1-(2,6-difluorophenyl)ethanone

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

Procedure: To a mixture of 2,6-difluoroacetophenone (4.7 g, 0.03 mol) and 1,2-diethyl ethanedioate (4.8 g, 0.033 mol) in ethanol (33 mL) was added sodium tert-butoxide (3.17 g, 0.033 mol). After 1 h, more ethanol (30 mL) was added to the reaction mixture and stirring was continued for 1 h. The reaction mixture was partitioned between hydrochloric acid (1 N) and diethyl ether. The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to half its original volume. To the resulting mixture was added methylhydrazine (1.52 g, 0.033 mol) and stirring was continued overnight. The reaction mixture was concentrated under reduced pressure and the resulting material was purified by silica gel chromatography (5 to 20% gradient of ethyl acetate in methylene chloride as eluant) to provide the title compound as a solid (1.0 g). was continued for 1 h The reaction mixture was partitioned between hydrochloric acid (1 N) and diethyl ether The organic phase was separated dried over magnesium sulfate filtered concentrated under reduced pressure to half its original volume stirring was continued overnight The reaction mixture was concentrated under reduced pressure the resulting material was purified by silica gel chromatography (5 to 20% gradient of ethyl acetate in methylene chloride as eluant)

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2,6-Difluoroacetophenone (5 g, 32 mmol) in dry THF (40 ml) and DMPU (8 ml) was added a solution of lithium bis(trimethylsilyl)amide (1.0M, 45 ml) at −60° C. under argon. After stirring for 10 minutes at −60° C., tert-Butyl bromoacetate (6.99 g, 35.8 mmol) was added rapidly. The reaction mixture was stirred for an additional 10 minutes and then warmed to room temperature for 4 hours. The crude mixture was taken in EtOAc and washed with water and brine. The aqueous layer was extracted one more time with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate, 2:1) to provide the title compound. The reaction mixture was stirred for an additional 10 minutes warmed to room temperature for 4 hours washed with water and brine The aqueous layer was extracted one more time with EtOAc The combined organic layers were dried over Na2SO4 filtered concentrated purified by flash chromatography on a silica gel column (hex:ethyl acetate, 2:1)

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2,6-Difluoroacetophenone (5 g, 32 mmol) in dry THF (40 ml) and DMPU (8 ml) was added a solution of lithium bis(trimethylsilyl)amide (1.0M, 45 ml) at −60° C. under argon. After stirring for 10 minutes at −60° C., tert-Butyl bromoacetate (6.99 g, 35.8 mmol) was added rapidly. The reaction mixture was stirred for an additional 10 minutes and then warmed to room temperature for 4 hours. The crude mixture was taken in EtOAc and washed with water and brine. The aqueous layer was extracted one more time with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate, 2:1) to provide the title compound. The reaction mixture was stirred for an additional 10 minutes warmed to room temperature for 4 hours washed with water and brine The aqueous layer was extracted one more time with EtOAc The combined organic layers were dried over Na2SO4 filtered concentrated purified by flash chromatography on a silica gel column (hex:ethyl acetate, 2:1)

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2,6-Difluoroacetophenone (5 g, 32 mmol) in dry THF (40 ml) and DMPU (8 ml) was added a solution of lithium bis(trimethylsilyl)amide (1.0M, 45 ml) at −60° C. under argon. After stirring for 10 minutes at −60° C., tert-Butyl bromoacetate (6.99 g, 35.8 mmol) was added rapidly. The reaction mixture was stirred for an additional 10 minutes and then warmed to room temperature for 4 hours. The crude mixture was taken in EtOAc and washed with water and brine. The aqueous layer was extracted one more time with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate, 2:1) to provide the title compound. The reaction mixture was stirred for an additional 10 minutes warmed to room temperature for 4 hours washed with water and brine The aqueous layer was extracted one more time with EtOAc The combined organic layers were dried over Na2SO4 filtered concentrated purified by flash chromatography on a silica gel column (hex:ethyl acetate, 2:1)

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a −40° C. mixture of concentrated H2SO4 (100 mL) and fuming HNO3 (100 mL) was added 1-(2,6-difluorophenyl)ethanone (20 g, 128 mmol) dropwise. The resulting mixture was stirred at −40° C. for 2 h then poured slowly onto ice. That mixture was diluted with DCM and the phases were separated. The aqueous layer was neutralized with sat. aq. NaHCO3 and then extracted with DCM. All organic portions were combined, dried over MgSO4, filtered, and concentrated to give 1-(2,6-difluoro-3-nitrophenyl)ethanone (26.3 g, 131 mmol, >theoretical) that was used without further purification. then poured slowly onto ice the phases were separated extracted with DCM dried over MgSO4 filtered concentrated

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

Procedure: To a solution of 1-(2,6-difluorophenyl)ethanone (10.0 g) in diethyl ether (50 mL) was added anhydrous aluminum chloride (86 mg) and the mixture was stirred for 5 min. Bromine (3.3 mL) was added dropwise at 10-15° C. After stirring at room temperature for 2 hr, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield 15.2 g, about 100%). After stirring at room temperature for 2 hr the mixture was extracted with ethyl acetate The obtained organic layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2,6-Difluoroacetophenone (5 g, 32 mmol) in dry THF (40 ml) and DMPU (8 ml) was added a solution of lithium bis(trimethylsilyl)amide (1.0M, 45 ml) at −60° C. under argon. After stirring for 10 minutes at −60° C., tert-Butyl bromoacetate (6.99 g, 35.8 mmol) was added rapidly. The reaction mixture was stirred for an additional 10 minutes and then warmed to room temperature for 4 hours. The crude mixture was taken in EtOAc and washed with water and brine. The aqueous layer was extracted one more time with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex: ethyl acetate, 2:1) to provide the title compound. The reaction mixture was stirred for an additional 10 minutes warmed to room temperature for 4 hours washed with water and brine The aqueous layer was extracted one more time with EtOAc The combined organic layers were dried over Na2SO4 filtered concentrated purified by flash chromatography on a silica gel column (hex: ethyl acetate, 2:1)

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2,6-Difluoroacetophenone (5 g, 32 mmol) in dry THF (40 ml) and DMPU (8 ml) was added a solution of lithium bis(trimethylsilyl)amide (1.0M, 45 ml) at −60° C. under argon. After stirring for 10 minutes at −60° C., tert-Butyl bromoacetate (6.99 g, 35.8 mmol) was added rapidly. The reaction mixture was stirred for an additional 10 minutes and then warmed to room temperature for 4 hours. The crude mixture was taken in EtOAc and washed with water and brine. The aqueous layer was extracted one more time with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex: ethyl acetate, 2:1) to provide the title compound. The reaction mixture was stirred for an additional 10 minutes warmed to room temperature for 4 hours washed with water and brine The aqueous layer was extracted one more time with EtOAc The combined organic layers were dried over Na2SO4 filtered concentrated purified by flash chromatography on a silica gel column (hex: ethyl acetate, 2:1)

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

Procedure: Using the method described in Example 30 by employing [1-(2,6-difluorophenyl)vinyl]pyrrolidine (freshly prepared before use from 2′,6′-difluoro acetophenone (Aldrich Chemical Company), pyrrolidine and TiCl4 (1.51 g, 7.22 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.20 g, 5.79 mmol), N,N-diisopropylethylamine (1.3 mL, 7.22 mmol), piperidine (1.2 mL, 11.6 mmol), NEt3 (1.2 mL) and SnCl2 (22 mL of a 2 M soln in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant to give 199 mg (11%) of 6-(2,6-difluorophenyl)-2-methyl-4-piperidylpyrrolo[3,2-d]pyrimidine as a beige colored powder. This material (199 mg, 0.61 mmol) was dissolved in 5:1 EtOAc/MeOH (20 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (0.60 mL, 0.60 mmol). The solution was left to cool to room temperature. The resulting crystals were collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 33 mg (2%) of the title compound as a pale yellow colored sandy solid. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.71 (br s, 6), 2.58 (s, 3), 4.02 (s, 4), 6.77 (s, 1), 7.35 (t, 2, J=8.3), 7.67 (dquintet, 1, J=1.4, 6.8), 12.41 (s, 1), 14.51 (s, 1). MS m/z: 329 (M+1 for free base). Anal. Calcd for C18H18F2N4.HCl.1.2H2O: C, 55.99; H, 5.58; N, 14.51; Cl, 9.18. Found: C, 55.99; H, 5.61; N, 14.41; Cl, 9.08. The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant

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

Procedure: Using the method described in Example 30 by employing [1-(2,6-difluorophenyl)vinyl]pyrrolidine (freshly prepared before use from 2′,6′-difluoro acetophenone (Aldrich Chemical Company), pyrrolidine and TiCl4 (1.51 g, 7.22 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.20 g, 5.79 mmol), N,N-diisopropylethylamine (1.3 mL, 7.22 mmol), piperidine (1.2 mL, 11.6 mmol), NEt3 (1.2 mL) and SnCl2 (22 mL of a 2 M soln in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant to give 199 mg (11%) of 6-(2,6-difluorophenyl)-2-methyl-4-piperidylpyrrolo[3,2-d]pyrimidine as a beige colored powder. This material (199 mg, 0.61 mmol) was dissolved in 5:1 EtOAc/MeOH (20 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (0.60 mL, 0.60 mmol). The solution was left to cool to room temperature. The resulting crystals were collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 33 mg (2%) of the title compound as a pale yellow colored sandy solid. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.71 (br s, 6), 2.58 (s, 3), 4.02 (s, 4), 6.77 (s, 1), 7.35 (t, 2, J=8.3), 7.67 (dquintet, 1, J=1.4, 6.8), 12.41 (s, 1), 14.51 (s, 1). MS m/z: 329 (M+1 for free base). Anal. Calcd for C18H18F2N4.HCl.1.2H2O: C, 55.99; H, 5.58; N, 14.51; Cl, 9.18. Found: C, 55.99; H, 5.61; N, 14.41; Cl, 9.08. The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2,6-Difluoroacetophenone (5 g, 32 mmol) in dry THF (40 ml) and DMPU (8 ml) was added a solution of lithium bis(trimethylsilyl)amide (1.0M, 45 ml) at −60° C. under argon. After stirring for 10 minutes at −60° C., tert-Butyl bromoacetate (6.99 g, 35.8 mmol) was added rapidly. The reaction mixture was stirred for an additional 10 minutes and then warmed to room temperature for 4 hours. The crude mixture was taken in EtOAc and washed with water and brine. The aqueous layer was extracted one more time with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex: ethyl acetate, 2:1) to provide the title compound. The reaction mixture was stirred for an additional 10 minutes warmed to room temperature for 4 hours washed with water and brine The aqueous layer was extracted one more time with EtOAc The combined organic layers were dried over Na2SO4 filtered concentrated purified by flash chromatography on a silica gel column (hex: ethyl acetate, 2:1)

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a −40° C. mixture of concentrated H2SO4 (100 mL) and fuming HNO3 (100 mL) was added 1-(2,6-difluorophenyl)ethanone (20 g, 128 mmol) dropwise. The resulting mixture was stirred at −40° C. for 2 h then poured slowly onto ice. That mixture was diluted with DCM and the phases were separated. The aqueous layer was neutralized with sat. aq. NaHCO3 and then extracted with DCM. All organic portions were combined, dried over MgSO4, filtered, and concentrated to give 1-(2,6-difluoro-3-nitrophenyl)ethanone (26.3 g, 131 mmol, >theoretical) that was used without further purification. then poured slowly onto ice the phases were separated extracted with DCM dried over MgSO4 filtered concentrated