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 PDFInfo
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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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- Prior art keywords
- chemical compounds
- omeprazole
- molar equivalent
- reaction
- methoxyl group
- Prior art date
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Links
- 238000000034 method Methods 0.000 title claims description 15
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 title description 2
- 230000002194 synthesizing effect Effects 0.000 title description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 21
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims abstract description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 16
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960000381 omeprazole Drugs 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 238000002425 crystallisation Methods 0.000 claims abstract description 8
- 230000008025 crystallization Effects 0.000 claims abstract description 8
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims abstract description 7
- -1 alkyl formate Chemical compound 0.000 claims abstract description 7
- 239000011541 reaction mixture Substances 0.000 claims abstract description 7
- 239000008346 aqueous phase Substances 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000007864 aqueous solution Substances 0.000 claims abstract description 4
- 238000000605 extraction Methods 0.000 claims abstract description 4
- 239000012074 organic phase Substances 0.000 claims abstract description 4
- 239000012071 phase Substances 0.000 claims abstract description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 238000010189 synthetic method Methods 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- JBJWASZNUJCEKT-UHFFFAOYSA-M sodium;hydroxide;hydrate Chemical compound O.[OH-].[Na+] JBJWASZNUJCEKT-UHFFFAOYSA-M 0.000 claims description 2
- 230000003068 static effect Effects 0.000 claims description 2
- 238000000207 volumetry Methods 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000013016 damping Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9002043 | 1990-06-07 | ||
| SE9002043A SE9002043D0 (sv) | 1990-06-07 | 1990-06-07 | Improved method for synthesis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1058211A true CN1058211A (zh) | 1992-01-29 |
| CN1040536C CN1040536C (zh) | 1998-11-04 |
Family
ID=20379708
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN91103923A Expired - Fee Related CN1040536C (zh) | 1990-06-07 | 1991-06-07 | 改进的合成奥美普拉唑的方法 |
Country Status (41)
| Country | Link |
|---|---|
| US (1) | US5386032A (zh) |
| EP (1) | EP0533752B1 (zh) |
| JP (1) | JP2993122B2 (zh) |
| KR (1) | KR0178045B1 (zh) |
| CN (1) | CN1040536C (zh) |
| AP (1) | AP216A (zh) |
| AT (1) | ATE162790T1 (zh) |
| AU (1) | AU640246B2 (zh) |
| BG (1) | BG61265B1 (zh) |
| CA (1) | CA2083605C (zh) |
| CZ (1) | CZ279928B6 (zh) |
| DE (1) | DE69128832T2 (zh) |
| DK (1) | DK0533752T3 (zh) |
| DZ (1) | DZ1504A1 (zh) |
| EG (1) | EG19392A (zh) |
| ES (1) | ES2113378T3 (zh) |
| FI (1) | FI102967B (zh) |
| GR (1) | GR3026642T3 (zh) |
| HR (1) | HRP920770B1 (zh) |
| HU (1) | HU214323B (zh) |
| IE (1) | IE911845A1 (zh) |
| IL (1) | IL98274A (zh) |
| IS (1) | IS1752B (zh) |
| LT (1) | LT3584B (zh) |
| LV (1) | LV10271B (zh) |
| MA (1) | MA22171A1 (zh) |
| NO (1) | NO300541B1 (zh) |
| NZ (1) | NZ238224A (zh) |
| PL (1) | PL165433B1 (zh) |
| PT (1) | PT97873B (zh) |
| RO (1) | RO111366B1 (zh) |
| RU (1) | RU2061693C1 (zh) |
| SA (1) | SA91120027B1 (zh) |
| SE (1) | SE9002043D0 (zh) |
| SG (1) | SG48053A1 (zh) |
| SK (1) | SK278505B6 (zh) |
| TN (1) | TNSN91042A1 (zh) |
| UA (1) | UA32524C2 (zh) |
| WO (1) | WO1991018895A1 (zh) |
| YU (1) | YU47570B (zh) |
| ZA (1) | ZA913779B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102786513A (zh) * | 2011-05-18 | 2012-11-21 | 中国医学科学院药物研究所 | 奥美拉唑晶e型物质及制备方法与在药品和保健品中应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE521100C2 (sv) * | 1995-12-15 | 2003-09-30 | Astra Ab | Förfarande för framställning av en bensimidazolförening |
| US6489346B1 (en) | 1996-01-04 | 2002-12-03 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| US5840737A (en) | 1996-01-04 | 1998-11-24 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
| US6699885B2 (en) | 1996-01-04 | 2004-03-02 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and methods of using same |
| US6645988B2 (en) * | 1996-01-04 | 2003-11-11 | Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| SE508669C2 (sv) * | 1996-04-26 | 1998-10-26 | Astra Ab | Nytt förfarande |
| SK283805B6 (sk) | 1996-09-09 | 2004-02-03 | Slovakofarma, A. S. | Spôsob prípravy omeprazolu |
| SE510666C2 (sv) * | 1996-12-20 | 1999-06-14 | Astra Ab | Nya Kristallmodifikationer |
| CA2204580A1 (en) * | 1997-05-06 | 1998-11-06 | Michel Zoghbi | Synthesis of pharmaceutically useful pyridine derivatives |
| US6437139B1 (en) | 1997-05-06 | 2002-08-20 | Pdi-Research Laboratories, Inc. | Synthesis of pharmaceutically useful pyridine derivatives |
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| SE510650C2 (sv) * | 1997-05-30 | 1999-06-14 | Astra Ab | Ny förening |
| SE510643C2 (sv) * | 1997-06-27 | 1999-06-14 | Astra Ab | Termodynamiskt stabil omeprazol natrium form B |
| ES2137862B1 (es) * | 1997-07-31 | 2000-09-16 | Intexim S A | Preparacion farmaceutica oral que comprende un compuesto de actividad antiulcerosa y procedimiento para su obtencion. |
| US6096340A (en) * | 1997-11-14 | 2000-08-01 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
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| SE9704183D0 (sv) | 1997-11-14 | 1997-11-14 | Astra Ab | New process |
| SI20019A (sl) * | 1998-07-13 | 2000-02-29 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Izboljšan postopek sinteze 5-metoksi -2-/(4-metoksi-3,5-dimetil-2-piridil)metil/ sulfinil-1H-benzimidazola |
| US6191148B1 (en) | 1998-08-11 | 2001-02-20 | Merck & Co., Inc. | Omerazole process and compositions thereof |
| US6166213A (en) * | 1998-08-11 | 2000-12-26 | Merck & Co., Inc. | Omeprazole process and compositions thereof |
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| UA72748C2 (en) * | 1998-11-10 | 2005-04-15 | Astrazeneca Ab | A novel crystalline form of omeprazole |
| IL142703A (en) | 1998-11-10 | 2006-04-10 | Astrazeneca Ab | Crystalline form of omeprazole |
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| US6268385B1 (en) | 1999-08-26 | 2001-07-31 | Robert R. Whittle | Dry blend pharmaceutical formulations |
| US6316020B1 (en) | 1999-08-26 | 2001-11-13 | Robert R. Whittle | Pharmaceutical formulations |
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| IN148930B (zh) * | 1977-09-19 | 1981-07-25 | Hoffmann La Roche | |
| SE7804231L (sv) * | 1978-04-14 | 1979-10-15 | Haessle Ab | Magsyrasekretionsmedel |
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| SE8300736D0 (sv) * | 1983-02-11 | 1983-02-11 | Haessle Ab | Novel pharmacologically active compounds |
| ZW4585A1 (en) * | 1984-04-19 | 1985-11-20 | Hoffmann La Roche | Imidazole derivatives |
| IL76839A (en) * | 1984-10-31 | 1988-08-31 | Byk Gulden Lomberg Chem Fab | Picoline derivatives,processes for the preparation thereof and pharmaceutical compositions containing the same |
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| SE8600658D0 (sv) * | 1986-02-14 | 1986-02-14 | Haessle Ab | Novel composition of matter |
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| DE3722810A1 (de) * | 1987-07-10 | 1989-01-19 | Hoechst Ag | Substituierte benzimidazole, verfahren zu deren herstellung, diese enthaltende pharmazeutische zubereitungen und deren verwendung |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102786513A (zh) * | 2011-05-18 | 2012-11-21 | 中国医学科学院药物研究所 | 奥美拉唑晶e型物质及制备方法与在药品和保健品中应用 |
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