3-fluoro-2-methylphenol

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: 0.65 g (3.69 mmol) of epoxide 2l (a mixture of 2l, 2l', 2l" above) in solution in 3 cm3 of anhydrous DMF were heated to reflux for 3 h; 91% of transposition ketone 6b was then detected by macrobore GC (verification by mass/GC coupling). 0.86 g (2 eq.) of DMAP were then added and the mixture was again heated to reflux for 3 h. It was acidified (pH=1) with 3N HCl, extracted with ether, concentrated, and a 3N sodium hydroxide solution was added to the ether phase (while the mixture was kept stirred for 5 to 10 min), the ether phase was removed and the material was washed once with ether. The aqueous phase was acidified using a solution with 3N HCl (pH=1) and was extracted with ether (4×15 cm3), dried over MgSO4, filtered and evaporated down. The crude product obtained was purified by flash chromatography on silica (eluent: ether/petroleum ether=5/95). 0.10 g of phenol 4h were obtained (macrobore GC purity>97%). The yield of compound 4h was 22%. were heated to reflux for 3 h the mixture was again heated to reflux for 3 h extracted with ether concentrated a 3N sodium hydroxide solution was added to the ether phase (while the mixture was removed the material was washed once with ether was extracted with ether (4×15 cm3) dried over MgSO4 filtered evaporated down The crude product obtained was purified by flash chromatography on silica (eluent: ether/petroleum ether=5/95)

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 2.19 g (17.36 mmol) of 3-fluoro-2-methylphenol in 87 mL of anhydrous acetonitrile was added 12.1 g (126.73 mmol) of MgCI2 portionwise followed by addition of 9.0 mL (64.93 mmol) of TEA to afford a pinkish reaction mixture. To this mixture was added 3.8 g (126.73 mmol) of paraformaldehyde and the resulting yellow colored mixture was heated to relux for 4 hours. After cooling to room temperature, to the mixture was added 5% HCl slowly. The reaction was extracted with EtOAc (3×), washed with satd NaCl (3×), dried over MgSO4, filtered, and concd to afford an oil, which was purified by silica gel chromatography with EtOAc/hexane (1:9) to afford 2.02 g (75%) of a pale tan oil which later solidified: 1H NMR (CDCl3/400 MHz) 2.14 (d, 3H, J=1.6 Hz), 6.68 (t, 1 H, J=8.8 Hz), 7.37 (dd, 1H, J=6.4, 8.4 Hz), 9.78 (s, 1H), 11.59 (d, 1H, J=2.0 Hz); HRMS (EI+) m/z calcd for (C8H7FO2) 154.0430, found 154.0428. to afford a pinkish reaction mixture the resulting yellow colored mixture was heated The reaction was extracted with EtOAc (3×) washed with satd NaCl (3×) dried over MgSO4 filtered concd to afford an oil, which was purified by silica gel chromatography with EtOAc/hexane (1:9)

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

実験手順: To 2.19 g (17.36 mmol) of 3-fluoro-2-methylphenol in 87 mL of anhydrous acetonitrile was added 12.1 g (126.73 mmol) of MgCI2 portionwise followed by addition of 9.0 mL (64.93 mmol) of TEA to afford a pinkish reaction mixture. To this mixture was added 3.8 g (126.73 mmol) of paraformaldehyde and the resulting yellow colored mixture was heated to relux for 4 hours. After cooling to room temperature, to the mixture was added 5% HCl slowly. The reaction was extracted with EtOAc (3×), washed with satd NaCl (3×), dried over MgSO4, filtered, and concd to afford an oil, which was purified by silica gel chromatography with EtOAc/hexane (1:9) to afford 2.02 g (75%) of a pale tan oil which later solidified: 1H NMR (CDCl3/400 MHz) 2.14 (d, 3H, J=1.6 Hz), 6.68 (t, 1 H, J=8.8 Hz), 7.37 (dd, 1H, J=6.4, 8.4 Hz), 9.78 (s, 1H), 11.59 (d, 1H, J=2.0 Hz); HRMS (EI+) m/z calcd for (C8H7FO2) 154.0430, found 154.0428. to afford a pinkish reaction mixture the resulting yellow colored mixture was heated The reaction was extracted with EtOAc (3×) washed with satd NaCl (3×) dried over MgSO4 filtered concd to afford an oil, which was purified by silica gel chromatography with EtOAc/hexane (1:9)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The 5.0 g (23.78 mmol) of 2-(3-fluoro-2-methylphenoxy)tetrahydro-2H-pyran was dissolved in 120 mL of methanol followed by addition of 3.21 g (35.67 mmol) of oxalic acid. The mixture was heat to 60° C. for 2 hours. The volatiles were removed in vacuo while maintaining a bath temperature of <29° C. to afford an oil, which was purified by silica gel chromatography with EtOAc/hexane (1:9). Concentration of the desired fractions afforded 2.19 g (73%) of a pale yellow oil, which later solidified upon standing: 1H NMR(CDCl3/400 MHz) 2.16 (d, 3H, J=2.0 Hz), 5.17 (s, 1H), 6.57 (d, 1H, J=8.4 Hz), 6.64 (t, 1H, J=8.8 hz), 7.00 (dd, 1H, J=8.4, 14.8 Hz); HRMS (EI+) m/z calcd for (C7H7FO) 126.0481, found 126.0470. The volatiles were removed in vacuo while maintaining a bath temperature of <29° C. to afford an oil, which was purified by silica gel chromatography with EtOAc/hexane (1:9)

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

実験手順: 0.65 g (3.69 mmol) of epoxide 2l (a mixture of 2l, 2l', 2l" above) in solution in 3 cm3 of anhydrous DMF were heated to reflux for 3 h; 91% of transposition ketone 6b was then detected by macrobore GC (verification by mass/GC coupling). 0.86 g (2 eq.) of DMAP were then added and the mixture was again heated to reflux for 3 h. It was acidified (pH=1) with 3N HCl, extracted with ether, concentrated, and a 3N sodium hydroxide solution was added to the ether phase (while the mixture was kept stirred for 5 to 10 min), the ether phase was removed and the material was washed once with ether. The aqueous phase was acidified using a solution with 3N HCl (pH=1) and was extracted with ether (4×15 cm3), dried over MgSO4, filtered and evaporated down. The crude product obtained was purified by flash chromatography on silica (eluent: ether/petroleum ether=5/95). 0.10 g of phenol 4h were obtained (macrobore GC purity>97%). The yield of compound 4h was 22%. were heated to reflux for 3 h the mixture was again heated to reflux for 3 h extracted with ether concentrated a 3N sodium hydroxide solution was added to the ether phase (while the mixture was removed the material was washed once with ether was extracted with ether (4×15 cm3) dried over MgSO4 filtered evaporated down The crude product obtained was purified by flash chromatography on silica (eluent: ether/petroleum ether=5/95)

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

実験手順: 0.65 g (3.69 mmol) of epoxide 2l (a mixture of 2l, 2l', 2l" above) in solution in 3 cm3 of anhydrous DMF were heated to reflux for 3 h; 91% of transposition ketone 6b was then detected by macrobore GC (verification by mass/GC coupling). 0.86 g (2 eq.) of DMAP were then added and the mixture was again heated to reflux for 3 h. It was acidified (pH=1) with 3N HCl, extracted with ether, concentrated, and a 3N sodium hydroxide solution was added to the ether phase (while the mixture was kept stirred for 5 to 10 min), the ether phase was removed and the material was washed once with ether. The aqueous phase was acidified using a solution with 3N HCl (pH=1) and was extracted with ether (4×15 cm3), dried over MgSO4, filtered and evaporated down. The crude product obtained was purified by flash chromatography on silica (eluent: ether/petroleum ether=5/95). 0.10 g of phenol 4h were obtained (macrobore GC purity>97%). The yield of compound 4h was 22%. were heated to reflux for 3 h the mixture was again heated to reflux for 3 h extracted with ether concentrated a 3N sodium hydroxide solution was added to the ether phase (while the mixture was removed the material was washed once with ether was extracted with ether (4×15 cm3) dried over MgSO4 filtered evaporated down The crude product obtained was purified by flash chromatography on silica (eluent: ether/petroleum ether=5/95)

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

実験手順: 0.65 g (3.69 mmol) of epoxide 2l (a mixture of 2l, 2l', 2l" above) in solution in 3 cm3 of anhydrous DMF were heated to reflux for 3 h; 91% of transposition ketone 6b was then detected by macrobore GC (verification by mass/GC coupling). 0.86 g (2 eq.) of DMAP were then added and the mixture was again heated to reflux for 3 h. It was acidified (pH=1) with 3N HCl, extracted with ether, concentrated, and a 3N sodium hydroxide solution was added to the ether phase (while the mixture was kept stirred for 5 to 10 min), the ether phase was removed and the material was washed once with ether. The aqueous phase was acidified using a solution with 3N HCl (pH=1) and was extracted with ether (4×15 cm3), dried over MgSO4, filtered and evaporated down. The crude product obtained was purified by flash chromatography on silica (eluent: ether/petroleum ether=5/95). 0.10 g of phenol 4h were obtained (macrobore GC purity>97%). The yield of compound 4h was 22%. were heated to reflux for 3 h the mixture was again heated to reflux for 3 h extracted with ether concentrated a 3N sodium hydroxide solution was added to the ether phase (while the mixture was removed the material was washed once with ether was extracted with ether (4×15 cm3) dried over MgSO4 filtered evaporated down The crude product obtained was purified by flash chromatography on silica (eluent: ether/petroleum ether=5/95)

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

実験手順: From the compound of step 3 (50 mg, 112 μmol), the title compound was prepared analogously as described in example 1, step 2, using 3-fluoro-2-methylphenol. Yield: 11 mg.

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

実験手順: The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-fluoro-2-methylphenol: 1H-NMR (CDCl3) δ 8.57 (1H, d, J=2.3 Hz), 8.14 (1H, d, J=7.5 Hz), 8.10 (1H, d, J=2.3 Hz), 8.00 (2H, d, J=8.3 Hz), 7.43 (2H, d, J=8.3 Hz), 7.25 (1H, m), 7.03 (1H, t, J=8.3 Hz), 6.91 (1H, d, J=8.1 Hz), 5.40 (1H, m), 3.90 (3H, s), 2.06 (3H, s), 1.60 (3H, d, J=7.5 Hz).