤离子或者硫酸根。
3、如权利要求1所述的方法，其特征在于反应是在极性溶剂中进行的。
4、如权利要求2所述的方法，其特征在于反应是在极性溶剂中进行的。
5、如权利要求3所述的方法，其特征在于所述溶剂是醇。
6、如权利要求4所述的方法，其特征在于所述溶剂是醇。
7、如权利要求3-6之一所述的方法，其特征在于所述溶剂是甲醇或乙醇。
8、如权利要求3所述的方法，其特征在于在反应之前或者反应期间添加氨。
9、如权利要求4所述的方法，其特征在于在反应之前或者反应期间添加氨。
10、如权利要求5所述的方法，其特征在于在反应之前或者反应期间添加氨。
11、如权利要求6所述的方法，其特征在于在反应之前或者反应期间添加氨。
12、如权利要求3-6和8-11之一所述的方法，其特征在于分离铵盐和/或蒸馏产物。
13、如权利要求3-6和8-11之一所述的方法，其特征在于分离铵盐和/或蒸馏产物，而溶剂是甲醇或乙醇。
CNB008087253A 1999-06-10 2000-04-11 噻唑烷的制备方法 Expired - Fee Related CN1169799C (zh)

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DE19926233A DE19926233C1 (de) 1999-06-10 1999-06-10 Verfahren zur Herstellung von Thiazolidin

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CA2373834A1 (en) 2000-12-21
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PT1185520E (pt) 2004-08-31
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AU758605B2 (en) 2003-03-27
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ES2215045T3 (es) 2004-10-01
ATE261946T1 (de) 2004-04-15
JP3803292B2 (ja) 2006-08-02
EP1185520A1 (de) 2002-03-13
KR20020022688A (ko) 2002-03-27
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US20020082427A1 (en) 2002-06-27
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US6559314B2 (en) 2003-05-06
AU4399600A (en) 2001-01-02
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CA2373834C (en) 2005-11-08
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