2,5-difluoro-4-(hydroxymethyl)benzonitrile

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

Procedure: To a stirred solution of 2,5-difluoro-4-(hydroxymethyl)benzonitrile (Preparation 21, 390 mg, 2.30 mmol) in DCM (12 mL) was added phosphorus tribromide (0.238 mL, 2.53 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with DCM to 30 mL and washed with saturated aqueous sodium bicarbonate (30 mL). The organic layer was dried over sodium sulphate, and evaporated to afford the title compound as a yellow oil, which was used in the next step without further purification (530 mg, 99%). washed with saturated aqueous sodium bicarbonate (30 mL) The organic layer was dried over sodium sulphate evaporated

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

Procedure: To a stirred solution of 2,5-difluoro-4-(hydroxymethyl)benzonitrile (Preparation 21, 390 mg, 2.30 mmol) in DCM (12 mL) was added phosphorus tribromide (0.238 mL, 2.53 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with DCM to 30 mL and washed with saturated aqueous sodium bicarbonate (30 mL). The organic layer was dried over sodium sulphate, and evaporated to afford the title compound as a yellow oil, which was used in the next step without further purification (530 mg, 99%). washed with saturated aqueous sodium bicarbonate (30 mL) The organic layer was dried over sodium sulphate evaporated

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,5-difluoro-4-formylbenzonitrile (Preparation 20, 280 mg, 1.68 mmol) in ethanol (8 mL) was cooled to 0° C. in an ice/water bath. Sodium borohydride (63.4 mg, 1.68 mmol) was added and the reaction stirred at 0-5° C. for 5 hours. The mixture was quenched with aqueous hydrochloric acid (2 N, 20 mL) and extracted with EtOAc (25 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (25 mL), dried over sodium sulphate, and concentrated in vacuo to afford the title compound as a yellow oil, which crystallised on standing (182 mg, 64%). The mixture was quenched with aqueous hydrochloric acid (2 N, 20 mL) extracted with EtOAc (25 mL) The organic layer was washed with saturated aqueous sodium bicarbonate (25 mL) dried over sodium sulphate concentrated in vacuo

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

Procedure: To an ice cooled solution of 2,5-difluoro-4-hydroxymethylbenzonitrile (3.10 g, 0.0183 mol; see step (iii) above) and methanesulfonyl chloride (2.21 g, 0.0192 mol) in 60 mL of methylene chloride was added triethyl amine (1.95 g, 0.0192 mol) with stirring. After 1.5 h at 0° C. the mixture was washed with water, dried (Na2SO4) and evaporated. The product could be used without further purification. Yield: 4.5 g (99%). After 1.5 h at 0° C. the mixture was washed with water dried (Na2SO4) evaporated The product could be used without further purification

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

Procedure: 2,5-Difluoro-4-formylbenzonitrile (3.60 g, 0.0215 mol; see step (ii) above) was dissolved in 50 mL of methanol and cooled on an ice bath. Sodium borohydride (0.815 g, 0.0215 mol) was added in portions with stirring and the reaction was left for 45 min. Water (300 mL) was added and thereafter carefully 2M HCl was added until an acidic pH was attained. The mixture was extracted three times with diethyl ether, and the combined ethereal phase was washed with water, dried (Na2SO4) and evaporated. The crude product crystallised soon and could be used without further purification. cooled on an ice bath The mixture was extracted three times with diethyl ether the combined ethereal phase was washed with water dried (Na2SO4) evaporated The crude product crystallised soon could be used without further purification

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

Procedure: To an ice cooled solution of 2,5-difluoro-4-hydroxymethylbenzonitrile (3.10 g, 0.0183 mol; see step (iii) above) and methanesulfonyl chloride (2.21 g, 0.0192 mol) in 60 mL of methylene chloride was added triethyl amine (1.95 g, 0.0192 mol) with stirring. After 1.5 h at 0° C. the mixture washed with water, dried (Na2SO4) and evaporated. The product could be used without further purification. Yield: 4.5 g (99%). After 1.5 h at 0° C. the mixture washed with water dried (Na2SO4) evaporated The product could be used without further purification

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

Procedure: 2,5-Difluoro-4-formylbenzonitrile (3.60 g, 0.0215 mol; see step (ii) above) was dissolved in 50 mL of methanol and cooled on an ice bath. Sodium borohydride (0.815 g, 0.0215 mol) was added in portions with stirring and the reaction was left for 45 min. Water (300 mL) was added and thereafter carefully 2M HCl was added until an acidic pH was attained. The mixture was extracted three times with diethyl ether, and the combined ethereal phase washed with water, dried (Na2SO4) and evaporated. The crude product crystallised soon and could be used without further purification. Yield: 3.1 g (85%). cooled on an ice bath The mixture was extracted three times with diethyl ether the combined ethereal phase washed with water dried (Na2SO4) evaporated The crude product crystallised soon could be used without further purification

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

Procedure: To an ice cooled solution of 2,5-difluoro-4-hydroxymethylbenzonitrile (3.10 g, 0.0183 mol; see step (iii) above) and methanesulfonyl chloride (2.21 g, 0.0192 mol) in 60 mL of methylene chloride was added triethyl amine (1.95 g, 0.0192 mol) with stirring. After 1.5 h at 0° C. the mixture was washed with water, dried (Na2SO4) and evaporated. The product could be used without further purification. Yield: 4.5 g (99%). After 1.5 h at 0° C. the mixture was washed with water dried (Na2SO4) evaporated The product could be used without further purification

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

Procedure: 2,5-Difluoro-4-formylbenzonitrile (3.60 g, 0.0215 mol; see step (ii) above) was dissolved in 50 mL of methanol and cooled on an ice bath. Sodium borohydride (0.815 g, 0.0215 mol) was added in portions with stirring and the reaction was left for 45 min. Water (300 mL) was added and thereafter carefully 2M HCl was added until an acidic pH was attained. The mixture was extracted three times with diethyl ether, and the combined ethereal phase was washed with water, dried (Na2SO4) and evaporated. The crude product crystallised soon and could be used without further purification. cooled on an ice bath The mixture was extracted three times with diethyl ether the combined ethereal phase was washed with water dried (Na2SO4) evaporated The crude product crystallised soon could be used without further purification

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

Procedure: To a stirred solution of 2,5-difluoro-4-(hydroxymethyl)benzonitrile (Preparation 21, 390 mg, 2.30 mmol) in DCM (12 mL) was added phosphorus tribromide (0.238 mL, 2.53 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with DCM to 30 mL and washed with saturated aqueous sodium bicarbonate (30 mL). The organic layer was dried over sodium sulphate, and evaporated to afford the title compound as a yellow oil, which was used in the next step without further purification (530 mg, 99%). washed with saturated aqueous sodium bicarbonate (30 mL) The organic layer was dried over sodium sulphate evaporated

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,5-difluoro-4-formylbenzonitrile (Preparation 20, 280 mg, 1.68 mmol) in ethanol (8 mL) was cooled to 0° C. in an ice/water bath. Sodium borohydride (63.4 mg, 1.68 mmol) was added and the reaction stirred at 0-5° C. for 5 hours. The mixture was quenched with aqueous hydrochloric acid (2 N, 20 mL) and extracted with EtOAc (25 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (25 mL), dried over sodium sulphate, and concentrated in vacuo to afford the title compound as a yellow oil, which crystallised on standing (182 mg, 64%). The mixture was quenched with aqueous hydrochloric acid (2 N, 20 mL) extracted with EtOAc (25 mL) The organic layer was washed with saturated aqueous sodium bicarbonate (25 mL) dried over sodium sulphate concentrated in vacuo