CN105924430A - Refinement method of esomeprazole sodium - Google Patents
Refinement method of esomeprazole sodium Download PDFInfo
- Publication number
- CN105924430A CN105924430A CN201610506394.7A CN201610506394A CN105924430A CN 105924430 A CN105924430 A CN 105924430A CN 201610506394 A CN201610506394 A CN 201610506394A CN 105924430 A CN105924430 A CN 105924430A
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- Prior art keywords
- esomeprazole sodium
- purification
- methanol
- acetonitrile
- ethyl acetate
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- 229960000496 esomeprazole sodium Drugs 0.000 title claims abstract description 49
- 238000000034 method Methods 0.000 title claims abstract description 31
- RYXPMWYHEBGTRV-JIDHJSLPSA-N sodium;5-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-3-ide Chemical compound [Na+].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C RYXPMWYHEBGTRV-JIDHJSLPSA-N 0.000 title claims abstract 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 72
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 61
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 58
- 239000000047 product Substances 0.000 claims abstract description 18
- 239000012043 crude product Substances 0.000 claims abstract description 16
- 238000003756 stirring Methods 0.000 claims abstract description 15
- 239000012046 mixed solvent Substances 0.000 claims abstract description 13
- 239000012065 filter cake Substances 0.000 claims abstract description 11
- 239000007787 solid Substances 0.000 claims abstract description 11
- 238000001291 vacuum drying Methods 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 7
- 238000000746 purification Methods 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 10
- 230000014759 maintenance of location Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 5
- 238000002425 crystallisation Methods 0.000 abstract description 3
- 230000008025 crystallization Effects 0.000 abstract description 3
- 239000013078 crystal Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000013341 scale-up Methods 0.000 abstract 2
- 238000001914 filtration Methods 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 239000002245 particle Substances 0.000 abstract 1
- 238000010992 reflux Methods 0.000 abstract 1
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 43
- 239000003814 drug Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 229960004770 esomeprazole Drugs 0.000 description 4
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229960000381 omeprazole Drugs 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 2
- 108010083204 Proton Pumps Proteins 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 229940126409 proton pump inhibitor Drugs 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- KWORUUGOSLYAGD-YPPDDXJESA-N esomeprazole magnesium Chemical compound [Mg+2].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C.C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C KWORUUGOSLYAGD-YPPDDXJESA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940112641 nexium Drugs 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229960004157 rabeprazole Drugs 0.000 description 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a refinement method of esomeprazole sodium. The method comprises the following steps: adding an esomeprazole sodium crude product into an organic solvent, heating to reflux, until the solid is completely dissolved, cooling to 40-20 DEG C by standing, cooling to 10 to -10 DEG C by stirring, keeping the temperature for 1-3 hours, filtering, and carrying out vacuum drying on the filter cake to obtain the esomeprazole sodium refined product, wherein the organic solvent is a mixed solvent composed of methanol, acetonitrile and ethyl acetate. The refinement method is simple in steps: the esomeprazole sodium crude product is heated and dissolved in the combination of the solvents, and is cooled to crystallize, thereby obtaining the esomeprazole sodium refined product. In the crystallization process, the stirring is controlled, so that the particle size of the refined product is smaller, thereby avoiding overproof solvent residues caused by easy solvent inclusion due to large precipitated crystals. The method does not have the scale-up effect after scale-up production, and thus, can obtain the high-yield high-purity refined product.
Description
Technical field
The present invention relates to a kind of process for purification, be specifically related to the process for purification of a kind of Esomeprazole sodium.Belong to medical science neck
Territory.
Background technology
Proton pump inhibitor (PPI) is the choice drug of the treatment acid related disorder such as peptic ulcer, gastroesophageal reflux disease.Mesh
Before PPI conventional clinically have omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole 5 kinds.Difficult to understand
U.S.A draws azoles to obtain consistent accreditation as the first PPI medicine, the curative effect of its therapic acid relevant disease.Esomeprazole, business
The resistance to letter of the name of an article (Nexium), is the individual isomer of omeprazole, i.e. (S)-isomer.Owing to having metabolic advantage, angstrom
Suo Meila azoles has higher bioavailability and more consistent pharmacokinetics compared with omeprazole, makes the medicine of arrival proton pump
Increasing, acid suppression effect is better than other PPI.
Esomeprazole is global first isomer proton pump inhibitor (PPI), suppresses parietal cell proton pump by specificity
Reduce gastric acid secretion.Confirming through a large amount of clinical experiments and drug research, the time of its maintenance gastric pH > 4 is longer, acid suppression efficiency
Higher, curative effect is better than front two generation PPI, and individual variation is little.As a new generation PPI, it is widely used in clinical treatment many
Acid related disorder.The most commonly used is its salt, and Esomeprazole sodium is one of them.
The Clinical practice dosage form of Esomeprazole sodium is injection powder pin, need highly purified Esomeprazole sodium as crude drug,
Therefore the purifying process of Esomeprazole sodium is extremely important.
Summary of the invention
It is an object of the invention to as overcoming above-mentioned the deficiencies in the prior art, it is provided that the process for purification of a kind of Esomeprazole sodium.
For achieving the above object, the present invention uses following technical proposals:
The process for purification of a kind of Esomeprazole sodium, comprises the concrete steps that: join in organic solvent by Esomeprazole sodium crude product,
Being heated to backflow, after solid is completely dissolved, stands and be cooled to 40 DEG C～20 DEG C, stirring afterwards is cooled to 10 DEG C～-10 DEG C, protects
Temperature 1～3 hour, filters, and filter cake is vacuum dried i.e. obtains Esomeprazole sodium highly finished product；Described organic solvent is methanol, second
Nitrile and the mixed solvent of ethyl acetate composition, the volume ratio of three is 1:2～3:1～4.
Preferably, Esomeprazole sodium crude product is 1g:6～13mL with the mass volume ratio of organic solvent.
Preferably, the volume ratio of methanol, acetonitrile and ethyl acetate is 1:2:3.
Preferably, after stirring cooling, temperature retention time is 2 hours.
Preferably, vacuum drying temperature is 40～80 DEG C, and drying time is 6～8 hours.
Beneficial effects of the present invention:
The purification process steps of the present invention is simple, after Esomeprazole sodium crude product is dissolved by the combined heated of three kinds of solvents,
Cooling crystallize and get final product.Present invention, avoiding after conventional recrystallization process first dissolves with good solvent with poor solvent separate out loaded down with trivial details
Step, and in conventional recrystallization process, addition opportunity and the impact of operation technique counterweight crystallization effect of solvent are very big, recrystallization
Successfully fidelity factor is poor, and the present invention is not required to consider factors above completely, adds as long as being added directly in combination solvent by crude product
Heat of solution, greatly reduces the requirement to experimental implementation person.It addition, control stirring in Crystallization Process so that refined
Product granularity is less, it is to avoid precipitation crystal is bigger than normal and easily sandwiches solvent, causes dissolvent residual to exceed standard.Amplify after producing without amplifying
Effect, it is possible to ensure to obtain the highly purified highly finished product of high yield, specific as follows:
(1) process for purification of the Esomeprazole sodium that the present invention provides, easy and simple to handle, stablizes controlled, gained esomeprazole
Purity and the yield of sodium raw materials medicine are higher, have preferable economic benefit, it is simple to industrialized production.
(2) dissolvent residual of crude drug is the key factor affecting its tablet safety, uses the Esomeprazole sodium of the present invention
Process for purification prepare Esomeprazole sodium crude drug, dissolvent residual is relatively low, and products obtained therefrom meets in Chinese Pharmacopoeia residual to solvent
The standard-required (the dissolvent residual limit of methanol, acetonitrile and ethyl acetate is respectively 0.3%, 0.041%, 0.5%) stayed.
Detailed description of the invention
Below in conjunction with embodiment, the present invention will be further elaborated, it should explanation, and the description below is merely to explain
The present invention, is not defined its content.
Embodiment 1:
The process for purification of a kind of Esomeprazole sodium of the present invention, comprises the concrete steps that: added by 10g Esomeprazole sodium crude product
In the mixed solvent (three's volume ratio is 1:2:1) of 60mL methanol, acetonitrile and ethyl acetate composition, it is heated to backflow,
After solid is completely dissolved, standing and be cooled to 40 DEG C, stirring afterwards is cooled to 10 DEG C, is incubated 1 hour, filters, and filter cake is through 40
DEG C vacuum drying 6 hours Esomeprazole sodium highly finished product 9g, purity 99.99% (HPLC mensuration), yield 90%.
Dissolvent residual: the dissolvent residual of methanol, acetonitrile and ethyl acetate is respectively 0.09%, 0.011%, 0.08% (GC survey
Fixed).
Embodiment 2:
The process for purification of a kind of Esomeprazole sodium of the present invention, comprises the concrete steps that: added by 10g Esomeprazole sodium crude product
In the mixed solvent (three's volume ratio is 1:3:4) of 130mL methanol, acetonitrile and ethyl acetate composition, it is heated to back
Stream, after solid is completely dissolved, stands and is cooled to 20 DEG C, and stirring afterwards is cooled to-10 DEG C, is incubated 3 hours, filters, filter cake
Within 8 hours, Esomeprazole sodium highly finished product 9.2g, purity 99.99% (HPLC mensuration), yield 92% is obtained through 80 DEG C of vacuum drying.
Dissolvent residual: the dissolvent residual of methanol, acetonitrile and ethyl acetate is respectively 0.12%, 0.012%, 0.07% (GC survey
Fixed).
Embodiment 3:
The process for purification of a kind of Esomeprazole sodium of the present invention, comprises the concrete steps that: added by 10g Esomeprazole sodium crude product
In the mixed solvent (three's volume ratio is 1:2:3) of 100mL methanol, acetonitrile and ethyl acetate composition, it is heated to back
Stream, after solid is completely dissolved, stands and is cooled to 30 DEG C, and stirring afterwards is cooled to 0 DEG C, is incubated 2 hours, filters, filter cake
Within 7 hours, Esomeprazole sodium highly finished product 9.5g, purity 99.99% (HPLC mensuration), yield 95% is obtained through 60 DEG C of vacuum drying.
Dissolvent residual: the dissolvent residual of methanol, acetonitrile and ethyl acetate is respectively 0.08%, 0.009%, 0.07% (GC survey
Fixed).
Embodiment 4:
The process for purification of a kind of Esomeprazole sodium of the present invention, comprises the concrete steps that: added by 1kg Esomeprazole sodium crude product
In the mixed solvent (three's volume ratio is 1:2:3) of 10L methanol, acetonitrile and ethyl acetate composition, it is heated to backflow,
After solid is completely dissolved, standing and be cooled to 30 DEG C, stirring afterwards is cooled to 0 DEG C, is incubated 2 hours, filters, and filter cake is through 60
DEG C vacuum drying 7 hours Esomeprazole sodium highly finished product 949g, purity 99.99% (HPLC mensuration), yield 94.9%.
Dissolvent residual: the dissolvent residual of methanol, acetonitrile and ethyl acetate is respectively 0.07%, 0.010%, 0.07% (GC survey
Fixed).
Embodiment 5:
The process for purification of a kind of Esomeprazole sodium of the present invention, comprises the concrete steps that: added by 10kg Esomeprazole sodium crude product
In the mixed solvent (three's volume ratio is 1:2:3) of 100L methanol, acetonitrile and ethyl acetate composition, it is heated to backflow,
After solid is completely dissolved, standing and be cooled to 30 DEG C, stirring afterwards is cooled to 0 DEG C, is incubated 2 hours, filters, and filter cake is through 60
DEG C vacuum drying 7 hours Esomeprazole sodium highly finished product 9.5kg, purity 99.99% (HPLC mensuration), yield 95%.
Dissolvent residual: the dissolvent residual of methanol, acetonitrile and ethyl acetate is respectively 0.08%, 0.009%, 0.08% (GC survey
Fixed).
Comparative example 1:
The process for purification of a kind of Esomeprazole sodium of the present invention, comprises the concrete steps that: added by 10g Esomeprazole sodium crude product
In the mixed solvent (three's volume ratio is 1:2:3) of 100mL methanol, acetonitrile and ethyl acetate composition, it is heated to back
Stream, after solid is completely dissolved, stands and is cooled to 30 DEG C, and stirring afterwards is cooled to 0 DEG C, is incubated 2 hours, filters, filter cake
Within 7 hours, Esomeprazole sodium highly finished product 8.7g, purity 98.7% (HPLC mensuration), yield 87% is obtained through 60 DEG C of vacuum drying.
Dissolvent residual: the dissolvent residual of methanol, acetonitrile and ethyl acetate is respectively 0.35%, 0.05%, 0.58% (GC mensuration).
Comparative example 1 directly stands cooling crystallize, and yield reduces, and highly finished product purity is on the low side, and dissolvent residual is the most up to standard.
Comparative example 2:
The process for purification of a kind of Esomeprazole sodium of the present invention, comprises the concrete steps that: added by 10g Esomeprazole sodium crude product
In the mixed solvent (three's volume ratio is 1:2) that 100mL methanol and acetonitrile form, being heated to backflow, solid is the most molten
Xie Hou, stands and is cooled to 30 DEG C, and stirring afterwards is cooled to 0 DEG C, is incubated 2 hours, filters, and filter cake is through 60 DEG C of vacuum drying
Within 7 hours, obtain Esomeprazole sodium highly finished product 7.3g, purity 87% (HPLC mensuration), yield 73%.
Dissolvent residual: the dissolvent residual of methanol and acetonitrile is respectively 0.4%, 0.08% (GC mensuration).
Comparative example 2 uses methanol and the mixed solvent of acetonitrile composition, and yield is low, and purity is low, and dissolvent residual is the most defective.
Comparative example 3:
The process for purification of a kind of Esomeprazole sodium of the present invention, comprises the concrete steps that: added by 10g Esomeprazole sodium crude product
In the mixed solvent (three's volume ratio is 1:3) that 100mL methanol and ethyl acetate form, being heated to backflow, solid is complete
After CL, standing and be cooled to 30 DEG C, stirring afterwards is cooled to 0 DEG C, is incubated 2 hours, filters, and filter cake is through 60 DEG C of vacuum
It is dried 7 hours to obtain Esomeprazole sodium highly finished product 8.6g, purity 85% (HPLC mensuration), yield 86%.
Dissolvent residual: the dissolvent residual of methanol and ethyl acetate is respectively 0.38%, 0.64% (GC mensuration).
Comparative example 3 uses methanol and the mixed solvent of ethyl acetate composition, and yield is low, and purity is low, and dissolvent residual is the most defective.
Although the above-mentioned detailed description of the invention to the present invention is described, but not limiting the scope of the invention,
On the basis of technical scheme, those skilled in the art need not pay the various amendments that creative work can be made
Or deformation is still within protection scope of the present invention.
Claims (5)
1. the process for purification of an Esomeprazole sodium, it is characterised in that comprise the concrete steps that: Esomeprazole sodium crude product is added
Enter in organic solvent, be heated to backflow, after solid is completely dissolved, stands and be cooled to 40 DEG C～20 DEG C, stir cooling afterwards
To 10 DEG C～-10 DEG C, being incubated 1～3 hour, filter, filter cake is vacuum dried i.e. obtains Esomeprazole sodium highly finished product；Described
Organic solvent is methanol, acetonitrile and the mixed solvent of ethyl acetate composition, and the volume ratio of three is 1:2～3:1～4.
Process for purification the most according to claim 1, it is characterised in that Esomeprazole sodium crude product and the matter of organic solvent
Amount volume ratio is 1g:6～13mL.
Process for purification the most according to claim 1, it is characterised in that the volume ratio of methanol, acetonitrile and ethyl acetate is
1:2:3.
Process for purification the most according to claim 1, it is characterised in that after stirring cooling, temperature retention time is 2 hours.
Process for purification the most according to claim 1, it is characterised in that vacuum drying temperature is 40～80 DEG C, when being dried
Between be 6～8 hours.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610506394.7A CN105924430A (en) | 2016-06-27 | 2016-06-27 | Refinement method of esomeprazole sodium |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610506394.7A CN105924430A (en) | 2016-06-27 | 2016-06-27 | Refinement method of esomeprazole sodium |
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| Publication Number | Publication Date |
|---|---|
| CN105924430A true CN105924430A (en) | 2016-09-07 |
Family
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1055469C (en) * | 1993-05-28 | 2000-08-16 | 阿斯特拉公司 | Optically pure salt of pyridylmethylsulfinyl-1H-benzimidazole compound, its preparation method and application |
| CN102887885A (en) * | 2012-09-26 | 2013-01-23 | 江苏正大丰海制药有限公司 | Preparation method of esomeprazole sodium |
| CN103570686A (en) * | 2013-10-14 | 2014-02-12 | 哈药集团技术中心 | Method for synthesizing and refining esomeprazole sodium |
-
2016
- 2016-06-27 CN CN201610506394.7A patent/CN105924430A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1055469C (en) * | 1993-05-28 | 2000-08-16 | 阿斯特拉公司 | Optically pure salt of pyridylmethylsulfinyl-1H-benzimidazole compound, its preparation method and application |
| CN102887885A (en) * | 2012-09-26 | 2013-01-23 | 江苏正大丰海制药有限公司 | Preparation method of esomeprazole sodium |
| CN103570686A (en) * | 2013-10-14 | 2014-02-12 | 哈药集团技术中心 | Method for synthesizing and refining esomeprazole sodium |
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