A method for purifying 4-acetylbenzoic acid

Abstract

The invention discloses a method for purifying 4-acetylbenzoic acid, wherein 4-acetylbenzoic acid crude product, water and alkali are added to a reaction vessel, stirred and dissolved, and pH is adjusted to alkaline; an aqueous solution of calcium halide or barium halide is added thereto, solid is precipitated by stirring, and 4-acetylbenzoic acid calcium salt or 4-acetylbenzoic acid barium salt is filtered to obtain; 4-acetylbenzoic acid calcium salt or 4-acetylbenzoic acid barium salt is added to water, acid is added dropwise to adjust pH to acidity, filtered, and filtration cakes are dried to obtain purified 4-acetylbenzoic acid. The method of the present invention can more easily obtain highly purified 4-acetylbenzoic acid, and greatly improves the purity of 4-acetylbenzoic acid, has simple process operation, low equipment requirements, low cost of raw materials used, high product yield, high purity, and is easy to industrialized production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for purifying 4-acetylbenzoic acid. Background Art

[0002] Molotinib is an oral JAK1 / 2 and activin A receptor type 1 (ACVR1) inhibitor. It is the first JAK inhibitor to demonstrate positive data across all key markers of disease symptoms, splenic response, and anemia. Molotinib inhibits multiple key signaling pathways, including ACVR1, JAK1, and JAK2, and is comparable in efficacy to ruxolitinib in treating two cardinal manifestations of myelofibrosis (MF): splenomegaly and systemic symptoms. Furthermore, molotinib effectively addresses anemia in MF patients.

[0003] 4-Acetylbenzoic acid is an important intermediate of the new generation tyrosine kinase 1 / 2 (JAK 1 / 2) inhibitor molotinib, with the structural formula:

[0004]

[0005] The methods for purifying 4-acetylbenzoic acid in the prior art are relatively complex and the product purity is low. For example, the patent method with patent publication number CN102701965A is as follows: (1) Oxidation: add p-methylacetophenone, water and anhydrous zinc chloride to a reaction pot, stir evenly, slowly heat up, divide potassium permanganate into five equal parts, add in batches, add and control the reaction temperature at 48-55°C, control the reaction temperature at 40-45°C after the addition is completed, keep the temperature for reaction, then cool to 17-22°C, centrifuge, and dry to obtain crude 4-acetylbenzoic acid. (2) Mix the prepared crude product with anhydrous acetic acid, heat and reflux, filter while hot, centrifuge, and dry to obtain 4-acetylbenzoic acid. This synthesis method is relatively complex and cannot completely remove the main by-product terephthalic acid. The product purity is low, about 95%. Summary of the Invention

[0006] The present invention aims to provide a method for purifying high-purity 4-acetylbenzoic acid, which has high product yield and high purity.

[0007] To achieve the above object, the technical solution provided by the present invention is:

[0008] A method for purifying 4-acetylbenzoic acid comprises the following steps:

[0009] (1) Add crude 4-acetylbenzoic acid, water and alkali into a reaction vessel, stir to dissolve and adjust the pH to alkaline to obtain a solution;

[0010] (2) adding an aqueous solution of calcium halide or barium halide to the above solution, stirring to precipitate a solid, and filtering to obtain 4-acetylbenzoic acid calcium salt or 4-acetylbenzoic acid barium salt;

[0011] The reaction equation is:

[0012]

[0013] (3) Add 4-acetylbenzoic acid calcium salt or 4-acetylbenzoic acid barium salt into water, add acid dropwise to adjust the pH to acidic, filter, and dry the filter cake to obtain purified 4-acetylbenzoic acid.

[0014] The reaction equation is:

[0015]

[0016] To optimize the above technical solutions, specific measures taken also include:

[0017] In step (1), the base is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.

[0018] Preferably, in step (1), the pH is adjusted to alkaline to make pH=10~12.

[0019] In step (2), the calcium halide or barium halide is selected from at least one of anhydrous calcium chloride, calcium bromide dihydrate, barium chloride dihydrate, and barium bromide dihydrate.

[0020] The reaction molar ratio of 4-acetylbenzoic acid and calcium halide or barium halide contained in the crude 4-acetylbenzoic acid is 1:1.5-2.

[0021] In step (3), the acid is glacial acetic acid or a diluted hydrochloric acid solution; preferably, the diluted hydrochloric acid solution is a 2-6 M hydrochloric acid aqueous solution.

[0022] Preferably, in step (3), the pH is adjusted to acidic to make pH=1~2.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The present invention converts a crude 4-acetylbenzoic acid product into a calcium salt or a barium salt under alkaline conditions, and then adjusts the acidity by dropwise addition of acid. This makes it easier to obtain high-purity 4-acetylbenzoic acid, and greatly improves the purity of the 4-acetylbenzoic acid.

[0025] The purification method has simple process operation, low requirements on equipment, low cost of raw materials, high product yield and purity, and is easy to industrialize. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 : HPLC chromatogram of crude 4-acetylbenzoic acid.

[0027] Figure 2 : The HPLC chromatogram of the 4-acetylbenzoic acid purified among Examples of the present invention 1.

[0028] Figure 3 : The HPLC chromatogram of the 4-acetylbenzoic acid purified among Examples of the present invention 2.

[0029] Figure 4 : The HPLC chromatogram of the 4-acetylbenzoic acid purified among Examples of the present invention 3.

[0030] Figure 5 : HPLC chromatogram of purified 4-acetylbenzoic acid in Comparative Example. DETAILED DESCRIPTION

[0031] The above contents of the present invention are further described in detail below in the form of embodiments, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following embodiments. All technologies implemented based on the above contents of the present invention fall within the scope of the present invention.

[0032] The test methods used in the following examples are conventional methods unless otherwise specified, and the reagents, methods and equipment used are conventional reagents, methods and equipment in the art unless otherwise specified.

[0033] The chromatographic conditions used in this application are shown in the "Purity Determination of 4-acetylbenzoic Acid" section below.

[0034] The HPLC purity of the crude 4-acetylbenzoic acid used in this application is 87.850% for 4-acetylbenzoic acid and 12.040% for terephthalic acid. Figure 1 .

[0035] The reaction environment temperature used in this application can be 20-35°C, and the reaction environment temperature of the following embodiments and comparative examples is specifically 23~25°C.

[0036] Example 1: Purification method for obtaining high-purity 4-acetylbenzoic acid

[0037] Follow these steps:

[0038] (1) Preparation of calcium 4-acetylbenzoate

[0039] Add 200 g of crude 4-acetylbenzoic acid, 1000 ml of water, and 800 ml of 2M sodium hydroxide aqueous solution into a 5000 ml reaction flask, adjust the pH to 11, and stir and dissolve at 23-25° C. to obtain an aqueous solution of sodium 4-acetylbenzoate.

[0040] Add 220 g of anhydrous calcium chloride and 2000 ml of water into another 5000 ml reaction flask, stir and dissolve at 23-25°C to obtain a calcium chloride aqueous solution.

[0041] Add the calcium chloride aqueous solution to the alkaline aqueous solution of 4-acetylbenzoic acid, stir and react at 23-25°C to precipitate a solid, stir for 30 minutes and then filter to obtain a wet product of calcium 4-acetylbenzoate.

[0042] (2) Preparation of 4-acetylbenzoic acid

[0043] The wet product of calcium 4-acetylbenzoate obtained in step (1) and 3000 ml of water were added to a 5000 ml reaction flask, stirred at 23-25° C., 600 ml of 2M hydrochloric acid solution was added, the pH was adjusted to 2, stirred at 23-25° C. for 30 minutes, and then filtered. The filter cake was dried with forced air at 60° C. to obtain purified 4-acetylbenzoic acid. The chromatogram is shown in FIG. Figure 2 , HPLC purity, i.e., the content of 4-acetylbenzoic acid: 98.696%, the content of terephthalic acid: 0.826%, and the yield: 94.6%.

[0044] Example 2: Purification method for obtaining high-purity 4-acetylbenzoic acid

[0045] Follow these steps:

[0046] (1) Preparation of barium 4-acetylbenzoate

[0047] Add 200 g of crude 4-acetylbenzoic acid, 1000 ml of water, and 750 ml of 2M potassium hydroxide aqueous solution into a 5000 ml reaction flask, adjust the pH to 11, and stir and dissolve at 23-25° C. to obtain an aqueous solution of potassium 4-acetylbenzoate.

[0048] Add 566 g of barium chloride dihydrate and 2000 ml of water into another 5000 ml reaction flask and stir to dissolve at 23-25 ​​°C.

[0049] Add the barium chloride aqueous solution to the alkaline aqueous solution of 4-acetylbenzoic acid, stir and react at 23-25°C to precipitate a solid, stir for 30 minutes and then filter to obtain a wet product of barium 4-acetylbenzoate.

[0050] (2) Preparation of 4-acetylbenzoic acid

[0051] The wet product of 4-acetylbenzoic acid barium obtained in step (1) and 3000 ml of water were added to a 5000 ml reaction flask, stirred at 23-25 ​​° C, and 400 ml of glacial acetic acid was added to adjust the pH to 1. After stirring at 23-25 ​​° C for 30 min, the mixture was filtered and the filter cake was dried at 60 ° C with forced air to obtain purified 4-acetylbenzoic acid. The chromatogram is shown in FIG. Figure 3 , HPLC purity, i.e., the content of 4-acetylbenzoic acid: 99.361%, the content of terephthalic acid: 0.371%, and the yield: 96.2%.

[0052] Example 3: Purification method for obtaining high-purity 4-acetylbenzoic acid

[0053] Follow these steps:

[0054] (1) Preparation of barium 4-acetylbenzoate

[0055] Add 200 g of crude 4-acetylbenzoic acid, 1000 ml of water, and 750 ml of 2M potassium hydroxide aqueous solution into a 5000 ml reaction flask, adjust the pH to 11, and stir and dissolve at 23-25° C. to obtain an aqueous solution of potassium 4-acetylbenzoate.

[0056] Add 720 g of barium bromide dihydrate and 2000 ml of water into another 5000 ml reaction flask and stir to dissolve at 23-25 ​​°C.

[0057] Add the barium bromide aqueous solution to the alkaline aqueous solution of 4-acetylbenzoic acid, stir and react at 23-25°C to precipitate a solid, stir for 30 minutes and then filter to obtain a wet product of barium 4-acetylbenzoate.

[0058] (2) Preparation of 4-acetylbenzoic acid

[0059] The wet product of 4-acetylbenzoic acid barium obtained in step (1) and 3000 ml of water were added to a 5000 ml reaction flask, stirred at 23-25 ​​° C, and 300 ml of 6M hydrochloric acid aqueous solution was added, and the pH was adjusted to 1. After stirring at 23-25 ​​° C for 30 minutes, the filter cake was dried with forced air at 60 ° C to obtain purified 4-acetylbenzoic acid. The chromatogram is shown in FIG. Figure 4 , HPLC purity, i.e., the content of 4-acetylbenzoic acid: 99.059%, the content of terephthalic acid: 0.442%, and the yield: 95.3%.

[0060] Comparative Example 1: Purification method according to Example 1 in CN102701965A

[0061] 200g of crude 4-acetylbenzoic acid and 1400g of anhydrous acetic acid were added to a 2500ml reaction flask, stirred and heated to reflux for 1.0 hour. Filtered while hot, the filtrate was concentrated to dryness under reduced pressure, and 3000ml of water was added to precipitate the solid, filtered, and the filter cake was dried at 60°C with forced air to obtain purified 4-acetylbenzoic acid. The chromatogram is shown in FIG. Figure 5 , HPLC purity: 95.043%, terephthalic acid content: 4.497%, yield: 84.2%

[0062] Purity determination of 4-acetylbenzoic acid:

[0063] 4-Acetylbenzoic acid prepared in Examples 1-3 of the present invention and Comparative Example 1 was respectively taken, and tested according to high performance liquid chromatography (General Rule 0512 of the 2020 edition of the Chinese Pharmacopoeia). A chromatographic column with octadecyl bonded silica as a filler was used. This determination example specifically used a Waters Symmetry C18 column, 250 mm × 4.6 mm, 5 μm; the mobile phase A was 10 mmol / L phosphate solution, pH 6.5, and this determination example specifically used 10 mmol / L potassium dihydrogen phosphate solution, and potassium hydroxide was adjusted to pH 6.5; the mobile phase B was acetonitrile, and gradient elution was performed according to the table below; the column temperature was 40 ° C; the flow rate was 1.0 ml / min; and the detection wavelength was 210 nm.

[0064] Table 1 Gradient elution conditions

[0065]

[0066] Take an appropriate amount of this product, weigh accurately, dissolve it in water and dilute it to make a solution containing about 0.1 mg per 1 ml, shake well, and use it as the test solution.

[0067] Accurately weigh an appropriate amount of 4-acetylbenzoic acid reference substance, dissolve it in water and dilute it to make a solution containing about 0.1 mg per 1 ml, shake well, and use it as the reference substance solution.

[0068] Accurately measure 10 μl of each of the above solutions, inject them into the liquid chromatograph, and record the chromatogram; calculate according to the external standard method; the test results are shown in the table below.

[0069] Table 2 Test results

[0070]

[0071] As shown in the results in the table above, according to the method of Examples 1-3, the crude 4-acetylbenzoic acid is purified to a calcium salt or a barium salt under alkaline conditions and then adjusted to an acidic state by hydrochloric acid. The purity and yield of the obtained product are significantly improved compared with the product obtained by the comparative example through the hot reflux purification of anhydrous acetic acid. In addition, no high temperature reaction and post-treatment are required, the requirements for production equipment are low, and it is suitable for industrial production.

[0072] The above description is only a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Any simple modification, equivalent replacement and improvement made by any technician familiar with the profession to the above embodiment without departing from the scope of the technical solution of the present invention and based on the technical essence of the present invention shall still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for purifying 4-acetylbenzoic acid, characterized in that, The following steps are involved: (1) Add crude 4-acetylbenzoic acid, water and alkali into a reaction vessel, stir to dissolve and adjust the pH to alkaline to obtain a solution; (2) adding an aqueous solution of calcium halide or barium halide to the above solution, stirring to precipitate a solid, and filtering to obtain 4-acetylbenzoic acid calcium salt or 4-acetylbenzoic acid barium salt; (3) adding 4-acetylbenzoic acid calcium salt or 4-acetylbenzoic acid barium salt into water, adding acid dropwise to adjust the pH to acidic, filtering, and drying the filter cake to obtain purified 4-acetylbenzoic acid; In step (2), the calcium halide or barium halide is at least one selected from anhydrous calcium chloride, calcium bromide dihydrate, barium chloride dihydrate, and barium bromide dihydrate; The reaction molar ratio of 4-acetylbenzoic acid and calcium halide or barium halide contained in the crude 4-acetylbenzoic acid is 1:1.5-2; The pH is adjusted to alkaline to make pH=10~12; in step (3), the acid is glacial acetic acid or 2~6M hydrochloric acid aqueous solution; in step (3), the pH is adjusted to acidic to make pH=1~2.

2. The method for purifying 4-acetylbenzoic acid according to claim 1, wherein: In step (1), the base is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.

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