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Convenient and quick method for preparing high-purity imatinib and mesylate thereof

A technology for imatinib and benzoic acid, which is applied in the field of synthetic methods of imatinib and its mesylate, can solve the problem of easy generation of demethyl imatinib impurities, many impurities produced by the reaction, difficult to remove and Purification and other issues to achieve complete transformation, product quality improvement, and good quality results

Inactive Publication Date: 2011-03-16
NANJING CAVENDISH BIO ENG TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] Although multiple methods are disclosed in the above-mentioned prior art, these synthetic methods all have disadvantages, such as harsh reaction conditions (need heating or strong base) or non-environmental friendliness in the indirect coupling method; the post-processing of the direct coupling method is complex , The reaction produces a lot of impurities, especially desmethylimatinib, which is difficult to remove and purify.

Method used

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  • Convenient and quick method for preparing high-purity imatinib and mesylate thereof
  • Convenient and quick method for preparing high-purity imatinib and mesylate thereof
  • Convenient and quick method for preparing high-purity imatinib and mesylate thereof

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preparation example Construction

[0034] 1. Preparation of imatinib

[0035] Reaction equation:

[0036]

Embodiment 1

[0038] Add 4-(4-methylpiperazine methyl)-benzoic acid dihydrochloride (122g, 0.397mol) in the four-necked flask, dichloromethane (1000ml), control room temperature dropwise diisopropylethylamine ( 138ml, 0.792mol), add and keep warm for 1 hour. Add N-(5-amino-2-methylphenyl)-4-(3-pyridine)-pyrimidinamine (100g, 0.361mol), HBTU (150g, 0.396mol) and diisopropylethylamine (75ml, 0.431mol). Add and keep warm overnight. Dilute aqueous sodium hydroxide (500ml) was added at room temperature and stirred for 1 hour. Suction filtration, rinse with appropriate amount of water and ethyl acetate to obtain filter cake 1.

[0039] The mother liquor was separated into phases, and the organic phase was separated, dried with anhydrous sodium sulfate, and filtered with suction. The filtrate was concentrated to dryness under reduced pressure to obtain a light yellow solid, which was crystallized by adding ethyl acetate and stirring. Suction filtration and rinsing with an appropriate amount o...

Embodiment 2

[0041] Add 4-(4-methylpiperazinemethyl)-benzoic acid dihydrochloride (24.4g, 0.079mol), DMF (120ml) in a four-neck flask, and add DIPEA (28ml, 0.161mol) dropwise at room temperature, After the addition, keep stirring for 30 minutes. N-(5-Amino-2-methylphenyl)-4-(3-pyridine)-pyrimidinamine (20 g, 0.072 mol), HCTU (32.7 g, 0.079 mol) and DIPEA (15 ml, 0.086 mol) were added. After the addition, the reaction was incubated for 8 hours. After the reaction is complete, add water and stir for 30 minutes, filter with suction, wash the filter cake with ethyl acetate, and dry at 50°C. 33.1 g (purity: 97.8%) of the target object was obtained as a pale yellow solid. "Desmethylimatinib" was not detected. Yield: 93.1%.

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Abstract

The invention discloses a method for synthesizing imatinib, which comprises the following step of: in the presence of a urea cation condensing agent, reacting N(5-amino-2-methylphenyl)-4-(3-pyridyl)-pyrimithamine (namely a compound shown in a formula I) with 4-(4-methylpiperazin methyl)-benzoic acid in an organic solvent to generate the imatinib. By adopting a specific coupling agent, the invention provides a method for synthesizing imatinib and mesylate thereof, which has the advantages of high efficiency, simple treatment, high product purity, low content of impurities of methyl-removed imatinib, good quality, and suitability for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, more specifically, relates to a synthetic method of imatinib and mesylate thereof suitable for industrialized production Background technique [0002] Imatinib mesylate (STI571) is a tyrosine kinase inhibitor drug developed by Novartis, Switzerland. In May 2001, imatinib mesylate was approved by the U.S. FDA for expedited approval by the U.S. FDA for granulocytic leukemia (CML) and gastrointestinal Glivec is a treatment for stromal tumors (GISTs). The chemical name of imatinib mesylate is 4-[(4-methyl-1-piperazine)methyl]-4-[4-methyl-3-[[4-(3-pyridyl)-2 -pyrimidinyl]amino]-phenyl]benzamide methanesulfonate, the chemical structure is: [0003] [0004] The method for the synthesis of imatinib often comprises the following final step: N-(5-amino-2-methylphenyl)-4-(3-pyridine)-pyrimidinamine (compound of formula I) and 4-(4- Methylpiperazine (methyl)-benzoic acid derivative (ie c...

Claims

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Application Information

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IPC IPC(8): C07D401/04
Inventor 严荣杨浩侯雯许永翔
Owner NANJING CAVENDISH BIO ENG TECH
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