Yield:129822-38-4 93%

Reaction Conditions:

in tetrahydrofuran; for 16 h;Heating / reflux;

Steps:

1 tert-Butyl 3-fluoro-2-methylphenylcarbamate

A 2-L round bottom flask, equipped with a magnetic stirrer and a reflux condenser and set in a heating mantle, was charged with 3-fluoro-2-methylaniline (99.1 g, 0.793 mol), di-tert-butyl dicarbonate (190.2 g, 0.872 mol, 1.1 eq) and THF (500 mL). The solution was heated at reflux for 16 hours. The completeness of the reaction was monitored by HPLC (see analytical method below). The reaction mixture was allowed to cool to room temperature and then the solution was concentrated in vacuo (bath temp. 37° C.). The oily residue (255 g) was mixed with heptane (250 mL) which caused slow crystallization of the product. More solvent was removed in vacuum (about 150 mL), thereby resulting in a thick slurry. The slurry was further diluted with 250 mL of heptane and the first crop of crystals was filtered, washed with small amount of cold heptane and dried in air on the filter (109.4 g as white crystals, purity>99.9%). The filtrate was concentrated in vacuum to about 100 mL and the second crop of crystals was collected by filtration, washed with heptane and dried in air (42.0 g). The filtrate was further concentrated (about 70 mL) and then chilled in an ice bath. The third crop of crystals was isolated the same way (14.9 g, purity 99%). Total yield of product was 166.3 g (93% theor.). LCMS (ES+), m/z: 226 (M+H⁺). HPLC analytical method: Prodigy ODS3 4.6×50 cm column, 1 mL/min flow rate, gradient 10 to 90% over 9 min of MeCN-water containing 0.02% of TFA. Retention times: tert-Butyl 3-fluoro-2-methylphenylcarbamate (6.88'), 3-fluoro-2-methylaniline (2.63').

References:

US2008/51585,2008,A1 Location in patent:Page/Page column 18