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Pyrrolo [2, 3-d] pyrimidine derivative targeting EGFR mutation as well as preparation method and application of pyrrolo [2, 3-d] pyrimidine derivative

A use and drug technology, applied in the field of pyrrolo[2,3-d]pyrimidine derivatives and their preparation, can solve problems such as the occurrence of osimertinib resistance, achieve good application prospects, significant inhibitory effect, and good inhibitory effect Active and Selective Effects

Active Publication Date: 2020-10-30
WEST CHINA HOSPITAL SICHUAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, however, a study showed that resistance to osimertinib has emerged

Method used

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  • Pyrrolo [2, 3-d] pyrimidine derivative targeting EGFR mutation as well as preparation method and application of pyrrolo [2, 3-d] pyrimidine derivative
  • Pyrrolo [2, 3-d] pyrimidine derivative targeting EGFR mutation as well as preparation method and application of pyrrolo [2, 3-d] pyrimidine derivative
  • Pyrrolo [2, 3-d] pyrimidine derivative targeting EGFR mutation as well as preparation method and application of pyrrolo [2, 3-d] pyrimidine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Embodiment 1, the synthesis of key intermediate 1

[0079] The synthetic route of key intermediate 1 is as follows:

[0080]

[0081] in,

[0082] When X=Br, intermediate 1 is compound 10, and key intermediate 1 is compound 14;

[0083] When X=I, intermediate 1 is compound 11, and key intermediate 1 is compound 15;

[0084] When X=OH, intermediate 1 is compound 12, and key intermediate 1 is compound 16;

[0085] X=OCH 3 , the intermediate 1 is compound 13, and the key intermediate 1 is compound 17.

[0086] Alternatively, the synthetic route of the key intermediate 1 is as follows:

[0087]

[0088] X=NO 2 , the key intermediate 1 is compound 18.

[0089] The specific preparation method is as follows:

[0090] (1) Synthesis of 1-(2-iodo-4-nitrobenzene)-4-methylpiperazine (11): 4-fluoro-3-iodonitrobenzene (1.34g, 5.0mmol), N- The mixed solution of methylpiperazine (about 6ml, 52mmol) was heated to 90°C, reacted for more than 5h, left at room temperature, d...

Embodiment 2

[0099] Embodiment 2, the synthesis of key intermediate 2

[0100] The synthetic route of key intermediate 2 is as follows:

[0101]

[0102] The specific preparation method is as follows:

[0103] Synthesis of compound 19: Add 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (4.68g, 0.025mol) into a round bottom flask, dissolve in THF, and then add chloromethyl pivalate (7.5g, 0.05mol) and potassium carbonate (0.1mol, 13.8g), stirred at room temperature for 5 minutes, then raised the temperature to 80°C to reflux. Continue to react for about 12h, TLC monitoring shows that the reaction is complete (developing agent: CH 2 Cl 2 ). After the reaction solution is cooled, spin the reaction solution to dryness, add 150ml of water and CH 2 Cl 2 (300ml×3) for extraction, combined the organic phases, added an appropriate amount of anhydrous sodium sulfate to dry, filtered, and concentrated. The crude product was separated by silica gel column chromatography (eluent: CH 2 Cl 2 ) to o...

Embodiment 3

[0105] Embodiment 3, the synthesis of compound 1 of the present invention

[0106] The synthetic route of compound 1 is as follows:

[0107]

[0108] The specific preparation method is as follows:

[0109] Synthesis of compound 21: add t-BuOH (50ml), key intermediate 2 (compound 20) (1.21g, 3mmol), 3-fluoro-4-(4-methylpiperazine)-aniline ( 522 mg, 2.5 mmol). The above reaction solution was stirred at room temperature for 5-10 min. Potassium carbonate (690mg, 5mmol), Pd 2 (dba) 3 (230mg, 0.25mmol, a catalyst that catalyzes the formation of carbon-nitrogen bonds), XPhos (ie 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl, 120mg, 0.25mmol), the reaction was mixed The solution was refluxed and stirred for about 6 hours at 110°C, and the reaction was monitored by TLC (developing agent: CH 2 Cl 2 / CH 3 OH=10 / 1, v / v). The reaction solution was cooled to room temperature, spin-dried, extracted, dried, concentrated, and separated by silica gel column chromatography (elu...

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Abstract

The invention provides a pyrrolo [2, 3-d] pyrimidine derivative targeting EGFR mutation as well as a preparation method and application thereof, and belongs to the field of chemical medicines. The derivative is a compound shown as a formula I, or a salt thereof, or a stereoisomer thereof. The compound disclosed by the invention is low in toxicity to normal cells, has an obvious inhibition effect on a lung cancer cell line, particularly has good selectivity on EGFR mutant cells HCC827, and has an obvious inhibition effect; meanwhile, the compound provided by the invention can effectively inhibit phosphorylation of EGFR. In addition, the compound provided by the invention has good inhibitory activity and selectivity on mutant EGFR. The compound disclosed by the invention can be used for treating lung cancer, particularly non-small cell lung cancer, has a relatively strong inhibition effect on EGFR mutant lung cancer, and is relatively low in toxicity; the compound can also be used for preparing tyrosine kinase inhibitors, especially EGFR phosphorylation inhibitors, and has good application prospects.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and specifically relates to a pyrrolo[2,3-d]pyrimidine derivative targeting EGFR mutation, a preparation method and application thereof. Background technique [0002] Lung cancer is the malignant tumor with the highest morbidity and mortality worldwide, and the number of deaths due to lung cancer reaches 1.6 million each year. It is the main cause of cancer-related deaths in men (22% of cancer deaths) and women (13.8% of cancer deaths) reason. In the United States, about 14 percent of new cancers are lung cancers. The American Cancer Society estimates there were approximately 234,000 lung cancer cases and 154,000 deaths in the United States in 2018. The situation in my country is equally serious. According to the latest cancer data in China released by the National Cancer Center in January 2019, lung cancer is the malignant tumor with the highest morbidity and mortality in my country. Come unde...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P35/00A61P35/02A61K31/519
CPCC07D487/04A61P35/00A61P35/02
Inventor 李为民夏贞强黄日东何杨周兴龙陈海罗雨蕉吴琼
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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