A kind of synthetic method of imatinib mesylate

Abstract

The invention discloses a method for synthesizing imatinib mesylate, comprising the following steps: S1. Synthesis of imatinib, under nitrogen protection, catalyst, potassium carbonate, 4-(3-pyridyl)-2-aminopyrimidine and 4-(N-methylpiperazine) methylbenzoyl (3-bromo-4-methylphenyl) amine are dispersed in ethanol, heated for reaction, and imatinib is obtained; S2. Synthesis of imatinib mesylate, imatinib is dispersed in an appropriate amount of isopropanol, heated to reflux, an isopropanol solution of methanesulfonic acid is added dropwise, and reflux reaction is performed to obtain imatinib mesylate. The present invention forms a polydopamine-graphite carrier by self-polymerization of dopamine hydrochloride coated graphite powder, which is mixed with urea and then calcined to increase the content of nitrogen in the carrier, and then impregnated with the metal after coordination, and finally forms the catalyst of the present invention, and the catalyst prepared by the present invention can obtain imatinib at a lower temperature and in a shorter time, and the yield is more than 94%, and has a higher purity.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical synthesis, and in particular to a method for synthesizing imatinib mesylate. Background Art

[0002] Imatinib mesylate, chemical name is 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide methanesulfonate, and its molecular structure is as follows:

[0003] .

[0004] Imatinib mesylate is obtained by sulfonation reaction of imatinib with methanesulfonic acid, and the most common synthesis method of imatinib was proposed by Loiseleur et al., as shown in the following formula:

[0005]

[0006] When using this method, the coupling reaction of compounds 4 and 5 requires the use of relatively expensive palladium catalysts and ligands under strong alkaline conditions, resulting in high production costs. Summary of the invention

[0007] In order to solve the problems mentioned in the above background technology, the present invention provides a method for synthesizing imatinib mesylate.

[0008] In order to achieve the above object, the present invention adopts the following technical solutions:

[0009] A method for synthesizing imatinib mesylate comprises the following steps:

[0010] S1. Synthesis of Imatinib

[0011] Under nitrogen protection, the catalyst, potassium carbonate, 4-(3-pyridyl)-2-aminopyrimidine and 4-(N-methylpiperazine)methylbenzoyl(3-bromo-4-methylphenyl)amine are dispersed in ethanol and heated to react to obtain imatinib;

[0012] S2. Synthesis of Imatinib Mesylate

[0013] Imatinib is dispersed in an appropriate amount of isopropanol, heated to reflux, an isopropanol solution of methanesulfonic acid is added dropwise, and refluxed to obtain imatinib mesylate.

[0014] Preferably, the preparation method of the catalyst is as follows:

[0015] Add graphite powder and dopamine hydrochloride to the prepared alkaline solution, heat and stir to react, dry, grind and mix the dried product with urea, and then calcine under a nitrogen atmosphere to obtain a carrier;

[0016] 4-methoxypyridine and diphenylmethoxyphosphine are dispersed in DMF to obtain a ligand solution, copper chloride, nickel chloride and titanium chloride are added to the ligand solution, heated and stirred for reaction, the above-mentioned carrier is added, the reaction is continued by stirring, and the catalyst is obtained by drying.

[0017] Preferably, the alkaline solution is any one of an aqueous ammonia solution, an aqueous sodium hydroxide solution, and an aqueous potassium hydroxide solution.

[0018] Preferably, the mass ratio of the graphite powder to dopamine hydrochloride is 1:(0.2-0.8).

[0019] Preferably, the mass ratio of the dried product to urea is 1:(0.05-0.2).

[0020] Preferably, the mass ratio of 4-methoxypyridine to diphenylmethoxyphosphine is 1:(0.4-0.6).

[0021] Preferably, the mass ratio of the copper chloride, nickel chloride, titanium chloride and carrier is 5:(1-3):(1-3):(10-20).

[0022] Preferably, the mass molar ratio of the catalyst, potassium carbonate, 4-(3-pyridyl)-2-aminopyrimidine, and 4-(N-methylpiperazine)methylbenzoyl(3-bromo-4-methylphenyl)amine is (3-10 g): (1-2 mol): (1-1.2 mol): 1 mol.

[0023] Preferably, the molar ratio of imatinib to methanesulfonic acid is 1:(1-1.1).

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] 1. The present invention forms a polydopamine-coated graphite powder by self-polymerization of dopamine hydrochloride under weak alkaline conditions to form a polydopamine-graphite carrier, which is mixed with urea and then calcined to increase the nitrogen content in the carrier, and then impregnated with a coordinated metal to finally form the catalyst of the present invention. The catalyst prepared by the present invention can obtain imatinib at a lower temperature (40°C) and a shorter time (2h), with a yield of more than 94% and a higher purity.

[0026] 2. The present invention regulates the structure of the catalyst by combining 4-methoxypyridine and diphenylmethoxyphosphine. Multiple metals are loaded on the carrier to form a unique pore structure and surface properties, with more active sites and a larger specific surface area, which greatly improves the reaction rate and selectivity. At the same time, two different types of coordination environments promote the interaction between the three metal ions, produce a certain synergistic effect, and improve the performance of the catalyst. DETAILED DESCRIPTION

[0027] Unless otherwise specified, the raw materials and reagents used in the present invention are commercially available or can be prepared by known methods.

[0028] Preparation Example 1

[0029] Method for preparing catalyst

[0030] Prepare 200 ml of ammonia solution with a pH of 9, add 20 g of graphite powder and 10 g of dopamine hydrochloride, stir at 40° C. for 10 h, dry, grind and mix 10 g of the dried product with 1 g of urea, and then calcine at 500° C. for 3 h under a nitrogen atmosphere to obtain a carrier;

[0031] Disperse 2 g of 4-methoxypyridine and 1 g of diphenylmethoxyphosphine in 100 ml of DMF to obtain a ligand solution, add 5 g of copper chloride, 2 g of nickel chloride and 2 g of titanium chloride to the ligand solution, stir and react at 50°C for 3 h, add 15 g of the above-mentioned carrier, continue stirring for 2 h, and dry to obtain a catalyst.

[0032] Preparation Example 2

[0033] The difference between this preparation example and preparation example 1 is that 20 g of graphite powder and 5 g of dopamine hydrochloride are added;

[0034] The rest is exactly the same as Preparation Example 1.

[0035] Preparation Example 3

[0036] The difference between this preparation example and preparation example 1 is that 20 g of graphite powder and 15 g of dopamine hydrochloride are added;

[0037] The rest is exactly the same as Preparation Example 1.

[0038] Preparation Example 4

[0039] The difference between this preparation example and preparation example 1 is that 10 g of the dried product and 0.5 g of urea are ground and mixed;

[0040] The rest is exactly the same as Preparation Example 1.

[0041] Preparation Example 5

[0042] The difference between this preparation example and preparation example 1 is that 10 g of the dried product and 2 g of urea are ground and mixed;

[0043] The rest is exactly the same as Preparation Example 1.

[0044] Preparation Example 6

[0045] The difference between this preparation example and preparation example 1 is that 2 g of 4-methoxypyridine and 0.8 g of diphenylmethoxyphosphine are dispersed in 100 ml of DMF;

[0046] The rest is exactly the same as Preparation Example 1.

[0047] Preparation Example 7

[0048] The difference between this preparation example and preparation example 1 is that the reaction is stirred at 50°C for 3h and 10g of the above-mentioned carrier is added;

[0049] The rest is exactly the same as Preparation Example 1.

[0050] Preparation Example 8

[0051] The difference between this preparation example and preparation example 1 is that 10 g of the dried product and 0 g of urea are ground and mixed;

[0052] The rest is exactly the same as Preparation Example 1.

[0053] Preparation Example 9

[0054] The difference between this preparation example and preparation example 1 is that 2 g of 4-methoxypyridine and 0 g of diphenylmethoxyphosphine are dispersed in 100 ml of DMF;

[0055] The rest is exactly the same as Preparation Example 1.

[0056] Preparation Example 10

[0057] The difference between this preparation example and preparation example 1 is that 0 g of 4-methoxypyridine and 1 g of diphenylmethoxyphosphine are dispersed in 100 ml of DMF;

[0058] The rest is exactly the same as Preparation Example 1. Example 1

[0059] A method for synthesizing imatinib mesylate comprises the following steps:

[0060] Synthesis of Imatinib

[0061] Under nitrogen protection, 0.5 g of catalyst (Preparation Example 1), 20.7 g of potassium carbonate, 18.92 g of 4-(3-pyridyl)-2-aminopyrimidine (background technology compound 5) and 40.2 g of 4-(N-methylpiperazine)methylbenzoyl(3-bromo-4-methylphenyl)amine (background technology compound 4) were dispersed in an appropriate amount of ethanol, stirred at 40 ° C for 2 h, filtered, concentrated, added ethyl acetate, and extracted with water, repeated 3 times, the organic phases were combined, and the organic phases were washed with a saturated sodium chloride aqueous solution until neutral, added with anhydrous sodium sulfate, dried, filtered, concentrated, washed with ice methanol, and vacuum dried to obtain imatinib with a yield of 95.8% and a purity of 99.8%;

[0062] Synthesis of Imatinib Mesylate

[0063] Disperse 20 g of imatinib in an appropriate amount of isopropanol, heat to reflux, slowly add an isopropanol solution of methanesulfonic acid (4 g, 40 mL), reflux for 3 h, stir at 5 °C for crystallization for 5 h, filter, wash with isopropanol, and vacuum dry to obtain imatinib mesylate with a yield of 88.6% and a purity of 99.9%.

[0064] Embodiment 2-10

[0065] The implementation conditions were the same as those in Example 1, except that catalysts obtained from different preparation examples were used. The results are shown in Table 1.

[0066] Table 1

[0067]

[0068] According to Table 1, it can be seen from Examples 1-7 that the yield of imatinib catalyzed by the catalyst prepared by the present invention is above 94%, and has a high purity, and can be directly used for the preparation of imatinib mesylate in the next step.

[0069] It can be seen from Example 8 that without adding urea (Example 8), the yield of imatinib is only 53.1%, the purity is only 92.5%, and the catalytic effect is significantly reduced.

[0070] It can be seen from Examples 9 and 10 that without adding diphenylmethoxyphosphine (Example 9), the yield of imatinib is only 38.5%, and the purity is only 82.6%. Without adding 4-methoxypyridine (Example 10), the yield of imatinib is only 41.6%, and the purity is only 88.3%. As a result, whether diphenylmethoxyphosphine or 4-methoxypyridine is lacking, the catalytic effect of the catalyst is significantly reduced, and the simultaneous use of the two produces a significant synergistic enhancement effect.

[0071] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for synthesizing imatinib mesylate, characterized in that: The steps include: S1. Synthesis of Imatinib Under nitrogen protection, the catalyst, potassium carbonate, 4-(3-pyridyl)-2-aminopyrimidine and 4-(N-methylpiperazine)methylbenzoyl(3-bromo-4-methylphenyl)amine are dispersed in ethanol and heated to react to obtain imatinib; S2. Synthesis of Imatinib Mesylate Dispersing imatinib in an appropriate amount of isopropanol, heating to reflux, adding dropwise an isopropanol solution of methanesulfonic acid, and subjecting to reflux reaction to obtain imatinib mesylate; The preparation method of the catalyst is as follows: Add graphite powder and dopamine hydrochloride to the prepared alkaline solution, heat and stir to react, dry, grind and mix the dried product with urea, and then calcine under a nitrogen atmosphere to obtain a carrier; 4-methoxypyridine and diphenylmethoxyphosphine are dispersed in DMF to obtain a ligand solution, copper chloride, nickel chloride and titanium chloride are added to the ligand solution, heated and stirred for reaction, the above-mentioned carrier is added, the reaction is continued by stirring, and the catalyst is obtained by drying.

2. The method for synthesizing imatinib mesylate according to claim 1, characterized in that: The alkaline solution is any one of an aqueous ammonia solution, an aqueous sodium hydroxide solution, and an aqueous potassium hydroxide solution.

3. The method for synthesizing imatinib mesylate according to claim 1, characterized in that: The mass ratio of the graphite powder to dopamine hydrochloride is 1:(0.2-0.8).

4. The method for synthesizing imatinib mesylate according to claim 1, characterized in that: The mass ratio of the dried product to urea is 1:(0.05-0.2).

5. The method for synthesizing imatinib mesylate according to claim 1, characterized in that: The mass ratio of the 4-methoxypyridine to the diphenylmethoxyphosphine is 1:(0.4-0.6).

6. The method for synthesizing imatinib mesylate according to claim 1, characterized in that: The mass ratio of the copper chloride, nickel chloride, titanium chloride and carrier is 5:(1-3):(1-3):(10-20).

7. The method for synthesizing imatinib mesylate according to claim 1, characterized in that: The mass molar ratio of the catalyst, potassium carbonate, 4-(3-pyridyl)-2-aminopyrimidine, and 4-(N-methylpiperazine)methylbenzoyl(3-bromo-4-methylphenyl)amine is (3-10 g): (1-2 mol): (1-1.2 mol): 1 mol.

8. The method for synthesizing imatinib mesylate according to claim 1, characterized in that: The molar ratio of imatinib to methanesulfonic acid is 1:(1-1.1).

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