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Method for preparing imatinib mesylate intermediate

A technology for imatinib mesylate and intermediates, which is applied in the field of preparation of imatinib mesylate intermediates, can solve the problems of reduced yield and many steps, and achieve reduced manufacturing steps, reduced costs, and improved Effects of Atom Economy

Active Publication Date: 2015-04-08
山东立新制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method has many steps, and it is also necessary to pass through the catalytic hydrogenation of the nitrate first, so that the total yield is reduced.

Method used

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  • Method for preparing imatinib mesylate intermediate
  • Method for preparing imatinib mesylate intermediate
  • Method for preparing imatinib mesylate intermediate

Examples

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Embodiment 1

[0045]Under nitrogen protection, add 400 mL of dioxane as a solvent into a 1L three-necked flask, start stirring, and then add 4-(3-pyridyl)pyrimidin-2-amine (20.7 g, 0.12 mol) and CuI (5.7 g, 0.03mol), anhydrous potassium carbonate (20.7g, 0.3mol). After stirring at room temperature for 15 minutes, 2-bromo-4-acetamido-toluene (22.7 g, 0.10 mol) of formula III and DMEDA (4.0 mL, 0.04 mol) were further added. The temperature was raised to reflux, and the reflux was maintained for 20 hours. After cooling to room temperature, trifluoroacetic acid (9.2 mL, 0.12 mol) was added to the system, stirred at room temperature for 2 hours, and the reaction was completed. Adjust the pH to pH=8-9 with concentrated ammonia water. Add 400mL of ethyl acetate saturated with 100mL of saturated saline, stir, stand still and separate layers, the aqueous phase is washed three times with ethyl acetate (100mLx3), the organic phases are combined, dried over anhydrous magnesium sulfate, concentrated t...

Embodiment 2

[0047] Under nitrogen protection, add 400 mL of dioxane as a solvent into a 1L three-necked flask, start stirring, and then add 4-(3-pyridyl)pyrimidin-2-amine (20.7 g, 0.12 mol) and CuI (5.7 g, 0.03mol), anhydrous potassium carbonate (20.7g, 0.3mol). After stirring at room temperature for 15 minutes, 2-bromo-4-acetamido-toluene III of formula III (22.7 g, 0.10 mol) and DMEDA (4.0 mL, 0.04 mol) were further added. The temperature was raised to reflux, and the reflux was maintained for 20 hours. After cooling to room temperature, 6N HCl (20 mL) was added to the system, heated to 50° C., stirred for 1 hour, and the reaction was completed. Adjust the acidity and alkalinity to pH=8-9 with concentrated ammonia water. Add 400 mL of ethyl acetate and 100 mL of saturated brine, stir, stand still and separate layers, wash the aqueous phase with ethyl acetate three times (100 mL x 3), combine the organic phases, dry over anhydrous magnesium sulfate, concentrate to give a yellow solid, ...

Embodiment 3

[0049] Under nitrogen protection, add 400 mL of dioxane as a solvent into a 1L three-necked flask, start stirring, and then add 4-(3-pyridyl)pyrimidin-2-amine (20.7 g, 0.12 mol) and CuI (5.7 g, 0.03mol), anhydrous potassium carbonate (20.7g, 0.3mol). After stirring at room temperature for 15 minutes, 2-bromo-4-acetamido-toluene (22.7 g, 0.1 mol) of formula III and DMEDA (4.0 mL, 0.04 mol) were further added. The temperature was raised to reflux, and the reflux was maintained for 20 hours. Cool to 0°C, add 10mL of 30% sodium hydroxide solution to the system, keep at 0°C, stir and react for 1 hour, and the reaction ends. First adjust the pH to pH=8-9 with dilute hydrochloric acid. Add 400mL of ethyl acetate saturated with 100mL of saturated saline, stir, stand still and separate layers, the aqueous phase is washed three times with ethyl acetate (100mLx3), the organic phases are combined, dried over anhydrous magnesium sulfate, concentrated to give a brownish yellow solid, and ...

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Abstract

The invention discloses a method for preparing N-(2-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrilamine (I) serving as an imatinib mesylate intermediate. The method comprises the following steps of: performing condensation reaction by using 4-(3-pyridyl) pyrimidine-2-amine (II) and 2-bromo-4-amino-toluene (III) in a one-pot mode; and removing amino protecting groups of the 2-bromo-4-amino-toluene (III) by strong acid or weak base to generate the N-(2-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrilamine (I) serving as the imatinib mesylate intermediate in one step. By the method, the steps for preparing the imatinib are reduced obviously, and the cost is reduced substantially.

Description

technical field [0001] The invention relates to the design of an organic synthesis method and the preparation technology of raw materials and intermediates, in particular to a preparation method of an imatinib mesylate intermediate. Background technique [0002] Imatinib mesylate is a tyrosine kinase inhibitor drug developed by Novartis, Switzerland, for the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal cell tumor (GIST). As the first molecular targeted therapy drug to be marketed, imatinib ushered in the era of tumor molecular targeted therapy and was hailed as a milestone discovery. Imatinib mesylate was launched in the US and China as Glivec (Gleevec) in 2001 and 2002, respectively. [0003] The medicinal active ingredient of imatinib mesylate is imatinib, and its chemical name is 4-[(4-methyl-1-piperazine)methyl]-N-[(4-methyl-3- [[4-(3-pyridine)-2-pyrimidine]amino]phenyl]benzamide, the molecular formula is as follows: [0004] [0005...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04
CPCY02P20/55
Inventor 许学农张青舒亮包志坚张佳生张爱青
Owner 山东立新制药有限公司
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