4-(4-Methylpiperazin-1-yl)aniline → HCID 57489643, compound

Temperature

-78 °C

To a mixture of 2,6-dichloro-5-fluoronicotinamide (1 g, 4.78 mmol) and 4-(4-methylpiperazin-1-yl)aniline (1.007 g, 5.26 mmol) in THF (30 mL) was added lithium bis(trimethylsilyl)amide (16.75 mL, 16.75 mmol) portionwise at −78° C. The mixture was stirred at −78° C. for 20 min and then removed from the dry ice bath. Next, the mixture was stirred at rt for 30 min. Two isomeric products were formed. The reaction mixture was quenched with water, extracted with ethyl acetate twice, washed the combined organic with water, and concentrated. The dark brown residue was triturated with methylene chloride, to give 570 mg of 2-chloro-5-fluoro-6-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide as light brown solid. The mother liquor was concentrated and triturated again with methylene chloride to give 540 mg of 6-chloro-5-fluoro-2-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide as brown solid. The mother liquor was purified twice by mPLC (ISCO, 7% ammonia/methanol/methylene chloride, 40 g+12 g stacked columns) to give an additional 490 mg of 6-chloro-5-fluoro-2-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide as brown solid.

1. customremoved from the dry ice bath
2. stirringNext, the mixture was stirred at rt for 30 min
3. customTwo isomeric products were formed
4. customThe reaction mixture was quenched with water
5. extractionextracted with ethyl acetate twice
6. washwashed the combined organic with water
7. concentrationconcentrated
8. customThe dark brown residue was triturated with methylene chloride

ORD record

ord-144c0eabd84e48d79ed0bc7f36464e1b

Source dataset

uspto-grants-2013_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08586751B2