Method for synthesizing N-(5-nitryl-2-methyl pyridyl-3-)-4-(3-pyridyl)-2-pyrilamine and intermediate thereof

A compound, the technology of dimethyl carbonate, which is applied in the field of preparation of pyrimidine derivatives, can solve the problems of scale-up that is difficult to industrialize, complex equipment, and increase the production of impurities in side reactions, so as to achieve increased yield, improved yield and purity, The effect of avoiding the use of more toxic phase transfer catalysts

Active Publication Date: 2013-11-20
TIANJIN PHARMACN MEDICAL TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When we use this method to carry out the methylation reaction of 2-mercapto-4-(3-pyridyl)pyrimidine, we find that the equipment required for microwave heating is complicated, the investment is large and it is difficult to scale up on an industrial scale
Moreover, although the high reaction temperature improves the conversion rate, it also increases the impurity output of the side reaction.
In addition, although phase transfer catalysts such as tetrabutylammonium bromide can catalyze the reaction, they are highly toxic, causing pollution to the environment and certain damage to the health of the operator.
[0008] Chinese patent application CN200910048833.4 discloses a method for preparing methylthio heterocyclic compounds under the catalysis of ionic liquids, and discloses a method of using ionic liquids such as 1-butyl-3-methylimidazole chloride to catalyze the aforementioned reaction method, although the temperature of the reaction is reduced to a maximum of 130°C, the content of the product obtained by the reaction is 95-97%, and the content of impurities is relatively high

Method used

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  • Method for synthesizing N-(5-nitryl-2-methyl pyridyl-3-)-4-(3-pyridyl)-2-pyrilamine and intermediate thereof
  • Method for synthesizing N-(5-nitryl-2-methyl pyridyl-3-)-4-(3-pyridyl)-2-pyrilamine and intermediate thereof
  • Method for synthesizing N-(5-nitryl-2-methyl pyridyl-3-)-4-(3-pyridyl)-2-pyrilamine and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1- Embodiment 4

[0026] The preparation of embodiment 1-embodiment 4 compound IV, formula is as follows

[0027]

[0028] Reaction process:

[0029] (1) Put compound II, HMPA, and dimethyl carbonate solution as raw materials into a reaction kettle, stir and dissolve, heat to 60-80°C, and the reaction is complete after 1.5 hours. Concentrate under reduced pressure to 80°C. Take a small amount of reaction solution and dilute it with a large amount of water to obtain a compound III sample and detect the content

[0030] (2) Cool the reaction solution in step (1) directly to -10°C~10°C, adjust the pH to 4-5 with 0.1M hydrochloric acid, then add hydrogen peroxide, react until complete at 20-50°C, add sodium sulfite to consume Excess H 2 o 2 , adjust the pH to 7.5-8, add water with a volume ratio of 20-50 to HMPA, stir while adding, until the precipitate solidifies, filter to obtain a filter cake, wash the filter cake with water and dry to obtain compound IV. The product was weighed and the ...

Embodiment 5

[0047] The preparation of embodiment 5 compound I

[0048] Get the compound IV prepared by the method of Example 1 as a raw material, adopt sodium hydride as a commercially available 60% product, and calculate the amount of feed in terms of sodium hydride

[0049] The preferred process of the step (3) is as follows: add compound IV and compound V with a molar ratio of 1:1.5 into the reactor, add DMF with a volume weight ratio of 8 to compound IV, stir and dissolve, then cool to -10°C and keep at Add sodium hydride () in batches at this temperature, and the molar ratio of added sodium hydride to compound IV is 2:1. After adding sodium hydride, keep the temperature at 20-30°C until the reaction is complete to obtain compound I.

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Abstract

The invention relates to a method for synthesizing N-(5-nitryl-2-methyl pyridyl-3-)-4-(3-pyridyl)-2-pyrilamine and an intermediate thereof. The method comprises the following steps: adding a compound IV and a compound V with the molar ratio of 1:(1-2) into a reactor; adding an organic solvent, wherein the volume weight ratio of the organic solvent to the compound IV is 5 to 10; stirring and dissolving; cooling to -20 to 0 DEG C; maintaining the temperature range and adding sodium hydride in batches, wherein the molar ratio of the sodium hydride to the compound IV is (2-6):1; and after adding the sodium hydride, maintaining the temperature to be 20 to 50 DEG C until the reaction is complete and a compound I is obtained.

Description

Technical field: [0001] The invention relates to a preparation method of pyrimidine derivatives. Background technique: [0002] In Example 1 of the Chinese patent CN1972917B description, a synthetic method of N-(5-nitro-2-methylpyridyl-3-)-4-(3-pyridyl)-2-pyrimidinamine is disclosed. 2-Methyl-3-amino-5-nitropyridine and 2-methylsulfonyl-4-(3-pyridyl)pyrimidine can be prepared by reaction. [0003] [0004] The Chinese patent application CN201110323144.7 also discloses a synthesis method of 2-methylsulfonyl-4-(3-pyridyl)pyrimidine as follows: [0005] [0006] When R is methyl and X is iodine, the synthetic method disclosed in this application is actually a method for preparing 2-methylsulfonyl-4-(3-pyridyl)pyrimidine using methyl iodide as a methylating reagent, The synthesis method of 2-methylsulfonyl-4-(3-pyridyl)pyrimidine is disclosed in Example 1 of the application specification, wherein methylation of iodomethane is used to prepare 2-mercapto-4-(3-pyridyl)pyrim...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D401/14
Inventor 何磊田东奎陈松
Owner TIANJIN PHARMACN MEDICAL TECH
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