benzyl 2,4-difluorophenylcarbaMate

To a 250-mL round-bottomed flask was added 2, 4-difluoroaniline (11, 4.62 mL, 45.4mmol), DCM (103 mL) and pyridine (7.40 mL, 91mmol). The solutionwas stirred at rt andwas treatedwith benzylchloroformate (8.15 mL, 54.5mmol) drop wise via an addition funnel.After being stirred at rt overnight, the mixture was poured intowater and was extracted with DCM. The combined extracts werewashed with water, brine, dried with anhydrous sodium sulfate, filtered, and concentrated to give the title compound (11.1 g, 42.2mmol, 93percent) as a white solid which was used without furtherpurification. LCMS (ESI, pos. ion) calcd for C14H11F2NO2: 263.1; found:286.1 (M+Na). 1H NMR (400MHz, DMSO-d6) d ppm 9.43 (br s, 1H), 7.51–7.66 (m, 1H), 7.24–7.46 (m, 6H), 7.01–7.12 (m, 1H), 5.15 (s, 2H).Step 1-Preparation of (2, 4-difluoro-phenyl)-carbamic acid benzyl ester (52)To 2, 4-difluoroaniline (47, 7.0 mL, 0.070 mol) in 100 mL of dichloromethane was added pyridine (11 mL, 0.14 mol) and benzyl chloroformate (11.9 mL, 0.0834 mol). The reaction mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and KHSOTo 2, 4-difluoroaniline (19, 7.0 mL, 70.0 mmol) in 100 mL of dichloromethane, pyridine (11 mL, 0.14 mol) and benzyl chloroformate (20, 11.9 mL, 83.4 mmol) were added. To 2, 4-difluoroaniline (42, 7.0 mL, 0.070 mol) in 100 mL of dichloromethane was added pyridine (11 mL, 0.14 mol) and benzyl chloroformate (11.9 mL, 0.0834 mol). The reaction mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and KHSOStep 1 - Preparation of (2, 4-difluoro-phenyl)-carbamic acid benzyl ester (32):[0229] To 2, 4-difluoro-phenylamine (30, 7.0 mL, 70.0 mmol) in 100 mL of dichloromethane, pyridine (11 mL, 0.14 mol) and benzyl chloroformate (31, 11.9 mL, 83.4 mmol) are added. The reaction mixture is stirred at ambient temperature for 1.5 hours. The reaction mixture is concentrated under vacuum and the residue is partitioned between ethyl acetate and potassium bisulfate solution. The organic layer is dried with magnesium sulfate, filtered, and the filtrate concentrated under vacuum. The resulting material is crystallized from hexanes to provide the desired compound (32, 15.6 g, 85percent).To 2, 4-difluoro-phenylamine (1, 7 0 mL, 70 0 mmol) in 100 mL of dichloromethane, pyπdine (1 1 mL, 140 0 mmol) and benzyl chloroformate (2, 11 9 mL, 83 4 mmol) were added The reaction mixture was stirred at room temperature for 1 5 hours The reaction mixture was concentrated under vacuum and the residue w as partitioned between ethyl acetate and potassium bisulfate solution The organic layer was dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum and crystallized from hexanes to give the desired compound (3, 15 6 g, 85percent)To 2, 4-difluoro-phenylamine (1, 50.00 g. 0.39 mol) were added 550 mL of anhydrous dichloromethane, and anhydrous pyridine (61.27 g, 0.77 mol), followed by addition of benzyl chloroformate (2, 79.28 g, 0.46 mol) dropvvise while maintaining the temperature at 0C. The reaction mixture was stirred at room temperature for 2 hours and an additional 6.61 g (0.04 mol) of benzyl chloroformate was added and the reaction stirred an additional 2 hours, followed by addition of another 6.61 g Li f ben/yl chlorofoπnate.

Molecular Weight:263.24
XLogP3:2.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:263.07578492
Monoisotopic Mass:263.07578492
Topological Polar Surface Area:38.3
Heavy Atom Count:19
Complexity:295
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes