A process for the preparation of low chloride mesalazine

Abstract

The present application belongs to the field of chemical medicine technology, and particularly relates to a preparation method of low-chloride mesalazine. The present application first mixes acid and a decolorized mesalazine crude product solution, then adjusts the pH value of the system to 2.5-3.0 by using sodium hydroxide and then cools; in the process of adjusting the pH value of the system, the sodium hydroxide first reacts with the acid to produce a salt, and then the salt and the mesalazine hydrochloride are replaced to remove the chlorides in the mesalazine crude product; the preparation method provided by the present application avoids the direct contact of strong acid and strong base, thereby reducing the large amount of chlorides wrapped in the product during crystallization and improving the product purity. Meanwhile, the present application uses a small amount of concentrated hydrochloric acid to dissolve the mesalazine crude product to introduce a small amount of chloride ions into the system, which is beneficial to the purification.

Description

Technical Field

[0001] This invention belongs to the field of chemical and pharmaceutical technology, specifically relating to a method for preparing low-chloride mesalazine. Background Technology

[0002] Mesalazine is primarily used for maintenance therapy in mild to moderate ulcerative colitis, exhibiting a significant inhibitory effect on intestinal wall inflammation. Furthermore, due to the presence of three reactive groups—amino, hydroxyl, and carboxyl—in its structure, mesalazine can undergo various reactions, making it suitable for manufacturing a wide range of high-quality reactive dyes in the dye industry.

[0003] There are numerous reports on methods for synthesizing mesalazine, such as the nitro reduction method, aniline synthesis method, and Kolbe-Schmitt synthesis method. However, mesalazine prepared using existing methods often contains significant amounts of chloride residues, which reduces its purity and affects its performance. Existing reports on methods for purifying crude mesalazine include the following patent: EP3044203 discloses a method for producing mesalazine with a bulk density greater than or equal to 0.30 g / mL and essentially solvent-free: mesalazine is dissolved in an aqueous hydrochloric acid solution to obtain an acidic mesalazine hydrochloride solution with a pH < 2.0. This acidic mesalazine hydrochloride solution is then added to an aqueous buffer system of acetic acid and sodium acetate, resulting in a pH of 3.5–4.5, to increase the pH of the solution and promote the crystallization of mesalazine with a bulk density greater than or equal to 0.30 g / mL. IN376069 discloses a method of adding an inorganic acid to an alkaline solution of mesalazine at a temperature range of 25-65°C, adding activated carbon to an acidic solution of mesalazine for decolorization, filtering to obtain a filtrate, and then adjusting the pH to between 2.5 and 5.0 by adding an alkaline aqueous solution. Mesalazine is then obtained by crystallization. Wo2015036920A1 discloses a method for preparing high-density crystals using an acetic acid and sodium acetate buffer system. Wo2023144678 discloses a method for purifying 5-aminosalicylic acid (mesalacin), which involves preparing an aqueous solution or suspension of 5-aminosalicylic acid, optionally adding at least one solvent, adding alkali to adjust the pH to 6-9, adding acid to the obtained solution until the pH is between 3.2 and 5.2, preferably between 4.3 and 4.6, and then precipitating mesalazine.

[0004] Although existing methods can purify mesalazine to some extent, the processed product still contains a large amount of chloride (chloride content > 300 ppm). Summary of the Invention

[0005] In view of this, the present invention provides a method for preparing low-chloride mesalazine. Purifying crude mesalazine according to the method provided by the present invention can efficiently remove chloride from crude mesalazine and significantly improve the purity of mesalazine.

[0006] To address the aforementioned technical problems, this invention provides a method for preparing low-chloride mesalazine, comprising the following steps:

[0007] Crude mesalazine, purified water, and concentrated hydrochloric acid solution were mixed to obtain a crude mesalazine solution; the mass concentration of the concentrated hydrochloric acid solution was 28-36%, and the molar ratio of hydrogen chloride to crude mesalazine in the concentrated hydrochloric acid solution was 1.05-1.2:1.

[0008] The crude mesalazine solution was mixed with activated carbon, decolorized, and then filtered to obtain the filtrate.

[0009] The filtrate and acid were mixed, and sodium hydroxide solution was added dropwise. After controlling the pH value to 2.5-3.0, the mixture was cooled and crystallized to obtain high-quality mesalazine.

[0010] Preferably, the acid includes formic acid, acetic acid, phosphoric acid, or benzoic acid.

[0011] Preferably, the mass ratio of the acid to purified water is 0.1 to 5:100.

[0012] Preferably, the mass concentration of the sodium hydroxide solution is 5-30%.

[0013] Preferably, the dripping rate is 80-100 mL / h.

[0014] Preferably, the temperature at which the drop is added is 60–70°C.

[0015] Preferably, the crude mesalazine, purified water, and concentrated hydrochloric acid solution are mixed under stirring conditions, and the stirring temperature is 60-70°C.

[0016] Preferably, the mass ratio of purified water to crude mesalazine is 18–22:1.

[0017] Preferably, the cooling crystallization temperature is 5–15°C and the time is 2–4 hours.

[0018] Preferably, the mass ratio of activated carbon to crude mesalazine is 2.4–2.6:100.

[0019] The present invention provides a method for preparing low-chloride mesalazine, comprising the following steps: mixing crude mesalazine, purified water, and concentrated hydrochloric acid solution to obtain a crude mesalazine solution; the mass concentration of the concentrated hydrochloric acid solution is 28-36%, and the molar ratio of hydrogen chloride to crude mesalazine in the concentrated hydrochloric acid solution is 1.05-1.2:1; mixing the crude mesalazine solution with activated carbon, decolorizing, and filtering to obtain a filtrate; mixing the filtrate with acid, adding sodium hydroxide solution dropwise, controlling the pH value to 2.5-3.0, and then cooling to crystallize, obtaining a refined mesalazine. The present invention first mixes the acid and the decolorized crude mesalazine solution, and then uses sodium hydroxide to adjust the pH value of the system and cools it; during the pH adjustment process, sodium hydroxide first reacts with the acid to neutralize and produce a salt, and then the salt reacts with the mesalazine hydrochloride salt to remove chloride from the crude mesalazine; the preparation method provided by the present invention avoids direct contact between strong acid and strong alkali, thereby reducing the large amount of chloride encapsulated in the product during crystallization and improving product purity. Meanwhile, the present invention uses a smaller amount of concentrated hydrochloric acid solution to dissolve crude mesalazine, introducing a smaller amount of chloride ions into the system, which is beneficial for purification. Attached Figure Description

[0020] Figure 1 This is a flowchart illustrating the chemical reaction that occurs when adjusting the pH of a system using sodium hydroxide solution, with acetic acid as an example.

[0021] Figure 2 The HPLC chromatogram of mesalazine after treatment in Example 1 is shown below.

[0022] Figure 3 The potentiometric titration chromatogram of chloride content of mesalazine after treatment in Example 1 is shown.

[0023] Figure 4 The HPLC chromatogram of mesalazine after treatment in Example 2 is shown below.

[0024] Figure 5 The potentiometric titration chromatogram of chloride content of mesalazine after treatment in Example 2 is shown.

[0025] Figure 6 The HPLC chromatogram of mesalazine after treatment in Example 3 is shown below.

[0026] Figure 7 The potentiometric titration chromatogram of chloride content of mesalazine after treatment in Example 3 is shown.

[0027] Figure 8 The HPLC chromatogram of mesalazine after treatment in Example 4 is shown below.

[0028] Figure 9 The potentiometric titration chromatogram of chloride content of mesalazine after treatment in Example 4 is shown.

[0029] Figure 10 The HPLC chromatogram of mesalazine after treatment in Comparative Example 1 is shown below.

[0030] Figure 11 The image shows the chloride content of mesalazine after treatment with Comparative Example 1, obtained by potentiometric titration. Detailed Implementation

[0031] This invention provides a method for preparing low-chloride mesalazine, comprising the following steps:

[0032] Crude mesalazine, purified water, and concentrated hydrochloric acid solution were mixed to obtain a crude mesalazine solution; the mass concentration of the concentrated hydrochloric acid solution was 28-36%, and the molar ratio of hydrogen chloride to crude mesalazine in the concentrated hydrochloric acid solution was 1.05-1.2:1.

[0033] The crude mesalazine solution was mixed with activated carbon, decolorized, and then filtered to obtain the filtrate.

[0034] The filtrate and acid were mixed, and sodium hydroxide solution was added dropwise. After controlling the pH value to 2.5-3.0, the mixture was cooled and crystallized to obtain high-quality mesalazine.

[0035] This invention involves mixing crude mesalazine, purified water, and concentrated hydrochloric acid solution to obtain a crude mesalazine solution. Preferably, the purity of the crude mesalazine is 98-99%. The mass ratio of purified water to crude mesalazine is preferably 18-22:1, more preferably 20:1. The concentration of the concentrated hydrochloric acid solution is 28-36%, preferably 30-32%; the molar ratio of hydrogen chloride to crude mesalazine in the concentrated hydrochloric acid solution is 1.05-1.2:1, preferably 1.05-1.1:1.

[0036] In this invention, the mixing of crude mesalazine, purified water, and concentrated hydrochloric acid solution is preferably carried out under stirring conditions. The stirring temperature is preferably 60–70°C, more preferably 63–68°C. This invention does not have special requirements for the stirring speed and time, as long as complete dissolution and a clear solution are achieved.

[0037] After obtaining the crude mesalazine solution, the present invention mixes the crude mesalazine solution with activated carbon, decolorizes it, and then filters it to obtain a filtrate. In the present invention, the mass ratio of activated carbon to crude mesalazine is preferably 2.4–2.6:100, more preferably 2.5:100. In the present invention, the decolorization is preferably accompanied by stirring, and the decolorization time is preferably 25–35 min, more preferably 30 min. The present invention has specific requirements for the filtration process; conventional methods in the art can be used.

[0038] After obtaining the filtrate, the present invention mixes the filtrate and acid, then adds sodium hydroxide solution dropwise, controls the pH value to 2.5-3.0, and then cools to crystallize, obtaining the refined mesalazine. In this invention, the acid preferably includes formic acid, acetic acid, phosphoric acid, or benzoic acid, more preferably acetic acid or phosphoric acid. In this invention, the acid can react with sodium hydroxide to form a buffer system, preventing the formation of chloride ions during the acid-base neutralization reaction of HCl and NaOH, thus avoiding chloride encapsulation. In this invention, the mass ratio of the acid to purified water is preferably 0.1-5:100, more preferably 0.1-1:100, and even more preferably 0.25-0.4:100. This invention does not have special requirements for the mixing of the filtrate and acid, as long as they are mixed evenly.

[0039] In this invention, the mass concentration of the sodium hydroxide solution is preferably 5-30%, more preferably 10-20%. The dropping rate is preferably 80-100 mL / h, more preferably 80-90 mL / h. The dropping temperature is preferably 60-70°C, more preferably 65-68°C. The pH of the system after adding the sodium hydroxide solution is 2.5-3.0, preferably 2.6-2.8. This invention does not have a particular limitation on the amount of sodium hydroxide solution used, as long as the desired pH value is achieved.

[0040] Figure 1 The following is a flowchart illustrating the chemical reaction that occurs when adjusting the pH of a system using sodium hydroxide solution, with acetic acid as an example. Specifically, acetic acid first undergoes a neutralization reaction with sodium hydroxide to produce sodium acetate. Sodium acetate then undergoes a displacement reaction with mesalazine hydrochloride to produce mesalazine. In this reaction process, direct contact between the strong acid (HCl in mesalazine hydrochloride) and the strong base (sodium hydroxide) is avoided, which reduces the reaction rate and prevents crystallization from occurring too quickly, resulting in a large amount of chloride being coated on the crystallized product, thus improving the purity of the crystallized product.

[0041] In this invention, the cooling crystallization temperature is preferably 5-15°C, more preferably 8-12°C; the cooling crystallization time is preferably 2-4 hours, more preferably 2-3 hours.

[0042] The present invention preferably further includes, after cooling and crystallization: solid-liquid separation of the cooled and crystallized system, and sequential washing and drying of the solid obtained from the solid-liquid separation to obtain the refined mesalazine. In the present invention, the solid-liquid separation is preferably filtration. In the present invention, the water used for washing is preferably purified water; the washing is preferably rinsing, and the mass of the rinsing water is preferably 90-110g, more preferably 100g. The present invention has no special requirements for the drying process, as long as the solvent on the surface of the solid is removed.

[0043] In this invention, the residual chloride content in the mesalazine product is preferably below 200 ppm, and more preferably 89 to 152 ppm.

[0044] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0045] Example 1

[0046] 800g of purified water, 40g (0.261mol) of crude mesalazine and 34.92g (0.287mol) of 30% concentrated hydrochloric acid solution were stirred and dissolved at 60℃ to obtain crude mesalazine solution.

[0047] Mix the crude mesalazine solution with 1g of activated carbon, stir and decolorize for 30 minutes, then hot filter to obtain the filtrate;

[0048] Add 3.2g of acetic acid to the filtrate and add 10% sodium hydroxide solution at a dropping rate of 85mL / h at 60℃. After adjusting the pH of the system to 2.8, cool to 10℃ and allow it to crystallize for 3 hours. Filter the solution and wash it with 100g of purified water. Dry the solid obtained from the filter to obtain the premium mesalazine.

[0049] Example 2

[0050] The crude mesalazine was treated according to the method in Example 1, except that 3.2g of acetic acid was replaced with 2.5g of formic acid, and the 10% sodium hydroxide solution was replaced with a 5% sodium hydroxide solution.

[0051] Example 3

[0052] Mesalazine crude product was treated according to the method in Example 1, except that 3.2g of acetic acid was replaced with 3g of phosphoric acid.

[0053] Example 4

[0054] Mesalazine crude product was treated according to the method in Example 1, except that 3.2g of acetic acid was replaced with 2g of benzoic acid.

[0055] Comparative Example 1

[0056] The crude mesalazine was processed according to the method in Example 1, except that no acid was added (the addition of 3.2g of acetic acid was omitted);

[0057] The equations for dissolving crude mesalazine in concentrated hydrochloric acid solution and the reaction of mesalazine hydrochloride with sodium hydroxide are shown in Equation 1:

[0058]

[0059] The yields of mesalazine after treatment in Examples 1-4 and Comparative Example 1 were calculated, and the results are listed in Table 1. The purity of mesalazine after treatment in Examples 1-4 and Comparative Example 1 was determined by high performance liquid chromatography (HPLC), and the results are listed in Table 1. The chloride content in mesalazine after treatment in Examples 1-4 and Comparative Example 1 was determined by potentiometric titration and visual colorimetry, and the results are listed in Table 1.

[0060] Table 1. Characteristic parameters of the processed mesalazine products in Examples 1-4 and Comparative Example 1.

[0061]

[0062] Figure 2 The image shows the HPLC chromatogram of mesalazine after treatment in Example 1. Figure 3 The potentiometric titration chromatogram of chloride content of mesalazine after treatment in Example 1 is shown. Figure 4 The image shows the HPLC chromatogram of mesalazine after treatment in Example 2. Figure 5 The potentiometric titration chromatogram of chloride content of mesalazine after treatment in Example 2 is shown. Figure 6 The image shows the HPLC chromatogram of mesalazine after treatment in Example 3. Figure 7 The potentiometric titration chromatogram of chloride content of mesalazine after treatment in Example 3 is shown. Figure 8 The image shows the HPLC chromatogram of mesalazine after treatment in Example 4. Figure 9 The potentiometric titration chromatogram of chloride content of mesalazine after treatment in Example 4 is shown. Figure 10 The image shows the HPLC chromatogram of mesalazine after treatment in Comparative Example 1. Figure 11 The image shows the chloride content of mesalazine after treatment with Comparative Example 1, obtained by potentiometric titration.

[0063] Combining Table 1 and Figures 2-11 It can be seen that the chloride content in the mesalazine treated according to the method provided by this invention is low, all below 200 ppm. In Comparative Example 1, no acid was added, and the pH was adjusted directly with sodium hydroxide solution. The rapid contact reaction between the strong acid and strong alkali resulted in a product precipitation rate that was too fast, causing the precipitated product to instantly encapsulate chloride, thus increasing the residual chloride content in the mesalazine.

[0064] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing low-chloride mesalazine, comprising the following steps: Crude mesalazine, purified water, and concentrated hydrochloric acid solution are mixed to obtain a crude mesalazine solution; the mass concentration of the concentrated hydrochloric acid solution is 28-36%, and the molar ratio of hydrogen chloride to crude mesalazine in the concentrated hydrochloric acid solution is 1.05-1.2:

1. The crude mesalazine solution was mixed with activated carbon, decolorized, and then filtered to obtain the filtrate. The filtrate and acid are mixed, and sodium hydroxide solution is added dropwise. After controlling the pH value to 2.5-3.0, the mixture is cooled and crystallized to obtain high-quality mesalazine. The acid is selected from formic acid, acetic acid, phosphoric acid, or benzoic acid, and the mass ratio of the acid to purified water is 0.1-5:

100.

2. The preparation method according to claim 1, characterized in that, The sodium hydroxide solution has a mass concentration of 5-30%.

3. The preparation method according to claim 1 or 2, characterized in that, The dripping rate is 80~100mL / h.

4. The preparation method according to claim 1, characterized in that, The temperature at which the drops are added is 60~70℃.

5. The preparation method according to claim 1, characterized in that, The crude mesalazine, purified water, and concentrated hydrochloric acid solution were mixed under stirring conditions at a temperature of 60-70°C.

6. The preparation method according to claim 1 or 5, characterized in that, The mass ratio of purified water to crude mesalazine is 18-22:

1.

7. The preparation method according to claim 1, characterized in that, The cooling and crystallization temperature is 5~15℃, and the time is 2~4h.

8. The preparation method according to claim 1, characterized in that, The mass ratio of activated carbon to crude mesalazine is 2.4~2.6:100.

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