Preparation method of 2-hydroxy-5-aminobenzoic acid

Abstract

The present application relates to a preparation method of 2-hydroxy-5-aminobenzoic acid, comprising the steps of: putting raw material 5-ASA into a reactor, adding hydrochloric acid solution to mix and then cooling, then adding sodium nitrite solution, realizing the aminodiazotization reaction of 5-ASA, and obtaining diazo salicylic acid hydrochloride; after cooling, adding sodium hydroxide solution and salicylic acid alkaline solution into the reactor, realizing the coupling reaction of diazo salicylic acid hydrochloride, and filtering by pressure after adding acetic acid to obtain the azo compound Olsalazine solid; sodium hydroxide solution and Olsalazine solid are added into the reduction reactor, slowly adding sodium dithionite solid after heating, passing nitrogen, cooling after reaction, then adding hydrochloric acid solution into the system, vacuum filtration after stirring to obtain crude product 5-ASA. This preparation method has simple circuit, low cost and can reduce the three wastes produced, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present application relates to organic synthesis technology, and in particular to a method for preparing 2-hydroxy-5-aminobenzoic acid. Background Art

[0002] 2-Hydroxy-5-aminobenzoic acid (5-ASA), also known as 5-aminosalicylic acid, is an important pharmaceutical and dye intermediate. It also has medicinal activity. The drug name is Mesalazine, and it is the first choice drug for the treatment of inflammatory bowel inflammation.

[0003] There are three main methods for the synthesis of traditional 5-ASA: Aniline synthesis method: This method uses aniline as the starting material, and obtains the final product 5-ASA through diazotization, coupling reaction, and reduction reaction. This route is long, the yield is low, and the reaction system is dark in color. In addition, aniline is highly toxic and is easily carried into the finished product. It is not easy to purify and remove it, and it is also harmful to the environment to a certain extent. Nitrosalicylic acid reduction method: This method uses salicylic acid (SA) as the starting material, first obtains 5-nitrosalicylic acid through a nitration reaction, and then uses iron powder to reduce the nitro group to an amino group under acidic conditions. After treatment, 5-ASA is precipitated under weakly acidic conditions. The total yield of this route is about 50%. The route is simple, but isomers are easily produced during the nitration process, which makes subsequent purification difficult. In addition, a large amount of nitric acid and iron powder are used in the reaction, and the three wastes are seriously polluted. Kolbe-Schmitt synthesis method, in which 4-aminophenol reacts with carbon dioxide under high temperature and high pressure to generate 5-ASA. This method has a long reaction time and high energy consumption. At the same time, the gas-solid two-phase reaction has poor contact, and the reaction materials are prone to local overheating and carbonization.

[0004] Therefore, it is of great significance to develop a low-cost, stable and safe 5-ASA process route suitable for large-scale industrial production. Summary of the invention

[0005] In order to overcome the above-mentioned defects, the present application provides a method for preparing 2-hydroxy-5-aminobenzoic acid, which has a simple circuit, low cost and can reduce the generation of three wastes, and is suitable for large-scale industrial production.

[0006] The technical solution adopted by this application to solve its technical problems is:

[0007] A method for preparing 2-hydroxy-5-aminobenzoic acid comprises the following steps:

[0008] Aminodiazotization reaction: the raw material 5-ASA is placed in a reactor, a hydrochloric acid solution is added, the mixture is cooled, and then a sodium nitrite solution is added to realize an aminodiazotization reaction of 5-ASA to obtain diazosalicylic acid hydrochloride, wherein the raw material 5-ASA is chemical grade 5-ASA or reagent grade 5-ASA;

[0009] Coupling reaction: After cooling, sodium hydroxide solution and salicylic acid alkaline solution are added to the reactor to achieve the coupling reaction of diazo salicylic acid hydrochloride, and acetic acid is added and filtered to obtain the azo compound olsalazine solid;

[0010] Reduction reaction: Sodium hydroxide solution and olsalazine solid are added to a reduction reactor, and after heating, sodium dithionite solid is slowly added, nitrogen is introduced, and after the reaction, the system is cooled, and hydrochloric acid solution is added to the system. After stirring, vacuum filtration is performed to obtain crude 5-ASA.

[0011] Optionally, in the aminodiazotization reaction, the purity of the raw material 5-ASA is 95-98%, and after adding the hydrochloric acid solution, it is cooled to 0°C-2°C, and a sodium nitrite solution is added, and the temperature is maintained at 0-10°C for 2.5±0.5h.

[0012] Optionally, in the aminodiazotization reaction, the concentration of the hydrochloric acid solution is 1±0.2 mol / L, and the hydrochloric acid solution is prepared by adding water to reagent-grade hydrochloric acid with a mass concentration of 36-38%, the amount of reagent-grade hydrochloric acid used is 2.2eq.-12eq. of the raw material 5-ASA, and the amount of sodium nitrite used is 1.0eq.-1.5eq. of the raw material 5-ASA.

[0013] Optionally, in the coupling reaction, the pH value in the system is 5-7, the reaction temperature is 5-20° C., and the reaction time is 10±1 h.

[0014] Optionally, the coupling reaction comprises the following steps:

[0015] Prepare sodium hydroxide solution A: weigh sodium hydroxide and dissolve it in water to obtain sodium hydroxide solution A;

[0016] Prepare salicylic acid alkaline solution: weigh sodium hydroxide and dissolve it in water to obtain sodium hydroxide solution B, stir until the solid is completely dissolved and then cool to room temperature, then add salicylic acid to obtain salicylic acid alkaline solution, stir evenly and then cool to 0°C;

[0017] Adding sodium hydroxide solution A: Add urea to the reaction kettle after the reaction is completed, stir until there are no obvious bubbles in the system, and slowly drop sodium hydroxide solution A into it. During the dropwise addition, keep the system temperature no higher than 10°C;

[0018] Adding salicylic acid alkaline solution: Continue to add salicylic acid alkaline solution to the reaction system, and keep the system temperature no higher than 15°C during the addition process;

[0019] Reaction: N2 is introduced into the system, the system temperature is maintained at 10-15°C, and the reaction is continued for 7-9 hours, and then samples are taken for analysis. The reaction is stopped when the mass content of 5-DASA-Cl is less than 2%;

[0020] Filtration: After the reaction is completed, cool the reaction system to 0°C, slowly add acetic acid to the system, continue stirring for 10-20 hours, and then vacuum filter the reaction system to obtain olsalazine solid, which can be directly used in the next reduction reaction.

[0021] Optionally, the amount of sodium hydroxide added to sodium hydroxide solution A is 1.2 eq.-1.6 eq. of the raw material 5-ASA, the amount of sodium hydroxide added to sodium hydroxide solution B is 3.0 eq.-3.8 eq. of the raw material 5-ASA, and the amount of salicylic acid used is 0.8 eq.-1.2 eq. of the raw material 5-ASA.

[0022] Optionally, the reduction reaction comprises the following steps:

[0023] Prepare sodium hydroxide solution: dissolve sodium hydroxide in water in a reduction reactor under ice bath conditions to prepare a sodium hydroxide solution, and then add the solid azo compound into the reduction reactor;

[0024] Add sodium dithionite: Heat the solution in the reduction reactor to 70-90°C, then slowly add sodium dithionite solid, control the adding speed to avoid excessive bubbles, and keep the system temperature no higher than 90°C;

[0025] Reaction: N2 was introduced into the system, the temperature of the system was maintained at 85±5°C, and the reaction was carried out for 2-3 hours. The intermediate olsalazine completely disappeared under TLC monitoring;

[0026] Cooling: Cool the reaction system to 0°C, slowly drop 60±5 mL of 1:1 hydrochloric acid solution into it, continue stirring for 25-40 minutes, vacuum filter the reaction system, and the resulting solid is the crude 5-ASA.

[0027] Optionally, decolorization and purification are also included: the crude 5-ASA is added to a decolorization kettle, and activated carbon and hydrochloric acid solution are added to decolorize the crude 5-ASA, and a liquid material is obtained by filter pressing, and the liquid material is put into a crystallization kettle, and a sodium hydroxide solution is added to recrystallize, and the product 5-ASA is obtained after cooling and drying.

[0028] Optionally, during decolorization and purification, the concentration of the hydrochloric acid solution is 1 mol / L, the amount of activated carbon used is 10-20% of the mass of the crude 5-ASA, the decolorization temperature is 50±5° C., and the decolorization time is 50-80 min.

[0029] Optionally, the purity of the product 5-ASA obtained after decolorization and purification is 99-99.7%, and the product 5-ASA is dried, crushed and packaged to obtain finished 5-ASA.

[0030] The beneficial effects of the present application are: in the present application, low-purity chemical grade or reagent grade 5-ASA is used as a raw material, and high-purity 5-ASA is obtained through a one-pot two-step aminodiazotization reaction / coupling reaction and a reduction reaction, and 0.5 parts of low-purity 5-ASA can produce about 1 part of high-purity 5-ASA; no additional amine impurities are introduced during the preparation process, which can effectively reduce the difficulty of product purification and improve product quality, and the intermediate 5,5'-azosalicylic acid (Olsalazine) is also a drug for treating inflammatory bowel inflammation, which has lower toxic and side effects on the human body, and the preparation method has a high practical application value. Therefore, the preparation method has a simple circuit, low cost, and can reduce the three wastes produced, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The DASA-Cl obtained by the aminodiazotization reaction in Example 1 of this application 1 H-NMR spectrum;

[0032] Figure 2 The crude 5-ASA obtained by reduction reaction in Example 1 of this application 1 H-NMR spectrum. DETAILED DESCRIPTION

[0033] The technical solutions in the embodiments of the present application will be described clearly and completely below in conjunction with the embodiments of the present application. Obviously, the embodiments described in the present application are only a part of the embodiments of the present application, rather than all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present application.

[0034] It should be noted that the terms "first", "second", etc. in the specification and claims of the present application and the following drawings are used to distinguish similar objects, and are not necessarily used to describe a specific order or sequence. It should be understood that the objects used in this way can be interchanged where appropriate, so that the embodiments of the present application described herein can be implemented in an order other than those illustrated or described herein. In addition, the terms "including" and "having" and any of their variations are intended to cover non-exclusive inclusions, for example, a process, method, system, product or device that includes a series of steps or units is not necessarily limited to those steps or units that are clearly listed, but may include other steps or units that are not clearly listed or inherent to these processes, methods, products or devices.

[0035] For ease of description, spatially relative terms such as "above", "above", "on the upper surface of", "above", etc. may be used here to describe the spatial positional relationship between a device or feature and other devices or features as shown in the figure. It should be understood that spatially relative terms are intended to include different orientations of the device in use or operation in addition to the orientation described in the figure. For example, if the device in the accompanying drawings is inverted, the device described as "above other devices or structures" or "above other devices or structures" will be positioned as "below other devices or structures" or "below other devices or structures". Thus, the exemplary term "above" can include both "above" and "below". The device can also be positioned in other different ways (rotated 90 degrees or in other orientations), and the spatially relative descriptions used here are interpreted accordingly.

[0036] A method for preparing 2-hydroxy-5-aminobenzoic acid comprises the following steps:

[0037] Aminodiazotization reaction: the raw material 5-ASA is put into a reactor, a hydrochloric acid solution is added, the mixture is cooled, and then a sodium nitrite solution is added to realize the aminodiazotization reaction of 5-ASA to obtain diazo salicylic acid hydrochloride, wherein the raw material 5-ASA is chemical grade 5-ASA or reagent grade 5-ASA; the raw material 5-ASA is dissolved in a hydrochloric acid solution by using chemical grade 5-ASA or reagent grade 5-ASA which is inexpensive and of low purity, and under the action of sodium nitrite, 5-ASA realizes an aminodiazotization reaction, thereby reducing the cost of raw materials, simplifying the process and reducing the generation of three wastes.

[0038] Coupling reaction: After cooling, sodium hydroxide solution and salicylic acid alkaline solution are added to the reactor to achieve the coupling reaction of diazosalicylic acid hydrochloride, and acetic acid is added and filtered to obtain the azo compound olsalazine solid; that is, the intermediate olsalazine (5,5'-azosalicylic acid, Olaslazine, OLZ);

[0039] Reduction reaction: sodium hydroxide solution and olsalazine solid are added to the reduction reactor, sodium dithionite solid is slowly added after heating, nitrogen is passed through, and the reaction is cooled, and hydrochloric acid solution is added to the system, and vacuum filtration is performed after stirring to obtain crude 5-ASA. In this application, low-purity chemical grade or reagent grade 5-ASA is used as a raw material, and high-purity 5-ASA is obtained through a one-pot two-step aminodiazotization reaction / coupling reaction and a reduction reaction, and 0.5 parts of low-purity 5-ASA can produce about 1 part of high-purity 5-ASA, and no additional amine impurities are introduced during the preparation process, which can effectively reduce the difficulty of product purification and improve product quality, and intermediate 5,5'-azosalicylic acid (olsalazine, Olsalazine) is also a drug for treating inflammatory bowel inflammation, which has lower toxic and side effects for human body and has a higher practical application value. Therefore, this preparation method has a simple circuit, low cost and can reduce the three wastes produced, and is suitable for large-scale industrial production.

[0040] In the aminodiazotization reaction, the purity of the raw material 5-ASA is 95-98%. After adding the hydrochloric acid solution, it is cooled to 0°C-2°C, and a sodium nitrite solution is added. The temperature is maintained at 0-10°C and the reaction is carried out for 2.5±0.5h.

[0041] In the aminodiazotization reaction, the concentration of the hydrochloric acid solution is 1±0.2mol / L. The hydrochloric acid solution is prepared by adding water to reagent-grade hydrochloric acid with a mass concentration of 36-38%. The amount of reagent-grade hydrochloric acid is 2.2eq.-12eq. of the raw material 5-ASA, and the amount of sodium nitrite is 1.0eq.-1.5eq. of the raw material 5-ASA. The sodium nitrite solution is prepared by dissolving sodium nitrite in water. Eq. (equivalent) refers to an amount equivalent to a specific or commonly accepted value; a chemical term used to refer to the ratio of moles or masses when substances interact.

[0042] Experiments show that the solubility of 5-ASA in a 1 mol / L hydrochloric acid solution at room temperature is the highest, about 5 g, so a 1 mol / L hydrochloric acid solution is selected as the reaction medium. Optionally, the amount of sodium nitrite used is 1.1 eq.-1.2 eq. of the raw material 5-ASA, and the reaction temperature is 5°C.

[0043] In the aminodiazotization reaction, in order to determine the amount of hydrochloric acid, the amount of hydrochloric acid refers to the amount of analytically pure hydrochloric acid before dilution. Under the condition that other conditions remain unchanged, the amount of hydrochloric acid is changed and the yield of diazosalicylic acid hydrochloride (5-DASA-Cl) is calculated. During the experiment, the system temperature was controlled to 5°C, the amount of NaNO2 was 1.1eq. of 5-ASA, and the amount of hydrochloric acid was 2.2eq., 2.4eq., 2.6eq., 6.0eq., and 12eq. of 5-ASA, respectively. The calculated yields of diazosalicylic acid hydrochloride (5-DASA-Cl) obtained were 91.2%, 97.3%, 97.5%, 96.6%, and 97.1%, respectively. It can be seen that the optimal amount of hydrochloric acid is 2.4eq., Figure 1 For DASA-Cl 1 H-NMR spectrum.

[0044] In the coupling reaction, the pH value in the system is 5-7, the reaction temperature is 5-20°C, and the reaction time is 10±1h.

[0045] The coupling reaction comprises the following steps:

[0046] Prepare sodium hydroxide solution A: weigh sodium hydroxide and dissolve it in water to obtain sodium hydroxide solution A;

[0047] Prepare salicylic acid alkaline solution: weigh sodium hydroxide and dissolve it in water to obtain sodium hydroxide solution B, stir until the solid is completely dissolved and then cool to room temperature, then add salicylic acid to obtain salicylic acid alkaline solution, stir evenly and then cool to 0°C;

[0048] Adding sodium hydroxide solution A: Add urea to the reaction kettle after the reaction is completed, stir until there are no obvious bubbles in the system, and slowly drop sodium hydroxide solution A into it. During the dropwise addition, keep the system temperature no higher than 10°C;

[0049] Adding salicylic acid alkaline solution: Continue to add salicylic acid alkaline solution to the reaction system, and keep the system temperature no higher than 15°C during the addition process;

[0050] Reaction: N2 is introduced into the system, the system temperature is maintained at 10-15°C, and the reaction is continued for 7-9 hours, and then samples are taken for analysis. The reaction is stopped when the mass content of 5-DASA-Cl is less than 2%;

[0051] Filtration: After the reaction is completed, cool the reaction system to 0°C, slowly add acetic acid to the system, continue stirring for 10-20 hours, and then vacuum filter the reaction system to obtain olsalazine solid, which can be directly used for the next reduction reaction. Acetic acid is used as an acidifying agent to prevent the unreacted salicylic acid from precipitating simultaneously with the intermediate OLZ (olsalazine) obtained by the coupling reaction and a small amount of inorganic salts, which has a certain effect on the reduction reaction. When the pH of the reaction system is 5-6, the unreacted salicylic acid is mainly present in the solution system; when the reaction system is acidified to a pH of about 1, a large amount of solids are rapidly precipitated in the system, and the unreacted salicylic acid, OLZ obtained by the coupling reaction, and a small amount of inorganic salts are precipitated simultaneously. In order to stabilize the process and reduce the discharge of the three wastes, acetic acid is selected as the acidifying agent.

[0052] The amount of sodium hydroxide added to sodium hydroxide solution A is 1.2 eq.-1.6 eq. of the raw material 5-ASA, the amount of sodium hydroxide added to sodium hydroxide solution B is 3.0 eq.-3.8 eq. of the raw material 5-ASA, and the amount of salicylic acid used is 0.8 eq.-1.2 eq. of the raw material 5-ASA.

[0053] The reduction reaction comprises the following steps:

[0054] Prepare sodium hydroxide solution: dissolve sodium hydroxide in water in a reduction reactor under ice bath conditions to prepare a sodium hydroxide solution, and then add the solid azo compound into the reduction reactor;

[0055] Add sodium dithionite: Heat the solution in the reduction reactor to 70-90°C, then slowly add sodium dithionite solid, control the adding speed to avoid excessive bubbles, and keep the system temperature no higher than 90°C;

[0056] Reaction: N2 was introduced into the system, the temperature of the system was maintained at 85±5°C, and the reaction was carried out for 2-3 hours. The intermediate olsalazine completely disappeared under TLC monitoring;

[0057] Cooling: Cool the reaction system to 0°C, slowly drop 60±5 mL of 1:1 hydrochloric acid solution into it, continue stirring for 25-40 minutes, vacuum filter the reaction system, and the resulting solid is the crude 5-ASA. Figure 2 For crude 5-ASA 1 H-NMR spectrum.

[0058] The preparation method also includes decolorization and purification: adding the crude 5-ASA to a decolorization kettle, and adding activated carbon and hydrochloric acid solution, decolorizing the crude 5-ASA, filtering to obtain a liquid material, and putting the liquid material into a crystallization kettle, adding sodium hydroxide solution to recrystallize, cooling and drying to obtain the product 5-ASA. According to comparative experiments, 1g of the product 5-ASA can be decolorized and recrystallized in 20mL of hydrochloric acid solution at 50°C, so the hydrochloric acid solution is used to decolorize and recrystallize 5-ASA.

[0059] In the decolorization and purification, the concentration of the hydrochloric acid solution is 1 mol / L, the amount of activated carbon used is 10-20% of the mass of the crude 5-ASA, the decolorization temperature is 50±5°C, and the decolorization time is 50-80 minutes. The purity of the product 5-ASA obtained after decolorization and purification is 99-99.7%, and the product 5-ASA is dried, crushed and packaged to obtain the finished product 5-ASA.

[0060] Example 1: Small-scale test

[0061] A method for preparing 2-hydroxy-5-aminobenzoic acid comprises the following steps:

[0062] Step 1: Aminodiazotization reaction: 20 g of raw material 5-ASA with a purity of 96% was placed in a reactor, 1 mol / L hydrochloric acid solution was added, mixed, cooled to 0°C, and then sodium nitrite solution was added. The mixture was kept warm at 0-5°C for 3 h to achieve aminodiazotization reaction of 5-ASA to obtain diazosalicylic acid hydrochloride;

[0063] The hydrochloric acid solution is prepared by adding water to reagent-grade hydrochloric acid with a mass concentration of 36-38%, and the dosage of reagent-grade hydrochloric acid is 26 ml and water is 75 ml. The sodium nitrite solution is prepared by dissolving sodium nitrite in water, and the dosage of sodium nitrite is 9.92 g and water is 30 ml.

[0064] Step 2: Coupling reaction

[0065] 2.1 Prepare sodium hydroxide solution A: weigh 7.85 g of sodium hydroxide and dissolve it in 18 mL of water to obtain sodium hydroxide solution A;

[0066] 2.2 Prepare salicylic acid alkaline solution: weigh 18.30 g of sodium hydroxide and dissolve it in 42 mL of water to obtain sodium hydroxide solution B. Stir until the solid is completely dissolved and then cool to room temperature. Then add 18.00 g of salicylic acid, stir evenly and then cool to 0°C.

[0067] 2.3 Add sodium hydroxide solution A: At 0°C, add 0.35 g of urea to the reactor after the reaction is completed, stir until there are no obvious bubbles in the system, and slowly add sodium hydroxide solution A dropwise, keeping the system temperature no higher than 10°C during the addition;

[0068] 2.4 Adding salicylic acid alkaline solution: Continue to add salicylic acid alkaline solution to the reaction system at a faster rate, and keep the system temperature no higher than 15°C during the addition process;

[0069] 2.5 Reaction: A small amount of N2 was introduced into the system, the system temperature was maintained at 15°C, and the reaction was continued for 8 hours. Samples were taken for analysis, and the reaction was stopped when the mass content of 5-DASA-Cl was less than 2%;

[0070] 2.6 Filtration: After the reaction is completed, cool the reaction system to 0°C, slowly add about 54 mL of acetic acid to the system, continue stirring for 12 hours, and then vacuum filter the reaction system to obtain the intermediate olsalazine. The obtained solid olsalazine can be directly used for the next reduction reaction. The pH during the coupling reaction is 5-6.

[0071] Step 3: Reduction reaction

[0072] 3.1 Preparation of sodium hydroxide solution C: In an ice bath, in a reduction reactor, dissolve 19.7 g of sodium hydroxide in 160 mL of water to prepare a sodium hydroxide solution, and then add solid olsalazine into the reduction reactor;

[0073] 3.2 Add sodium dithionite: Heat the solution in the reduction reactor to 75°C, and slowly add sodium dithionite Na2S2O4 solid into it, controlling the addition speed to avoid excessive bubbles, and keeping the system temperature no higher than 90°C;

[0074] 3.3 Reaction: A small amount of N2 was introduced into the system, the temperature of the system was maintained at 85°C, and the reaction was carried out for 2 h. The intermediate OLZ completely disappeared under TLC monitoring;

[0075] 3.4 Cooling: Cool the reaction system to 0°C, slowly add 60 mL of 1:1 hydrochloric acid solution, continue stirring for 0.5 h, vacuum filter the reaction system, and the resulting solid is the crude 5-ASA.

[0076] Among them, the reaction formulas of aminodiazotization reaction, coupling reaction and reduction reaction are as follows:

[0077]

[0078] Step 4: Decolorization and purification: Add the crude 5-ASA into a decolorization kettle, and add activated carbon and a 1 mol / L hydrochloric acid solution to decolorize the crude 5-ASA. The amount of activated carbon is 10-20% of the mass of the crude 5-ASA. The decolorization temperature is 50°C and the decolorization time is 1h. After filter pressing, the liquid is obtained. The liquid is put into a crystallization kettle, and sodium hydroxide solution is added dropwise for recrystallization. After cooling and drying, about 38g of product 5-ASA is obtained.

[0079] Example 2: Amplification experiment 1

[0080] Using 200.3 g of 5-ASA as raw material, the pilot test process was scaled up in parallel, and the one-pot two-step process of aminodiazotization / coupling reaction finally determined in the pilot test was adopted to obtain olsalazine sodium solid reduction to synthesize 5-ASA. The whole process took about 6 days. After purification and drying, 370.56 g of 5-ASA product was obtained with a purity of 99.3% and a yield of 92.6%.

[0081] Example 3: Amplification Experiment 2

[0082] Using 2990.8 g of 5-ASA as raw material, the process was adjusted according to the scale-up experiment 1, and the one-pot two-step process of aminodiazotization / coupling reaction finally determined by the small-scale test was also used to obtain olsalazine sodium solid reduction synthesis of 5-ASA. The whole process took about 5 days. After purification and drying, 5443.3 g of 5-ASA product was obtained with a purity of 99.1% and a yield of 90.8%.

[0083] It should be noted that, for those skilled in the art, several modifications and improvements can be made without departing from the concept of the present application, and these modifications and improvements are all within the scope of protection of the present application. Therefore, the scope of protection of the patent of the present application shall be subject to the attached claims.

Claims

1. A method for preparing 2-hydroxy-5-aminobenzoic acid, characterized in that: The steps include: Aminodiazotization reaction: the raw material 5-ASA is placed in a reactor, a hydrochloric acid solution is added, the mixture is cooled, and then a sodium nitrite solution is added to realize an aminodiazotization reaction of 5-ASA to obtain diazosalicylic acid hydrochloride, wherein the raw material 5-ASA is chemical grade 5-ASA or reagent grade 5-ASA; Coupling reaction: After cooling, sodium hydroxide solution and salicylic acid alkaline solution are added to the reactor to achieve the coupling reaction of diazo salicylic acid hydrochloride, and acetic acid is added and filtered to obtain the azo compound olsalazine solid; Reduction reaction: Sodium hydroxide solution and olsalazine solid are added to a reduction reactor, and after heating, sodium dithionite solid is slowly added, nitrogen is introduced, and after the reaction, the system is cooled, and hydrochloric acid solution is added to the system. After stirring, vacuum filtration is performed to obtain crude 5-ASA.

2. The method for preparing 2-hydroxy-5-aminobenzoic acid according to claim 1, wherein: In the aminodiazotization reaction, the purity of the raw material 5-ASA is 95-98%. After adding the hydrochloric acid solution, it is cooled to 0°C-2°C, and a sodium nitrite solution is added. The temperature is maintained at 0-10°C and the reaction is carried out for 2.5±0.5h.

3. The method for preparing 2-hydroxy-5-aminobenzoic acid according to claim 1, wherein: In the aminodiazotization reaction, the concentration of the hydrochloric acid solution is 1±0.2 mol / L. The hydrochloric acid solution is prepared by adding water to reagent-grade hydrochloric acid with a mass concentration of 36-38%. The amount of reagent-grade hydrochloric acid used is 2.2eq.-12eq. of the raw material 5-ASA, and the amount of sodium nitrite used is 1.0eq.-1.5eq. of the raw material 5-ASA.

4. The method for preparing 2-hydroxy-5-aminobenzoic acid according to claim 1, wherein: In the coupling reaction, the pH value in the system is 5-7, the reaction temperature is 5-20°C, and the reaction time is 10±1h.

5. The method for preparing 2-hydroxy-5-aminobenzoic acid according to claim 1, wherein: The coupling reaction comprises the following steps: Prepare sodium hydroxide solution A: weigh sodium hydroxide and dissolve it in water to obtain sodium hydroxide solution A; Prepare salicylic acid alkaline solution: weigh sodium hydroxide and dissolve it in water to obtain sodium hydroxide solution B, stir until the solid is completely dissolved and then cool to room temperature, then add salicylic acid to obtain salicylic acid alkaline solution, stir evenly and then cool to 0°C; Adding sodium hydroxide solution A: Add urea to the reaction kettle after the reaction is completed, stir until there are no obvious bubbles in the system, and slowly drop sodium hydroxide solution A into it. During the dropwise addition, keep the system temperature no higher than 10°C; Adding salicylic acid alkaline solution: Continue to add salicylic acid alkaline solution to the reaction system, and keep the system temperature no higher than 15°C during the addition process; Reaction: N2 is introduced into the system, the system temperature is maintained at 10-15°C, and the reaction is continued for 7-9 hours, and then samples are taken for analysis. The reaction is stopped when the mass content of 5-DASA-Cl is less than 2%; Filtration: After the reaction is completed, cool the reaction system to 0°C, slowly add acetic acid to the system, continue stirring for 10-20 hours, and then vacuum filter the reaction system to obtain olsalazine solid, which can be directly used in the next reduction reaction.

6. The method for preparing 2-hydroxy-5-aminobenzoic acid according to claim 5, characterized in that: The amount of sodium hydroxide added to sodium hydroxide solution A is 1.2 eq.-1.6 eq. of the raw material 5-ASA, the amount of sodium hydroxide added to sodium hydroxide solution B is 3.0 eq.-3.8 eq. of the raw material 5-ASA, and the amount of salicylic acid used is 0.8 eq.-1.2 eq. of the raw material 5-ASA.

7. The method for preparing 2-hydroxy-5-aminobenzoic acid according to claim 6, wherein: The reduction reaction comprises the following steps: Prepare sodium hydroxide solution: dissolve sodium hydroxide in water in a reduction reactor under ice bath conditions to prepare a sodium hydroxide solution, and then add the solid azo compound into the reduction reactor; Add sodium dithionite: Heat the solution in the reduction reactor to 70-90°C, then slowly add sodium dithionite solid, control the adding speed to avoid excessive bubbles, and keep the system temperature no higher than 90°C; Reaction: N2 was introduced into the system, the temperature of the system was maintained at 85±5°C, and the reaction was carried out for 2-3 hours. The intermediate olsalazine completely disappeared under TLC monitoring; Cooling: Cool the reaction system to 0°C, slowly add 60±5 mL of 1:1 hydrochloric acid solution, continue stirring for 25-40 min, vacuum filter the reaction system, and the resulting solid is the crude 5-ASA.

8. The method for preparing 2-hydroxy-5-aminobenzoic acid according to claim 1, characterized in that: The process also includes decolorization and purification: adding crude 5-ASA into a decolorization kettle, and adding activated carbon and hydrochloric acid solution, decolorizing the crude 5-ASA, filtering to obtain a liquid material, and putting the liquid material into a crystallization kettle, adding sodium hydroxide solution to recrystallize, cooling and drying to obtain the product 5-ASA.

9. The method for preparing 2-hydroxy-5-aminobenzoic acid according to claim 8, characterized in that: In the decolorization and purification, the concentration of the hydrochloric acid solution is 1 mol / L, the amount of activated carbon used is 10-20% of the mass of the crude 5-ASA, the decolorization temperature is 50±5°C, and the decolorization time is 50-80min.

10. The method for preparing 2-hydroxy-5-aminobenzoic acid according to claim 8, characterized in that: The purity of the product 5-ASA obtained after decolorization and purification is 99-99.7%. The product 5-ASA is dried, crushed and packaged to obtain the finished product 5-ASA.

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