CN104557865A - Preparation method of esomeprazole sodium - Google Patents
Preparation method of esomeprazole sodium Download PDFInfo
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- CN104557865A CN104557865A CN201510017621.5A CN201510017621A CN104557865A CN 104557865 A CN104557865 A CN 104557865A CN 201510017621 A CN201510017621 A CN 201510017621A CN 104557865 A CN104557865 A CN 104557865A
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- esomeprazole
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- 0 Cc1cnc(CC(C(*2)=Nc(cc3)c2cc3OC=C=C)=O)c(C)c1O*=C Chemical compound Cc1cnc(CC(C(*2)=Nc(cc3)c2cc3OC=C=C)=O)c(C)c1O*=C 0.000 description 1
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- 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
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Abstract
The invention relates to a preparation method of esomeprazole sodium. The preparation method comprises the following steps: dissolving esomeprazole free acid in a benign solvent in azeotropy with the water, adding sodium hydroxide to form salt, dehydrating through distillation azeotropy to reduce the water content in a solution system to be less than 0.2%, and cooling for crystallizing, thereby obtaining the esomeprazole sodium with high yield. The preparation method is simple in operation, the process yield is greatly promoted, the obtained product has high purity, the excellent single solvent is adopted, and the industrialization can be easily realized.
Description
Technical field
The preparation method of the Esomeprazole sodium that the present invention relates to.
Technical background
Esomeprazole sodium (Esomeprazole Sodium), chemistry S-5-methoxyl group-2-{ [(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl by name }-1H-benzoglyoxaline sodium.Structural formula is as follows:
Proton pump inhibitor of new generation is researched and developed, Initial Public Offering in 1999, now in multinational listing by AstraZeneca.Esomeprazole is the S-optically active isomer of omeprazole, is global first isomer proton pump inhibitor (PPI), suppresses parietal cell proton pump to reduce gastric acid secretion by specificity.Esomeprazole sodium is the sodium salt of esomeprazole.
The oxidizable unstable of Esomeprazole sodium not easily recrystallization and esomeprazole free acid itself, cause the yield of solvent and the salify post crystallization used in its salification process to be affect a higher major issue of Product industrialization production cost always, therefore research tool is carried out to the crystallization yield of this product and be of great significance.
Adopt the esomeprazole of synthesis to concentrate after ethyl acetate is extracted in CN102321071A and add acetone and sodium hydroxide solution salify crystallization, obtain Esomeprazole sodium, because a small amount of water generated when not considering esomeprazole free acid and sodium hydroxide salt-forming reaction is on the impact of whole crystallizing system in technique, cause the yield of final technique at 50-70%, large-tonnage product is trapped among mother liquor, and process recovery ratio is lower.
In CN102603621A, esomeprazole free acid is prepared in ethanol, adds methyl alcohol salify after concentrated, after add again toluene and acetone carries out crystallization.Whole crystallization processes have employed nearly four kinds of solvents, and reclaim difficulty, the three wastes are higher.
All mixed solvent crystallization is adopted in the many sections of patents such as CN102746274A, CN102887885A, CN1029931A77, solve the problem that process recovery ratio is lower, but many employing ethers and alkanes low boiling point solvent, suitability for industrialized production danger coefficient is higher, and mixed solvent reclaims also more difficult simultaneously.
WO2007/013743A1 discloses the preparation method of esomeprazole and salt thereof, the extraction liquid of esomeprazole and sodium hydroxide salify, adds crystal seed and carries out induction crystallization, obtained Esomeprazole sodium.Simple steaming needs higher Heating temperature except moisture, Esomeprazole sodium not only may be made to decompose, be also not suitable for suitability for industrialized production.
Summary of the invention
The preparation method that the invention provides a kind of Esomeprazole sodium adopts single solvent, by reaching the object improving crystallization yield to the control of moisture in solution system, solve the mixed solvent that adopts in prior art more and carry out crystallization, difficult solvent recovery, the shortcoming that yield is lower.
Enforcement the preferred embodiments of the invention are generally: after synthesizing the esomeprazole free acid organic solvent extraction obtained, underpressure distillation is to dry, obtain esomeprazole acid dissociable dissolution in alcoholic solvent, acetone or ethyl acetate, add sodium hydroxide salify, normal pressure or underpressure distillation dehydration, when moisture reaches requirement, stop distillation, decrease temperature crystalline, is separated and obtains target product.
Preferred recrystallisation solvent of the present invention is alcohols, acetone or ethyl acetate, the preferred Virahol of alcohols, ethanol, methyl alcohol.
Moisture controlled scope of the present invention preferably≤0.2%.
The why Esomeprazole sodium reason that crystallization yield is lower in alcohols equal solvent, be not that Esomeprazole sodium solubleness of in these organic solvents itself is higher, but moisture a small amount of in system have high solubilizing effect in organic solvent to Esomeprazole sodium.
The solubility curve of Esomeprazole sodium in several organic solvent as shown in Figure 1
Solubleness when can find Esomeprazole sodium low temperature by solubility curve in methyl alcohol, ethanol, acetone is not high, and every 100g solvent only can dissolve the Esomeprazole sodium of 1-2g, and such solubleness is less for yield impact during crystallization.
The solubility curve of Esomeprazole sodium in moisture methyl alcohol as shown in Figure 2
Can find that in the methyl alcohol that Esomeprazole sodium is moisture, solubleness has obvious change by solubility curve, when moisture is more than 0.5%, solubleness increase clearly, and can there be obvious impact a small amount of Shuifu County in a small amount of moisture that the water generated during Esomeprazole sodium salt-forming reaction, esomeprazole free acid bring, organic solvent on the crystallization yield of product after collecting, so dewater to crystallizing system, dehydration operation seems very necessary.
By anhydrous sodium sulphate, the conventional drying agent such as molecular sieve dewater to solution, and effect is very limited, and when solution moisture content testing is down to 1-2%, conventional drying agent cannot play due effect.So we adopt the method for distillation azeotropic dehydration to control the moisture in solution, monitor system in still-process, can stop distillation when moisture meets the requirements, decrease temperature crystalline, can obtain Esomeprazole sodium with higher yields.
Beneficial effect:
The method purified product that the present invention adopts organic solvent azeotropic to dewater, the product obtained not only purity is high, and yield is high, and technique adopts single solvent salify, and solvent easily reclaims, and production cost is low, is applicable to technical scale and implements.
The present invention can with single solvent at lower cost, the satisfactory Esomeprazole sodium salt of purity is produced with higher productive rate under better simply operational condition, and be amplified to technical scale also without any problem, therefore, save complicated operating process and mixed solvent use, and the recycling of single solvent also more easily realizes, thus reduce production cost, improve production production capacity, improve the operability in production significantly.
Accompanying drawing explanation
Fig. 1 is the solubility curve of Esomeprazole sodium in several organic solvent
Fig. 2 is the solubility curve of Esomeprazole sodium in moisture methyl alcohol
Embodiment
The following examples describe laboratory and plant-scale the inventive method, and embodiment illustrates the present invention, but and unrestricted the present invention
The preparation of esomeprazole free acid
In the present invention, the preparation method of esomeprazole free acid adopts current WO94/27988 disclosed general synthetic method, and method is as follows:
30kg toluene is dropped into successively in dry reaction still, 5kg D-(-)-diethyl tartrate, 40kg5-methoxyl group-2-[[(4-methoxyl group-3, 5-dimethyl-2-pyridyl) methyl] sulfenyl]-1H-benzoglyoxaline, stirring is warming up to 60 ±, add 3.0kg titanium isopropylate and 2.2kgN again, N-diisopropylethylamine, insulated and stirred 30 minutes, thinking to drip 26kg hydrogen phosphide cumene in still, react 1 hour under dropwising room temperature, react complete, add 45kg potassium hydroxide methanol solution (potassium hydroxide 10kg, methyl alcohol 35kg), stir extraction, gained aqueous phase adds 16kg sodium bicarbonate, use 200kg dichloromethane extraction, extract complete, dichloromethane layer adds 5kg anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains 32kg viscous brown oily thing, be esomeprazole free acid, HPLC analytical chemistry purity 99.0%, optical purity 99.9%.
Embodiment 1
The preparation of Esomeprazole sodium
5kg (14.5mol) esomeprazole, 25kg methyl alcohol are dropped into reactor, in stirring and dissolving under room temperature, slowly in still, adds 0.57kg (14.4mol) sodium hydroxide, add, stirring reaction 0.5 hour.React complete, reaction solution is evaporated to moisture≤0.15% 40 times, concentrated complete, separate out a large amount of white solid in still, slowly temperature in the kettle is down to 0 ± 5, stirs 2 hours, filter, vacuum-drying obtains Esomeprazole sodium finished product 4.5kg, yield 84.9%.
Embodiment 2
The preparation of Esomeprazole sodium
5kg (14.5mol) esomeprazole, 50kg Virahol are dropped into reactor, in stirring and dissolving under room temperature, slowly in still, adds 0.57kg (14.4mol) sodium hydroxide, add, stirring reaction 0.5 hour.React complete, reaction solution is evaporated to moisture≤0.15% 40 times, concentrated complete, separate out a large amount of white solid in still, slowly temperature in the kettle is down to 0 ± 5, stirs 2 hours, filter, vacuum-drying obtains Esomeprazole sodium finished product 4.8kg, yield 90.5%.
Embodiment 3
The preparation of Esomeprazole sodium
5kg (14.5mol) esomeprazole, 40kg acetone are dropped into reactor, in stirring and dissolving under room temperature, slowly in still, adds 0.57kg (14.4mol) sodium hydroxide, add, stirring reaction 0.5 hour.React complete, by reaction solution 50 times air distillations to moisture≤0.10%, distill complete, separate out a large amount of white solid, slowly temperature in the kettle is down to 0 ± 5, stirs 4 hours in still, filter, vacuum-drying obtains Esomeprazole sodium finished product 4.9kg, yield 92.5%.
Embodiment 4
The preparation of Esomeprazole sodium
5kg (14.5mol) esomeprazole, 50kg ethanol are dropped into reactor, in stirring and dissolving under room temperature, slowly in still, adds 0.57kg (14.4mol) sodium hydroxide, add, stirring reaction 1 hour.React complete, by reaction solution 40 times underpressure distillation to moisture≤0.10%, distill complete, separate out a large amount of white solid, slowly temperature in the kettle is down to 0 ± 5, stirs 4 hours in still, filter, vacuum-drying obtains Esomeprazole sodium finished product 4.7kg, yield 88.7%.
Claims (6)
1. the preparation method of a high-purity esomeprazole sodium, comprise the steps: esomeprazole free acid with the good solvent of water azeotropic in dissolve after, add sodium hydroxide salify, by distillation azeotropic dehydration, the moisture in solution system is reduced to less than 0.2%, decrease temperature crystalline again, obtains Esomeprazole sodium.
2. preparation method according to claim 1, is characterized in that: described good solvent is C1-C4 alcohols, acetone, ethyl acetate.
3. preparation method according to claim 1, is characterized in that: the temperature of distillation dehydration controls at 30-60 DEG C.
4. preparation method according to claim 2, is characterized in that: described azeotropic dehydration method is normal pressure or underpressure distillation dehydration.
5. preparation method according to claim 3, is characterized in that: the quantity of solvent of the good solvent of employing is 5 ~ 20 times (ml/g) of the quality of esomeprazole free acid.
6. preparation method according to claim 1, is characterized in that: the temperature of crystallization is-10 ~ 25 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001202A (en) * | 2015-08-09 | 2015-10-28 | 朗天药业(湖北)有限公司 | Esomeprazole sodium compound and drug composition thereof |
| CN107400117A (en) * | 2017-08-29 | 2017-11-28 | 信泰制药（苏州）有限公司 | The preparation method of esomeprazole and its sodium salt |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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- 2015-01-13 CN CN201510017621.5A patent/CN104557865A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001202A (en) * | 2015-08-09 | 2015-10-28 | 朗天药业(湖北)有限公司 | Esomeprazole sodium compound and drug composition thereof |
| CN107400117A (en) * | 2017-08-29 | 2017-11-28 | 信泰制药（苏州）有限公司 | The preparation method of esomeprazole and its sodium salt |
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Application publication date: 20150429 |