Method for preparing imatinib

A compound and structural formula technology, applied in the field of imatinib preparation, can solve the problem of low reaction yield, and achieve the effects of simple reaction steps, less environmental pollution, and short production cycle

Active Publication Date: 2010-12-22
山东金城昆仑药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But the disadvantage of this process is that the reaction yield is low (85%)

Method used

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  • Method for preparing imatinib
  • Method for preparing imatinib
  • Method for preparing imatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Magnetic stirring, a thermometer and a reflux condenser were installed in a 2000ml three-necked flask, and 27.7g (100mmol) of compound (II), 24.6g of compound (III), 0.5ml of pyridine and 450ml of N,N-dimethyl Acetamide was heated to 80-85°C, 32.6g of trimethyl phosphite was added dropwise within half an hour, and the reaction was continued for 2 hours at this temperature. Cool down to room temperature, add 450ml of water, extract with dichloromethane, spin dry, recrystallize with acetonitrile, and dry in vacuo to obtain 46.9g of imatinib (HPLC: 99.6%), with a yield of 95.0%.

Embodiment 2

[0034] Magnetic stirring, thermometer and reflux condenser are installed in the there-necked flask of 2000ml, add the imatinib intermediate (II) of 27.7g (100mmol), the imatinib intermediate (III) of 23.4g (100mmol), 0.5ml of pyridine and 500ml of N,N-dimethylformamide were heated to 50°C, 31.0g (100mmol) of triphenyl phosphite was added dropwise within 2 hours, and the reaction was continued at this temperature for 3 hours. Cool down to room temperature, add 500ml of water, extract with dichloromethane, spin dry, recrystallize with acetonitrile, and dry in vacuo to obtain 43.9g of imatinib (HPLC: 99.45%), with a yield of 89.0%.

Embodiment 3

[0036] In the there-necked flask of 2000ml, magnetic stirring, thermometer and reflux condenser are installed, add the imatinib intermediate (II) of 27.7g (100mmol), the imatinib intermediate (III) of 28.1g (120mmol), 0.1 ml of pyridine and 180 ml of N-methylpyrrolidone were heated to 90° C., 37.2 g (120 mmol) of triphenyl phosphite were added dropwise within 2 hours, and the reaction was continued at this temperature for 1.5 hours. Cool down to room temperature, add 180 ml of water, extract with dichloromethane, spin dry, recrystallize with acetonitrile, and dry in vacuo to obtain 40.0 g of imatinib (HPLC: 99.6%), with a yield of 81.2%.

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Abstract

The invention relates to a method for preparing imatinib, which comprises the following steps of: with a compound N-(5-Amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine shown as the structural formula (II) and a compound 4-[(4-Methylpiperazin-l-yl)methyl]benzoic acid shown as the structural formula (III) as initial raw materials, dropwise adding phosphite ester at 50-90 DEG C for 1-2 hours inthe presence of a catalyst in an organic solvent; and continuously insulating and reacting at 50-90 DEG C to obtain the compound imatinib shown as the structural formula (I). The organic solvent is N,N-dimethylformamide, N,N-dimethylacetylamide or N-methylpyrrolidone. The catalyst is pyridine; and the phosphite ester is trimethyl phosphate, triethyl phosphate or triphenyl phosphate. The technical scheme of the invention has the advantages of simple reaction step, easy control of reaction, short production cycle, low toxicity of used raw materials, less pollution to the environment and higher product quality, and the yield can reach 95 percent, and the purity reaches 99.5 percent.

Description

technical field [0001] The invention relates to a preparation method of a drug for treating chronic myelogenous leukemia and gastrointestinal stromal tumors, in particular to a preparation method of imatinib. Background technique [0002] Imatinib is used for the treatment of Chronic Myelogenous Leukemia (CML) in blast phase, accelerated phase or chronic phase after failure of α-interferon therapy and for the treatment of unresectable and / or metastatic malignant gastrointestinal Adult patients with GastrointestInal stroml tumor (GIST). [0003] Imatinib, trade name: Gleevec, chemical name: 4-[(4-methyl-1-piperazinyl)methyl]N-[4-methyl-3-[4-(3-pyridine) Base)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate, white or off-white crystalline powder, the structural formula is as follows: [0004] [0005] Chemagis Ltd disclosed in the patent US 2006149061 that N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyrimidine (II) and 4-(4-methylpiperazine Methyl) benzoyl chl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
Inventor 赵叶青李湛江刘刚刘承平徐立臣
Owner 山东金城昆仑药业有限公司
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