CN103214458B - Esomeprazole magnesium dihydrate preparation method - Google Patents

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

Preparation method of esomeprazole magnesium dihydrate

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 ℃.