methyl 3-fluoro-4-hydroxybenzoate

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 a solution of 3-fluoro-4-hydroxybenzoic acid methyl ester (1.0 g) in THF (10 mL) was added N-bromosuccinimide (1.26 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours The reaction solution was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1, v/v) to give the title compound (1.16 g). (In the above, THF is tetrahydrofuran) cooling washed successively with saturated aqueous sodium bicarbonate and saturated brine dried over anhydrous sodium sulfate concentrated The residue was purified by column chromatography on silica gel (hexane

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-fluoro-4-hydroxybenzoic acid (3.0 g) in methanol (30 mL) was added conc. sulfuric acid (3 mL), and the mixture was heated for 5 hours under reflux. The reaction solution was allowed to stand for cooling down to room temperature, and then concentrated in vacuo. The residue was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (2.99 g). the mixture was heated for 5 hours under reflux concentrated in vacuo The residue was diluted with ethyl acetate washed successively with water, saturated aqueous sodium bicarbonate, water, and saturated brine dried over anhydrous sodium sulfate concentrated

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 in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 3-fluoro-4-hydroxy benzoic acid methyl ester (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White foam (81%). MS (Turbo Spray): m/z=543.0 [M+H].

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

実験手順: (Step A: To a solution of (R)-tert-butyl 4-(3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (Preparation D; 2 g, 5.5 mmol) in DMF (20 mL) was added potassium carbonate (0.99 g, 7.2 mmol) and methyl 3-fluoro-4-hydroxybenzoate (1.1 g, 6.6 mmol) and the reaction was heated to 60° C. overnight. The reaction was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with 1 N NaOH (20 mL), and brine (20 mL), dried over MgSO4, filtered and concentrated under vacuum to give (S)-tert-butyl 4-(3-(2-fluoro-4-(methoxycarbonyl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2 g, 83%). extracted with EtOAc (100 mL) The organic layer was washed with 1 N NaOH (20 mL), and brine (20 mL) dried over MgSO4 filtered concentrated under vacuum

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (R)-tert-butyl 4-(3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (Preparation D; 1.0 g, 2.8 mmol) was dissolved in dry DMSO (15 mL) and methyl 3-fluoro-4-hydroxybenzoate (0.56 g, 3.3 mmol) and K2CO3 (0.46 g, 3.3 mmol) were added and the reaction heated to 70° C. under nitrogen. The reaction became purple and then black. The reaction was cooled to ambient temperature after 3 hours, stirred at ambient temperature overnight, partitioned between water and EtOAc, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (60% EtOAc in hexanes) to afford (S)-tert-butyl 4-(3-(2-fluoro-4-(methoxycarbonyl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.2 g, 2.7 mmol, 100% yield) as a white solid. The reaction was cooled to ambient temperature after 3 hours partitioned between water and EtOAc extracted with EtOAc washed with brine dried over Na2SO4 filtered concentrated The residue was purified over silica gel (60% EtOAc in hexanes)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a round bottom flask containing 3-fluoro-4-hydroxybenzoic acid (5.03 g, 32.22 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) was added a cold solution of MeOH (50.0 mL) and sulfuric acid (2.0 mL). The mixture was heated to 80° C. and monitored with TLC. After 20.5 hours, the solvent was removed and the mixture was diluted with diethyl ether. The organic phase was washed carefully twice with saturated aqueous NaHCO3 and once with brine. The organic phase was then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to afford T33.1 as a white solid (4.79 g, 87% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.81 (2H, m), 7.06 (1H, t, J=8.4 Hz), 5.62 (1H, d, J=4.3 Hz), 3.91 (3H, s). the solvent was removed the mixture was diluted with diethyl ether The organic phase was washed carefully twice with saturated aqueous NaHCO3 and once with brine The organic phase was then dried over anhydrous sodium sulfate After filtration the organic solvent was removed in vacuo

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a round bottom flask containing 3-fluoro-4-hydroxybenzoic acid (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (5.03 g, 32.22 mmol) was added a cold solution of MeOH (50.0 mL) and sulfuric acid (2.0 mL). The mixture was heated to 80° C. and monitored with TLC. After 20.5 hours, the solvent was removed and the resulting mixture was diluted with diethyl ether. The organic phase was washed carefully two times with saturated aqueous NaHCO3, once with brine, and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to afford T10.1 as a white solid (4.79 g, 87% yield). 1H NMR (400 MHz, CDCl3) 7.81 (2H, m), 7.06 (1H, t, J=8.4 Hz), 5.62 (1H, d, J=4.3 Hz), 3.91 (3H, s). the solvent was removed the resulting mixture was diluted with diethyl ether The organic phase was washed carefully two times with saturated aqueous NaHCO3 once with brine, and then dried over anhydrous sodium sulfate After filtration the organic solvent was removed in vacuo

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir: