Yield: 73%

Reaction Conditions:

Stage #1:2-fluoro-4-chloroaniline with hydrogenchloride;sodium nitrite in water;acetic acid at 0; for 0.666667 h;Sandmeyer Reaction;
Stage #2: with sulfur dioxide;copper(l) chloride in water;acetic acid at 0 - 20; for 1 h;
Stage #3: at 0 - 20;

Steps:

XIX
Compound 53. 2-fluoro-4-chloroaniline (22.90 g, 151 mmol) was dissolved in 120 mL of AcOH and 80 mL of concentrated HCl was added with stirring. The reaction mixture was cooled to 0 C. and a solution of NaNO2 (27.2 g, 0.4 mol) dissolved in 40 mL of H2O was added over 10 min. The reaction mixture was stirred for 30 min at 0 C. In a separate flask, 500 mg of CuCl was dissolved in 200 mL of AcOH. The flask was cooled to 0 C. and SO2 gas was bubbled into the solution for 40 minutes. The contents of the “aniline” flask were added to the contents of the second flask over 20 minutes causing a vigorous evolution of gas. After the addition was complete, the ice bath was removed, and the reaction mixture was allowed to warm to rt. The reaction mixture was poured into 500 g of chipped ice and the resulting solids were collected, washed and dried to give 26.1 g (73%) of compound 53.

References:

Schering Corporation US2003/232859, 2003, A1 Location in patent:Page 56