CN1053444C - Process for refining omeprazole - Google Patents
Process for refining omeprazole Download PDFInfo
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- CN1053444C CN1053444C CN96116288A CN96116288A CN1053444C CN 1053444 C CN1053444 C CN 1053444C CN 96116288 A CN96116288 A CN 96116288A CN 96116288 A CN96116288 A CN 96116288A CN 1053444 C CN1053444 C CN 1053444C
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Abstract
The present invention relates to a method for refining omeprazole. The stability and the product purity of an omeprazole agent are greatly influenced by a coarse product refining method. The present invention provides a new refining method that coarse products are reacted with strong alkali in water or an organic solvent; the obtained omeprazole salt solution is decolored and filtered by active carbon, an organic solvent or water is added for stirring, solid acidic salt is added in batches, and crystals are separated; the final pH value is from 7.0 to 8.5, and the white omeprazole crystals are obtained via filtration, water washing crystallization and drying at the temperature lower than 40 DEG C. The products have the advantages of good stability, high purity and simple refining method, and are suitable for industrial production.
Description
The present invention relates to a kind of process for purification of omeprazole.
Omeprazole is 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methyl] sulfinyl-1II-benzoglyoxaline.Be the hydrochloric acid in gastric juice proton pump inhibitor that is widely used in the treatment digestive tract ulcer in recent years, its formulation mainly contains enteric solubility particulate capsule.And the purity of stability of formulation and product is influenced greatly by the process for purification of omeprazole crude product.At present, the process for purification of omeprazole such as US-4,255,431, US-4,689,333, EP-0,533,264, CN-1, report in 058,211, mainly contain following several: 1, single-solvent process: make solvent with acetonitrile, make the omeprazole saturated solution below 30 ℃, be cooled to then that crystallization makes below 0 ℃.This method yield is low, and the toxicity of residual solvent is big.2, mixed solvent method: omeprazole is dissolved in methylene dichloride or the chloroform, adds ether or ethyl acetate again, separate out crystallization and make.This method solvent for use amount is big, reclaims difficulty.3, acid-base method: omeprazole is dissolved in methylene dichloride, and the hydro-oxidation sodium water solution keeps PH greater than 12, separates out crystallization at aqueous phase adding methyl-formiate then and makes.This method is because crystallisation process needs elevated temperature, and the time is long again, can influence quality product.
The objective of the invention is to overcome the weak point of aforesaid method, invent a kind of method of easy and simple to handle, the cycle is short, yield is high, product stability is good refining omeprazole.
The inventor had once reported the method for preparing the high purity omeprazole sodium salt with resin method in Chinese patent application numbers 95111640, improve after further research, and a kind of process for purification of new omeprazole is provided.
Method of the present invention is that the crude product omeprazole is doubly measured at 3-8, in the best water of doubly measuring for 4-5, with highly basic (1: 1 mol proportional quantity) reaction 0.5-2 hour, the whole PH of manipulated variable is 10.5-11.5, obtain the solution of form of omeprazole salts, after activated carbon decolorizing filters, add 1-5 again and doubly measure organic solvent; Maybe the crude product omeprazole doubly can be measured at 2-5, in the best organic solvent of doubly measuring for 2-3, with highly basic (1: 1 mol proportional quantity) reaction 0.5-2 hour, obtain the solution of form of omeprazole salts, after activated carbon decolorizing filters, add the water that 3-8 doubly measures again, above-mentioned then two kinds of reaction solutions all can be 18-25 ℃ 0-35 ℃ of the best respectively and stir down that add solid acid salt, solid acid salt is very fast dissolved in batches, in the reaction of solution neutralization bases, generate corresponding salt.Because this corresponding salt solubleness in the mixture of water and organic solvent is less, therefore along with the continuous adding of solid acid salt, dissolving and and alkali reaction, it generates salt and reaches capacity very soon and separate out.The reaction of separating out generates salt pair omeprazole crystalline and separates out the heteronuclear induced crystallization effect of playing.Soon, the omeprazole crystallization begins to separate out after the reaction generation salts out.The add-on of control solid acid salt, the final PH that makes reaction solution is 7.0-8.5.Filter, wash crystallization, dry below 40 ℃, get the omeprazole white crystals.
Highly basic in the aforesaid method can be sodium hydroxide or potassium hydroxide or other alkali; Organic solvent can be C
1-3Alkyl alcohol, acetone, tetrahydrofuran (THF), diox, acetonitrile or other can with miscible organic solvent of water etc.; Acid salt can be acid salt of dihydrogen phosphate, supercarbonate, hydrosulphite, EDTA (disodium EDTA) or other organic dibasic acid and polyprotonic acid etc.
Analyze consistent with the crystallization crystal formation that obtains with methylene dichloride-ether mixed solvent method (seeing Fig. 1 and Fig. 2) through the rotating anode X-ray diffraction with the crystallization of the inventive method purified omeprazole.
Fig. 1 is with the inventive method purified omeprazole crystalline rotating anode X-ray diffraction analysis chart.
Fig. 2 is with methylene dichloride-ether mixed solvent method purified omeprazole crystalline rotating anode X-ray diffraction analysis chart.
The Omeprazole crystallization refining with the inventive method has good stability, can Confirm from following test.
1, under the condition of 40 ℃ and relative humidity 75%, reveal put one month after, this The quality of the Omeprazole crystallization that inventive method is refining is uninfluenced, and mixed solvent method Refining Omeprazole crystalline content descends 9%.
2, under 20-30 ℃, Clear glass bottles and jars packings, 2000-4000LX condition, Investigate a week, the quality of the Omeprazole crystallization that the inventive method is refining is uninfluenced, Outward appearance is constant, and the Omeprazole crystallization of mixed solvent legal system quality is just after 24 hours Influenced, outward appearance reddens brown.
Thereby the Omeprazole product stability refining with the inventive method is good, is beneficial to Clinical practice, the inventive method raw material sources are convenient in addition, low price, avirulence, Short, refining yield height of simple to operate, cycle is suitable for suitability for industrialized production.
Example 1, refining omeprazole
Add crude product omeprazole (93.2%) 10 gram in the 250ml four-hole boiling flask, about 22 grams of aqueous sodium hydroxide solution (5%) stir, and control final PH=10.5-11.5, add water 40ml, gac 2 grams again, stir suction filtration 0.5 hour.In filtrate, add 30ml ethanol, stir, add the SODIUM PHOSPHATE, MONOBASIC solid in batches, the final PH=7.0-8.5 suction filtration of the hierarchy of control, deionization washing solid is to the water till the no phosphoric acid salt.40 ℃ dry down, gets omeprazole white crystals 8.5g (99.5%).
Example 2, refining omeprazole
In 250ml four neck flasks, add the ethanolic soln (making) that 50 grams contain Omeprazole Sodium 20% with resin method, water 40 grams stir, add EDTA in batches, have solid to separate out gradually, the final PH of the hierarchy of control is at 7.0-8.5, suction filtration, deionization washing solid is in water till the no EDTA.40 ℃ dry down, gets omeprazole white crystals 8.6g (99.3%).
Example 3, refining omeprazole
In 50 liters of enamel reactors, add (93.2%) 5 kilogram of crude product omeprazole, (5%) 11 kilogram of potassium hydroxide aqueous solution, 18 kilograms in water stirred 0.5 hour, treat that omeprazole changes sylvite into after, add 1 kilogram of activated carbon again.Stirred press filtration 1 hour.In filtrate, add 15 kilograms of ethanol, stir, add the potassium primary phosphate solid in batches, have solid to separate out gradually, control final PH=7.0-8.5, finish, stirred 0.5 hour, get rid of filter, with a large amount of deionized water wash solids, in water till the no phosphoric acid salt at 20 ℃.40 ℃ dry down, gets 4.2 kilograms of omeprazole white crystals (99.7%).
Claims (3)
1, a kind of method of refining omeprazole is characterized in that the crude product omeprazole in the water that 3-8 doubly measures, with highly basic mol proportional quantity reaction in 1: 1 0.5-2 hour, controlling final PH is 10.5-11.5, obtain the solution of form of omeprazole salts, after activated carbon decolorizing filters, add 1-5 again and doubly measure C
1-8Alkyl alcohol, maybe the crude product omeprazole doubly can be measured C at 2-5
1-8Alkyl alcohol in, with 1: 1 mol proportional quantity of highly basic reaction 0.5-2 hour, obtain the solution of form of omeprazole salts, after activated carbon decolorizing filters, add the water that 3-8 doubly measures again, above-mentioned then two kinds of reaction solutions all can stir down at 0-35 ℃ respectively, add solid acid salt in batches, separate out crystallization, till control reaction solution final PH is 7.0-8.5, filter the washing crystallization, dry below 40 ℃, get the omeprazole white crystals.
2, the method for refining omeprazole according to claim 1 is characterized in that wherein said highly basic can be sodium hydroxide or potassium hydroxide.
3, the method for refining omeprazole according to claim 1 is characterized in that wherein said acid salt is dihydrogen phosphate, supercarbonate, hydrosulphite or disodium EDTA.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96116288A CN1053444C (en) | 1996-03-20 | 1996-03-20 | Process for refining omeprazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96116288A CN1053444C (en) | 1996-03-20 | 1996-03-20 | Process for refining omeprazole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1160050A CN1160050A (en) | 1997-09-24 |
| CN1053444C true CN1053444C (en) | 2000-06-14 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96116288A Expired - Lifetime CN1053444C (en) | 1996-03-20 | 1996-03-20 | Process for refining omeprazole |
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| CN (1) | CN1053444C (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL142703A (en) | 1998-11-10 | 2006-04-10 | Astrazeneca Ab | Crystalline form of omeprazole |
| HU230155B1 (en) * | 2001-07-16 | 2015-09-28 | Janssen Pharmaceutica N.V. | Improved process for preparing benzimidazole-type compounds |
| CN100358525C (en) * | 2006-02-27 | 2008-01-02 | 锦州九泰药业有限责任公司 | Prepn process of Lansoprazole sodium for treating peptic ulcer |
| CN101412710B (en) * | 2008-12-16 | 2010-04-21 | 海南百那医药发展有限公司 | Omeprazole sodium compound and preparation thereof |
| 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 |
| CN102977078A (en) * | 2012-11-30 | 2013-03-20 | 河南中帅医药科技发展有限公司 | Preparation method of solid form neutral esomeprazole |
| CN104086533A (en) * | 2014-07-24 | 2014-10-08 | 孙巧玲 | Refinement method of esomeprazole |
| CN104592201A (en) * | 2015-01-13 | 2015-05-06 | 江苏中邦制药有限公司 | Method for refining omeprazole |
| CN112194650A (en) * | 2020-02-26 | 2021-01-08 | 南京国星生物技术研究院有限公司 | Omeprazole refining method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1009112B (en) * | 1988-05-03 | 1990-08-08 | 河北农业技术师范学院 | From sunflower shell, extract the method for vegetable wax |
| CN1071169A (en) * | 1991-09-20 | 1993-04-21 | 麦克公司 | The novel method of preparation anti ulcer agent |
-
1996
- 1996-03-20 CN CN96116288A patent/CN1053444C/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1009112B (en) * | 1988-05-03 | 1990-08-08 | 河北农业技术师范学院 | From sunflower shell, extract the method for vegetable wax |
| CN1071169A (en) * | 1991-09-20 | 1993-04-21 | 麦克公司 | The novel method of preparation anti ulcer agent |
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| CN1160050A (en) | 1997-09-24 |
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