CN102850323A - Refining method of esomeprazole sodium - Google Patents
Refining method of esomeprazole sodium Download PDFInfo
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- CN102850323A CN102850323A CN2011101807974A CN201110180797A CN102850323A CN 102850323 A CN102850323 A CN 102850323A CN 2011101807974 A CN2011101807974 A CN 2011101807974A CN 201110180797 A CN201110180797 A CN 201110180797A CN 102850323 A CN102850323 A CN 102850323A
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- esomeprazole sodium
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Abstract
The invention discloses a refining method of esomeprazole sodium crude product, in order to remove impurities from the crude product. The method includes dissolving esomeprazole sodium crude product in methanol at room temperature under stirring, dropping water until the esomeprazole sodium crude product is completely dissolved, stirring to separate out solid, filtering, concentrating the filtrate to dryness, dissolving in 2-butanone, stirring to separate out white solid, and filtering to obtain esomeprazole sodium refined product.
Description
Technical field
The present invention relates to the method for recrystallizing and refining of Esomeprazole sodium crude product, belong to medical technical field.
Background technology
Esomeprazole sodium (Esomeprazole Sodium), chemistry S-5-methoxyl group by name-2-{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline sodium.Structural formula is as follows:
Research and develop proton pump inhibitor of new generation by AstraZeneca, Initial Public Offering in 1999 is now in multinational listing.Esomeprazole is the S-optically active isomer of omeprazole, is global first isomer proton pump inhibitor (PPI), suppresses the parietal cell proton pump by specificity and reduces gastric acid secretion.Confirm through a large amount of clinical experiments and drug research: its time of keeping pH in the stomach＞4 is longer, and it is higher to press down sour efficient, and curative effect is better than front two generation PPI, and individual difference is little.As PPI of new generation, the many acid related disorders of clinical treatment now have been widely used in.Indication: gastro oesophageal reflux disease (GORD) (GERD); The treatment of-erosive reflux esophagitis;-esophagitis the patient that cured prevents the long term maintenance treatment of recurring; The symptom control of-gastro oesophageal reflux disease (GORD) (GERD); With suitable antimicrobial therapy drug combination eradicate helicobacter pylori, the duodenal ulcer relevant with helicobacter pylori infection heals; Prevent the recurrent peptic ulcer relevant with helicobacter pylori.
Summary of the invention
The invention discloses a kind of process for purification of Esomeprazole sodium crude product.It is all very general that traditional literature is announced, and seldom reports the method for recrystallization.For example: among the patent WO9602535, asymmetric oxidation is disclosed after, after aftertreatment, salify, then recrystallization can obtain purity 95.2%, the esomeprazole sodium salt of e.e. value 99.8%, but how it does not announce recrystallization.Among the patent WO2010091652, obtained purity 99.85%, the esomeprazole sodium salt of e.e. value 99.8%, but how it obtained behind purifying, and not mentioned.And that the present invention has is simple to operate, and production cost is low, the characteristics that the purity of finished product is high.Can be used for the Esomeprazole sodium crude product is carried out the industrialization processing.
The synthetic of the used Esomeprazole sodium crude product of the present invention can be with reference to processing methodes such as US5948789A, WO2008102145A2, WO2009066321A2, WO2010091652A1.
Technical scheme of the present invention.The process for purification of Esomeprazole sodium crude product, carry out according to the following steps: the Esomeprazole sodium crude product is added the first alcohol and water, at room temperature stir fully dissolving, continue to stir, have solid to separate out, filter, filtrate is concentrated into dried repeatedly, adds 2-butanone, stirs after the dissolving, the adularescent solid is separated out, and filtering drying obtains the Esomeprazole sodium highly finished product.
Add methyl alcohol consumption be 5～10 times (v/v) of crude product consumption, the consumption that is preferably methyl alcohol is 8 times of crude product consumption;
Add water consumption be 0.2 times (v/v) of crude product consumption;
Add 2-butanone consumption be 5～10 times of crude product consumptions (v/v), be preferably add 2-butanone consumption be 8 times of crude product consumptions (v/v);
The temperature of crystallization is 20～35 ℃, is preferably 28 ℃;
The time of crystallization is 0.5～4 hour, is preferably 1.5 hours.
The present invention uses is that the method for the mixed solvent of water, methyl alcohol and 2-butanone recrystallization is removed the impurity in the sample.Show that according to the HPLC collection of illustrative plates content of impurity is controlled in 0.2% in the highly finished product.Reached good refining effect.The present invention has simple to operate, and production cost is low, and yield is high, and the characteristics that the Control of Impurities of highly finished product must be low.Can be used for the Esomeprazole sodium crude product carries out in the accurately machined suitability for industrialized production.
Embodiment
The preparation of Esomeprazole sodium crude product
In the dry reaction still, add successively 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfenyl]-1H-benzoglyoxaline 6.2kg (18.8mol), toluene 25L, be warming up to 60 ℃ under stirring.Add successively purified water 44mL (2.4mol), D-(-)-diethyl tartrate 2.35kg (11.4mol) and titanium isopropylate (IV) 1.6kg (5.6mol), 60 ℃ of stirring reaction 50min, be cooled to 30 ℃, add N, N-diisopropylethylamine 0.72kg (5.6mol), and cumyl hydroperoxide (80%) 3.47kg (18.2mol), stir lower room temperature reaction 1h.Add 12% ammonia soln (3*20L) extraction, merge water, regulating the pH value with acetic acid-water (1: 4) is 7, use again ethyl acetate (2*9L) extraction, merge organic phase, saturated common salt washing, anhydrous sodium sulphate (2kg) drying, filter, concentrating under reduced pressure gets brown thickness oily matter (4.8kg).Add 2-butanone (6L) dissolving, stir the NaOH solution (2.88L) of the lower 5M of adding, stir 0.5h, add an amount of toluene, the adularescent solid produces, after repeatedly concentrating, add 2-butanone (3L), have a large amount of white solids to generate, filter, washing, vacuum-drying obtains 3.9kg Esomeprazole sodium crude product.HPLC analytical chemistry purity 98.5%, polarimetry purity 99.8%e.e.
Making with extra care of example 1 Esomeprazole sodium crude product
Carry out according to the following steps:
To be dissolved in the 25L methyl alcohol under the 5kg Esomeprazole sodium crude product stirring at room, drip water 1L to entirely molten, have solid to separate out under stirring, filter, filtrate is concentrated into dried, is dissolved in the 25L 2-butanone, and 20 ℃ were stirred 0.5 hour, the adularescent solid is separated out, filter washing, vacuum-drying, obtain Esomeprazole sodium highly finished product 4.7kg, it is 99.82% that HPLC detects purity.
Making with extra care of example 2 Esomeprazole sodium crude products
Carry out according to the following steps:
To be dissolved in the 35L methyl alcohol under the 5kg Esomeprazole sodium crude product stirring at room, drip water 1L to entirely molten, have solid to separate out under stirring, filter, filtrate is concentrated into dried, is dissolved in the 30L 2-butanone, and 35 ℃ were stirred 4 hours, the adularescent solid is separated out, filter washing, vacuum-drying, obtain Esomeprazole sodium highly finished product 4.67kg, it is 99.85% that HPLC detects purity.
Making with extra care of example 3 Esomeprazole sodium crude products
Carry out according to the following steps:
To be dissolved in the 40L methyl alcohol under the 5kg Esomeprazole sodium crude product stirring at room, drip water 1L to entirely molten, have solid to separate out under stirring, filter, filtrate is concentrated into dried, is dissolved in the 40L 2-butanone, and 25 ℃ were stirred 1 hour, the adularescent solid is separated out, filter washing, vacuum-drying, obtain Esomeprazole sodium highly finished product 4.65kg, it is 99.87% that HPLC detects purity.
Making with extra care of example 4 Esomeprazole sodium crude products
Carry out according to the following steps:
To be dissolved in the 50L methyl alcohol under the 5kg Esomeprazole sodium crude product stirring at room, drip water 1L to entirely molten, have solid to separate out under stirring, filter, filtrate is concentrated into dried, is dissolved in the 50L 2-butanone, and 23 ℃ were stirred 1.5 hours, the adularescent solid is separated out, filter washing, vacuum-drying, obtain Esomeprazole sodium highly finished product 4.5kg, it is 99.85% that HPLC detects purity.
Making with extra care of example 5 piperacillin sodium crude products
Carry out according to the following steps:
To be dissolved in the 40L methyl alcohol under 28 ℃ of stirrings of 5kg Esomeprazole sodium crude product, drip water 1L to entirely molten, have solid to separate out under stirring, filter, filtrate is concentrated into dried, is dissolved in the 40L 2-butanone, and 30 ℃ are stirred 3.5h, the adularescent solid is separated out, filter washing, vacuum-drying, obtain Esomeprazole sodium highly finished product 4.7kg, it is 99.82% that HPLC detects purity.
Making with extra care of example 6 Esomeprazole sodium crude products
Carry out according to the following steps:
To be dissolved in the 40L methyl alcohol under 30 ℃ of stirrings of 5kg Esomeprazole sodium crude product, drip water 1L to entirely molten, have solid to separate out under stirring, filter, filtrate is concentrated into dried, is dissolved in the 40L 2-butanone, and 26 ℃ are stirred 2.0h, the adularescent solid is separated out, filter washing, vacuum-drying, obtain Esomeprazole sodium highly finished product 4.3kg, it is 99.80% that HPLC detects purity.
Making with extra care of example 7 esomeprazole crude products
Carry out according to the following steps:
To be dissolved in the 40L methyl alcohol under 30 ℃ of stirrings of 5kg Esomeprazole sodium crude product, drip water 1L to entirely molten, have solid to separate out under stirring, filter, filtrate is concentrated into dried, is dissolved in the 40L 2-butanone, and 28 ℃ are stirred 2.5h, the adularescent solid is separated out, filter washing, vacuum-drying, obtain Esomeprazole sodium highly finished product 4.55kg, it is 99.86% that HPLC detects purity.
Making with extra care of example 8 piperacillin sodium crude products
Carry out according to the following steps:
To be dissolved in the 40L methyl alcohol under 35 ℃ of stirrings of 5kg Esomeprazole sodium crude product, drip water 1L to entirely molten, have solid to separate out under stirring, filter, filtrate is concentrated into dried, is dissolved in the 40L 2-butanone, and 32 ℃ are stirred 3.0h, the adularescent solid is separated out, filter washing, vacuum-drying, obtain Esomeprazole sodium highly finished product 4.64kg, it is 99.81% that HPLC detects purity.
Claims (10)
1. the process for purification of an Esomeprazole sodium crude product is characterized in that, carries out according to the following steps:
The Esomeprazole sodium crude product is added the first alcohol and water, at room temperature stir fully dissolving, continue to stir, have solid to separate out, filter, filtrate is concentrated into dried, adds 2-butanone, stirring and crystallizing, and the adularescent solid is separated out, and filters, and drying obtains the Esomeprazole sodium highly finished product.
2. the process for purification of Esomeprazole sodium crude product according to claim 1 is characterized in that, the consumption of the methyl alcohol that adds in the step is 5～10 times of crude product consumption.
3. the process for purification of Esomeprazole sodium crude product according to claim 1 is characterized in that, the consumption of the water that adds in the step is 0.2 times of crude product consumption.
4. the process for purification of Esomeprazole sodium crude product according to claim 2 is characterized in that, the consumption of the methyl alcohol that adds in the step is 8 times of crude product consumption.
5. the process for purification of Esomeprazole sodium crude product according to claim 1 is characterized in that, the consumption of 2-butanone is 5～10 times of crude product consumptions in the step.
6. the process for purification of Esomeprazole sodium crude product according to claim 5 is characterized in that, the consumption of 2-butanone is 8 times of crude product consumptions in the step.
7. the process for purification of Esomeprazole sodium crude product according to claim 1 is characterized in that, the temperature of crystallization is 20～35 ℃ in the step.
8. the process for purification of Esomeprazole sodium crude product according to claim 7 is characterized in that, the temperature of crystallization is 28 ℃ in the step.
9. the process for purification of Esomeprazole sodium crude product according to claim 1 is characterized in that, the time of crystallization is 0.5～4 hour in the step.
10. the process for purification of Esomeprazole sodium crude product according to claim 9 is characterized in that, the time of crystallization is 1.5 hours in the step.
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| CN2011101807974A CN102850323A (en) | 2011-06-30 | 2011-06-30 | Refining method of esomeprazole sodium |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103087048A (en) * | 2013-02-26 | 2013-05-08 | 四川尚锐生物医药有限公司 | Method for purifying esomeprazole sodium |
| CN103755685A (en) * | 2014-01-16 | 2014-04-30 | 山东科源制药有限公司 | Purifying and refining method of esomeprazole sodium |
| CN104277031A (en) * | 2013-07-10 | 2015-01-14 | 江苏豪森药业股份有限公司 | Method for preparing high-purity esomeprazole sodium |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1110477A (en) * | 1993-05-28 | 1995-10-18 | 阿斯特拉公司 | Optically pure salts of pyridinylmethyl sulfinyl-1H-benzimidazole compounds |
| WO2003089408A2 (en) * | 2002-04-22 | 2003-10-30 | Sun Pharmaceutical Industries Limited | Optically active substituted pyridinylmethyl-sulphinyl-benzimidazole and salts |
| US20070259921A1 (en) * | 2006-05-04 | 2007-11-08 | Vijayabhaskar Bolugoddu | Polymorphic forms of esomeprazole sodium |
| CN101208330A (en) * | 2005-07-28 | 2008-06-25 | 韩美药品株式会社 | Method of preparing esomeprazole and salts thereof |
| CN102089296A (en) * | 2008-07-09 | 2011-06-08 | 力奇制药公司 | Process for preparation of esomeprazole sodium of high chemical purity and new forms of esomeprazole sodium |
-
2011
- 2011-06-30 CN CN2011101807974A patent/CN102850323A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1110477A (en) * | 1993-05-28 | 1995-10-18 | 阿斯特拉公司 | Optically pure salts of pyridinylmethyl sulfinyl-1H-benzimidazole compounds |
| WO2003089408A2 (en) * | 2002-04-22 | 2003-10-30 | Sun Pharmaceutical Industries Limited | Optically active substituted pyridinylmethyl-sulphinyl-benzimidazole and salts |
| CN101208330A (en) * | 2005-07-28 | 2008-06-25 | 韩美药品株式会社 | Method of preparing esomeprazole and salts thereof |
| US20070259921A1 (en) * | 2006-05-04 | 2007-11-08 | Vijayabhaskar Bolugoddu | Polymorphic forms of esomeprazole sodium |
| CN102089296A (en) * | 2008-07-09 | 2011-06-08 | 力奇制药公司 | Process for preparation of esomeprazole sodium of high chemical purity and new forms of esomeprazole sodium |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103087048A (en) * | 2013-02-26 | 2013-05-08 | 四川尚锐生物医药有限公司 | Method for purifying esomeprazole sodium |
| CN103087048B (en) * | 2013-02-26 | 2014-04-09 | 四川唯拓生物医药有限公司 | Method for purifying esomeprazole sodium |
| CN104277031A (en) * | 2013-07-10 | 2015-01-14 | 江苏豪森药业股份有限公司 | Method for preparing high-purity esomeprazole sodium |
| CN103755685A (en) * | 2014-01-16 | 2014-04-30 | 山东科源制药有限公司 | Purifying and refining method of esomeprazole sodium |
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Application publication date: 20130102 |