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Synthetic method of N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidinamine

A synthetic method, aminophenyl technology, applied in the direction of organic chemistry, etc., can solve problems affecting product yield and quality, unsuitable for industrial production, unsuitable for scale-up production, etc., to achieve good product quality, low price, and production cost control Effect

Active Publication Date: 2020-07-24
SUZHOU HEALTH COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this route still has room for improvement: (1) In the synthesis of compound 2 reported in literature [7], flammable n-butyl lithium was used in the synthesis, and it reacts at low temperature, which is not suitable for Industrialized production; (2) The negishi reaction of compound 2 and 2,4-dichloropyrimidine has poor selectivity, and generates 2-substituted isomers, which affects product yield and quality; (3) Patent [8 ] The route reported uses the potential carcinogen hexamethylphosphoric triamide (HMPA) as a solvent in the synthesis of compound 5, which is not suitable for large-scale production. In the process of synthesizing compound 6, the original patent only used Hydrogen oxide is used as an oxidant, and the reaction is not complete during the synthesis process of this method, and there are many impurities

Method used

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  • Synthetic method of N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidinamine
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  • Synthetic method of N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidinamine

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Embodiment 1

[0033] The screening of embodiment 1 synthetic raw materials

[0034] (1) Synthesis of Compound 5

[0035] Compound 5 can also be synthesized by one-step Grignard reagent of 4-chloro-2thiomethylpyrimidine and 3-chloropyridine [9] (Such as Figure 8 ), but the reaction temperature needs-30°C, and the yield is low (45%), so the synthetic route described in the application was selected.

[0036] Adopt the synthetic route of this application to generate the reaction of compound 5 by intermediate thiol methylation (such as Figure 9 ), the methylation reagents were screened as shown in Table 1:

[0037] Table 1

[0038]

[0039] *Remarks: The yield is the yield of the two-step reaction of ring closure and methylation.

[0040] The reaction results of methyl triflate, methyl p-toluenesulfonate and dimethyl sulfate are equivalent to those of methyl iodide, but methyl iodide, dimethyl sulfate and methyl trifluoromethanesulfonate are highly toxic and are not suitable for indust...

Embodiment 2

[0049] The synthetic route of embodiment 2N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidinamine

[0050] (1) Synthesis of 2-(methylthio)-4-(3-pyridyl)pyrimidine

[0051] In a 500mL three-necked flask equipped with a drying tube, under nitrogen protection, add 200mL of molecular sieve-dried ethanol, and under stirring, add thiourea 18g (236mmol) and (E)-3-(dimethylamino)-1-( 31.7g (180mmol) of pyridin-3-yl)prop-2-en-1-one was added, and 72mL (180mmol) of 2.5M sodium methoxide in methanol was added, heated to 78°C, and stirred for 6h. After the reaction was completed, the temperature was lowered to room temperature, and the pH was adjusted to 3-4 with glacial acetic acid. Solids were precipitated, filtered, and the filter cake was washed with 100 mL of water. Dissolve the filter cake in 200 mL of sodium hydroxide (1M) solution, slowly add 34.6 g (186 mmol) of methyl p-toluenesulfonate dissolved in 100 mL of acetonitrile dropwise, stir at room temperature for 30 min, distill...

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Abstract

The invention discloses a synthetic method of N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidinamine. The synthetic method comprises the following steps: (1) synthesizing 2-(methylthio)-4-(3-pyridyl) pyrimidine; (2) synthesizing 2-(methylsulfonyl)-4-(3-pyridine) pyrimidine; (3) synthesizing N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidinamine and (4) synthesizing the N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidinamine. Synthesis raw materials used in the method are low in price and easy to obtain, reaction conditions are mild, the product yield and purity are high, and the methodis suitable for industrial production. Therefore, the synthetic method disclosed by the invention has good advantages in the aspects of production cost control, environmental friendliness and productquality improvement.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidinamine, an intermediate of imatinib. Background technique [0002] Gleevec (Gleevec), the active ingredient is imatinib mesylate, chemical name: 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3 -{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide methanesulfonate [1] , is a small molecule tyrosine kinase inhibitor (TKI) indicated for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors [2] . As the first tumor targeted therapy drug, it has quick onset and few side effects, and is widely used clinically. N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidinamine (compound 1) is an important intermediate in the synthesis of imatinib [3] . [0003] Current literature reports [4,5] The main difference in the synthetic route of imatinib is the introduct...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04Y02P20/55
Inventor 张立光杨税龚逸奕
Owner SUZHOU HEALTH COLLEGE