Improved method for preparation process of p-aminosalicylic acid

Abstract

The invention provides the improved method of the preparation process of the p-aminosalicylic acid, the HPLC (High Performance Liquid Chromatography) content of the prepared p-aminosalicylic acid can reach 99-99.5%, and the content of the prepared p-aminosalicylic acid can also reach 99.5 or above by a permanent stop titration method, so that the quality of the prepared p-aminosalicylic acid is high. Moreover, according to the preparation process disclosed by the invention, the probability of generating quinones is reduced through low-temperature flash drying, meanwhile, tetrabutylammonium bromide can accelerate the reaction, and quinones impurities generated due to excessive sodium bicarbonate do not exist, so that the product quality and yield are greatly improved, and the yield can be improved by 23-30%.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly relates to an improved method for the preparation process of para-aminosalicylic acid. Background Art

[0002] Pasiniazid, also known as isoniazid para-aminosalicylate, is used to treat various types of pulmonary tuberculosis, endobronchial tuberculosis, and extrapulmonary tuberculosis. Pasiniazid is an antituberculosis drug synthesized from para-aminosalicylic acid and isoniazid. Para-aminosalicylic acid is an important intermediate for the preparation of pasiniazid.

[0003] The existing preparation process of para-aminosalicylic acid is specifically as follows: The filter cake retained from the previous preparation, as well as the proportioned water, m-aminophenol, and sodium bicarbonate are placed into a batching kettle for emulsification. After emulsification is completed, it is transferred to a carboxylation kettle for two vacuum and carbon dioxide replacements. After completion, the crude solution of sodium para-aminosalicylate in the carboxylation kettle is suction filtered into a neutralization kettle. Among them, after the suction filtration of the crude solution is completed, the remaining filter cake is washed with sodium sulfite and water, and the washed filter cake can be used for the next preparation. Subsequently, in the neutralization kettle, the pH value of the crude solution is neutralized to 7.5 - 8 with dilute sulfuric acid, sodium sulfite and activated carbon are added and the temperature is raised to decolorize the crude solution. Then, after decolorization is completed, the crude solution is filtered through a pressure filter and transferred to an acidification kettle. In an environment of 30 - 35 °C, the pH value of the filtrate is acidified to 3.0 - 3.5 with dilute sulfuric acid, then transferred to a centrifuge for standing, water washing, and centrifugal filtration. Finally, under an environment of 120 - 130 °C, flash drying is carried out to obtain para-aminosalicylic acid.

[0004] However, the para-aminosalicylic acid prepared by the existing technology has a low HPLC content and a low mass yield for m-aminophenol. In addition, the method of flash drying to obtain para-aminosalicylic acid in the existing preparation process at an environment of 120 - 130 °C is extremely likely to generate quinone impurities, and the usage amount of sodium bicarbonate in the existing preparation process is too high, which will generate sodium hydroxide after decomposition at high temperature, thereby exacerbating the generation of quinone impurities, and further leading to a reduction in the quality and yield of the produced para-aminosalicylic acid. Moreover, the existing preparation process also has problems such as energy consumption and emissions increase, so the existing technology has limitations. Summary of the Invention

[0005] The present invention is made to solve the above problems, and the purpose is to provide an improved method for the preparation process of para-aminosalicylic acid.

[0006] The present invention provides an improved method for the preparation process of para-aminosalicylic acid, having the following characteristics, including the following steps:

[0007] S1. Put the recycled filter cake and catalyst into a batching kettle, and proportionally place water, m-aminophenol, and sodium bicarbonate into the batching kettle for emulsification,

[0008] The catalyst is tetrabutylammonium bromide, and the ratio of the catalyst, water, m-aminophenol, and sodium bicarbonate is 0.003:1.2:1:0.9;

[0009] S2, the emulsified slurry is transferred to a carboxylation kettle, and vacuum and carbon dioxide replacement are performed three times. After completion, the temperature in the carboxylation kettle is raised to 70-75°C, the pressure is adjusted to 1.5-1.6Mpa, and maintained for 4 hours;

[0010] S3, lowering the temperature in the carboxylation kettle to below 10°C, and then filtering the reaction materials in the carboxylation kettle to obtain a crude sodium p-aminosalicylate solution and a filter cake;

[0011] S31, filtering the crude sodium p-aminosalicylate solution into a neutralization kettle;

[0012] S32, spreading sodium sulfite on the surface of the filter cake, and then washing the filter cake with water at room temperature to obtain a filter cake;

[0013] S4. In the neutralization kettle, use dilute sulfuric acid to neutralize the pH value of the crude sodium p-aminosalicylate solution to 7.2-7.5, then add a high-efficiency desulfonating agent and activated carbon into the neutralization kettle, and heat it to 35-40°C for decolorization. After completion, filter the product into the acidification kettle.

[0014] Wherein, the decolorization time is at least 30 minutes;

[0015] S5, the temperature in the acidification kettle is controlled at 20-23°C, and then the pH value of the filtrate is acidified to 3.0-3.2 by dropwise addition of dilute sulfuric acid at 0-5°C. After completion, the filtrate is stirred for 1 hour, and the pH value of the filtrate is re-measured. If the pH value is between 3.0 and 3.2, the reaction product is placed in a centrifuge.

[0016] Wherein, the dropping time of dilute sulfuric acid is not less than 1 hour;

[0017] S6, washing the reaction product in a centrifuge until it is salt-free, and then running the centrifuge to dehydrate the reaction product, and after completion, flash drying is performed at 80-90° C. to obtain p-aminosalicylic acid,

[0018] Among them, the dehydration time is at least 1.5 to 2 hours.

[0019] In the improved method for preparing p-aminosalicylic acid provided by the present invention, the following features can also be present: step S2 includes the following sub-steps:

[0020] S21. First vacuum and carbon dioxide replacement: Evacuate the carboxylation kettle until the pointer of the vacuum pressure gauge reaches -0.08 Mpa, then fill it with carbon dioxide until the pointer of the vacuum pressure gauge reaches 0.05 Mpa, and finally vent until the pointer of the vacuum pressure gauge reaches 0;

[0021] S22. Second vacuum and carbon dioxide replacement: Evacuate the carboxylation kettle until the pointer of the vacuum pressure gauge reaches -0.08 Mpa, then fill it with carbon dioxide until the pointer of the vacuum pressure gauge reaches 0.05 Mpa, and finally vent until the pointer of the vacuum pressure gauge reaches 0;

[0022] S23. Third vacuum and carbon dioxide replacement: Evacuate the carboxylation kettle until the pointer of the vacuum pressure gauge reaches -0.08 Mpa, then fill it with carbon dioxide until the pointer of the vacuum pressure gauge reaches 0.25 - 0.3 Mpa.

[0023] Functions and effects of the invention

[0024] According to an improved method for the preparation process of para - aminosalicylic acid involved in the present invention, the HPLC content of the prepared para - aminosalicylic acid can reach 99% - 99.5%, and the content determined by the dead - stop titration method can also reach more than 99.5%, thus making the quality of the para - aminosalicylic acid prepared by the present invention high. Moreover, the low - temperature flash drying in the preparation process of the present invention reduces the probability of forming quinones. At the same time, tetrabutylammonium bromide can also accelerate the reaction, and there is no generation of quinone impurities due to excessive sodium bicarbonate, which greatly improves the product quality and yield. The yield can be increased by 23 - 30%. Description of the drawings

[0025] Figure 1 It is the chromatogram of para - aminosalicylic acid prepared by the existing process;

[0026] Figure 2 It is the chromatogram of para - aminosalicylic acid prepared by an improved method for the preparation process of para - aminosalicylic acid of the present invention;

[0027] Figure 3 It is the process flow schematic diagram of an improved method for the preparation process of para - aminosalicylic acid of the present invention. Detailed implementation manners

[0028] In order to make the technical means, creative features, achieved purposes and functions of the present invention easy to understand, the following examples are specifically described in conjunction with the drawings of the present invention.

[0029] Examples

[0030] This example provides an improved method for the preparation process of para - aminosalicylic acid, including the following steps:

[0031] S1. Put the recycled filter cake and catalyst into the batching kettle, and proportionally put water, m-aminophenol, and sodium bicarbonate into the batching kettle for emulsification.

[0032] Among them, the catalyst is tetrabutylammonium bromide, and the ratio among the catalyst, water, m-aminophenol, and sodium bicarbonate is 0.003:1.2:1:0.9.

[0033] In this embodiment, it is preferred to put 1.5 kg of tetrabutylammonium bromide, 600 kg of water, 500 kg of m-aminophenol, and 450 kg of sodium bicarbonate into the batching kettle.

[0034] In this embodiment, the recycled filter cake is the filter cake left over from the previous preparation of para-aminosalicylic acid. Among them, the batching data of the recycled filter cake varies according to the test results. Preferably, the recycled filter cake includes 225 kg of m-aminophenol and 200 kg of sodium bicarbonate.

[0035] S2. Transfer the emulsified slurry into the carboxylation kettle, conduct three times of vacuum and carbon dioxide replacement. After completion, raise the temperature in the carboxylation kettle to 70 - 75 °C, adjust the pressure to 1.5 - 1.6 Mpa, and maintain for 4 hours.

[0036] Among them, for the first vacuum and carbon dioxide replacement, evacuate the carboxylation kettle until the pointer of the vacuum pressure gauge reaches -0.08 Mpa, then fill it with carbon dioxide until the pointer of the vacuum pressure gauge reaches 0.05 Mpa, and finally vent until the pointer of the vacuum pressure gauge reaches 0.

[0037] For the second vacuum and carbon dioxide replacement, evacuate the carboxylation kettle until the pointer of the vacuum pressure gauge reaches -0.08 Mpa, then fill it with carbon dioxide until the pointer of the vacuum pressure gauge reaches 0.05 Mpa, and finally vent until the pointer of the vacuum pressure gauge reaches 0.

[0038] For the third vacuum and carbon dioxide replacement, evacuate the carboxylation kettle until the pointer of the vacuum pressure gauge reaches -0.08 Mpa, then fill it with carbon dioxide until the pointer of the vacuum pressure gauge reaches 0.25 - 0.3 Mpa.

[0039] S3. Lower the temperature in the carboxylation kettle below 10 °C, and then filter the reaction materials in the carboxylation kettle to obtain a crude sodium para-aminosalicylate solution and a filter cake.

[0040] S31. Filter the crude sodium para-aminosalicylate solution into the neutralization kettle by suction filtration.

[0041] S32. Disperse sodium sulfite on the surface of the filter cake, and then wash the filter cake with normal temperature water to obtain a recycled filter cake.

[0042] In this embodiment, the mass of sodium sulfite dispersed on the surface of the filter cake is preferably 1.6 kg, and the mass of normal temperature water is preferably 500 kg.

[0043] S4. In the neutralization kettle, use dilute sulfuric acid to neutralize the pH value of the crude sodium p-aminosalicylate solution to 7.2-7.5, then add a high-efficiency desulfonating agent and activated carbon into the neutralization kettle, and heat it to 35-40°C for decolorization. After completion, filter the product into the acidification kettle.

[0044] The decolorization time is at least 30 minutes.

[0045] In this embodiment, the mass of the high-efficiency desulfonating agent added to the neutralization kettle is preferably 1.2 kg, and the mass of the activated carbon is preferably 3 kg.

[0046] In this embodiment, step S4 may also include: using liquid alkali to neutralize the p-aminosalicylic acid mother liquor left in the neutralization kettle, so that its pH value is neutralized to 6-7, and then transferred to the recovery kettle after completion. Then, after the p-aminosalicylic acid mother liquor is decompressed and evaporated to a certain amount in the recovery kettle, the filter residue is washed with hot water, and the pH value of the filtered liquid is neutralized to 7-7.5 with dilute sulfuric acid. Then, the temperature is lowered to 40-45°C for centrifugation, and then rinsed with water once to obtain meta-aminophenol. Finally, the liquid filter can also be transferred to the recovery kettle for application.

[0047] Among them, the mass of hot water is preferably 100L, the mass of flushing water is preferably 50kg, and the centrifugal temperature is not lower than 40°C.

[0048] S5. The temperature in the acidification kettle is controlled at 20-23°C, and then the pH value of the filtrate is acidified to 3.0-3.2 by dropwise addition of dilute sulfuric acid at 0-5°C. After completion, the filtrate is stirred for 1 hour, and the pH value of the filtrate is re-measured. If the pH value is between 3.0 and 3.2, the reaction product is placed in a centrifuge.

[0049] If the pH value of the filtrate is not between 3.0 and 3.2, the pH value of the filtrate is adjusted until the pH value of the filtrate is within the range of 3.0 to 3.2.

[0050] In this embodiment, the dilute sulfuric acid is added dropwise for no less than 1 hour.

[0051] S6. The reaction product is rinsed in a centrifuge until it is free of salt, and then the centrifuge is operated to dehydrate the reaction product. After completion, the reaction product is flash dried at 80-90° C. to obtain p-aminosalicylic acid.

[0052] Among them, the dehydration time is at least 1.5 to 2 hours.

[0053] In this embodiment, for the preparation of dilute sulfuric acid, 700 kg of water is added to the proportioning kettle. Meanwhile, chilled brine is introduced into the heat exchange jacket of the proportioning kettle for cooling. Then, 300 kg of concentrated sulfuric acid is added dropwise into the proportioning kettle, and the dropping temperature is controlled at 19 - 21°C. After completion, the temperature is reduced to 0°C to finish the preparation, which can be used for acidification.

[0054] The HPLC content of the para - aminosalicylic acid prepared by the improved method of the para - aminosalicylic acid preparation process of the present invention can reach 99 - 99.5%, and the content determined by the dead - stop titration method can also reach over 99.5%. Moreover, low - temperature flash drying can reduce the probability of forming quinones. At the same time, tetrabutylammonium bromide can also accelerate the reaction, and there is no formation of quinone impurities due to excessive sodium bicarbonate, which significantly improves the product quality and yield. The yield can be increased by 23 - 30%. In addition, for every 1 ton of para - aminosalicylic acid produced by the preparation process of the present invention, the wastewater volume is reduced to 10 - 13 tons. The ratio of the wastewater volume to that of the existing preparation process is 1:2 - 1:2.5. Compared with the existing preparation process, the wastewater volume can be reduced by 10 - 13 tons, and the wastewater volume decreases by 50 - 65%. Therefore, the preparation process of the present invention has a high yield, high output, and can achieve energy conservation and emission reduction.

[0055] Functions and effects of the embodiment

[0056] According to the improved method of the para - aminosalicylic acid preparation process involved in the present invention, the HPLC content of the prepared para - aminosalicylic acid can reach 99% - 99.5%, and the content determined by the dead - stop titration method can also reach over 99.5%, thus making the quality of the para - aminosalicylic acid prepared by the present invention high. And, the low - temperature flash drying in the preparation process of the present invention reduces the probability of forming quinones. At the same time, tetrabutylammonium bromide can also accelerate the reaction, and there is no formation of quinone impurities due to excessive sodium bicarbonate, which significantly improves the product quality and yield. The yield can be increased by 23 - 30%.

[0057] The above - mentioned implementation manners are preferred cases of the present invention and are not used to limit the protection scope of the present invention.

Claims

1. An improved method for the preparation process of para-aminosalicylic acid, characterized in that, The following steps are involved: S1. Put the filter cake and the catalyst into a batching kettle, and put water, m-aminophenol and sodium bicarbonate into the batching kettle in proportion for emulsification. Wherein, the catalyst is tetrabutylammonium bromide, and the ratio of the catalyst, the water, the m-aminophenol, and the sodium bicarbonate is 0.003:1.2:1:0.9; S2, the emulsified slurry is transferred to a carboxylation kettle, and vacuum and carbon dioxide replacement are performed three times. After completion, the temperature in the carboxylation kettle is raised to 70-75° C., the pressure is adjusted to 1.5-1.6 MPa, and maintained for 4 hours; S3, lowering the temperature in the carboxylation kettle to below 10° C., and then filtering the reaction mass in the carboxylation kettle to obtain a crude sodium p-aminosalicylate solution and a filter cake; S31, filtering the crude sodium p-aminosalicylate solution into a neutralization kettle; S32, spreading sodium sulfite on the surface of the filter cake, and then washing the filter cake with water at room temperature to obtain the filter cake; S4, in the neutralization kettle, using dilute sulfuric acid to neutralize the pH value of the crude sodium p-aminosalicylate solution to 7.2-7.5, then adding a high-efficiency desulfonating agent and activated carbon into the neutralization kettle, and heating to 35-40° C. for decolorization, after completion, the product is filtered and put into the acidification kettle, Wherein, the decolorization time is at least 30 minutes; S5, controlling the temperature in the acidification kettle at 20-23°C, then acidifying the pH value of the filtrate to 3.0-3.2 by dropwise addition of dilute sulfuric acid at 0-5°C, stirring the filtrate for 1 hour, retesting the pH value of the filtrate, and placing the reaction product in a centrifuge if the pH value is between 3.0 and 3.

2. Wherein, the dilute sulfuric acid is added for no less than 1 hour; S6, washing the reaction product in the centrifuge until it is salt-free, then running the centrifuge to dehydrate the reaction product, and after completion, flash drying at 80-90° C. to obtain p-aminosalicylic acid, Among them, the dehydration time is at least 1.5 to 2 hours.

2. The improved method for the preparation process of para-aminosalicylic acid according to claim 1, wherein: : Step S2 includes the following sub-steps, S21, the first vacuum, carbon dioxide replacement, evacuate the carboxylation kettle until the vacuum pressure gauge pointer reaches -0.08Mpa, then fill with carbon dioxide until the vacuum pressure gauge pointer reaches 0.05Mpa, and finally vent until the vacuum pressure gauge pointer reaches 0; S22, the second vacuum, carbon dioxide replacement, evacuate the carboxylation kettle until the vacuum pressure gauge pointer reaches -0.08Mpa, then fill with carbon dioxide until the vacuum pressure gauge pointer reaches 0.05Mpa, and finally vent until the vacuum pressure gauge pointer reaches 0; S23, vacuum and carbon dioxide replacement for the third time, evacuate the carboxylation kettle until the vacuum pressure gauge pointer reaches -0.08Mpa, and then fill it with carbon dioxide until the vacuum pressure gauge pointer reaches 0.25-0.3Mpa.

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