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
Links
- 238000000034 method Methods 0.000 title claims description 18
- 230000015572 biosynthetic process Effects 0.000 title claims description 6
- 238000003786 synthesis reaction Methods 0.000 title claims description 5
- 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 15
- 229960000381 omeprazole Drugs 0.000 claims abstract description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical group COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 10
- -1 4-methoxy-3,5-dimethyl-2-pyridinyl Chemical group 0.000 claims description 8
- 239000008346 aqueous phase Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000000872 buffer Substances 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 230000003068 static effect Effects 0.000 claims description 2
- 238000004448 titration Methods 0.000 claims description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- 150000007513 acids Chemical class 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000000605 extraction Methods 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
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 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
Landscapes
- 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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AP 0 0 0 2 1 6 f
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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AP Ο Ο Ο 2 1 6
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.
bad original $
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 (41)
| 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) |
| 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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| 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 (en) * | 1996-04-26 | 1998-10-26 | Astra Ab | New procedure |
| SK283805B6 (en) | 1996-09-09 | 2004-02-03 | Slovakofarma, A. S. | Method of omeprazole preparation |
| SE510666C2 (en) * | 1996-12-20 | 1999-06-14 | Astra Ab | New Crystal Modifications |
| 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 |
| KR100463031B1 (en) * | 1997-05-26 | 2005-04-06 | 동아제약주식회사 | New preparation method of 5-methoxy-2- [3,5-dimethyl-4-methoxypyridylmethyl) sulfinyl] -1H-benzimidazole |
| SE510650C2 (en) * | 1997-05-30 | 1999-06-14 | Astra Ab | New association |
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| ES2137862B1 (en) * | 1997-07-31 | 2000-09-16 | Intexim S A | ORAL PHARMACEUTICAL PREPARATION INCLUDING A COMPOUND OF ANTI-ULCER ACTIVITY AND PROCEDURE FOR ITS OBTAINING. |
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| US6353005B1 (en) | 1999-03-02 | 2002-03-05 | Sepracor, Inc. | Method and compositions using (+) norcisapride in combination with proton pump inhibitors or H2 receptor antagonist |
| 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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| US6369087B1 (en) | 1999-08-26 | 2002-04-09 | Robert R. Whittle | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6312712B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Method of improving bioavailability |
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| DK2125698T3 (en) | 2007-03-15 | 2016-11-07 | Auspex Pharmaceuticals Inc | Deuterated d9-VENLAFAXINE |
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-
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
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- 1991-06-05 ES ES91910929T patent/ES2113378T3/en not_active Expired - Lifetime
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- 1991-06-05 DK DK91910929.8T patent/DK0533752T3/en active
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- 1991-06-06 EG EG35291A patent/EG19392A/en active
- 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
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- 1991-10-18 KR KR1019910701379A patent/KR0178045B1/en not_active Expired - Fee Related
-
1992
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- 1992-12-04 FI FI925529A patent/FI102967B/en active
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1993
- 1993-05-25 US US08/067,406 patent/US5386032A/en not_active Expired - Lifetime
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1998
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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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