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Preparation method of imatinib mesylate

The technology of imatinib mesylate and benzoic acid dihydrochloride is applied in the field of preparation of imatinib mesylate, and can solve the problems of difficulty in removing reaction by-products, long total reaction time, many reaction steps, and the like, Achieve the effects of being beneficial to environmental protection, stable and feasible process, and moderate reaction conditions

Inactive Publication Date: 2011-05-04
韩南银 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] 3) The purity of the reaction product in step 5 is 98.3% (beige solid), and the purity after purification is 99.7% (off-white solid). Impurities are likely to be introduced into the product
[0015] 1) There are many reaction steps and the total reaction time is long
[0016] 2) Catalytic hydrogenation is required, which brings certain safety hazards to industrial production
[0020] 1) The trimethylaluminum used is extremely flammable, which brings potential danger to large-scale production
[0021] 2) The use of expensive palladium catalysts, and the need for catalytic hydrogenation, brings certain safety hazards to industrial production
[0031] 3) After the reaction, only wash with water to remove impurities, and dry to get the final product. It is difficult to remove reaction by-products and unreacted reagents
[0036] 2) The total yield is relatively low

Method used

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  • Preparation method of imatinib mesylate
  • Preparation method of imatinib mesylate
  • Preparation method of imatinib mesylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Implementation example 1: the first preparation method of imatinib mesylate

[0091] (1) Take Intermediate I (50.3g, 0.181mol), suspend it in 250ml of dimethylformamide (DMF), and add Intermediate II (75.2g, 0.245mol), and N-hydroxy Succinimide (1.04 g, 0.009 mol) was added to a solution of dicyclohexylcarbodiimide (39.2 g, 0.190 mol) in DMF within 10 minutes with stirring at room temperature. The reaction was stirred at 20°C for 17 hours, and the reaction was monitored by HPLC. After the reaction was completed, it was filtered, and the product was dried under reduced pressure at 60°C for 6 hours to obtain 60.1 g of the product as a light yellow solid.

[0092] (2) Dissolve 60 g of the light yellow solid obtained in step (1) in 240 ml of water, add 0.5% activated carbon, heat to 60° C. in a water bath, stir for 30 minutes, and filter. The pH of the filtrate was adjusted to 10.2 with aqueous ammonia, and the precipitate was filtered and dried in vacuo to obtain 49.8 g o...

Embodiment 2

[0098] Implementation example 2: the second preparation method of imatinib mesylate

[0099] (1) Take intermediate II (2350g, 7.65mol), add 20L of thionyl chloride under constant stirring, heat to boiling, slowly add 27ml of DMF dropwise, keep boiling for 2 hours, recover dichloromethane under reduced pressure For sulfone, appropriate amount of toluene was added several times and evaporated to dryness under reduced pressure to remove excess thionyl chloride, and dried under vacuum at 60°C.

[0100] (2) Take intermediate I (1450g, 5.23mol), add 7.2L of DMF, stir to dissolve, add the acid chloride generated by the above reaction, heat to 70°C, add 1L of pyridine, stir for about 15 hours, and monitor the progress of the reaction by HPLC After the reaction is completed, cool to room temperature, stir for 2 hours, filter, and dry the product under reduced pressure at 60°C.

[0101] (3) Take the imatinib hydrochloride obtained by the above reaction, add 7.5L of water, stir to disso...

Embodiment 3

[0106] Implementation example 3: HPLC purity detection of imatinib mesylate

[0107] Chromatographic conditions:

[0108] Chromatographic column: Venusil C18 (250×4.6mm, 5μm)

[0109] Mobile phase: sodium octane sulfonate solution (take 7.5 g of sodium octane sulfonate, add 1000 ml of water to dissolve, adjust the pH value to 2.5 with 10% phosphoric acid) + methanol-acetonitrile (1:1), gradient elution, the gradient conditions are the same as above .

[0110] Column temperature: room temperature

[0111] Flow rate: 1.0ml / min

[0112] Detection wavelength: 267nm

[0113] Injection volume: 10μl

[0114] Preparation of mixed resolution solution: Take intermediate I, intermediate II, imatinib mesylate, appropriate amount of impurity A, and impurity B, and add methanol to make a solution containing 0.1 mg per 1 ml as a resolution solution.

[0115] Precisely measure 10 μl, inject it into the chromatograph, and record the chromatogram. The results show that the resolution of eac...

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Abstract

The invention relates to a preparation method of imatinib mesylate using N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine and 4-[(4-methyl piperazine-1-yl) methyl] benzoic acid hydrochloride as starting materials, and quality control method for intermediate in the preparation process and the final product. The overall yield of the process is about 40%, and the process is characterized in that reaction conditions are mild, operations are simple, column chromatography and other time and energy consuming steps can be avoided, quality of obtained products is stable, the purity is greater than 99%, the production cost is low, and the technology is stable and feasible.

Description

technical field [0001] The invention relates to a preparation method of imatinib mesylate, an intermediate control method and its application in the field of medicine. Background technique [0002] Imatinib mesylate is a derivative of aniline and is a specific tyrosine kinase inhibitor (tyrosine kinase inhibitors, TKI). In May 2001, it was approved by the FDA for the treatment of chronic myelogenous leukemia (CML). It was approved by the FDA in 2003 for the treatment of gastrointestinal stromal tumors (GIST). [0003] As the world's first approved tumorigenesis-related signal transduction inhibitor, the launch of imatinib mesylate has won unanimous praise from all parties in the international medical community: it not only represents a new class of anti-tumor drugs with a new mechanism of action This has officially entered into clinical application, and it has already indicated the direction of the development of a disease treatment drug, that is, the target of the drug wi...

Claims

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Application Information

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IPC IPC(8): C07D401/04G01N30/36
Inventor 韩南银陈鑫
Owner 韩南银
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