1-(3,5-difluorophenyl)ethanone

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: A solution of 1-(3,5-difluoro-phenyl)-ethanone (156 g, 1 mol, 1 eq) in THF (500 mL) was added dropwise under argon to the commercially available solution of methymagnesium bromide (143 g, 1.2 mol, 1.2 eq) in THF at such a rate that gentle refluxing was maintained. After the addition was complete the reaction mixture was stirred at ambient temperature for an hour and poured into ice-cold aqueous saturated ammonium chloride. Phases were separated and aqueous layer extracted two times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent title compound was purified by distillation under reduced pressure (145 g, 0.84 mol, 84%). that gentle refluxing was maintained After the addition poured into ice-cold aqueous saturated ammonium chloride Phases were separated aqueous layer extracted two times with ethyl acetate The combined organic layers were washed with brine dried over anhydrous magnesium sulfate After removal of the solvent title compound was purified by distillation under reduced pressure (145 g, 0.84 mol, 84%)

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′-difluoroacetophenone (3 g, 19.2 mmol) (Lancaster Synthesis) in dioxane (30 mL) was added dropwise a solution of bromine (3.67 g, 23 mmol) in dioxane (75 mL). After stirring for 10 minutes, the mixture was concentrated in vacuo and the residue was purified by flash chromatography, with 10:2 hexanes/dichloromethane as an eluant, to provide 2-bromo-1-(3,5-difluorophenyl)ethanone as a colorless oil (2.9 g, 64% yield). the mixture was concentrated in vacuo the residue was purified by flash chromatography, with 10:2 hexanes/dichloromethane as an eluant

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

実験手順: To a solution of 1-(3,5-difluorophenyl)ethanone (1.0 equiv) in THF (0.2 M) at 0° C. was added methylmagnesium bromide (1.0 M in THF, 1.15 equiv). After stirring for 4 hours the reaction was quenched by addition of NH4Cl(sat.), diluted with EtOAc, washed with NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield 2-(3,5-difluorophenyl)propan-2-ol. To a solution of 2-(3,5-difluorophenyl)propan-2-ol in CH2Cl2 (0.1 M) at 0° C. was added 2.6 lutidine (6 equiv.) and than triisopropylsilyl trifluoromethanesulfonate (3.0 equiv.). After stirring for 3 hours at 0° C. and six hours at rt the solution was partitioned between EtOAc and NaHCO3(sat.), separated, washed with NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield (2-(3,5-difluorophenyl)propan-2-yloxy)triisopropylsilane. (400 MHz, <cdcl3>) δ ppm 1.05-1.08 (m, 21H) 1.57 (s, 6H) 6.63 (s, 1H) 7.00 (dd, J=9.39, 2.35 Hz, 2H). was quenched by addition of NH4Cl(sat.) diluted with EtOAc washed with NaCl(sat.) dried over MgSO4 filtered concentrated purified by ISCO SiO2 chromatography

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

実験手順: To a solution of 1-(3,5-difluorophenyl)ethanone (1.0 equiv) in THF (0.2 M) at 0° C. was added methylmagnesium bromide (1.0 M in THF, 1.15 equiv). After stirring for 4 hours the reaction was quenched by addition of NH4Cl(sat.), diluted with EtOAc, washed with NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield 2-(3,5-difluorophenyl)propan-2-ol. To a solution of 2-(3,5-difluorophenyl)propan-2-ol in CH2Cl2 (0.1 M) at 0° C. was added 2.6 lutidine (6 equiv.) and than triisopropylsilyl trifluoromethanesulfonate (3.0 equiv.). After stirring for 3 hours at 0° C. and six hours at rt the solution was partitioned between EtOAc and NaHCO3(sat.), separated, washed with NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield (2-(3,5-difluorophenyl)propan-2-yloxy)triisopropylsilane. (400 MHz, <cdcl3>) δ ppm 1.05-1.08 (m, 21H) 1.57 (s, 6H) 6.63 (s, 1H) 7.00 (dd, J=9.39, 2.35 Hz, 2H). was quenched by addition of NH4Cl(sat.) diluted with EtOAc washed with NaCl(sat.) dried over MgSO4 filtered concentrated purified by ISCO SiO2 chromatography

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

実験手順: To a solution of 1-(3,5-difluorophenyl)ethanone (1.0 equiv) in THF (0.2 M) at 0° C. was added methylmagnesium bromide (1.0 M in THF, 1.15 equiv). After stirring for 4 hours the reaction was quenched by addition of NH4Cl(sat), diluted with EtOAc, washed with NaCl(sat), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield 2-(3,5-difluorophenyl)propan-2-ol. To a solution of 2-(3,5-difluorophenyl)propan-2-ol in CH2Cl2 (0.1 M) at 0° C. was added 2,6 lutidine (6 equiv.) and than triisopropylsilyl trifluoromethanesulfonate (3.0 equiv.). After stirring for 3 hours at 0° C. and six hours at rt the solution was partitioned between EtOAc and NaHCO3(sat), separated, washed with NaCl(sat), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield (2-(3,5-difluorophenyl)propan-2-yloxy)triisopropylsilane. (400 MHz, <cdcl3>) δ ppm 1.05-1.08 (m, 21 H) 1.57 (s, 6 H) 6.63 (s, 1 H) 7.00 (dd, J=9.39, 2.35 Hz, 2 H). was quenched by addition of NH4Cl(sat) diluted with EtOAc washed with NaCl(sat) dried over MgSO4 filtered concentrated purified by ISCO SiO2 chromatography

反応条件: temp:0.00; 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)vinyl]pyrrolidine (freshly prepared before use from 3,5-difluoro acetophenone (Oakwood Products Inc.), pyrrolidine and TiCl4 (1.32 g, 6.32 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.30 g, 6.32 mmol), N,N-diisopropylethylamine (1.1 mL, 6.32 mmol), piperidine (1.0 mL, 10.1 mmol), NEt3 (1.1 mL) and SnCl2 (19 mL of a 2 M soln in DMF). In this example the 2 M SnCl2 solution was added to the reaction mixture at 140° C. Heating was then discontinued and the mixture was allowed to cool to room temperature. The mixture was stirred at room temperature for an additional 48 h. The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant to give 820 mg (40%) of 6-(3,5-difluorophenyl)-2-methyl-4-piperidylpyrrolo[3,2-d]pyrimidine as a brown colored gummy solid. This compound (820 mg, 2.52 mmol) was dissolved in 5:1 EtOAc/MeOH (40 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (2.50 mL, 2.50 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 440 mg (19%) of the title compound as pale yellow colored needles. Mp: >280° C. 1H NMR (DMSO-d6; 500 MHz): δ 1.61 (br s, 6), 2.47 (s, 3), 3.97 (br s, 4), 6.97 (s, 1), 7.28 (tt, 1, J=2.1, 7.1), 7.74 (d, 2, J=6.6), 11.93 (s, 1), 14.35 (s, 1). MS m/z: 329 (M+1 for free base). Anal. Calcd for C18H18F2N4.HCl.H2O: C, 56.47; H, 5.53; N, 14.64; Cl, 9.26. Found: C, 56.52; H, 5.54; N, 14.74; Cl, 9.38. was added to the reaction mixture at 140° C Heating 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:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of (−)-DIP-Cl ((−)-diisopinocampheylboron chloride) (2.67 g, 8.33 mmol, 1.3 eq) in THF (20 mL) kept under inert atmosphere (Ar) and cooled to −27° C. to −25° C., 3′,5′-difluoroacetophenone (1.00 g, 6.40 mmol) was added drop wise over 2 min. The reaction was maintained at this temperature for 17 h. The reaction mixture was then treated with acetaldehyde (0.44 mL, 7.69 mmol, 1.2 eq). Thereafter, the temperature was allowed to reach room temperature and the reaction mixture was stirred at for 7 h. The solvent was then removed in vacuo and the resulting residue was partitioned between water (10 mL) and TBME (tert-butyl-methyl ether) (20 mL). The aqueous phase was extracted again with TBME (20 mL). The organic layer was washed with an aqueous 2 N NaOH solution (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to give a residue, which was purified by two subsequent column chromatographic steps: First by normal phase chromatography (silica gel, heptane/ethyl acetate, v/v=1/0-9/1) followed by a reversed phase chromatography (90 C18-silica gel, acetonitrile for the second one). This gave the title compound (0.40 g, 40%) as a colorless oil with a specific rotation of [α]25D=−26.66 (c=1.054 g/100 mL, CH2Cl2, 589 nm). cooled to −27° C. to −25° C. The reaction was maintained at this temperature for 17 h to reach room temperature The solvent was then removed in vacuo the resulting residue was partitioned between water (10 mL) and TBME (tert-butyl-methyl ether) (20 mL) The aqueous phase was extracted again with TBME (20 mL) The organic layer was washed with an aqueous 2 N NaOH solution (20 mL), brine (20 mL) dried over anhydrous Na2SO4 filtered The solvent was removed in vacuo to give a residue, which was purified by two subsequent column chromatographic steps

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

実験手順: To a stirred solution of (−)-DIP-Cl ((−)-diisopinocampheylboron chloride) (2.67 g, 8.33 mmol, 1.3 eq) in THF (20 mL) kept under inert atmosphere (Ar) and cooled to −27° C. to −25° C., 3′,5′-difluoroacetophenone (1.00 g, 6.40 mmol) was added drop wise over 2 min. The reaction was maintained at this temperature for 17 h. The reaction mixture was then treated with acetaldehyde (0.44 mL, 7.69 mmol, 1.2 eq). Thereafter, the temperature was allowed to reach room temperature and the reaction mixture was stirred at for 7 h. The solvent was then removed in vacuo and the resulting residue was partitioned between water (10 mL) and TBME (tert-butyl-methyl ether) (20 mL). The aqueous phase was extracted again with TBME (20 mL). The organic layer was washed with an aqueous 2 N NaOH solution (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to give a residue, which was purified by two subsequent column chromatographic steps: First by normal phase chromatography (silica gel, heptane/ethyl acetate, v/v=1/0-9/1) followed by a reversed phase chromatography (90 C18-silica gel, acetonitrile for the second one). This gave the title compound (0.40 g, 40%) as a colorless oil with a specific rotation of [α]25D=−26.66 (c=1.054 g/100 mL, CH2Cl2, 589 nm). cooled to −27° C. to −25° C. The reaction was maintained at this temperature for 17 h to reach room temperature The solvent was then removed in vacuo the resulting residue was partitioned between water (10 mL) and TBME (tert-butyl-methyl ether) (20 mL) The aqueous phase was extracted again with TBME (20 mL) The organic layer was washed with an aqueous 2 N NaOH solution (20 mL), brine (20 mL) dried over anhydrous Na2SO4 filtered The solvent was removed in vacuo to give a residue, which was purified by two subsequent column chromatographic steps

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

実験手順: To a colorless stirred solution of 3′,5′-difluoroacetophenone (50.00 g, 320.24 mmol) in methanol (320 mL), sodium borohydride (3.41 g, 86.47 mmol, 0.27 eq) was added portion wise over 20 minutes at room temperature under inert atmosphere (Ar). Then the reaction mixture was stirred for 45 min at room temperature and then quenched carefully by the addition of a saturated aqueous ammonium chloride solution (150 mL). The extraction was carried out with ethyl acetate (2×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to give the title compound (50.29 g, 99%) as a colorless oil. The alcohol was used as such in the subsequent step. quenched carefully by the addition of a saturated aqueous ammonium chloride solution (150 mL) The extraction The combined organic layers were washed with brine (200 mL) dried over anhydrous Na2SO4 filtered The solvent was removed in vacuo

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

実験手順: A solution of 1-(3,5-difluoro-phenyl)-ethanone (156 g, 1 mol, 1 eq) in THF (500 mL) was added dropwise under argon to the commercially available solution of methymagnesium bromide (143 g, 1.2 mol, 1.2 eq) in THF at such a rate that gentle refluxing was maintained. After the addition was complete the reaction mixture was stirred at ambient temperature for an hour and poured into ice-cold aqueous saturated ammonium chloride. Phases were separated and aqueous layer extracted two times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent title compound was purified by distillation under reduced pressure (145 g, 0.84 mol, 84%). that gentle refluxing was maintained After the addition poured into ice-cold aqueous saturated ammonium chloride Phases were separated aqueous layer extracted two times with ethyl acetate The combined organic layers were washed with brine dried over anhydrous magnesium sulfate After removal of the solvent title compound was purified by distillation under reduced pressure (145 g, 0.84 mol, 84%)

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′-difluoroacetophenone (3 g, 19.2 mmol) (Lancaster Synthesis) in dioxane (30 mL) was added dropwise a solution of bromine (3.67 g, 23 mmol) in dioxane (75 mL). After stirring for 10 minutes, the mixture was concentrated in vacuo and the residue was purified by flash chromatography, with 10:2 hexanes/dichloromethane as an eluant, to provide 2-bromo-1-(3,5-difluorophenyl)ethanone as a colorless oil (2.9 g, 64% yield). the mixture was concentrated in vacuo the residue was purified by flash chromatography, with 10:2 hexanes/dichloromethane as an eluant