Preparation method of high-purity imatinib

A high-purity, pyridine technology, applied in the field of medicine, can solve the problems of a large amount of pyridine solvent, no recovery, large pollution, etc., and achieve the effects of simple operation process, mild reaction conditions, and reduced production costs.

Active Publication Date: 2010-12-01
TIANJIN WEIJIE TECH
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

[0005] But, the common shortcoming that above-mentioned this preparation method exists is that purity is mostly between 97%-98%, impurity content also does not see detailed report, and used pyridine solvent amount is large (volume / mass=40 / 1) and does not reclaim, Therefore, the pollution caused is large, and the cost is high, and the residual amount of solvent in the product is relatively large, resulting in insufficient purity
According to the Q3A regulations of ICH (International Council for Harmonization of Technical Requirements for Registration of Drugs for Human Use), the requirement for the bulk drug is that the purity is greater than 99.0%, and the content of a single impurity is less than 0.10%, so the above-mentioned preparation method cannot meet this requirement.

Method used

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  • Preparation method of high-purity imatinib

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Embodiment 1

[0015] Install a mechanical stirrer and a thermometer on a 250mL four-necked bottle, and then add 1.77g (6.4mmol) of N-(5-amino-2-methylphenyl)-4-(3-pyridine)-2-pyrimidinamine and 50ml of pyridine, cooled to 5-10°C in an ice-water bath with stirring, and then added 3.0g (12.8mmol) of 4-[(4-methyl-1-piperazine)methyl]benzoyl chloride in batches After the addition of dihydrochloride, the ice-water bath was removed, and the temperature was raised to room temperature. After reacting for 2-3 hours, the reaction was stopped when the reaction was detected by HPLC, and the pyridine was evaporated under reduced pressure to recover it. Add 18ml of water to the residue and stir to dissolve the residue to form a transparent brown liquid, then extract twice with an appropriate amount of ethyl acetate, separate the organic phase and the water phase, and then use the water phase in an ice-water bath Adjust the pH to 9-10 with 25% ammonia water, then add 20ml of methanol, remove the ice-water...

Embodiment 2

[0017] Install a mechanical stirrer and a thermometer on a 1000mL four-necked bottle, then add 10g (36.1mmol) N-(5-amino-2-methylphenyl)-4-(3-pyridine)-2-pyrimidinamine and 250ml of pyridine, cooled to 5-10°C in an ice-water bath with stirring, then added 23.5g (72.12mmol) of 4-[(4-methyl-1-piperazine)methyl]benzoyl chloride di After the addition of hydrochloride, the ice-water bath was removed, and the temperature was raised to room temperature. After reacting for 2-3 hours, the reaction was stopped when the reaction was detected by HPLC, and the pyridine was evaporated under reduced pressure to recover it. Add 100ml of water to the residue and stir to dissolve the residue to form a transparent brown liquid, then extract twice with an appropriate amount of ethyl acetate, separate the organic phase and the water phase, and then use the water phase in an ice-water bath Adjust the pH to 9-10 with 25% ammonia water, then add 110ml of methanol, remove the ice-water bath, naturally...

Embodiment 3

[0019] Install a mechanical stirrer and a thermometer on a 1000mL four-necked flask, blow nitrogen into it, and then add 10g (36.1mmol) of N-(5-amino-2-methylphenyl)-4-(3-pyridine)-2 -Pyrimidinamine, 250ml acetonitrile and 23.7g (234.65mmol) triethylamine, placed in an ice-water bath to cool to 5-10°C under stirring conditions, then added 23.5g (72.12mmol) 4-[(4-methyl Base-1-piperazine) methyl] benzoyl chloride dihydrochloride. After the addition, the ice-water bath was removed, and the temperature was raised to room temperature. After reacting for 2-3 hours, the reaction was stopped when the HPLC detection reaction was complete, and evaporated under reduced pressure. Remove acetonitrile to recover it. Add 100ml of water to the residue and stir to dissolve the residue to form a transparent brown liquid, then extract twice with ethyl acetate, 75ml each time, separate the organic phase and the aqueous phase, then place the aqueous phase on ice Use 25% ammonia water in the wate...

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Abstract

The invention relates to a preparation method of high-purity imatinib, which comprises the following steps: taking 4-[(4-methyl-1-piperazine) methyl] benzoyl chloride dihydrochloride and N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-2-pyrilamine as raw materials, taking acetonitrile or pyridine as a solvent, and adding triethylamine as an acid-binding agent when the acetonitrile is taken as the solvent to react at the reaction temperature of -5-50 DEG C; removing the solvent in the reaction liquid to recycle the solvent; adding water into the residues; extracting impurities by ethyl acetate; separating the organic phase from the water phase; then neutralizing the water phase by ammonia water until the PH is 9-10; and adding saturated fatty alcohol to precipitate imatinib crystals. Because the purity of the product obtained by the preparation method of the invention is higher than 99.5%, the single impurity is less than 0.10%, and the solvent has low dosage and can be recycled, the production cost can be greatly reduced, and the pollution on the environment can be reduced. Moreover, the method has simple operation processes and mild reaction conditions, thus the method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a preparation method of high-purity imatinib. Background technique [0002] Imatinib is the precursor for the preparation of imatinib mesylate, which is clinically used to treat various tumors, especially for the treatment of chronic myeloid leukemia (CML). It was originally successfully developed by Swiss Novartis , and was approved by the FDA in 2001. In 2002, the FDA approved the drug as a drug for the treatment of gastrointestinal stromal tumors. The chemical name of this drug is 4-[(4-methyl-1-piperazine)methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine]amino] Phenyl]benzamide. [0003] In the prior art, many documents have reported the preparation method of imatinib, among which EP0564409, US20060149061, US20060223817, WO2004 / 074502, US2008 / 0103305 and WO2008 / 051597 and other patent documents all adopt the method shown in the following formula or A similar method is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
Inventor 宋红海彭啸许野马春磊
Owner TIANJIN WEIJIE TECH
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