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Process for preparing N-phenyl-2-pyrimidyl amine derivative

A technology of phenyl and pyrimidine, which is applied in the field of preparation of N-phenyl-2-pyrimidinamine derivatives, can solve the problems of high price, long reaction steps, harsh reaction conditions, etc., and achieve great social and economic benefits, synthetic The effect of scientific route and high product yield

Inactive Publication Date: 2007-01-24
ZHEJIANG ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The above-mentioned preparation method has the disadvantages that the reaction starting materials are difficult to obtain in the Chinese market, some raw materials are highly toxic, expensive, the reaction steps are long, and the reaction conditions are relatively harsh. It is not suitable for domestic production.

Method used

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  • Process for preparing N-phenyl-2-pyrimidyl amine derivative
  • Process for preparing N-phenyl-2-pyrimidyl amine derivative
  • Process for preparing N-phenyl-2-pyrimidyl amine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: 2-Chloro-4-(3-pyridyl)pyrimidine

[0031] 2.25 g of 3-bromopyridine was dissolved in 5 mL of anhydrous ether, and under nitrogen protection, 3 mL of 1.6 M n-butyllithium was added dropwise at -40°C, and stirring was continued for 0.5 h after dropping. Then, a solution of 3.3 g of zinc bromide in 10 mL of anhydrous ether was added at one time, and the mixture was incubated and stirred for 1 h. After rising to room temperature, a solution of 1.49 g of 2,4-dichloropyrimidine in 5 mL of anhydrous tetrahydrofuran and a catalytic amount of tetrakis(triphenylphosphine)palladium were added, and the mixture was refluxed for 18 hours. After the reaction is completed, first extract with ethyl acetate, then add dilute hydrochloric acid to extract, then adjust the pH to 10 with sodium hydroxide, and precipitate a flocculent solid. Collected and purified to obtain 1.65 g of 2-chloro-4-(3-pyridyl)pyrimidine, mp142-143°C, 1 H-NMR (CDCl 3 ): 748(1H, m, 5'-H), 7.71(1H, d, 5...

Embodiment 2

[0032] Example 2: N-(2-methyl-4-nitrophenyl)-4-(3-pyridyl)-pyrimidin-2-amine

[0033] The above-mentioned 1.91 g of 2-chloro-4-(3-pyridyl)pyrimidine, 1.6 g of p-nitro-o-toluidine, and 0.6 g of methanesulfonic acid were refluxed in 10 mL of anhydrous dioxane for 6 h. After the reaction was completed, the solvent was recovered, and a large amount of cold water was added to the residue, which was basified with sodium bicarbonate. The precipitated solid was collected and dried to give 2.5g, mp 195-196°C. 13 C-NMR: 164.1, 156.2, 155.5, 149.4, 148.8, 148.6, 139.7, 135.4, 132.3, 132.1, 130.2, 121.9, 121.8, 118.5, 108.9, 18.2.

Embodiment 3

[0034] Example 3: N-phenyl-4-(3-pyridyl)-pyrimidin-2-amine

[0035] Using a method similar to Example 2, 1.91 g of 2-chloro-4-(3-pyridyl)pyrimidine, 1.0 g of aniline, and 0.6 g of p-toluenesulfonic acid were refluxed in 10 mL of anhydrous dioxane for 6 h to obtain the target product , mp.147-148℃. 13 C-NMR: 164.1, 155.5, 154.4, 151.2, 149.3, 148.8, 135.5, 132.3, 130.2, 129.3, 129.3, 122.1, 113.5, 113.5, 108.9.

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Abstract

The present invention relates to new organic compound, and is especially the preparation process of N-(2-methyl-5-nitro) phenyl-4-(3-pyridyl) pyrimidiyl-2-amine as the key intermediate for imatinib, which is tyrosine protein kinase inhibitor for treating chronic myeloid leukemia and other diseases, and its analog N- phenyl-pyrimidiyl-2-amine derivative. The target product may be prepared through condensation of 4-aromatic heterocycle-2-halogenated pyrimidine and substituted aniline in the presence of catalyst. The preparation process has low material cost, scientific synthesis path, high product yield and other advantages.

Description

technical field [0001] The present invention relates to a new organic chemical synthesis method, especially the key intermediate N-(2-methyl-5-nitro ) Preparation method of phenyl-4-(3-pyridyl)pyrimidin-2-amine and its structural analog N-phenyl-2-pyrimidinamine derivatives. Background technique [0002] Imatinib is the first anticancer drug designed rationally based on the theoretical guidance of the mechanism of action of cancer cells, invented by the Swiss Novartis pharmaceutical company. In May 2001, the U.S. Food and Drug Administration (FDA) approved it as a new oral anticancer drug for the treatment of chronic myelogenous leukemia in just two and a half months. In February 2002, FDA approved it as a drug for the treatment of gastrointestinal stromal tumors. [0003] Imatinib is a new type of tyrosine protein kinase inhibitor, which can inhibit the tyrosine kinase activity of abl / bcr, thereby inhibiting the proliferation of granulocytes, and inducing abl / bcr positive...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D239/00C07D213/00
Inventor 王尊元马臻沈正荣
Owner ZHEJIANG ACAD OF MEDICAL SCI
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