Probenecid refining process

Abstract

The invention relates to a refining process of probenecid, which is characterized in that a two-step refining process of acidification crystallization separation and mixed solvent crystallization purification is adopted, a crude probenecid product is put into an alkaline solution to be dissolved, activated carbon wetted by purified water is added, heat preservation and decoloration are performed for 30-40 minutes, and feed liquid is pressed into a crystallization kettle through a filter. Slowly dropwise adding an acetic acid aqueous solution, centrifugally filtering, and collecting a wet product; adding the wet product into a mixed solvent, heating and dissolving, adding activated carbon, refluxing and decoloring for 30-40 minutes, pressing the feed liquid into a crystallization kettle through a filter, starting low-speed stirring, slowly reducing the temperature in the crystallization kettle, and standing for crystallization. And carrying out spin-filtration on the filtrate, collecting a wet competitive product, and carrying out drying treatment to prepare a competitive probenecid product. According to the probenecid refining process disclosed by the invention, the process parameters are easy to control, the solvent ratio is reduced, and the batch yield is greatly increased; the refined probenecid is a white body, the appearance property and quality are greatly improved, the HPLC purity is greater than or equal to 99.9%, and the single impurity is less than or equal to 0.10%.

Description

Technical Field

[0001] The invention relates to a probenecid refining process and belongs to the technical field of probenecid crude product refining. Background Art

[0002] Probenecid is a white crystalline powder. Melting point is 198-201℃. It is soluble in acetone, slightly soluble in ethanol or chloroform, and almost insoluble in water. It is soluble in dilute sodium hydroxide solution and almost insoluble in dilute acid. It is odorless and tastes slightly bitter. It is an anti-gout drug and an adjuvant drug for antibiotic treatment.

[0003] In addition to its role in treating chronic gout, probenecid can also significantly optimize the pharmacokinetic properties of various β-lactam antibiotics. Currently, a compound preparation consisting of probenecid and ampicillin has been used clinically. [1] , which can not only significantly reduce the dosage of corresponding antibiotics, thereby reducing the incidence of adverse reactions to antibiotics, but also increase the compliance of antibiotic treatment and reduce the selection of drug-resistant bacteria. The development of the combined use of probenecid and various β-lactam antibiotics has extremely important clinical value and also has a very positive social significance for reducing the use of antibiotics and alleviating bacterial resistance.

[0004] Improving the refining or purification process, increasing the purity of active ingredients, and controlling the level of impurities are of great significance to improving the quality and safety of drugs. At present, the research on the refining process of probenecid is not in-depth. Traditional processes such as the "National Compilation of API Processes" [2] The included refining method is ethanol recrystallization. Experiments have shown that this process can remove some organic impurities in crude probenecid, such as p-carboxybenzenesulfonamide, p-carboxybenzenesulfonic acid, bromopropane, ethyl probenecid, and propyl probenecid. However, the removal capacity of monosubstituted impurities and inorganic salt impurities in crude products is limited; Patent CN201210522104.X [3]A method for purifying probenecid is provided, which utilizes the operation of alkali dissolution and acid precipitation to purify crude probenecid in a pure water environment. Experiments have shown that the purification method is effective in removing inorganic impurities and some organic impurities, such as sodium chloride, sodium acetate, p-carboxybenzenesulfonamide, and monosubstituted impurities. It also controls the use of organic solvents and saves production costs. However, there are many disadvantages: ① The method has a weak ability to remove most water-insoluble organic impurities, such as probenecid ethyl and probenecid propyl, especially a very weak ability to remove bromopropane residues, resulting in excessive residual harmful substances; ② The method adopts alkaline dissolution and secondary acid precipitation operations, and the precipitation end point is very close to probenecid, such as 4-carboxy-N-propylbenzenesulfonamide, which is not completely removed and is very easy to precipitate with probenecid; ③ The method precipitates in pure water, and when it is close to the acid precipitation end point, probenecid will precipitate in large quantities, which makes it very easy to encapsulate other impurities, including inorganic salt impurities; ④ The method uses pure water as the crystallization solvent, and probenecid is difficult to dissolve in water. The crystals precipitated in water are very small. It is difficult to remove the mother liquor during centrifugation and drying operations, resulting in impurities in the mother liquor remaining in the probenecid. Summary of the invention

[0005] The invention aims to provide a refining process of probenecid, which adopts two-step refining of acid precipitation crystallization separation and mixed solvent crystallization purification, and the impurity removal ability is greatly improved; the process parameters are easy to control, the solvent ratio is reduced, and the batch output is greatly expanded; after refining, the probenecid is a white crystal, the appearance and quality are greatly improved, the HPLC purity is ≥99.9%, and the unknown single impurity is ≤0.10%.

[0006] The technical solution of the present invention is achieved in this way: a refining process for probenecid, characterized in that: a two-step refining process of acid precipitation crystallization separation and mixed solvent crystallization purification is adopted, and the specific steps are as follows: (1) placing the crude probenecid product into a refining kettle containing 1-1.05 times the mole of an alkaline substance and 4-8 times the weight of purified water, stirring and heating until the crude probenecid product is completely dissolved; (2) Add 1-5% activated carbon moistened with purified water and keep warm for 30-40 minutes for decolorization; (3) Pressing the feed liquid into the crystallization kettle through the filter while it is hot, and flushing the refining kettle and pipeline with purified water, and pressing it into the crystallization kettle through the filter; (4) Controlling the temperature of the liquid in the crystallization kettle, adding 40-60% acetic acid aqueous solution, adjusting the pH value of the reaction liquid to 4.0-6.0 to precipitate a white solid, lowering the temperature in the crystallization kettle to 10-20° C., and standing for crystallization for 1-2 hours; then placing the filtrate in a centrifuge for filtering, washing the filter cake with 2 times the weight of purified water, and continuing to spin dry. After centrifugation, collect the wet product; (5) Add the wet product from step (4) into a refining kettle filled with 4-8 times the weight ratio of the mixed solvent, heat until the wet product is dissolved, add 1-5% activated carbon, and reflux for decolorization for 30-40 minutes.

[0007] (6) Press the feed liquid into the crystallization kettle through the filter while it is still hot, and use a mixed solvent to flush the refining kettle and pipeline, and press it into the crystallization kettle through the filter; (7) Under low-speed stirring, slowly cool the temperature in the crystallization kettle to below 0-10°C, let it stand for crystallization for more than 2 hours, then put the filtrate into a centrifuge for filtering, collect the wet product after centrifugation, dry the wet product, and prepare probenecid product.

[0008] The alkaline substance in the step (1) is an inorganic base or an organic base, preferably sodium hydroxide or potassium hydroxide; the weight ratio of the crude probenecid to purified water is 1:4-8, the molar ratio of probenecid to the alkaline substance is 1:1-1.05; the molar ratio of the alkaline substance to the crude probenecid is 1.0-1.05, preferably 1.02; the mass ratio of water to the crude probenecid is 4-6 times, preferably 5 times.

[0009] In the step (2), the weight ratio of activated carbon to crude probenecid is 0.01-0.05:1, the decolorization temperature is 70-80° C., and the decolorization time is 30-40 minutes; the amount of activated carbon is preferably 3%.

[0010] In the step (3), the liquid feed is pressed into a crystallization kettle through a filter while hot, and the filtering temperature is 55-65°C.

[0011] In the step (4), the temperature of the liquid in the crystallization kettle is controlled to be 50-60° C.; the concentration of the acetic acid aqueous solution is preferably 50%.

[0012] In the step (5), the mixed solvent is purified water and anhydrous ethanol, and the mass concentration of anhydrous ethanol is 70-90%, preferably 80%.

[0013] The solvent ratio of the mixed solvent in step (5) is 4-8 times by mass, preferably 5 times. The amount of activated carbon used is preferably 3%.

[0014] In the step (6), the liquid feed is pressed into a crystallization kettle through a filter while hot, and the material temperature is 65-75° C. The amount of the mixed solvent used is 1-10% of the amount used for dissolution, preferably 5%.

[0015] The step (7) is performed by stirring at a low speed of 5-10 revolutions per minute, and the temperature inside the crystallization kettle is slowly cooled at a cooling rate of 0.5-1°C / minute.

[0016] Under the low-speed stirring described in step (7), the rotation speed of the low-speed stirring is 10-20 r / min.

[0017] The step (7) of slowly cooling the temperature in the crystallization kettle to below 0-10°C at a cooling rate of 0.5-1.0°C / min; The step (7) is described as cooling to below 0-10°C, standing for crystallization for more than 2 hours, the crystallization end point is 0-10°C, and the crystallization time is more than 2 hours; The wet fine product described in step (7) is dried under reduced pressure conditions, with a vacuum degree of -0.08-0.09 MPa and a temperature of 45-50°C.

[0018] The positive effects of the present invention are: (1) The refining process of probenecid described in the present invention has controllable process parameters, a simple production process, greatly improved yield and purity of the obtained probenecid product, and a good product crystal form.

[0019] (2) The purification process of probenecid described in the present invention adopts two-step purification of acid precipitation crystallization separation and mixed solvent crystallization purification, and the impurity removal ability is greatly improved, and the inorganic impurities and organic impurities are basically completely removed.

[0020] (3) The probenecid is purified by the process of the present invention, and the HPLC purity of the purified probenecid is not less than 99.9%, and the impurities are not more than 0.10%. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is the HPLC chromatogram of the refining process of crude probenecid in Example 1.

[0022] Figure 2 This is the HPLC spectrum of probenecid in Example 1.

[0023] Figure 3 This is the HPLC spectrum of the fine product of probenecid in Example 1.

[0024] Figure 4 It is the HPLC chromatogram of the crude probenecid product refining process of Example 2.

[0025] Figure 5 This is the HPLC spectrum of probenecid in Example 2.

[0026] Figure 6 This is the HPLC spectrum of the fine product of probenecid in Example 2.

[0027] Figure 7 It is the HPLC chromatogram of the crude probenecid product refining process of Example 3.

[0028] Figure 8 This is the HPLC spectrum of probenecid in Example 3.

[0029] Fig. 9 This is the HPLC spectrum of the fine product of probenecid in Example 3. Implementation

[0030] The present invention will be further described below in conjunction with the accompanying drawings and embodiments; Figure 1-9 As shown, a process for refining probenecid is characterized in that the specific steps are as follows: (1) placing the crude probenecid product into a refining kettle containing 1.02 times the mole of sodium hydroxide and 5 times the weight of purified water, stirring and heating until the crude probenecid product is completely dissolved; (2) Add 3% activated carbon moistened with purified water into the dissolving kettle, heat to 70-80 degrees Celsius, and decolorize for 30 minutes; (3) Cooling the decolorized liquid in the dissolving kettle to 55-65° C., filtering it through a titanium rod filter to the crystallization kettle, flushing the refining kettle and pipeline with purified water, and then pressing it into the crystallization kettle through the filter; (4) Control the temperature of the feed liquid in the crystallization kettle at 50-60° C., add 50% acetic acid aqueous solution dropwise, adjust the pH value of the reaction liquid to 5.0-5.5, precipitate a white solid, slowly reduce the temperature in the crystallization kettle to 10-20° C., and let it stand for more than 1 hour for crystallization; then put the filtrate into a centrifuge for filtering, wash the filter cake with purified water twice the weight of the crude product, continue to spin dry, and collect the wet product after centrifugation; (5) Add the wet product from step (4) and 5 times the weight of 80% ethanol into a refining kettle, heat until the wet product is dissolved, add 3% activated carbon, and reflux at 70-80°C for 30-40 minutes for decolorization.

[0031] (6) Control the temperature of the feed liquid at 65-70°C, press it into the crystallization kettle through the titanium rod filter, and use the mixed solvent to flush the dissolution kettle and pipeline, and press it into the crystallization kettle through the filter; (7) Turn on low-speed stirring, the speed of low-speed stirring is 10-20r / min. Control the cooling rate to 0.5-1.0℃ / min, slowly cool the temperature in the crystallization kettle to below 0-10℃, let it stand for more than 2 hours to crystallize, then put the filtrate into a centrifuge for filtering, collect the wet fine product after centrifugation, dry the wet fine product, and prepare probenecid fine product.

[0032] In the step (4), the temperature of the feed liquid in the crystallization kettle is controlled at 50-60°C, 50% acetic acid aqueous solution is added dropwise, the pH value of the reaction solution is adjusted to 5.0-5.5, and a white solid is precipitated. At this temperature, the solid will not precipitate too quickly, which will easily encapsulate impurities, and at the same time, the precipitate crystals will be prevented from being too small and powdery, which will make it difficult to separate the solid and liquid in the later stage. The pH value of the reaction system is adjusted to 5.0-5.5. At this acidity, probenecid is precipitated most completely, and impurities will not precipitate. The filter cake is washed with purified water multiple times to thoroughly wash away the mother liquor and inorganic salts.

[0033] In the step (5), the wet product and a mixed solvent of 80% ethanol at 5 times the weight are added to the refining kettle. At this concentration of the mixed solvent and a 5-fold solvent ratio, the crystal form of probenecid crystallization is the best and the yield is the highest.

[0034] In step (7), low-speed stirring is turned on, and the speed of low-speed stirring is 10-20r / min. The cooling rate is controlled to be 0.5-1.0℃ / min, and the temperature in the crystallization kettle is slowly cooled to below 0-10℃, and the crystallization is allowed to stand for more than 2 hours. The speed of the reaction kettle is too fast, and the cooling rate is too fast, which is not conducive to crystal growth. Under this cooling rate and stirring speed, the crystal form of probenecid crystallization can be guaranteed, the removal of mother liquor during solid-liquid separation can be guaranteed, and the purity of the product can be improved; the temperature is lowered from 0-10℃ to below and the crystallization is allowed to stand for more than 2h. 0-10℃ is the crystallization end point of probenecid under this environment, which can ensure that probenecid crystallization is complete and the best yield is obtained. Example

[0035] like Figure 1-3 As shown, after HPLC detection, the impurity changes of the crude probenecid, the fine probenecid and the fine probenecid can be clearly seen in the spectrum, and the impurities of the crude product have been basically removed after being refined by the refining process of the present invention.

[0036] 1) Dissolution and decolorization of crude product: Add 50kg of water and 1.43kg of sodium hydroxide to a 100L dissolving kettle in turn, stir until completely dissolved, add 10kg of crude probenecid, open the high and low temperature circulation heating valve of the dissolving kettle, heat and stir until completely dissolved, add 0.3kg of activated carbon, and decolorize at 72℃ for 30mins. After decolorization, turn off the heating and lower the material temperature to below 60℃. Open the dissolving kettle discharge valve, and use nitrogen to filter the feed liquid through the titanium rod filter element filter to a 100L crystallization kettle. Rinse the dissolving kettle and filter with 5kg of purified water, and filter them together to the crystallization kettle.

[0037] 2) Acid separation centrifugation: Open the heating valve of the crystallization kettle, control the feed liquid at 55-60℃, open the dripping valve of the acetic acid high-level tank, slowly drip 50% acetic acid aqueous solution, and stop dripping when the pH is controlled at 5.13. Turn off the heating, turn on the cooling cycle, stir and cool to below 20℃, stand for crystallization for 1h, and then centrifuge. Rinse the filter cake with 20kg of purified water, dry it, and collect 14.89kg of wet product, with a dry yield of 95.43%.

[0038] 3) Alcohol refining: Add 3.73kg of purified water and 38.17kg of anhydrous ethanol to a 100L refining kettle and start stirring. Add 14.89kg of filter cake from the previous process. Turn on the reactor to heat, and add 0.3kg of activated carbon after the materials in the refining kettle are dissolved. Control the temperature in the reactor at 70-80℃ and decolorize for 30mins. After decolorization, filter the feed liquid through a titanium rod filter element filter to the crystallization kettle, rinse the reactor and filter with 2kg of 80% ethanol solution, and press them into the crystallization kettle together.

[0039] 4) Crystallization centrifugation: Open the cooling valve of the crystallization kettle, start stirring at 10 rpm, slowly reduce the temperature of the liquid to 0-10°C, and let it stand for more than 2 hours. After the crystallization is completed, centrifuge and filter, wash the crystallization kettle and filter cake with 2 kg of ethanol solution, and collect the filter cake.

[0040] 5) Drying: The filter cake was evenly dispersed in the tray, 2.0-3.0 kg per tray. It was placed in a vacuum drying oven, the temperature rise valve of the drying oven was opened, the vacuum was turned on, the oven temperature was maintained at 60-70°C, the vacuum degree was maintained at - (0.08-0.098) MPa, and 8.61 kg of probenecid fine product was obtained by drying, with a yield of 90.35%. Example

[0041] like Figure 4-6 As shown, 1) Dissolution and decolorization of crude product: Add 40kg water and 1.14kg sodium hydroxide to a 100L dissolving kettle in turn, stir until completely dissolved, add 8kg probenecid crude product, open the high and low temperature circulation heating valve of the dissolving kettle, heat and stir until completely dissolved, add 0.24kg activated carbon, and decolorize at 75℃ for 30mins. After decolorization, turn off the heating and lower the material temperature to below 60℃. Open the dissolving kettle discharge valve, and use nitrogen to filter the feed liquid through the titanium rod filter element filter to a 100L crystallization kettle. Rinse the dissolving kettle and filter with 4kg of purified water, and filter them together to the crystallization kettle.

[0042] 2) Acid separation centrifugation: Open the crystallization kettle heating valve, control the feed liquid at 55-60℃, open the acetic acid high-level tank dripping valve, slowly drip 50% acetic acid aqueous solution, and stop dripping when the pH is controlled at 5.33. Turn off the heating, turn on the cooling cycle, stir and cool to below 20℃, stand for crystallization for 1h, and then centrifuge. Rinse the filter cake with 16kg of purified water, spin dry, collect 8.7kg of wet product, and the yield after dryness is 90.06%.

[0043] 3) Alcohol refining: Add 3.83kg of purified water and 31.5kg of anhydrous ethanol to a 100L refining kettle and start stirring. Add 8.7kg of filter cake from the previous process. Turn on the reactor to heat, and add 0.24kg of activated carbon after the materials in the refining kettle are dissolved. Control the temperature in the reactor at 70-80℃ and decolorize for 30mins. After decolorization, filter the feed liquid through a titanium rod filter element filter to the crystallization kettle, rinse the reactor and filter with 2kg of 80% ethanol solution, and press them into the crystallization kettle together.

[0044] 4) Crystallization centrifugation: Open the cooling valve of the crystallization kettle, start stirring at a speed of 15 rpm, slowly reduce the temperature of the liquid to 0-10°C, and let it stand for more than 2 hours. After the crystallization is completed, centrifuge and filter, wash the crystallization kettle and filter cake with 2 kg of ethanol solution, and collect the filter cake.

[0045] 5) Drying: The filter cake was evenly dispersed in the tray, 2.0-3.0 kg per tray. It was placed in a vacuum drying oven, the temperature rise valve of the drying oven was opened, the vacuum was turned on, the oven temperature was maintained at 60-70°C, the vacuum degree was maintained at - (0.08-0.098) MPa, and 6.61 kg of probenecid fine product was obtained by drying, with a yield of 92.32%. Example

[0046] like Figure 7-9 Shown 1) Dissolution and decolorization of crude product: Add 45.3kg water and 1.39kg sodium hydroxide to the 100L dissolving kettle in turn, stir until completely dissolved, add 9.06kg probenecid crude product, open the high and low temperature circulation heating valve of the dissolving kettle, heat and stir until completely dissolved, add 0.27kg activated carbon, and decolorize at 70.8℃ for 30mins. After decolorization, turn off the heating and lower the material temperature to below 60℃. Open the dissolving kettle discharge valve, and use nitrogen to filter the feed liquid through the titanium rod filter element filter to the 100L crystallization kettle. Rinse the dissolving kettle and filter with 5kg of purified water, and filter them to the crystallization kettle together.

[0047] 2) Acid separation centrifugation: Open the heating valve of the crystallization kettle, control the feed liquid at 55-60℃, open the dripping valve of the acetic acid high-level tank, slowly drip 50% acetic acid aqueous solution, and stop dripping when the pH is controlled at 5.07. Turn off the heating, turn on the cooling cycle, stir and cool to below 20℃, stand for crystallization for 1h, and then centrifuge. Rinse the filter cake with 20kg of purified water, spin dry, collect 13.9kg of wet product, and the yield after dryness is 96.24%.

[0048] 3) Alcohol refining: Add 3.54kg of purified water and 34.9kg of anhydrous ethanol to a 100L refining kettle and start stirring. Add 13.9kg of filter cake from the previous process. Turn on the reactor to heat, and add 0.27kg of activated carbon after the materials in the refining kettle are dissolved. Control the temperature in the reactor at 70-80℃ and decolorize for 30mins. After decolorization, filter the feed liquid through a titanium rod filter element filter to the crystallization kettle, rinse the reactor and filter with 2kg of 80% ethanol solution, and press them into the crystallization kettle together.

[0049] 4) Crystallization centrifugation: Open the cooling valve of the crystallization kettle, start stirring at 18 rpm, slowly reduce the temperature of the liquid to 0-10°C, and let it stand for more than 2 hours. After the crystallization is completed, centrifuge and filter, wash the crystallization kettle and filter cake with 2 kg of ethanol solution, and collect the filter cake.

[0050] 5) Drying: The filter cake was evenly dispersed in the tray, 2.0-3.0 kg per tray. It was placed in a vacuum drying oven, the temperature-raising valve of the drying oven was opened, the vacuum was turned on, the oven temperature was maintained at 60-70°C, the vacuum degree was maintained at - (0.08-0.098) MPa, and 7.99 kg of probenecid fine product was obtained by drying, with a yield of 91.63%.

Claims

1. A process for refining probenecid, Features: A two-step refining process of acid precipitation crystallization separation and mixed solvent crystallization purification is adopted. The specific steps are as follows: (1) placing the crude probenecid product into a refining kettle containing 1-1.05 times the mole of an alkaline substance and 4-8 times the weight of purified water, stirring and heating until the crude probenecid product is completely dissolved; (2) Add 1-5% activated carbon moistened with purified water and keep warm for 30-40 minutes for decolorization; (3) The feed liquid is pressed into the crystallization kettle through the filter while hot. After the pressure filtration is completed, the probenecid crude product refining kettle and pipeline are rinsed with 0.5 times purified water, and then pressed into the crystallization kettle through the filter; (4) Control the temperature of the liquid in the crystallization kettle, add 40-60% acetic acid aqueous solution, adjust the pH value of the reaction liquid to 4.0-6.0 to precipitate a white solid, lower the temperature in the crystallization kettle to 10-20°C, and let it stand for 1-2 hours to crystallize; then put the filtrate into a centrifuge for filtering, wash the filter cake with 2 times the weight of purified water after filtering, continue to dry, and collect the wet product after centrifugation; (5) Add the wet product from step (4) into a refining kettle filled with 4-8 times the weight ratio of the mixed solvent, heat until the wet product is dissolved, add 1-5% activated carbon, and reflux for decolorization for 30-40 minutes; (6) Press the feed liquid into the crystallization kettle through the filter while it is still hot, and use a mixed solvent to flush the refining kettle and pipeline, and press it into the crystallization kettle through the filter; (7) Under low-speed stirring, slowly cool the temperature in the crystallization kettle to below 0-10°C, let it stand for crystallization for more than 2 hours, then put the filtrate into a centrifuge for filtering, collect the wet product after centrifugation, dry the wet product, and prepare probenecid product.

2. A process for refining probenecid according to claim 1, Features The weight ratio of the crude probenecid to purified water in the step (1) is 1:4-8, and the molar ratio of probenecid to the alkaline substance is 1:1-1.

05.

3. A process for refining probenecid according to claim 1, Features: In the step (2), the weight ratio of activated carbon to crude probenecid is 0.01-0.05:1, the decolorization temperature is 70-80° C., and the decolorization time is 30-40 minutes.

4. A process for refining probenecid according to claim 1, Features In the step (3), the liquid feed is pressed into a crystallization kettle through a filter while hot, and the filtering temperature is 55-65°C.

5. A process for refining probenecid according to claim 1, Features In the step (4), the temperature of the liquid in the crystallization kettle is controlled to be 50-60°C.

6. A process for refining probenecid according to claim 1, Features The mixed solvent in step (5) is purified water and anhydrous ethanol, and the mass concentration of anhydrous ethanol is 70-90%.

7. A process for refining probenecid according to claim 1, Features The solvent ratio of the mixed solvent in step (5) is 4-8 times the mass ratio.

8. A process for refining probenecid according to claim 1, Features In the step (6), the liquid feed is pressed into a crystallization kettle through a filter while hot, and the material temperature is 65-75°C.

9. A process for refining probenecid according to claim 1, Features The step (7) is performed by stirring at a low speed of 5-10 revolutions per minute, and the temperature inside the crystallization kettle is slowly cooled at a cooling rate of 0.5-1°C / minute.

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