A kind of purification method of Mizolastine

Abstract

The present invention belongs to the field of pharmaceutical technology, and in particular relates to a method for refining mizolastine, comprising the steps of: adding a crude mizolastine product to anhydrous ethanol at room temperature, stirring and refluxing the crude product to dissolve the crude product, cooling and crystallizing, growing crystals, washing the filter cake with anhydrous ethanol, centrifuging, and vacuum drying; adding the crude mizolastine product treated with anhydrous ethanol to tetrahydrofuran, stirring and refluxing, filtering while hot, washing the filter cake with tetrahydrofuran, vacuum drying the material, performing a tetrahydrofuran central control residual monitoring, obtaining a dry product, and setting aside; dissolving the above-mentioned dry product in anhydrous ethanol at a certain temperature, stirring and refluxing, cooling to crystallize, growing crystals, washing with anhydrous ethanol, centrifuging, and vacuum drying to obtain a finished mizolastine product. The invention has the beneficial effects of obtaining a fine product of mizolastine with a purity of more than 99.5%, a maximum single impurity of less than 0.1%, and a total impurity of less than 0.5%; effectively removing dimer impurities with a high content in currently available products, thereby improving product purity; and being suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, in particular to a method for refining mizolastine. Background Art

[0002] Mizolastine is a second-generation antihistamine that not only has a strong antihistamine effect but also inhibits other inflammatory mediators. For example, it inhibits the production of leukotrienes and reduces edema. Mizolastine possesses both antihistamine and anti-allergic effects, as well as anti-inflammatory activity, making it a preferred treatment for acute urticaria. Clinical studies have shown that it is significantly more effective than other antihistamines in treating acute urticaria.

[0003] The chemical name of Mizolastine is: 2-[[1-[1-(4-fluorobenzyl)-2-benzimidazolyl]-4-piperidinyl]methylamino]-4(3H)-pyrimidinone, and its molecular formula is C 24 H 25 FN6O, molecular weight is 432.50, and the structural formula is as follows:

[0004]

[0005] Since the effects of impurities on the human body are not carefully and thoroughly studied, the toxicity to the human body is also far from known, so controlling the quality of the medicine, i.e. improving the purity of the medicine and reducing the content of impurities, becomes a prerequisite for rational drug use. The synthetic method of the domestic mizolastine commercially available product is generally: piperidinamine and 2-methylmercapto-4-pyrimidone carry out melt reaction to obtain mizolastine. Prepare mizolastine as described above, there will be mizolastine dimer impurity in the product, and the structural formula is as follows. In the current commercially available product, this impurity content is all higher. How to reduce the dimer impurity content in mizolastine has not been reported.

[0006] Summary of the Invention

[0007] In order to solve the problems raised in the above background technology, the present invention provides a method for refining mizolastine.

[0008] To achieve the above object, the present invention provides the following technical solution: a method for refining mizolastine, comprising the following steps:

[0009] S1. Add crude mizolastine to anhydrous ethanol at room temperature, stir and reflux to dissolve the crude product, cool to crystallize, grow crystals, wash the filter cake with anhydrous ethanol, centrifuge, and vacuum dry;

[0010] S2. Add the crude mizolastine treated with anhydrous ethanol to tetrahydrofuran, stir and reflux, filter while hot, wash the filter cake with tetrahydrofuran, vacuum dry the material, perform tetrahydrofuran in-process residual monitoring, and obtain a dry product for standby use;

[0011] S3. Dissolve the dried product in anhydrous ethanol at a certain temperature, stir and reflux, cool to crystallize, grow the crystals, wash with anhydrous ethanol, centrifuge, and vacuum dry to obtain the finished product of mizolastine.

[0012] Preferably, the stirring and reflux time in S1, S2 and S3 is 2 hours.

[0013] Preferably, the temperature in S1 and S3 is lowered to 10°C to 30°C.

[0014] Preferably, the crystal growing temperature in S1 and S3 is 10-30° C., the crystal growing time is 2-3 hours, and the centrifugal speed is 800-1000 rpm.

[0015] Preferably, the weight ratio of the crude mizolastine to anhydrous ethanol in S1 is 1:3; and the weight of tetrahydrofuran in S2 is 2-3 times the weight of the crude mizolastine.

[0016] Preferably, the vacuum drying temperature in S1 is 60-65° C., and the vacuum drying time is 4 hours.

[0017] Preferably, the vacuum drying temperature in S2 is 60-80° C., and the vacuum drying time is 4 hours.

[0018] Preferably, the monitoring standard for the tetrahydrofuran residual in-process control performed in S2 is that the residual tetrahydrofuran solvent is less than 3.0%.

[0019] Preferably, the vacuum drying temperature in S3 is 75-80°C and the vacuum drying time is 6h.

[0020] Preferably, the vacuum drying in S3 is performed to a loss on drying of less than 0.5%.

[0021] The beneficial effects of the present invention are:

[0022] 1) The crude mizolastine product is purified by anhydrous ethanol-tetrahydrofuran-anhydrous ethanol, achieving an unexpectedly excellent impurity removal effect. The purity of the obtained refined mizolastine is above 99.5%, the maximum single impurity is less than 0.1%, and the total impurity is less than 0.5%.

[0023] 2) The tetrahydrofuran reflux beating treatment can effectively remove the dimer impurities with a high content in the currently available products, thereby improving product purity, reducing impurity content, and improving drug safety.

[0024] 3) Impurities are removed by solvent dissolution and crystallization. Compared with methods such as silica gel column, it is simple to operate, environmentally friendly, and suitable for large-scale industrial production.

[0025] 4) The method can effectively remove impurities from commercially available crude mizolastine or crude mizolastine prepared according to existing technology, and has universal applicability. DETAILED DESCRIPTION

[0026] The preferred embodiments of the present invention are described below. It should be understood by those skilled in the art that these embodiments are only used to explain the technical principles of the present invention and are not intended to limit the scope of protection of the present invention.

[0027] Example 1:

[0028] Transfer 132.6 g of the crushed crude mizolastine into a reaction flask, add 330 g of anhydrous ethanol, stir and reflux for 2 h, cool to 10°C-30°C, stir for 2 hours, filter, rinse with 97.5 g of anhydrous ethanol, filter and dry at a vacuum degree of ≤-0.09 MPa and a temperature of 60°C-65°C for 4 h to obtain a dry product.

[0029] The dried product was transferred to a reaction flask again, 300 g of tetrahydrofuran was added and refluxed for 2 h, hot filtered, the filter cake was rinsed with 60 g of tetrahydrofuran, filtered and dried under vacuum at a vacuum degree of ≤-0.09 MPa and 60°C to 80°C, and the residual solvent content of tetrahydrofuran was monitored.

[0030] The dried product was again added to 260 g of anhydrous ethanol, refluxed with stirring for 2 h, cooled to 10°C-30°C, filtered, washed once with 50 g of anhydrous ethanol, filtered, and vacuum dried at a vacuum degree of ≤-0.09 MPa and 75°C-80°C to a loss on drying of <0.5%, and pulverized to obtain the mizolastine product.

[0031] Table 1 Results of three batches of purified Mizolastine

[0032]

[0033] The purity of Mizolastine is above 99.5%, the maximum single impurity is less than 0.1%, and the total impurity is less than 0.5%.

[0034] Comparative Example 1:

[0035] Transfer 36.11 g of the crushed material into a reaction flask, add 113.6 g of anhydrous ethanol, stir and reflux for 2 h, cool to 10°C-30°C, stir for 2 hours, filter, rinse with 25.8 g of anhydrous ethanol, filter and dry at a vacuum degree of ≤-0.09 MPa and a temperature of 60°C-65°C for 4 h to obtain a dry product.

[0036] The dried product was added to 113.6 g of anhydrous ethanol again, refluxed with stirring for 2 h, cooled to 10°C-30°C, filtered, washed once with 50 g of anhydrous ethanol, filtered and dried, vacuum dried at 75°C-80°C with a vacuum degree of ≤-0.09 MPa to a loss on drying of <0.5%, and crushed to obtain the mizolastine product.

[0037] Comparison of the test results of the second batch of refined Mizolastine and the commercial product

[0038]

[0039] The 16.4-minute impurity content of mizolastine in the homemade samples and Beijing Jialin Pharmaceutical's raw materials was greater than 0.30%, and the 2-methylthio-4-pyrimidinone, piperidinamine and some unknown impurities were greater than 0.10%.

[0040] Example 2: Solvent Screening Experiment - Solvent Removal of Dimers

[0041] Changes in mizolastine dimer before and after treatment with various solvents

[0042]

[0043]

[0044] As can be seen from the above table, tetrahydrofuran can effectively reduce the content of dimer impurities.

[0045] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. A method for refining mizolastine, characterized in that: S1. Add crude mizolastine to anhydrous ethanol at room temperature, stir and reflux to dissolve the crude product, cool to crystallize, grow crystals, wash the filter cake with anhydrous ethanol, centrifuge, and vacuum dry; S2. Add the crude mizolastine treated with anhydrous ethanol to tetrahydrofuran, stir and reflux, filter while hot, wash the filter cake with tetrahydrofuran, vacuum dry the material, perform tetrahydrofuran in-process residual monitoring, and obtain a dry product for standby use; S3. Dissolve the dried product in anhydrous ethanol at a certain temperature, stir and reflux, cool to crystallize, grow the crystals, wash with anhydrous ethanol, centrifuge, and vacuum dry to obtain the finished product of mizolastine.

2. A method for refining mizolastine according to claim 1, characterized in that: The stirring and reflux time in S1, S2 and S3 is 2 hours.

3. A method for refining mizolastine according to claim 1, characterized in that: The temperature in S1 and S3 is lowered to 10°C to 30°C.

4. A method for refining mizolastine according to claim 1, characterized in that: The crystal growing temperature in S1 and S3 is 10-30° C., the crystal growing time is 2-3 hours, and the centrifugal speed is 800-1000 rpm.

5. A method for refining mizolastine according to claim 1, characterized in that: The weight ratio of the crude mizolastine to anhydrous ethanol in S1 is 1:3; the weight of tetrahydrofuran in S2 is 2-3 times the weight of the crude mizolastine.

6. A method for refining mizolastine according to claim 1, characterized in that: The vacuum drying temperature in S1 is 60-65° C., and the vacuum drying time is 4 hours.

7. A method for refining mizolastine according to claim 1, characterized in that: The vacuum drying temperature in S2 is 60-80° C., and the vacuum drying time is 4 hours.

8. A method for refining mizolastine according to claim 1, characterized in that: The monitoring standard for the residual tetrahydrofuran in the intermediate control performed in S2 is that the residual tetrahydrofuran solvent is less than 3.0%.

9. A method for refining mizolastine according to claim 1, characterized in that: The vacuum drying temperature in S3 is 75-80° C., and the vacuum drying time is 6 hours.

10. The method for refining mizolastine according to claim 1, wherein: The S3 is vacuum dried to a loss on drying of less than 0.5%.

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