CN103570686B - Method for synthesizing and refining esomeprazole sodium - Google Patents
Method for synthesizing and refining esomeprazole sodium Download PDFInfo
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- 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
Abstract
The invention relates to a method for synthesizing and refining esomeprazole sodium. The method comprises the following several steps: (1) carrying out condensation by taking 2-sulfydryl-5-methoxybenzimidazole and 2-chloromethyl-3.5-dimethyl-4-methoxypyridine hydrochloride as raw materials to generate prochiral thioether; (2) synthesizing the prochiral thioether into an esomeprazole crude product under the action of D-(-) diethyl tartrate, water, tetraisopropyl titanate, diisopropylethylamine and cumene hydroperoxide, and refining to generate esomeprazole potassium salt; (3) dissolving the esomeprazole potassium salt, then transforming into esomeprazole sodium salt, and refining to obtain a final product. The process of the esomeprazole sodium has the advantages of easiness for operation, good reaction repeatability and higher yield; the obtained product is high in purity and suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of production synthesis and process for refining of Esomeprazole sodium, belong to medical art.
Background technology
Esomeprazole sodium chemistry is by name: 5-methoxyl group-2-((S)-((4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl) sulfinyl-1 H-benzimidazole sodium
Structural formula is:
Molecular formula: C
17h
18n
3naO
3s
Molecular weight: 367.41
Esomeprazole sodium is the levoisomer of Omeprazole Sodium, is researched and developed and in 1999 in U.S.'s Initial Public Offering by Astrazeneca AB, is the isomer proton pump inhibitor (PPI) of first listing.Esomeprazole sodium suppresses parietal cell proton pump to reduce gastric acid secretion, therefore, it is possible to effectively treat the illnesss such as stomach ulcer, duodenal ulcer, functional dyspepsia and reflux esophagitis by specificity.Compared with Omeprazole Sodium, Esomeprazole sodium in vivo metabolic rate is very slow, so its bioavailability and plasma concentration are higher than omeprazole, drug effect is also more lasting.Esomeprazole sodium is little by liver metabolism effect in addition, and clinical metabolic individual difference is little, so its side effect is also less.Esomeprazole sodium substitutes the choice drug that Omeprazole Sodium becomes the acid related disorders such as clinical treatment peptide ulceration, gastroesophageal reflux disease at present gradually.
The preparation method of Esomeprazole sodium is mainly divided into biological enzyme oxidation style; Racemic modification omeprazole Split Method and asymmetry catalysis oxidation style.Patent WO9617076 reports the method utilizing biological enzyme to be oxidized pro-chiral sulphide thing generation esomeprazole, obtains good effect.Although biochemical method represents the trend of future development, at present technique is immature, complicated operation and production cost is high, so its application is also restricted; The patents such as WO2010072759, WO9427988, CN200980126581.0 describe the method split racemic modification omeprazole.The method technique is more ripe, but the omeprazole dextrorotatory isomer that fractionation obtains cannot reclaim, and causes waste and causes raw materials cost too high.Resolution reagent general toxicity is larger and expensive in addition, and chiral chromatographic column is difficult to amplify, and therefore Split Method is difficult to carry out industry's enlarging production.In addition also have the special methods such as microwave cooperating reaction method to prepare Esomeprazole sodium, but be all not suitable for industrial production.Another kind method is asymmetry catalysis oxidation style, under WO2004052881, US20080319195, WO2005054288 etc. patent reports the existence of the metal complex compounds such as chiral ligand and titanium, vanadium, zirconium, use hydrogen peroxide analog derivative to the method for pro-chiral sulphide oxidative synthesis Esomeprazole sodium.Although the method facilitates feasible, but relative to catalyzed by biological enzyme and Split Method, the easier effect being subject to oxygen and illumination in reaction process generates sulfone compound (oxidation impurities), be difficult to control in commercial process, easily cause the purity of product lower, and then affect the yield of qualified product.Therefore, process modification is carried out on the basis of asymmetric oxidation method, develop one can high yield to obtain the production technique that qualified product are suitable for again suitability for industrialized production be very necessary.
Summary of the invention
The object of the invention is the deficiency overcoming existing technique, existing Esomeprazole sodium synthesis and purifying process are improved, a kind of synthesis and purifying process of Esomeprazole sodium is provided.The oxidation system of cumene hydroperoxide and titanium isopropylate can well the generation of controlled oxidization impurity; Especially, after optimizing, purifying process had both greatly reduced the content of impurity, turn avoid the crystal formation change and yield reduction that use recrystallization method to cause.This technological operation is easy, reaction conditions is gentleer, and total molar yield can reach more than 50%, particularly effectively controls the content of oxidation impurities (area normalization method) below 0.03%, finished product purity can reach more than 99.8%, is suitable for large-scale industrial production.
The invention provides a kind of preparation method of Esomeprazole sodium, the method comprises the following steps:
(1) 2-sulfydryl-5-methoxybenzimidazol and 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride condensation generates 5-methoxyl group-2 [[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfenyl]-1H-benzoglyoxaline, i.e. pro-chiral sulphide thing, and recrystallizing and refining is carried out to it, react as follows:
One or more mixture in the solvent particular methanol that this reaction adopts, ethanol, acetonitrile, more preferably methyl alcohol.
The temperature of this reaction needs to control at 60 DEG C ~ 80 DEG C, and preferable reaction temperature is 60 ~ 65 DEG C.
One or more mixture in the solvent ethyl acetate that recrystallization adopts, butylacetate, acetone, toluene, more preferably ethyl acetate.
In recrystallization process, pro-chiral sulphide thing crude product and preferred 1:2 ~ 3 of recrystallization solvent mass ratio, more preferably 1:2.5.
The recrystallization temperature of recrystallization preferably-5 DEG C ~ 10 DEG C, more preferably 0 DEG C ~ 3 DEG C.
(2) after pro-chiral sulphide thing dissolves with toluene, add D – (–) diethyl tartrate, titanium isopropylate, water form chiral catalytic system, then diisopropylethylamine is added and cumene hydroperoxide carries out chiral oxidization reaction, potassium hydroxide methanol solution was added after reaction terminates, obtain esomeprazole potassium crude product, to its carry out refining after obtain esomeprazole potassium product, react as follows:
The temperature of reaction preferably 40 DEG C ~ 50 DEG C of chiral catalytic system is formed, more preferably 47 DEG C ~ 50 DEG C in this reaction; Preferably 2.5 hours reaction times.
The temperature dripping cumene hydroperoxide in this reaction and the temperature of carrying out oxidizing reaction preferably 0 DEG C ~ 10 DEG C, more preferably 0 DEG C ~ 5 DEG C.
The preferred mass concentration of the oxygenant cumene hydroperoxide toluene solution used in this reaction is 83% ~ 87%.
D – (– in this reaction) the mol ratio preferably 1.2 ~ 1:1 of diethyl tartrate and pro-chiral sulphide thing; The mol ratio preferably 0.7 ~ 0.5:1 of titanium isopropylate and pro-chiral sulphide thing; The mol ratio preferably 1.2 ~ 1:1 of diisopropylethylamine and pro-chiral sulphide thing; The mol ratio preferably 1.5 ~ 1:1 of cumene hydroperoxide and pro-chiral sulphide thing, more preferably 1.2:1.
Refine one or more mixed solvents in the preferred acetone of solvent of employing, acetonitrile, toluene, methyl alcohol, ethyl acetate, more preferably ratio is methyl alcohol, the acetonitrile mixing solutions of 1:2.
Refining Heating temperature preferably 55 DEG C ~ 70 DEG C, more preferably 60 DEG C ~ 65 DEG C; Cooling recrystallization temperature preferably 0 DEG C ~ 5 DEG C.
(3) esomeprazole potassium is dissolved in after in water, adds sodium hydrate methanol solution, obtains Esomeprazole sodium crude product, to crude product carry out refining after obtain finished product, react as follows:
In this reaction esomeprazole sylvite water-soluble after, adjust pH value scope preferably between 7 ~ 8, more preferably 7.5 ~ 8; Adjust pH value acid solution preferably 20% acetic acid aqueous solution.
The mol ratio preferably 1.5 ~ 1.1:1 of the sodium hydroxide added in this reaction and esomeprazole sylvite, more preferably 1.3:1.
The refining preferred acetone of solvent, acetonitrile, toluene, ethyl acetate, one or more mixed solvents in tetrahydrofuran (THF) adopted, the more preferably acetone of equal proportion and acetonitrile.
Esomeprazole sodium crude product and preferred 1:3 ~ 4 of recrystallization solvent mass ratio in refining, more preferably 1:3.5.
Refining Heating temperature preferably 55 DEG C ~ 65 DEG C, more preferably 55 DEG C ~ 60 DEG C; Cooling recrystallization temperature preferably 15 DEG C ~ 25 DEG C, more preferably 15 DEG C ~ 20 DEG C.
The present invention is further illustrated below by way of experimental data:
Advantage 1: the synthetic route that document WO200707499 reports is with 5-methoxyl group-2 [[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfenyl]-1H-benzoglyoxaline (pro-chiral sulphide thing) is starting raw material, be that oxygenant is oxidized production omeprazole with metachloroperbenzoic acid, then to dissociate esomeprazole generate sodium salt with acetic acid with S-triphenyl ethylene glycol inclusion resolution, total recovery is 13%.
Pro-chiral sulphide thing is carried out asymmetric oxidation through the oxidation system of D-diethyl tartrate, titanium isopropylate, cumene hydroperoxide by the present invention, obtains esomeprazole, and last and sodium hydroxide salify obtains sodium salt, and yield can reach 50%.
As can be seen from experimental result, Split Method is to less waste 50% raw material, and complicated operation, be not suitable for suitability for industrialized production, process recovery ratio of the present invention is higher and stable, simple to operate, and ee value also can meet the requirements, and is applicable to suitability for industrialized production.
Advantage 2: because committed step of the present invention is an oxidizing reaction, the sulphur atom of pro-chiral sulphide thing is probably generated sulfone by peroxidation in reaction process, so need to carry out strict control to the condition of oxidizing reaction.But still have the oxidized generation sulfone of a small amount of esomeprazole, this just needs content purifying products removing being reduced to oxidation impurities in process for refining.The screening of purification condition is as shown in the table.
As can be seen from experimental result, use the method for three kinds of poor solvent making beating purifying can control below 0.05% by oxidative impurity levels, the yield of Simultaneous purification also can meet the expected requirements.Although foreign matter content can reduce by the method for recrystallization, in the process of dissolve-repreparation, easily cause the change of crystal formation, and yield is not high yet.
Beneficial effect:
The present invention by technical optimization, provides that a kind of raw material sources are easy to get, easy and simple to handle, reaction preference is high, production efficiency is high, be suitable for the preparation method of the Esomeprazole sodium of suitability for industrialized production, and its advantage is mainly reflected in:
(1) present invention employs the asymmetric oxidation system of cumene hydroperoxide and titanium isopropylate, this method is easy and simple to handle, and reaction conditions milder improves the selectivity of reaction, and the ee value of product can reach more than 99.8%.
(2) with the purification process that acetone, acetonitrile, toluene, ethyl acetate etc. are solvent, the content that effectively can control the oxidation impurities (sulfone) in product can control below 0.03% (area normalization method), and make product purity reach more than 99.8%, improve quality and the security of product.
(3) molar yield of the present invention can reach more than 50%, greatly reduces production cost, also mitigates the pressure of environmental protection while decreasing waste.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1 prepares pro-chiral sulphide thing
Get 80.0g(2.0mol) after sodium hydroxide adds 300ml water dissolution, be cooled to less than 40 DEG C, then add in 900ml methyl alcohol under whipped state.By 150.0g(0.83mol) 2-sulfydryl-5-methoxybenzimidazol adds in above-mentioned solution, is stirred to dissolving, about needs 30 minutes.Dissolve in backward reaction solution and add 185.0g(0.83mol) 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride.Be heated to 65 DEG C, react 3 hours.Question response liquid temp is down to less than 30 DEG C, adds 600ml methylene dichloride and 300ml water, stirs about ten minutes, make muddy clearly molten, separate dichloromethane layer, water layer 300ml dichloromethane extraction 3 times, combined dichloromethane layer also adds 300ml saturated common salt water washing 1 time.Anhydrous sodium sulfate drying, vacuum concentration obtains pro-chiral sulphide thing crude product.Crude product is added in 600ml ethyl acetate, after reflux makes oily matter dissolve, Temperature fall to 30 DEG C, then be cooled to 0 DEG C ~ 3 DEG C, stir 2 hours.Filter, vacuum-drying obtains product 245.8g, productive rate 89.7%.
Embodiment 2 prepares esomeprazole potassium crude product
By thioether 240.0g(0.73mol) be added in 1500ml toluene, be heated under stirring 70 DEG C clearly molten, then 47 DEG C ~ 50 DEG C are cooled to, add D-(-)-diethyl tartrate 150.4g(0.73mol), titanium isopropylate 103.8g(0.37mol), water 4g(0.06mol), keep 47 DEG C ~ 50 DEG C to react 2.5h.Then be cooled to 0 DEG C ~ 5 DEG C, add diisopropylethylamine 94.4g(0.73mol), stir 10min, keeps 0 DEG C ~ 5 DEG C dropping 196.6g(1.09mol) cumene hydroperoxide toluene solution (mass concentration 85%).After dropwising, 0 DEG C ~ 5 DEG C are kept to continue reaction 4.5 hours.By 81.8g(0.73mol) potassium hydroxide is dissolved in 800ml methyl alcohol, after question response terminates, keeps 0 DEG C ~ 5 DEG C and drops in reaction solution by potassium hydroxide methanol solution, stirs stirred crystallization 2 hours.Filter, a small amount of methanol wash, vacuum-drying obtains esomeprazole potassium crude product 243.4g, productive rate 87.1%, purity 99.0%, oxidative impurity levels 0.38%.
Embodiment 3 prepares esomeprazole potassium crude product
By thioether 240.0g(0.73mol) be added in 1500ml toluene, be heated under stirring 70 DEG C clearly molten, then 47 DEG C ~ 50 DEG C are cooled to, add D-(-)-diethyl tartrate 150.4g(0.73mol), titanium isopropylate 103.8g(0.37mol), water 4g(0.06mol), keep 47 DEG C ~ 50 DEG C to react 2.5h.Then be cooled to 5 DEG C ~ 10 DEG C, add diisopropylethylamine 94.4g(0.73mol), stir 10min, keeps 7 DEG C ~ 10 DEG C dropping 157.3g(0.87mol) cumene hydroperoxide toluene solution (mass concentration 85%).After dropwising, 7 DEG C ~ 10 DEG C are kept to continue reaction 5 hours.By 81.8g(0.73mol) potassium hydroxide is dissolved in 800ml methyl alcohol, after question response terminates, is cooled to 0 DEG C ~ 5 DEG C and drops in reaction solution by potassium hydroxide methanol solution, stirs stirred crystallization 2 hours.Filter, a small amount of methanol wash, vacuum-drying obtains esomeprazole potassium crude product 245.7g, productive rate 87.9%, purity 98.9%, oxidative impurity levels 0.41%.
Embodiment 4 prepares esomeprazole potassium crude product
By thioether 240.0g(0.73mol) be added in 1500ml toluene, be heated under stirring 70 DEG C clearly molten, then 47 DEG C ~ 50 DEG C are cooled to, add D-(-)-diethyl tartrate 150.4g(0.73mol), titanium isopropylate 103.8g(0.37mol), water 4g(0.06mol), keep 47 DEG C ~ 50 DEG C to react 2.5h.Then be cooled to 0 DEG C ~ 5 DEG C, add diisopropylethylamine 94.4g(0.73mol), stir 10min, keeps 0 DEG C ~ 5 DEG C dropping 157.3g(0.87mol) cumene hydroperoxide toluene solution (mass concentration 85%).After dropwising, 0 DEG C ~ 5 DEG C are kept to continue reaction 6 hours.By 81.8g(0.73mol) potassium hydroxide is dissolved in 800ml methyl alcohol, after question response terminates, keeps 0 DEG C ~ 5 DEG C and drops in reaction solution by potassium hydroxide methanol solution, stirs stirred crystallization 2 hours.Filter, a small amount of methanol wash, vacuum-drying obtains esomeprazole potassium crude product 242.1g, productive rate 86.6%, purity 99.2%, oxidative impurity levels 0.29%.
Refining of embodiment 5 esomeprazole potassium
Get esomeprazole potassium crude product 120.0g obtained in above-described embodiment 3, add 120ml methyl alcohol and 240ml acetonitrile, be heated to 60 DEG C ~ 65 DEG C stir 2.5 hours, then 0 DEG C ~ 5 DEG C stirring and crystallizing 1 hour is cooled to gradually, filter, vacuum-drying obtains esomeprazole potassium product 113.8g, productive rate 94.8%, purity 99.4%, oxidative impurity levels 0.28%.
Refining of embodiment 6 esomeprazole potassium
Get esomeprazole potassium crude product 120.0g obtained in above-described embodiment 3, add 120ml methyl alcohol, 120ml acetonitrile and 120ml acetone, be heated to 55 DEG C ~ 60 DEG C stir 2.5 hours, then 0 DEG C ~ 5 DEG C stirring and crystallizing 1 hour is cooled to gradually, filter, vacuum-drying obtains esomeprazole potassium product 111.3g, productive rate 92.8%, purity 99.2%, oxidative impurity levels 0.31%.
Embodiment 7 prepares Esomeprazole sodium crude product
Get gained esomeprazole sylvite 110.0g(0.29mol in above-described embodiment 5), add 700ml water stirring and dissolving, then add 800ml methylene dichloride.Stir lower dropping 20% acetic acid aqueous solution and regulate PH to 7.69, stir 10min, extraction, aqueous phase 150ml methylene dichloride back extraction 1 time.Combined dichloromethane mutually after, wash 3 times with 150ml.Get sodium hydroxide 14.9g(0.37mol) add in 250ml methyl alcohol, stirring and dissolving, is down to room temperature.Sodium hydrate methanol solution is dropped to methylene dichloride mutually in, stirring at room temperature 30min.Anhydrous sodium sulfate drying, vacuum concentration obtains Esomeprazole sodium crude product 99.2g, productive rate 94.1%, purity 99.7%, oxidative impurity levels 0.10%.
Refining of embodiment 8 Esomeprazole sodium
Get Esomeprazole sodium crude product 30.0g obtained in above-described embodiment 7, add 65ml acetone and 65ml acetonitrile, be heated to 55 DEG C ~ 60 DEG C, vigorous stirring 2 hours.Then be cooled to 15 DEG C ~ 20 DEG C gradually and stir 1 hour crystallization, filter, a small amount of washing with acetone, vacuum-drying obtains Esomeprazole sodium product 28.6g, productive rate 95.3%, purity 99.8%, oxidative impurity levels 0.03%.
Refining of embodiment 9 Esomeprazole sodium
Get Esomeprazole sodium crude product 30.0g obtained in above-described embodiment 7, add 65ml acetonitrile and 65ml toluene, be heated to 60 DEG C ~ 65 DEG C, vigorous stirring 2 hours.Then be cooled to 15 DEG C ~ 20 DEG C gradually and stir 1 hour crystallization, filter, a small amount of washing with acetone, vacuum-drying obtains Esomeprazole sodium product 27.4g, productive rate 91.3%, purity 99.7%, oxidative impurity levels 0.05%.
Refining of embodiment 10 Esomeprazole sodium
Get Esomeprazole sodium crude product 30.0g obtained in above-described embodiment 7, add 30ml ethyl acetate, 30ml acetone and 30ml acetonitrile, be heated to 55 DEG C ~ 60 DEG C, vigorous stirring 2 hours.Then be cooled to 15 DEG C ~ 20 DEG C gradually and stir 1 hour crystallization, filter, a small amount of washing with acetone, vacuum-drying obtains Esomeprazole sodium product 27.5g, productive rate 91.7%, purity 99.8%, oxidative impurity levels 0.05%.
Claims (1)
1. a preparation method for Esomeprazole sodium, is characterized in that, the method comprises the following steps:
(1) 2-sulfydryl-5-methoxybenzimidazol is added in the sodium hydrate methanol solution prepared, 2-chloromethyl-3 is added after dissolving, 5-dimethyl-4-methoxypyridine hydrochloride is also warming up to back flow reaction, monitoring is down to room temperature after extremely reacting and terminating and is added dichloromethane extraction and drying, underpressure distillation removing methylene dichloride obtains 5-methoxyl group-2 [[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfenyl]-1
h-benzoglyoxaline crude product, is dissolved in crude product in the ethyl acetate of heating, is then cooled to-5 DEG C ~ 10 DEG C, at the uniform velocity stirring and crystallizing 2h, and filter, drying obtains pro-chiral sulphide produce product;
(2) pro-chiral sulphide thing is added in q. s. toluene, be heated to 70 DEG C of dissolvings, molten clear after be cooled to 50 DEG C, and keep this temperature to add D – (– successively) diethyl tartrate, titanium isopropylate, water, reaction 2 ~ 3, then 0 DEG C ~ 10 DEG C are cooled to, add diisopropylethylamine and slowly drip cumene hydroperoxide toluene solution, be added dropwise to complete this temperature of rear maintenance and carry out chiral oxidization reaction, monitoring is to reacting end, reaction times is 4 ~ 6 hours, the potassium hydroxide methanol solution prepared 0 DEG C ~ 10 DEG C of droppings after reaction terminates, and react 2 ~ 3 hours, filter, washing, obtain esomeprazole potassium crude product, methyl alcohol is added and acetonitrile volume ratio is the mixed solvent of 1:2 in crude product, be heated to 60 DEG C ~ 65 DEG C stir 2.5 hours, be cooled to 0 DEG C ~ 5 DEG C crystallizatioies 1 hour, filtration obtains esomeprazole potassium product,
(3) esomeprazole potassium is dissolved in suitable quantity of water, molten clear after add q. s. methylene chloride, stir, dripping 20% acetic acid aqueous solution regulates between ph value of aqueous phase to 7 ~ 8, then extracting and demixing, drip to methylene dichloride the sodium hydrate methanol solution prepared mutually under room temperature and stir 1 hour, dry, underpressure distillation removing methylene dichloride obtains Esomeprazole sodium crude product, acetone and the acetonitrile of equal proportion is added in Esomeprazole sodium crude product, be heated to 55 DEG C ~ 60 DEG C vigorous stirring 2 hours, be cooled to 15 DEG C ~ 25 DEG C gradually and stir 1 hour, filter, washing, dry, obtain.
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| CN103936715B (en) * | 2014-04-17 | 2016-08-24 | 哈尔滨珍宝制药有限公司 | The process for purification of a kind of Esomeprazole sodium and synthetic method |
| CN104447699A (en) * | 2014-12-10 | 2015-03-25 | 哈药集团技术中心 | Preparation method of esomeprazole magnesium trihydrate |
| CN104478856A (en) * | 2014-12-25 | 2015-04-01 | 北京华禧联合科技发展有限公司 | Purificationmethod of esomeprazole magnesiumkey intermediate |
| CN104926791B (en) * | 2015-07-02 | 2017-10-27 | 山东金诃药物研究开发有限公司 | A kind of preparation method of Esomeprazole sodium |
| CN105924430A (en) * | 2016-06-27 | 2016-09-07 | 杭州富阳伟文环保科技有限公司 | Refinement method of esomeprazole sodium |
| CN107056752A (en) * | 2017-04-01 | 2017-08-18 | 上海华源医药科技发展有限公司 | A kind of preparation method of esomeprazole potassium |
| CN110229141A (en) * | 2019-06-20 | 2019-09-13 | 福安药业集团重庆博圣制药有限公司 | A kind of novel preparation method of high-purity esomeprazole sodium |
| CN110627771B (en) * | 2019-10-23 | 2022-01-07 | 山东鲁抗医药股份有限公司 | Preparation method of esomeprazole thioether |
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| CN1258295A (en) * | 1997-05-30 | 2000-06-28 | 阿斯特拉公司 | Novel form of S-omeprazole |
| CN102584792A (en) * | 2012-01-06 | 2012-07-18 | 南京优科生物医药研究有限公司 | Method for preparing high-purity esomeprazole |
| CN103242295A (en) * | 2013-05-14 | 2013-08-14 | 山东罗欣药业股份有限公司 | Esomeprazole sodium crystal-form compound and synthesis method thereof |
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| CN1258295A (en) * | 1997-05-30 | 2000-06-28 | 阿斯特拉公司 | Novel form of S-omeprazole |
| CN102584792A (en) * | 2012-01-06 | 2012-07-18 | 南京优科生物医药研究有限公司 | Method for preparing high-purity esomeprazole |
| CN103242295A (en) * | 2013-05-14 | 2013-08-14 | 山东罗欣药业股份有限公司 | Esomeprazole sodium crystal-form compound and synthesis method thereof |
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