methyl 4-(chlorosulfonyl)-2-fluorobenzoate synthesis

Yield:1063733-16-3 90%

Reaction Conditions:

Stage #1: methyl 4-amino-2-fluorobenzoatewith hydrogenchloride;sodium nitrite in water at 10; for 0.333333 h;
Stage #2: with sulfur dioxide;acetic acid;copper(l) chloride in water at 0 - 20; for 2 h;

Steps:

1

Step 1: To a solution of methyl 4~amino-2-fluorobenzoate (64.0 g, 378 mmol) in concentrated aq. hydrochloric acid (640 mL) was added aqueous NaN0₂ solution (28.7 g, 416 mmol, in 50 mL) at 10 °C. After stirring at 10 °C for 20 min, the mixture was added dropwise at 0 °C into a solution of CuCl (375 mg, 3.8 mmol) in HO Ac (500 mL) which was saturated with S0₂ gas. The resulting mixture was warmed up to room temperature, and stirred for 2 h. The reaction mixture was poured into ice- water and extracted with ethyl acetate. The combined organic phase was washed with saturated aq. NaHC0₃ solution and then brine, dried over Na₂S0₄, and concentrated under reduced pressure to afford methyl 4-(chlorosulfonyl)-2- fluorobenzoateas a brown oil (86.1g, 90%). ¹H NMR (400 MHz, CDC1₃) d 8.18 (dd, ./= 6.8 Hz, 8.4 Hz, 1H), 7.89 (dd, = 2.0 Hz, 8.4 Hz, 1H), 7.83 (dd, J= 2.0 Hz, 8.8 Hz, 1H), 4.00 (s, 3H).

References:

WO2020/33782,2020,A1 Location in patent:Paragraph 0220