methyl 3-bromo-4-fluorobenzoate

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: 221 g (1 mole) of 4-fluoro-3-bromobenzoyl fluoride were added dropwise to a mixture of 96 g (3 moles) of methanol and 1 g of pyridine. The reaction mixture was then boiled for a further 2 hours under reflux and was subsequently worked up by distillation. 217 g (93% of theory) of 4-fluoro-3-bromobenzoic acid methyl ester were thus obtained in the form of a colorless oil which solidified when cold and had a boiling point of 124° C./22 mm Hg (melting point 29° to 30° C.). under reflux was subsequently worked up by distillation

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

実験手順: A mixture of 87.6 g (0.38 mole) of 95% pure 4-fluoro-3-bromo-benzoic acid, 200 ml of methanol and 3 ml of sulphuric acid was boiled under for 18 hours. The excess methanol was then distilled off in vacuo, 300 ml of toluene were added and the solution was shaken first with 50 ml of water, then with 50 ml of saturated sodium bicarbonate solution and subsequently with 50 ml of water again. Thereafter, the solvent was distilled off in vacuo and the residue was distilled in vacuo. 86 g (97% of theory) of 4-fluoro-3-bromo-benzoic acid methyl ester were obtained in this manner in the form of a colorless oil which solidified as crystals when cold and had a boiling point of 64° C./0.1 mm Hg. was boiled under for 18 hours The excess methanol was then distilled off in vacuo, 300 ml of toluene were added Thereafter, the solvent was distilled off in vacuo the residue was distilled in vacuo

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

実験手順: First 3.8 g (0.1 mole) of sodium borohydride and then 4.5 g (0.033 mole) of aluminum chloride were added in portions to a solution of 23.3 g (0.1 mole) of 4-fluoro-3-bromobenzoic acid methyl ester in 50 ml of diglyme at 5° C. The mixture was subsequently stirred, without cooling, until the exothermic reaction had ended (a rise in temperature up to about 50° C.) and the reaction was then allowed to go to completion in the course of 1 hour at 100° C. The reaction solution was then poured onto a mixture of 125 ml of icewater and 12 ml of concentrated hydrochloric acid and the benzyl alcohol which had separated out was separated off and distilled in vacuo. 18.7 g (91% of theory) of 4-fluoro-3-bromobenzyl alcohol were obtained in this manner as a colorless oil with a boiling point of 65° to 70° C. (0.1 mbar). "One-pot process" without cooling, until the exothermic reaction up to about 50° C. to go to completion in the course of 1 hour at 100° C the benzyl alcohol which had separated out was separated off distilled in vacuo

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

実験手順: The same operation as in Example (42a) was performed using benzyl cis(±)-[3-methoxypiperidin-4-yl]carbamate obtained in Example (160a) (100 mg, 0.38 mmol), methyl 3-bromo-4-fluorobenzoate (264 mg, 1.13 mmol), palladium acetate (25.5 mg, 0.11 mmol), BINAP (141 mg, 0.23 mmol) and cesium carbonate (370 mg, 1.13 mmol), to obtain 97.4 mg of the title compound as a yellow oily substance. mass spectrum (ESI): m/z 417 (M+H)+.

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: The same operation as in Example (42a) was performed using benzyl cis(±)-[3-methoxypiperidin-4-yl]carbamate obtained in Example (160a) (100 mg, 0.38 mmol), methyl 3-bromo-4-fluorobenzoate (264 mg, 1.13 mmol), palladium acetate (25.5 mg, 0.11 mmol), BINAP (141 mg, 0.23 mmol) and cesium carbonate (370 mg, 1.13 mmol), to obtain 97.4 mg of the title compound as a yellow oily substance. mass spectrum (ESI): m/z 417 (M+H)+.

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 3-bromo-4-fluorobenzoate (Preparation 122, 500 mg, 2.15 mmol), 3,4-dichlorophenol (350 mg, 2.15 mmol) and caesium carbonate (1.4 g, 4.29 mmol) were stirred in dimethylsulfoxide (10 mL). The reaction mixture was heated to 120° C. and stirred overnight under an atmosphere of nitrogen. A 1M aqueous solution of sodium hydroxide was added and the mixture extracted with ethyl acetate. The aqueous phase was acidified and extracted with ethyl acetate. The organic phase from the second extraction was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (30%-100% ethyl acetate in heptane) to afford the title compound as a white solid (244 mg, 31%). the mixture extracted with ethyl acetate extracted with ethyl acetate The organic phase from the second extraction was concentrated in vacuo the resulting residue was purified by silica gel column chromatography (30%-100% ethyl acetate in heptane)

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 3-bromo-4-fluorobenzoate (Preparation 122, 500 mg, 2.15 mmol), 3,4-dichlorophenol (350 mg, 2.15 mmol) and caesium carbonate (1.4 g, 4.29 mmol) were stirred in dimethylsulfoxide (10 mL). The reaction mixture was heated to 120° C. and stirred overnight under an atmosphere of nitrogen. A 1M aqueous solution of sodium hydroxide was added and the mixture extracted with ethyl acetate. The aqueous phase was acidified and extracted with ethyl acetate. The organic phase from the second extraction was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (30%-100% ethyl acetate in heptane) to afford the title compound as a white solid (244 mg, 31%). the mixture extracted with ethyl acetate extracted with ethyl acetate The organic phase from the second extraction was concentrated in vacuo the resulting residue was purified by silica gel column chromatography (30%-100% ethyl acetate in heptane)

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

実験手順: 3-Bromo-4-fluoro-benzoic acid (2.5 g, 11.42 mmol) was placed in a 100 ml round bottom flask charged with a stir bar, sealed with a septum and placed under a nitrogen atmosphere and dissolved in 9 ml dry THF and 3 ml dry MeOH. A 2.0M solution of TMS diazomethane in ether (6.28 ml, 12.56 mmol) was added dropwise to the stirring solution of the acid. Conversion of the acid to the ester was complete after twenty minutes according to LC/MS analysis. The solvent was removed under reduced pressure and product was used without further purification. Recovered a light oil (2.66 g, 100% yield) LC/MS (10-99%) M/Z 234, retention time 3.09 minutes. charged with a stir bar sealed with a septum The solvent was removed under reduced pressure and product was used without further purification