CN103214458B - Esomeprazole magnesium dihydrate preparation method - Google Patents
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- DBOUSUONOXEWHU-VCKZSRROSA-N magnesium;5-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide;dihydrate Chemical compound O.O.[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 DBOUSUONOXEWHU-VCKZSRROSA-N 0.000 title claims abstract description 21
- 229960000914 esomeprazole magnesium dihydrate Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 31
- 239000007787 solid Substances 0.000 claims abstract description 26
- 239000013078 crystal Substances 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 18
- 238000001035 drying Methods 0.000 claims abstract description 15
- 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 claims abstract description 14
- 238000003756 stirring Methods 0.000 claims abstract description 10
- 238000005406 washing Methods 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 13
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 238000007605 air drying Methods 0.000 claims description 2
- 238000005119 centrifugation Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000012452 mother liquor Substances 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 229960000197 esomeprazole magnesium Drugs 0.000 abstract description 2
- 230000002411 adverse Effects 0.000 abstract 1
- 239000012046 mixed solvent Substances 0.000 abstract 1
- 230000001376 precipitating effect Effects 0.000 abstract 1
- 229960004770 esomeprazole Drugs 0.000 description 18
- -1 (S) -omeprazole Chemical compound 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- MQEUGMWHWPYFDD-JIDHJSLPSA-N magnesium;6-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical compound [Mg].C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C MQEUGMWHWPYFDD-JIDHJSLPSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 6
- 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 5
- 239000011259 mixed solution Substances 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 229940126409 proton pump inhibitor Drugs 0.000 description 3
- 239000000612 proton pump inhibitor Substances 0.000 description 3
- 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 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 229960000381 omeprazole Drugs 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000825 ultraviolet detection Methods 0.000 description 2
- UIQGEWJEWJMQSL-UHFFFAOYSA-N 2,2,4,4-tetramethylpentan-3-one Chemical compound CC(C)(C)C(=O)C(C)(C)C UIQGEWJEWJMQSL-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 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
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000002467 anti-pepsin effect Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- WRUGWIBCXHJTDG-UHFFFAOYSA-L magnesium sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Mg+2].[O-]S([O-])(=O)=O WRUGWIBCXHJTDG-UHFFFAOYSA-L 0.000 description 1
- 229940061634 magnesium sulfate heptahydrate Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940112641 nexium Drugs 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- FOFFPEFVSRGLOZ-UHFFFAOYSA-N potassium;5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-3-ide Chemical compound [K+].N=1C2=CC(OC)=CC=C2[N-]C=1[S+]([O-])CC1=NC=C(C)C(OC)=C1C FOFFPEFVSRGLOZ-UHFFFAOYSA-N 0.000 description 1
- FOFFPEFVSRGLOZ-JIDHJSLPSA-N potassium;5-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide Chemical compound [K+].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C FOFFPEFVSRGLOZ-JIDHJSLPSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an esomeprazole magnesium dihydrate preparation method. The method comprises the following steps: dissolving an esomeprazole magnesium trihydrate in a single or mixed solvent, adding an adverse solvent, stirring for precipitating a solid, separating the solid, washing the solid, and drying the solid to obtain an esomeprazole magnesium dehydrate having an A crystal form. The method has the advantages of economy, simple operation, single product crystal form, and high repeatability, and is suitable for the industrialized production.
Description
Technical Field
The invention belongs to the field of chemical synthesis of pharmaceutical compositions, and relates to preparation of esomeprazole magnesium salt which can be used in pharmaceutical compositions.
Background
Omeprazole (Omepizole) has a chemical structure of 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridine) methyl ] sulfoxide ] -1H-benzimidazole, is a novel anti-peptic ulcer drug and a proton pump inhibitor, is developed by Astra company in Sweden, and is the first clinical Proton Pump Inhibitor (PPI) in the world. The S-enantiomer of omeprazole, i.e. (S) -omeprazole, has better safety and efficacy and became the first globally marketed chiral proton pump inhibitor in 2001, under the common name Esomeprazole (Esomeprazole), known as naif (Nexium). In recent years, the medicine is always positioned in the front of global popular medicines, and has wide market prospect. The esomeprazole magnesium salt trihydrate is a medicinal composition on the market, and the structural formula of the esomeprazole magnesium salt trihydrate is shown in the following figure:
WO 9427988 discloses sodium, magnesium, lithium, potassium, calcium and quaternary ammonium salts of esomeprazole and methods of making the same.
WO 9854171 discloses esomeprazole magnesium salt trihydrate and a method for its preparation. It also discloses two crystal forms (A and B) of esomeprazole magnesium salt dihydrate and a method for respectively preparing the same by esomeprazole potassium salt, and the difference of the methods for preparing the two crystal forms is very small, so that the obtained product has the risk of containing mixed crystal forms. In addition, he discloses a process for converting esomeprazole magnesium dihydrate crystal form B to esomeprazole magnesium trihydrate crystal.
WO 04/102145 discloses crystal form II of esomeprazole magnesium trihydrate and a process for its preparation.
WO 04/020436, WO06/096709, WO 07/071753 and WO 10/120750 disclose processes for the preparation of amorphous forms of esomeprazole magnesium.
WO 10/010056 discloses a process for preparing esomeprazole magnesium dihydrate crystal form a by other forms of esomeprazole magnesium salt hydrate forms.
WO 09/099933 and WO 11/012957 disclose a process for preparing esomeprazole magnesium dihydrate in crystal form B from esomeprazole magnesium salt trihydrate, respectively.
US 10/267959 discloses a process for the preparation of crystal form a of esomeprazole magnesium dihydrate by potassium esomeprazole salt, wherein toxic chlorinated solvents are used and the yield is low.
From the above, it is necessary to develop a process for preparing esomeprazole magnesium dihydrate stably in high yield. The invention discloses a method for preparing an esomeprazole dihydrate crystal form A in an industrially amplified, stable and efficient manner.
Disclosure of Invention
The invention aims to solve the technical problem of providing a novel method for preparing esomeprazole magnesium dihydrate from esomeprazole magnesium trihydrate, in particular to an A crystal form of the dihydrate, aiming at the defects of the existing method for preparing the esomeprazole magnesium salt. The method has the advantages of simple operation, high yield, high repeatability and easy production and amplification.
The technical problem to be solved by the invention can be realized by the following technical scheme:
a process for preparing esomeprazole magnesium dihydrate, comprising the steps of:
(a) dissolving esomeprazole magnesium trihydrate into a first organic solvent to form a solution;
(b) adding a poor solvent into the solution, and stirring to separate out a solid;
(c) separating and washing the solid;
(d) and drying to obtain the crystal form A of the esomeprazole magnesium dihydrate of the crystal form A.
Wherein,
the esomeprazole magnesium trihydrate may be prepared according to known literature data (e.g. WO98/54171), preferably example 1 of the present invention.
The first organic solvent is an alcohol solvent, and the alcohol solvent is one or a mixture of any two of methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, preferably methanol and ethanol, and more preferably methanol.
The temperature range for dissolving the esomeprazole magnesium trihydrate in the step (a) is 15-45 ℃, and the mixture is stirred for 20-180 minutes to achieve a completely dissolved state.
The poor solvent in the step (b) is a mixture of a second organic solvent and water, and the volume ratio of the second organic solvent to the water is 2: 1-6: 1, preferably 3: 1-4: 1.
The second organic solvent is one of ketone solvent and ester solvent or the mixture of the ketone solvent and the ester solvent.
The ketone solvent is one or a mixture of any two of acetone, methyl ethyl ketone, methyl isobutyl ketone and tert-butyl ketone;
the ester solvent is one of ethyl acetate and isopropyl acetate or a mixture of the ethyl acetate and the isopropyl acetate.
The second organic solvent is preferably acetone and ethyl acetate.
In the step (b), the temperature for stirring and separating out the solid is-10 ℃ to 30 ℃, preferably-5 ℃ to 25 ℃, and more preferably 0 ℃ to 20 ℃.
The separation in step (c) is filtration or centrifugation.
The washing in the step (c) is to wash the mother liquor remained on the solid by using the poor solvent in the step (b), and a product with higher purity can be obtained.
The drying in the step (d) is selected from one of vacuum drying, heating drying, flow-through drying or air drying; the drying temperature is 20-60 ℃, and the drying time is 1-30 hours. Preferably, vacuum drying is carried out, wherein the vacuum value is 0-10 mmHg, and drying is carried out for 10 hours at the temperature of 40 ℃.
The esomeprazole magnesium dihydrate crystal form A obtained in the step (d) has an X-ray powder diffraction pattern shown in figure 2.
The method is economical, simple and convenient to operate, single in product crystal form and high in repeatability, and is suitable for industrial production.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of esomeprazole magnesium trihydrate;
figure 2 is an X-ray powder diffraction pattern of esomeprazole magnesium dihydrate crystal form a.
Detailed Description
The foregoing aspects of the invention are explained in further detail with reference to specific embodiments. However, it should be understood that the scope of the present invention is not limited to the following examples, and any techniques implemented based on the description of the present invention are within the scope of the present invention.
The HPLC purity provided by the invention is measured by high performance liquid chromatography, and the detection conditions of related substances are as follows:
a chromatographic column: agilent XDB-C8, 4.6X 150mm, 5um
Mobile phase: ACN Na2HPO4 buffer pH7.6 ═ 22: 78
Flow rate: 1mL/min
UV detection wavelength: 302nm
Retention time: 15min
The ee value given by the invention is determined by chiral high performance liquid chromatography, and the conditions for detecting the enantiomer purity are as follows:
a chromatographic column: daicel a1-AGP, 4X 100mm, 5um
Mobile phase: ACN Na2HPO4 buffer pH6 ═ 15: 85
Flow rate: 1mL/min
UV detection wavelength: 302nm
Retention time: dextro-esomeprazole: 2.8min
Levorotatory esomeprazole: 4.2min
The powder X-ray diffraction pattern (XRPD) given in the present invention is measured by the following conditions: the powder X-ray diffraction pattern was obtained by a method known in the art using a DX-2700 type X-ray diffractometer manufactured by the Dandong Yuan instruments factory. The ray is Cu target Ka (40KV, 30mA), the 2 theta range is 5-40 degrees, and the scanning speed is 2 degrees/minute.
Example 1 preparation of esomeprazole magnesium trihydrate
In a 1L three-necked flask, esomeprazole potassium (76.8g, 85% absolute content, 170mmol) was dissolved in deionized water (300mL), magnesium sulfate heptahydrate (49.3g, 200mmol) was dissolved in deionized water (150mL) and slowly added dropwise to the solution, and a large amount of solid was precipitated by reaction at 35 ℃ for 3 hours. The heating was stopped, the solid was filtered off, washed four times with water and dried under vacuum at 40 ℃ overnight. 62.0g of esomeprazole trihydrate was obtained with a yield of 95%. The product was analyzed by chromatography for HPLC purity 99.90% and ee 99.80%. The X-ray powder diffraction pattern is shown in FIG. 1.
Example 2 preparation of esomeprazole magnesium dihydrate form A
In a 250mL flask, esomeprazole trihydrate (11.5g, 15mmol) was suspended in dry methanol (15mL) and stirred for 30 min to give a clear solution. After stirring at 25 ℃ for 2 hours, a mixed solution (75mL) of acetone and water (4: 1 by volume) was added at 10 ℃ and stirred at this temperature overnight to precipitate a large amount of solid. The solid was filtered, washed twice with acetone and dried under vacuum at 40 ℃ for 10 hours. 10.2g of esomeprazole dihydrate form A was obtained in a yield of 91%. The product was analyzed by chromatography for HPLC purity 99.98% and ee 99.94%. The X-ray powder diffraction pattern is shown in FIG. 2.
Example 3 preparation of esomeprazole magnesium dihydrate form A
In a 250mL flask, esomeprazole trihydrate (11.5g, 15mmol) was suspended in dry methanol (15mL) and stirred for 30 min to give a clear solution. After stirring at 45 ℃ for 1 hour, a mixed solution (60mL) of acetone and water (3: 1 by volume) was added at 10 ℃ and stirred at this temperature overnight to precipitate a large amount of solid. The solid was filtered, washed twice with acetone and dried under vacuum at 20 ℃ for 30 hours. 10.0g of esomeprazole dihydrate form A was obtained in 89% yield. The product was analyzed by chromatography for HPLC purity 99.98% and ee 99.92%. The X-ray powder diffraction pattern is shown in FIG. 2.
Example 4 preparation of esomeprazole magnesium dihydrate form A
In a 250mL flask, esomeprazole trihydrate (11.5g, 15mmol) was suspended in absolute ethanol (15mL) and stirred for 45 minutes to give a clear solution. After stirring at 15 ℃ for 3 hours, a mixed solution (75mL) of ethyl acetate and water (volume ratio: 4: 1) was added at 10 ℃ and stirred at this temperature overnight to precipitate a large amount of solid. The solid was filtered, washed twice with acetone and dried under vacuum overnight at 60 ℃ to give 9.8g of esomeprazole dihydrate with a yield of 87%. The product was analyzed by chromatography for HPLC purity 99.96% and ee 99.90%. The X-ray powder diffraction pattern is shown in FIG. 2.
Example 5 preparation of Esomeprazole magnesium dihydrate form A
In a 250mL flask, esomeprazole trihydrate (11.5g, 15mmol) was suspended in dry methanol (15mL) and stirred for 30 min to give a clear solution. After stirring at room temperature for 2 hours, a mixed solution (75mL) of acetone and water (4: 1 by volume) was added at 0 ℃ and stirred overnight at this temperature to precipitate a large amount of solid. The solid was filtered, washed twice with acetone and dried under vacuum at 40 ℃ overnight. 10.3g of esomeprazole dihydrate form A was obtained in a yield of 92%. The product was analyzed by chromatography for HPLC purity 99.98% and ee 99.94%. The X-ray powder diffraction pattern is shown in FIG. 2.
Example 6 preparation of Esomeprazole magnesium dihydrate form A
In a 250mL flask, esomeprazole trihydrate (11.5g, 15mmol) was suspended in dry methanol (15mL) and stirred for 30 min to give a clear solution. After stirring at room temperature for 3 hours, a mixed solution (75mL) of acetone and water (4: 1 by volume) was added at 20 ℃ and stirred overnight at this temperature to precipitate a large amount of solid. The solid was filtered, washed twice with acetone and dried under vacuum at 40 ℃ overnight. 9.6g of esomeprazole dihydrate form A was obtained with a yield of 85%. The product was analyzed by chromatography for HPLC purity 99.96% and ee 99.94%. The X-ray powder diffraction pattern is shown in FIG. 2.
Claims (14)
1. A process for the preparation of esomeprazole magnesium dihydrate, comprising the steps of:
(a) dissolving esomeprazole magnesium trihydrate into a first organic solvent to form a solution;
(b) adding a poor solvent into the solution, and stirring to separate out a solid;
(c) separating and washing the solid;
(d) drying to obtain crystal form A of esomeprazole magnesium dihydrate;
the esomeprazole magnesium dihydrate crystal form A obtained in the step (d) has an X-ray powder diffraction pattern shown in figure 2;
the poor solvent in the step (b) is a mixture of a second organic solvent and water, and the volume ratio of the second organic solvent to the water is 2: 1-6: 1;
the second organic solvent is acetone or ethyl acetate.
2. The method of claim 1, wherein the first organic solvent comprises an alcohol solvent.
3. The method of claim 2, wherein the alcoholic solvent is one or a mixture of any two of methanol, ethanol, n-propanol, isopropanol, n-butanol, and t-butanol.
4. The method of claim 2, wherein the alcoholic solvent is methanol or ethanol.
5. The method of claim 2, wherein the alcoholic solvent is methanol.
6. The method according to claim 1, wherein the step (a) of dissolving the esomeprazole magnesium trihydrate is carried out at a temperature ranging from 15 ℃ to 45 ℃ and stirring is carried out for 20 to 180 minutes.
7. The method according to claim 1, wherein the poor solvent in the step (b) is a mixture of a second organic solvent and water, and the volume ratio of the second organic solvent to the water is 3: 1-4: 1.
8. The method of claim 1, wherein in step (b), the temperature at which the solids are stirred out is from-10 ℃ to 30 ℃.
9. The method of claim 1, wherein in step (b), the temperature at which the solids are stirred out is from-5 ℃ to 25 ℃.
10. The method of claim 1, wherein in step (b), the temperature at which the solids are stirred out is from 0 ℃ to 20 ℃.
11. The method of claim 1, wherein said separating in step (c) is filtration or centrifugation.
12. The method of claim 1, wherein the washing in step (c) is carried out by washing the mother liquor remaining on the solids with the poor solvent of step (b).
13. The method of claim 1, wherein the drying of step (d) is selected from one of vacuum drying, heat drying, flow-through drying, or air drying; the drying temperature is 20-60 ℃, and the drying time is 1-30 hours.
14. The method of claim 1, wherein the drying of step (d) is vacuum drying at a vacuum of 0 to 10 mmhg for 10 hours at 40 ℃.
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| CN104725357A (en) * | 2013-12-24 | 2015-06-24 | 苏州联友制药技术有限公司 | Preparation method of esomeprazole magnesium dihydrate crystal form B |
| CN105218520A (en) * | 2014-06-27 | 2016-01-06 | 苏州朗科生物技术有限公司 | A kind of preparation method of esomeprazole magnesium crystallization dihydrate |
| CN104356113A (en) * | 2014-10-31 | 2015-02-18 | 广东东阳光药业有限公司 | Method for preparing esomeprazole magnesium dihydrate |
| CN114315797B (en) * | 2022-03-08 | 2022-07-05 | 寿光富康制药有限公司 | Preparation method of high-crystal-form-purity esomeprazole magnesium dihydrate crystal |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009099933A2 (en) * | 2008-02-01 | 2009-08-13 | Dr. Reddy's Laboratories Ltd. | Preparation of esomeprazole magnesium and hydrates thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2009099933A2 (en) * | 2008-02-01 | 2009-08-13 | Dr. Reddy's Laboratories Ltd. | Preparation of esomeprazole magnesium and hydrates thereof |
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