1-(2-amino-3-chloro-4-hydroxyphenyl)ethanone

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

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

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(2-Amino-3-chloro-4-hydroxyphenyl)ethanone (40 g, 215 mmol) was dissolved in DMF (360 ml). Cesium carbonate (140 g, 430 mmol) was added, followed by bromoacetaldehyde dimethyl acetal (54.5 g, 323 mmol). The mixture was then vigorously stirred at 65° C. for 24 h. Upon cooling to room temperature, EtOAc (1 L) and H2O (1 L) were added to the mixture. The organic layer was extracted with EtOAc (1×400 ml). The combined organic layer was washed with aqueous 3% LiCl solution (2×1 L), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography to give 1-[2-amino-3-chloro-4-(2,2-dimethoxyethoxy)phenyl]-ethanone as a white solid (39 g, 67% yield). Upon cooling to room temperature The organic layer was extracted with EtOAc (1×400 ml) The combined organic layer was washed with aqueous 3% LiCl solution (2×1 L), brine dried (Na2SO4) concentrated in vacuo The residue was purified by silica gel chromatography

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

Procedure: 1-(2-Amino-3-chloro-4-methoxyphenyl)ethanone (prepared according to Raboisson, P. J.-M. B., et al., WO2007014926, p 78; 70.7 g, 354 mmol) was stirred in 48% aq. HBr (500 mL) at 110° C. for 72 h. After the mixture was cooled to 0° C. with stirring, the solids were filtered and washed with water. The resulting solids were triturated with a saturated NaHCO3 solution (˜350 mL), filtered, washed with water, and dried under vacuum to give 40 g (61% yield) of 1-(2-amino-3-chloro-4-hydroxyphenyl)ethanone as a dark brown solid. the solids were filtered washed with water The resulting solids were triturated with a saturated NaHCO3 solution (˜350 mL) filtered washed with water dried under vacuum

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(2-Amino-3-chloro-4-hydroxyphenyl)ethanone (40 g, 215 mmol) was dissolved in DMF (360 ml). Cesium carbonate (140 g, 430 mmol) was added, followed by bromoacetaldehyde dimethyl acetal (54.5 g, 323 mmol). The mixture was then vigorously stirred at 65° C. for 24 h. Upon cooling to room temperature, EtOAc (1 L) and H2O (1 L) were added to the mixture. The organic layer was extracted with EtOAc (1×400 ml). The combined organic layer was washed with aqueous 3% LiCl solution (2×1 L), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography to give 1-[2-amino-3-chloro-4-(2,2-dimethoxyethoxy)phenyl]-ethanone as a white solid (39 g, 67% yield). Upon cooling to room temperature The organic layer was extracted with EtOAc (1×400 ml) The combined organic layer was washed with aqueous 3% LiCl solution (2×1 L), brine dried (Na2SO4) concentrated in vacuo The residue was purified by silica gel chromatography

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

Procedure: 1-(2-Amino-3-chloro-4-methoxyphenyl)ethanone (prepared according to Raboisson, P. J.-M. B., et al., WO2007014926, p 78; 70.7 g, 354 mmol) was stirred in 48% aq. HBr (500 mL) at 110° C. for 72 h. After the mixture was cooled to 0° C. with stirring, the solids were filtered and washed with water. The resulting solids were triturated with a saturated NaHCO3 solution (−350 mL), filtered, washed with water, and dried under vacuum to give 40 g (61% yield) of 1-(2-amino-3-chloro-4-hydroxyphenyl)ethanone as a dark brown solid. the solids were filtered washed with water The resulting solids were triturated with a saturated NaHCO3 solution (−350 mL) filtered washed with water dried under vacuum

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(2-Amino-3-chloro-4-hydroxy-phenyl)-ethanone (15.5 g, 83.8 mmol), Cs2CO3 (54.6 g, 167 mmol) and 2-bromo-1,1-dimethoxy-ethane (14.78 mL, 126 mmol) was dissolved in DMF (125 mL) under an atmosphere of nitrogen. The reaction was heated to 65° C. for 6 hours. The reaction was determined to be complete by LC/MS. The reaction was taken up in EtOAc (500 mL) and washed with 5% LiCl(aq) (3×250 mL). Organics were dried over Na2SO4, filtered and solvent removed under reduced pressure. 1-[2-Amino-3-chloro-4-(2,2-dimethoxy-ethoxy)-phenyl]-ethanone (12.99 g, 57%) was isolated by silica gel chromatography as a white solid. washed with 5% LiCl(aq) (3×250 mL) Organics were dried over Na2SO4 filtered solvent removed under reduced pressure

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(2-Amino-4-methoxy-3-chloro-phenyl)ethanone (71.55 g, 358 mmol) was dissolved in HBr (500 mL, 48% in H2O). The reaction was heated to 110° C. for 2 days. The reaction was cooled to rt then the solids were filtered. The solids were partitioned between EtOAc and ½ sat Na2CO3(aq). Organics were dried over Na2SO4, filtered and solvent removed under reduced pressure. 1-(2-Amino-3-chloro-4-hydroxy-phenyl)-ethanone (15.5 g, 16%) was isolated by silica gel chromatography as an off-white solid. The reaction was cooled to rt the solids were filtered The solids were partitioned between EtOAc and ½ Organics were dried over Na2SO4 filtered solvent removed under reduced pressure