N-(4-chlorophenyl)-2,2-dimethylpropanamide

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

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

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

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

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-(4-chlorophenyl)-2,2-dimethylpropanamide (6.7 g, 30 mmol) in anhydrous THF (100 mL) under nitrogen at 0° C. was added a solution of n-BuLi (2.5M, 30 mL, 70 mmol) in hexane in a dropwise fashion. After addition, the solution was kept stirring at 0° C. for 40 minutes and treated with a solution of 1-(trifluoroacetyl)imidazole (9 mL, 78 mmol) in anhydrous THF (10 mL). The reaction mixture was warmed to ambient temperature and kept for 18 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution (50 mL) followed by addition of ethyl acetate (100 mL). The organic layer was separated and the solvent was removed in vacuo. The residue obtained was suspended in 3N aqueous hydrochloride solution (50 mL) and heated at reflux overnight. The reaction solution was cooled to room temperature and treated with a cold ammonium hydroxide solution to a pH above 8. The aqueous mixture was extracted with ethyl acetate (3×50 mL) and the organic layers were washed with brine and dried (MgSO4). After removal of solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethylacetate/4:1) to afford the title compound as a yellow solid (1 g, 15%): mp 93-94° C.; 1H-NMR (CDCl3) δ7.70 (m, 1H), 7.33 (dd, 1H, J=9.0, 2.3 Hz), 6.70 (d, 1H, J=9.1 Hz), 6.45 (bs, 2H); MS (ESI) m/z 222(M−H, 100%), 224(M−H, 33%). After addition The reaction mixture was warmed to ambient temperature kept for 18 hours The organic layer was separated the solvent was removed in vacuo The residue obtained heated at reflux overnight The reaction solution was cooled to room temperature The aqueous mixture was extracted with ethyl acetate (3×50 mL) the organic layers were washed with brine dried (MgSO4) After removal of solvent the residue was purified by a flash chromatography (silica gel, hexane:ethylacetate/4:1)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(4-Chlorophenyl)-2,2-dimethyl propanamide (36.7 kg, 173 mol) was charged to a solution of TMEDA (20.2 kg, 174 mol) in anhydrous t-butyl methyl ether (271.5 kg) and cooled to -20° C. To the cold slurry was added 2.7 N n-butyllithium in hexane (101.9 kg, 393 mol) while keeping the temperature below 5° C. After aging 2 hr at 0 to 5° C., the solution was cooled below -15° C. then rapidly reacted with ethyl trifluoroacetate (34.5 kg, 243 mol). After 30 min, the resulting solution was quenched into 3N HCl (196 L, 589 mol) keeping the temperature below 25° C. After removal of the aqueous phase, the organic solution was concentrated by distilling approximately 200 L of solvent. Acetic acid (352 kg) was added while distilling 325 kg solvent under 100 mm vacuum. After cooling the solution to 30° C., 12 N HCl (43.4 kg, 434 mol) was added and the mixture heated to 65 to 70° C. and held 4 hours. The resulting slurry was cooled to 5° C. and the product was collected by filtration, washed with ethyl acetate (50.5 kg) and dried in vacuo to give 42.1 kg (87%) of the title compound as a white crystalline solid: mp 159-162 dec; 1H NMR (300 MHz, DMSO-d6) d 7.65-7.5 (complex, 2H), 7.1 (d, J=8 Hz, 1H), 7.0 (brs, 3H); 19F NMR (282 MHz, DMSO-d6) δ-69.5. the temperature below 5° C the solution was cooled below -15° C. After 30 min the temperature below 25° C After removal of the aqueous phase the organic solution was concentrated by distilling approximately 200 L of solvent Acetic acid (352 kg) was added while distilling 325 kg solvent under 100 mm vacuum After cooling the solution to 30° C. the mixture heated to 65 to 70° C. held 4 hours The resulting slurry was cooled to 5° C. the product was collected by filtration washed with ethyl acetate (50.5 kg) dried in vacuo

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloroaniline (52.7 kg, 413 mol) was dissolved in a mixture of t-butyl methyl ether (180 kg), 30% aqueous sodium hydroxide (61.6 kg, 463 mol) and water (24.2 kg), then cooled to 15° C. To the resulting slurry was charged trimethylacetyl chloride (52.2 kg, 448 mol) over 1 h, keeping the temperature below 40° C. After stirring 30 min at 30° C. the slurry was cooled to -10° C. and held for 2 hours. The product was collected by filtration, washed with a solution of 90/10 water/methanol (175 kg), then dried in vacuo to give 85 kg (97% yield) of the title compound as a crystalline solid: mp 152-153° C.; 1H NMR (300 MHz, CDCl3) δ7.48 (d, J=9 Hz, 2H) 7.28 (d, J=9 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 176.7, 136.6, 129.1, 128.9, 121.4, 39.6, 27.6. the temperature below 40° C was cooled to -10° C. held for 2 hours The product was collected by filtration washed with a solution of 90/10 water/methanol (175 kg) dried in vacuo

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

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

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 4-chloroaniline (5.0 g, 39.2 mmol) in 25 mL pyridine was added 5.3 mL (43.1 mmol) of pivaloyl chloride and the reaction mixture stirred overnight at room temperature. The mixture was poured into vigorously stirring 6M HCl, and the solids were collected by vacuum filtration, washed well with H2O, and dried in vacuo to yield the title compound. 1H NMR (CDCl3) δ 7.47 (d, J=9.2 Hz, 2H) 7.30 (s, 1H) 7.27 (d, J=8.8 Hz, 2H) 1.32 (s, 9H) MS (ES) m/z=212.1 The mixture was poured the solids were collected by vacuum filtration washed well with H2O dried in vacuo