{3-[(Benzyloxy)carbonyl]-2,4-difluorophenyl}amine synthesis

Yield:918523-44-1 79.7%

Reaction Conditions:

Stage #1: 2,4-difluorophenylaminewith n-butyllithium in tetrahydrofuran;hexane; for 0.5 h;Cooling with acetone-dry ice;
Stage #2: with 1,2-bis-(chlorodimethylsilyl)ethane in tetrahydrofuran;hexane; for 1 h;Cooling with acetone-dry ice;
Stage #3: benzyl chloroformatewith hydrogenchloride;n-butyllithium;potassium carbonatemore than 3 stages;

Steps:

1.1

To 2,4-difluoro-phenylamine (42, 5.11 mL, 50.7 mmol) in tetrahydrofuran (250 mL), cooled with dry ice/acetone bath under an atmosphere of nitrogen, was added n-butyllithium (1.60 M in hexane, 34.0 mL, 54.4 mmol) slowly. After 30 minutes, l,2-Bis-(chloro-dimethyl-silanyl)-ethane (11.5 g, 53.4 mmol) dissolved in tetrahydrofuran (40.0 mL) was added to the reaction slowly. After 1 hour, n-butyllithium (1.60 M in hexane, 31.9 mL, 51.0 mmol) was added slowly to the reaction. The reaction was stirred at -78 ⁰C for 30 minutes and then allowed to warm to room temperature over 40 minutes. The reaction was cooled to -78 ⁰C, followed by addition of n-butyllithium (1.60 M in hexane, 35.1 mL, 56.2 mmol) slowly. After 70 minutes, benzyl chloroformate (7.97 mL, 55.8 mmol) was added to the reaction. The reaction mixture was stirred at -78 °C overnight followed by addition of 2 N HCl (120 mL). The reaction was allowed to warm to room temperature for 2 hours. The EPO organic layer was separated. The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated by silica gel column chromatography (ethyl acetate/hexane 20%) to give a colorless oil (43, 10.6 g, 79.7%). MS(ESI) [M+irT = 264.1.

References:

WO2007/2325,2007,A1 Location in patent:Page/Page column 74-75