Recrystallization method of dotenorad and application thereof

Abstract

The invention belongs to the technical field of chemical medicines, and discloses a recrystallization method of dotenorad (3-(3, 5-dichloro-4-hydroxybenzoyl)-1, 1-dioxo-2, 3-dihydro-1, 3-benzothiazole) and an application of the dotenorad (3-(3, 5-dichloro-4-hydroxybenzoyl)-1, 1-dioxo-2, 3-dihydro-1, 3-benzothiazole). According to the recrystallization method, the dotenorad type II crystal can be stably obtained, and the dotenorad type II crystal is uniform in particle size distribution, low in solvent residue, high in product purity and high in yield. Moreover, the method has the advantages of simple steps, small solvent dosage and low production cost, and is beneficial to industrial application.

Description

Technical Field

[0001] This invention relates to the field of chemical and pharmaceutical technology, specifically to a method for recrystallizing dotenoroxetine and its application. Background Technology

[0002] Dotinurad, chemically named 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, is a urate reabsorption inhibitor that targets and inhibits the activity of the urate reabsorption transporter (URAT1). Developed jointly by Fujiyama Pharmaceutical and Mochida Pharmaceutical in Japan, this drug is used to treat certain types of hyperuricemia and gout. It controls urate reabsorption and lowers blood uric acid levels by selectively inhibiting URAT1, the reabsorption pathway for uric acid in the kidneys.

[0003] Chinese patent CN102639518B discloses a method for preparing dotenoramide, including a step of crystallizing the synthesized product with ethanol. However, the amount of ethanol required to dissolve dotenoramide is large (e.g., approximately 160 times the volume of ethanol is needed to dissolve 1g of dotenoramide), and the yield of the precipitated product is low (approximately 60-70%). Chinese patent CN110914246B discloses the crystal form of dotenoramide and its crystallization method, wherein type II crystallization can be obtained, for example, by crystallization from an organic solvent. This method suffers from drawbacks such as large solvent consumption, low yield (approximately 50-60%), and significant solvent residue in the resulting API. Other crystallization methods disclosed in the prior art (such as CN118580197A and CN111662247A) also often suffer from problems such as large solvent consumption, low yield, and difficulty in impurity removal. Summary of the Invention

[0004] To overcome the shortcomings of the prior art, the present invention provides a method for recrystallizing dotenorphine and its application.

[0005] In a first aspect of the present invention, a method for recrystallizing 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (dotenorazole) is provided, comprising the following steps: adding crude 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole compound to a forward solvent, dissolving it, adding a reverse solvent, and then cooling to allow crystallization.

[0006] Furthermore, the forward solvent is selected from one or more of acetone, tetrahydrofuran, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

[0007] In some embodiments of the present invention, the forward solvent is acetone; further, the ratio of the crude compound to the forward solvent is 1g:10-30ml (e.g., 1g:10ml, 1g:11ml, 1g:12ml, 1g:13ml, 1g:14ml, 1g:15ml, 1g:16ml, 1g:18ml, 1g:20ml, 1g:22ml, 1g:24ml, 1g:25ml, 1g:30ml), particularly 1g:10-20ml, 1g:10-12ml, 1g:15-20ml.

[0008] In some embodiments of the present invention, the forward solvent is tetrahydrofuran; further, the ratio of the crude compound to the forward solvent is 1g:3-10ml (e.g., 1g:3ml, 1g:3.5ml, 1g:4ml, 1g:4.5ml, 1g:5ml, 1g:5.5ml, 1g:6ml, 1g:7ml, 1g:8ml, 1g:9ml, 1g:10ml), particularly 1g:3-6ml.

[0009] In some embodiments of the present invention, the forward solvent is DMF; further, the ratio of the crude compound to the forward solvent is 1g:1-6ml (e.g., 1g:1ml, 1g:2ml, 1g:2.5ml, 1g:3ml, 1g:3.5ml, 1g:4ml, 1g:4.5ml, 1g:5ml, 1g:5.5ml, 1g:6ml).

[0010] In some embodiments of the present invention, the forward solvent is DMSO; further, the ratio of the crude compound to the forward solvent is 1g:1-6ml (e.g., 1g:1ml, 1g:2ml, 1g:2.5ml, 1g:3ml, 1g:3.5ml, 1g:4ml, 1g:4.5ml, 1g:5ml, 1g:5.5ml, 1g:6ml).

[0011] Furthermore, the reverse solvent is water, such as purified water.

[0012] Furthermore, the ratio of the crude compound to the reverse solvent is 1g:10-100ml (e.g., 1g:10ml, 1g:15ml, 1g:20ml, 1g:25ml, 1g:30ml, 1g:35ml, 1g:40ml, 1g:45ml, 1g:50ml, 1g:55ml, 1g:60ml, 1g:65ml, 1g:70ml, 1g:75ml, 1g:80ml, 1g:85ml, 1g:90ml, 1g:95ml, 1g:100ml), particularly 1g:20-50ml.

[0013] Further, the reverse solvent is added dropwise. Even further, the dropwise addition time is 0.5-2 hours (e.g., 30, 40, 50, 60, 70, 80, 90, 100, 110, 120 minutes), particularly 1-1.5 hours. For the method described in this invention, the dropwise addition time of the reverse solvent affects the particle size of the resulting product; the longer the dropwise addition time (the slower the dropwise rate), the larger the particle size of the resulting product. The particle size of the resulting product can be adjusted by controlling the dropwise addition time of the reverse solvent. Even further, the temperature at which the reverse solvent is added is 15-60°C (e.g., 15, 20, 25, 30, 35, 40, 42, 44, 45, 46, 48, 50, 52, 54, 55, 56, 58, 60°C), particularly 25-60°C, 40-60°C, 50-60°C, 50-54°C, 56-60°C.

[0014] Furthermore, the dissolution temperature of the dotenoroxetine is 20-60°C (e.g., 20, 25, 30, 35, 40, 42, 44, 45, 46, 48, 50, 52, 54, 55, 56, 58, 60°C), particularly 25-60°C, 40-60°C, 50-60°C, 50-54°C, 56-60°C.

[0015] Furthermore, the cooling is to reduce the temperature to 5-30°C (e.g., 25°C), for example, by natural cooling at room temperature or by reducing the temperature from room temperature to 5-10°C.

[0016] Furthermore, the dissolution and / or addition of the reverse solvent step is carried out under stirring; even further, the stirring rate is 100 rpm to 300 rpm (e.g., 100, 150, 200, 250, 300 rpm).

[0017] In some embodiments of the present invention, the method includes the following steps: (1) Add the crude product of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole compound to the forward solvent, dissolve, and filter; (2) Add the reverse solvent dropwise while stirring; (3) Cooling down, crystallization; Further, the forward solvent is acetone; or, the forward solvent is selected from one of tetrahydrofuran, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

[0018] In some embodiments of the present invention, the method includes the following steps: adding crude compound to acetone, heating to dissolve, then adding water dropwise, cooling, and crystallizing.

[0019] In some embodiments of the present invention, the method includes the following steps: adding crude compound to acetone, heating to 55°C to dissolve, filtering, then adding water dropwise at a speed of 250 rpm, and cooling to room temperature after the addition is complete; wherein the ratio of crude compound to acetone is 6g:78ml, and the ratio of crude compound to water is 6g:200ml.

[0020] In some other embodiments of the present invention, the method includes the following steps: adding crude compound to acetone, heating to 55°C to dissolve, filtering, then adding water dropwise at a speed of 200 rpm, and cooling to room temperature after the addition is complete; wherein the ratio of crude compound to acetone is 6g:78ml, and the ratio of crude compound to water is 6g:120ml.

[0021] Furthermore, the method may also include a post-processing step, such as separating and collecting crystals (by filtration); even further, the post-processing may include drying the collected crystals.

[0022] Furthermore, the crude 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole compound used in the recrystallization method of the present invention can be prepared using methods known in the prior art, such as those described in Example 1 of CN102639518B. Even further, the purity of the crude compound can be above 95% (e.g., 96%, 96.5%, 97%, 97.5%, 98%). The recrystallization method of the present invention does not require that the crude compound used be crystalline.

[0023] Furthermore, the crude 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole compound used in the recrystallization method of the present invention is prepared by demethoxylating 3-(3,5-dichloro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole.

[0024] In some embodiments of the present invention, the crude 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole compound used in the recrystallization method of the present invention is prepared by the synthetic route shown below. .

[0025] In a second aspect of the present invention, a 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole active pharmaceutical ingredient is provided, which is prepared by the method described in the first aspect of the present invention.

[0026] Furthermore, the particle size D90 of the active pharmaceutical ingredient is 200-300 μm (e.g., 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300 μm).

[0027] Furthermore, the particle size D50 of the active pharmaceutical ingredient is 100-200 μm (e.g., 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 μm).

[0028] Furthermore, the particle size D10 of the active pharmaceutical ingredient is 5-100 μm (e.g., 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 μm), particularly 5-60 μm.

[0029] Furthermore, the purity of the active pharmaceutical ingredient is above 99.9% (e.g., 99.90%, 99.91%, 99.92%, 99.93%, 99.94%, 99.95%, 99.96%, 99.97%, 99.98%, 99.99%).

[0030] Furthermore, the residual solvent of the active pharmaceutical ingredient is less than 0.1% (e.g., less than 0.09%, less than 0.08%, less than 0.07%, less than 0.06%, less than 0.05%, less than 0.04%, less than 0.03%, less than 0.02%, less than 0.01%).

[0031] In a third aspect of the invention, a pharmaceutical composition is provided comprising the 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole active pharmaceutical ingredient as described in the second aspect, and one or more pharmaceutically acceptable excipients.

[0032] Furthermore, the excipient may be selected from one or more of the following: fillers, binders, disintegrants, lubricants, and flow aids.

[0033] Furthermore, the pharmaceutical composition can be administered via any suitable route of administration, such as gastrointestinal (e.g., oral, sublingual, rectal) or non-gastrointestinal (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory, etc.). In some embodiments of the invention, the pharmaceutical composition is an oral formulation, such as tablets, capsules, granules, etc.

[0034] In a fourth aspect of the invention, the use of the 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole active pharmaceutical ingredient as described in the second aspect is provided in the preparation of a pharmaceutical composition, including pulverizing the active pharmaceutical ingredient.

[0035] Furthermore, the pharmaceutical composition is used to promote uric acid excretion, for example for the prevention and / or treatment of hyperuricemia, gout, urinary tract stones, obesity, hyperlipidemia, dyslipidemia, impaired glucose tolerance, diabetes, metabolic syndrome, kidney disease, cardiovascular disease, etc., especially the prevention and / or treatment of hyperuricemia and gout.

[0036] Furthermore, the use further includes the steps of granulating and sieving the pulverized active pharmaceutical ingredient; even further, the use further includes the step of mixing the granulated and sieved active pharmaceutical ingredient with one or more pharmaceutically acceptable excipients (as described in the third aspect of the invention).

[0037] The recrystallization method provided by this invention can stably obtain dotenoroxetine type II crystals with uniform particle size distribution, low solvent residue, high product purity, and high yield. The method has simple steps, low solvent consumption, and low production cost, which is conducive to industrial application. Attached Figure Description

[0038] Figure 1 The image shows the HPLC chromatogram of crude dotenorazole.

[0039] Figure 2 The image shown is the XRPD spectrum of crude dotenoroxetine.

[0040] Figure 3 The figure shown is the HPLC chromatogram of the product obtained in Example 1.

[0041] Figure 4 The image shown is the XRPD spectrum of the product obtained in Example 1.

[0042] Figure 5 The figure shows the HPLC spectrum of the product obtained in Example 3.

[0043] Figure 6 The image shown is the XRPD spectrum of the product obtained in Example 3.

[0044] Figure 7 The figure shows the HPLC chromatogram of the product obtained in Example 5.

[0045] Figure 8 The figure shows the HPLC chromatogram of the product obtained in Example 6.

[0046] Figure 9 The figure shows the HPLC spectrum of the product obtained in Comparative Example 2.

[0047] Figure 10 The HPLC chromatogram of the product obtained in Comparative Example 3 is shown. Detailed Implementation

[0048] Unless otherwise defined, all scientific and technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0049] In this invention, the term "active pharmaceutical ingredient" refers to the active pharmaceutical ingredient used in the production of various formulations. It is the active ingredient (also known as the active component) in the formulation, prepared by chemical synthesis or biotechnology, and is a substance used as a medicine in the form of powder, crystals, etc., but which cannot be directly taken by the subject.

[0050] In this invention, the term "particle size D90" refers to the particle size corresponding to a sample when the cumulative particle size distribution number reaches 90%; the term "particle size D50" refers to the particle size corresponding to a sample when the cumulative particle size distribution number reaches 50%; and the term "particle size D10" refers to the particle size corresponding to a sample when the cumulative particle size distribution number reaches 10%.

[0051] All publications, patents, and published patent specifications cited in this article are incorporated herein in their entirety through citation.

[0052] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0053] [Purity and Related Substances Testing Methods] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0512).

[0054] Accurately weigh an appropriate amount of this product, dissolve it in acetonitrile, and quantitatively dilute it to prepare a solution containing approximately 0.2 mg of dotenorpra per ml. Chromatographic conditions: use octadecylsilane-bonded silica gel as the packing material (3.0 mm * 150 mm, 2.7 μm column); use 0.1% phosphoric acid aqueous solution as mobile phase A and acetonitrile as mobile phase B; flow rate: 0.6 ml / min; column temperature: 30 °C; detection wavelength: 210 nm; injection volume: 5 μl; gradient elution detection; record the HPLC chromatogram.

[0055] [Residual Solvent Detection Method] Residual solvent: determined by gas chromatography (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0861).

[0056] Test solution: Weigh approximately 0.2 g of this product accurately, place it in a headspace vial, add 2 ml of solvent (N-methylpyrrolidone) precisely to dissolve it, and seal.

[0057] Reference solution: Accurately weigh an appropriate amount of the solvent to be tested, and quantitatively dilute it with the solvent (N-methylpyrrolidone) to prepare a solution containing approximately 500 μg of the solvent to be tested per 1 ml. Accurately measure 2 ml of the solution, place it in an empty bottle, and seal it.

[0058] Chromatographic conditions: A capillary column with 6% cyanopropylphenyl and 94% polydimethylsiloxane as stationary phase was used; the initial temperature was 40℃, maintained for 5 minutes, and then increased to 200℃ at a rate of 25℃ per minute, maintained for 5 minutes; the detector temperature was 250℃; the injection port temperature was 220℃; the headspace vial equilibration temperature was 100℃, and the equilibration time was 30 minutes; the split ratio was 10; and the carrier gas flow rate was 2 ml / min.

[0059] [Particle Size Detection Method] The particle size distribution of the materials prepared in the embodiments and comparative examples of this invention was determined using a Mastersizer 3000 laser particle size analyzer (Malvern Panalytical, UK). Specifically, approximately 150 mg of the material prepared in the embodiments or comparative examples of this invention (such as the off-white solid product obtained in Example 1) was taken, 1 ml of 0.5% sodium dodecyl sulfate was added to wet the sample, followed by 4 ml of water. After sonication for 5 minutes, the sample was added to the sample dispersion unit until the opacity was 8-20% before measurement. The stirring speed in the dispersion chamber was 2500 rpm for 10 seconds.

[0060] [Crystal Form Detection] The crystal form of the active pharmaceutical ingredient in this embodiment of the invention was determined using an X-ray powder diffractometer (Ultimal V). Specifically, a copper target was used in the X-ray tube, with a step size of 2θ = 0.01°, a voltage of 40 kV, a current of 40 mA, a scanning range angle of 8.0~40°, a scanning rate of 10° / min, and a rotating sample disk with slits of DHL: 10 mm, DS: 1 degree, SS: 8 mm, RS: open, and a rotation speed of 30 rpm. The sample to be tested was placed in the central area of ​​the sample holder groove, compacted with a glass plate, and then measured.

[0061] Preparation of crude dotenorazole used in the following examples: Dotenoxetine crude product was prepared according to the method described in Example 1 of CN 102639518B. The purity of the crude product was 98.18%, and the organic solvent residue was 0.2%. The HPLC chromatogram is shown below. Figure 1 As shown, the XRPD spectrum is as follows: Figure 2 As shown.

[0062] Example 1 Take 6g of crude dotenorazole and add it to 78ml of acetone. Heat to 55℃ to dissolve, filter, and then add 300ml of purified water dropwise at 250 rpm for 1 hour. After the addition is complete, cool to room temperature to obtain an off-white solid (its HPLC chromatogram is shown below). Figure 3 As shown, the XRPD spectrum is as follows: Figure 4 (As shown).

[0063] The crystal form, particle size distribution, purity, and solvent residue of the obtained off-white solid product were analyzed, and the results are as follows: Crystal form: Type II crystals; Particle size distribution: D10: 9.17 μm, D50: 130 μm, D90: 277 μm; Purity: 99.95%, Acetone Residue: 0.051%, Yield: 96.5%.

[0064] Example 2 Take 6g of crude dotenorazole and add it to 72ml of acetone. Heat the solution to 55℃ and filter. Then add 120ml of purified water dropwise at 250 rpm for 1.5 hours. After the addition is complete, cool the solution to room temperature to obtain an off-white solid.

[0065] The crystal form, particle size distribution, purity, and solvent residue of the obtained off-white solid product were analyzed, and the results are as follows: Crystal form: Type II crystals; Particle size distribution: D10: 30.1 μm, D50: 125 μm, D90: 296 μm; Purity: 99.96%, Acetone residue: 0.032%, Yield: 95.6%.

[0066] Example 3 Take 6g of crude dotenorazole and add it to 27ml of tetrahydrofuran. Heat to 35℃ to dissolve, filter, and then add 180ml of purified water dropwise at 150 rpm for 1 hour. After the addition is complete, cool to room temperature to obtain an off-white solid (its HPLC chromatogram is shown below). Figure 5 As shown, the XRPD spectrum is as follows: Figure 6 (As shown).

[0067] The crystal form, particle size distribution, purity, and solvent residue of the obtained off-white solid product were analyzed, and the results are as follows: Crystal form: Type II crystals; Particle size distribution: D10: 38.8 μm, D50: 125 μm, D90: 279 μm; Purity: 99.75%, THF residue: 0.013%, yield: 94.3%.

[0068] Example 4 Take 6g of crude dotenorazole and add it to 27ml of tetrahydrofuran. Heat to 55℃ to dissolve, filter, and then add 210ml of purified water dropwise over 1 hour at a speed of 250 rpm. After the addition is complete, cool to room temperature to obtain an off-white solid.

[0069] The crystal form, particle size distribution, purity, and solvent residue of the obtained off-white solid product were analyzed, and the results are as follows: Crystal form: Type II crystals; Particle size distribution: D10: 52.6 μm, D50: 130 μm, D90: 253 μm; Purity: 99.92%, THF residue: 0.009%, yield: 96.1%.

[0070] Example 5 Take 6g of crude dotenorazole and add it to 12ml of N,N-dimethylformamide. Stir to dissolve, then add 300ml of purified water dropwise at room temperature (20-25℃) at a speed of 250 rpm for 0.5 hours. After the addition is complete, cool to 5-10℃, filter, and dry to obtain an off-white solid (HPLC chromatogram as shown). Figure 7 (As shown).

[0071] The crystal form, particle size distribution, purity, and solvent residue of the obtained off-white solid product were analyzed, and the results are as follows: Crystal form: Type II crystals; Particle size distribution: D10: 37.1 μm, D50: 118 μm, D90: 238 μm; Purity: 99.92%, DMF residue: 0.013%, yield: 93.5%.

[0072] Example 6 Dissolve 6g of crude dotenorazole in 12ml of DMSO by stirring. Add 300ml of purified water dropwise at room temperature (20-25℃) at a speed of 250 rpm for 1.5 hours. After the addition is complete, cool to 5-10℃, filter, and dry to obtain a white solid (HPLC chromatogram as shown). Figure 8 (As shown).

[0073] The crystal form, particle size distribution, purity, and solvent residue of the obtained off-white solid product were analyzed, and the results are as follows: Crystal form: Type II crystals; Particle size distribution: D10: 31.3 μm, D50: 122 μm, D90: 290 μm; Purity: 99.97%, DMSO residue: 0.09%, yield: 95.5%.

[0074] Comparative Example 1 Take 6g of crude dotenorazole and add it to 78ml of acetone. Heat to 55℃ to dissolve, filter, and then add 150ml of n-heptane dropwise at 200 rpm for 1 hour. Cool to room temperature, filter, and dry under vacuum at 60℃ to obtain an off-white solid.

[0075] The crystal form, particle size distribution, purity, and solvent residue of the obtained off-white solid product were analyzed, and the results are as follows: Crystal form: Type II crystals; Particle size distribution: D10: 64.2 μm, D50: 252 μm, D90: 475 μm; Purity: 98.85%, Acetone residue: 0.29%, n-Heptane residue: 0.21%, Yield: 81.6%.

[0076] Comparative Example 2 Take 6g of crude dotenorazole and add it to 27ml of tetrahydrofuran. Heat to 55℃ to dissolve, filter, then add 180ml of n-heptane dropwise at 200 rpm for 1 hour. Cool to room temperature, filter, and dry under vacuum at 60℃ to obtain an off-white solid (HPLC chromatogram as shown). Figure 9 (As shown).

[0077] The crystal form, particle size distribution, purity, and solvent residue of the obtained off-white solid product were analyzed, and the results are as follows: Crystal form: Type II crystals; Particle size distribution: D10: 58.0 μm, D50: 221 μm, D90: 424 μm; Purity: 98.91%, THF residue: 0.42%, n-heptane residue: 0.045%, yield: 82.3%.

[0078] Comparative Example 3 Take 6g of crude dotenorazole, add 120mL of ethyl acetate and heat to dissolve. Concentrate under reduced pressure until a large amount of solid precipitates out. Add 30mL of ethanol and slurry. Filter and dry under vacuum at 60℃.

[0079] The obtained product (HPLC chromatogram as shown) Figure 10 The crystal form, particle size distribution, purity, and solvent residue of the sample (as shown) were analyzed, and the results are as follows: Crystal form: Type II crystals; Particle size distribution: D10: 5.97 μm, D50: 83.1 μm, D90: 172 μm; Purity: 98.83%, Ethyl acetate residue: 0.27%, Ethanol residue: 0.15%, Yield: 83.5%.

[0080] That is, when crude dotenoroxetine is dissolved in ethyl acetate, a large amount of solvent is required, the residual solvent content in the product is high, and there are several impurities greater than 0.1%, resulting in a low yield.

[0081] Comparative Example 4 Take 6 g of crude dotenorazole, add 150 ml of 1,4-dioxane, stir, heat to 75°C to dissolve, keep warm at 55°C, slowly add 200 ml of water dropwise at 200 rpm, after the addition is complete, cool to room temperature and filter to obtain an off-white solid.

[0082] The crystal form, purity, and solvent residue of the obtained product were tested, and the results are as follows: Crystal form: Type II crystals; HPLC purity 99.15% (with 3 impurities exceeding 0.1%), 1,2-dioxane residue: 0.22%, yield 85.3%.

[0083] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

[0084] The foregoing embodiments and methods described in this invention may vary based on the capabilities, experience, and preferences of those skilled in the art.

[0085] Listing the steps of the method in a certain order in this invention does not constitute any restriction on the order of the method steps.

Claims

1. A method for recrystallizing 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, comprising the following steps: adding crude 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole compound to a forward solvent, dissolving it, adding a reverse solvent, then cooling, and crystallizing. Preferably, the forward solvent is selected from one or more of acetone, tetrahydrofuran, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

2. The recrystallization method as described in claim 1, characterized in that, The forward solvent is acetone, and the ratio of the crude compound to the forward solvent is 1g:10-30ml, preferably 1g:10-12ml or 1g:15-20ml.

3. The recrystallization method as described in claim 1, characterized in that, The forward solvent is tetrahydrofuran, and the ratio of the crude compound to the forward solvent is 1g:3-10ml; or, The forward solvent is DMF, and the ratio of the crude compound to the forward solvent is 1g:1-6ml; or, The forward solvent is DMSO, and the ratio of the crude compound to the forward solvent is 1g:1-6ml.

4. The recrystallization method as described in claim 1, characterized in that, The reverse solvent is water; Preferably, the ratio of the crude compound to the reverse solvent is 1g:10-100ml; Preferably, the reverse solvent is added dropwise; More preferably, the dripping time is 0.5-2 hours.

5. The recrystallization method as described in claim 1, characterized in that, The dissolution temperature of the dotenoroxetine is 20-60°C; and / or the cooling is to reduce the temperature to 5-30°C.

6. The recrystallization method as described in claim 1, characterized in that, The dissolution and / or addition of the reverse solvent step is carried out under stirring; Preferably, the stirring rate is 100 rpm to 300 rpm.

7. The recrystallization method according to any one of claims 1-6, characterized in that, The method includes the following steps: (1) Add the crude product of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole compound to a forward solvent, heat to 40-60℃, dissolve, and filter; (2) Add the reverse solvent dropwise while stirring; (3) Cool to room temperature to allow crystallization; Preferably, the method further includes the steps of separating and collecting the crystals; More preferably, the method further includes drying the collected crystals.

8. The recrystallization method as described in claim 1, characterized in that, The method includes the following steps: adding crude compound to acetone, heating to 55°C to dissolve, filtering, then adding water dropwise at a speed of 250 rpm, and cooling to room temperature after the addition is complete; wherein the ratio of crude compound to acetone is 6 g:78 ml, and the ratio of crude compound to water is 6 g:200 ml; or, The method includes the following steps: adding crude compound to acetone, heating to 55°C to dissolve, filtering, then adding water dropwise at a speed of 200 rpm, and cooling to room temperature after the addition is complete; wherein, the ratio of crude compound to acetone is 6g:78ml, and the ratio of crude compound to water is 6g:120ml.

9. A 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole active pharmaceutical ingredient, which is prepared by the method according to any one of claims 1-7; Preferably, the particle size D90 of the active pharmaceutical ingredient is 200-400 μm; Preferably, the particle size D50 of the active pharmaceutical ingredient is 100-200 μm; Preferably, the particle size D10 of the active pharmaceutical ingredient is 5-100 μm.

10. The use of the active pharmaceutical ingredient prepared by the recrystallization method according to any one of claims 1-6 in the preparation of a pharmaceutical composition, characterized in that, The active pharmaceutical ingredient prepared by the recrystallization method according to any one of claims 1-6 is subjected to pulverization.

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