2-bromo-1-(2,4-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: To a solution of example 14B (0.21 g, 0.75 mmol) in ethanol (10 mL) was added 2-bromo-1-(2,4-difluorophenyl)ethanone (0.18 g, 0.75 mmol). The mixture was heated to reflux for 3 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M aqueous NaHCO3, dried (Na2SO4), filtered and concentrated. Purification by preparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile:ammonium acetate (10 mM) over 15 minutes at a flow rate of 70 mL/minutes provided 65 mg (20%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.47-1.64 (m, 4 H), 1.68-1.84 (m, 4 H), 2.05-2.20 (m, J=11.5 Hz, 2 H), 2.27 (s, 2 H), 2.58 (t, J=6.6 Hz, 1 H), 3.03 (s, 3 H), 3.52 (t, J=5.6 Hz, 2 H), 4.07 (t, J=5.4 Hz, 2 H), 6.99 (s, 1 H), 7.18-7.34 (m, 1 H), 7.48 (td, J=9.7, 2.5 Hz, 1 H), 7.60 (td, J=8.6, 6.6 Hz, 1 H); MS (ESI+) m/z 419 (M+H)+; Anal. Calculated for C22H24F2N2O2S: C, 63.14; H, 5.78; N, 6.69. Found: C, 63.18; H, 5.80; N, 6.72. The mixture was heated to reflux for 3 hours concentrated under reduced pressure The residue was dissolved in ethyl acetate washed with 1 M aqueous NaHCO3 dried (Na2SO4) filtered concentrated Purification by preparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size)

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

実験手順: To a solution of example 14B (0.21 g, 0.75 mmol) in ethanol (10 mL) was added 2-bromo-1-(2,4-difluorophenyl)ethanone (0.18 g, 0.75 mmol). The mixture was heated to reflux for 3 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M aqueous NaHCO3, dried (Na2SO4), filtered and concentrated. Purification by preparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile:ammonium acetate (10 mM) over 15 minutes at a flow rate of 70 mL/minutes provided 65 mg (20%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.47-1.64 (m, 4 H), 1.68-1.84 (m, 4 H), 2.05-2.20 (m, J=11.5 Hz, 2 H), 2.27 (s, 2 H), 2.58 (t, J=6.6 Hz, 1 H), 3.03 (s, 3 H), 3.52 (t, J=5.6 Hz, 2 H), 4.07 (t, J=5.4 Hz, 2 H), 6.99 (s, 1 H), 7.18-7.34 (m, 1 H), 7.48 (td, J=9.7, 2.5 Hz, 1 H), 7.60 (td, J=8.6, 6.6 Hz, 1 H); MS (ESI+) m/z 419 (M+H)+; Anal. Calculated for C22H24F2N2O2S: C, 63.14; H, 5.78; N, 6.69. Found: C, 63.18; H, 5.80; N, 6.72. The mixture was heated to reflux for 3 hours concentrated under reduced pressure The residue was dissolved in ethyl acetate washed with 1 M aqueous NaHCO3 dried (Na2SO4) filtered concentrated Purification by preparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size)

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

実験手順: Sodium borohydride (0.367 g, 10.85 mmol) was added to a stirred solution of 2-bromo-2′,4′-difluoroacetophenone ([CAS 102429-07-2], 5.1 g, 21.7 mmol) in MeOH (152 mL) at 10° C. The mixture was stirred at RT for 1 h. Then, K2CO3 (4.499 g, 32.55 mmol) was added and the mixture was stirred at RT for 1 h. The mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The residue was treated with water and extracted with CH2Cl2/THF. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield I-19 (2.24 g, 66%) as a yellow oil. the mixture was stirred at RT for 1 h The mixture was filtered through diatomaceous earth the filtrate was concentrated in vacuo The residue was treated with water extracted with CH2Cl2/THF The organic layer was separated dried (Na2SO4) filtered the solvents evaporated in vacuo to yield I-19 (2.24 g, 66%) as a yellow oil

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

実験手順: Sodium borohydride (0.367 g, 10.85 mmol) was added to a stirred solution of 2-bromo-2′,4′-difluoroacetophenone ([CAS 102429-07-2], 5.1 g, 21.7 mmol) in MeOH (152 mL) at 10° C. The mixture was stirred at RT for 1 h. Then, K2CO3 (4.499 g, 32.55 mmol) was added and the mixture was stirred at RT for 1 h. The mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The residue was treated with water and extracted with CH2Cl2/THF. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield I-19 (2.24 g, 66%) as a yellow oil. the mixture was stirred at RT for 1 h The mixture was filtered through diatomaceous earth the filtrate was concentrated in vacuo The residue was treated with water extracted with CH2Cl2/THF The organic layer was separated dried (Na2SO4) filtered the solvents evaporated in vacuo to yield I-19 (2.24 g, 66%) as a yellow oil

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

実験手順: To a solution of example 14B (0.21 g, 0.75 mmol) in ethanol (10 mL) was added 2-bromo-1-(2,4-difluorophenyl)ethanone (0.18 g, 0.75 mmol). The mixture was heated to reflux for 3 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M aqueous NaHCO3, dried (Na2SO4), filtered and concentrated. Purification by preparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile:ammonium acetate (10 mM) over 15 minutes at a flow rate of 70 mL/minutes provided 65 mg (20%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.47-1.64 (m, 4 H), 1.68-1.84 (m, 4 H), 2.05-2.20 (m, J=11.5 Hz, 2 H), 2.27 (s, 2 H), 2.58 (t, J=6.6 Hz, 1 H), 3.03 (s, 3 H), 3.52 (t, J=5.6 Hz, 2 H), 4.07 (t, J=5.4 Hz, 2 H), 6.99 (s, 1 H), 7.18-7.34 (m, 1 H), 7.48 (td, J=9.7, 2.5 Hz, 1 H), 7.60 (td, J=8.6, 6.6 Hz, 1 H); MS (ESI+) m/z 419 (M+H)+; Anal. Calculated for C22H24F2N2O2S: C, 63.14; H, 5.78; N, 6.69. Found: C, 63.18; H, 5.80; N, 6.72. The mixture was heated to reflux for 3 hours concentrated under reduced pressure The residue was dissolved in ethyl acetate washed with 1 M aqueous NaHCO3 dried (Na2SO4) filtered concentrated Purification by preparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size)

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 2-bromo-1-(2,4-difluorophenyl)ethanone (5.0 g, 21.3 mmol) and potassium thiocyanate (2.07 g, 21.3 mmol) in ethanol (50 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture. A crystal was collected by filtration and washed with 50% aqueous ethanol to give 3.39 g (74.7%) of the desired product as a solid. A crystal was collected by filtration washed with 50% aqueous ethanol

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-bromo-1-(2,4-difluorophenyl)ethanone (107.31 g, 442.89 mmol) and 3-chloropyrazin-2-amine (98.00 g, 756.5 mmol) in ACN (800 mL) was stirred at reflux for about 20 h. The reaction mixture was cooled to about 25° C. before the resultant solid was collected. The filtrate solvent was removed in vacuo to yield a brown solid. This filtration was done to negate the bumping associated with the removal of the ACN. The combined solids were then suspended in water (750 mL) and basified, whilst stirring, with 2N NaOH (750 mL). After about 30 min, the product was partitioned between DCM (9×1000 mL) and filtered from the insoluble material to aid extraction process. The organic extracts were combined and stirred with 2.5N HCl (4×750 mL). The organic layer was finally washed with 2.0N NaOH (500 mL) and water (2×500 mL), dried over MgSO4, and filtered through a Florisil® pad (3 inch diameter×3 inch depth) to remove origin material. The Florisil® pad was washed with repeated amounts of solvent until no product was detected by TLC. The organic solvent was removed in vacuo to yield a yellow solid. The solid was suspended in IPA (200 mL) at about 80° C. for about 15 min and then cooled to about 20° C. The solid was collected and washed with ice-cold IPA (2×40 mL), followed by petroleum ether [bp 30-60° C.] (3×80 mL) to remove impurities. The solid was dried in vacuo at about 70° C. overnight to yield the title compound as a yellow powdery solid (69.75 g, 57%): LC/MS (Table 1, Method g) Rt=2.70 min; MS m/z: 266.1 (M+H)+. at reflux for about 20 h was collected The filtrate solvent was removed in vacuo to yield a brown solid This filtration bumping associated with the removal of the ACN whilst stirring, with 2N NaOH (750 mL) the product was partitioned between DCM (9×1000 mL) filtered from the insoluble material extraction process stirred with 2.5N HCl (4×750 mL) The organic layer was finally washed with 2.0N NaOH (500 mL) and water (2×500 mL) dried over MgSO4 filtered through a Florisil® pad (3 inch diameter×3 inch depth) to remove origin material The Florisil® pad was washed with repeated amounts of solvent until no product The organic solvent was removed in vacuo to yield a yellow solid cooled to about 20° C The solid was collected washed with ice-cold IPA (2×40 mL) to remove impurities The solid was dried in vacuo at about 70° C. overnight

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-bromo-1-(2,4-difluorophenyl)ethanone (107.31 g, 442.89 mmol) and 3-chloropyrazin-2-amine (98.00 g, 756.5 mmol) in ACN (800 mL) was stirred at reflux for about 20 h. The reaction mixture was cooled to about 25° C. before the resultant solid was collected. The filtrate solvent was removed in vacuo to yield a brown solid. This filtration was done to negate the bumping associated with the removal of the ACN. The combined solids were then suspended in water (750 mL) and basified, whilst stirring, with 2N NaOH (750 mL). After about 30 min, the product was partitioned between DCM (9×1000 mL) and filtered from the insoluble material to aid extraction process. The organic extracts were combined and stirred with 2.5N HCl (4×750 mL). The organic layer was finally washed with 2.0N NaOH (500 mL) and water (2×500 mL), dried over MgSO4, and filtered through a Florisil® pad (3 inch diameter×3 inch depth) to remove origin material. The Florisil® pad was washed with repeated amounts of solvent until no product was detected by TLC. The organic solvent was removed in vacuo to yield a yellow solid. The solid was suspended in IPA (200 mL) at about 80° C. for about 15 min and then cooled to about 20° C. The solid was collected and washed with ice-cold IPA (2×40 mL), followed by petroleum ether [bp 30-60° C.] (3×80 mL) to remove impurities. The solid was dried in vacuo at about 70° C. overnight to yield the title compound as a yellow powdery solid (69.75 g, 57%): LC/MS (Table 1, Method g) Rt=2.70 min; MS m/z: 266.1 (M+H)+. at reflux for about 20 h was collected The filtrate solvent was removed in vacuo to yield a brown solid This filtration bumping associated with the removal of the ACN whilst stirring, with 2N NaOH (750 mL) the product was partitioned between DCM (9×1000 mL) filtered from the insoluble material extraction process stirred with 2.5N HCl (4×750 mL) The organic layer was finally washed with 2.0N NaOH (500 mL) and water (2×500 mL) dried over MgSO4 filtered through a Florisil® pad (3 inch diameter×3 inch depth) to remove origin material The Florisil® pad was washed with repeated amounts of solvent until no product The organic solvent was removed in vacuo to yield a yellow solid cooled to about 20° C The solid was collected washed with ice-cold IPA (2×40 mL) to remove impurities The solid was dried in vacuo at about 70° C. overnight

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

実験手順: A mixture of 2-bromo-1-(2,4-difluorophenyl)ethanone (150 g, 640 mmol, Example #8, Step A), pyrrolidin-2-imine hydrochloride (108 g, 894 mmol) and Na2CO3 (134 mL, 3190 mmol) in DMF (650 mL) was stirred and heated at about 80° C. in a 3 L 3 necked flask for about 24 h. The mixture was cooled to ambient temperature and poured into water (about 5 L). The product was partitioned between EtOAc (800 mL) and the basic aqueous phase. The aqueous layer was extracted with additional EtOAc (3×800 mL). The combined organic extracts were washed with water (4×800 mL), dried over MgSO4 and filtered through a pad of Florisil® (2″ depth×3″ diameter). The pad was washed with EtOAc (4×250 mL) and the filtrate was concentrated to dryness under reduced pressure to yield the title compound as a solid (98.6 g, 70%): LC/MS (Table 1, Method a) Rt=2.72 min; MS m/z: 221.0 (M+H)+. The product was partitioned between EtOAc (800 mL) The aqueous layer was extracted with additional EtOAc (3×800 mL) The combined organic extracts were washed with water (4×800 mL) dried over MgSO4 filtered through a pad of Florisil® (2″ depth×3″ diameter) The pad was washed with EtOAc (4×250 mL) the filtrate was concentrated to dryness under reduced pressure

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The 2-bromo-1-(2,4-difluorophenyl)ethanone (7.50 g, 31.9 mmol) and thiazol-2-amine (3.20 g, 31.9 mmol) were added to EtOH (85 mL) and then heated to about 85° C. in an oil bath for about 16 h. The mixture was cooled in ice water, filtered, and washed with EtOH. Drying under vacuum at about 60° C. provided the title compound (5.84 g, 77%): LC/MS (Table 1, Method a) Rt=2.68 min; MS m/z: 237.3 (M+H)+. filtered washed with EtOH Drying under vacuum at about 60° C.