1-(3,5-difluorophenyl)propan-1-one

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 3',5'-difluoropropiophenone (56.0 g. 0 33 mole) was added a solution of dioxane dibromide (81.8 g. 0.33 mole) in dioxane (500 ml) The reaction mixture was worked up as in Example 1 to yield crude 2-bromo-3',5'-difluoropropiophenone (83.9 g).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3,5-difluorobenzonitrile (Aldrich Chemical Co . Milwaukee. WI 53233)(50.0 g. 0.36 mole) in 500 mL of diethyl ether at 0° C. was added dropwise a solution of ethylmagnesium bromide (135 mL of a 3.OM solution 0.41 mole) in diethyl ether. The reaction mixture was refluxed for 3 hr. then chilled in an ice bath and hydrolyzed with 100 mL of 6N aqueous hydrogen chloride. The mixture was heated on a steam bath for 0.5 hr. The pH was adjusted to acid (litmus) and two phases were separated by extraction of the aqueous phase with diethyl ether. The combined extracts were dried (sodium sulfate) and concentrated in vacuo to give 61.3 g (91% of theory) of crude 3',5'-difluoropropiophenone. The reaction mixture was refluxed for 3 hr The mixture was heated on a steam bath for 0.5 hr were separated by extraction of the aqueous phase with diethyl ether The combined extracts were dried (sodium sulfate) concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3,5-difluorobenzonitrile (Aldrich Chemical Co . Milwaukee. WI 53233)(50.0 g. 0.36 mole) in 500 mL of diethyl ether at 0° C. was added dropwise a solution of ethylmagnesium bromide (135 mL of a 3.OM solution 0.41 mole) in diethyl ether. The reaction mixture was refluxed for 3 hr. then chilled in an ice bath and hydrolyzed with 100 mL of 6N aqueous hydrogen chloride. The mixture was heated on a steam bath for 0.5 hr. The pH was adjusted to acid (litmus) and two phases were separated by extraction of the aqueous phase with diethyl ether. The combined extracts were dried (sodium sulfate) and concentrated in vacuo to give 61.3 g (91% of theory) of crude 3',5'-difluoropropiophenone. The reaction mixture was refluxed for 3 hr The mixture was heated on a steam bath for 0.5 hr were separated by extraction of the aqueous phase with diethyl ether The combined extracts were dried (sodium sulfate) concentrated in vacuo

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using the method described in Example 30 by employing (1-(3,5-difluorophenyl)prop-1-enyl) pyrrolidine (freshly prepared before use from 3,5-difluoropropiophenone (Lancaster Chemical Company), pyrrolidine and TiCl4 (2.29 g, 10.3 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (2.10 g, 10.3 mmol), N,N-diisopropylethylamine (1.8 mL, 10.3 mmol), piperidine (1.6 mL, 16.4 mmol), NEt3 (1.6 mL) and SnCl2 (31 mL of a 2 M soln in DMF). In this example the SnCl2 solution was added to the reaction mixture at 140° C. The mixture was stirred at 140° C. for an additional 16 h then the heating was discontinued and the mixture was allowed to cool to room temperature. The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant to give 605 mg (17%) of 6-(3,5-difluorophenyl)-2,7-dimethyl-4-piperidylpyrrolo[3,2-d]pyrimidine as a beige colored foam. This compound (600 mg, 1.75 mmol) was dissolved in 10:1 EtOAc/MeOH (20 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.80 mL, 1.80 mmol). The solution was allowed 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 291 mg (7%) of the title compound as a beige colored solid. Mp: 242-245° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.52 (br s, 6), 2.28 (s, 3), 2.55 (s, 3), 3.97 (br s, 4), 7.36-7.41 (m, 3), 11.89 (s, 1), 13.82 (s, 1). MS m/z: 343 (M+1 for free base). Anal. Calcd for C19H20F2N4.HCl.0.5H2O: C, 58.83; H, 5.72; N, 14.45; Cl, 9.24. Found: C, 58.86; H, 5.72; N, 14.50; Cl, 9.29. was added to the reaction mixture at 140° C to cool to room temperature The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using the method described in Example 30 by employing (1-(3,5-difluorophenyl)prop-1-enyl) pyrrolidine (freshly prepared before use from 3,5-difluoropropiophenone (Lancaster Chemical Company), pyrrolidine and TiCl4 (2.29 g, 10.3 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (2.10 g, 10.3 mmol), N,N-diisopropylethylamine (1.8 mL, 10.3 mmol), piperidine (1.6 mL, 16.4 mmol), NEt3 (1.6 mL) and SnCl2 (31 mL of a 2 M soln in DMF). In this example the SnCl2 solution was added to the reaction mixture at 140° C. The mixture was stirred at 140° C. for an additional 16 h then the heating was discontinued and the mixture was allowed to cool to room temperature. The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant to give 605 mg (17%) of 6-(3,5-difluorophenyl)-2,7-dimethyl-4-piperidylpyrrolo[3,2-d]pyrimidine as a beige colored foam. This compound (600 mg, 1.75 mmol) was dissolved in 10:1 EtOAc/MeOH (20 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.80 mL, 1.80 mmol). The solution was allowed 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 291 mg (7%) of the title compound as a beige colored solid. Mp: 242-245° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.52 (br s, 6), 2.28 (s, 3), 2.55 (s, 3), 3.97 (br s, 4), 7.36-7.41 (m, 3), 11.89 (s, 1), 13.82 (s, 1). MS m/z: 343 (M+1 for free base). Anal. Calcd for C19H20F2N4.HCl.0.5H2O: C, 58.83; H, 5.72; N, 14.45; Cl, 9.24. Found: C, 58.86; H, 5.72; N, 14.50; Cl, 9.29. was added to the reaction mixture at 140° C to cool to room temperature The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using the method described in Example 30 by employing (1-(3,5-difluorophenyl)prop-1-enyl) pyrrolidine (freshly prepared before use from 3,5-difluoropropiophenone (Lancaster Chemical Company), pyrrolidine and TiCl4 (2.29 g, 10.3 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (2.10 g, 10.3 mmol), N,N-diisopropylethylamine (1.8 mL, 10.3 mmol), piperidine (1.6 mL, 16.4 mmol), NEt3 (1.6 mL) and SnCl2 (31 mL of a 2 M soln in DMF). In this example the SnCl2 solution was added to the reaction mixture at 140° C. The mixture was stirred at 140° C. for an additional 16 h then the heating was discontinued and the mixture was allowed to cool to room temperature. The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant to give605 mg (17%) of 6-(3,5-difluorophenyl)-2,7-dimethyl-4-piperidylpyrrolo[3,2-d]pyrimidine as a beige colored foam. This compound (600 mg, 1.75 mmol) was dissolved in 10:1 EtOAc/MeOH (20 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.80 mL, 1.80 mmol). The solution was allowed 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 291 mg (7%) of the title compound as a beige colored solid. Mp: 242-245° C. 1H HMR (DMSO-d6; 400 MHz): δ 1.52 (br s, 6), 2.28 (s, 3), 2.55 (s, 3), 3.97 (br s, 4), 7.36-7.41 (m, 3), 11.89 (s, 1), 13.82 (s, 1). MS m/z: 343 (M+1 for free base). Anal. Calcd for C19H20F2N4.HCl.0.5H2O: C, 58.83; H, 5.72; N, 14.45; Cl, 9.24. Found: C, 58.86; H, 5.72; N, 14.50; Cl, 9.29. was added to the reaction mixture at 140° C to cool to room temperature The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant to give605 mg (17%) of 6-(3,5-difluorophenyl)-2,7-dimethyl-4-piperidylpyrrolo[3,2-d]pyrimidine as a beige colored foam heated to boiling to cool to room temperature The resulting crystals were collected by filtration washed with EtOAc (2×10 mL), Et2O (3×15 mL) dried under vacuum at 60° C.