CN103145694B - Crystal R of Esomeprazole sodium salt and its production and use - Google Patents

Abstract

The invention discloses a crystal R of esomeprazole sodium salt, a preparation method and application thereof. The crystal R of the present invention is a new crystal form of esomeprazole sodium salt, has good chemical purity (no isomer, ee value is 100%) and physical stability, and is easy to be separated by filtration and washed. After vacuum drying at 35° C. for 5 minutes, the moisture content is low (1.31%) and the stability is good. The esomeprazole sodium salt crystal samples prepared by using the method in different batches were detected by HPLC, and the purity was above 99.8%, and no isomer was detected. The preparation method of the invention can prepare the crystal R with stable and consistent product properties in each batch, and has simple preparation process and good repeatability.

Description

Crystal R of esomeprazole sodium salt and its preparation method and use

technical field

The invention relates to a crystal R of esomeprazole sodium salt, a preparation method and application thereof.

Background technique

Esomeprazole as the S-configuration isomer of omeprazole, namely (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2 -pyridyl)-methyl]sulfinyl]-1H-benzimidazole.

Formula I

Esomeprazole (preparation method: Tetrahedron: Asymmetry11, 3819-3825), as a proton pump inhibitor, can be used to treat diseases related to gastric acid; at the same time, it has improved pharmacokinetics as a single isomer of omeprazole Kinetic and metabolic properties, resulting in an improved therapeutic spectrum.

Because amorphous esomeprazole sodium salt (as shown in formula I) easily absorbs the moisture in the air and deliquesces, thereby brings very big difficulty to filtration separation and washing, and the wet filter cake that separation obtains is viscous , It needs to be dried for a long time before the moisture content can be qualified. At present, there are 11 kinds of crystal forms of esomeprazole sodium salt that have been reported, namely WO06001755 (B crystal form), CN1982928 (C, E, H crystal form), US20070259921 (J, K, L, M, N crystal form), and EP2143722 (P, Q crystal form).

The crystal form B reported in the literature is obtained by mixing 50 mg of sodium salt with 10 ml of water and then filtering. It should be the hydrate of esomeprazole sodium salt. Its purity is not high, only 95.2%, and the chiral purity is 99.8%.

Crystal forms C, E, and H are modified esomeprazole sodium salts, which are wet filter cakes containing part of solvent and water, obtained by X-ray analysis after drying for 2-5 minutes, and no specific water content data is reported.

Among crystal forms J, K, L, M, and N, the water contents of J and K are 1.35% and 8.87%, respectively, and there is no relevant water content report for other crystal forms.

Crystal forms P and Q are solvated crystal forms, P crystal form contains 9.5% methanol, Q crystal form contains 0.5%, and the X-ray pattern of Q crystal is close to amorphous.

Contents of the invention

The technical problem to be solved by the present invention is to provide a new crystal R of esomeprazole sodium salt and its preparation method and application. The crystal R has low water content and high chemical and physical stability, thereby avoiding the defect that the amorphous esomeprazole sodium salt is easy to deliquescence.

The present invention provides a crystal R of esomeprazole sodium salt as shown in formula I,

In the powder X-ray diffraction spectrum using the radiation source Cu-Kα, the crystal R has main peaks at diffraction angles 2θ=6.194, 11.542, 12.407, 15.453, 16.319, 18.489, 24.665, 24.906 and 33.761 degrees, and at diffraction angles 2θ ＝10.282、13.081、14.624、16.900、19.832、20.660、21.471、21.744、21.964、22.891、23.147、23.978、24.409、25.949、26.343、27.057、27.570、28.056、29.524、30.052、30.573、31.358、34.882、36.332、37.812 There are minor peaks at , 39.645, 40.162, 41.345, 41.816, 42.523, 43.733 and 44.263 degrees, with a 2θ error range of ±0.2 degrees.

Wherein, the decomposition point of crystal R of the esomeprazole sodium salt is generally 220±2°C.

The present invention also provides the use of the crystal R of esomeprazole sodium salt in preparing gastric parietal cell proton pump inhibitors.

The present invention also provides a preparation method a of the crystal R of the esomeprazole sodium salt, which comprises the following steps: (1) dissolving esomeprazole in non-salt form in methanol to obtain a solution ①; (2) Under stirring conditions, add a solution containing sodium hydroxide or sodium alkoxide dropwise to solution ① to obtain solution ②, and the dropwise addition is carried out below 25°C; (3) Stir solution 2 until there are crystals Precipitation, cooling to -30 ~ 10 ° C, to obtain the crystal R of esomeprazole sodium salt; wherein the solvent ii in the solution containing sodium hydroxide or sodium alkoxide is selected from methanol, ethanol and isopropanol one or more of.

The mass volume ratio of esomeprazole in non-salt form and methanol in step (1) is preferably 1 g/ml˜1 g/100 ml.

Wherein, the volume ratio of methanol in step (1) to the solvent ii is preferably 5:1-1:10.

In step (2), the molar ratio of sodium hydroxide and sodium alkoxide to esomeprazole is preferably 1:1-5:1, more preferably 2:1-3:1.

In step (2), the sodium alkoxide is preferably sodium methoxide and/or sodium ethoxide.

In step (2), the dropping is preferably carried out at -30-10°C, more preferably at -10-0°C.

In step (3), the stirring time is subject to crystal precipitation, generally 1-48 hours, preferably 10-20 hours. The stirring is generally carried out at room temperature, more preferably at 25-30°C.

In step (3), the cooling conditions are conventional cooling conditions in the art, preferably -10-10°C, more preferably -10-0°C.

After step (3) is completed, it is preferably washed successively with ice methanol and isopropyl ether, and dried.

The present invention also provides another preparation method b of crystal R of esomeprazole sodium salt, which comprises the following steps: (1) dissolving esomeprazole in non-salt form in solvent i To obtain solution ③; (2) under stirring conditions, dropwise add a solution containing sodium hydroxide or sodium alkoxide to the solution ③ to obtain solution ④, and the dropwise addition is carried out below 25°C; (3) add seed crystals , cooled to -30-10°C to obtain the crystal R of esomeprazole sodium salt; wherein, the solvent i is selected from one or more of acetone, dichloromethane, tetrahydrofuran and acetonitrile; The solvent ii in the solution containing sodium hydroxide or sodium alkoxide is selected from one or more of methanol, ethanol and isopropanol; the seed crystal is esomeprazole sodium obtained by using preparation method a Crystals of salt R.

The mass volume ratio of the esomeprazole in non-salt form and solvent i in step (1) is preferably 1 g/ml-1 g/100 ml.

Wherein, the volume ratio between the solvent i and the solvent ii is preferably 5:1˜1:10.

In step (2), the molar ratio of sodium hydroxide and sodium alkoxide to esomeprazole is preferably 1:1-5:1, more preferably 2:1-3:1.

In step (2), the sodium alkoxide is preferably sodium methoxide and/or sodium ethoxide.

In step (2), the dropping is preferably carried out at -30-10°C, more preferably at -10-0°C.

In step (3), the cooling conditions are conventional cooling conditions in this field, preferably -10-10°C, more preferably -10-0°C.

In a preferred embodiment of the present invention, after adding the seed crystal, the mixture is stirred for more than 30 minutes and then cooled to -30-10° C., thereby obtaining crystal R with higher purity.

After step (3) is completed, it is preferably washed successively with ice methanol and isopropyl ether, and dried.

The room temperature mentioned in the present invention generally refers to 20-30°C.

As used herein, the term "crystal" refers to a solid in which complexes of molecules or atoms are arranged in a specific arrangement.

In the present invention, the above-mentioned preferred conditions can be combined arbitrarily on the basis of conforming to common knowledge in the field, so as to obtain various preferred embodiments of the present invention.

The starting materials and reagents of the present invention are all commercially available.

The positive progress effect of the present invention is:

1. The crystal R of the present invention is a new crystal form of esomeprazole sodium salt, has good chemical purity (no isomers, ee value is 100%) and physical stability, and is easy to be separated by filtration and washed. After vacuum drying at 35° C. for 5 minutes, the moisture content is low (1.31%) and the stability is good.

2. The esomeprazole sodium salt crystal sample prepared by using this method in different batches is detected by HPLC, the purity is all above 99.8%, no isomers are detected (ee value is 100%), and the same batch of Esomeprazole The crystals of meprazole sodium salt were sampled at different points, and the content was basically the same. Different batches of esomeprazole sodium salt crystals were sampled and subjected to X-ray powder diffraction, and the obtained crystal forms were basically consistent.

Description of drawings

Fig. 1 is the powder X-ray diffraction pattern of crystal R of esomeprazole sodium salt of Example 1, the ordinate shows the X-ray intensity expressed in cps, and the abscissa shows the diffraction angle expressed in 2θ.

Fig. 2 is the HPLC picture of the crystal R of esomeprazole sodium salt of embodiment 1.

Fig. 3 is the HPLC spectrum of amorphous esomeprazole sodium salt.

Fig. 4 is the HPLC spectrum of the crystal of esomeprazole sodium salt of Example 1 R after 30 days.

Figure 5 is the HPLC spectrum of amorphous esomeprazole sodium salt after 30 days.

detailed description

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, usually follow the conventional conditions or the conditions suggested by the manufacturer. All percentages, ratios, ratios, or parts are by weight unless otherwise indicated.

X-ray polycrystalline diffraction is also called X-ray powder diffraction. When X-rays pass through the crystal, a series of diffractions can be produced. X-ray diffraction patterns can be obtained by using an X-ray diffractometer in the laboratory. In the patterns, different diffraction The intensity of the X-ray diffraction line and each diffraction line is determined by the atomic group of a certain structure. The diffraction patterns produced by crystals with different structures are different. Therefore, the X-ray diffraction pattern can be used to determine the structure of the crystal, that is, the crystal form.

Methods for determining X-ray diffraction patterns of crystals are known in the art. For example, use RIGAKUD/max2550VB/PC model X-ray powder diffractometer to obtain spectra at a scanning speed of 2° per minute during measurement. A copper radiation target is used.

When a substance exists in an amorphous form, it does not have an exact melting point and decomposition point during heating. The pure crystal of the present invention has a definite decomposition point, that is, the crystal will change from solid to gas phase within a narrow temperature range during heating.

The esomeprazole used in the embodiment of the present invention is prepared according to the following steps:

Ufeprazole (molecular weight 329.4) 200.0g, D-diethyl tartrate 76.0g toluene solution 820ml, add water 0.8ml, heat to 54 ℃ and stir for 30 minutes, add tetraisopropyloxytitanium 52.0g, stir for 70 minute. Cool to 30°C, add 140.0 g of cumene peroxide dropwise, and stir for 1 hour after dropping. Add 600 ml of 10% sodium hydroxide solution, and stir at room temperature for 2 hours. After filtering, wash with 150ml of 10% sodium hydroxide solution, after layering, extract the toluene layer with 600ml of 10% sodium hydroxide, wash the combined water layer with 500ml of toluene twice, adjust the pH of the water layer to 7-8 with acetic acid, extract twice with 600ml of dichloromethane , dried, and concentrated dry to obtain esomeprazole oil (crude product) 256.6g (molecular weight 345.4).

The preparation a of embodiment 1 esomeprazole sodium salt crystal R

At room temperature, 54.7g (0.16mol) of esomeprazole oil was dissolved in 69ml of methanol, and at -10°C, 125ml of methanol solution containing 10.4g (0.26mol) of sodium hydroxide was added dropwise, and stirred at 25°C for 1 After 1 hour, it was cooled to 0° C., and a white solid precipitated out. It was suction-filtered, washed with ice methanol, washed with isopropyl ether, and dried under reduced pressure in vacuo to obtain 34.3 g of a white solid. Yield: 65.8%, ee value 100%, decomposition point 220±2°C.

Preparation a of the crystal R of embodiment 2 esomeprazole sodium salt

At room temperature, dissolve 46.6g (0.13mol) of esomeprazole oil in 64ml of methanol, and at 0°C, add dropwise 105ml of methanol solution containing 23.8g (0.44mol) of sodium methoxide, and stir at 30°C for 20 hours , cooled to -30°C, a white solid was precipitated, filtered with suction, washed with ice methanol, washed with isopropyl ether, and dried under reduced pressure in vacuo to obtain 26.2 g of a white solid. Yield: 65.8%, ee value 100%, decomposition point 220±2°C.

Preparation a of embodiment 3 esomeprazole sodium salt crystal R

At room temperature, dissolve 5.2 g (0.015 mol) of esomeprazole oil in 500 ml of methanol, and at -30 ° C, dropwise add 100 ml of ethanol solution containing 3.0 g (0.075 mol) of sodium hydroxide, and stir at 25 ° C for 10 hours After cooling to -10°C, a white solid precipitated out, which was suction filtered, washed with ice methanol, washed with isopropyl ether, and dried under reduced pressure in vacuo to obtain 1.2 g of a white solid. Yield: 21.0%, ee value is 100%, decomposition point is 220±2°C.

The preparation a of embodiment 4 esomeprazole sodium salt crystal R

At room temperature, dissolve 12.0g (0.035mol) of esomeprazole oil in 12ml of methanol, and at 10°C, add dropwise 120ml of isopropanol solution containing 1.4g (0.036mol) of sodium hydroxide, and stir at 25°C After 48 hours, it was cooled to 10° C., and a white solid precipitated out. It was suction filtered, washed with ice methanol, washed with isopropyl ether, and dried under reduced pressure in vacuo to obtain 7.5 g of a white solid. Yield: 56.0%, ee value is 100%, decomposition point is 220±2°C.

The preparation b of the crystal R of embodiment 5 esomeprazole sodium salt

At room temperature, dissolve 210.0g (0.61mol) of esomeprazole oil in 286ml of dichloromethane, and at -10°C, add dropwise 475ml of methanol solution containing 40.0g (1mol) of sodium hydroxide, at 25°C After adding the seed crystal R obtained in Example 1, stir at 25°C for 30 minutes, cool to 0°C, a white solid precipitates, filter with suction, wash with ice methanol, wash with isopropyl ether, and dry under vacuum to obtain a white solid 138.0 g. The yield is 75.9%, the ee value is 100%, and the decomposition point is 220±2°C.

The preparation b of the crystal R of embodiment 6 esomeprazole sodium salt

At room temperature, 19.8g (0.06mol) of esomeprazole oil was dissolved in 25ml of tetrahydrofuran, and at -30°C, 45ml of methanol solution containing 3.8g (0.095mol) of sodium hydroxide was added dropwise, and Example 2 was added. The obtained seed crystal R was cooled to 10° C., and a white solid was precipitated, which was filtered by suction, washed with ice methanol, washed with isopropyl ether, and dried under reduced pressure in vacuum to obtain 16.6 g of a white solid. Yield: 75.5%, ee value is 100%, decomposition point is 220±2°C.

The preparation b of the crystal R of embodiment 7 esomeprazole sodium salt

At room temperature, 40.0 g (0.116 mol) of esomeprazole oily matter was dissolved in 45 ml of acetonitrile, and at 0° C., 200 ml of methanol solution of 17.5 g (0.44 mol) of sodium hydroxide was added dropwise, and Example 1 was added to obtain After the seed crystal R was stirred at 30°C for 1 hour, cooled to -30°C, a white solid was precipitated, filtered with suction, washed with ice methanol, washed with isopropyl ether, and dried under reduced pressure in vacuo to obtain 25.6 g of a white solid. Yield: 60.1%, ee value 100%, decomposition point 220±2°C.

Preparation b of the crystal R of embodiment 8 esomeprazole sodium salt

At room temperature, dissolve 5.25g (0.0152mol) of esomeprazole oil in 500ml of acetone, and at 10°C, add dropwise 100ml of methanol solution containing 3.0g (0.076mol) of sodium oxide, and add Example 1 to obtain The seed crystal R was stirred at 25°C for 1 hour, cooled to -10°C, and a white solid was precipitated, filtered with suction, washed with ice methanol, washed with isopropyl ether, and dried under reduced pressure in vacuo to obtain 2.5 g of a white solid. Yield: 45.0%, ee value is 100%, decomposition point is 220±2°C.

The preparation b of the crystal R of embodiment 9 esomeprazole sodium salt

At room temperature, 20.0 g (0.0607 mol) of esomeprazole oil was dissolved in 100 ml of isopropanol, and at 0° C., 1,000 ml of acetone solution of 2.4 g (0.0607 mol) of sodium hydroxide was added dropwise, and Example 1 was added. After the prepared seed crystal R was stirred at 25°C for 1 hour, cooled to 0°C, a white solid was precipitated, filtered with suction, washed with ice methanol, washed with isopropyl ether, and dried under reduced pressure in vacuo to obtain 12.3 g of a white solid. Yield: 55.0%, ee value 100%, decomposition point 220±2°C.

Effect Example 1 Powder X-ray Diffraction of Crystal R of Esomeprazole Sodium Salt

Measuring method: Instrument model: Bruker D8Advance. At a scanning speed of 2° per minute, the XRPD pattern of the crystal R of Example 1 was obtained by using a copper radiation target Cu-Kα, as shown in FIG. 1 . The specific characteristic peaks of crystal R are shown in Table 1. The test result of the powder X-ray diffraction of other embodiments is the same as that of embodiment 1.

Table 1

The HPLC of effect embodiment 2 esomeprazole sodium salt crystal

Determination method: use octaalkylsilane bonded silica gel as filler; use acetonitrile-phosphate buffer saline as mobile phase (the volume ratio of acetonitrile: phosphate buffer saline (please confirm whether it is the volume ratio) is 27:73, phosphate buffer saline The concentration is 1.4g/L, pH=7.6), and the detection wavelength is 280nm. HPLC instrument: HITACHI-L2000; column is carbon octagon column; length 0.125m, diameter 4.6mm, 5μm; flow rate: 1ml/min; column temperature: 30 degrees Celsius.

Measurement results: the HPLC purity of crystal R of esomeprazole sodium salt in Example 1 is 99.827%, and the impurity content is less than 0.1% (see Figure 2). The HPLC test result of other embodiments is the same as the crystal of embodiment 1.

The stability test of the crystal R of effect embodiment 3 esomeprazole sodium salt

Table 2 shows the stability comparison between the crystal R of esomeprazole sodium salt in Example 1 and the amorphous esomeprazole sodium salt. Wherein the moisture content is the content 30 days ago, and is determined by Karl-Fischer analysis.

Fig. 2 and Fig. 4 are respectively the HPLC figure of the crystal R of esomeprazole sodium salt of embodiment 1 before and after standing for 30 days. Fig. 3 and Fig. 5 are respectively the HPLC figure of amorphous esomeprazole sodium salt before and after standing for 30 days. It can be seen from Table 2 and Figures 2-5 that the crystal R of the present invention can still retain a relatively high purity after 30 days.

Table 2

Esomeprazole sodium salt moisture content HPLC purity thirty days Crystal R 1.31% 99.827% 99.769% not finalized 5.50% 99.759% 99.205%

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

The above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the essential technical content of the present invention. The essential technical content of the present invention is broadly defined in the scope of the claims of the application, and any technical entity completed by others or method, if it is exactly the same as that defined in the scope of the claims of the application, or an equivalent change, it will be deemed to be included in the scope of the claims.

Claims (7)

1. a preparation method of the crystal R of esomeprazole sodium salt, it comprises the steps: (1) the esomeprazole of non-salt form is dissolved in solvent i to obtain solution 3.; (2) in Under the condition of stirring, add the solution containing sodium hydroxide or sodium alkoxide dropwise to the solution ③ to obtain the solution ④, the dropwise addition is carried out below 25°C; (3) Add seed crystals and cool to -30～10°C , to obtain the crystal R of the esomeprazole sodium salt; wherein, the solvent i is selected from one or more of acetone, dichloromethane, tetrahydrofuran and acetonitrile; the sodium hydroxide or alcohol The solvent ii in the sodium solution is selected from one or more of ethanol and isopropanol; the seed crystal is the crystal R of esomeprazole sodium salt; In the powder X-ray diffraction spectrum of the described esomeprazole sodium salt, the radiation source is Cu-Kα, at diffraction angles 2θ=6.194, 11.542, 12.407, 15.453, 16.319, 18.489, 24.665, 24.906 and 33.761度处有主峰，在衍射角2θ＝10.282、13.081、14.624、16.900、19.832、20.660、21.471、21.744、21.964、22.891、23.147、23.978、24.409、25.949、26.343、27.057、27.570、28.056、29.524、30.052 , 30.573, 31.358, 34.882, 36.332, 37.812, 39.645, 40.162, 41.345, 41.816, 42.523, 43.733 and 44.263 degrees with minor peaks, the 2θ error range is ±0.2 degrees. 2. preparation method as claimed in claim 1 is characterized in that: the mass volume ratio of the esomeprazole of non-salt form described in step (1) and solvent i is 1g/ml～1g/100ml; The volume ratio of solvent i to solvent ii is 5:1 to 1:10; in step (2), the ratio of the total molar weight of sodium hydroxide and sodium alkoxide to the molar weight of esomeprazole is 1:1 ~5:1. 3. the preparation method as claimed in claim 2 is characterized in that: in step (2), the ratio of the total molar weight of sodium hydroxide and sodium alkoxide to the molar weight of esomeprazole is 2: 1～3: 1; the sodium alkoxide is sodium methylate and/or sodium ethylate. 4. the preparation method as claimed in claim 1 is characterized in that: in step (2), described dropping is carried out at -30～10 ℃; In step (3), the temperature of described cooling is-10～10 ℃; 10°C. 5. the preparation method as claimed in claim 4 is characterized in that: in step (2), described dropping is carried out at -10～0 ℃; In step (3), the temperature of described cooling is-10～0 ℃; 0°C. 6. The preparation method according to any one of claims 1-5, characterized in that: after adding the seed crystal, stir for more than 30 minutes and then cool to -30-10°C. 7. The preparation method according to claim 1, characterized in that: after step (3) is completed, wash with glacial methanol and isopropyl ether successively, and dry.