2,6-difluoro-4-methoxybenzonitrile

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: The subtitle compound was prepared from 4-cyano-3,5-difluoroanisole and cyclobutanol following the procedure described in Example 14(a). The crude product was purified on silica gel eluting with dichloromethane:hexane (60:40 v/v) to give the subtitle compound as a white solid (92%). Rf 0.26 (dichloromethane:hexane 1:2, v/v). MS m/z 239 (MNH4)+. The crude product was purified on silica gel eluting with dichloromethane:hexane (60:40 v/v)

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

Procedure: Sodium hydride (1.6 g, 60%, 0.040 mol) was added to a solution of trifluoroethanol (4.0 g, 0.040 mol) in dimethylformamide (50 ml) and the solution stirred for 90 minutes. This solution was then added to 4-cyano-3,5-difluoroanisole [Grey et al, Mol Cryst Liq Cryst, 172, 165-189 (1989)] (6.30 g, 0.037 mol) in tetrahydrofuran (50 ml) and the reaction stirred at room temperature for 2 hours. The reaction mixture was poured into diethyl ether (250 ml) washed with water (2×150 ml) and then brine (50 ml). The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure, then triturated with diethyl ether:hexane to give the subtitle compound as white crystals (5.92 g, 59%). Rf 0.14 (dichloromethane:hexane, 1:2, v/v). MS m/z 267 (MNH4)+. the reaction stirred at room temperature for 2 hours washed with water (2×150 ml) The organic layer was dried (MgSO4) filtered evaporated under reduced pressure triturated with diethyl ether

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ammonia gas was bubbled through a solution of 2,6-difluoro-4-methoxybenzonitrile (1.0 g, 5.91 mmol) in dimethylsulfoxide (11.83 mL) for 10 minutes. The reaction was then sealed and stirred at 90° C. for 24 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to afford a tan residue. The residue was triturated with water, collected be vacuum filtration, and dried in vacuo to afford the title intermediate (0.9 g, 5.42 mmol) as a white solid. LC/MS (ESI+) m/z=167 (M+H). The reaction was then sealed The reaction mixture was cooled to ambient temperature concentrated in vacuo to afford a tan residue The residue was triturated with water collected vacuum filtration dried in vacuo

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ammonia gas was bubbled through a solution of 2,6-difluoro-4-methoxybenzonitrile (1.0 g, 5.91 mmol) in dimethylsulfoxide (11.83 mL) for 10 minutes. The reaction was then sealed and stirred at 90° C. for 24 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to afford a tan residue. The residue was triturated with water, collected be vacuum filtration, and dried in vacuo to afford the title intermediate (0.9 g, 5.42 mmol) as a white solid. LC/MS (ESI+) m/z=167 (M+H). The reaction was then sealed The reaction mixture was cooled to ambient temperature concentrated in vacuo to afford a tan residue The residue was triturated with water collected vacuum filtration dried in vacuo

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ammonia gas was bubbled through a solution of 2,6-difluoro-4-methoxybenzonitrile (1.0 g, 5.91 mmol) in dimethylsulfoxide (11.83 mL) for 10 minutes. The reaction was then sealed and stirred at 90° C. for 24 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to afford a tan residue. The residue was triturated with water, collected be vacuum filtration, and dried in vacuo to afford the title intermediate (0.9 g, 5.42 mmol) as a white solid. LC/MS (ESI+) m/z=167 (M+H). The reaction was then sealed The reaction mixture was cooled to ambient temperature concentrated in vacuo to afford a tan residue The residue was triturated with water collected vacuum filtration dried in vacuo

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,6-Difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst. 1989, 172) (200 mg, 1.18 mmol) was dissolved in ethanolic ammonia (2M solution, 10 ml) and the mixture was heated at 140° C. in an autoclave for 16 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate in pentane as eluant (20:80) to give the title compound as a white solid (165 mg). LRMS: m/z (ES+) 189 [MNa+] The reaction mixture was cooled to room temperature the solvent was evaporated under reduced pressure The residue was purified by chromatography on silica gel

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

Procedure: Sodium hydride (60% in mineral oil, 0.88 g, 22 mmol) was added to 2-methoxyethanol (1.84 g, 24 mmol) in tetrahydrofuran (20 ml) and the mixture was stirred at room temperature for 20 minutes. 2,6-Difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst. 1989, 172) (3.38 g, 20 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and the solution was extracted with dichloromethane (3×50 ml). The combined organic solutions were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane as eluant (gradient from 0:100 to 3:97) to give the title compound (3.8 g). the mixture was stirred at room temperature for 1 hour the solution was extracted with dichloromethane (3×50 ml) The combined organic solutions were dried over magnesium sulphate evaporated under reduced pressure The residue was purified by chromatography on silica gel

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

Procedure: Sodium hydride (60% in mineral oil, 0.88 g, 22 mmol) was added to 2-methoxyethanol (1.84 g, 24 mmol) in tetrahydrofuran (20 ml) and the mixture was stirred at room temperature for 20 minutes. 2,6-Difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst. 1989, 172) (3.38 g, 20 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and the solution was extracted with dichloromethane (3×50 ml). The combined organic solutions were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane as eluant (gradient from 0:100 to 3:97) to give the title compound (3.8 g). the mixture was stirred at room temperature for 1 hour the solution was extracted with dichloromethane (3×50 ml) The combined organic solutions were dried over magnesium sulphate evaporated under reduced pressure The residue was purified by chromatography on silica gel

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

Procedure: Sodium hydride (60% in mineral oil, 0.83 g, 21 mmol) was added portionwise to 3-hydroxytetrahydrofuran (1.82 g, 21 mmol) in tetrahydrofuran (40 ml) at 0° C. under a nitrogen atmosphere. The suspension was warmed to room temperature and was stirred for 1 hour. The mixture formed was added over 30 minutes to 2,6-difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst. 1989, 172) (3.5 g, 21 mmol) in tetrahydrofuran (50 ml) and the resulting solution was held at room temperature for 16 hours. Water (75 ml) was added and the aqueous mixture was extracted with ethyl acetate (3×200 ml) The combined organic solutions were dried over magnesium sulphate and evaporated under reduced pressure. The material obtained was dried under vacuum to give the title compound as a brown solid (5.1 g). The mixture formed the resulting solution was held at room temperature for 16 hours the aqueous mixture was extracted with ethyl acetate (3×200 ml) The combined organic solutions were dried over magnesium sulphate evaporated under reduced pressure The material obtained was dried under vacuum

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred, homogeneous mixture of finely powdered, compound 27 (17.0 g, 0.10 mol), aluminium chloride (29.4 g, 0.22 mol) and sodium chloride (7.1 g, 0.12 mol) was heated to 180° C. over 25 min and then at 180° C. for 1 h (glc and tlc analyses both revealed a complete reaction). Ice-water was added, and the product was extracted into ether (twice). The combined ethereal extracts were washed with water, and the product was extracted into 10% sodium hydroxide (twice) and the combined basic extracts were acidified with 36% hydrochloric acid. The product was extracted into ether (twice), and the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to give a fawn solid. a complete reaction) the product was extracted into ether (twice) The combined ethereal extracts were washed with water the product was extracted into 10% sodium hydroxide (twice) and the combined basic extracts The product was extracted into ether (twice), and the combined ethereal extracts were washed with water dried (MgSO4) The solvent was removed in vacuo to give a fawn solid