Preparation method of high-purity dotenorad

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of high-purity dotenorad. The preparation method comprises the following steps: mixing a dotenorad crude product with a good solvent, heating, dissolving, filtering, adding a poor solvent into filtrate, cooling, crystallizing, carrying out solid-liquid separation, and drying to obtain the dotenorad crystal form compound. The preparation method of dotenorad provided by the invention can meet the refining requirements of dotenorad crude products from different sources. According to the method, the dotenomer crystal form II compound can be stably obtained, and the product is high in crystal form purity and low in impurity content.

Description

Technical Field

[0001] The invention relates to a method for preparing high-purity polytinorel, and belongs to the technical field of drug synthesis. Background Art

[0002] The chemical name of Dotinurad is (3,5-dichloro-4-hydroxyphenyl)(1,1-dioxidebenzothiazol-3(2H)-yl)methanone, and its chemical structure is as follows:

[0003]

[0004] Dotinorel is an oral tablet jointly developed by Fuji Yakuhin and Mochida Pharmaceutical of Japan for the treatment of hyperuricemia and gout. It is a urate transporter 1 (URAT1) inhibitor that mainly inhibits the function of URAT1, promotes the excretion of uric acid from the kidneys, and thus reduces blood uric acid levels.

[0005] Most of the polytinol refining methods disclosed in the prior art are single-solvent methods. For example, patent CN111793039A reports a method for refining polytinol using a single solvent, ethyl acetate. This method has the disadvantages of low product purity, unstable product crystal form, and large solvent demand. US2012184587A1 reports another method for refining polytinol using ethanol. Although this method can obtain a stable polytinol crystal form II compound, it still has the disadvantages of low product purity and large solvent demand.

[0006] Therefore, there is an urgent need to develop a refining process that is simple to operate and can stably obtain high-purity polytinol crystals. Summary of the Invention

[0007] In view of the above, the present invention provides a method for preparing high-purity polytinorel, which solves the problems of impurity residue and crystal form control, and improves product purity and process stability.

[0008] To achieve the above object, the technical solution of the present invention is:

[0009] A method for preparing high-purity polytinoride comprises the following steps:

[0010] (1) mixing the crude polytinol with a good solvent, heating to dissolve, and then filtering to obtain a filtrate;

[0011] (2) adding a poor solvent to the filtrate, stirring at 40-50° C. for 1-2 hours, then cooling to crystallize and performing solid-liquid separation to obtain a solid product;

[0012] (3) drying the solid product to obtain a polytinorel crystalline compound.

[0013] Preferably, the good solvent in step (1) is at least one of acetone, 2-butanone or tetrahydrofuran.

[0014] Further preferably, the mass volume ratio of the crude polytinoride to the good solvent in step (1) is 1:4 to 1:12 g / mL.

[0015] Preferably, the heating temperature in step (1) is 50°C.

[0016] Preferably, the poor solvent in step (2) is at least one of n-heptane, n-hexane or dichloromethane.

[0017] Further preferably, the volume ratio of the filtrate to the poor solvent in step (2) is 1:4 to 1:20.

[0018] Preferably, the cooling rate in step (2) is 0.5 to 1°C / min, and the end temperature is -10 to 10°C.

[0019] More preferably, the crystallization time in step (2) is 1 to 2 hours.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] (1) The polytinoride preparation method provided by the present invention can meet the refining requirements of polytinoride crude products from different sources.

[0022] (2) The method of the present invention can stably obtain polytinorel crystalline form II compound, and the product crystalline form has high purity and low impurity content. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the HPLC spectrum of the polytinol form II compound prepared in Example 1.

[0024] Figure 2 This is the XRD spectrum of the polytinol form II compound prepared in Example 1.

[0025] Figure 3 This is the HPLC spectrum of the polytinol form II compound prepared in Example 2.

[0026] Figure 4 This is the XRD spectrum of the polytinol form II compound prepared in Example 2. DETAILED DESCRIPTION

[0027] To make the purpose, technical solutions and advantages of the present invention more clear, the preferred embodiments of the present invention are further described in detail below with reference to the examples. Based on the examples in the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0028] The chromatogram and spectrogram used in the present invention are obtained by testing under the following conditions:

[0029] Chromatographic conditions: Phenylsilane bonded silica gel as the filler (Kromasil 100-5phenyl, 4.6 mm × 250 mm, 5 μm or equivalent performance column); phosphoric acid-water (1:1000) solution as mobile phase A, acetonitrile as mobile phase B, gradient elution according to the table below; flow rate, 1.0 ml / min; column temperature, 30°C; detection wavelength, 254 nm; injection volume, 10 μL.

[0030] Spectral conditions: Bruker-D8Advance X-ray powder diffractometer, Cukα radiation, detector LynxEye, radiation source condition 40kV / 25mA, scanning range 2-60°, step size 0.02° / s.

[0031] Example 1

[0032] A method for preparing high-purity polytinorel comprises the following steps:

[0033] Take 10.0g of crude polytinol, add 120mL of acetone, stir and dissolve at 50℃, and filter to obtain a filtrate; add 200mL of n-heptane dropwise at a constant speed to the filtrate at 50℃, and stir at this temperature for 1 hour; then cool to 5℃ at 0.5℃ / min, and crystallize at 5℃ for 2 hours; filter to obtain a solid product, and vacuum dry the solid product to obtain 8.3g of polytinol crystal form II compound, with a yield of 83.0% and a purity of 99.94%. The HPLC and XRD test patterns of the polytinol crystal form II compound are shown in Figure 2. Figure 1 、 Figure 2 .

[0034] Example 2

[0035] A method for preparing high-purity polytinorel comprises the following steps:

[0036] Take 13.0g of crude polytinol, add 130mL of acetone-2-butanone, stir and dissolve at 50℃, and filter to obtain a filtrate; add 221mL of n-hexane dropwise at a uniform rate to the filtrate at 40℃, and keep warm and stir for 1 hour; then cool to 5℃ at 0.5℃ / min, keep warm at 5℃ for 2 hours to crystallize; filter to obtain a solid product, and vacuum dry the solid product to obtain 10.9g of polytinol crystal form II compound, with a yield of 83.8% and a purity of 99.95%. The HPLC and XRD detection patterns of the polytinol crystal form II compound are shown in Figure 2. Figure 3 、 Figure 4 .

[0037] Example 3

[0038] A method for preparing high-purity polytinorel comprises the following steps:

[0039] 10.0 g of crude polytinol was added to 120 mL of acetone, stirred and dissolved at 50°C, and filtered to obtain a filtrate. 200 mL of n-heptane was added dropwise at a constant rate at 50°C, and the mixture was stirred at this temperature for 1 hour. The temperature was then lowered to 15°C at a rate of 0.5°C / min, and the mixture was kept at 15°C for 2 hours to allow crystallization. The solid product was filtered to obtain polytinol Form II, which was then vacuum dried. The yield of the polytinol Form II compound was calculated to be 76.0%, with a purity of 99.95%.

[0040] Example 4

[0041] A method for preparing high-purity polytinorel comprises the following steps:

[0042] 10.0 g of crude polytinol was added to 120 mL of acetone, stirred and dissolved at 50°C, and filtered to obtain a filtrate. 200 mL of n-heptane was added dropwise at a constant rate at 50°C, and the mixture was stirred at this temperature for 1 hour. The temperature was then lowered to 5°C at a rate of 1.5°C / min, and the mixture was kept at 5°C for 2 hours to allow crystallization. The solid product was filtered to obtain polytinol Form II, which was then vacuum dried. The yield of the polytinol Form II compound was calculated to be 83.0%, with a purity of 99.87%.

[0043] Comparative Example 1

[0044] According to the ethyl acetate recorded in CN111793039A as the solvent, the good solvent and the poor solvent of the present invention were replaced to carry out the reaction, specifically as follows:

[0045] 10.0 g of crude polytinol was added to 120 mL of ethyl acetate, stirred and dissolved at 50°C, and filtered to obtain a filtrate. 200 mL of ethyl acetate was added dropwise at a constant rate at 50°C, and the mixture was stirred at this temperature for 1 hour. The temperature was then lowered to 5°C at a rate of 1.5°C / min, and the mixture was kept at 5°C for 2 hours to allow crystallization. The solid product was filtered to obtain polytinol Form II, which was then vacuum dried. The yield of the polytinol Form II compound was calculated to be 56.0%, with a purity of 99.18%.

[0046] Comparative Example 2

[0047] According to the ethanol described in US2012184587A1 as the solvent, the good solvent and the poor solvent of the present invention were replaced to carry out the reaction, specifically as follows:

[0048] 10.0 g of crude polytinol was added to 120 mL of ethanol, stirred at 50°C for dissolution, and filtered to obtain a filtrate. 200 mL of ethanol was added dropwise at a constant rate at 50°C, and the mixture was stirred for 1 hour. The temperature was then lowered to 5°C at a rate of 1.5°C / min, and the mixture was kept at 5°C for crystallization for 2 hours. The solid product was filtered to obtain polytinol Form II, which was then vacuum dried. The yield of the polytinol Form II compound was calculated to be 64.5%, with a purity of 99.22%.

[0049] The embodiments described above are some, but not all, of the embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but rather merely represents selected embodiments of the present invention. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are also within the scope of protection of the present invention.

Claims

1. A method for preparing high-purity polytinoride, characterized in that: The following steps are involved: (1) mixing the crude polytinol with a good solvent, heating to dissolve, and then filtering to obtain a filtrate; (2) adding a poor solvent to the filtrate, stirring at 40-50° C. for 1-2 hours, then cooling to crystallize and performing solid-liquid separation to obtain a solid product; (3) drying the solid product to obtain a polytinorel crystalline compound.

2. The method for preparing high-purity polytinorel according to claim 1, characterized in that: The good solvent in step (1) is at least one of acetone, 2-butanone or tetrahydrofuran.

3. The method for preparing high-purity polytinoride according to claim 2, characterized in that: The mass volume ratio of the crude polytinoride to the good solvent in step (1) is 1:4 to 1:12 g / mL.

4. The method for preparing high-purity polytinoride according to claim 1, characterized in that: The heating temperature in step (1) is 50°C.

5. The method for preparing high-purity polytinoride according to claim 1, characterized in that: The poor solvent in step (2) is at least one of n-heptane, n-hexane or dichloromethane.

6. The method for preparing high-purity polytinoride according to claim 5, characterized in that: The volume ratio of the filtrate to the poor solvent in step (2) is 1:4 to 1:

20.

7. The method for preparing high-purity polytinoride according to claim 1, characterized in that: In step (2), the cooling rate is 0.5 to 1°C / min, and the terminal temperature is -10 to 10°C.

8. The method for preparing high-purity polytinoride according to claim 7, characterized in that: The crystallization time of step (2) is 1 to 2 hours.

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