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Synthesis method of imatinib

A synthesis method and technology of imatinib, applied in the field of pharmaceutical intermediate synthesis, can solve the problems of large environmental pollution, large DMF-containing wastewater, large pollution, etc., and achieve large reagents, high reactivity, and product yield to avoid environmental pollution. high effect

Inactive Publication Date: 2018-11-06
ANHUI HAIKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The shortcoming of this method is: produce a large amount of waste water containing DMF, pollute the environment
[0006] U.S. Patent US2013 / 41149 reports the acylation of ethyl imatate and imaamide to obtain imatinib. The advantage of this method is that the yield is high, but the disadvantage is that the product purity is less than 98%, which does not meet the requirements for the preparation of raw materials.
[0007] Patent documents such as CN103848813, US2012 / 46463 and WO2012 / 131711 all use the acyl chloride of imacic acid and imaamide to acylate imatinib. The advantage of this type of method is low cost, and the disadvantage is that thionyl chloride is corrosive high, polluted
[0008] WO2015 / 188243 reported that imatinib and imatinib were produced under the action of condensing agents HOBT and EDC.HCl. Although the product obtained by this method can meet the purity requirements, the price of the condensing agent used is relatively expensive, and it will be used later. During the treatment process, a large amount of water washing is required to remove the by-products brought by the condensing agent
[0009] The existing imatinib synthesis technology has the disadvantages of many impurities, large environmental pollution and high cost, so it is necessary to seek a new imatinib synthesis method that can simplify the process steps, reduce environmental pollution and reduce production costs

Method used

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  • Synthesis method of imatinib
  • Synthesis method of imatinib
  • Synthesis method of imatinib

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Synthesis of compound (IV)

[0030] The first step, N-(5-amino-2-methylphenyl)-4-(3-pyridine)-2-pyrimidinamine 27.7g (100.0mmol, 1.0eq), hexamethyldisilazane 96.9g (600.0mmol, 6.0eq) was placed in a reaction flask, heated to reflux and reacted overnight, the reaction of the raw material in TLC was complete, the temperature was lowered, and the solvent and excess hexamethyldisilazane were concentrated under reduced pressure to obtain 41.3g of yellow oil , HPLC purity 95.3%, yield 98.1%. 1 H-NMR (400MHz, DMSO-d6): 0.11(s, 9H, NSi(CH3)3), 0.15(s, 9H, Si(CH3)3), 2.06(s, 3H, CH3), 2.84(broad, 1H,NH),6.33(dd,1H,J=8.0 and2.3Hz,Ph-H-4),6.71(d,1H,J=2.3Hz,Ph-H-2),6.79(d,1H,J =8.0Hz, Ph-H-5),7.22(d,1H,J=5.2Hz,pyrim-H-5),7.51(ddd,1H,J=8.0 and 4.8Hz,pyr-H-5),8.25 (td,1H,J=8.0 and 1.7Hz,pyr-H-4),8.42(d,1H,J=5.2Hz,pyrim-H-6),8.60(dd,1H,J=4.8 and1.7Hz, pyr-H-6), 9.17 (d, 1H, J = 1.7 Hz, pyr-H-2) ppm. ESI + [M + H] + = 422.2.

[0031] Synthesis of compound (I)

[0032] In the seco...

Embodiment 2

[0034] Synthesis of compound (IV)

[0035] The first step, N-(5-amino-2-methylphenyl)-4-(3-pyridine)-2-pyrimidinamine 138.5g (0.5mol, 1.0eq), solid ammonium chloride 2.8g, hexamethyl Hexamethyldisilazane 242.0g (1.5mol, 3.0eq) was placed in a reaction flask, heated to reflux for 5 hours, the reaction of the raw materials in TLC was complete, the temperature was lowered, and the solvent and excess hexamethyldisilazane were concentrated under reduced pressure to obtain 209.7 g of yellow oil, HPLC purity 95.7%, yield 99.6%. ESI+[M+H]+=422.2.

[0036] Synthesis of compound (I)

[0037]In the second step, 4-[(4-methyl-1-piperazine) methyl] benzoic acid dihydrochloride 168.3g (0.548mol, 1.1eq) and 500g methylene chloride are put in the reaction flask, and the temperature control is 10- Add 28.2g (218.2mmol, 2.2eq) of diisopropylethylamine at 20°C and stir for 30 minutes, then add 6.5g (49.8mmol, 1%eq) of tetrabutylammonium fluoride, and add N,N' in batches -Carbonyldiimidazole 8...

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Abstract

The invention discloses a synthesis method of imatinib and belongs to the field of synthesis of medical intermediates. The method comprises the following steps: taking N-(5-amino-2-methylphenyl)-4-(3-pyridine)-2-pyrilamine as a raw material, carrying out silanization reaction, then enabling the raw material to carry out condensation reaction with 4-[(4-methyl-1-piperazine)methyl]dihydrochloride benzoate in the presence of alkali and a catalyst in N,N'-carbonyl diimidazole to obtain the imatinib. The synthesis method of imatinib is high in yield and simple to operate, and is suitable for industrial production; the product is easy to purify, high in quality and high in purity.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, and in particular relates to a synthesis method of imatinib. Background technique [0002] Imatinib mesylate, developed by Novartis, is the world's first approved tumorigenesis-related signal transduction inhibitor. Imatinib mesylate was approved by the U.S. Food and Drug Administration (FDA) on May 10, 2001, for the treatment of α-interferon (interfer on-alfa) treatment failure blast crisis stage, accelerated Patients with chronic myelogenous leukemia in the disease stage or chronic stage. Imatinib chemical name 4-(4-methylpiperazinyl-1-methyl)-N-[4-methyl-3-[4-(3-pyridyl)pyrimidine-2-amino]-benzene Formamide (structure shown in formula (I)). [0003] [0004] Many documents in the prior art have reported the synthesis method of imatinib, mainly by constructing the amide bond of imatinib to synthesize imatinib. [0005] Chinese patent document CN101921260A disclose...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 张小顺
Owner ANHUI HAIKANG PHARMA
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