A method for preparing 3-aminophthalate

Abstract

This invention discloses a method for preparing 3-aminophthalic acid salt, which uses 3-nitrophthalic acid as a raw material and an inorganic alkaline aqueous solution as a solvent for a catalytic reduction reaction. After the reaction is completed, the catalyst is removed by filtration, and the pH of the filtrate is adjusted to precipitate a solid, thus obtaining 3-aminophthalic acid salt. By optimizing the reduction system, the occurrence of intramolecular cyclization side reactions can be reduced, improving the utilization rate of raw materials and the purity of the product. At the same time, the product is easily separated from the catalyst, unreacted reducing agent, and byproducts. The reaction is highly efficient, convenient to operate, and environmentally friendly, making it more suitable for industrial-scale preparation.

Description

Technical Field

[0001] This invention relates to a method for preparing 3-aminophthalic acid salt, and more particularly to a method for preparing high-purity 3-aminophthalic acid salt, belonging to the pharmaceutical field. Background Technology

[0002] Apmisit, a small molecule phosphodiesterase 4 (PDE4) inhibitor, exerts its anti-psoriatic effect by regulating the immune response of psoriasis-related pathogenic genes and inflammatory cells, as well as the expression of cytokines, and is used for adult patients with active psoriatic arthritis.

[0003] In the preparation method disclosed in the original patent WO03080049A1, 3-aminophthalic acid is used as a preparation intermediate. It is obtained by hydrogenation of 3-nitrophthalic acid under high pressure. This type of reaction has high requirements for explosion-proof production environment and also requires the use of high pressure resistant equipment, which poses safety risks and limits its industrial application.

[0004]

[0005] Preparation route of Apmist J AGR FOOD CHEM (2010, 58, 10999-11006) disclosed a method for preparing 3-aminophthalic acid by reducing 3-nitrophthalic acid with iron powder. This method is relatively cumbersome, with a conversion rate of only 72% after a long reaction time. Furthermore, the post-treatment requires alkalization followed by acidification, and the final crystallization is also quite difficult.

[0006]

[0007] Patent CN105669478A discloses a method for preparing 3-aminophthalic acid by reducing 3-nitrophthalic acid with elemental sulfur, sulfides, or a mixture of elemental sulfur and sulfides. This method requires the addition of cuprous chloride and ferrous chloride as post-processing reagents to remove residual hydrosulfide ions and thiosulfate ions generated in the reaction, making the post-processing operation cumbersome. Furthermore, the reaction conversion rate is less than 90%, and the product purity is less than 99%, which is not conducive to the subsequent preparation of apromisc.

[0008]

[0009] J Label Compd Radiopharm (2017, 60, 420 - 430) discloses a method for nitro reduction in ethanol using an ammonium formate / palladium on carbon system.

[0010]

[0011] When 3-aminophthalic acid is prepared using this method, more than 10% of self-condensation impurities are generated, resulting in significant side reactions, low material utilization, and increased difficulty in subsequent purification.

[0012]

[0013] Self-condensation impurities Given the numerous problems with existing methods, there is a need to develop an efficient, energy-saving, and environmentally friendly method for preparing 3-aminophthalic acid to facilitate the industrial-scale production of apromis. Summary of the Invention

[0014] Purpose of the invention: The present invention aims to provide an industrially feasible method for preparing 3-aminophthalate.

[0015] Technical solution: The method for preparing 3-aminophthalate according to the present invention, where X represents hydrochloric acid, formic acid, acetic acid, sulfuric acid, trifluoroacetic acid, or trifluoromethanesulfonic acid. , It includes the following steps: (1) Catalytic reduction of 3-nitrophthalic acid in an inorganic alkaline aqueous solution; (2) Acidify the reduction product obtained in step (1) with acid X; (3) The acidified product obtained in step (2) is post-treated to obtain the 3-aminophthalate.

[0016] This invention uses 3-nitrophthalic acid as a raw material and an inorganic alkaline aqueous solution as a solvent for a catalytic reduction reaction. After the reaction is complete, the catalyst is removed by filtration, and the pH of the filtrate is adjusted to precipitate a solid, thus yielding 3-aminophthalate.

[0017] Preferably, the inorganic alkaline aqueous solution is selected from sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium bicarbonate aqueous solution, sodium carbonate aqueous solution, potassium carbonate aqueous solution, and lithium hydroxide aqueous solution.

[0018] Further preferably, the inorganic alkaline aqueous solution is selected from sodium hydroxide aqueous solution.

[0019] Preferably, the molar ratio of 3-nitrophthalic acid to inorganic base is 1:1.1 to 1:2.5.

[0020] More preferably, the molar ratio of 3-nitrophthalic acid to sodium hydroxide is 1:1.3 to 1:1.7.

[0021] Specifically, the molar ratio of 3-nitrophthalic acid to sodium hydroxide is selected from 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, and 2.5.

[0022] Preferably, the mass concentration of the inorganic alkaline aqueous solution is 10% to 23%.

[0023] Further preferably, the mass concentration of the inorganic alkaline aqueous solution is 10%~15%.

[0024] Specifically, the mass concentration of the inorganic alkaline aqueous solution is selected from 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, and 23%.

[0025] Preferably, the endpoint pH of the acidification is 0.5 to 2.

[0026] Further preferably, the endpoint pH value of the acidification is 1 to 2.

[0027] Specifically, the endpoint pH value of the acidification is selected from 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2. It should be noted that when the pH detection device has a detection error, the actual allowable range of pH values ​​is the target value ± the error range. For example, when the pH meter's detection error is 0.02 and the target pH is set to 1, its actual allowable range is 1 ± 0.02, i.e., 0.98 to 1.02.

[0028] Preferably, the acid X used in the acidification is selected from hydrochloric acid, formic acid, acetic acid, sulfuric acid, trifluoroacetic acid, or trifluoromethanesulfonic acid.

[0029] Further preferably, the acidification is performed using concentrated hydrochloric acid or 6-12M hydrochloric acid.

[0030] Preferably, the reduction catalyst is selected from palladium on carbon catalyst, palladium hydroxide on carbon catalyst, platinum on carbon catalyst, palladium acetate, palladium chloride, and Raney nickel catalyst.

[0031] More preferably, the catalyst for reduction is selected from palladium on carbon catalyst and palladium hydroxide on carbon catalyst.

[0032] More preferably, the mass ratio of 3-nitrophthalic acid to the catalyst is 20:1 to 6:1.

[0033] More preferably, the mass ratio of the 3-nitrophthalic acid to the palladium on carbon catalyst and the palladium hydroxide on carbon catalyst is 20:1 to 10:1.

[0034] Specifically, the mass ratio of 3-nitrophthalic acid to palladium on carbon catalyst and palladium hydroxide on carbon catalyst is selected from 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, and 20:1.

[0035] Preferably, the reducing agent is selected from ammonium formate.

[0036] Further preferably, the reducing agent is selected from ammonium formate with a purity of not less than 97%.

[0037] More preferably, the reducing agent is added to the reaction system in the form of solid ammonium formate or an aqueous solution of ammonium formate.

[0038] Further preferably, the molar ratio of 3-nitrophthalic acid to the reducing agent is 1:3 to 1:6.

[0039] More preferably, the molar ratio of 3-nitrophthalic acid to ammonium formate is 1:3 to 1:4.

[0040] Specifically, the molar ratio of 3-nitrophthalic acid to ammonium formate is selected from 1:3, 1:4, 1:5, and 1:6.

[0041] Preferably, the reducing agent is first added to 1 / 4 to 1 / 6 of the preset total mass to initiate the reaction, and then the remaining reducing agent is added in batches.

[0042] In a further preferred embodiment, the reducing agent is first added to 1 / 6 of the preset total mass to initiate the reaction, and then the remaining reducing agent is added in batches.

[0043] Preferably, the reduction reaction temperature is 40~100℃.

[0044] Further preferably, the reduction reaction temperature is 50~70℃.

[0045] More preferably, the reaction temperature of the reduction reaction initiation stage is 60~70℃, and the reaction temperature of the heat preservation reaction stage is 50~60℃.

[0046] Specifically, the reduction reaction temperature is selected from 50℃, 51℃, 52℃, 53℃, 54℃, 55℃, 56℃, 57℃, 58℃, 59℃, 60℃, 61℃, 62℃, 63℃, 64℃, 65℃, 66℃, 67℃, 68℃, 69℃, and 70℃. It should be noted that when there is a control error in the temperature control module of the reaction equipment, the actual range that the reaction temperature can cover is the target value ± the error range. For example, when the control error of the temperature control module is 1℃ and the target reaction temperature is set to 55℃, the actual allowable range is 55℃ ± 1℃, that is, 54~56℃.

[0047] Preferably, the acidification is carried out at 5~30°C.

[0048] Further preferably, the acidification is carried out by adding acid at 25~30℃, followed by heat preservation acidification at 5~10℃.

[0049] Preferably, the post-processing includes solid-liquid separation, washing, and drying. Solid-liquid separation includes atmospheric pressure filtration, vacuum filtration, pressure filtration, and centrifugal filtration; washing includes rinsing and pulping; and drying includes forced-air drying, fluidized bed drying, freeze-drying, and inert gas purging drying.

[0050] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: This invention employs an alkaline aqueous phase reduction system, which reduces intramolecular cyclization side reactions, improves raw material utilization (yield over 80%) and product purity (over 99%). Simultaneously, the catalyst can be effectively removed through filtration, unreacted reducing agent and byproducts can be removed with the aqueous phase, and the product automatically precipitates after acidification, eliminating the need for additional differentiation and separation steps. The reaction is highly efficient, convenient to operate, and environmentally friendly, making it more suitable for industrial-scale preparation. Attached Figure Description

[0051] Figure 1 The mass spectrometry spectrum of the 3-aminophthalate prepared in Example 1; Figure 2 The 1H NMR spectrum of the 3-aminophthalate prepared in Example 1; Figure 3 The high-performance liquid chromatography (HPLC) chromatogram of the 3-aminophthalate prepared in Example 1; Figure 4 The high-performance liquid chromatography (HPLC) chromatogram of the 3-aminophthalate prepared in Comparative Example 1 is shown. Detailed Implementation

[0052] The technical solution of the present invention will be further described below with reference to the embodiments.

[0053] Example 1

[0054] Pour purified water (19.04 kg) into a plastic bucket, add sodium hydroxide (3.36 kg) and stir until dissolved. Pump the sodium hydroxide aqueous solution (15% mass concentration) into the reactor, start stirring, and add 3-nitrophthalic acid (12 kg), Pd(OH)2 / C (0.60 kg) and ammonium formate (1.80 kg) into the reactor. Heat to 60°C to initiate the reaction. Add the remaining ammonium formate (9.00 kg) to the reactor in batches (500 g / batch, 5 min interval). After the addition is complete, keep at 60°C for 1 h. HPLC detection shows that the residual 3-nitrophthalic acid is less than 1%.

[0055] After the reaction was completed, the material was discharged and filtered. The filtrate was pumped into the reaction vessel and the temperature was controlled at 25°C. Concentrated hydrochloric acid was added dropwise to adjust the pH to 1.0. After the addition was complete, the temperature was controlled at 25°C and stirred for 2 hours. Then the temperature was lowered to 10°C and stirred for 1 hour. The material was discharged and centrifuged to collect the filter cake. The filter cake was added to ice water and stirred for 1 hour at 5°C. Then the material was discharged and centrifuged to collect the filter cake. The filter cake was dried in hot air circulation at 25°C for 24 hours to obtain 9.91 kg of light yellow powder, with a yield of 80.12%, a purity of 99.94%, and a chloride ion content of 12.05%.

[0056] Example 2

[0057] Pour purified water (40.32 kg) into a plastic bucket, add sodium hydroxide (4.48 kg) and stir until dissolved. Pump the sodium hydroxide aqueous solution (10% mass concentration) into the reactor, start stirring, and add 3-nitrophthalic acid (12 kg), Pd(OH)2 / C (0.60 kg) and ammonium formate (1.80 kg) into the enamel reactor. Heat to 60°C to initiate the reaction. Add the remaining ammonium formate (9.00 kg) to the reactor in batches (500 g / batch, 5 min interval). After the addition is complete, keep at 60°C for 1 h. HPLC detection shows that the residual 3-nitrophthalic acid is less than 1%.

[0058] After the reaction was completed, the material was discharged and filtered. The filtrate was pumped into the reaction vessel and the temperature was controlled at 25°C. Concentrated hydrochloric acid was added dropwise to adjust the pH to 1.0. After the addition was complete, the temperature was controlled at 25°C and stirred for 2 hours. Then the temperature was lowered to 10°C and stirred for 1 hour. The material was discharged and centrifuged to collect the filter cake. The filter cake was added to ice water and stirred for 1 hour at 5°C. The material was then discharged and centrifuged to collect the filter cake. The filter cake was dried in hot air circulation at 25°C for 24 hours to obtain 9.94 kg of light yellow powder, with a yield of 80.35% and a purity of 99.78%.

[0059] Comparative Example 1 Purified water (6.35 kg) was pumped into the reactor, and stirring was started. 3-Nitrophthalic acid (4.0 kg), Pd(OH)2 / C (0.40 kg) and ammonium formate (0.60 kg) were added to the reactor. The temperature was raised to 60°C to initiate the reaction. The remaining ammonium formate (3.0 kg) was added to the reactor in batches (500 g / batch, 5 min interval). After the addition was complete, the mixture was kept at 60°C for 1 h. HPLC analysis was performed until the residual 3-nitrophthalic acid was less than 1%.

[0060] After the reaction was completed, the material was discharged and filtered. The filtrate was pumped into the reaction vessel and the temperature was controlled at 25°C. Concentrated hydrochloric acid was added dropwise to adjust the pH to 1.0. After the addition was complete, the temperature was controlled at 25°C and stirred for 2 hours. Then the temperature was lowered to 10°C and stirred for 1 hour. The material was discharged and centrifuged to collect the filter cake. The filter cake was added to ice water and stirred for 1 hour at 5°C. Then the material was discharged and centrifuged to collect the filter cake. The filter cake was dried in hot air circulation at 25°C for 24 hours to obtain 3.10 kg of light yellow powder, with a yield of 75.16%, a purity of 83.84%, and a self-condensation impurity content of 14.96% (retention time 18.970 min).

[0061] Comparative Example 2 Ethanol (5.08 kg) was pumped into the reactor and stirred. 3-Nitrophthalic acid (4.0 kg), Pd(OH)2 / C (0.40 kg) and ammonium formate (0.60 kg) were added to the reactor. The temperature was raised to 60°C to initiate the reaction. The remaining ammonium formate (3.0 kg) was added to the reactor in batches (500 g / batch, 5 min interval). After the addition was complete, the mixture was kept at 60°C for 1 h. HPLC analysis was performed until the residual 3-nitrophthalic acid was less than 1%.

[0062] After the reaction was completed, the material was discharged and filtered. The filtrate was pumped into the reaction vessel, concentrated under controlled temperature, and then cooled to 5°C. Methyl tert-butyl ether was added at 25°C, and the mixture was stirred for 1 hour. The material was discharged and centrifuged, and the filter cake was collected to obtain 2.60 kg of light yellow powder, with a yield of 63.04%, a purity of 60.68%, a self-condensation impurity content of 15.34%, and a residue on ignition of 10.3% (inorganic salts exceeded the standard).

[0063] Example 3

[0064] Following the preparation method disclosed in the original patent WO03080049A1, the 3-aminophthalate (5.0 g, 1.0 eq) prepared in Example 1 and Comparative Example 1 were reacted with acetic anhydride (20.0 g, 16.1 eq) at 100 °C for 3 hours. The reaction solution was then subjected to HLPC purity testing, and the results are shown in Table 1.

[0065] Table 1. Results of subsequent cyclization reactions of 3-aminophthalates from different sources.

[0066] As can be seen from the above experimental results, this invention achieves efficient preparation of the target product by optimizing the reduction system, without the need for additional operation steps. The product is easy to separate and purify, has better quality, and is more conducive to the quality control of subsequent apromiscal API.

Claims

1. A method for preparing 3-aminophthalate, ， X represents hydrochloric acid, formic acid, acetic acid, sulfuric acid, trifluoroacetic acid, or trifluoromethanesulfonic acid, characterized in that... Includes the following steps: (1) Catalytic reduction of 3-nitrophthalic acid in an inorganic alkaline aqueous solution; (2) Acidify the reduction product obtained in step (1) with acid X; (3) The acidified product obtained in step (2) is post-treated to obtain the 3-aminophthalate.

2. The preparation method according to claim 1, characterized in that, The inorganic alkaline aqueous solution is selected from sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium bicarbonate aqueous solution, sodium carbonate aqueous solution, potassium carbonate aqueous solution, and lithium hydroxide aqueous solution.

3. The preparation method according to claim 1, characterized in that, The molar ratio of 3-nitrophthalic acid to inorganic base is 1:1.1 to 1:2.

5.

4. The preparation method according to claim 1, characterized in that, The inorganic alkaline aqueous solution has a mass concentration of 10% to 23%.

5. The preparation method according to claim 1, characterized in that, The endpoint pH value of the acidification is 0.5~2.

6. The preparation method according to claim 1, characterized in that, The reduction catalyst is selected from palladium on carbon catalyst, palladium hydroxide on carbon catalyst, platinum on carbon catalyst, palladium acetate, palladium chloride, and Raney nickel catalyst.

7. The preparation method according to claim 6, characterized in that, The mass ratio of 3-nitrophthalic acid to the catalyst is 20:1 to 6:

1.

8. The preparation method according to claim 1, characterized in that, The reducing agent is selected from ammonium formate.

9. The preparation method according to claim 7, characterized in that, The molar ratio of 3-nitrophthalic acid to the reducing agent is 1:3 to 1:

6.

10. The preparation method according to claim 1, characterized in that, The reduction reaction temperature is 40~100℃.

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