methyl 2-(4-fluorophenyl)acetate

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:

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

実験手順: A catalytic amount (0.5 mL) of concentrated sulfuric acid was added to a solution of 4-fluorophenylacetic acid (30.8 g, 0.20 mol) in 500 mL of methanol. The solution was stirred at reflux for 4 hours. The volatile materials were removed under reduced pressure to furnish a colorless oil which was dissolved in ether/ethyl acetate and washed with 2 N aqueous Na2CO3, brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide an oil which was dried overnight under high vacuum (yield: 33.6 g; 95%). 1H NMR (300 MHz, CDCl3) δ 3.59 (s, 2H), 3.65 (s, 3H), 7.01 (t, J=9 Hz, 2H), 7.20-7.28 (m, 2H). MS (DCI/NH3) m/z 186 (M+NH4)+. at reflux for 4 hours The volatile materials were removed under reduced pressure to furnish a colorless oil which washed with 2 N aqueous Na2CO3, brine dried over MgSO4 filtered The filtrate was concentrated under reduced pressure to provide an oil which was dried overnight under high vacuum (yield: 33.6 g; 95%)

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

実験手順: To a solution of 10.8 g of 60% sodium hydride in 400 mL of tetrahydrofuran was added 44.7 g of methyl 4-fluorophenylacetate dropwise. Then, 50 g of 3-fluorobenzyl bromide was added dropwise. The mixture was then heated to reflux for approximately 18 hours. After this time, the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ether and 5% aqueous sodium bicarbonate, and the ether extracts were dried over magnesium sulfate and concentrated to 77.57 g of a yellow oil. The crude product was combined with 275 mL of methanol, 20 mL of 50% aqueous NaOH and 50 mL of H2O and the mixture was refluxed for about 18 hours. The reaction was then cooled to room temperature, concentrated and partitioned between water and ether. The aqueous extracts were made acidic with concentrated HCl and extracted with ether. The ether extracts were dried over MgSO4, filtered, concentrated and the crude product was triturated with hexane to afford 43.62 g of a white solid; mp 92°-94° C. The mixture was then heated to reflux for approximately 18 hours filtered The filtrate was partitioned between ether and 5% aqueous sodium bicarbonate the ether extracts were dried over magnesium sulfate concentrated to 77.57 g of a yellow oil the mixture was refluxed for about 18 hours The reaction was then cooled to room temperature concentrated partitioned between water and ether extracted with ether The ether extracts were dried over MgSO4 filtered concentrated the crude product was triturated with hexane

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

実験手順: To a cold (−78° C.) solution of lithium diisopropylamide (21.4 mL of 2M solution in THF, 42.8 mmol) in THF (70 mL) is added dropwise a solution of methyl 4-fluorophenyl-acetate (6.0 g, 35.7 mmol) in THF (30 mL). The solution is stirred for 1 hour at −78° C. after which a solution of 2-methylsulfanyl-pyrimidine-4-carbaldehyde, 1, (6.0 g, 39.3 mmol) in THF (30 mL) is added dropwise to the reaction mixture. Stirring is continued for 45 minutes at −78° C. then the reaction is quenched by pouring the reaction solution into aqueous saturated NH4Cl. The aqueous phase is extracted with ethyl acetate. The organic phases combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue is purified over silica (33% EtOAc/hexanes) to afford 8.7 g (76%) of the desired product as a mixture (1:1) of diastereomers. is added dropwise to the reaction mixture the reaction is quenched by pouring the reaction solution into aqueous saturated NH4Cl The aqueous phase is extracted with ethyl acetate dried (MgSO4) filtered concentrated in vacuo The crude residue is purified over silica (33% EtOAc/hexanes)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of diisopropylamine (13.0 g) in tetrahydrofurane (160 mL) was added a solution of n-butyllithium in hexane (51.4 mL; c=2.5 M) at −78° C. The solution was stirred at 0° C. for 15 minutes. The solution was cooled to −78° C. and a solution of methyl (4-fluorophenyl)acetate (18.0 g), dissolved in tetrahydrofurane (40 mL) was added. The solution was stirred at −78° C. for 30 minutes. Methyl iodide (10.0 mL) was added at −78° C., and the solution was allowed to warm up to 0° C. within 1 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 18.9 g of the title compound. The solution was cooled to −78° C. was added The solution was stirred at −78° C. for 30 minutes to warm up to 0° C. within 1 h the reaction mixture was extracted with ethyl acetate The organic phase was dried (sodium sulfate) the solvent was removed in vacuum

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

実験手順: To a stirred solution of methyl (4-fluorophenyl)acetate (5.5 g) in DMSO (220 mL) was added 1,3,5-trioxane (3.24 g) and sodium methoxide (88 mg). The mixture was stirred at room temperature for 16 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 3.8 g of the title compound. the reaction mixture was extracted with ethyl acetate The organic phase was washed with saturated sodium chloride solution dried (sodium sulfate) the solvent was removed in vacuum

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

実験手順: To a stirred solution of methyl (4-fluorophenyl)acetate (5.5 g) in DMSO (220 mL) was added 1,3,5-trioxane (3.24 g) and sodium methoxide (88 mg). The mixture was stirred at room temperature for 16 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 3.8 g of the title compound. the reaction mixture was extracted with ethyl acetate The organic phase was washed with saturated sodium chloride solution dried (sodium sulfate) the solvent was removed in vacuum

反応条件: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of methyl 2-(4-fluorophenyl)acetate (2.35 g, 14 mmol) in THF (15 mL), at −78° C., was treated dropwise with 1 N lithium bis(trimethylsilyl)amide (14 mL, 14 mmol). After 15 minutes a suspension of 4-(methylsulphonyl)benzoyl chloride (3.3 g, 15 mmol) in THF (25 mL) was added in portions. The reaction mixture was stirred for 60 minutes at −78° C. and at 0 to 5° C. for 12 hours. The mixture was quenched with 10% citric acid, the THF removed in vacuo, and the residue triturated with hexanes to provide the desired product as a solid (yield: 3.4 g; 69%). MS (DCI-NH3) m/z 368 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ3.27 (s, 3H), 3.69 (s, 3H), 6.35 (s, 1H), 7.21 (m, 2H), 7.44 (m, 2H), 8.06 (d, J=9 Hz, 2H), 8.25 (d, J=9 Hz, 2H). was added in portions The mixture was quenched with 10% citric acid the THF removed in vacuo the residue triturated with hexanes

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

実験手順: Analogously to the procecure of Example 5, the title compound is prepared from 1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 1.92 g (11.4 mmol) of methyl 4-fluorophenylacetate.