AP216A - Improved method for synthesis. - Google Patents
Improved method for synthesis. Download PDFInfo
- Publication number
- AP216A AP216A APAP/P/1991/000274A AP9100274A AP216A AP 216 A AP216 A AP 216A AP 9100274 A AP9100274 A AP 9100274A AP 216 A AP216 A AP 216A
- Authority
- AP
- ARIPO
- Prior art keywords
- omeprazole
- phase
- reaction mixture
- compound
- aqueous phase
- Prior art date
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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
Omeprazole is obtained by reacting
Description
Technical field
The present invention relates to an improved method for the synthesis of 5-methoxy-2-[[(4-methcxy-3,5-dimethyl-2pyridinyl)-methyl]sulfinyl-lH-benizimidazoie, referred to under its generic name omeprazole throughout the following specification and claims.
Prior art
US-A-4 255 431 discloses a process for the synthesis of omeprazole comprising the steps of reacting 5-methoxy-2[ ( 4-methoxy-3,5-dimethyl-2-pyridinyl)-methyithio]-1Hbenzimidazole in a methylene chloride solution with mchloroperoxybenzoic acid resulting in the formation of omeprazole and m-chlorobenzoic acid, omeprazole is highly sensitive to acids, and the reaction mixture has to be maintained at a low temperature to prevent excessive decomposition in the reaction mixture.
The product is worked-up by filtering-off of m-chlorobenzoic acid formed during the reaction. The filtrate is diluted with methylene chloride, is extiacted with ^200^ solution, dried and evaporated. The resultinq omeprazole product is contaminated with starting materials and byproducts .
Summary of the invention
The object of the present invention is to provide an improved method for the synthesis of omeprazole, which eliminates the drawbacks of previously known methods.
This object is achieved according to the present inven-
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tion, which is characterized by the steps of reacting 5methoxy-2-[(4-methoxy-3,5-dimethy1-2-pyridinyl)-methylthioj-ΙΗ-benzimidazole (below denoted Compound I) with mchloroperoxybenzoic acid in a methylene chloride solution at a substantially constant pE of about 8.0 to 8.6; extracting the reaction with aqueous NaCH; separating the aqueous phase from the organic phase; and adding an alkyl formate to the aqueous phase, resulting in crystallization of omeprazole.
The m-chloroperoxybenzoic acid is suitably used in an amount of 0.7 - 1.4 molar equivalents of Compound I, and preferably in an amount of 0.9 - 1.2 molar equivalents.
According to one embodiment of the invention, the alkyl formate is methylformate or ethylformate, methylformate being preferred.
The alkyl formate is suitably used in an amount of 1.2 2.0 molar equivalents of Compound I, and preferably in an amount of 1.5 - 1.8 molar eqv.ivalents.
One important feature of the method according to the invention is that unreacted sulfide is not transferred into the aqueous phase upon the extraction with aqueous NaOH. Another important feature is that m-chlorobenzoic acid does not crystallize upon the addition of methylformate to the aqueous phase, thereby eliminating the need of filtering-off of m-chlcrobenzoic acid in a previous step.
The pH of the reaction mixture may be maintained within the pH range of 8.0 - 8.6 with the aid of pH static titration with NaOH or with the. use of a buffer. Preferred buffers are sodium bicarbonate and potassium bicarbonate.
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it
A great advantage of the method according to the invention is that the reaction takes place in the organic methylene chloride phase while the m-chlorobenzoic acid formed during the reaction goes into the aqueous phase containing the buffer, in the case a buffer is used. Because of this, omeprazole formed does not stay in contact with the acid and the reaction may be performed at a temperature above 0°C.
According to one embodiment of the invention the pH of the aqueous NaCH phase is kept at above about 12.
According to another embodiment of the invention the crystallization of omeprazole is performed at a pH of above 9.
The invention will be further illustrated below with a non-limiting example.
Example
5-methoxy-2-[ ( 4-rnethoxy-3,5-dimethyl-2-pyridinyl) methylthio]-lH-benzimidazole (16.2 g; 0.0492 mol) is reacted with m-chlcroperoxybenzoic acid (13.6 g; 0.0537 mol) in CH2C12 acting as a solvent at a pH of 8.6, which is maintained by the presence of KHCO^ (5.6 g; 0.056 mol) acting as a buffer. The temperature is maintained at about 0°C during the addition.
Diluted NaOH is added to a pH above 12 and the CH2C12 phase is separated off.
Methylformate (1.7 g) is charged to the water phase and the pH is kept above 9, whereupon omeprazole crystallizes. The crystals are filtered off and are washed with water and methanol at a temperature of about 0°C. The washed crystals are dried under vacuum. Yield: 15.6 g (92 %).
Claims (11)
1. A method for the synthesis of omeprazole comprising reacting 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl) methylthio J-ΙΗ-benzimidazole (Compound I) with m-chloropercxybenzoic acid in a methylene chloride solution at a substantially constant pH of about 3.0 to 8.6; extracting the reaction mixture with aqueous NaOH; separating the aqueous phase from the organic phase; and adding an alkyl formate to the aqueous phase; whereby omeprazole crystallises from the aqueous phase.
2. Method according to claim 1, wherein the m-chloroperoxybenzoic acid is used in an amount of 0.7 1.4, preferably 0.9 - 1.2, molar equivalents of Compound I.
3. Method according to claim 1 or 2, wherein the alkyl formate is methyl formate .
4. Method according to any one of the preceding claims wherein the pH of the reaction mixture is maintained within the pH range of 8.0 - 8.6 by means of pH static titration with NaOH.
5. Method according to any one of the preceding claims wherein the pH of the reaction mixture is maintained within the pH range of 8.0 - 8.6 with the use of a buffer.
6. Method according to claim 5, wherein the buffer is sodium bicarbonate or potassium bicarbonate.
7. Method according to any one of the preceding claims wherein the pH of the aqueous NaOH phase is kept at above about 12.
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8. Method according to any one of the preceding claims wherein the alkyl formate is added in an amount of 1.2 2.0, preferably 1.5 - 1.8, molar equivalents of Compound I.
9. Method according to any one of the preceding claims
5 wherein the omeprazole crystallises at a pH of above 9.
10. Method according to claim 1 substantially as hereinbefore described.
11. Omeprazole when obtained by a method according to any one of'the preceding claims.
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Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9002043A SE9002043D0 (en) | 1990-06-07 | 1990-06-07 | IMPROVED METHOD FOR SYNTHESIS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP9100274A0 AP9100274A0 (en) | 1991-07-31 |
| AP216A true AP216A (en) | 1992-09-02 |
Family
ID=20379708
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1991/000274A AP216A (en) | 1990-06-07 | 1991-06-07 | Improved method for synthesis. |
Country Status (42)
| Country | Link |
|---|---|
| US (1) | US5386032A (en) |
| EP (1) | EP0533752B1 (en) |
| JP (1) | JP2993122B2 (en) |
| KR (1) | KR0178045B1 (en) |
| CN (1) | CN1040536C (en) |
| AP (1) | AP216A (en) |
| AT (1) | ATE162790T1 (en) |
| AU (1) | AU640246B2 (en) |
| BG (1) | BG61265B1 (en) |
| CA (1) | CA2083605C (en) |
| CZ (1) | CZ279928B6 (en) |
| DE (1) | DE69128832T2 (en) |
| DK (1) | DK0533752T3 (en) |
| DZ (1) | DZ1504A1 (en) |
| EG (1) | EG19392A (en) |
| ES (1) | ES2113378T3 (en) |
| FI (1) | FI102967B (en) |
| GR (1) | GR3026642T3 (en) |
| HK (1) | HK1003831A1 (en) |
| HR (1) | HRP920770B1 (en) |
| HU (1) | HU214323B (en) |
| IE (1) | IE911845A1 (en) |
| IL (1) | IL98274A (en) |
| IS (1) | IS1752B (en) |
| LT (1) | LT3584B (en) |
| LV (1) | LV10271B (en) |
| MA (1) | MA22171A1 (en) |
| NO (1) | NO300541B1 (en) |
| NZ (1) | NZ238224A (en) |
| PL (1) | PL165433B1 (en) |
| PT (1) | PT97873B (en) |
| RO (1) | RO111366B1 (en) |
| RU (1) | RU2061693C1 (en) |
| SA (1) | SA91120027B1 (en) |
| SE (1) | SE9002043D0 (en) |
| SG (1) | SG48053A1 (en) |
| SK (1) | SK278505B6 (en) |
| TN (1) | TNSN91042A1 (en) |
| UA (1) | UA32524C2 (en) |
| WO (1) | WO1991018895A1 (en) |
| YU (1) | YU47570B (en) |
| ZA (1) | ZA913779B (en) |
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| SE521100C2 (en) * | 1995-12-15 | 2003-09-30 | Astra Ab | Process for the preparation of a benzimidazole compound |
| 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 |
| US6489346B1 (en) | 1996-01-04 | 2002-12-03 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| SK283805B6 (en) * | 1996-09-09 | 2004-02-03 | Slovakofarma, A. S. | Method of omeprazole preparation |
| US6437139B1 (en) | 1997-05-06 | 2002-08-20 | Pdi-Research Laboratories, Inc. | Synthesis of pharmaceutically useful pyridine derivatives |
| CA2204580A1 (en) * | 1997-05-06 | 1998-11-06 | Michel Zoghbi | Synthesis of pharmaceutically useful pyridine derivatives |
| KR100463031B1 (en) * | 1997-05-26 | 2005-04-06 | 동아제약주식회사 | New preparation method of 5-methoxy-2- [3,5-dimethyl-4-methoxypyridylmethyl) sulfinyl] -1H-benzimidazole |
| SE9704183D0 (en) | 1997-11-14 | 1997-11-14 | Astra Ab | New process |
| US6096340A (en) * | 1997-11-14 | 2000-08-01 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6174548B1 (en) | 1998-08-28 | 2001-01-16 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| SI20019A (en) | 1998-07-13 | 2000-02-29 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | An improved process for synthesis of 5-methoxy-2-/(4-methoxy-3,5-dimethyl-2-pyridyl)methyl/ sulphynyl-1h-benzimidazol |
| US6166213A (en) * | 1998-08-11 | 2000-12-26 | Merck & Co., Inc. | Omeprazole process and compositions thereof |
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| US6262085B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
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| US6268385B1 (en) | 1999-08-26 | 2001-07-31 | Robert R. Whittle | Dry blend pharmaceutical formulations |
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| DE19951960C2 (en) | 1999-10-28 | 2002-06-27 | Gruenenthal Gmbh | Process for the preparation of benzimidazole derivatives suitable as ulcer therapeutics |
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| WO2010134099A1 (en) | 2009-05-21 | 2010-11-25 | Cadila Healthcare Limited | One pot process for preparing omeprazole and related compounds |
| CN102786513A (en) * | 2011-05-18 | 2012-11-21 | 中国医学科学院药物研究所 | Omeprazole crystal E substance, its preparation method and its applications in medicines and healthcare products |
| CN104203938A (en) | 2012-01-21 | 2014-12-10 | 朱比兰特生命科学有限公司 | Process for the preparation of 2-pyridinylmethylsulfinyl benzimidazoles, their analogs and optically active enantiomers |
| EP4034143A1 (en) | 2019-09-24 | 2022-08-03 | Prolacta Bioscience, Inc. | Compositions and methods for treatment of inflammatory and immune diseases |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3404610A1 (en) * | 1983-02-11 | 1984-08-16 | Aktiebolaget Hässle, Mölndal | BENZIMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAME |
| EP0197013A1 (en) * | 1985-03-01 | 1986-10-08 | Aktiebolaget Hässle | Substituted benzimidazoles for the manufacture of a medicament for treatment of intestinal inflammatory diseases |
| EP0242341A1 (en) * | 1986-02-14 | 1987-10-21 | Aktiebolaget Hässle | Benzimidazoles, process for their preparation and preparations containing same |
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| IN148930B (en) * | 1977-09-19 | 1981-07-25 | Hoffmann La Roche | |
| SE7804231L (en) * | 1978-04-14 | 1979-10-15 | Haessle Ab | Gastric acid secretion |
| US4307102A (en) * | 1981-02-19 | 1981-12-22 | Sterling Drug Inc. | Phenanthro[2,3-c]pyrazole |
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| NZ244301A (en) * | 1991-09-20 | 1994-08-26 | Merck & Co Inc | Preparation of 2-pyridylmethylsulphinylbenzimidazole and pyridoimidazole derivatives from the corresponding sulphenyl compounds |
-
1990
- 1990-06-07 SE SE9002043A patent/SE9002043D0/en unknown
-
1991
- 1991-05-17 ZA ZA913779A patent/ZA913779B/en unknown
- 1991-05-20 DZ DZ910065A patent/DZ1504A1/en active
- 1991-05-22 NZ NZ238224A patent/NZ238224A/en not_active IP Right Cessation
- 1991-05-27 IL IL9827491A patent/IL98274A/en not_active IP Right Cessation
- 1991-05-30 IE IE184591A patent/IE911845A1/en not_active IP Right Cessation
- 1991-06-04 TN TNTNSN91042A patent/TNSN91042A1/en unknown
- 1991-06-05 CA CA002083605A patent/CA2083605C/en not_active Expired - Lifetime
- 1991-06-05 EP EP91910929A patent/EP0533752B1/en not_active Expired - Lifetime
- 1991-06-05 DK DK91910929.8T patent/DK0533752T3/en active
- 1991-06-05 SG SG1996006672A patent/SG48053A1/en unknown
- 1991-06-05 ES ES91910929T patent/ES2113378T3/en not_active Expired - Lifetime
- 1991-06-05 AT AT91910929T patent/ATE162790T1/en not_active IP Right Cessation
- 1991-06-05 AU AU80807/91A patent/AU640246B2/en not_active Ceased
- 1991-06-05 YU YU99291A patent/YU47570B/en unknown
- 1991-06-05 RU RU9192016535A patent/RU2061693C1/en not_active IP Right Cessation
- 1991-06-05 PL PL91297169A patent/PL165433B1/en not_active IP Right Cessation
- 1991-06-05 HU HU9203855A patent/HU214323B/en unknown
- 1991-06-05 JP JP3510790A patent/JP2993122B2/en not_active Expired - Fee Related
- 1991-06-05 PT PT97873A patent/PT97873B/en not_active IP Right Cessation
- 1991-06-05 DE DE69128832T patent/DE69128832T2/en not_active Expired - Fee Related
- 1991-06-05 RO RO92-01512A patent/RO111366B1/en unknown
- 1991-06-05 UA UA93004176A patent/UA32524C2/en unknown
- 1991-06-05 MA MA22445A patent/MA22171A1/en unknown
- 1991-06-05 WO PCT/SE1991/000402 patent/WO1991018895A1/en active IP Right Grant
- 1991-06-06 CZ CS911726A patent/CZ279928B6/en unknown
- 1991-06-06 EG EG35291A patent/EG19392A/en active
- 1991-06-06 SK SK1726-91A patent/SK278505B6/en unknown
- 1991-06-07 IS IS3711A patent/IS1752B/en unknown
- 1991-06-07 CN CN91103923A patent/CN1040536C/en not_active Expired - Fee Related
- 1991-06-07 AP APAP/P/1991/000274A patent/AP216A/en active
- 1991-07-29 SA SA91120027A patent/SA91120027B1/en unknown
- 1991-10-18 KR KR1019910701379A patent/KR0178045B1/en not_active IP Right Cessation
-
1992
- 1992-10-01 HR HR920770A patent/HRP920770B1/en not_active IP Right Cessation
- 1992-12-04 FI FI925529A patent/FI102967B/en active
- 1992-12-04 NO NO924682A patent/NO300541B1/en unknown
- 1992-12-04 BG BG97146A patent/BG61265B1/en unknown
-
1993
- 1993-05-25 US US08/067,406 patent/US5386032A/en not_active Expired - Lifetime
- 1993-08-10 LV LVP-93-1020A patent/LV10271B/en unknown
- 1993-12-30 LT LTIP1711A patent/LT3584B/en not_active IP Right Cessation
-
1998
- 1998-04-08 HK HK98102920A patent/HK1003831A1/en not_active IP Right Cessation
- 1998-04-14 GR GR980400843T patent/GR3026642T3/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3404610A1 (en) * | 1983-02-11 | 1984-08-16 | Aktiebolaget Hässle, Mölndal | BENZIMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAME |
| GB2174988A (en) * | 1983-02-11 | 1986-11-19 | Haessle Ab | Intermediates for pyridyl alkylthio-benzimidazole derivatives |
| EP0197013A1 (en) * | 1985-03-01 | 1986-10-08 | Aktiebolaget Hässle | Substituted benzimidazoles for the manufacture of a medicament for treatment of intestinal inflammatory diseases |
| EP0242341A1 (en) * | 1986-02-14 | 1987-10-21 | Aktiebolaget Hässle | Benzimidazoles, process for their preparation and preparations containing same |
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