A method for preparing toptipeptide

Abstract

The application belongs to the technical field of topiroxostat, and discloses a preparation method of topiroxostat, which comprises the following steps: compound IV is condensed with hydrazine hydrate to generate compound III, then the compound III is reacted with compound V to generate compound II, the compound II is cyclized to generate topiroxostat I crude product, the topiroxostat I crude product is salted with an organic sulfonic acid, then the salt is dissolved by potassium carbonate, a certain amount of metal ion complexing agent is added in the salt dissolution process to remove residual heavy metal ions, then the I crystal form topiroxostat is obtained through water beating and beating with a water-miscible solvent. The preparation method can effectively control a plurality of mutagenic warning structure impurities generated in the production process, can significantly reduce the generation of cyano hydrolysis impurities, improves the product quality, the production process is simple, the yield is high, the cost is low, and the method is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of Topiroxostat, and particularly relates to a preparation method of Topiroxostat for treating hyperuricemia and gout. BACKGROUND

[0002] Topiroxostat (FYX-051, I) is a new generation of anti-hyperuricemia and gout drug developed by Japan Fuji Pharmaceutical Co., Ltd. and Sanwa Chemical, which is a non-purine xanthine oxidase inhibitor, can inhibit xanthine oxidase in oxidized and reduced forms, inhibit the generation of uric acid, and is an anti-gout drug colchicine, non-steroidal anti-inflammatory drugs, etc. The product has the advantages of strong uric acid lowering effect, less adverse reactions, good safety, etc.

[0003] On June 23, 2013, Topiroxostat tablets were approved for marketing in Japan. Topiroxostat is chemically named 5-(2-cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole, and the structural formula is as follows:

[0004]

[0005] Topiroxostat is mainly prepared by the following two methods:

[0006] Method one (compound II is not isolated):

[0007]

[0008] In the preparation method disclosed in the patent CN1561340B applied by Japan Fuji Pharmaceutical Co., Ltd., the intermediate II after condensation of compound III and compound V is not isolated, and Topiroxostat is directly prepared by cyclization. The disadvantage of this method is that the risk of cyano hydrolysis is high, the risk of mutagenic warning structure impurities is high, and it is not conducive to the quality control of industrial production. The main impurities II, III, A, B, C, D, E, F and G are the main impurities affecting the quality of Topiroxostat, which need to be strictly controlled.

[0009] The main cyano hydrolysis impurity A is produced in the following way:

[0010]

[0011] The main mutagenic warning structure impurities II, III, B, C, D, E, F and G are introduced in the following way:

[0012]

[0013] Method two (compound II is isolated):

[0014] The filter cake of the isolated compound II is washed with acid in the preparation method disclosed by the patent CN105294656, which obviously reduces the content of the cyano hydrolysis impurity, has certain removal effect on the mutagenic impurities and derived impurities generated before the step, but further measures need to be taken to remove other mutagenic impurities generated in subsequent steps.

[0015]

[0016] There are mainly two ways for refining topiroxostat:

[0017] One is to use recrystallization, the patent CN104411700B uses organic solvents (including one or more combinations of various alcohols, amides, ethers, esters, alkanes and aromatic hydrocarbons) to recrystallize to prepare II crystal form topiroxostat, and the patent CN107778292 uses a mixed solvent of ethyl acetate and alcohol to recrystallize, which has good refining effect, but the obtained is II crystal form topiroxostat, which cannot directly obtain the medicinal I crystal form, and further crystal transformation is still needed.

[0018] The other is to use salt formation and salt decomposition, the patent CN104411700B uses topiroxostat p-toluenesulfonate, treats with alkali, and then neutralizes with acid. This method obtains medicinal I crystal form topiroxostat, and since alcohol solvents are inevitably used in the refining process, p-toluenesulfonate mutagenic impurities may be generated, and the post-treatment method only uses water to wash the filter cake, so the residual risk of mutagenic warning structure impurities is high, which is not conducive to impurity control. SUMMARY

[0019] PURPOSE

[0020] The present application provides a method which can effectively control multiple mutagenic impurities generated in the production process and significantly reduce the generation of cyano hydrolysis impurities, improve product quality, has a simple production process, high yield and is suitable for industrial production.

[0021] TECHNICAL SCHEME

[0022] In order to achieve the above-mentioned purposes of the present application, the present application adopts the following technical scheme:

[0023] A preparation method of topiroxostat, characterized by the following implementation steps:

[0024]

[0025] (1) Compound IV reacts with hydrazine hydrate in a solvent to generate compound III;

[0026] (2) Compound III reacts with compound V under the action of sodium methoxide to generate compound II;

[0027] (3) the cyclization reaction of compound II to obtain crude topiroxostat I;

[0028] (4) the purification of crude topiroxostat I to obtain finished topiroxostat.

[0029] In the step (1), the molar ratio of hydrazine hydrate to compound IV is 2:1-7:1; ethanol and compound IV are sequentially added into the reaction kettle under stirring, and the temperature is controlled at 20-30°C; 80% hydrazine hydrate is added dropwise; after the dropwise addition is completed, the reaction is stirred at 20-30°C for 1.5 h, the temperature is lowered to -10--5°C, and stirring is performed for 2 h; then, centrifugation, slurry washing, and ethanol washing are performed.

[0030] In the step (2), the molar ratio of compound III, compound V, and sodium methoxide is 1:1:0.05-1:1.2:0.1; methanol and compound V are sequentially added, sodium methoxide is slowly added under stirring and temperature control at 25-30°C, stirring is performed at 0-10°C for 3 h, and then compound III is added; the temperature is controlled at 0-10°C, and stirring is performed for 6 h; after the reaction is completed, a mixed solution of anhydrous methanol and purified water is added, the temperature is controlled at 20-30°C, and stirring is performed for 3 h followed by centrifugation.

[0031] In the step (3), methanol, purified water, and compound II are sequentially added into the reaction kettle under stirring, the temperature is raised to 85°C, and stirring is performed for 5 h; the temperature is lowered to 20-30°C, and stirring is performed for 3 h; after drying by centrifugation, 10 kg of crude topiroxostat I is obtained.

[0032] In the step (4), the purification process includes the following steps:

[0033] a. the crude topiroxostat I is salted with an organic sulfonic acid in a solvent at a certain temperature;

[0034] b. the organic sulfonic acid salt of topiroxostat is desalted with potassium carbonate in a solvent at a certain temperature, and a certain amount of a metal ion complexing agent is added during the desalting process;

[0035] c. the filter cake after desalting is washed with water and a water-miscible solvent, and the filter cake is dried at a certain temperature to obtain I crystal topiroxostat (compound I).

[0036] In the step (4), the purification process includes the following steps:

[0037] In the step a, the reaction solvent is water and isopropyl alcohol or 2-butanol, and the organic sulfonic acid includes but is not limited to naphthalenesulfonic acid and camphorsulfonic acid. The molar ratio of the organic sulfonic acid to the crude topiroxostat I is 1:1-3:1, and preferably 2:1; the reaction temperature is 40-80°C.

[0038] In step b, the reaction solvent is ethanol and water, the metal ion complexing agent is EDTA-2Na, the molar ratio of EDTA-2Na to topropisterit organic sulfonate is 0.0005:1-0.005:1, preferably 0.001:1-0.002:1; the reaction temperature is 20-40°C, preferably 25-30°C.

[0039] In step c, the water-miscible solvent is isopropyl alcohol; the drying temperature is 70-90°C, preferably 75-80°C; the drying time is 10-50 hours, preferably 15-25 hours.

[0040] The refined topropisterit crystal is in crystal form I, the single impurity of mutagenic warning structure impurity is not more than 9ppm, other general single impurity is not more than 0.10%, and the purity is not less than 99.8%.

[0041] Beneficial effects

[0042] The preparation method of the application has the following advantages compared with the prior art:

[0043] 1. The process control efficiency of impurities is improved by isolating compound II;

[0044] 2. In the refining process, the salt of topropisterit and large-structure naphthalenesulfonic acid and camphorsulfonic acid is selected, and the large-structure naphthalenesulfonic acid and camphorsulfonic acid are more difficult to react with large-structure isopropyl alcohol or 2-butanol to generate mutagenic sulfonate impurities, so that the introduction of sulfonate impurities can be effectively avoided;

[0045] 3. By adding EDTA-2Na to complex residual metal ions, the risk of heavy metal exceeding the limit can be avoided, and the generation of cyanogen hydrolysis impurities caused by metal ion catalysis can also be avoided;

[0046] 4. After desalination, topropisterit is beaten with water and isopropyl alcohol respectively, water can remove residual inorganic salt impurities, the use of isopropyl alcohol can improve the refining effect of mutagenic warning structure impurities, improve the drying efficiency, significantly reduce the drying time, further reduce the risk of cyanogen hydrolysis, and at the same time, the obtained product does not undergo crystal transformation and is still a pharmaceutical I crystal;

[0047] 5. The entire process of the application can effectively control multiple mutagenic warning structure impurities and cyanogen hydrolysis impurities generated in the production process, improve the product quality, the production process is simple, the yield is high, the cost is low, and it is suitable for industrial production.

[0048]

[0049] 5. The entire process of the application can effectively control multiple mutagenic warning structure impurities and cyanogen hydrolysis impurities generated in the production process, improve the product quality, the production process is simple, the yield is high, the cost is low, and it is suitable for industrial production.

[0050] BRIEF DESCRIPTION OF DRAWINGS

[0051] ​​Figure 1 XRD pattern of topropistat of Example 1;

[0052] Figure 2 HPLC pattern of topropistat of Example 1;

[0053] Figure 3 HPLC pattern of topropistat of Example 3. DETAILED DESCRIPTION

[0054] The following detailed description of the embodiments of the present application is made on the premise of the technical solution of the present application, and detailed implementation modes and specific operation processes are given, but the protection scope of the present application is not limited to the following embodiments.

[0055] Example 1

[0056] Preparation of compound III:

[0057]

[0058] Into a reaction kettle, 13 kg (80.2 mol) of compound IV was added under stirring, and 80% hydrazine hydrate 12.4 kg (308.4 mol) was added dropwise under temperature control of 20-30 °C; after the dropping, the reaction was stirred at 20-30 °C for 1.5 h, and then cooled to -10 to -5 °C and stirred for 2 h. After centrifugation, the slurry was washed with ethanol and dried to obtain 8.01 kg (49.4 mol) of yellow powder of compound III, with a yield of 61.6%.

[0059] Preparation of compound II:

[0060]

[0061] Into a reaction kettle, methanol and 5.4 kg (52.3 mol) of compound V were added under stirring, and sodium methoxide was slowly added under temperature control of 25-30 °C. After stirring for 3 h at 0-10 °C, 8 kg (49.3 mol) of compound III was added. After temperature control at 0-10 °C, the reaction was stirred for 6 h. After the reaction, a mixed solution of anhydrous methanol 2 and purified water 1 was added, and the reaction was stirred for 3 h at 20-30 °C. After centrifugation, the filter cake was washed with purified water and dried to obtain 11.9 kg of compound II, with a yield of 90.3%.

[0062] Preparation of crude compound I:

[0063]

[0064] Into a reaction kettle, methanol, purified water and 11.5 kg (41.2 mol) of compound II were added successively under stirring, the temperature was raised to 85°C and stirred for 5 h, the temperature was lowered to 20-30°C and stirred for 3 h, centrifuged, the filter cake was washed with purified water and dried to obtain 10 kg of crude topiroxostat I with a yield of 93.7%.

[0065] Preparation of topiroxostat I:

[0066] Into a reaction kettle, isopropanol, purified water, 10 kg (40.3 mol) of crude topiroxostat I and 10.1 kg (48.3 mol) of naphthalenesulfonic acid were added successively under stirring, refluxed, stirred for 0.5 h, slowly lowered to 20-30°C, stirred for 3 h, centrifuged, slurried with isopropanol and water, centrifuged and dried to obtain 16.1 kg (35.3 mol) of topiroxostat naphthalenesulfonate salt with a yield of 87.6%.

[0067] Into a reaction kettle, ethanol, purified water, 11.5 kg (83.3 mol) of anhydrous potassium carbonate were added successively under stirring, the temperature was controlled at 20-30°C to dissolve, 16 kg (33.3 mol) of topiroxostat naphthalenesulfonate salt was added, stirred to dissolve, 112 g (0.333 mol) of EDTA-2Na and activated carbon slurry were added, stirred for 0.5 h to decolorize, pressure filtered, the temperature was controlled at 20-30°C, 6M hydrochloric acid was added quickly into the filtrate to adjust the pH value to 6.5-7.0, continued to stir for 5 h, centrifuged, the filter cake was slurried with purified water, the filter cake was slurried with isopropanol, dried at 75-80°C to obtain 7.8 kg (31.4 mol) of topiroxostat I in Form I with a yield of 94.4%. The XRD spectrum is shown in Figure 1 , the obtained product is topiroxostat in Form I; the HPLC spectrum is shown in Figure 2 , the purity of topiroxostat is 99.97%, and impurity A is not detected. All mutagenic impurities are not detected.

[0068] Example 2

[0069] Preparation of topiroxostat I:

[0070] Into a reaction kettle, 2-butanol, purified water, 100 g (0.403 mol) of crude topiroxostat I and 102.2 g (0.44 mol) of camphorsulfonic acid were added successively under stirring, the temperature was raised to 80°C and stirred for 1 h, the temperature was slowly lowered to 25-30°C and stirred for 3 h, centrifuged, the filter cake was slurried with 2-butanol and water, centrifuged and dried at 80°C to obtain 159 g (0.331 mol) of topiroxostat camphorsulfonate salt with a yield of 82.1%.

[0071] Into a reaction kettle, 2-butanol, purified water, 114 g (0.828 mol) of anhydrous potassium carbonate were added successively under stirring, and the temperature was controlled at 20-30°C to dissolve the clear solution. Then, 159 g (0.331 mol) of topropisate camphorsulfonate was added and stirred to dissolve the clear solution. Then, 1.1 g (0.0033 mol) of EDTA-2Na and activated carbon paste were added, and the mixture was stirred for 0.5 h to decolorize. Then, the mixture was filtered under pressure. The temperature was controlled at 20-30°C, and 6M hydrochloric acid was added to the filtrate to adjust the pH to 6.5-7.0. The mixture was continuously stirred for 5 h, and then centrifuged. The filter cake was slurried with purified water and then with isopropyl alcohol. After drying at 80°C, 76.7 g (0.309 mol) of topropisate I in crystal form was obtained, with a yield of 93.3%. No mutagenic impurities were detected.

[0072] Example 3

[0073] The inventor repeated the comparative example of the process of patent CN104411700 as follows:

[0074] Preparation of compound III:

[0075] 10 g (0.062 mol) of compound IV was added with methanol, and then 2.7 g (0.068 mol) of 80% hydrazine hydrate was added. The mixture was stirred at room temperature under nitrogen atmosphere for 2 h, and then the solvent was removed by evaporation under reduced pressure. Chloroform was added, and the mixture was stirred at room temperature for 1 h. After filtration, the filter cake was washed with chloroform and then dried under vacuum to obtain 4.17 g (0.026 mol) of compound III, with a yield of 41.7%.

[0076] Preparation of compound I crude product:

[0077] 2.77 g (0.027 mol) of compound V was dissolved in methanol, and then 0.86 g (0.016 mol) of sodium methoxide was added. The mixture was stirred at room temperature for 1 h, and then 4 g (0.025 mol) of compound III was added. The mixture was refluxed for 40 h. After the reaction was completed, the mixture was filtered, and the filter cake was washed with methanol and then dried under vacuum to obtain 3.68 g (0.015 mol) of compound I crude product, with a yield of 60%.

[0078] The inventor repeated the comparative example of the process of patent CN104411700 as follows:

[0079] Preparation of topropisate I:

[0080] Into a reaction kettle, 2-butanol, purified water, 114 g (0.828 mol) of anhydrous potassium carbonate were added successively under stirring, and the temperature was controlled at 20-30°C to dissolve the clear solution. Then, 159 g (0.331 mol) of topropisate camphorsulfonate was added and stirred to dissolve the clear solution. Then, 1.1 g (0.0033 mol) of EDTA-2Na and activated carbon paste were added, and the mixture was stirred for 0.5 h to decolorize. Then, the mixture was filtered under pressure. The temperature was controlled at 20-30°C, and 6M hydrochloric acid was added to the filtrate to adjust the pH to 6.5-7.0. The mixture was continuously stirred for 5 h, and then centrifuged. The filter cake was slurried with purified water and then with isopropyl alcohol. After drying at 80°C, 76.7 g (0.309 mol) of topropisate I in crystal form was obtained, with a yield of 93.3%. No mutagenic impurities were detected.

[0081] Into a reaction kettle, 120 g (0.87 mol) of anhydrous potassium carbonate was added into ethanol and purified water under stirring, and the temperature was controlled at 20-30 °C. After the solution was clear, 145 g (0.345 mol) of topropisteril p-toluenesulfonate was added and stirred until the solution was clear. Activated carbon slurry was added, and the solution was decolorized for 0.5 h under stirring. Filtration was performed under the temperature control at 20-30 °C. 2.2 L of 6M hydrochloric acid was added into the filtrate, and stirring was continued for 5 h. Centrifugation was performed, and the filter cake was washed with purified water. After drying at 80 °C, 79.4 g (0.32 mol) of Form I topropisteril I was obtained, with a yield of 92.8%. The HPLC spectrum is shown in Figure 3 , the purity of topropisteril I was 99.769%, the impurity A was 0.071%, and the impurity II content was 0.059%.

Claims

1. A method for preparing topipusta, characterized in that, This includes the following steps: (1) Compound IV reacts with hydrazine hydrate in a solvent to form compound III; (2) Compound III reacts with compound V in the presence of sodium methoxide to form compound II; (3) Compound II underwent a cyclization reaction to give crude topiptostat I; (4) Topipasta I crude product is refined to obtain finished product topipasta; In step (4), the refining process includes the following steps: a. Topipusta I crude product forms a salt with an organic sulfonic acid in a solvent, wherein the organic sulfonic acid is naphthalene sulfonic acid or camphor sulfonic acid; b. Topisoprene organic sulfonate is desalted in a solvent using potassium carbonate, with a metal ion complexing agent added during the desalting process, wherein the metal ion complexing agent is EDTA-2Na; c. The filter cake after desalting is slurried with water and a water-miscible solvent, and then dried to obtain topipusta I. The water-miscible solvent is isopropanol. The refined topipsestat crystals are of crystal form I, with no more than 9 ppm of single mutagenic warning structures and no more than 0.10% of other general single impurities, and a purity of not less than 99.8%.

2. The method for preparing topipsestat according to claim 1, characterized in that... In step (1), the molar ratio of hydrazine hydrate to compound IV is 2:1 to 7:

1. Ethanol and compound IV are added sequentially to the reaction vessel under stirring, and the temperature is controlled at 20 to 30°C. 80% hydrazine hydrate is added dropwise. After the addition is complete, the mixture is stirred at 20 to 30°C for 1.5 hours, cooled to -10 to -5°C and stirred for 2 hours. The mixture is then centrifuged, slurried, and washed with ethanol.

3. The method for preparing topipsestat according to claim 1, characterized in that... In step (2), the molar ratio of compound III, compound V and sodium methoxide is 1:1:0.05 to 1:1.2:0.

1. Methanol and compound V are added sequentially, the temperature is controlled at 25 to 30°C, sodium methoxide is slowly added under stirring, the temperature is controlled at 0 to 10°C for 3 hours, then compound III is added; the temperature is controlled at 0 to 10°C and stirred for 6 hours. After the reaction is complete, anhydrous methanol and purified water mixed solution is added, the temperature is controlled at 20 to 30°C, the temperature is controlled at 3 hours and stirred for 3 hours, and then centrifuged.

4. The method for preparing topipsestat according to claim 1, characterized in that... In step (3), methanol, purified water and compound II are added sequentially to the reaction vessel under stirring. The temperature is raised to 85°C and stirred for 5 hours. The temperature is lowered to 20-30°C and stirred for 3 hours. After centrifugation and drying, 10 kg of crude topiptostat I is obtained.

5. The method for preparing topipsestat according to claim 1, characterized in that: In step a, the reaction solvent is water and isopropanol or 2-butanol; the molar ratio of organic sulfonic acid to crude topipsestat I is 1:1 to 3:1; and the reaction temperature is 40 to 80°C. In step b, the reaction solvents are ethanol and water, and the molar ratio of EDTA-2Na to topipseta organic sulfonate is 0.0005:1 to 0.005:1; the reaction temperature is 20 to 40°C. In step c, the drying temperature is 70–90°C, and the drying time is 10–50 hours.

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