Preparation method of Iguratimod

Abstract

The invention provides a preparation method of iguratimod, and belongs to the technical field of medicine synthesis. The preparation method comprises the following steps: firstly, preparing mixed anhydride from acetone, pivaloyl chloride and anhydrous sodium formate, then adding a compound 2 to react to obtain a compound 3, reacting with anhydrous aluminum trichloride and sodium iodide in an acetonitrile solvent, and adding a sodium sulfite aqueous solution to react to obtain a compound 4; the preparation method comprises the following steps: reacting iguratimod with N, N-dimethylformamide dimethyl acetal and triethylamine in a dichloromethane solvent to obtain an iguratimod crude product, and refining to obtain an iguratimod pure product. The preparation method is simple and efficient, and the prepared iguratimod is high in purity.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for preparing iguratimod. Background Art

[0002] Iguratimod is a new drug for the treatment of arthritis that not only selectively inhibits COX-2, but also regulates T-cells and has autoimmune regulatory effects. It has better efficacy and fewer side effects than existing therapies.

[0003] The prior art method for preparing iguratimod is complicated and the product purity is low. Summary of the invention

[0004] In view of this, the present invention provides a method for preparing iguratimod.

[0005] The preparation method of Iguratimod of the present invention, the reaction process is as shown in formula (I):

[0006]

[0007] The following steps are involved:

[0008] (1) Preparation of compound 3: Pivaloyl chloride and anhydrous sodium formate (HCOONa) were added to acetone, and the mixture was stirred under sealed conditions to generate a mixed anhydride. Compound 2 (a-amino-2-methoxy-4-methanesulfonylamino-5-phenoxyacetophenone hydrochloride) was then added to the mixed anhydride, and the mixture was stirred until the reaction was complete. Purified water was then added and stirred continuously. The obtained reaction solution was centrifuged, washed, and dried to obtain compound 3 (a-formylamino-2-methoxy-4-methanesulfonylamino-5-phenoxyacetophenone);

[0009] (2) Preparation of compound 4: Under stirring conditions, anhydrous aluminum chloride (AlCl3) and sodium iodide (NaI) are added to acetonitrile (CH3CN) in sequence, and compound 3 is added and stirred for reaction. After the reaction is completed, the reaction solution is slowly added dropwise to an aqueous sodium sulfite solution for dispersion and quenching, and the reaction is stirred. The obtained reaction solution is centrifuged, washed, and dried to obtain compound 4 (a-formamido-2-hydroxy-4-methanesulfonamido-5-phenoxyacetophenone);

[0010] (3) Preparation of crude iguratimod: Compound 4, N,N-dimethylformamide dimethyl acetal (DMF-DMA) and triethylamine (Et3N) were added to dichloromethane (DCM), and the mixture was stirred until the reaction was complete. Purified water was added and stirred, and the pH of the aqueous layer was adjusted to 1-2. The reaction was continued by stirring. The obtained reaction solution was centrifuged, washed and dried to obtain crude iguratimod.

[0011] (4) Purification of Iguratimod: Add crude Iguratimod to N,N-dimethylformamide, then add activated carbon for decolorization, filter the activated carbon, add anhydrous ethanol to the filtrate, and after heat preservation and crystallization, centrifuge, rinse and dry to obtain compound 1, i.e., the reaction product Iguratimod.

[0012] Preferably, the mass ratio of acetone, pivaloyl chloride, anhydrous sodium formate, compound 2 and purified water in step (1) is 90-100:20-30:30-40:35-50:350-400.

[0013] Preferably, in step (2), the mass ratio of acetonitrile, anhydrous aluminum chloride, sodium iodide, compound 3, and sodium sulfite is 130-150:30-40:15-20:30-40:10-15.

[0014] Preferably, the mass ratio of dichloromethane, compound 4, N,N-dimethylformamide dimethyl acetal, triethylamine and purified water in step (3) is 200-220:25-40:30-40:10-15:220-250.

[0015] Preferably, in step (4), the mass ratio of N,N-dimethylformamide, crude iguratimod, activated carbon and anhydrous ethanol is 110-120:20-30:0.12-0.13:40-45.

[0016] Preferably, the method for preparing compound 3 in step (1) comprises the following steps:

[0017] Preheat the reactor to 22-24°C, add acetone and pivaloyl chloride in sequence, and stir evenly. After maintaining the temperature at 20±2°C for 5-10 minutes, add anhydrous sodium formate, seal and stir, control the temperature at 18-22°C and stir for 4-8 hours to form a mixed anhydride. After the reaction is completed, cool to 10-15°C, add compound 2 to the reactor while stirring, continue stirring for 1-2 hours until the reaction is complete, finally control the temperature at 10-15°C, slowly add purified water, and stir for 1-2 hours after the addition is complete. The obtained reaction solution is centrifuged, washed, and dried to obtain compound 3.

[0018] Preferably, the centrifugal separation and washing method in step (1) is: centrifugally drying the reaction liquid, rinsing the filtered solid with purified water, centrifugally drying, then adding purified water at 10-30°C for 1-2h, and centrifugally drying again; repeating the steps of rinsing, centrifugation drying, slurrying, centrifugation drying, rinsing, and centrifugation drying to obtain a solid reactant.

[0019] Preferably, the drying temperature in step (1) is 60-80° C., and the drying time is 20-30 hours.

[0020] Preferably, the preparation of compound 4 in step (2) comprises the following steps:

[0021] Add acetonitrile to the reaction kettle and start stirring, cool to 10-15°C, slowly add anhydrous aluminum chloride, the temperature does not exceed 30°C during the addition process, then add sodium iodide, stir for 30-40 minutes, then add compound 3, raise the temperature to 28-32°C and stir for 4-8 hours until the reaction is completed, slowly drop the reaction solution into a 2% sodium sulfite aqueous solution, and control the temperature at 10-15°C, control the dropping time at 2-4 hours, and after the dropwise addition, continue to control the temperature at 10-15°C and stir for 1-2 hours; the obtained reaction solution is centrifuged, washed, and dried to obtain compound 4.

[0022] Preferably, the centrifugal separation and washing method in step (2) is: centrifuge the reaction solution to dryness, rinse the filtered solid with purified water, then add it to ethanol, beat for 0.5h, centrifuge the reaction solution to dryness, add ethanol to rinse the filtered solid, and obtain a wet product.

[0023] Preferably, the drying temperature in step (2) is 55-65° C., and the drying time is 10-20 hours.

[0024] Preferably, the preparation of the crude iguratimod in step (3) comprises the following steps:

[0025] Under stirring conditions, dichloromethane, compound 4, N,N-dimethylformamide dimethyl acetal, and triethylamine were added to the reactor in sequence, the temperature was raised to 28-32° C., and the reaction was stirred for 5-8 hours until the reaction was complete. The reaction solution was cooled to 10-15° C., purified water was slowly added, and the water addition time was controlled to 0.5-1h. After the addition was completed, it was stirred for 1-2 hours, and hydrochloric acid was added dropwise to adjust the pH of the water layer to 1-2. The dropping speed was controlled to ensure that the feed liquid temperature was not higher than 15° C. After the dropwise addition reached the end point, stirring was continued for 0.5 hours, and the pH was re-measured until the pH of the water layer was stable at 1-2. If there was no change within 0.5 hours, the dropwise addition was completed, and stirring was continued for 1-2 hours. The obtained reaction solution was centrifuged and dried, and the chlorine solid was washed twice with dichloromethane and a 50% ethanol aqueous solution in sequence, and dried to obtain a crude product of elamod.

[0026] Preferably, the drying temperature in step (3) is 60-65° C., and the drying time is 10-20 hours.

[0027] Preferably, the refining of iguratimod in step (4) comprises the following steps:

[0028] Under stirring conditions, N,N-dimethylformamide and crude iguratimod were added to the reaction kettle in sequence, and the temperature was raised to 70-75°C. After all the solids were dissolved, activated carbon was added for decolorization, and stirring was continued for 0.5-1h until the decolorization was completed. The reaction solution was filtered through a filter to filter the activated carbon, and the temperature was maintained at 68-72°C during filtration; anhydrous ethanol was added to the filtrate, and the mixture was kept warm at 70-75°C for 0.5-1h until all the solids were dissolved, and the mixture was cooled to 40°C and kept warm for 2h for crystallization, and then cooled to 5-10°C and kept warm for 1h for crystallization. The obtained reaction solution was centrifuged, and the filtered solid was added with a DMF ethanol mixed solvent for elution, and the mixture was centrifuged for 5-10min, dried at 55-65°C for 8h, and then the temperature was raised to 80-85°C and continued to be dried for 16h, and then crushed to obtain pure iguratimod.

[0029] More preferably, the volume ratio of DMF to ethanol is 7:3.

[0030] More preferably, the activated carbon is wetted with DMF and then added, and the mass ratio of the activated carbon to DMF is 0.12-0.13:3-3.5.

[0031] Compared with the prior art, the present invention has the following beneficial effects: the present invention provides a method for preparing iguratimod, firstly, acetone, pivaloyl chloride and anhydrous sodium formate are used to prepare a mixed anhydride, then compound 2 is added to react to obtain compound 3, in acetonitrile solvent, anhydrous aluminum chloride and sodium iodide are reacted, and sodium sulfite aqueous solution is added to react to obtain compound 4; then in dichloromethane solvent, N,N-dimethylformamide dimethyl acetal and triethylamine are reacted to obtain a crude iguratimod product, and a pure iguratimod product is obtained by refining. The preparation method of the present invention is simple and efficient, and the prepared iguratimod is of high quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is the high performance liquid chromatogram of the pure iguratimod prepared in Example 1. DETAILED DESCRIPTION

[0033] The present invention will be further described below in conjunction with the embodiments.

[0034] Example 1

[0035] A method for preparing iguratimod, comprising the following steps:

[0036] Step 1: Preparation of compound 3:

[0037] Step 1-1: preheat a 200L reactor to 23°C, add 96kg of acetone, then add 28kg of pivaloyl chloride, stir evenly, and maintain the temperature at 20±2°C. After the temperature stabilizes for 10 minutes, add 32kg of anhydrous sodium formate (if sodium formate is agglomerated, it needs to be processed into soybean-sized particles in advance), cover the reactor tightly, start stirring (speed: 400 rpm), control the temperature at 18-22°C, stir and react to form a mixed anhydride (this process is exothermic, and when the temperature exceeds 22°C, use circulating water to cool down and monitor the temperature); when the reaction time is 4h, the solution turns milky white and the reaction is completed;

[0038] Step 1-2: After the reaction is completed, cool to 12°C, adjust the speed to 130 r / min, add 240 kg of compound into a 200 L reactor, adjust the speed to 400 r / min, and stir for 1.5 h to complete the reaction;

[0039] Step 1-3: After the reaction is complete, transfer the reaction solution in the 200L reactor into a 1000L reactor, control the temperature at 10-15°C, slowly add 360kg of purified water, and stir for 2h after the addition is completed;

[0040] Step 1-4: Add the reaction solution to a centrifuge, spin dry, rinse the filtered solid with about 40 kg of purified water once, spin dry, return the filtered solid to a 1000L reactor, add 400 kg of purified water, and beat at 25°C for 2h. Add the reaction solution to a centrifuge, spin dry, rinse the filtered solid with about 40 kg of purified water once, spin dry, return the filtered solid to a 1000L reactor, add 320 kg of purified water, and beat at 25°C for 2h. Add the reaction solution to a centrifuge, spin dry, rinse the filtered solid with about 40 kg of purified water once, and spin dry;

[0041] Step 1-5: Turn on the hot air circulation oven, spread the wet material evenly on a drying tray with a special tray cloth with a thickness of 2-4 cm, dry at 70±2°C, dry for 25 hours, cool to room temperature, and obtain compound 3.

[0042] Step 2: Preparation of compound 4:

[0043] 2-1: Add 145 kg of acetonitrile to a 500 L reactor, start stirring, cool to 15 ° C, slowly add 32.6 kg of anhydrous aluminum chloride, control the feeding speed, and ensure that the feed liquid temperature does not exceed 30 ° C; after the addition, add 17.6 kg of sodium iodide, the solution first turns black and then orange-yellow, stir for 30 min, then add 37 kg of compound 3, heat to 30 ° C and stir for 7 h; after the reaction, slowly add the reaction solution dropwise to a 2% sodium sulfite aqueous solution (composed of 543.90 kg of purified water and 11.10 kg of anhydrous sodium sulfite solid) in a 1500 L reactor, control the temperature at 13 ° C, and control the dropping time at 3 h. During the dropping process, an orange-yellow oily solid precipitates. After the dropwise addition, control the temperature at 13 ° C and stir for 2 h;

[0044] 2-2: Add the reaction liquid to a centrifuge, spin dry, add 37 kg of purified water to the filtered solid for rinsing, add the filtered solid to a 500 L reactor, add 44.4 kg of ethanol, and beat for 0.5 h. Add the reaction liquid to a centrifuge, spin dry, add 6 kg of ethanol to the filtered solid for rinsing once to obtain a wet material;

[0045] 2-3: Turn on the hot air circulation oven, spread the wet material evenly on a drying tray with a special tray cloth to a thickness of 2-4 cm, dry at 60±2°C, dry for 15 hours, cool to room temperature, and obtain compound 4.

[0046] Step 3: Preparation of crude iguratimod:

[0047] 3-1: Add 210kg of dichloromethane to a 1000L reactor, start stirring, add 430kg of compound, 33.4kg of N,N-dimethylformamide dimethyl acetal, and 11.7kg of triethylamine, heat to 30℃, stir and react, the solution gradually changes from turbid to clear, and finally becomes wine red and transparent, the reaction is complete in 5-8h, cool the reaction solution to 13℃, slowly add 240kg of purified water, control the water addition time to 0.7h, and white solid precipitates during the dropwise addition. After the addition is completed, stir for 1.5h, add 36% hydrochloric acid dropwise, adjust the pH of the water layer to 1.8, control the dropwise addition speed, and ensure that the feed liquid temperature is not higher than 15℃. After the dropwise addition reaches the end point, continue stirring for 0.5h, re-measure the pH, until the pH of the water layer is stable at 1-2, and the dropwise addition is complete if there is no change within 0.5h, and continue stirring for 2h.

[0048] 3-2: Add the reaction solution into a centrifuge, spin dry, and wash the filtered solid twice with 66.25 kg of dichloromethane and 100 kg of 50% ethanol aqueous solution to obtain a wet material.

[0049] 3-3: Open the hot air circulation oven, spread the wet material evenly on a drying tray with a special tray cloth with a thickness of 3 cm, dry at 60±2°C for 18 hours, and cool to room temperature to obtain a crude product of Iguratimod.

[0050] Step 4: Ailamod Refining

[0051] 4-1: Add 113 kg of N,N-dimethylformamide to the reactor, start stirring, add 25 kg of crude elamod, raise the temperature to 74°C, wait until all the solids are dissolved, add 0.125 kg of activated carbon (the activated carbon is wetted with 3.1 kg of DMF), continue stirring for 1 hour, after the decolorization is completed, filter the activated carbon through the filter, and maintain the temperature at about 70±2°C during filtration. Filter the filtrate into another 1000L reactor, then add 41.4 kg of anhydrous ethanol, keep warm at 75°C for 0.5 hour, wait until all the solids are dissolved, cool to 40°C and keep warm for 2 hours for crystallization, after the crystallization is completed, continue to cool to 8°C, keep warm for 1 hour for crystallization, and prepare for separation.

[0052] 4-2: Add the reaction solution into the centrifuge and separate until no liquid flows out. Add 15L of DMF ethanol mixed solvent to the filtered solid for elution and separate until no liquid flows out. Continue centrifugation for 8 minutes, stop centrifugation, weigh the wet product, and put the solid centrifuge in the centrifuge into a turnover bucket or a medicinal low-density polyethylene bag for drying.

[0053] 4-3: The wet material is evenly spread on a drying tray with a special tray cloth with a thickness of 2-4 cm, and placed in an oven at a drying temperature of 60±2°C for 8 hours, and then the drying temperature is increased to 85±2°C for continued drying for 16 hours, and then the heating is stopped, the material temperature is reduced to 55°C, and the material is crushed to a particle size of less than 20 meshes, and mixed evenly with a medicinal low-density polyethylene bag and continued to dry. The continued drying is: the drug is evenly spread on a drying tray with a special tray cloth with a thickness of 2-4 cm, the drying temperature is 85±2°C, and the drying is carried out for 32 hours, and then cooled to room temperature to obtain pure iguratimod.

[0054] The test results of the product obtained in Example 1 are shown in Table 1:

[0055] Table 1

[0056] purity Loss on drying Ignition residue Pure Ailamod 99.9％ 0.75％ 0.1％

[0057] The purity of the product in Example 1 of the present application was detected by high performance liquid chromatography (injection volume 25 μL, VWD1A, wavelength = 235 nm), and the high performance liquid chromatogram was obtained as shown in Figure 1 .

[0058] Figure 1 The detection results are shown in Table 2.

[0059] Table 2

[0060]

[0061] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing iguratimod, characterized in that: The reaction process is as follows: The preparation method comprises the following steps: (1) Preparation of Compound 3: Pivaloyl chloride and anhydrous sodium formate are added to acetone, and the mixture is mixed and stirred under sealed conditions to generate a mixed acid anhydride. Compound 2 is then added to the mixed acid anhydride and stirred until the reaction is complete. Purified water is then added and stirred continuously. The resulting reaction solution is centrifuged, washed, and dried to obtain Compound 3. (2) Preparation of compound 4: under stirring conditions, anhydrous aluminum chloride and sodium iodide were added to acetonitrile in sequence, and compound 3 was then added to react with stirring. After the reaction was completed, the reaction solution was slowly added dropwise to a sodium sulfite aqueous solution and reacted with stirring. The obtained reaction solution was centrifuged, washed, and dried to obtain compound 4; (3) Preparation of crude iguratimod: Compound 4, N,N-dimethylformamide dimethyl acetal and triethylamine were added to dichloromethane, and the mixture was stirred until the reaction was complete. Purified water was added and stirred, and the pH of the water layer was adjusted to 1-2. The reaction was continued by stirring. The obtained reaction solution was centrifuged, washed and dried to obtain crude iguratimod; (4) Purification of Iguratimod: Add crude Iguratimod to N,N-dimethylformamide, then add activated carbon for decolorization, filter the activated carbon, add anhydrous ethanol to the filtrate, and after heat preservation and crystallization, centrifuge, rinse and dry to obtain compound 1, i.e., the reaction product Iguratimod.

2. The method for preparing Iguratimod according to claim 1, characterized in that: The mass ratio of acetone, pivaloyl chloride, anhydrous sodium formate, compound 2 and purified water in step (1) is 90-100:20-30:30-40:35-50:350-400; The mass ratio of acetonitrile, anhydrous aluminum chloride, sodium iodide, compound 3 and sodium sulfite in step (2) is 130-150:30-40:15-20:30-40:10-15; The mass ratio of the dichloromethane, compound 4, N,N-dimethylformamide dimethyl acetal, triethylamine and purified water in step (3) is 200-220:25-40:30-40:10-15:220-250; The mass ratio of N,N-dimethylformamide, crude iguratimod, activated carbon and anhydrous ethanol in step (4) is 110-120:20-30:0.12-0.13:40-45.

3. The method for preparing iguratimod according to claim 1, characterized in that: The preparation method of compound 3 described in step (1) comprises the following steps: Preheat the reactor to 22-24°C, add acetone and pivaloyl chloride in sequence, and stir evenly. After maintaining the temperature at 20±2°C for 5-10 minutes, add anhydrous sodium formate, seal and stir, control the temperature at 18-22°C and stir for 4-8 hours to form a mixed anhydride. After the reaction is completed, cool to 10-15°C, add compound 2 to the reactor while stirring, continue stirring for 1-2 hours until the reaction is complete, finally control the temperature at 10-15°C, slowly add purified water, and stir for 1-2 hours after the addition is complete. The obtained reaction solution is centrifuged, washed, and dried to obtain compound 3.

4. The method for preparing Iguratimod according to claim 1, characterized in that: The centrifugal separation and washing method in step (1) is as follows: centrifugally drying the reaction liquid, rinsing the filtered solid with purified water, centrifugally drying, then adding purified water at 10-30° C. for 1-2 hours, and centrifugally drying again; repeating the steps of rinsing, centrifugation drying, slurrying, centrifugation drying, rinsing, and centrifugation drying to obtain a solid reactant; The drying temperature in step (1) is 60-80° C. and the drying time is 20-30 hours.

5. The method for preparing iguratimod according to claim 1, characterized in that: The preparation of compound 4 in step (2) comprises the following steps: Add acetonitrile to the reaction kettle and start stirring, cool to 10-15°C, slowly add anhydrous aluminum chloride, the temperature does not exceed 30°C during the addition process, then add sodium iodide, stir for 30-40 minutes, then add compound 3, raise the temperature to 28-32°C and stir for 4-8 hours until the reaction is completed, slowly drop the reaction solution into a 2% sodium sulfite aqueous solution, and control the temperature at 10-15°C, control the dropping time at 2-4 hours, and after the dropwise addition, continue to control the temperature at 10-15°C and stir for 1-2 hours; the obtained reaction solution is centrifuged, washed, and dried to obtain compound 4.

6. The method for preparing iguratimod according to claim 1, characterized in that: The centrifugal separation and washing method in step (2) is as follows: centrifuge the reaction solution to dryness, rinse the filtered solid with purified water, then add it to ethanol, beat for 0.5h, centrifuge the reaction solution to dryness, rinse the filtered solid with ethanol, and obtain a wet product; The drying temperature in step (2) is 55-65° C. and the drying time is 10-20 hours.

7. The method for preparing iguratimod according to claim 1, characterized in that: The preparation of the crude iguratimod product in step (3) comprises the following steps: Under stirring conditions, dichloromethane, compound 4, N,N-dimethylformamide dimethyl acetal, and triethylamine are added to the reactor in sequence, the temperature is raised to 28-32° C., and the reaction is stirred for 5-8 hours until the reaction is complete. The reaction solution is cooled to 10-15° C., purified water is slowly added, and the water addition time is controlled to be 0.5-1 hour. After the addition is completed, it is stirred for 1-2 hours, and hydrochloric acid is added dropwise to adjust the pH of the water layer to 1-2. The dropping speed is controlled to ensure that the feed liquid temperature is not higher than 15° C. After the dropwise addition reaches the end point, the stirring is continued for 0.5 hours, and the pH is repeatedly measured until the pH of the water layer is stable at 1-2. If there is no change within 0.5 hours, the dropwise addition is completed, and the stirring is continued for 1-2 hours. The obtained reaction solution is centrifuged and dried, and the chlorine solid is washed twice with dichloromethane and a 50% ethanol aqueous solution in sequence, and dried to obtain a crude product of ilamod; Preferably, the drying temperature in step (3) is 60-65° C., and the drying time is 10-20 hours.

8. The method for preparing iguratimod according to claim 1, characterized in that: The purification of iguratimod in step (4) comprises the following steps: Under stirring conditions, N,N-dimethylformamide and crude iguratimod were added to the reaction kettle in sequence, and the temperature was raised to 70-75°C. After all the solids were dissolved, activated carbon was added for decolorization, and stirring was continued for 0.5-1h until the decolorization was completed. The reaction solution was filtered through a filter to filter the activated carbon, and the temperature was maintained at 68-72°C during filtration; anhydrous ethanol was added to the filtrate, and the mixture was kept warm at 70-75°C for 0.5-1h until all the solids were dissolved, and the mixture was cooled to 40°C and kept warm for 2h for crystallization, and then cooled to 5-10°C and kept warm for 1h for crystallization. The obtained reaction solution was centrifuged, and the filtered solid was added with a DMF ethanol mixed solvent for elution, and the mixture was centrifuged for 5-10min, dried at 55-65°C for 8h, and then the temperature was raised to 80-85°C and continued to be dried for 16h, and then crushed to obtain pure iguratimod.

9. The method for preparing iguratimod according to claim 8, characterized in that: The volume ratio of DMF to ethanol is 7:

3.

10. The method for preparing iguratimod according to claim 8, characterized in that: The activated carbon is wetted with DMF and then added, and the mass ratio of the activated carbon to DMF is 0.12-0.13:3-3.5.

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