Preparation method of ilaprazole crystal form B

Abstract

The invention relates to a preparation method of an ilaprazole crystal form B. The preparation method comprises the following steps: dissolving ilaprazole sodium salt in a mixed solution of an organic solvent and water, adding a certain amount of acid for dissociation, separating out salt, adding a seed crystal for crystallization, pulping the obtained solid with water, and washing with leacheate to obtain the target crystal ilaprazole crystal form B. A single solvent is used for crystallization, the method has the advantage of low cost, distillation is not needed, the working hours and energy consumption are shortened, and the operation process is simplified; the use of dangerous solvent ethers is avoided, and industrialization is easy; the problem that the residual solvent is easy to exceed the standard is solved, and the purity and yield of the target product are improved.

Description

Technical Field

[0001] The present invention relates to the technical field of the preparation of compound crystal forms, and specifically refers to a method for preparing esaprazole crystal form B. Background Art

[0002] Esaprazole, a substituted benzimidazole proton pump inhibitor, was developed by Livzon Pharmaceutical Factory of Livzon Group. It is the first innovative drug in the field of digestive treatment in China. It was approved by China's CFDA for marketing on December 11, 2007, and is used for the treatment of duodenal ulcer, with the trade name Yilian. Esaprazole belongs to an irreversible benzimidazole proton pump inhibitor. After oral administration, the drug selectively enters gastric parietal cells and is transformed into a sulfenamide active metabolite to exert its therapeutic effect. Compared with previous gastric drugs, esaprazole has obvious advantages. First, it has stronger acid inhibition activity, and the efficacy of the same dose is 4 times higher; second, there is no individual difference among patients with different metabolic types; third, it has fewer toxic and side reactions.

[0003]

[0004] According to literature reports, esaprazole has polymorphic phenomena, and the common crystal forms are A, B, E, F, I, etc. When comparing the physicochemical properties of different crystal forms, it was found that crystal form B has better stability and is an ideal crystal. However, in the reported preparation processes, mixed solvents are mostly used as crystallization solvents, such as dichloromethane / ethanol / ether. On the one hand, ether has a low boiling point, is flammable and explosive, and is particularly dangerous for industrialization, so its use is restricted; on the other hand, the risk of residual solvents is very high, and dichloromethane is difficult to remove during the drying process, resulting in low yields and purities of the prepared products. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a method for preparing esaprazole crystal form B that uses a single solvent for crystallization, is simple to operate, and has high yields and purities, in view of the current situation of the prior art.

[0006] The technical solution adopted by the present invention to solve the above technical problems is as follows:

[0007] A method for preparing esaprazole crystal form B includes the following steps: dissolving sodium esaprazole in an organic solvent or a mixed solution of an organic solvent and water, adding a certain amount of acid for liberation, separating out the salt, adding a seed crystal for crystallization, and pulping the obtained solid with water and washing it with a washing solution to obtain the target crystal esaprazole crystal form B.

[0008] Preferably, the organic solvent is selected from isopropyl acetate, ethyl acetate, dichloromethane, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, acetone, and butanone. Further preferably, the organic solvent is isopropyl acetate.

[0009] Preferably, in the mixed solution of the organic solvent and water, the volume ratio of the organic solvent to water is 1:(1-10).

[0010] Preferably, the amount of the organic solvent used is 5-40 times the volume of ilaprazole sodium, more preferably 20-30 times the volume.

[0011] Preferably, the acid is selected from formic acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc., and acetic acid is preferred. The amount of the acid used is 0.9-2.0 equivalents, preferably 1.2-1.4 equivalents.

[0012] Preferably, ilaprazole polymorph B is added as a seed crystal, and the amount of the seed crystal used is 0.1%-10%, preferably 2%-5%.

[0013] Preferably, the eluent is selected from solvents such as n-heptane, n-hexane, isopropyl ether, methyl tert-butyl ether, acetone, water, etc., and methyl tert-butyl ether is preferred.

[0014] A preparation method of ilaprazole polymorph B includes the following steps: dissolving ilaprazole sodium salt in a mixed solution of an organic solvent and water, adding a certain amount of acid for liberation, then continuously adding a seed crystal for crystallization, and pulping the obtained solid with water and washing it with an eluent to obtain the target crystal ilaprazole polymorph B.

[0015] Compared with the prior art, the advantages of the present invention are as follows: the present invention uses a single solvent for crystallization, which has the advantages of low cost, does not require distillation, shortens the working hours and energy consumption, and simplifies the operation process; it avoids using dangerous solvent ethers and is easy to industrialize; it solves the problem that the residual solvent is easy to exceed the standard, and is beneficial to improving the purity and yield of the target product. Description of the Drawings

[0016] Figure 1 It is the XRD pattern of the product obtained in Example 1 of the present invention;

[0017] Figure 2 It is the DSC pattern of the product obtained in Example 1 of the present invention. Detailed Description of the Invention

[0018] The present invention will be further described in detail below with reference to the drawings and examples.

[0019] Example 1:

[0020] The preparation method of ilaprazole polymorph B in this example includes the following steps:

[0021] At room temperature, 10 g of ilaprazole sodium salt and 200 mL of isopropyl acetate / water (the volume ratio of isopropyl acetate to water is 8:2) were added to a reaction flask, and stirred until it became clear. 1.7 g of acetic acid was added and stirred. The organic layer was separated to remove the salt. Ilaprazole polymorph B was added to the mother liquor as a seed crystal (the addition amount was 3%), cooled and aged, and then filtered to obtain a wet crude product. The wet crude product was slurried with water, washed with n-heptane, and dried under vacuum to obtain 6.7 g of ilaprazole finished product, with a molar yield of 77% and an HPLC purity > 99.0%.

[0022] The DSC pattern of the obtained product is as Figure 2 shown.

[0023] The X-ray powder diffraction pattern of the sample was measured using a Bruker D8 Advance diffractometer, as Figure 1 characterized as follows.

[0024] It is consistent with polymorph B disclosed in Patent WO2008083333A.

[0025] 2θ diffraction angle Relative intensity / % 6.8 67 6.9 100 9.1 9 11.8 6 12.1 5 12.6 26 14.8 9 15.8 44 18.1 21 19.4 13 20.2 12 20.7 6 21.2 34 22.0 29 22.7 10 23.2 11 23.6 30 24.1 26 24.4 14 25.5 34

[0026] Example 2:

[0027] The preparation method of ilaprazole polymorph B in this example includes the following steps:

[0028] At room temperature, 10 g of ilaprazole sodium salt and 300 mL of ethyl acetate / water (the volume ratio of isopropyl acetate to water is 8:2) were added to a reaction flask, and stirred until it became clear. 1.9 g of acetic acid was added and stirred. Then ilaprazole polymorph B was added to the system as a seed crystal (the addition amount was 3%), cooled and aged, and then filtered to obtain a wet crude product. The wet crude product was slurried with water, washed with methyl tert-butyl ether, and dried under vacuum to obtain 6.6 g of ilaprazole finished product, with a molar yield of 76%.

Claims

1. A preparation method of ilaprazole polymorph B, characterized in that It includes the following steps: Dissolve ilaprazole sodium salt in an organic solvent or a mixed solution of an organic solvent and water, add a certain amount of acid for liberation, after separating out the salt, add seed crystals for crystallization, and the obtained solid is slurried with water and washed with a washing solution to obtain the target crystal, ilaprazole polymorph B.

2. The preparation method of ilaprazole polymorph B according to claim 1, characterized in that: The organic solvent selected from isopropyl acetate, ethyl acetate, dichloromethane, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone.

3. The preparation method of ilaprazole polymorph B according to claim 2, characterized in that: The organic solvent is isopropyl acetate.

4. The preparation method of ilaprazole polymorph B according to claim 1, characterized in that: In the mixed solution of the organic solvent and water, the volume ratio of the organic solvent to water is 1:(1 - 10).

5. The preparation method of ilaprazole polymorph B according to claim 4, characterized in that: The amount of the organic solvent used is 5 - 40 times the volume of the ilaprazole sodium used.

6. The preparation method of ilaprazole polymorph B according to claim 5, characterized in that: The amount of the organic solvent used is 20 - 30 times the volume of the ilaprazole sodium used.

7. The preparation method of ilaprazole polymorph B according to claim 1, characterized in that: The acid selected from formic acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, and the amount of the acid used is 0.9 - 2.0 equivalents.

8. The preparation method of ilaprazole polymorph B according to claim 1, wherein: Add ilaprazole polymorph B as seed crystals, and the amount of the seed crystals used is 0.1% - 10%.

9. The preparation method of ilaprazole polymorph B according to claim 1, wherein: The washing solution selected from n-heptane, n-hexane, isopropyl ether, methyl tert-butyl ether, acetone, water.

10. A preparation method of ilaprazole polymorph B, characterized in that It includes the following steps: Dissolve ilaprazole sodium salt in a mixed solution of an organic solvent and water, add a certain amount of acid for liberation, then continue to add seed crystals for crystallization, and the obtained solid is slurried with water and washed with a washing solution to obtain the target crystal, ilaprazole polymorph B.

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