A preparation method of imatinib mesylate

Abstract

The present invention provides a preparation method of imatinib mesylate, belonging to the technical field of drug synthesis. The present invention first utilizes imamidine having a structure of formula II and imamoyl chloride having a structure of formula III to carry out an amidation reaction in a weakly acidic solvent to promote the reaction to proceed in the forward direction and reduce the residual imamidine in the reaction product. After post-treatment, imatinib free base having a structure of formula I is obtained. An organic solvent is then added, and methanesulfonic acid is added dropwise under an inert atmosphere and heating conditions to carry out mesylation. Activated carbon is then added, and adsorption treatment and hot filtration are sequentially carried out to further reduce the residual imamidine. After crystallization after adding seed crystals, cooling and filtration are sequentially carried out to obtain imatinib mesylate with high purity and high yield. The method provided by the present invention has an excellent imamidine removal effect, and its residual can be controlled to an extremely low level (below 2 ppm). In addition, the reaction conditions are mild, easy to operate, and conducive to industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for preparing imatinib mesylate. Background Art

[0002] Imatinib mesylate is a signal transduction inhibitor (formerly STI571) successfully developed by Novartis after seven years of research. It is the world's first approved tumorigenesis-related signal transduction inhibitor. Imatinib mesylate has been granted orphan drug status in the United States, the European Union, Japan, and other countries. On May 10, 2001, it was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with chronic myeloid leukemia in the blast crisis, accelerated disease, or chronic disease phases who have failed interferon-alfa therapy.

[0003] The compound having the structure of the following formula I, 4-(4-methylpiperazin-1-ylmethyl)-N-[(4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide, is the free base of imatinib.

[0004]

[0005] There are multiple synthetic routes for imatinib free base in the prior art, three of which are suitable for industrialization. Route 1, as shown in the following formula, uses 2-methyl-5-nitroaniline as a starting material, which first reacts with cyanamide to form guanidine, which is then cyclized with 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one. The nitro group is then reduced to an amino group, which is then directly condensed with 4-(4-methylpiperazinylmethyl)benzoyl chloride dihydrochloride (shown in Formula III) to produce imatinib (EP0564409, WO2008 / 136010, and WO2008 / 117298). Among them, patent WO2008136010 reports a method for synthesizing high-purity imatinib free base. In a chloroform solvent, potassium hydroxide is used as a base. Imatinyl chloride (shown in Formula III) reacts with imamamine. After the reaction is completed, the reaction is filtered, potassium hydroxide solution is added, the liquid is separated, and the chloroform phase is washed with water. Then, water is added to the organic phase, and the pH is adjusted to 3-4 with hydrochloric acid (imatinib free base is in the aqueous phase). After separation, the organic phase is washed with water and then with chloroform. The aqueous phase is collected and the pH is adjusted to 9-12 with potassium hydroxide. Then, it is extracted with chloroform, concentrated, crystallized by adding ethyl acetate, and dried. Finally, the maleate is salted in a pure solvent to obtain high-purity imatinib maleate. The residual amount of imamamine is not reported. The first route uses unfriendly chloroform as a solvent, generating a large amount of wastewater and chloroform waste liquid. The operation is cumbersome and environmentally unfriendly.

[0006]

[0007] Route 2, shown below, uses 2-methyl-5-nitroaniline as a starting material, which first reacts with cyanamide to form guanidine, which then undergoes a cyclization reaction with 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one. The nitro group is then reduced to an amino group, and then condensed with p-chloromethylbenzoyl chloride and N-methylpiperazine to produce imatinib (WO 2004 / 108699).

[0008]

[0009] Route 3, shown in the following formula, uses 4-methyl-3-nitroaniline as the starting material, which is first subjected to a condensation reaction with p-chloromethylbenzoyl chloride and N-methylpiperazine. The nitro group is then reduced to an amino group, which is then reacted with cyanamide to form guanidine. This is followed by a cyclization reaction with 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one to produce imatinib (WO 03 / 066613).

[0010]

[0011] The biggest difference between the three routes mentioned above is the different reaction order of the cyclization of the pyrimidine ring. Comparison of the three routes: 1) Route 1 has a high synthesis yield, fewer steps, and the obtained imatinib free base having the structure of Formula I is of high purity. However, in the literature that has been reported, in the process of synthesizing imatinib free base from compounds having the structure of Formula II and compounds having the structure of Formula III, the process is carried out in an organic solvent and under alkaline conditions. The organic solvent is mostly chloroform, dichloromethane, tetrahydrofuran, etc., and the base used is mostly pyridine, potassium hydroxide or (aq), sodium hydroxide or (aq), and post-treatment requires The present invention relates to a novel synthesis method for the synthesis of imatinib free base, which is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture. The method is simple and easy to manufacture.

[0012] In addition, since imatinib (shown in Formula II) is genotoxic, a large residual amount has a significant impact on human health; existing literature reports all use imatinib free base purification, crystallization and other operations to remove imatinib (shown in Formula II). Through the above comparative analysis of the imatinib base (Formula I) synthesis route, the preparation method in the synthesis route will face the problem of controlling the residual limit of the key genotoxic impurity imatinib (Formula II); multiple acid-base return operations or crystallization are required, sacrificing yield to improve the purity of imatinib free base. Therefore, it is necessary to develop a method for preparing high-purity imatinib mesylate with a simple and efficient removal of imatinib (shown in Formula II), a genotoxic impurity. Summary of the Invention

[0013] The object of the present invention is to provide a method for preparing imatinib mesylate. The method provided by the present invention has low cost, simple operation, high purity of the prepared imatinib mesylate, extremely low imatinib residue (less than 2 ppm), and high yield.

[0014] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0015] The present invention provides a method for preparing imatinib mesylate, which is characterized by comprising the following steps:

[0016] (1) subjecting imatinib having a structure of Formula II and imatinib chloride having a structure of Formula III to an amidation reaction in a weakly acidic solvent, and obtaining imatinib free base having a structure of Formula I through post-treatment;

[0017] (2) mixing the imatinib free base having the structure of formula I obtained in step (1) with an organic solvent, adding methanesulfonic acid dropwise under an inert atmosphere and heating conditions, then adding activated carbon, sequentially performing adsorption treatment and hot filtration, then adding seed crystals and crystallizing, and then sequentially cooling and filtering to obtain imatinib mesylate;

[0018]

[0019] Preferably, the molar ratio of imamamine to imamyl chloride in step (1) is 1:(1.1-2.0).

[0020] Preferably, the weakly acidic solvent in step (1) is a mixture of water, a water-soluble organic solvent and an acid.

[0021] Preferably, the temperature of the amidation reaction in step (1) is 0-35° C., and the pH value of the reaction system of the amidation reaction is 3-4.

[0022] Preferably, after the amidation reaction in step (1) is completed, the residual amount of imamidine in the amidation reaction product is monitored to be ≤40 ppm.

[0023] Preferably, in step (2), the ratio of the mass of imatinib free base to the volume of the organic solvent is 1 g: (3-15) mL.

[0024] Preferably, in step (2), the molar ratio of imatinib free base to methanesulfonic acid is 1:(0.9-1.2).

[0025] Preferably, in step (2), the weight ratio of imatinib free base to activated carbon is 1:(0.05-0.5).

[0026] Preferably, the hot filtration in step (2) is performed by diatomaceous earth filtration or filtration with a Tairo filter element.

[0027] Preferably, the temperature for adding seed crystals in step (2) is 45-55°C; the crystallization is carried out under a protective atmosphere, and the temperature for the crystallization is 40-55°C.

[0028] The present invention provides a method for preparing imatinib mesylate. First, imamidine having a structure of Formula II and imamoyl chloride having a structure of Formula III are subjected to an amidation reaction in a weakly acidic solvent to promote the forward progress of the reaction and reduce residual imamidine in the reaction product. After post-treatment, imatinib free base having a structure of Formula I is obtained. Then, an organic solvent is added, and methanesulfonic acid is added dropwise under an inert atmosphere and heating conditions to perform mesylation. Activated carbon is then added, and adsorption treatment and hot filtration are sequentially performed to further reduce residual imamidine. Then, seed crystals are added and crystallized, followed by cooling and filtration to obtain imatinib mesylate with high purity and high yield. The method provided by the present invention has an excellent imamidine removal effect, and its residual can be controlled to an extremely low level (below 2 ppm). Moreover, the reaction conditions are mild, the operation is easy, and it is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The present invention provides a flow chart for the preparation of imatinib mesylate;

[0030] Figure 2 This is the H NMR spectrum of imatinib free base having the structure of Formula I prepared in Example 4 of the present invention;

[0031] Figure 3 This is the H NMR spectrum of imatinib mesylate prepared in Example 9 of the present invention. DETAILED DESCRIPTION

[0032] The present invention provides a method for preparing imatinib mesylate, which is characterized by comprising the following steps:

[0033] (1) subjecting imatinib having a structure of Formula II and imatinib chloride having a structure of Formula III to an amidation reaction in a weakly acidic solvent, and obtaining imatinib free base having a structure of Formula I through post-treatment;

[0034] (2) mixing the imatinib free base having the structure of formula I obtained in step (1) with an organic solvent, adding methanesulfonic acid dropwise under an inert atmosphere and heating conditions, then adding activated carbon, sequentially performing adsorption treatment and hot filtration, then adding seed crystals and crystallizing, and then sequentially cooling and filtering to obtain imatinib mesylate;

[0035]

[0036] In the present invention, unless otherwise specified, the raw materials used are conventional commercial products in the field.

[0037] According to the present invention, imatinine with a structure of formula II and imatinib chloride with a structure of formula III are subjected to an amidation reaction in a weakly acidic solvent, and imatinib free base with a structure of formula I is obtained through post-treatment.

[0038] In the present invention, the weakly acidic solvent is preferably a mixture of water, a water-soluble organic solvent, and an acid; the water-soluble organic solvent is preferably at least one of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, dioxane, DMF, DMSO, DMAC, and ethylene glycol, more preferably at least one of methanol, ethanol, and isopropanol; the acid is preferably at least one of hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid, acetic acid, formic acid, and sulfonic acid, more preferably at least one of hydrochloric acid, sulfuric acid, and nitric acid. In the present invention, the pH value of the weakly acidic solvent is preferably 1 to 4. The present invention uses a weakly acidic solvent as the reaction solvent for the amidation reaction to promote the forward reaction and reduce residual imamidine in the reaction product.

[0039] In the present invention, the molar ratio of imamamine to imamyl chloride is preferably 1:(1.1-2.0), more preferably 1:(1.2-1.5).

[0040] In the present invention, the temperature of the amidation reaction is preferably 0 to 35°C, more preferably 5 to 15°C. In the present invention, the pH value of the reaction system of the amidation reaction is preferably 3 to 4. Ordinary amidation reactions are generally carried out under alkaline conditions (usually using organic amines, etc.). However, imamidine formula (II) is an aromatic amine compound and an alkaline compound, which has good solubility in acidic solutions. The method provided by the present invention first dissolves imamidine (Formula II) in a weakly acidic solvent, adds imamoyl chloride (Formula III), and then controls the pH value of the reaction system solution to 3 to 4, performs an amidation reaction, and produces imatinib (Formula I). Since imatinib contains an amide bond, it is easily hydrolyzed into imamidine (Formula II) under both strong acidic and strong alkaline conditions. Therefore, the residual imamidine in the reaction system comes partly from the imamidine raw material that has not reacted completely, and the other part comes from the hydrolysis of imatinib. The present invention controls the pH value of the amidation reaction system within the range of 3 to 4, which is more conducive to the forward advancement of the reaction. At the same time, the hydrolysis rate of imatinib is slow under low temperature and weak acid conditions, thereby reducing the residual imatinib in the reaction product imatinib. In addition, in chemical reactions, acid and base are relative. Under the conditions of 3 to 4 pH value of the amidation reaction system of the present invention, imatinib (Formula II) is a base and a nucleophilic reagent, and imamoyl chloride (Formula III) is an acid and an electrophilic reagent, which promotes the effective conduct of the reaction. In addition, the present invention has found that when the pH value of the reaction system of imatinib (II) and imamoyl chloride (III) is between 5 and 7, imatinib (II) is not easily soluble, the reaction solution is a colloid, and it is difficult to stir, and the amidation reaction cannot be effectively carried out.

[0041] In the present invention, after the amidation reaction is completed, the residual amount of imamidine in the amidation reaction product is monitored to be ≤40 ppm; the monitoring method is preferably to take samples for liquid chromatography analysis.

[0042] In the present invention, the post-treatment preferably comprises: adjusting the pH value of the amidation reaction product with a base, cooling and crystallizing, filtering, eluting and drying to obtain imatinib free base having the structure of formula I.

[0043] In the present invention, the base used to adjust the pH value is preferably to adjust the pH value of the amidation reaction product to 7-12, more preferably 7-9; the base used is preferably an aqueous solution of at least one of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, triethylamine, diethylamine, piperidine, morpholine, and pyridine, more preferably an aqueous solution of at least one of sodium hydroxide, potassium hydroxide, and potassium carbonate.

[0044] The present invention has no particular limitation on the methods of cooling, crystallizing, filtering and rinsing, and any of the well-known technical solutions in the art can be used. In the present invention, the drying is preferably vacuum drying; and the drying temperature is preferably 45-55°C.

[0045] After obtaining the imatinib free base having the structure of formula I, the present invention mixes the imatinib free base having the structure of formula I with an organic solvent, adds methanesulfonic acid dropwise under an inert atmosphere and heating conditions, then adds activated carbon, sequentially performs adsorption treatment and hot filtration, then adds seed crystals and crystallizes, and then sequentially cools and filters to obtain imatinib mesylate.

[0046] In the present invention, the organic solvent is preferably at least one of methanol, ethanol, isopropanol, n-propanol, tetrahydrofuran, methyltetrahydrofuran, ethyl acetate, propyl acetate, methyl acetate, dichloromethane, and acetonitrile, more preferably at least one of methanol, ethanol, and isopropanol.

[0047] In the present invention, the ratio of the mass of the imatinib free base to the volume of the organic solvent is preferably 1 g: (3-15) mL, more preferably 1 g: (4-13) mL.

[0048] In the present invention, the molar ratio of imatinib free base to methanesulfonic acid is preferably 1:(0.9-1.2), more preferably 1:(0.95-1.05).

[0049] In the present invention, the inert atmosphere is preferably a nitrogen atmosphere; the temperature for adding methanesulfonic acid dropwise is preferably 20°C to 80°C, more preferably 40°C to 55°C;

[0050] In the present invention, the weight ratio of imatinib free base to activated carbon is preferably 1:(0.05-0.5), more preferably 1:(0.1-0.3). In the present invention, the activated carbon is preferably pharmaceutical activated carbon; and the particle size of the activated carbon is preferably ≤100 mesh.

[0051] In the present invention, the adsorption treatment is preferably carried out under stirring at 30 to 80° C., more preferably under stirring at 40 to 55° C.; the time of the adsorption treatment is preferably 0.5 to 3 h, more preferably 1 to 2 h.

[0052] In the present invention, the hot filtration method is preferably diatomaceous earth filtration or Tairo filter element filtration.

[0053] In the present invention, the crystallization reaction is carried out under a protective atmosphere, more preferably a nitrogen atmosphere, and the temperature for adding the seed crystals is 40-55°C.

[0054] In the present invention, the temperature for adding the seed crystals is preferably 45-55°C; the crystallization is carried out under a protective atmosphere, and the temperature for the crystallization is preferably 40-55°C, more preferably 40-50°C.

[0055] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions of the present invention. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0056] Example 1

[0057] 4-[(4-methyl-1-piperazine)methyl]-N-[4-methyl-3-[4-(3-pyridine)-2-pyrimidinyl]amino]phenyl]-benzamide, i.e., imatinib free base having the structure of Formula I, is prepared by the following steps:

[0058] In a 250 mL dry three-necked flask, 100 mL of purified water, 20 mL of ethanol, 10 g of imamidine having a structure of formula II, and 1.1 g of hydrochloric acid were added in sequence, and the temperature was lowered to 5-10° C., and 18.7 g of imatinib chloride having a structure of formula III was added in batches. The temperature was controlled at 5-10° C. during the addition process, and the pH value of the reaction system was adjusted to 3-4 with a base (the base was prepared by mixing 20 mL of purified water, 3.0 g of sodium hydroxide, and 0.5 g of sodium carbonate). After the addition was completed, the amidation reaction was carried out at 5-10° C. for 1 h. The residual imamidine was detected by high performance liquid chromatography analysis and was 30.4 ppm. The reaction was terminated, and then 20% aqueous sodium hydroxide solution was added dropwise to adjust the pH value to 8. The temperature was then lowered to room temperature, filtered, and rinsed with ethanol. The obtained solid wet product was dried in vacuo at 50° C. to obtain 17.0 g of imatinib free base having a structure of formula I as an off-white solid with a molar yield of 95.5% and a purity of 99.9%.

[0059] The molar ratio of imamamine to imamyl chloride is 1:1.8.

[0060] Example 2

[0061] The synthesis of 4-[(4-methyl-1-piperazine)methyl]-N-[4-methyl-3-[4-(3-pyridine)-2-pyrimidinyl]amino]phenyl]-benzamide, i.e., the preparation of imatinib free base having the structure of Formula I, is as follows:

[0062] In a 1L dry three-necked flask, 600mL of purified water, 50g of imamidine having a structure of formula II, and 5.5g of hydrochloric acid were added in sequence, and the temperature was lowered to 5-10°C. 82.0g of imatinib chloride having a structure of formula III was added in batches. The temperature was controlled at 5-10°C during the addition process. The pH value of the reaction system was adjusted to 3-4 with a base (the base was prepared by mixing 40mL of purified water, 6.0g of sodium hydroxide, and 1.0g of sodium carbonate). After the addition was completed, the amidation reaction was carried out at 5-10°C for 1h. The residual imamidine was detected by high performance liquid chromatography analysis and found to be 23.6ppm. The reaction was terminated, and then 25% potassium carbonate aqueous solution was added dropwise to adjust the pH value to 7.5-8. The mixture was stirred for 1h, then cooled to room temperature, filtered, and rinsed with ethanol. The obtained solid wet product was dried in vacuo at 50°C to obtain 83.0g of imatinib free base having a structure of formula I as an off-white solid with a molar yield of 93.2% and a purity of 99.9%.

[0063] The molar ratio of imamamine to imamyl chloride is 1:1.6.

[0064] Example 3

[0065] The synthesis of 4-[(4-methyl-1-piperazine)methyl]-N-[4-methyl-3-[4-(3-pyridine)-2-pyrimidinyl]amino]phenyl]-benzamide, i.e., the preparation of imatinib free base having the structure of Formula I, is as follows:

[0066] In a 3L dry three-necked flask, 1800mL of purified water, 150g of imamylamine having the structure of formula II, and 16.5g of hydrochloric acid were added in sequence, mechanically stirred, cooled to below 10°C, and 282.0g of imamyl chloride having the structure of formula III was added in batches. The temperature was controlled at 5-10°C during the addition process, and the pH value of the reaction system was adjusted to 3-4 with a base (the base was obtained by mixing 120mL of purified water, 18.0g of sodium hydroxide, and 3.0g of sodium carbonate). After the addition was completed, the reaction was kept at 0-10°C for 1h and the sample was taken. High-performance liquid chromatography analysis detected 25.9 ppm of residual imatinib, and then a 20% aqueous sodium hydroxide solution was added dropwise to adjust the pH to 6-7. The temperature was raised to 50-60° C., and the pH was further adjusted to 8-9 with a 20% aqueous sodium hydroxide solution. 150 mL of ethanol was added and stirred for 1 hour. The mixture was then cooled to room temperature, filtered, and rinsed with ethanol. The resulting wet solid was dried in vacuo at 50° C. to obtain 246.0 g of an off-white solid imatinib free base having the structure of Formula I, with a molar yield of 92.1% and a purity of 99.8%.

[0067] The molar ratio of imamamine to imamyl chloride is 1:1.8.

[0068] Example 4

[0069] 4-[(4-methyl-1-piperazine)methyl]-N-[4-methyl-3-[4-(3-pyridine)-2-pyrimidinyl]amino]phenyl]-benzamide, i.e., imatinib free base having the structure of Formula I, is prepared by the following steps:

[0070] In a 1000L glass-lined reactor, 300kg of primary reverse osmosis water, 40kg of methanol, 35.20kg of imamyl amine having a structure of Formula II, and 3.90kg of hydrochloric acid were added in sequence, stirring was started, the temperature was lowered to below 10°C, and 64.42kg of imamyl chloride having a structure of Formula III was added in 12 batches. The temperature was controlled at 5-10°C during the addition process, and the pH value of the reaction system was adjusted to 3-4 with sodium carbonate solution. After the addition was completed, the reaction was kept at 5-10°C for 1h. The residual imamyl amine was detected by high-performance liquid chromatography analysis and was 19.2ppm. Then, 20% aqueous sodium hydroxide solution was added dropwise to adjust the pH value to 7.5-8. The temperature was controlled at 15-20°C, stirred for 2h, centrifuged, and washed with ethanol. The obtained solid wet product was vacuum dried at 50°C to obtain 57.0kg of imatinib free base having a structure of Formula I as an off-white solid with a molar yield of 90.9% and a purity of 99.8%.

[0071] The molar ratio of imamamine to imamyl chloride is 1:1.8.

[0072] The H NMR spectrum of the imatinib free base having the structure of Formula I prepared in Example 4 is as follows: Figure 2 As shown by Figure 2 It can be seen that Example 4 successfully prepared imatinib free base having the structure of Formula I with high purity.

[0073] Example 5

[0074] The preparation of 4-[(4-methyl-1-piperazine)methyl]-N-[4-methyl-3-[4-(3-pyridine)-2-pyrimidinyl]amino]phenyl]-benzamide methanesulfonate, i.e., imatinib mesylate, is as follows:

[0075] At room temperature, in a 100 mL dry three-necked flask, 10.9 g of imatinib free base having the structure of formula I in Example 2 (wherein the residual amount of imamidine is 23.6 ppm) and 55 mL of methanol were added, and then nitrogen protection (subsequent operations were carried out under nitrogen protection) was added, and stirred into a slurry; heated to 45 ° C, and 2.11 g of methanesulfonic acid was added dropwise at a temperature of 40-50 ° C. After the addition was complete, the temperature was controlled at 50 ± 5 ° C and stirred until the solution was clear. After confirming that the solution was clear, 1.1 g of granules were added. 100 mesh medicinal activated carbon, heat-insulated and stirred for adsorption treatment for 1 hour, then filtered using diatomaceous earth as a filter aid, the filter cake was rinsed with 5 mL of methanol, the combined filtrate was kept at 50 ± 5 ° C, 50 mg of seed crystals were added, stirred and crystallized for 2 hours, cooled to room temperature, filtered, and rinsed with methanol. The obtained solid wet product was vacuum-dried below 50 ° C for 12 hours to obtain 12.0 g of off-white imatinib mesylate, with a molar yield of 92.3%, an imatinib content of 1.1 ppm by HPLC, and a purity of 99.9%;

[0076] The ratio of the mass of the imatinib free base to the volume of the organic solvent methanol is 1 g:5 mL;

[0077] The molar ratio of imatinib free base to methanesulfonic acid is 1:1.0;

[0078] The weight ratio of the imatinib free base to the activated carbon is 1:0.1.

[0079] Example 6

[0080] The preparation of 4-[(4-methyl-1-piperazine)methyl]-N-[4-methyl-3-[4-(3-pyridine)-2-pyrimidinyl]amino]phenyl]-benzamide methanesulfonate, i.e., imatinib mesylate, is as follows:

[0081] At room temperature, 10 g of imatinib free base (30.4 ppm of imatinib residue) and 80 mL of methanol were added to a 100 mL dry three-necked flask with the structure of formula I in Example 1, and then nitrogen protection (subsequent operations were carried out under nitrogen protection) was added and stirred into a slurry; the mixture was heated to 45 ° C, and 1.95 g of methanesulfonic acid was added dropwise at a temperature of 40-50 ° C. After the addition was completed, the mixture was stirred at a temperature of 50 ± 5 ° C until the solution was clear. After confirming that the solution was clear, 1.1 g of 1,000 tantalum (1000 tantalum) and 1,000 tantalum (1000 tantalum) were added. 00 mesh medicinal activated carbon, keep warm and stir for adsorption treatment for 1 hour, then use diatomaceous earth to filter the filter, rinse the filter cake with 5 mL of methanol, and after combining, keep the filtrate warm at 50±5°C, add 50 mg of seed crystals, stir and crystallize for 2 hours, cool to room temperature, filter, rinse with methanol, and the obtained solid wet product is dried under vacuum below 50°C for 12 hours to obtain 11.2 g of off-white imatinib mesylate, with a molar yield of 93.7%, an imatinib content of 1.5 ppm by HPLC, and a purity of 99.9%;

[0082] The ratio of the mass of the imatinib free base to the volume of the organic solvent methanol is 1 g:8 mL;

[0083] The molar ratio of imatinib free base to methanesulfonic acid is 1:1.0;

[0084] The weight ratio of the imatinib free base to the activated carbon is 1:0.11.

[0085] Example 7

[0086] The preparation of 4-[(4-methyl-1-piperazine)methyl]-N-[4-methyl-3-[4-(3-pyridine)-2-pyrimidinyl]amino]phenyl]-benzamide methanesulfonate, i.e., imatinib mesylate, is as follows:

[0087] At room temperature, 10 g of imatinib free base (19.2 ppm of imatinib residue) of Example 4 and 50 mL of methanol were added to a 100 mL dry three-necked flask, and then nitrogen protection (subsequent operations were carried out under nitrogen protection) was added and stirred into a slurry; the mixture was heated to 45 ° C, and 2.05 g of methanesulfonic acid was added dropwise at a temperature of 40-50 ° C. After the addition was complete, the mixture was stirred at a temperature of 50 ± 5 ° C until the solution was clear. After confirming that the solution was clear, 1.1 g of 1,000 tantalum (100 μg) of particle size ≤ 10 was added. 0 mesh medicinal activated carbon, keep warm and stir for adsorption treatment for 1 hour, then use diatomaceous earth to assist filtration, filter the filter cake with 5 mL of methanol, and after combining, keep the filtrate at 50±5°C, add 50 mg of seed crystals, stir and crystallize for 2 hours, cool to room temperature, filter, and rinse with methanol. The obtained solid wet product is dried under vacuum below 50°C for 12 hours to obtain 11.0 g of off-white imatinib mesylate, with a molar yield of 92.1%. The imatinib content is 0.7 ppm and the purity is 99.9% by HPLC.

[0088] The ratio of the mass of the imatinib free base to the volume of the organic solvent methanol is 1 g:5 mL;

[0089] The molar ratio of imatinib free base to methanesulfonic acid is 1:1.1;

[0090] The weight ratio of the imatinib free base to the activated carbon is 1:0.11.

[0091] Example 8

[0092] The preparation of 4-[(4-methyl-1-piperazine)methyl]-N-[4-methyl-3-[4-(3-pyridine)-2-pyrimidinyl]amino]phenyl]-benzamide methanesulfonate, i.e., imatinib mesylate, is as follows:

[0093] At room temperature, 150 g of imatinib free base (25.9 ppm of imatinib residue) and 600 mL of ethanol were added to a 1 L dry three-necked flask, and then nitrogen protection (subsequent operations were carried out under nitrogen protection) was mechanically stirred to form a slurry; the mixture was heated to 40-50 ° C, and 29.2 g of methanesulfonic acid was added dropwise under temperature control. After the addition was completed, the mixture was stirred at 45 ± 5 ° C until the solution was clear. After confirming that the solution was clear, 22.5 g of medicinal active ingredient with a particle size of ≤100 mesh was added. The mixture was adsorbed on charcoal, stirred and kept warm for 1 hour, then filtered using diatomaceous earth as a filter aid, the filter cake was rinsed with 50 mL of methanol, the combined filtrate was heated to 50±5°C, 1.0 g of seed crystals were added, stirred and crystallized for 4 hours, cooled to 10-20°C, filtered, and rinsed with ethanol. The obtained solid wet product was vacuum dried below 50°C for 12 hours to obtain 167.0 g of off-white imatinib mesylate, with a molar yield of 93.2%. The imatinib content was 0.8 ppm by HPLC, and the purity was 99.9%.

[0094] The ratio of the mass of the imatinib free base to the volume of the organic solvent methanol is 1 g:4 mL;

[0095] The molar ratio of imatinib free base to methanesulfonic acid is 1:1.0;

[0096] The weight ratio of the imatinib free base to the activated carbon is 1:0.15.

[0097] Example 9

[0098] The preparation of 4-[(4-methyl-1-piperazine)methyl]-N-[4-methyl-3-[4-(3-pyridine)-2-pyrimidinyl]amino]phenyl]-benzamide methanesulfonate, i.e., imatinib mesylate, is as follows:

[0099] To a 500 L glass-lined reactor, 116.65 kg of methanol and 29.0 kg of imatinib free base having the structure of Formula I in Example 4 (19.2 ppm of imatinib residue) were added in sequence. After the addition was completed, nitrogen protection was applied (all subsequent operations were carried out under nitrogen protection conditions), and the temperature was raised with stirring. The temperature in the autoclave was controlled at 45±5°C, and 5.80 kg of methanesulfonic acid was slowly added dropwise, and the addition was completed within about 20 to 60 minutes. After the addition was completed, the temperature in the autoclave was raised to 50±5°C. After confirming that the solution in the autoclave was clear, a mixture of methanol (11.60 kg) and medicinal activated carbon (3.48 kg, particle size ≤ 100 mesh) was added to the reactor. After the addition was completed, the temperature in the autoclave was controlled at 50±5°C, and stirring was continued for 60±5 minutes. After stirring for a certain period of time, the feed liquid was filtered through a decarbonization filter (titanium rod pore size 1.0 μm) and a secondary filter (filter element pore size 1.0 μm, size 10 inches, material PTFE) into a clean 500 L stainless steel reactor, and the inner wall and related pipelines of the 500 L glass-lined reactor were rinsed with methanol (8.85 kg). The liquid after pressure filtration was heated to an autoclave temperature of 50±5°C, and then 30g of imatinib mesylate seed crystals were added. After the addition was completed, the autoclave temperature was controlled at 50±5°C, and crystallization was started by insulated stirring for 5±1 hours. After crystallization was completed, the autoclave temperature was slowly lowered to 15±5°C, and the crystals were grown by insulated stirring for 1 hour, centrifuged, and washed with methanol. The resulting solid was vacuum-dried in a biconical oven at 60±5°C for more than 4 hours to obtain 31.56kg of off-white imatinib mesylate, with a molar yield of 91.1%. The imatinib content was 0.6ppm by HPLC, and the purity was 99.9%.

[0100] The ratio of the mass of the imatinib free base to the volume of the organic solvent methanol is 1 g:5 mL;

[0101] The molar ratio of imatinib free base to methanesulfonic acid is 1:1.0;

[0102] The weight ratio of the imatinib free base to the activated carbon is 1:0.12.

[0103] The H NMR spectrum of imatinib mesylate prepared in Example 9 is as follows: Figure 3 As shown by Figure 3 It can be seen that Example 9 successfully prepared imatinib mesylate with high purity.

[0104] Examples 10 to 14

[0105] Imatinib mesylate was prepared using the imatinib free base prepared in Example 3 as a raw material according to the method of Example 5. The difference from Example 5 was that the mass percentage of activated carbon in Examples 10 to 14 to the imatinib free base was 5%, 10%, 15%, 20% and 30%, respectively.

[0106] Comparative Example 1

[0107] Imatinib mesylate was prepared using the imatinib free base prepared in Example 1 as a raw material according to the method of Example 5, except that no activated carbon was added for adsorption treatment in Example 1.

[0108] In order to explore the effect of the amount of activated carbon on the residual amount of imine in the prepared imatinib mesylate, the residual amount of imine in the imatinib mesylate prepared in Examples 10 to 14 and Comparative Example 1 was detected by HPLC. The results are shown in Table 1.

[0109] Table 1 Imatinib free base prepared in Example 3, and the residual amount of imatinib in imatinib mesylate prepared in Examples 10 to 14 and Comparative Example 1

[0110] - sample condition Imamidine residue Example 3 Imatinib free base - 25.9ppm Comparative Example 1 Imatinib mesylate Without activated carbon 22.5ppm Example 10 Imatinib mesylate 5% activated carbon 2.0ppm Example 11 Imatinib mesylate 10% activated carbon 1.7ppm Example 12 Imatinib mesylate 15% activated carbon 0.8ppm Example 13 Imatinib mesylate 20% activated carbon 0.6ppm Example 14 Imatinib mesylate 30% activated carbon 0.6ppm

[0111] Comparative Examples 2 to 5

[0112] Imatinib free base was prepared according to the method of Example 2, except that the pH values of the reaction systems in Comparative Examples 2 to 5 were adjusted to 1-2, 2-3, 8-9, and 9-10, respectively, with a base (the base was prepared by mixing 40 mL of purified water, 6.0 g of sodium hydroxide, and 1.0 g of sodium carbonate).

[0113] In order to explore the influence trend of the pH value of the reaction system of imamamine (II) and imacinyl chloride (III) on the residual amount of imamamine in the prepared imatinib free base, HPLC was used to detect the residual amount of imamamine in the imatinib free base prepared in Example 2 and Comparative Examples 2 to 5, respectively. The results are shown in Table 2. In addition, the present invention found that when the pH value of the reaction system of imamamine (II) and imacinyl chloride (III) was between 5 and 7, the reaction solution was a colloid that was difficult to stir, and therefore no further experiments were performed.

[0114] Table 2 Residual amount of imatinib in imatinib free base prepared in Example 2 and Comparative Examples 2 to 5

[0115] - sample condition Imamidine residue Example 2 Imatinib free base 3～4 23.6ppm Comparative Example 2 Imatinib free base 1～2 168.5ppm Comparative Example 3 Imatinib free base 2～3 96.3ppm Comparative Example 4 Imatinib free base 8～9 164.1ppm Comparative Example 5 Imatinib free base 9～10 188.1ppm

[0116] In summary, the present invention can effectively promote the forward reaction and reduce the residual imamine by controlling the pH value of the reaction system of imamine (II) and imatinib chloride (III), wherein the pH value of the reaction system of the amidation reaction is between 3 and 4, which is most conducive to the forward reaction, and the hydrolysis rate of the product imatinib is the slowest, and the residual amount of imamine in the prepared imatinib free base product is the smallest; compared with Comparative Example 1, the method provided by the present invention uses activated carbon for adsorption treatment, which can greatly reduce the residual amount of imamine in the prepared final product imatinib mesylate.

[0117] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing imatinib mesylate, characterized in that: The following steps are involved: (1) subjecting imatinib having a structure of Formula II and imatinib chloride having a structure of Formula III to an amidation reaction in a weakly acidic solvent, and obtaining imatinib free base having a structure of Formula I through post-treatment; In step (1), the weakly acidic solvent is a mixture of water, a water-soluble organic solvent and an acid; The temperature of the amidation reaction in step (1) is 0 to 35° C., and the pH value of the reaction system of the amidation reaction is 3 to 4; (2) mixing the imatinib free base having the structure of formula I obtained in step (1) with an organic solvent, adding methanesulfonic acid dropwise under an inert atmosphere and heating conditions, then adding activated carbon, sequentially performing adsorption treatment and hot filtration, then adding seed crystals and crystallizing, and then sequentially cooling and filtering to obtain imatinib mesylate; The temperature for adding the seed crystals in step (2) is 45-55°C; the crystallization is carried out under a protective atmosphere, and the temperature for the crystallization is 40-55°C; 2. The preparation method according to claim 1, characterized in that The molar ratio of imamylamine to imamyl chloride in the step (1) is 1:(1.1-2.0).

3. The preparation method according to claim 1, characterized in that After the amidation reaction in step (1) is completed, the residual amount of imamidine in the amidation reaction product is monitored to be ≤40 ppm.

4. The preparation method according to claim 1, characterized in that In the step (2), the ratio of the mass of imatinib free base to the volume of the organic solvent is 1 g: (3-15) mL.

5. The preparation method according to claim 1, characterized in that The molar ratio of imatinib free base to methanesulfonic acid in step (2) is 1:(0.9-1.2).

6. The preparation method according to claim 1, characterized in that The weight ratio of imatinib free base to activated carbon in the step (2) is 1:(0.05-0.5).

7. The preparation method according to claim 1, characterized in that The hot filtration in step (2) is carried out by diatomaceous earth filtration or titanium rod filter element filtration.

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