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Synthesis method of 2-isopropyl-3-amino-4-methylpyridine

A kind of methyl pyridine, synthetic method technology, applied in the direction of organic chemistry etc., can solve the problem such as not giving post-treatment mode, reaction yield and purity, L-proline catalytic effect is poor, environment is not friendly, reach product The effect of clean production, environmental friendliness and reduction of environmental pollution

Active Publication Date: 2021-11-19
杭州科耀医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The raw materials and reagents used in this method are relatively cheap and easy to obtain, but parameters such as post-treatment method, reaction yield and purity are not given in all steps, so it is difficult to evaluate its effect. The applicant repeated the test process and found that This method has the following unspecified defects: (1) step from compound 33 (ethyl isobutyrate) to compound 34 (2-isobutyryl-3-methyl-2-butenenitrile), the second step is L-proline is used as the catalyst, but the inventors found that for this substrate, the catalytic effect of L-proline is extremely poor, and a certain amount of molecular sieve reaction needs to be added to occur, and the yield is low, see Comparative Example 1 and Comparative Example 2; (2) Compound 35 (2-isopropyl-4-methyl-3-cyanopyridine) in this route needs to be hydrolyzed with sulfuric acid, neutralized and then processed by Hofmann In the step of degradation to 2-isopropyl-3-amino-4-picoline
At first 85% of sulfuric acid reacts in the process of acidolysis at 90°C, the color of the reaction solution turns black, some intermediates are carbonized by sulfuric acid, and the yield is low, see Comparative Example 3 for details; secondly, neutralizing sulfuric acid in production will produce a large amount of waste water, not friendly to the environment

Method used

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  • Synthesis method of 2-isopropyl-3-amino-4-methylpyridine
  • Synthesis method of 2-isopropyl-3-amino-4-methylpyridine

Examples

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Effect test

Embodiment 1

[0041]

[0042] Synthesis of 2-isobutyryl-3-methyl-2-butenenitrile: In a four-necked flask equipped with a thermometer and a stirrer, add 11.6g of ethyl isobutyrate, 60ml of THF and 20g of potassium tert-butoxide, and start stirring , control the reaction temperature at 45-50°C, add 70g of acetonitrile dropwise, and keep the temperature for 4 hours. After the reaction of the raw materials, cool down to below 10°C, then add glacial hydrochloric acid to adjust the pH to 3-4, filter, and spin dry the organic phase to obtain 11.1g of crude product .

[0043] In a four-necked flask equipped with a thermometer and a stirrer, add 11.1g of the crude product obtained above, 80ml of acetone, 100g of 4A molecular sieve and 1.11g of L-alanine, start stirring, raise the temperature to reflux for reaction, keep the temperature for 4 hours, and the reaction of the raw materials is complete Finally, filter and recover 4A molecular sieve, evaporate the organic phase to dryness and recover a...

Embodiment 2

[0055]

[0056] Synthesis of 5-N,N-dimethyl-2-isobutyryl-2,4-dipentenenitrile: Add 15.1g of 2-isobutyryl-3- Methyl-2-butenenitrile, 60ml ethanol and 11.9g DMF-DMA, start stirring, heat up to reflux reaction, keep warm for 3h, after the reaction of the raw materials is completed, evaporate the solvent, add 50ml water for beating, filter, and dry to obtain 5 -N,N-Dimethyl-2-isobutyryl-2,4-dipentenenitrile 19.1 g, purity 99.5%, yield 93%.

Embodiment 3

[0058]

[0059] Synthesis of 2-isopropyl-4-methyl-3-cyanopyridine: Add 20.6g of 5-N,N-dimethyl-2-isobutyryl- 2,4-dipentenenitrile, 80ml of ethanol and 30.8g of ammonium acetate, start stirring, raise the temperature to reflux reaction, keep warm for 6h, after the reaction of raw materials, evaporate the solvent, add 50ml of water to wash, and extract with dichloromethane, separate the liquid , spin-dried to recover dichloromethane to obtain 12.5 g of 2-isopropyl-4-methyl-3-cyanopyridine with a purity of 99.3% and a yield of 78%.

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Abstract

The invention discloses a synthesis method of 2-isopropyl-3-amino-4-methylpyridine, wherein the synthesis method comprises the steps: by taking ethyl isobutyrate as a raw material, sequentially carrying out condensation, aldol condensation, methylation condensation and aminopyridine cyclization to obtain AMG-2, and then carrying out hydrolysis and Hofmann degradation to obtain the 2-isopropyl-3-amino-4-methylpyridine. The method has the advantages of cheap and easily available raw materials, mild conditions, simple and safe operation, high reaction selectivity, high product yield and purity, low cost and wide application prospect.

Description

technical field [0001] The invention relates to a preparation method of a chemical intermediate, in particular to a synthesis method of high-grade 2-isopropyl-3-amino-4-picoline. Background technique [0002] The KRAS G12C inhibitor is a drug for treating pancreatic cancer, colorectal cancer and lung cancer, and 2-isopropyl-4-methylpyridin-3-amine is an important intermediate for preparing the KRAS G12C inhibitor. [0003] There are few reports on the preparation method of 2-isopropyl-4-methylpyridin-3-amine. Now known clear reports are WO2020 / 81636, US2019 / 374542 and CN111377918. These methods use 3-amino-4 -Methylpyridine as raw material, using NBS / trifluoroacetic acid as bromination reagent, synthesize 3-amino-2-bromo-4-methylpyridine, and then carry out coupling synthesis with isopropylzinc bromide / isopropylmagnesium chloride 2-isopropyl-4-methylpyridin-3-amine; In addition, CN112159405 carries out coupling with isopropenylboronic acid pinacol ester and 3-nitro-2-chloro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/73
CPCC07D213/73Y02P20/55
Inventor 周军明许发达吴烨挺
Owner 杭州科耀医药科技有限公司
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