3-(2-chloropyriMidin-4-yl)-1-Methylindole Chemical Properties

Boiling point:

486.3±28.0 °C(Predicted)

Density 

1.31±0.1 g/cm3(Predicted)

storage temp. 

under inert gas (nitrogen or Argon) at 2-8°C

pka

-0.89±0.31(Predicted)

Appearance

Off-white to light yellow Solid

InChI

InChI=1S/C13H10ClN3/c1-17-8-10(9-4-2-3-5-12(9)17)11-6-7-15-13(14)16-11/h2-8H,1H3

InChIKey

IIBWXYHPBMUNJP-UHFFFAOYSA-N

SMILES

N1(C)C2=C(C=CC=C2)C(C2C=CN=C(Cl)N=2)=C1

3-(2-chloropyriMidin-4-yl)-1-Methylindole Usage And Synthesis

Description

3-(2-Chloropyrimidin-4-yl)-1-methylindole is a key intermediate in the synthesis of Osimertinib Mesylate. Osimertinib Mesylate (Trade Name: Tagrisso) is a targeted anticancer drug developed by AstraZeneca. It received marketing approval from the U.S. Food and Drug Administration (FDA) on November 13, 2015, and from the European Medicines Agency (EMA) on February 2, 2016, respectively. Later, it was also approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on March 28, 2016. This medication is indicated for the treatment of non-small cell lung cancer (NSCLC) positive for the EGFR-T790M mutation.

Uses

3-(2-chloropyriMidin-4-yl)-1-Methylindole is an ositinib intermediate that can be used to synthesise targeted therapeutics.

Synthesis

The general procedure for the synthesis of 3-(2-chloropyrimidin-4-yl)-1-methylindole from 2,4-dichloropyrimidine and N-methylindole is as follows: Intermediate 7: Synthesis of 3-(2-chloropyrimidin-4-yl)-1-methylindole 40g of 2,4-dichloropyrimidine and 200mL of 1,2-dimethoxyethane (DME) were added to a 1L three-neck flask and stirred until complete dissolution. After cooling the reaction system to 10-15°C, 45 g of anhydrous ferric chloride (FeCl3) was added rapidly and in batches, controlling the reaction temperature to not exceed 35°C. Stirring of the reaction mixture was continued for 15 minutes after each portion of FeCl3 was added. Subsequently, 52.8 g of N-methylindole was slowly added dropwise to the reaction system. After the dropwise addition, the reaction mixture was slowly heated to 50°C and stirred at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography (TLC) until the reaction was completed. Upon completion of the reaction, the mixture was cooled to 5-10°C and about 300 mL of a mixture of methanol and water (1:2 by volume) was slowly added dropwise, at which time a large amount of viscous solid precipitated. The reaction mixture was filtered, the solid product was collected and the filter cake was washed twice with methanol. Finally, the resulting solid was dried under reduced pressure at 50°C to give the target product in 85% yield.

References

[1] Patent: CN106957304, 2017, A. Location in patent: Paragraph 0013
[2] Patent: EP3181559, 2017, A1. Location in patent: Paragraph 0048
[3] Patent: WO2013/14448, 2013, A1. Location in patent: Page/Page column 160
[4] Patent: EP3205650, 2017, A1. Location in patent: Paragraph 0119; 0120
[5] Patent: EP3181560, 2017, A1. Location in patent: Paragraph 0131; 0132; 0133

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