Dimethylformamide → 2,6-Dichloro-N-((1-hydroxycycloheptyl)methyl)quinoline-5-carboxamide

To a stirred solution of 2,6-dichloroquinoline-5-carboxylic acid (40.0 g) (WO2004/106305, Example 76, step b) under nitrogen at room temperature in dichloromethane (600 ml) was added dimethylformamide (0.13 ml) and oxalyl chloride (36.2 ml) dropwise over 2 hours in 3 portions. The mixture was then stirred at room temperature for 18 hours. The mixture was concentrated in vacuo, dichloromethane (400 ml) was added and the mixture was added dropwise to a solution of 1-(aminomethyl)cycloheptanol hydrochloride (32.7 g) (W. C. Vincek, C. S. Aldrich, R. T. Borchardt and G. L. Grunewald, J. Med. Chem., 1981, 21(1), 7-12) and triethylamine (69.1 ml) in dichloromethane (600 ml) at 0° C. over 15 minutes. The mixture was stirred for 1 hour and then water (400 ml) was added. The mixture was filtered under vacuum and the solid washed sequentially with water (2×400 ml), acetonitrile (400 ml) and diethyl ether (400 ml), then dried in vacuo to afford the subtitle product as a colourless solid (59.0 g).

1. concentrationThe mixture was concentrated in vacuo, dichloromethane (400 ml)
2. additionwas added
3. additionthe mixture was added dropwise to a solution of 1-(aminomethyl)cycloheptanol hydrochloride (32.7 g) (W. C. Vincek, C. S. Aldrich, R. T. Borchardt and G. L. Grunewald, J. Med. Chem., 1981, 21(1), 7-12) and triethylamine (69.1 ml) in dichloromethane (600 ml) at 0° C. over 15 minutes
4. stirringThe mixture was stirred for 1 hour
5. additionwater (400 ml) was added
6. filtrationThe mixture was filtered under vacuum
7. washthe solid washed sequentially with water (2×400 ml), acetonitrile (400 ml) and diethyl ether (400 ml)
8. customdried in vacuo

ORD record

ord-cda417d7644f49ab97748598329e1e56

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08106073B2