2,3,5,6-tetrafluorophenol

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: Potassium fluoride (2.8 g) was added portionwise to a stirred solution of (S)-3-benzyloxycarbonylamino-5-bromo-4-oxo-pentanoic acid tert-butyl ester (18.6 g) and 2,3,5,6-tetrafluorophenol (9.3 g) in anhydrous DMF (250 mL) under nitrogen at room temperature. The mixture was then stirred for 18 hours before being quenched with ethyl acetate and water. The organic layer was removed and washed with sodium bicarbonate solution, dried (magnesium sulfate) and concentrated to give the sub-title product as an off-white solid (21.1 g, 96%). 1H NMR (400 MHz, CDCl3) δ 1.43 (9H, s), 2.76 (1H, dd), 3.06 (1H, dd), 4.67-4.71 (1H, m), 5.12 (1 h, d), 5.22 (1H, d), 5.86 (1H, d), 7.35-7.38 (5H, m) ppm; 19F NMR (376 MHz, CDCl3) (proton decoupled) δ −139.98, −140.00, −140.04, −140.06, −157.05, −157.07, −157.11, −157.13; MS ES (+) 486.23 (M+H). before being quenched with ethyl acetate and water The organic layer was removed washed with sodium bicarbonate solution dried (magnesium sulfate) concentrated

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

実験手順: Potassium fluoride (2.8 g) was added portionwise to a stirred solution of (S)-3-benzyloxycarbonylamino-5-bromo-4-oxo-pentanoic acid tert-butyl ester (18.6 g) and 2,3,5,6-tetrafluorophenol (9.3 g) in anhydrous DMF (250 mL) under nitrogen at room temperature. The mixture was then stirred for 18 hours before being quenched with ethyl acetate and water. The organic layer was removed and washed with sodium bicarbonate solution, dried (magnesium sulfate) and concentrated to give the sub-title product as an off-white solid (21.1 g, 96%). 1H NMR (400 MHz, CDCl3) δ 1.43 (9H, s), 2.76 (1H, dd), 3.06 (1H, dd), 4.67-4.71 (1H, m), 5.12 (1 h, d), 5.22 (1H, d), 5.86 (1H, d), 7.35-7.38 (5H, m) ppm; 19F NMR (376 MHz, CDCl3) (proton decoupled) δ −139.98, −140.00, −140.04, −140.06, −157.05, −157.07, −157.11, −157.13; MS ES (+) 486.23 (M+H). before being quenched with ethyl acetate and water The organic layer was removed washed with sodium bicarbonate solution dried (magnesium sulfate) concentrated

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

実験手順: In scheme II above, the following abbreviations are used: KF is potassium fluoride; DMF is N,N-dimethylformamide; Ar2OH is either 2,3,5,6-tetrafluorophenol, 2,4,6-trifluorophenol or 2,3,6-trifluorophenol; THF is tetahydrofuran; MeOH is methanol. Commercially available bromoketone D is reacted with the appropriately substituted fluorophenol and potassium fluoride to give phenoxy ketone E. The ketone is then reduced with sodium borohydride to give the alcohol F, which is hydrogenated using palladium on carbon as catalyst to give the amino alcohol B′ (Ar2=fluoro-substituted phenyl).

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

実験手順: Potassium fluoride (2.8 g), was added portionwise to a stirred solution of (S)-3-benzyloxycarbonylamino-5-bromo-4-oxo-pentanoic acid tert-butyl ester (18.6 g) and 2,3,5,6-tetrafluorophenol (9.3 g) in anhydrous DMF (250 mL) under nitrogen at room temperature. The mixture was then stirred for 18 hours before being quenched with ethyl acetate and water. The organic layer was removed and washed with sodium bicarbonate solution, dried (magnesium sulfate) and concentrated to give the sub-title product as an off-white solid (21.1 g, 96%); 1H NMR (400 MHz, CDCl3) δ 1.43 (9H, s), 2.76 (1H, dd), 3.06 (1H, dd), 4.67-4.71 (1H, m), 5.12 (1h, d), 5.22 (1H, d), 5.86 (1H, d), 7.35-7.38 (5H, m); 19F NMR (376 MHz, CDCl3) (proton decoupled) δ −139.98, −140.00, −140.04, −140.06, −157.05, −157.07, −157.11, −157.13; MS ES (+) 486.23 (M+H). before being quenched with ethyl acetate and water The organic layer was removed washed with sodium bicarbonate solution dried (magnesium sulfate) concentrated

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

実験手順: The titled product was prepared as described in Example 82 using N-[(1-methyl-3-isobutyl-indole-2-carbonyl)cyclohexylalaninyl]-3-amino-5-bromo-4-oxo-pentanoic acid, tert-butyl ester (50.8 mg, 0.08 mmol), potassium fluoride (12.0 mg, 0.21 mmol), and 2,3,5,6-tetrafluorophenol (13.3 mg, 0.08 mmol) in DMF (2.0 ml). TLC (hexane/EtOAc, 3/1): Rf=0.25.

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

実験手順: The titled product (47.6 mg, 72%, white solid) was prepared as described in Example 82 using the product of Example 88 (57.6 mg, 0.097 mmol), potassium fluoride (18.5 mg, 0.24 mmol), and 2,3,5,6-tetrafluorophenol (21.1 mg, 0.097 mmol) in DMF (2.0 ml). TLC (hexane/EtOAc, 50/50): Rf=0.55.

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

実験手順: The titled product (47.6 mg, 72%, white solid) was prepared as described in Example 82 using the product of Example 88 (57.6 mg, 0.097 mmol), potassium fluoride (18.5 mg, 0.24 mmol), and 2,3,5,6-tetrafluorophenol (21.1 mg, 0.097 mmol) in DMF (2.0 ml). TLC (hexane/EtOAc, 50/50): Rf=0.55.

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

実験手順: Potassium fluoride (21.6 mg, 0.37 mmol) was added to a solution of N-[(1-methyl-3-isobutyl-indole-2-carbonyl)valinyl]-3-amino-5-bromo-4-oxo-pentanoic acid, tert-butyl ester (86.1 mg, 0.149 mmol) and 2,3,5, 6-tetrafluorophenol (27.0 mg, 0.163 mmol) in DMF (2.0 ml). After stirring at room temperature for 3 hours, the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layers were combined, washed with saturated NaHCO3 solution, and brine, dried over sodium sulfate, and concentrated. The residue was triturated with ether to give the titled product, N-(1-methyl-3-isobutyl-indole-2-carbonyl)-valinyl-3-amino-4-oxo-5-(2,3,5,6-tetral]uorophenyloxy)-pentanoic acid, tert-butyl ester as a white solid (43.8 mg, 44%). TLC (hexane/EtOAc, 50/50): Rf=0.50. the reaction mixture was partitioned between ethyl acetate and water The aqueous layer was back-extracted with ethyl acetate washed with saturated NaHCO3 solution, and brine dried over sodium sulfate concentrated The residue was triturated with ether

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

実験手順: Potassium fluoride (21.6 mg, 0.37 mmol) was added to a solution of N-[(1-methyl-3-isobutyl-indole-2-carbonyl)valinyl]-3-amino-5-bromo-4-oxo-pentanoic acid, tert-butyl ester (86.1 mg, 0.149 mmol) and 2,3,5, 6-tetrafluorophenol (27.0 mg, 0.163 mmol) in DMF (2.0 ml). After stirring at room temperature for 3 hours, the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layers were combined, washed with saturated NaHCO3 solution, and brine, dried over sodium sulfate, and concentrated. The residue was triturated with ether to give the titled product, N-(1-methyl-3-isobutyl-indole-2-carbonyl)-valinyl-3-amino-4-oxo-5-(2,3,5,6-tetral]uorophenyloxy)-pentanoic acid, tert-butyl ester as a white solid (43.8 mg, 44%). TLC (hexane/EtOAc, 50/50): Rf=0.50. the reaction mixture was partitioned between ethyl acetate and water The aqueous layer was back-extracted with ethyl acetate washed with saturated NaHCO3 solution, and brine dried over sodium sulfate concentrated The residue was triturated with ether