3-FLUORO-6-NITRO-O-XYLENE synthesis

Yield: 54%

Reaction Conditions:

with nitric acid;acetic anhydride at 0; for 0.583333 h;

Steps:

16
Example 16 2- (2, 3-D6hyl-4-nitro-phenylamino} 2-methyl-propan-1-ol Fuming nitric acid (1.4 g, 20.3 mmol) was cooled to 0°C and acetic anhydride (2.89 g, 28.4 mmol) was added. This solution was added to a cold (0°C) solution of 3-fluoro-1, 2- dimethylbenzene (1.0 g, 8.1 mmol) in acetic anhydride (4 ml) over 10 min. The reaction mixture was stirred for 25 min, poured slowly over ice and the water solution extracted with EtOAc (x 3). The collected organic phase was washed with diluted saturated aqueous solution of NaHCO3 followed by brine before evaporation to dryness. The residue was flash purified on a silica gel column using hexane as a mobile phase to give 2, 3-dimethyl-4-fluoro-1-nitro-benzene 0.74 g (54%) as a yellow oil which crystallised upon standing. The fluoride (0.576 g, 3. 4 mmol) was mixed with 2-amino-2-methylpropanol (0.61 g, 6.8 mmol) in a tube, and the tube was sealed before immersing it into an oil bath and heating at 160°C for 5 days. TLC (Hexane) showed remaining starting material. The reaction mixture was cooled and diluted with EtOAc before purification by flash silica gel chromatography (dry application; 6: 4 hexane and EtOAc) to give 0.34 g (59% recovery) of the starting material 2, 3-dimethyl-4-fluoro-1-nitro-benzene and 0.20 g (61% based on recovered starting material) of the 2- (2, 3-dimethyl-4-nitro-phenylamino)-2-methyl- propan-1-ol.

References:

KARO BIO AB;ELSY, David WO2005/42464, 2005, A1 Location in patent:Page/Page column 38-39