1,2-Dichloroethane → 1-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic Acid

To a mixture of 1-(methoxycarbonyl)cyclopropanecarboxylic acid (4.2 g) and 4-fluoroaniline (3.3 g) in DCM (40 ml) was added EDC (7.4 g) and HOBt (4 g), the reaction was stirred at RT for 4 hours and washed with 1N HCl, NaHCO3 solution, water, brine and dried over Na2SO4. The solution was evaporated and the residue was mixed with NaOH (3.2 g) and MeOH/H2O (60 ml/6 ml). The mixture was refluxed for 30 minutes then was evaporated. The residue was acidified with 4N HCl and the precipitate was filtered. The filter cake was washed with water followed by cold EtOH to give the product as 1-(4-fluorophenylcarbamoyl)-cyclopropanecarboxylic acid 2.8 g. This product (1.8 g) was mixed with DCM (30 ml) and two drops of DMF. Oxalyl chloride (1.2 ml) was added into the solution and the reaction was refluxed for one hour. The solvent was removed followed by adding DCM (20 ml) and DIPEA (1.3 ml). To the above solution was added 4-methoxybenzyl 1-((4-(2-fluoro-4-aminophenoxy)-6-methoxyquinolin-7-yloxy)-methyl)cyclopropylcarbamate (1.5 g), the reaction was stirred at RT for 4 hours. Saturated NaHCO3 (30 ml) and DCM (80 ml) were added into the reaction, the solution was further extracted with DCM twice. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated and purified with silica gel column to give the titled compound 2.1 gram. Mass: (M+1), 739

1. washwashed with 1N HCl, NaHCO3 solution, water, brine
2. dry with materialdried over Na2SO4
3. customThe solution was evaporated
4. additionthe residue was mixed with NaOH (3.2 g) and MeOH/H2O (60 ml/6 ml)
5. temperatureThe mixture was refluxed for 30 minutes
6. customthen was evaporated
7. filtrationthe precipitate was filtered
8. washThe filter cake was washed with water

ORD record

ord-48add35bbd2040f0804564e2d74424f9

Source dataset

uspto-grants-2014_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08664244B2