CN103936715A - Refining method and synthesis method of esomeprazole - Google Patents
Refining method and synthesis method of esomeprazole Download PDFInfo
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Abstract
The invention relates to a refining method and a synthesis method of esomeprazole. The refining method comprises the following steps: firstly, suspending a crude esomeprazole product in 2-5 times of good organic solvents, stirring at low temperature, filtering to remove the impurities, slowly adding 10-20 times of adverse organic solvents, stirring to crystallize over night, and centrifuging to dry, thereby obtaining a refined esomeprazole product. The refining method of the esomeprazole is stable and controllable in process, simple and convenient to operate and easy to industrialize; the prepared esomeprazole is hihg in purity, high in yield, high in optical purity and stable in component, and happening of adverse reaction accidents is greatly avoided.
Description
Technical field
The present invention relates to the preparation method of esomeprazole salt, be specifically related to process for purification and the synthetic method thereof of Esomeprazole sodium.
Background technology
Omeprazole, as first proton pump inhibitor, had aspect diseases related at therapic acid more than ten years historical.This medicine has two kinds of optical isomers, the racemic mixture of esomprazole and R-omeprazole composition, wherein esomprazole is called again Esso omeprazole, its to the restraining effect of gastric acid secretion apparently higher than the administration of omeprazole single dose.
Esomeprazole sodium (Esomeprazole sodium), esomprazole sodium, is common a kind of esomeprazole salt, molecular formula: C
17h
18n
3naO
3s; outward appearance is white in color to buff powder; its chemical name is: 5-methoxyl group-2-((S)-((4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline sodium, and its chemical structure is:
Omeprazole isomer and salt patent thereof, see that CN94190335.4(publication number is CN1110477A), this patent discloses and has protected the salt of two kinds of isomer of omeprazole, as sodium salt, calcium salt, magnesium salts, and concrete preparation method disclosed, as described in the embodiment 1 in the document: by 100mg(0.33mmol) (-)-5-methoxyl group-2-[[(4-methoxyl group-3, 5-dimethyl-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline is dissolved in 1ml2-butanone, add 60 μ l5.0M aqueous sodium hydroxide solutions and 2ml toluene, the mixture forming is heterogeneous, add 1ml2-butanone, and stir and spend the night at ambient temperature, filtering the precipitation forming washs with ether.
At present, the synthetic method of Esomeprazole sodium is to synthesize taking omeprazole thioether as raw material mostly, and omeprazole thioether is not basic synthesis material, so price is higher; Or obtain esomeprazole by asymmetric oxidation legal system, and with esomeprazole, reaction generates sodium salt in recycling sodium source, bad if processing parameter is controlled, in asymmetric oxidation step, hyperoxidation easily produces superoxide sulfone impurity.Or reaction not exclusively, remains unreacted material, cause that product impurity is many, purity is on the low side.
Therefore, developing the synthetic and refining method of the esomeprazole salt of the applicable suitability for industrialized production that a kind of process stabilizing is controlled, purity good, yield is high, optical purity is high, is very necessary.
About esomeprazole or the synthetic method of (S)-omeprazole or salifying method, there is following report:
CN201210002536.8(application publication number: CN102584792A, Shen Qing Publication day: on July 18th, 2012) a kind of synthetic method of Esomeprazole sodium disclosed, the invention discloses the synthetic and refining method of the salt of esomeprazole, the method comprises: using 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline as start material material, by optimizing reaction conditions, reaction is remained under a mild conditions and carry out, and effectively reduce the foreign matter content in product.Synthetic product is after further refining, and its purity and enantiomeric excess all reach more than 99%, thereby increases medication effect and security.Adopt this patented method, the Esomeprazole sodium related substance of preparation is high, and impurity is many, has isomer.
CN201310478482.7(publication number is CN103570686A) a kind of preparation method of Esomeprazole sodium disclosed, the method comprises following step: with 2-sulfydryl-5-methoxyl group benzo imidazoles and 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride is that raw material condensation generates prochirality thioether.2. prochirality thioether synthetic esomeprazole crude product under the effect of D – (–) diethyl tartrate, water, titanium isopropylate, diisopropylethylamine, cumene hydroperoxide, and the refining esomeprazole sylvite that generates.3. esomeprazole sylvite converts esomeprazole sodium salt the refining finished product that obtains to after dissolving.
The synthetic method of Esomeprazole sodium has had a variety of, but in preparation process, mostly can produce more impurity, the selection of the control of processing parameter, material proportion, endpoint monitoring, process for purification is all the key factors that affect quality product, if product purity is on the low side, easily cause Adverse Event.Therefore, the synthetic and refining method of the esomeprazole salt of the applicable suitability for industrialized production that a kind of process stabilizing is controlled, purity good, yield is high, optical purity is high if can develop, certainly will have huge application prospect and marketable value.
Summary of the invention
The object of this invention is to provide the synthetic and refining method of the Esomeprazole sodium of the applicable suitability for industrialized production that a kind of process stabilizing is controlled, purity good, yield is high, optical purity is high.
The invention provides the process for purification of Esomeprazole sodium, the method comprises the following steps: the good organic solvent low temperature that Esomeprazole sodium crude product is first suspended in 2～5 times of amounts stirs, filtering and impurity removing, slowly add 10～20 times of bad organic solvents, stirring and crystallizing is spent the night, centrifugal drying, obtains Esomeprazole sodium highly finished product.
In described process for purification:
Described dissolving is one or both in acetone, butanone with good organic solvent;
Described bad organic solvent is one or more in ethyl acetate, acetonitrile, ether or sherwood oil, tetrahydrofuran (THF), preferably acetonitrile and ethyl acetate;
The envelope-bulk to weight ratio of described good organic solvent and Esomeprazole sodium crude product is 3～5 times.
The envelope-bulk to weight ratio of described bad organic solvent and Esomeprazole sodium crude product is 1:10～12 times.
Described low temperature span of control is 0 DEG C～10 DEG C, preferably 2 DEG C～6 DEG C.
The crude product of described Esomeprazole sodium is prepared by following methods, and the method comprises the following steps: by the esomeprazole potassium stirring and dissolving that adds water, add organic solvent dissolution, be cooled to 10～20 DEG C; Add acid to adjust pH to 6.5～7.5, with organic solvent extraction, after concentrated organic solvent, add another organic solvent dissolution, add the organic solvent solution of sodium hydroxide, add ether stirring and crystallizing, obtain Esomeprazole sodium crude product.
Describedly be dissolved in water, when organic solvent dissolution, another dissolution with solvents, the weightmeasurement ratio of esomeprazole potassium and water, organic solvent, another organic solvent is 1:1-2:2-3:0.5-1, is preferably 1:1.5～2:2.3～2.6:0.7～0.9;
When described tune pH, acid used is glacial acetic acid;
Described organic solvent is methylene dichloride or ethyl acetate;
Described another solvent is one or more in ethanol, methyl alcohol, Virahol, particular methanol, ethanol;
The organic solvent solution of described sodium hydroxide refers to the methanol solution of sodium hydroxide or the ethanolic soln of sodium hydroxide, and the weightmeasurement ratio of sodium salt and organic solvent is 1:8～11;
Described esomeprazole potassium and sodium hydroxide mol ratio are 1:1～1.2.
Synthetic, the esomeprazole sylvite crude product that the preparation method of described esomeprazole potassium comprises omeprazole thioether synthetic.
In aforesaid method:
The synthetic method of described omeprazole thioether comprises the following steps: in organic solvent, add inorganic sodium, after dissolving, add 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline, after dissolving, add 3,5-dimethyl-2-chloromethyl-4-methoxypyridine hydrochloride, be warming up to back flow reaction, TLC monitoring is reacted to the disappearance of raw material point, and aftertreatment obtains highly purified omeprazole thioether.
Described organic solvent is one or more in toluene, methyl alcohol, ethanol, methylene dichloride, ethyl acetate or acetone, and preferably organic solvent is methyl alcohol or ethanol;
Described inorganic sodium is one or more in sodium hydroxide, sodium bicarbonate or sodium pyrosulfate, and preferably inorganic sodium is sodium hydroxide or sodium bicarbonate;
The consumption of described organic solvent is that the 2-5 of the weight of 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline doubly measures;
The mol ratio of described inorganic sodium, 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline and 3,5-dimethyl-2-chloromethyl-4-methoxypyridine hydrochloride is 1.8～3:1:0.8～1.1, is preferably 1.9～2.5:1:0.9～1.0;
The envelope-bulk to weight ratio of described organic solvent and 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline is 8.5～9.0:1, is preferably 8.70:1.
The developping agent of described TLC monitoring is the mixture of ethyl acetate or sherwood oil and ethyl acetate, and the volume ratio of mixture PetroChina Company Limited. ether and ethyl acetate is 1:4～1:6.
Described aftertreatment is for using second acid for adjusting pH value to neutrality, extraction, recrystallization, centrifugal drying.The thioether of preparing by this technique, starting material reacts completely, and side reaction is few, and purity high impurity content is low, and the thioether purity of preparation reaches more than 99.8%.
The synthetic method of described esomeprazole sylvite crude product comprises the following steps: in organic solvent, omeprazole thioether reacts at 25 DEG C～45 DEG C temperature controls with D-(-)-diethyl tartrate, water, tetraisopropoxy titanium, after finishing, reaction is down to room temperature, add organic bases, slowly drip oxygenant and carry out oxidizing reaction, TLC monitors reaction end, then slowly add sylvite, make esomeprazole sylvite.
The molecular volume of described omeprazole thioether, organic solvent, D-(-)-diethyl tartrate, water, tetraisopropoxy titanium, organic bases, oxygenant, sylvite is than being 1:10～14:0.15～0.4:0.03～0.04:0.05～0.15:0.12～0.18:1.00～1.5:1.30～2.0;
Described organic solvent is one or both in toluene, dimethylbenzene, preferably toluene;
Described organic bases is triethylamine, DIPEA, diethylamine, preferably DIPEA;
Described oxide compound is hydrogen phosphide cumene;
Described sylvite is potassium hydroxide, saleratus, salt of wormwood, potassium methylate, preferably potassium hydroxide or potassium methylate;
The developping agent of described TLC monitoring is the mixture of chloroform and methyl alcohol, and the volume ratio of the two is 10:1～20:1, preferably 10:1～12:1.
The present invention also provides a kind of preparation method of Esomeprazole sodium, and the method comprises the following steps:
(1) omeprazole thioether is synthetic: first in conversion unit, add organic solvent (volume is 5～10 times of 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline weight), add inorganic sodium, after dissolving, add 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline, after dissolving, add 3,5-dimethyl-2-chloromethyl-4-methoxypyridine hydrochloride, temperature reaction is to refluxing, keep back flow reaction, TLC monitoring reaction end to raw material point disappears, regulate pH value to neutral, through extraction, concentrate, recrystallization makes highly purified omeprazole thioether;
(2) esomeprazole potassium is synthetic: in organic solvent, omeprazole thioether reacts (25 DEG C～45 DEG C) with D-(-)-diethyl tartrate, water, tetraisopropoxy titanium temperature control, after finishing, reaction is down to room temperature, add organic bases, slowly drip oxygenant and carry out oxidizing reaction, TLC monitors reaction end, then slowly add sylvite, make esomeprazole potassium;
(3) Esomeprazole sodium crude product is synthetic: the esomeprazole potassium stirring and dissolving that adds water, add organic solvent dissolution, and be cooled to 10～20 DEG C; Add acid to adjust pH to 6.5～7.5, with organic solvent extraction, after concentrated organic solvent, add another organic solvent dissolution, add the organic solvent solution of sodium hydroxide, add ether stirring and crystallizing, obtain Esomeprazole sodium crude product;
(4) Esomeprazole sodium is refining: the good organic solvent low temperature that Esomeprazole sodium crude product is first suspended in 2～5 times of amounts stirs, filtering and impurity removing, slowly adds the bad organic solvent of 10～20 amount, and stirring and crystallizing is spent the night, centrifugal drying, obtains Esomeprazole sodium highly finished product.
Preparation method's tool of Esomeprazole sodium of the present invention has the following advantages:
1, in process for purification provided by the invention:
By repetition test, adopt effectively dissolved product and remove the impurity such as isomer of solvent provided by the invention, in addition, what the present invention adopted is that low temperature is 0-10 DEG C, general process for purification all needs heated and stirred, is beneficial to dissolving crude product, but simultaneously a large amount of impurity also dissolves thereupon; The present invention is changed into low temperature, can not only reach same solute effect, and this temperature not yet reaches the solubleness of impurity, is beneficial to removal of impurities, and therefore, the purity of the Esomeprazole sodium obtaining is higher.
2, the preparation method from esomeprazole potassium to esomeprazole sodium salt
Before esomeprazole potassium reacts with sodium hydroxide, the present invention first uses dissolve with ethanol esomeprazole potassium, its objective is a solution environmental is provided, so that better salify, adopting alcoholic solution is in order to obtain the product that purity is higher and to improve the yield of reaction.
3, with CN201310478482.7(publication number be CN103570686A) difference be:
1) prepare esomeprazole potassium step:
When omeprazole sulfide oxidation is esomeprazole, temperature is controlled at room temperature reaction, easy handling, and save energy, is beneficial to large production.
2) purification step: adopt a kind of solvent first to dissolve Esomeprazole sodium crude product (controlling temperature at 0～10 DEG C), filtering and impurity removing, removes the impurity such as isomer, and then adds another kind of solvent, and stirring and crystallizing, guarantees to obtain highly purified finished product.
4, key of the present invention is formerly to prepare esomeprazole sylvite, then is converted into sodium salt, ensures the higher yield of technique.In addition, adopt organic solvent dissolution in low temperature in the purification step of Esomeprazole sodium, filtering and impurity removing, then add another bad organic solvent crystallization, guarantee the purity that product is higher.The inventive method is easy and simple to handle, and mild condition is easy to be converted into suitability for industrialized production.
5, the present invention passes through repetition test, in optimization material rational proportion, and found applicable process for purification, and adopt two kinds of solvents to refine, effectively remove the impurity such as corresponding isomer, superoxide sulfone and prepared highly purified esomeprazole sodium sample.The method process stabilizing is controlled, easy and simple to handle, is easy to industrialization; Preparation Esomeprazole sodium purity high, yield is high, optical purity is high, stable components, can avoid the generation of Adverse Event greatly.
Embodiment
Following examples are used for illustrating the present invention, but are not used for limiting the scope of the invention.
If do not specialize, experiment material, reagent and instrument etc. used in the embodiment of the present invention are all commercially available, if specifically do not indicate, and the conventional means that in embodiment, technique means used is well known to the skilled person.
Conversion unit is: 50L reactor, 20L reactor and 20L Rotary Evaporators.
Embodiment 1: omeprazole thioether synthetic
Be first 8.70 times of volumes of 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline weight to adding ethanol 20L(consumption in conversion unit), add sodium bicarbonate 2.12kg(25.2mol), after dissolving, add 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline 2.3kg(12.72mol), after dissolving, add 3,5-dimethyl-2-chloromethyl-4-methoxypyridine hydrochloride 2.8kg(12.56mol), be warming up to back flow reaction (TLC monitoring terminal GF254 plate, developping agent: ethyl acetate) disappear to raw material point, extremely neutral with second acid for adjusting pH value, filter filtrate decompression precipitation; After resistates adds 10L methylene dichloride to dissolve, 2L × 2 washing (use 2L washing 2 times), with anhydrous sodium sulfate drying, filter, filtrate decompression precipitation, after adding 8L dimethylbenzene that material stirring is dissolved, add 100g gac, stir about 15min, filtered while hot, filtrate stirring and crystallizing under room temperature is spent the night; Centrifuging, vacuum-drying, makes highly purified omeprazole thioether.
Embodiment 2: omeprazole thioether synthetic
Be first 8.70 times of volumes of 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline weight to adding methyl alcohol 20L(consumption in conversion unit), add sodium hydroxide 1kg(25mol), after dissolving, add 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline 2.3kg(12.72mol), after dissolving, add 3,5-dimethyl-2-chloromethyl-4-methoxypyridine hydrochloride 2.8kg(12.56mol), be warming up to back flow reaction (TLC monitoring terminal GF254 plate, developping agent: ethyl acetate) disappear to raw material point, extremely neutral with second acid for adjusting pH value, filter filtrate decompression precipitation; After resistates adds 10L methylene dichloride to dissolve, 2L × 2 washing, with anhydrous sodium sulfate drying; Filter, filtrate decompression precipitation, after adding 8L dimethylbenzene that material stirring is dissolved, adds 100g gac, stir about 15min, and filtered while hot, filtrate stirring and crystallizing under room temperature is spent the night; Centrifuging, vacuum-drying, makes highly purified omeprazole thioether.
Embodiment 3: omeprazole thioether synthetic
Be first 8.70 times of volumes of 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline weight to adding methyl alcohol 20L(consumption in conversion unit), add sodium bicarbonate 2.6kg(30.9mol), after dissolving, add 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline 2.3kg(12.72mol), after dissolving, add 3, 5-dimethyl-2-chloromethyl-4-methoxypyridine hydrochloride 2.8kg(12.56mol), be warming up to back flow reaction (TLC monitoring GF254 plate, developping agent: sherwood oil and ethyl acetate, the two volume ratio is 1:6) react to raw material point and disappear, extremely neutral with second acid for adjusting pH value, filter, filtrate decompression precipitation, after resistates adds 10L methylene dichloride to dissolve, 2L × 2 washing, with anhydrous sodium sulfate drying, filter, filtrate decompression precipitation, after adding 8L dimethylbenzene that material stirring is dissolved, adds 100g gac, stir about 15min, and filtered while hot, filtrate stirring and crystallizing under room temperature is spent the night, centrifuging, vacuum-drying, makes highly purified omeprazole thioether.
Embodiment 4: omeprazole thioether synthetic
Be first 8.70 times of volumes of 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline weight to adding ethanol 20L(consumption in conversion unit), add sodium hydroxide 1kg(25mol), after dissolving, add 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline 2.3kg(12.72mol), after dissolving, add 3, 5-dimethyl-2-chloromethyl-4-methoxypyridine hydrochloride 2.8kg(12.56mol), be warming up to back flow reaction (TLC monitoring GF254 plate, developping agent: sherwood oil and ethyl acetate, the two volume ratio is 1:5) react to raw material point and disappear, extremely neutral with second acid for adjusting pH value, filter, filtrate decompression precipitation, after resistates adds 10L methylene dichloride to dissolve, 2L × 2 washing, with anhydrous sodium sulfate drying, filter, filtrate decompression precipitation, after adding 8L dimethylbenzene that material stirring is dissolved, adds 100g gac, stir about 15min, and filtered while hot, filtrate stirring and crystallizing under room temperature is spent the night, centrifuging, vacuum-drying, makes highly purified omeprazole thioether.
Embodiment 5: omeprazole thioether synthetic
Be first 8.70 times of volumes of 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline weight to adding methyl alcohol 20L(consumption in conversion unit), add sodium hydroxide 1kg(25mol), after dissolving, add 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline 2.3kg(12.72mol), after dissolving, add 3, 5-dimethyl-2-chloromethyl-4-methoxypyridine hydrochloride 2.8kg(12.56mol), be warming up to back flow reaction (TLC monitoring GF254 plate, developping agent: sherwood oil and ethyl acetate, volume ratio is 1:4) react to raw material point and disappear, extremely neutral with second acid for adjusting pH value, filter, filtrate decompression precipitation, after resistates adds 10L methylene dichloride to dissolve, 2L × 2 washing, with anhydrous sodium sulfate drying, filter, filtrate decompression precipitation, after adding 8L dimethylbenzene that material stirring is dissolved, adds 100g gac, stir about 15min, and filtered while hot, filtrate stirring and crystallizing under room temperature is spent the night, centrifuging, vacuum-drying, makes highly purified omeprazole thioether.
Comparative example 1: omeprazole thioether synthetic
Method with reference to embodiment 1 in patent of invention 201210002536.8 specification sheetss makes omeprazole thioether.
The relatively preparation of omeprazole thioether, compares comparative example 1 with embodiment 1,3,4,5, its reaction process is decomposed following (in table 1):
Table 1: the synthetic method comparison of omeprazole thioether
Table 1 content shows:
Raw material is the same, and proportioning is slightly variant, the especially consumption of organic solvent and Organic Sodium Salt, and Organic Sodium Salt comparative example 1 consumption is less than the present invention, and organic solvent consumption of the present invention is slightly more than comparative example 1;
Temperature of reaction, temperature of the present invention is for reaching backflow, i.e. boiling point, and the temperature of comparative example 1 is 50 DEG C, lower than the present invention;
The selection of developping agent: ethyl acetate that what the present invention selected is or the sherwood oil and the ethyl acetate that are 1:4-6 according to volume ratio, comparative example 1 use be sherwood oil and ethyl acetate, volume ratio is 1:3.
The scheme that contriver adopts comparative example 1 repeatedly revision test is prepared thioether, finds that its yield and purity can not reach the disclosed content of former specification sheets.
Experimental example 6: esomeprazole potassium synthetic
In conversion unit, add omeprazole thioether 3kg(9.10mol prepared by embodiment 1), add toluene 12L, D-(-)-diethyl tartrate 300ml, water 5ml, tetraisopropoxy titanium 260ml, temperature control reaction (40 DEG C～45 DEG C), after finishing, reaction is down to room temperature, add N, N-diisopropylethylamine 228ml, slowly drip the about 2.0kg(9.47mol of hydrogen phosphide cumene), (TLC monitors reaction end to carry out oxidizing reaction, developping agent: chloroform: methyl alcohol=12:1), then add potassium hydroxide 0.7kg, make esomeprazole potassium.
Embodiment 7: esomeprazole potassium synthetic
Prepare omeprazole thioether 2.9kg to adding embodiment 3 in conversion unit, add toluene 12L, D-(-)-diethyl tartrate 300ml, water 5ml, tetraisopropoxy titanium 260ml, temperature control reaction (25 DEG C～35 DEG C), after finishing, reaction is down to room temperature, add N, N-diisopropylethylamine 228ml, slowly drip hydrogen phosphide cumene 2.0kg, carry out oxidizing reaction, TLC monitoring reaction end (chloroform: methyl alcohol=20:1), then add potassium hydroxide 0.7kg, make esomeprazole potassium.
Embodiment 8: esomeprazole potassium synthetic
Prepare omeprazole thioether 3kg to adding embodiment 5 in conversion unit, add toluene 12L, D-(-)-diethyl tartrate 300ml, water 5ml, tetraisopropoxy titanium 260ml, temperature control reaction (35 DEG C～40 DEG C), after finishing, reaction is down to room temperature, add N, N-diisopropylethylamine 228ml, slowly drip hydrogen phosphide cumene 2.0kg, carry out oxidizing reaction, TLC monitoring reaction end (chloroform: methyl alcohol=20:1), then add hydroxide potassium methylate 1kg, make esomeprazole potassium;
Comparative example 2-1:
With reference to the method for embodiment 1 in patent of invention 201210002536.8 specification sheetss, the thioether of being prepared by comparative example 1 continues and other raw material reactions, prepares esomeprazole.
Comparative example 2-2:
Being CN103570686A with reference to patent of invention CN201310478482.7(publication number) method of embodiment 3 makes esomeprazole sylvite in specification sheets.
By thioether 3kg(9.1mol) be added in 8.75L toluene, under stirring, be heated to 70 DEG C molten clear, then be cooled to 47-50 DEG C, add D-(-)-diethyl tartrate 1880g(9.1mol), titanium isopropylate 1.3kg(4.6mol), water 50ml(0.75mol), keep 47-50 DEG C of reaction 2.5h, then be cooled to 5-10 DEG C, add diisopropylethylamine 1.18kg(9.1mol), stir 10min, keep 7-10 DEG C drip 1.97kg(10.9mol) cumene hydroperoxide toluene solution (mass concentration 85%), after dropwising, keep 7-10 DEG C to continue reaction 5 hours, by 1kg(9.1mol) potassium hydroxide is dissolved in 10L methyl alcohol, after question response finishes, keeping 0-5 DEG C drops to potassium hydroxide methanol solution in reaction solution, stirred crystallization 2 hours, filter, a small amount of methanol wash, vacuum-drying obtains esomeprazole potassium crude product.
The preparation method of comparing embodiment 6-8 and comparative example 2, specifically in table 2:
Table 2: preparation method's comparison of esomeprazole potassium
By more known above:
The consumption of reaction substrate (omeprazole thioether) and oxygenant (hydrogen phosphide cumene) embodiment 6-8 and comparative example 2-1,2-2 is basically identical, and maintain the organic solvent of asymmetric oxidation system, as comparative example 2-1,2-2 such as diethyl tartrate, tetraisopropoxy titanium, diisopropylethylamine compared with the consumption of embodiment 6-8 more than the present invention;
Temperature of reaction: temperature of the present invention is 25 DEG C～45 DEG C, and the temperature of comparative example 2-1 is 55-60 DEG C, and the temperature of comparative example 2-2 is 47-50 DEG C, a little more than the present invention;
The selection of developping agent: what the present invention selected is that volume ratio is chloroform and the methanol mixed solution of 12-20:1, and what comparative example 2-1 used is the methylene dichloride of 25:1 and the mixing solutions of methyl alcohol.
It should be noted that: comparative example 2-2 also needs to carry out the treating process of sylvite, and the present invention does not need.
Embodiment 9: the preparation of Esomeprazole sodium
Get the add water weight ratio 1:2 of 7L(esomeprazole potassium and water of esomeprazole potassium 3.5kg prepared by embodiment 6) stirring and dissolving, add 9L ethyl acetate (the weightmeasurement ratio 1:2.57 of esomeprazole potassium and ethyl acetate) to dissolve, be cooled to 10～20 DEG C; Add glacial acetic acid to adjust pH to 6.95, be extracted with ethyl acetate, after concentrated organic solvent, add 3L ethanol (the weightmeasurement ratio 1:0.86 of esomeprazole potassium and ethanol) to dissolve, add ethanolic soln (0.5kg sodium hydroxide the is dissolved in 5L ethanol) solution containing 0.5kg sodium hydroxide, add ether stirring and crystallizing, obtain Esomeprazole sodium crude product;
Esomeprazole sodium crude product is 6 DEG C of stirrings that suspend of 11.2L butanone (being equivalent to 4 times of volumes of Esomeprazole sodium crude product weight) for 2.8kg, filtering insolubles, add 28L ethyl acetate (being equivalent to 10 times of volumes of Esomeprazole sodium crude product weight) stirring and crystallizing to spend the night, centrifugal, dry, obtain Esomeprazole sodium highly finished product 2.41kg.
Embodiment 10: the preparation of Esomeprazole sodium
Getting the add water weight ratio of 7L(esomeprazole potassium and water of esomeprazole potassium 3.8kg prepared by embodiment 7 is 1:1.84) stirring and dissolving, add 9L ethyl acetate (the weightmeasurement ratio 1:2.37 of esomeprazole potassium and ethyl acetate) to dissolve, be cooled to 10～20 DEG C; Add glacial acetic acid to adjust pH to 6.5, be extracted with ethyl acetate, after concentrated organic solvent, add 3L ethanol (the weightmeasurement ratio 1:0.79 of esomeprazole potassium and ethanol) to dissolve, add the ethanolic soln (0.48kg sodium hydroxide is dissolved in 5L ethanol) containing 0.48kg sodium hydroxide, add ether stirring and crystallizing, obtain Esomeprazole sodium crude product;
Esomeprazole sodium crude product is 5 DEG C of stirrings that suspend of 9L acetone (being equivalent to 3.3 times of volumes of Esomeprazole sodium crude product weight) for 2.7kg, filtering insolubles, add 30L ethyl acetate (being equivalent to 11.1 times of volumes of Esomeprazole sodium crude product weight) stirring and crystallizing to spend the night, centrifugal, the dry Esomeprazole sodium highly finished product 2.33kg that obtains.
Embodiment 11: the preparation of Esomeprazole sodium
Getting the add water weight ratio of 7L(esomeprazole potassium and water of esomeprazole potassium 3.6kg prepared by embodiment 7 is 1:1.94) stirring and dissolving, add 9L ethyl acetate (the weightmeasurement ratio 1:2.5 of esomeprazole potassium and ethyl acetate) to dissolve, be cooled to 10～20 DEG C; Add glacial acetic acid to adjust pH to 7.5, be extracted with ethyl acetate, after concentrated organic solvent, add 3L ethanol (the weightmeasurement ratio 1:0.83 of esomeprazole potassium and ethanol) to dissolve, add the methanol solution (0.48kg sodium hydroxide is dissolved in 5L methyl alcohol) containing 0.48kg sodium hydroxide, add ether stirring and crystallizing, obtain Esomeprazole sodium crude product;
Esomeprazole sodium crude product 2.7kg, suspend and stir with 8 DEG C, 12L acetone (being equivalent to 4.4 times of volumes of Esomeprazole sodium crude product weight), filtering insolubles, add 30L ethyl acetate (being equivalent to 11.1 times of volumes of Esomeprazole sodium crude product weight) stirring and crystallizing to spend the night, centrifugal, dry, obtain Esomeprazole sodium highly finished product 2.34kg.
Embodiment 12: the preparation of Esomeprazole sodium
Getting the add water weight ratio of 7L(esomeprazole potassium and water of esomeprazole potassium 3.8kg prepared by embodiment 8 is 1:1.84) stirring and dissolving, add 9L ethyl acetate (the weightmeasurement ratio 1:2.37 of esomeprazole potassium and ethyl acetate) to dissolve, be cooled to 10～20 DEG C; Add glacial acetic acid to adjust pH to 6.8, be extracted with ethyl acetate, after concentrated organic solvent, add 3L ethanol (the weightmeasurement ratio 1:0.79 of esomeprazole potassium and ethanol) to dissolve, add the ethanolic soln (0.5kg sodium hydroxide is dissolved in 4L ethanol) containing 0.5kg sodium hydroxide, add ether stirring and crystallizing, obtain Esomeprazole sodium crude product;
Esomeprazole sodium crude product is 3 DEG C of stirrings that suspend of 10L butanone (being equivalent to 3.8 times of volumes of Esomeprazole sodium crude product weight) for 2.6kg, filtering insolubles, add 28L acetonitrile (being equivalent to 10.8 times of volumes of Esomeprazole sodium crude product weight) stirring and crystallizing to spend the night, centrifugal, dry, obtain Esomeprazole sodium highly finished product 2.26kg.
Embodiment 13: the preparation of Esomeprazole sodium
Getting the add water weight ratio of 7L(esomeprazole potassium and water of esomeprazole potassium 3.8kg prepared by embodiment 8 is 1.84) stirring and dissolving, add 9L methylene dichloride (the weightmeasurement ratio 1:2.37 of esomeprazole potassium and methylene dichloride) to dissolve, be cooled to 10～20 DEG C; Add glacial acetic acid to adjust pH to 7.2, with dichloromethane extraction, after concentrated organic solvent, add 3L ethanol (the weightmeasurement ratio 1:0.79 of esomeprazole potassium and ethanol) to dissolve, add the methanol solution (0.5kg sodium hydroxide is dissolved in 5L methyl alcohol) containing 0.5kg sodium hydroxide, add ether stirring and crystallizing, obtain Esomeprazole sodium crude product;
Esomeprazole sodium crude product is 2 DEG C of stirrings that suspend of 12L acetone (being equivalent to 4.8 times of volumes of Esomeprazole sodium crude product weight) for 2.5kg, filtering insolubles, add 28L acetonitrile (being equivalent to 11.2 times of volumes of Esomeprazole sodium crude product weight) stirring and crystallizing to spend the night, centrifugal, dry, obtain Esomeprazole sodium highly finished product 2.15kg.
Comparative example 3-1
Being CN103570686A with reference to patent of invention CN201310478482.7(publication number) method of embodiment 7 makes esomeprazole sodium salt in specification sheets, be specially:
Esomeprazole potassium 110.0g(0.29mol), add 700ml water stirring and dissolving, add again 800ml methylene dichloride to stir the lower 20% acetic acid aqueous solution submission pH to 7.69 that drips, stir 10min, extraction, 150ml methylene dichloride back extraction 1 time for water, combined dichloromethane mutually after, with 150ml washing 3 times, get sodium hydroxide 14.9g(0.37mol) add in 250ml methyl alcohol, stirring and dissolving, near room temperature, by sodium hydrate methanol solution drop to methylene dichloride mutually in, stirring at room temperature 30min, anhydrous sodium sulfate drying, vacuum-drying obtains Esomeprazole sodium crude product.
Relatively esomeprazole sylvite is made the preparation method of Esomeprazole sodium crude product, specifically relatively in table 3:
Table 3: preparation method's comparison of Esomeprazole sodium crude product
Table 3 result shows: prepare esomeprazole sodium salt from esomeprazole sylvite, in raw material difference, especially embodiment 9-12, organic solvent is ethyl acetate, and similar to comparative example 3-1 be embodiment 13, be relatively specifically:
The consumption of methylene dichloride, comparative example 3-1 is a little more than embodiment 13, and pH comparative example 3-1 is higher than other embodiment;
After concentrated, embodiment 13 use dissolve with ethanol, then add the methanol solution of sodium hydroxide, and comparative example 3-1 directly adds the methanol solution of sodium hydroxide.
Ultimate yield, purity, embodiment provided by the invention is apparently higher than comparative example 3-1.
Comparative example 3-2: the process for purification of Esomeprazole sodium
Being CN103570686A with reference to patent of invention CN201310478482.7(publication number) method of embodiment 8 makes esomeprazole sodium salt in specification sheets, be specially:
By crude product 30.0g, add 65ml acetone and 65ml acetonitrile, be heated to 55-60 DEG C, vigorous stirring 2 hours, is then cooled to 15-20 DEG C and stir 1 hour crystallization gradually, filters, a small amount of washing with acetone, vacuum-drying obtains esomeprazole.
The process for purification of Esomeprazole sodium, relatively in table 4:
Table 4: the process for purification comparison of Esomeprazole sodium
Table 4 result shows: the present invention is during by esomeprazole sodium salt crude product refining, and the solvent using when the solvent of use and crystallization is all had any different, the product of final preparation, and yield and purity are all apparently higher than comparative example 3-2.
Therefore, the process for purification of Esomeprazole sodium provided by the invention is better than prior art.
Comparative example 4: the preparation of Esomeprazole sodium
(1) omeprazole thioether is synthetic: the method with reference to embodiment 1 in patent of invention 201210002536.8 specification sheetss makes omeprazole thioether;
(2) Esomeprazole sodium crude product is synthetic: the method with reference to embodiment 2 in patent of invention 201210002536.8 specification sheetss makes Omeprazole Sodium crude product;
(3) esomeprazole is refining: with reference to patent of invention 201210002536.8 specification sheetss
The method of embodiment 2 obtains finished product.
Comparative example 5: the preparation of Esomeprazole sodium
(1) omeprazole thioether is synthetic: the method with reference to embodiment 1 in patent of invention 201010255206.0 specification sheetss makes omeprazole thioether;
(2) Esomeprazole sodium crude product is synthetic: the method with reference to embodiment 2 in patent of invention 94190335.4 specification sheetss makes Omeprazole Sodium crude product;
(3) esomeprazole is refining: the method with reference to patent of invention 94190335.4 specification sheets embodiment 2 obtains finished product.
Experimental example 1: Esomeprazole sodium is prepared pilot process and detected
The intermediate of respectively embodiment 1 being prepared to each intermediate of Esomeprazole sodium and the Esomeprazole sodium of comparative example 1-2 carries out the detection of following index: purity (%), related substance (%), isomer, (detection method: HPLC method, with octadecylsilane chemically bonded silica (YMC Triart C18, 4.6 × 250mm, 5 μ are m) weighting agent, taking phosphate buffered saline buffer (solution of phosphoric acid sodium dihydrogen 0.0052mol and Sodium phosphate dibasic 0.032mol in every 1L)-water-acetonitrile-methyl alcohol (20:130:25:25) of pH7.6 as mobile phase A, taking phosphate buffered saline buffer-water-acetonitrile-methyl alcohol (4:56:70:70) of pH7.6 as Mobile phase B, gradient elution, detection wavelength is 280nm, column temperature is 40 DEG C), detected result is as shown in table 5.
Table 5: embodiment 1 detects data with comparative example 1-2 intermediate
Table 5 result shows, the Esomeprazole sodium that the present invention makes is compared with prior art, and the purity of intermediate is higher, and particularly to record foreign matter content very little for finished product, and quality product is higher and do not have isomer to detect.
Experimental example 2: active constituent content detects
The Esomeprazole sodium respectively embodiment 9-13 being made and comparative example 4, 5 Esomeprazole sodium carries out the detection of following index: proterties, active component content, moisture (%), related substance (%), (concrete detection method: HPLC method, with octadecylsilane chemically bonded silica (YMC Triart C18, 4.6 × 250mm, 5 μ are m) weighting agent, taking phosphate buffered saline buffer (solution of phosphoric acid sodium dihydrogen 0.0052mol and Sodium phosphate dibasic 0.032mol in every 1L)-water-acetonitrile-methyl alcohol (20:130:25:25) of pH7.6 as mobile phase A, taking phosphate buffered saline buffer-water-acetonitrile-methyl alcohol (4:56:70:70) of pH7.6 as Mobile phase B, gradient elution, detection wavelength is 280nm, column temperature is 40 DEG C) detected result is as shown in table 6.
Table 6: embodiment 9-13 and comparative example 4-5 detect data
Table 6 result shows, the comparing of the effective constituent of the Esomeprazole sodium that the present invention makes and prior art, and purity is higher, and particularly foreign matter content is very little, and quality product is higher.
Experimental example 3: stability test
1, accelerated test
The esomeprazole sodium sample of embodiment 9-13 and comparative example 4-5 is placed in and under 40 DEG C ± 2 DEG C, relative humidity 75% ± 5% condition, accelerates test in 6 months.Respectively at the 0th, the sampling at the end of month of 1,2,3,6 month, detect by stability high spot reviews project.Detect and investigate index: proterties, active component content, moisture (%), related substance (%), the investigation of each index the results are shown in Table 7.
Table 7: embodiment 9-13 and comparative example 4-5 accelerated test are investigated data
The result of accelerating test in 6 months in table 7 shows: its proterties of the Esomeprazole sodium that embodiment of the present invention 9-13 makes, active component content, moisture (%), related substance (%) with the comparing of prior art, change less, the stability that shows the Esomeprazole sodium that the present invention makes is better, and security is higher.
2, test of long duration
The sample of embodiment 9-13 and comparative example 4-5 is placed in to 25 ± 2 ° of C of temperature, under the condition of relative humidity 60 ± 10%, places 24 months.Respectively at the 0th, the sampling at the end of month of 3,6,9,12,18,24 months, detect by stability high spot reviews project.Detect and investigate index: proterties, active component content, moisture (%), related substance (%).The investigation of each index the results are shown in Table 8.
Table 8: embodiment 9-13 and comparative example 4-5 test of long duration are investigated data
The long-term test results of table 8 shows: the Esomeprazole sodium that embodiment of the present invention 9-13 makes, proterties, active component content, moisture (%), related substance (%) are compared with prior art, change littlely, show that the stability of the Esomeprazole sodium that the present invention makes is better, security is higher.
To sum up show, the Esomeprazole sodium that the present invention makes, known through study on the stability, sample quality is stablized controlled, particularly the control of impurity is compared with prior art greatly improved, the untoward reaction of having avoided impurity of the drug to cause in clinical application, when improving drug effect, has increased the security of medicine.
Although, above use general explanation, embodiment and test, the present invention is described in detail, on basis of the present invention, can make some modifications or improvements it, and this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (10)
1. the process for purification of Esomeprazole sodium, the method comprises the following steps: the good organic solvent low temperature that Esomeprazole sodium crude product is first suspended in 2～5 times of amounts stirs, filtering and impurity removing, slowly add 10～20 times of bad organic solvents, stirring and crystallizing is spent the night, centrifugal drying, obtains Esomeprazole sodium highly finished product.
2. process for purification according to claim 1, is characterized in that, described dissolving is one or both in acetone, butanone with good organic solvent.
3. process for purification according to claim 1, is characterized in that, described bad organic solvent is one or more in ethyl acetate, acetonitrile, ether or sherwood oil, tetrahydrofuran (THF), preferably acetonitrile and ethyl acetate.
4. process for purification according to claim 1, is characterized in that, the envelope-bulk to weight ratio of described good organic solvent and Esomeprazole sodium crude product is 3～5 times; The envelope-bulk to weight ratio of described bad organic solvent and Esomeprazole sodium crude product is 10～12 times.
5. process for purification according to claim 1, is characterized in that, described low temperature span of control is 0 DEG C～10 DEG C, preferably 2 DEG C～6 DEG C.
6. process for purification according to claim 1, is characterized in that, the crude product of described Esomeprazole sodium is prepared by following methods, and the method comprises the following steps: by the esomeprazole potassium stirring and dissolving that adds water, add organic solvent dissolution, be cooled to 10～20 DEG C; Add acid to adjust pH to 6.5～7.5, with organic solvent extraction, after concentrated organic solvent, add another organic solvent dissolution, add the organic solvent solution of sodium hydroxide, add ether stirring and crystallizing, obtain Esomeprazole sodium crude product.
7. method according to claim 6, it is characterized in that, describedly be dissolved in water, when organic solvent dissolution, another dissolution with solvents, the bulking value of esomeprazole potassium and water, organic solvent, another organic solvent is 1:1～2:2～3:0.5～1, is preferably 1:1.5～2:2.3～2.6:0.7～0.9;
When described tune pH, acid used is glacial acetic acid;
Described organic solvent is methylene dichloride or ethyl acetate;
Described another solvent is one or more in ethanol, methyl alcohol, Virahol, particular methanol, ethanol;
The organic solvent solution of described sodium hydroxide refers to the methanol solution of sodium hydroxide or the ethanolic soln of sodium hydroxide, and the weightmeasurement ratio of sodium salt and organic solvent is 1:8～11;
Described esomeprazole potassium and sodium hydroxide mol ratio are 1:1～1.2.
8. method according to claim 6, is characterized in that, the preparation method of described esomeprazole potassium comprises: synthesizing of omeprazole thioether and synthesizing of esomeprazole sylvite crude product.
9. method according to claim 8, it is characterized in that, the synthetic method of described omeprazole thioether comprises the following steps: in organic solvent, add inorganic sodium, after dissolving, add 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline, after dissolving, add 3,5-dimethyl-2-chloromethyl-4-methoxypyridine hydrochloride, be warming up to back flow reaction, TLC monitoring is reacted to the disappearance of raw material point, and aftertreatment obtains highly purified omeprazole thioether;
In the synthetic method of described omeprazole thioether:
Described organic solvent is one or more in toluene, methyl alcohol, ethanol, methylene dichloride, ethyl acetate or acetone, and preferably organic solvent is methyl alcohol or ethanol; Described inorganic sodium is one or more in sodium hydroxide, sodium bicarbonate or sodium pyrosulfate, and preferably inorganic sodium is sodium hydroxide or sodium bicarbonate; The consumption of described organic solvent is that the 2-5 of the weight of 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline doubly measures;
The mol ratio of described inorganic sodium, 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline and 3,5-dimethyl-2-chloromethyl-4-methoxypyridine hydrochloride is 1.8～3:1:0.8～1, is preferably 1.9～2.5:1:0.9～1.0;
The envelope-bulk to weight ratio of described organic solvent and 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline is 8.5～9.0:1, is preferably 8.70:1; The developping agent of described TLC monitoring is the mixture of ethyl acetate or sherwood oil and ethyl acetate, and the volume ratio of mixture PetroChina Company Limited. ether and ethyl acetate is 1:4～1:6;
The synthetic method of described esomeprazole sylvite crude product comprises the following steps: in organic solvent, omeprazole thioether reacts at 25 DEG C～45 DEG C temperature controls with D-(-)-diethyl tartrate, water, tetraisopropoxy titanium, after finishing, reaction is down to room temperature, add organic bases, slowly drip oxygenant and carry out oxidizing reaction, TLC monitors reaction end, then slowly add sylvite, make esomeprazole sylvite;
In the synthetic method of described esomeprazole sylvite crude product:
The mol ratio of described omeprazole thioether, organic solvent, D-(-)-diethyl tartrate, water and tetraisopropoxy titanium, organic bases and oxygenant, sylvite is 1:10～14:0.15～0.4:0.03～0.04:0.05～0.15:0.12～0.18:1.00～1.5:1.30～2.0;
Described organic solvent is one or both in toluene, dimethylbenzene, preferably toluene;
Described organic bases is triethylamine, DIPEA, diethylamine, preferably DIPEA;
Described oxide compound is hydrogen phosphide cumene;
Described sylvite is potassium hydroxide, saleratus, salt of wormwood, potassium methylate, preferably potassium hydroxide or potassium methylate;
The developping agent of described TLC monitoring is the mixture of chloroform and methyl alcohol, and the volume ratio of the two is 10:1～20:1, preferably 10:1～12:1.
10. a preparation method for Esomeprazole sodium, the method comprises the following steps:
(1) omeprazole thioether is synthetic: first in conversion unit, add organic solvent, volume is 5～10 times of 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline weight, add inorganic sodium, after dissolving, add 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline, after dissolving, add 3,5-dimethyl-2-chloromethyl-4-methoxypyridine hydrochloride, temperature reaction is to refluxing, keep back flow reaction, TLC monitoring reaction end to raw material point disappears, and regulates pH value to neutral, through extracting, concentrate, recrystallization makes highly purified omeprazole thioether;
(2) esomeprazole potassium is synthetic: in organic solvent, omeprazole thioether reacts with D-(-)-diethyl tartrate, water, tetraisopropoxy titanium temperature control, temperature is 25 DEG C～45 DEG C, after finishing, reaction is down to room temperature, add organic bases, slowly drip oxygenant and carry out oxidizing reaction, TLC monitors reaction end, then slowly add sylvite, make esomeprazole potassium;
(3) Esomeprazole sodium crude product is synthetic: the esomeprazole potassium stirring and dissolving that adds water, add organic solvent dissolution, and be cooled to 10～20 DEG C; Add acid to adjust pH to 6.5～7.5, with organic solvent extraction, after concentrated organic solvent, add another organic solvent dissolution, add the organic solvent solution of sodium hydroxide, add ether stirring and crystallizing, obtain Esomeprazole sodium crude product;
(4) Esomeprazole sodium is refining: the good organic solvent low temperature that Esomeprazole sodium crude product is first suspended in 2～5 times of amounts stirs, filtering and impurity removing, slowly adds the bad organic solvent of 10～20 amount, and stirring and crystallizing is spent the night, centrifugal drying, obtains Esomeprazole sodium highly finished product.
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| CN106083818A (en) * | 2016-06-08 | 2016-11-09 | 扬子江药业集团有限公司 | A kind of preparation method of high-purity 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 |
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| 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 |
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| CN106008464A (en) * | 2016-05-23 | 2016-10-12 | 江苏中邦制药有限公司 | Method for refining 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio-1H-benzimidazole crude product |
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| CN107400118B (en) * | 2017-08-29 | 2020-07-28 | 信泰制药（苏州）有限公司 | Preparation method of esomeprazole intermediate |
| 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 |
| CN113461663A (en) * | 2020-03-30 | 2021-10-01 | 江苏奥赛康药业有限公司 | Membrane separation and purification method of proton pump inhibitor esomeprazole sodium |
| CN113461663B (en) * | 2020-03-30 | 2023-11-28 | 江苏奥赛康药业有限公司 | Membrane separation and purification method of proton pump inhibitor Esomeprazole sodium |
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Effective date of registration: 20170630 Address after: 158400, 72 Hongxing street, Jixi, Heilongjiang, Hulin Co-patentee after: Haerbin Zhenbao Pharmaceutical Co., Ltd. Patentee after: Heilongjiang ZBD Pharmaceutical Co., Ltd. Address before: Haping Road Development Zone in Harbin City, Heilongjiang province 150060 Central Road District No. 8 Yantai Patentee before: Haerbin Zhenbao Pharmaceutical Co., Ltd. |