CN1058211A - 改进的苯并咪唑合成方法 - Google Patents

改进的苯并咪唑合成方法 Download PDF

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CN1058211A
CN1058211A CN91103923A CN91103923A CN1058211A CN 1058211 A CN1058211 A CN 1058211A CN 91103923 A CN91103923 A CN 91103923A CN 91103923 A CN91103923 A CN 91103923A CN 1058211 A CN1058211 A CN 1058211A
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chemical compounds
omeprazole
molar equivalent
reaction
methoxyl group
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CN1040536C (zh
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阿尼·E·布兰斯特伦
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Feeding, Discharge, Calcimining, Fusing, And Gas-Generation Devices (AREA)

Abstract

在二氯甲烷溶液中和pH基本保持在8.0-8.6 左右的条件下，将5-甲氧基-2-[(4-甲氧基-3，5-二 甲基-2-吡啶基]-甲硫基]-1H-苯并咪唑(化合物I) 与间氯过苯甲酸反应，用NaOH水溶液提取反应混 合物，分离水相和有机相，将甲酸烷基酯加到水相中， 生成omeprazole结晶。

Description

本发明涉及5-甲氧基-2-[[（4-甲氧基-3，5-二甲基-2-吡啶基）-甲基]亚磺酰-1H-苯并咪唑改进的合成方法，为方便起见，在以下的说明书和权利要求书中将该化合物简称为“omeprazole”。
US-A-4255431公开了omeprazole的合成方法，包括将5-甲氧基-2-[（4-甲氧基-3，5-二甲基-2-吡啶基）-甲硫基]-1H-苯并咪唑在二氯甲烷溶液中与间氯过苯甲酸反应，生成omeprazole和间氯苯甲酸。omeprazole对酸非常敏感，反应混合物必须保存在低温条件下，以防止在反应混合物中过量分解。
该产物通过滤去反应期间生成的间氯苯甲酸后得到，滤液用二氯甲烷稀释，经Na2CO3溶液提取，干燥和蒸发。生成的omeprazole产物由于存在起始原料和副产物而被污染。
本发明的任务在于提供改进omeprazole的合成方法，以摒除以往已知各种方法的种种缺点。
根据本发明的方法，可以完成上述任务。该方法的特征在于在二氯甲烷溶液中和基本保持约8.0-8.6的pH值的条件下，将5-甲氧基-2-[（4-甲氧基-3，5-二甲基-2-吡啶基）-甲硫基]-1H-苯并咪唑（以下用化合物Ⅰ表示）与间氯过苯甲酸反应，用NaOH水溶液提取反应物，分离水相与有机相，将甲酸烷基酯加到水相中，生成omeprazole结晶。
间氯过苯甲酸与0.7-1.4摩尔当量的化合物Ⅰ反应较为适宜，尤以与0.9-1.2摩尔当量的化合物Ⅰ反应为佳。
按本发明的一个实施例，甲酸烷基酯是甲酸甲酯或甲酸乙酯，以甲酸甲酯为佳。
甲酸烷基酯与1.2-2.0摩尔当量的化合物Ⅰ反应较为适宜，尤以与1.5-1.8摩尔当量的化合物Ⅰ反应为佳。
本发明方法的一个重要特征在于，由于用NaOH水溶液提取，未反应的硫化物并不转化为水相，另一个重要特征在于由于将甲酸甲酯加到水相中，间氯苯甲酸并不结晶，从而省去了已知方法中必须过滤间氯苯甲酸的步骤。
用NaOH的pH静态滴定方法或使用缓冲溶液，使反应混合物的pH值保持在8.0-8.6范围内。较佳的缓冲溶液是碳酸氢钠和碳酸氢钾。
本发明方法的一个重要优点在于反应是在二氯甲烷有机相中进行的，在使用缓冲液的情况下，反应期间形成的间氯苯甲酸进入到含缓冲液的水相中。由此所生成的omeprazole并不与酸接触，并且反应可在0℃以上的温度条件下完成。
按本发明的一个实施例，NaOH水相的pH值保持在大约12以上。
按本发明的另一个实施例，omeprazole的结晶是在pH9以上的条件下完成。
以下的实施例将进一步说明本发明，但不是限制本发明。
实施例
在pH8.6和CH2Cl2溶液中，5-甲氧基-2-[（4-甲氧基-3，5-二甲基-2-吡啶基）-甲硫基]-1H-苯并咪唑（16.2g;0.0492mol）与间氯过苯甲酸（13.6g;0.0537mol）反应，在KHCO3（5.6g;0.056mol）缓冲液存在下保持反应。加料期间，温度保持在0℃左右。
将经过稀释的NaOH加到pH12以上，分离CH2Cl2相。
将甲酸甲酯（4.7g）加到水相中，在pH保持在9以上的条件下，使omeprazole结晶。在0℃以上温度条件下，滤出结晶，并用水和甲醇洗涤。经过洗涤的结晶在真空下干燥。得率：15.6g（92%）。

Claims (9)

1、改进的omeprazole合成方法，其特征在于在二氯甲烷溶液中和pH基本保持在8.0-8.6左右的条件下，将5-甲氧基-2-[(4-甲氧基-3，5-二甲基-2-吡啶基]-甲硫基]-1H-苯并咪唑(化合物Ⅰ)与间氯过苯甲酸反应，用NaOH水溶液提取反应混合物，分离水相和有机相，将甲酸烷基酯加到水相中，生成omeprazole结晶。
2、按权利要求1的方法，其特征在于间氯过苯甲酸与0.7-1.4摩尔当量的化合物Ⅰ反应，优选与0.9-1.2摩尔当量的化合物Ⅰ反应。
3、按权利要求1或2的方法，其特征在于所述甲酸烷基酯是甲酸甲酯。
4、按权利要求1-3的方法，其特征在于用NaOH的pH静态滴定法使反应混合物的pH值保持在8.0-8.6的范围内。
5、按权利要求1-4的方法，其特征在于使用缓冲溶液使反应混合物的pH值保持在8.0-8.6的范围内。
6、按权利要求5的方法，其特征在于所述缓冲溶液是碳酸氢钠或碳酸氢钾。
7、按权利要求1-6的方法，其特征在于NaOH水相的pH值保持在大约12以上。
8、按权利要求1-7的方法，其特征在于将甲酸烷基酯加到1.2-2.0摩尔当量的化合物Ⅰ中，尤以加到1.5-1.8摩尔当量的化合物Ⅰ中为佳。
9、按权利要求1-8的方法，其特征在于omeprazole的结晶是在pH9以上的条件下完成的。
CN91103923A 1990-06-07 1991-06-07 改进的合成奥美普拉唑的方法 Expired - Fee Related CN1040536C (zh)

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SE9002043A SE9002043D0 (sv) 1990-06-07 1990-06-07 Improved method for synthesis
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IS3711A7 (is) 1991-12-08
AP216A (en) 1992-09-02
HU214323B (hu) 1998-03-02
IS1752B (is) 2000-07-21
JPH05507699A (ja) 1993-11-04
DE69128832D1 (de) 1998-03-05
KR0178045B1 (en) 1999-03-20
RO111366B1 (ro) 1996-09-30
DE69128832T2 (de) 1998-05-28
PT97873B (pt) 1998-10-30
CA2083605A1 (en) 1991-12-08
SG48053A1 (en) 1998-04-17
FI925529A (fi) 1992-12-04
DZ1504A1 (fr) 2004-09-13
EG19392A (en) 1995-06-29
NO300541B1 (no) 1997-06-16
LT3584B (en) 1995-12-27
CN1040536C (zh) 1998-11-04
IE911845A1 (en) 1991-12-18
CA2083605C (en) 1998-12-08
IL98274A (en) 1995-03-30
ATE162790T1 (de) 1998-02-15
EP0533752A1 (en) 1993-03-31
ZA913779B (en) 1992-02-26
NZ238224A (en) 1993-11-25
AU640246B2 (en) 1993-08-19
JP2993122B2 (ja) 1999-12-20
SK278505B6 (en) 1997-08-06
AP9100274A0 (en) 1991-07-31
FI102967B (fi) 1999-03-31

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