1-(2,5-二氟苯基)乙酮

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2',5'-difluoroacetophenone (20 g), methylamine (33% w/w solution in industrial methylated spirit, 31ml), industrial methylated spirit (30 ml) and copper powder (0.2 g) was heated at 80° in a sealed pressure vessel for 24 hours. The reaction mixture was allowed to cool to ambient temperature and the mixture washed out of the vessel with industrial methylated spirit (2×30 ml). A solution of sodium sulphide nonahydrate (1 g) in water (10 ml) was added to the combined reaction mixture and washings and the mixture heated to 50° for 15 minutes. The mixture was filtered through diatomaceous earth (sold under the trade name CELITE) and the filter bed washed with industrial methylated spirit (50 ml). The combined filtrate and washings were evaporated to give an oil which was stirred with hydrochloric acid (5M, 80 ml) overnight. The mixture was adjusted to pH 8-9 using aqueous sodium hydroxide (specific gravity 1.5) and then extracted with dichloromethane (3×100 ml). The combined extracts were dried over magnesium sulphate and the solvent removed by distillation. The residue was extracted with diethyl ether (100 ml), the extract treated with activated charcoal (5 g) and the solvent removed by distillation. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:petroleum ether (1:1) to give the novel compound 5'-fluoro-2'-(methylamino)acetophenone, m.p. 43°-45°. was heated at 80° in a sealed pressure vessel for 24 hours the mixture washed out of the vessel with industrial methylated spirit (2×30 ml) A solution of sodium sulphide nonahydrate (1 g) in water (10 ml) was added to the combined reaction mixture and washings the mixture heated to 50° for 15 minutes The mixture was filtered through diatomaceous earth ( washed with industrial methylated spirit (50 ml) The combined filtrate and washings were evaporated to give an oil which extracted with dichloromethane (3×100 ml) The combined extracts were dried over magnesium sulphate the solvent removed by distillation The residue was extracted with diethyl ether (100 ml) the extract treated with activated charcoal (5 g) the solvent removed by distillation The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:petroleum ether (1:1)

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 28.5 g of 2,5-difluoroacetophenone and 26 g of ethyl trifluoroacetate were stirred in 400 ml of anhydrous ether and cooled in an ice bath. 42 ml of 25 wt % sodium methoxide in methanol was then added over 5 minutes. After stirring 1 hour at room temperature, the reaction mixture was extracted with water, the water acidified and extracted with methylene chloride to give 42 g of 1-(2,5-difluorophenyl)-3-(trifluoromethyl)-propane-1,3-dione. cooled in an ice bath the reaction mixture was extracted with water extracted with methylene chloride

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 28.5 g of 2,5-difluoroacetophenone and 26 g of ethyl trifluoroacetate were stirred in 400 ml of anhydrous ether and cooled in an ice bath. 42 ml of 25 wt % sodium methoxide in methanol was then added over 5 minutes. After stirring 1 hour at room temperature, the reaction mixture was extracted with water, the water acidified and extracted with methylene chloride to give 42 g of 1-(2,5-difluorophenyl)-3-(trifluoromethyl)-propane-1,3-dione. cooled in an ice bath the reaction mixture was extracted with water extracted with methylene chloride

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-(2,5-Difluorophenyl)ethanone (3.00 g) and 1H-triazole (1.99 g) were dissolved in N-methylpyrrolidone (5 ml). To the solution, potassium carbonate (2.66 g) was added, and the mixture was stirred at 140° C. for 4.5 hours. After standing to cool, water and ethyl acetate were added to the reaction solution to separate the aqueous and organic layers. The aqueous layer was subjected to extraction with ethyl acetate. The organic layers were combined, washed three times with saturated saline, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (1.05 g). to cool to separate the aqueous and organic layers The aqueous layer was subjected to extraction with ethyl acetate washed three times with saturated saline dried over anhydrous sodium sulfate concentrated under reduced pressure The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Using 2′,5′-difluoroacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Using 2′,5′-difluoroacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Using the method described in Example 30 by employing [1-(2,5-difluorophenyl)vinyl]pyrrolidine (freshly prepared before use from 2′,5′-difluoro acetophenone (Aldrich Chemical Company), pyrrolidine and TiCl4 (1.45 g, 6.94 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.00 g, 4.83 mmol), N,N-diisopropylethylamine (1.2 mL, 6.94 mmol), piperidine (1.1 mL, 11.1 mmol), NEt3 (1.2 mL) and SnCl2 (21 mL of a 2 M soln in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant to give 417 mg (26%) of 6-(2,5-difluorophenyl)-2-methyl-4-piperidylpyrrolo[3,2-d]pyrimidine as a tan colored foam. This material (415 mg, 1.25 mmol) was dissolved in 5:1 EtOAc/MeOH (30 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.30 mL, 1.30 mmol). The solution was left to cool to room temperature. The resulting crystals were collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 337 mg (19%) of the title compound as white colored needles. Mp: 279-281° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.71 (br s, 6), 2.58 (s, 3), 4.06 (s, 4), 6.85 (s, 1), 7.42-7.55 (m, 2), 7.86-7.91 (m, 1), 12.13 (s, 1), 14.41 (s, 1). MS m/z: 329 (M+1 for free base). Anal. Calcd for C18H18F2N4.HCl.1.0H2O: C, 56.54; H, 5.50; N, 14.65. Found: C, 56.29; H, 5.61; N, 14.53. The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 2,5-difluorobenzaldehyde (24.6 g) in tetrahydrofuran (100 ml) was added dropwise to an ice-cooled solution (207 ml) of 0.92N magnesium methylbromide in tetrahydrofuran. The resulting solution was stirred at room temperature for 1.5 hours, and the organic phase was washed in an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, to subsequently distill off the solvents under reduced pressure. To the residue were added anhydrous dichloromethane (500 ml), sodium acetate (14.2 g) and pyridinium chlorochromate (55.94 g), prior to stirring at room temperature for 10 hours. To the resulting mixture was added an aqueous saturated sodium hydrogen carbonate solution, prior to extraction in ethyl acetate three times. The organic phase was washed in water and in an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, to distill off the solvents under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=85:15), to recover 2′,5′-difluoroacetophenone (22.73 g; yield of 84%). By 1H-NMR (90 MHz, CDCl3), the compound has the peaks shown below. the organic phase was washed in an aqueous saturated sodium chloride solution dried over anhydrous magnesium sulfate to subsequently distill off the solvents under reduced pressure To the residue were added anhydrous dichloromethane (500 ml), sodium acetate (14.2 g) and pyridinium chlorochromate (55.94 g) to stirring at room temperature for 10 hours To the resulting mixture was added an aqueous saturated sodium hydrogen carbonate solution to extraction in ethyl acetate three times The organic phase was washed in water and in an aqueous saturated sodium chloride solution dried over anhydrous magnesium sulfate to distill off the solvents under reduced pressure The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=85:15)