A process for the preparation of imatinib mesylate

Abstract

The application provides a preparation method of imatinib mesylate, wherein 4-(4-methylpiperazin-1-yl)methyl benzoic acid dihydrochloride (compound 5) is neutralized by sodium hydroxide to be free, then directly subjected to condensation with N-(5-amino-2-methylphenyl)-4-(pyridin-3-yl)pyrimidin-2-amine (compound 4) to obtain imatinib, and then the imatinib is subjected to salt formation with methanesulfonic acid to obtain imatinib mesylate. The preparation method is safe and environment-friendly, simple and convenient to operate, low in cost and has industrialization value.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis. Specifically, this invention provides a method for preparing imatinib mesylate. Background Technology

[0002] Imatinib mesylate is a tyrosine kinase inhibitor targeting the bcr / abl fusion protein, developed by Novartis in Switzerland and marketed as Gleevec. It was approved by the FDA in May 2001 for the treatment of chronic myeloid leukemia (CML) and in February 2002 for the treatment of gastrointestinal stromal tumors (GIST). It is currently marketed in the United States, the European Union, Japan, China, and many other countries. It has ushered in a new era of molecularly targeted cancer therapy and is considered a milestone.

[0003] The chemical name of imatinib mesylate is 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]phenyl]-benzamide methanesulfonate, and its structural formula is:

[0004] There are numerous literature reports on the preparation methods of imatinib mesylate. In summary, the most advantageous synthetic route is the one originally reported by Novartis in 1994 (US5521184), and the synthetic route is as follows:

[0005] This route prepares imatinib mesylate in a convergent manner with a high yield. However, in this route, after the substitution reaction between N-methylpiperazine and 4-chloromethylbenzoic acid, the product often exists in the form of a dihydrochloride to improve the yield and purity. This dihydrochloride, i.e., compound 5, has poor solubility in organic solvents. In the process of activating the carboxyl group of compound 5 to prepare compound 6 acyl chloride, a large amount, or even the solvent amount, of the high-risk reagent thionyl chloride is often required, and a high-temperature reflux reaction of up to 24-31 hours is required (as reported in CN103570676, WO2008070350, Bioorganic and Medicinal Chemistry, 2014, 22(1): 623-632, etc.); or an acid-binding agent such as pyridine or other organic bases are required (as reported in WO2008098949). These methods involve highly toxic organic reagents such as thionyl chloride and pyridine, are cumbersome to operate, have redundant steps, high energy consumption, high pollution, and high environmental safety pressure.

[0006] Therefore, it is essential to research and develop a safe, environmentally friendly, easy-to-operate, low-cost, and industrially viable method for preparing imatinib mesylate. Summary of the Invention

[0007] The method for preparing imatinib mesylate provided by this invention includes the following steps: (a) Imatinib was prepared by reacting compound 5 and two moles of sodium hydroxide in dimethylformamide solvent with N-(5-amino-2-methylphenyl)-4-(pyridin-3-yl)pyrimidin-2-amine (compound 4) in magnesium oxide catalysis without separation. (b) Imatinib mesylate was prepared by reacting imatinib with mesylate via a salt formation reaction.

[0008]

[0009] In step (a), the molar ratio of compound 4 to compound 5 is 1:1 to 1:1.2, the reaction temperature of the acid-base neutralization reaction is 10-30℃, the amount of magnesium oxide is 5-10% of the weight of compound 4, the reaction temperature of the condensation reaction is 60-80℃, the reaction time of the condensation reaction is 0.5-1.5 hours, and the amount of dimethylformamide is 2-3 times the weight of compound 5.

[0010] In step (b), imatinib mesylate can be prepared by reacting imatinib with mesylate in an aqueous ethanol solution.

[0011] The detailed reaction process of the imatinib mesylate preparation method presented in this invention is as follows: Compound 5 and two moles of sodium hydroxide react in dimethylformamide in an acid-base neutralization reaction to produce the free form of compound 5 and two moles of sodium chloride. Without separation and purification, compound 4 and magnesium oxide catalyst are directly added to this reaction system, resulting in a condensation reaction. After the reaction is complete, sodium chloride and magnesium oxide are filtered off, and the filtrate is cooled with an appropriate amount of methanol to induce crystallization. Filtering yields imatinib. Magnesium oxide plays a crucial role as a catalyst in the high-yield synthesis of important molecules. However, magnesium oxide particles are prone to agglomeration, affecting their catalytic activity. In this invention, the sodium chloride byproduct generated during the acid-base reaction of compound 5 with sodium hydroxide can prevent the agglomeration of magnesium oxide in subsequent reactions, or rather, disperse magnesium oxide, ensuring a large specific surface area and catalytic activity throughout the reaction. Furthermore, no additional post-treatment is required after the acid-base neutralization reaction, simplifying the operation.

[0012] The method for preparing imatinib mesylate provided by this invention shortens the reaction steps by one, uses milder reaction conditions, and is simpler to operate. The entire process does not use high-risk reagents, making it green, safe, and environmentally friendly. Overall, this method has advantages in both technical and economic indicators and shows promising industrial potential.

[0013] The present invention will continue to be described below through embodiments. Various substitutions or combinations made based on ordinary technical knowledge and conventional means in the art should be included within the scope of the present invention. Detailed Implementation Example 1: Preparation of Imatinib

[0014] 100 g (325.5 mmol) of 4-(4-methylpiperazin-1-yl)methylbenzoic acid dihydrochloride (compound 5) and 26 g (651 mmol) of sodium hydroxide were added to 300 g of dimethylformamide. The mixture was stirred at 10-20 °C for 0.5 h, and the system gradually became a turbid milky white suspension. 86.0 g (310.1 mmol) of N-(5-amino-2-methylphenyl)-4-(pyridin-3-yl)pyrimidin-2-amine (compound 4) and 4.3 g of magnesium oxide were added to the suspension. After the addition was complete, the mixture was heated to 60-70 °C and reacted for 1.5 h. Sodium chloride and magnesium oxide were filtered off while hot. The filtrate was slowly poured into 900 g of methanol, stirred at 20-30 °C for 1 h to crystallize, filtered, and dried by forced air at 50-60 °C to obtain 145.4 g of imatinib, with a molar yield of 95% and a purity of 99.5% by HPLC area normalization. Example 2: Preparation of Imatinib

[0015] 100 g (325.5 mmol) of 4-(4-methylpiperazin-1-yl)methylbenzoic acid dihydrochloride (compound 5) and 26 g (651 mmol) of sodium hydroxide were added to 200 g of dimethylformamide. The mixture was stirred at 20-30 °C for 0.5 h, and the system gradually turned into a turbid milky white suspension. 75.2 g (271.3 mmol) of N-(5-amino-2-methylphenyl)-4-(pyridin-3-yl)pyrimidin-2-amine (compound 4) and 7.5 g of magnesium oxide were added to the suspension. After the addition was complete, the mixture was heated to 70-80 °C and reacted for 1.0 h. Sodium chloride and magnesium oxide were removed by filtration while hot. The filtrate was slowly poured into 800g of methanol, stirred at 20-30℃ for 0.5 hours to induce crystallization, filtered, and dried at 50-60℃ to obtain 128.6g of imatinib, with a molar yield of 96% and a purity of 99.6% as determined by HPLC area normalization. Comparative Example 1: Preparation of Imatinib

[0016] 100 g (325.5 mmol) of 4-(4-methylpiperazin-1-yl)methylbenzoic acid dihydrochloride (compound 5) and 26 g (651 mmol) of sodium hydroxide were added to 300 g of dimethylformamide. The mixture was stirred at 10-20 °C for 0.5 h, and the system gradually became a turbid milky white suspension. Sodium chloride was removed by filtration. 86.0 g (310.1 mmol) of N-(5-amino-2-methylphenyl)-4-(pyridin-3-yl)pyrimidin-2-amine (compound 4) and 4.3 g of magnesium oxide were added to the filtrate. After the addition was complete, the mixture was heated to 60-70 °C and reacted for 1.5 h. Magnesium oxide was removed by filtration while hot. The filtrate was slowly poured into 900 g of methanol, stirred at 20-30 °C for 1 h to crystallize, filtered, and dried by forced air at 50-60 °C to obtain 87.2 g of imatinib, with a molar yield of 57% and a purity of 96.8% by HPLC area normalization. Example 3

[0017] 120g of imatinib and 24g of mesylate were added to 400g of ethanol and 60g of water, respectively, and stirred at 50-60℃ for 2 hours. Then, 400g of ethanol was added, and the mixture was cooled to 25-30℃ to crystallize for 3 hours. The crystals were filtered and dried under reduced pressure at 60℃ to obtain 139g of imatinib mesylate, with a molar yield of 97% and a purity of 99.7% as determined by HPLC area normalization.

Claims

1. A method for preparing imatinib mesylate. ； The method includes the following steps: (a) Imatinib was prepared by reacting compound 5 and two moles of sodium hydroxide in dimethylformamide solvent with compound 5 via an acid-base neutralization reaction, without separation, and then directly reacting with compound 4 via a condensation reaction catalyzed by magnesium oxide. ； (b) Imatinib mesylate was prepared by reacting imatinib with mesylate via a salt formation reaction.

2. The method as described in claim 1, characterized in that: In step (a), the molar ratio of compound 4 and compound 5 is 1:1 to 1:1.

2.

3. The method as described in claim 1, characterized in that: The reaction temperature for the acid-base neutralization reaction described in step (a) is 10-30℃.

4. The method as described in claim 1, characterized in that: In step (a), the amount of magnesium oxide used is 5-10% of the weight of compound 4.

5. The method as described in claim 1, characterized in that: The reaction temperature of the condensation reaction in step (a) is 60-80℃.

6. The method as described in claim 1, characterized in that: The reaction time for the condensation reaction described in step (a) is 0.5-1.5 hours.

7. The method as described in claim 1, characterized in that: The amount of dimethylformamide used in step (a) is 2-3 times the weight of compound 5.

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