CN103214462A - Preparation method of esomeprazole sodium salt - Google Patents
Preparation method of esomeprazole sodium salt Download PDFInfo
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- CN103214462A CN103214462A CN2013101820770A CN201310182077A CN103214462A CN 103214462 A CN103214462 A CN 103214462A CN 2013101820770 A CN2013101820770 A CN 2013101820770A CN 201310182077 A CN201310182077 A CN 201310182077A CN 103214462 A CN103214462 A CN 103214462A
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- esomeprazole
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Abstract
The invention discloses a preparation method of an esomeprazole sodium salt and belongs to the technical field of chemical synthesis. The preparation method of the esomeprazole sodium salt is characterized by comprising the following steps of: dissolving esomeprazole in an organic solvent, and adding a sodium hydroxide aqueous solution and a phase transfer catalyst; carrying out a salt forming reaction under stirring at the room temperature and separating out esomeprazole sodium; and cooling, stirring, filtering, washing and drying under reduced pressure to obtain the esomeprazole sodium finished product. According to the preparation method of the esomeprazole sodium, the esomeprazole sodium finished product is prepared by enabling the esomeprazole and the sodium hydroxide aqueous solution to react and separating out crystals in the organic solvent under the action of the phase transfer catalyst. The preparation method can be used for producing the esomeprazole sodium, and is simple to operate, easy for solvent recovery, high in yield, high in purity and extremely high in industrial value.
Description
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Technical field:
The present invention relates to a kind of technique for synthesizing compounds field, be specifically related to a kind of preparation method of esomeprazole sodium salt.
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Background technology:
Esomeprazole sodium, English Esomeprazole by name, chemistry 5-methoxyl group-2-by name ((S)-((4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl) sulfinyl-1 H-benzimidazole sodium, molecular formula is C17H18N3NaO3S; Molecular weight is 367.4.
Esomeprazole is the individual isomer of omeprazole, i.e. (S)-isomer.Reduce gastric acid secretion by specific targeting mechanism, for proton pump in the parietal cell specific inhibitor.Site of action and mechanism: esomeprazole is a weak base, in parietal cell secretes the high acid environment of sour microtubule, concentrate and be converted into activity form, thereby the H+/K+-ATP enzyme (proton pump) that suppresses this position all produces inhibition to the gastric acid secretion of basal gastric acid secretion and stimulation.
At present, the synthetic of esomeprazole sodium generally synthesized in organic solvent by esomeprazole and highly basic, and the preparation method who is reported has following several:
Mention esomeprazole among the CN9880616 after reacting in Virahol with the high-concentration sodium hydroxide aqueous solution, the crystallization filtration drying obtains esomeprazole sodium.
Mention esomeprazole among the CN1110477 and in butanone, react, obtain esomeprazole sodium behind the crystallizing at room temperature filtration drying with aqueous sodium hydroxide solution.
Mention the esomeprazole and the high-concentration sodium hydroxide aqueous solution among the CN1157614 in acetonitrile after the pyroreaction, the low temperature crystallization filtration drying obtains esomeprazole sodium.
These methods generally exist long reaction time, temperature of reaction than characteristics such as height, because esomeprazole is very unstable under high temperature and low pH, easily decompose variable color, so the product yield that these methods obtain is not high and content is lower.
In addition:
Mention esomeprazole among the US2011213155 and react with aqueous sodium hydroxide solution (or methanol solution of sodium methylate) in methyl alcohol, low temperature crystallization filters, and with obtaining esomeprazole sodium after the isopropyl ether washing drying.
Mention among the CN10274627 esomeprazole in dehydrated alcohol with anhydrous sodium phosphate reaction after, concentrate dried ethanol and add the inert solvent again and carry out crystallization and obtain the U.S. azoles sodium of Esso.
Though more than two pieces of patents mention method reaction conditions gentleness, yield and quality are better, but what crystallization or concentrate drying obtained from alcohol is esomeprazole sodium alcohol mixture, must handle with double solventss such as isopropyl ether or ethyl acetate and just can obtain solvent-free esomeprazole sodium.Its shortcoming is a complicated operation, and solvent recovery process is loaded down with trivial details, is unfavorable for industrialization.
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Summary of the invention:
The purpose of this invention is to provide that a kind of industrialization is feasible, environmental protection economy, have the esomeprazole sodium preparation method of better yield and purity.
For realizing above-mentioned target, the technical solution adopted in the present invention is as follows:
A kind of preparation method of esomeprazole sodium salt is characterized in that, may further comprise the steps:
1, with esomeprazole with dissolving in the organic solvent, add aqueous sodium hydroxide solution and phase-transfer catalyst; Salt-forming reaction and separate out esomeprazole sodium under the stirring at room;
2, cooling, stirring, filtration, washing, drying under reduced pressure gets esomeprazole sodium finished product.
Further be provided with and be:
In the step 1:
Described organic solvent is one or more in methylene dichloride, trichloromethane, toluene, ethyl acetate, isopropyl acetate, the methyl tertbutyl ketone, preferably adopts methylene dichloride.
The mass concentration of described aqueous sodium hydroxide solution is 30～80%, preferred 50%.This is because water is bigger to esomeprazole sodium solubleness, and low excessively naoh concentration will reduce the yield of product, and therefore, control aqueous sodium hydroxide solution concentration can effectively improve product yield.
The mol ratio of described sodium hydroxide and esomeprazole is 1:1～3:1, preferred 1.2～1.5.Cross low reaction ratio, product transforms not exclusively, and yield can be lower; And too high reaction ratio can't influence quality product in this reaction system, but because the yield that influence product is understood in increasing of water.The present invention has utilized the used water of preparation aqueous sodium hydroxide solution very cleverly, and the existence of suitable quantity of water can be removed some inorganic salt that generate in that the raw material esomeprazole brings or the reaction process, thereby improves the quality of product.
Described phase-transfer catalyst is one or both in Tetrabutyl amonium bromide, the benzyltriethylammoinium chloride, preferably adopts Tetrabutyl amonium bromide.
Described Tetrabutyl amonium bromide and esomeprazole weight ratio are 0.1%～5%, preferred 0.3%.The carrying out of Tetrabutyl amonium bromide meeting accelerated reaction, the Tetrabutyl amonium bromide add-on is very few, reaction is carried out very slow and can not be arrived reaction end, and too much adding can't add the speed of fast response, influence the quality of product on the contrary owing to increasing of catalyst residue, be determined by experiment, the Tetrabutyl amonium bromide add-on was controlled at 0.1%～5% o'clock, can obtain best yield and quality product.
The temperature of reaction of described salt-forming reaction is 0～40 ℃, preferred 20～30 ℃.Temperature of reaction is too high, owing to the instability of Ai Meila azoles, can reduce the yield and the quality of product; And that reaction temperature is spent is low, and the reaction times can prolong, and other considers that industrialization also can increase the power cost of production.
The time of described salt-forming reaction is 2～4 hours, and the long reaction times can not influence the quality and the yield of product.In reaction in earlier stage, the reaction system clarification, esomeprazole sodium growing amount is less, but along with the carrying out that reacts, esomeprazole sodium can slowly separate out from reaction system.
In the step 2:
Before the filtration, cool to 0～10 ℃, and stirred 0.5～1 hour.Low excessively as temperature, the aqueous solution can freeze and allow impurity is wrapped in influences product in the product quality; Too high or churning time is too short as temperature, the yield of product can be influential.
After the filtration, product is washed the Impurity removals such as other inorganic salt that sodium hydroxide that phase-transfer catalyst, unreacted is intact and reaction process generate with reaction solvent.
After the washing, carry out vacuum-drying and obtain esomeprazole sodium, drying temperature is 20～60 ℃.Vacuum drying temperature can not be too high, and must not heat up too fast early stage, otherwise the easy caking of product causes particle harder, is unfavorable for the drying of product on the contrary.
In order to reduce production costs, can be with the mother liquor straight run distillation after step 1 crystallization, but after water is removed in the recovered solvent layering direct reuse in step 1.According to the boiling point of solvent, preferably under 40～100 ℃ of temperature, carry out normal pressure or underpressure distillation and reclaim.
The present invention has following beneficial effect with respect to existing esomeprazole sodium preparation method:
1, yield height, the purity height.The present invention is by the selection to organic solvent, cooperate phase-transfer catalyst, consumption and temperature of reaction by the control phase-transfer catalyst, make entire reaction mild condition, speed of response fast, in salification process, product is difficult for destroyed, the experiment proved that simultaneously, the yield of reaction and the purity of product all have a distinct increment, and see specific embodiment for details.
2, be easy to industrial production.The technology of relative its document or patent report, the present invention is easier to operation, and labor strength is low.
3, reaction and recrystallisation solvent use and reclaim conveniently.Present method solvent only needs to get final product the solvent recovering rate height by the simple distillation recovery.With respect in the additive method or use multiple solvent, or use the mixture of water-soluble solvent and water, the recovery of these solvents need could realize by rectifying, the production cost height, and solvent recovering rate is low, the production process complexity.
4, it is consistent with esomeprazole asymmetric oxidation reaction solvent for use that the present invention reacts solvent for use, finishes oxidizing reaction after can directly carry out the salify crystallization after handling the simple turnout reason of the esomeprazole solution process that obtains later.The production technique that this has simplified esomeprazole sodium on the one hand greatly also can further reduce production costs simultaneously.
Embodiment:
Further set forth the present invention below in conjunction with specific embodiments, but not as limitation of the present invention.
Embodiment 1:
Esomeprazole 50 grams, add 200 milliliters of methylene dichloride, add 0.15 gram Tetrabutyl amonium bromide and 10 gram aqueous sodium hydroxide solutions (sodium hydrate content 50%) after the stirring and dissolving, temperature control 20～30 ℃ the reaction 3 hours after, being cooled to 0～5 ℃ stirred 0.5 hour, filtration washing, vacuum (below 60 ℃) is dry that white crystalline powder 48.1 restrains weight yield 96.2%.Content 99.3%, purity 99.94%, isomer 0.01%, moisture 0.5%.
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Embodiment 2:
Esomeprazole 50 grams, add 200 milliliters of methylene dichloride, add 0.15 gram Tetrabutyl amonium bromide, 12 gram aqueous sodium hydroxide solutions (sodium hydrate content 60%) after the stirring and dissolving, temperature control 20～30 ℃ the reaction 3 hours after, being cooled to 0～5 ℃ stirred 0.5 hour, filtration washing, vacuum (below 60 ℃) is dry that white crystalline powder 48.4 restrains weight yield 96.8%.Content 98.7%, purity 99.96%, isomer 0.01%, moisture 0.4%.
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Embodiment 3:
Esomeprazole 50 grams, add 300 milliliters of toluene, add 0.3 gram benzyltriethylammoinium chloride, 10 gram aqueous sodium hydroxide solutions (sodium hydrate content 50%) after the stirring and dissolving, temperature control 20～30 ℃ the reaction 4 hours after, being cooled to 0～5 ℃ stirred 0.5 hour, filtration washing, vacuum (below 60 ℃) is dry that white crystalline powder 45 restrains weight yield 90%.Content 98.5%, purity 99.90%, isomer 0.02%, moisture 0.2%.
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Embodiment 4:
Esomeprazole 50 grams, add 180 milliliters of trichloromethanes, add 0.15 gram Tetrabutyl amonium bromide and 10 gram aqueous sodium hydroxide solutions (sodium hydrate content 50%) after the stirring and dissolving, temperature control 20～30 ℃ the reaction 3 hours after, being cooled to 0～5 ℃ stirred 0.5 hour, filtration washing, vacuum (below 60 ℃) is dry that white crystalline powder 42.1 restrains weight yield 84.2%.Content 99.7%, purity 99.94%, isomer 0.01%, moisture 0.5%.
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Embodiment 5:
Esomeprazole 50 grams, add 150 milliliters of ethyl acetate, add 0.15 gram Tetrabutyl amonium bromide and 10 gram aqueous sodium hydroxide solutions (sodium hydrate content 50%) after the stirring and dissolving, temperature control 20～30 ℃ the reaction 2 hours after, being cooled to 0～5 ℃ stirred 0.5 hour, filtration washing, vacuum (below 60 ℃) is dry that white crystalline powder 46.8 restrains weight yield 93.6%.Content 98.2%, purity 99.94%, isomer 0.04%, moisture 0.2%.
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Embodiment 6:
Esomeprazole 50 grams, add 400 milliliters of isopropyl acetates, add 0.15 gram Tetrabutyl amonium bromide and 10 gram aqueous sodium hydroxide solutions (sodium hydrate content 50%) after the stirring and dissolving, temperature control 20～30 ℃ the reaction 3 hours after, being cooled to 0～5 ℃ stirred 0.5 hour, filtration washing, vacuum (below 60 ℃) is dry that white crystalline powder 45.7 restrains weight yield 91.4%.Content 99.1%, purity 99.94%, isomer 0.01%, moisture 0.3%.
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Embodiment 7:
Esomeprazole 50 grams, add 200 milliliters of methyl tertbutyl ketone, add 0.15 gram Tetrabutyl amonium bromide and 10 gram aqueous sodium hydroxide solutions (sodium hydrate content 50%) after the stirring and dissolving, temperature control 20～30 ℃ the reaction 3 hours after, being cooled to 0～5 ℃ stirred 0.5 hour, filtration washing, vacuum (below 60 ℃) is dry that white crystalline powder 50.1 restrains weight yield 100.%.Content 98.9%, purity 99.94%, isomer 0.03%, moisture 0.5%.
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Embodiment 8:
Synthesizing of esomeprazole:
Add toluene 54kg and Ufiprazole 7.5kg, evenly the back adds D-(-)-diethyl tartrate 5kg and less water, titanium isopropoxide 3.4kg and diisopropylethylamine 1.6kg, and temperature control drips hydrogen phosphide cumene (4kg) at-2～5 ℃.After reaction finishes, extract with 90 kg ammoniacal liquor.Ammoniacal liquor layer second acid for adjusting pH value to 7.0～9.0;
The preparation of esomeprazole sodium:
Above-mentioned water layer 40L dichloromethane extraction, with sodium bicarbonate aqueous solution washing once, the organic layer air distillation divide water up to solution moisture less than 0.05%, distill out the 10L methylene dichloride.Add 24g Tetrabutyl amonium bromide and 1.6kg aqueous sodium hydroxide solution (sodium hydrate content 50%), temperature control 20～30 ℃ the reaction 3 hours after, being cooled to 0～5 ℃ stirred 0.5 hour, centrifuge washing, 20～30 ℃ of vacuum-drying 2 hours, 50～60 ℃ of vacuum-drying 10 hours, white crystalline powder 6.1kg, weight yield 81.3% (in Ufiprazole).Content 97.2%, purity 99.74%, isomer 0.12%, sulfonyl compound 0.13%, moisture 0.2%.
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Embodiment 9:
Synthesizing of esomeprazole: step is with embodiment 8.
The preparation of esomeprazole sodium:
Water layer is with the extraction of 50L methyl-tert butanone, with the sodium bicarbonate aqueous solution washing once, the organic layer distillation divide water up to solution moisture less than 0.05%.Add 24g Tetrabutyl amonium bromide and 1.8kg aqueous sodium hydroxide solution (sodium hydrate content 50%), temperature control 20～30 ℃ the reaction 4 hours after, being cooled to 0～5 ℃ stirred 0.5 hour, centrifuge washing, 20～30 ℃ of vacuum-drying 2 hours, 50～60 ℃ of vacuum-drying 16 hours, white crystalline powder 5.6kg, weight yield 74.7% (in Ufiprazole).Content 98.4%, purity 99.51%, isomer 0.34%, sulfonyl compound 0.27%, moisture 0.3%.
Claims (10)
1. the preparation method of an esomeprazole sodium salt is characterized in that, may further comprise the steps:
(1), with esomeprazole with dissolving in the organic solvent, add aqueous sodium hydroxide solution and phase-transfer catalyst; Salt-forming reaction and separate out esomeprazole sodium under the stirring at room;
(2), cooling, stir, filter, washing, drying under reduced pressure gets esomeprazole sodium finished product.
2. the preparation method of a kind of esomeprazole sodium salt according to claim 1 is characterized in that: in the step 1: described organic solvent is one or more in methylene dichloride, trichloromethane, toluene, ethyl acetate, isopropyl acetate, the methyl tertbutyl ketone.
3. the preparation method of a kind of esomeprazole sodium salt according to claim 1 is characterized in that: in the step 1: the mass concentration of described aqueous sodium hydroxide solution is 30～80%.
4. the preparation method of a kind of esomeprazole sodium salt according to claim 1 is characterized in that: in the step 1: the mol ratio of described sodium hydroxide and esomeprazole is 1:1～3:1.
5. the preparation method of a kind of esomeprazole sodium salt according to claim 1 is characterized in that: in the step 1: described phase-transfer catalyst is one or both in Tetrabutyl amonium bromide, the benzyltriethylammoinium chloride.
6. the preparation method of a kind of esomeprazole sodium salt according to claim 5 is characterized in that: in the step 1: described phase-transfer catalyst is a Tetrabutyl amonium bromide.
7. the preparation method of a kind of esomeprazole sodium salt according to claim 6 is characterized in that: described Tetrabutyl amonium bromide and esomeprazole weight ratio are 0.1%～5%.
8. the preparation method of a kind of esomeprazole sodium salt according to claim 1 is characterized in that: in the step 1: the temperature of reaction of described salt-forming reaction is 0～40 ℃, and the reaction times is 2～4 hours.
9. the preparation method of a kind of esomeprazole sodium salt according to claim 1 is characterized in that: in the step 2: before the filtration, cool to 0～10 ℃, and stirred 0.5～1 hour; After the filtration, product is washed with reaction solvent; After the washing, carry out vacuum-drying and obtain esomeprazole sodium, drying temperature is 20～60 ℃.
10. the preparation method of a kind of esomeprazole sodium salt according to claim 1 is characterized in that: step 1 is separated out the crystalline mother solution straight run distillation behind the esomeprazole sodium, and direct reuse was in step 1 after water was removed in the recovered solvent layering.
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| CN108409714A (en) * | 2018-03-29 | 2018-08-17 | 成都通德药业有限公司 | The preparation method of esomeprazole, esomeprazole salt and esomeprazole magnesium |
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Non-Patent Citations (1)
| Title |
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| 李谢，等，: "S-（-）-奥美拉唑钠的合成研究", 《化工时刊》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108409714A (en) * | 2018-03-29 | 2018-08-17 | 成都通德药业有限公司 | The preparation method of esomeprazole, esomeprazole salt and esomeprazole magnesium |
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Application publication date: 20130724 |