3-ethoxy-2,6-difluoroaniline

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the 8.22 g (34.7 mmol) of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 170 mL of toluene was added 6.00 g 34.7 mmol, 1 equivalent) of 3-ethoxy-2,6-difluoro-phenylamine and 2.01 g (8.66 mmol, 0.25 equivalents) of camphorsulfonic acid. The reaction was warmed to reflux and the formed water was removed with the aid of a Dean-Stark trap. After reacting for 48 hours, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane and neutralized with a saturated aqueous solution of sodium bicarbonate. The resulting emulsion was filtered through fiberglass filter paper. The methylene chloride layer was isolated from the filtrate, then washed first with a saturated aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium chloride. The methylene chloride layer was dried with magnesium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane, stirred with silica gel, and concentrated in vacuo. The residue was placed in the sample injection module of a Biotage FLASH 75 chromatographic apparatus. Chromatography of the crude material on a Biotage 500 g silica gel column with 4:1 hexane/ethyl acetate gave 11.1 g (82%) of the title compound as a solid: mp 136° C.–141° C. MS (APCI) (m+1)/z 393.2 Analysis calculated for C19H22F2N4SO: C, 58.15; H, 5.65; N, 14.28. Found: C, 58.22; H, 5.68; N, 14.26. The reaction was warmed to reflux the formed water was removed with the aid of a Dean-Stark trap the reaction was concentrated in vacuo The residue was dissolved in dichloromethane The resulting emulsion was filtered through fiberglass filter paper The methylene chloride layer was isolated from the filtrate washed first with a saturated aqueous solution of sodium bicarbonate The methylene chloride layer was dried with magnesium sulfate concentrated in vacuo The residue was dissolved in dichloromethane concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (3-ethoxy-2,6-difluoro-phenyl)-carbamic acid tert-butyl ester (135 g, 0.525 mol) in a mixture of dichloromethane and 10 equivalents trifluoroacetic acid (598 g, 5.25 mol) was stirred at room temperature for 1 hour and concentrated in vacuo. The pH of the residue was adjusted to pH 8 with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer is extracted with ethyl acetate (3×250 mL). The organic extracts were combined, washed with a saturated aqueous solution of sodium chloride (2×), dried and concentrated in vacuo. Chromatography of the yellow residual liquid down silica gel using 25:1 hexane:ethyl acetate gave 65 g (66%) of the title compound as oil. concentrated in vacuo The organic layer was separated the aqueous layer is extracted with ethyl acetate (3×250 mL) washed with a saturated aqueous solution of sodium chloride (2×) dried concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the 8.22 g (34.7 mmol) of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 170 mL of toluene was added 6.00 g 34.7 mmol, 1 equivalent) of 3-ethoxy-2,6-difluoro-phenylamine and 2.01 g (8.66 mmol, 0.25 equivalents) of camphorsulfonic acid. The reaction was warmed to reflux and the formed water was removed with the aid of a Dean-Stark trap. After reacting for 48 hours, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane and neutralized with a saturated aqueous solution of sodium bicarbonate. The resulting emulsion was filtered through fiberglass filter paper. The methylene chloride layer was isolated from the filtrate, then washed first with a saturated aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium chloride. The methylene chloride layer was dried with magnesium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane, stirred with silica gel, and concentrated in vacuo. The residue was placed in the sample injection module of a Biotage FLASH 75 chromatographic apparatus. Chromatography of the crude material on a Biotage 500 g silica gel column with 4:1 hexane/ethyl acetate gave 11.1 g (82%) of the title compound as a solid: mp 136° C.–141° C. MS (APCI) (m+1)/z 393.2 Analysis calculated for C19H22F2N4SO: C, 58.15; H, 5.65; N, 14.28. Found: C, 58.22; H, 5.68; N, 14.26. The reaction was warmed to reflux the formed water was removed with the aid of a Dean-Stark trap the reaction was concentrated in vacuo The residue was dissolved in dichloromethane The resulting emulsion was filtered through fiberglass filter paper The methylene chloride layer was isolated from the filtrate washed first with a saturated aqueous solution of sodium bicarbonate The methylene chloride layer was dried with magnesium sulfate concentrated in vacuo The residue was dissolved in dichloromethane concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (3-ethoxy-2,6-difluoro-phenyl)-carbamic acid tert-butyl ester (135 g, 0.525 mol) in a mixture of dichloromethane and 10 equivalents trifluoroacetic acid (598 g, 5.25 mol) was stirred at room temperature for 1 hour and concentrated in vacuo. The pH of the residue was adjusted to pH 8 with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer is extracted with ethyl acetate (3×250 mL). The organic extracts were combined, washed with a saturated aqueous solution of sodium chloride (2×), dried and concentrated in vacuo. Chromatography of the yellow residual liquid down silica gel using 25:1 hexane:ethyl acetate gave 65 g (66%) of the title compound as oil. concentrated in vacuo The organic layer was separated the aqueous layer is extracted with ethyl acetate (3×250 mL) washed with a saturated aqueous solution of sodium chloride (2×) dried concentrated in vacuo