2-bromo-1-(3-fluorophenyl)ethanone

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 mixture of 2-bromo-1-(3-fluoro-phenyl)-ethanone (5.0 g; 23.04 mmol; 1.0 eq.), piperidine (2.30 ml; 23.04 mmol; 1.0 eq.) and DIEA (4.89 ml; 27.65 mmol; 1.20 eq.) in CHCl3 (100 mL) was heated for reflux overnight. The mixture was partitioned between CHCl3 and saturated aqueous NaHCO3. The separated organic layer was dried over MgSO4, filtered and concentrated. The residue was purified through flash chromatography on silica gel to afford the title compound. LC-MS: 222 (M+H). was heated for reflux overnight The mixture was partitioned between CHCl3 and saturated aqueous NaHCO3 The separated organic layer was dried over MgSO4 filtered concentrated The residue was purified through flash chromatography on silica gel

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

実験手順: To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376 mg, 4.48 mmol) in isopropanol (30 mL), 3-fluorophenacyl bromide (0.97 g, 4.48 mmol) was added. After heating the reaction mixture at 75°-80° C. for 18 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed (silica gel, hexane/ethyl acetate, 6/4) to give 2-(4-chlorophenyl)-4-(3-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (481 mg, 50%) as a white solid: mp 194°-196° C. Anal. Calc'd. for C22H16N2SO2FCl: C, 61.90, H, 3.78, N, 6.56, S, 7.51. Found: C, 61.71, H, 3.59, N, 6.42, S, 7.69. was added After heating the reaction mixture at 75°-80° C. for 18 hours the solvent was removed The residue was redissolved in methylene chloride washed with aqueous sodium bicarbonate and water dried over sodium sulfate filtered concentrated in vacuo The crude product was chromatographed (silica gel, hexane/ethyl acetate, 6/4)

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

実験手順: At 20° C., a mixture of 4-isothiocyanatopiperidine-1-carboxylic acid tert-butyl ester (2.4 g, 10 mmol) (Example 1) and cyanamide (0.42 g, 10 mmol) (Aldrich) in tert-butanol (5 mL) and acetonitrile (35 mL) was treated with potassium tert-butoxide (1.0 M/THF, 10 mL, 10 mmol, Aldrich) for 15 min. 2-bromo-1-(3-fluorophenyl)ethanone (2.0 g, 9.2 mmol)(Example 2) was added and the suspension was stirred for 2 h. Solvent was removed and the solid residue purified by silica gel chromatography (60%-70% ethyl acetate/hexane) to give 2.4 g (57% yield) of 4-[4-amino-5-(3-fluorobenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (DMSOd6, 300 MHz) δ1.36 (m, 2H, NCH2), 1.41 (s, 9H, 3CH3), 1.88 (m, 2H, NCH2), 2.88 (brd, 2H, NCH2), 3.6-4.0 (m, 1H, CH), 3.87 (m, 2H, NCH2), 7.31 (t, 1H, Aromatic), 7.38 (d, 1H, Aromatic), 7.48 (t, 1H, Aromatic), 7.51 (q, 1H, Aromatic), 8.01 (brd, 1H, NH), 8.48 (brd, 1H, NH), 8.48 (brd, 1H, NH), 8.70 (brd, 1H, NH). Solvent was removed the solid residue purified by silica gel chromatography (60%-70% ethyl acetate/hexane)

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

実験手順: A solution of 1-(3-fluorophenyl)ethanone (14.0 g, 100 mmol) (Aldrich) in dioxane (250 mL) at 12-15° C. was treated with a solution of bromine (17 g, 105 mmol) in dioxane (120 mL) drop wise over 0.5 h. This was stirred for 15 min and most of the solvent removed. The residue was taken up in hexane (200 mL), washed 2× water, and dried (MgSO4). Solvent was removed to give 2-bromo-1-(3-fluorophenyl)ethanone. 1H NMR (CDCl3), 300 MHz) δ3.71 (s, 2H, CH2), 7.30-7.77(m, 4H, Aromatic). removed washed 2× water dried (MgSO4) Solvent was removed

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

実験手順: This compound was prepared from cyanamide, 1-(4-isothiocyanatphenyl)-4-cyclopropylmethylpiperazine (of Example 14G) and 2-bromo-1-(3-fluorophenyl)ethanone (Aldrich) following the procedure used in Example 24 Mass spectrum (ES) MH+=452.

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

実験手順: To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376 mg, 4.48 mmol) in isopropanol (30 mL), 3-fluorophenacyl bromide (0.97 g, 4.48 mmol) was added. After heating the reaction mixture at 75°-80° C. for 18 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed (silica gel, hexane/ethyl acetate, 6/4) to give 2-(4-chlorophenyl)-4-(3-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (481 mg, 50%) as a white solid: mp 194°-196° C. Anal. Calc'd. for C22H16N2SO2FCl: C, 61.90, H, 3.78, N, 6.56, S, 7.51. Found: C, 61.71, H, 3.59, N, 6.42, S, 7.69. was added After heating the reaction mixture at 75°-80° C. for 18 hours the solvent was removed The residue was redissolved in methylene chloride washed with aqueous sodium bicarbonate and water dried over sodium sulfate filtered concentrated in vacuo The crude product was chromatographed (silica gel, hexane/ethyl acetate, 6/4)

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

実験手順: At 20° C., a mixture of 4-isothiocyanatopiperidine-1-carboxylic acid tert-butyl ester (2.4 g, 10 mmol) (Example 1) and cyanamide (0.42 g, 10 mmol) (Aldrich) in tert-butanol (5 mL) and acetonitrile (35 mL) was treated with potassium tert-butoxide (1.0 M/THF, 10 mL, 10 mmol, Aldrich) for 15 min. 2-bromo-1-(3-fluorophenyl)ethanone (2.0 g, 9.2 mmol)(Example 2) was added and the suspension was stirred for 2 h. Solvent was removed and the solid residue purified by silica gel chromatography (60%-70% ethyl acetate/hexane) to give 2.4 g (57% yield) of 4-[4-amino-5-(3-fluorobenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (DMSOd6, 300 MHz) δ1.36 (m, 2H, NCH2), 1.41 (s, 9H, 3CH3), 1.88 (m, 2H, NCH2), 2.88 (brd, 2H, NCH2), 3.6-4.0 (m, 1H, CH), 3.87 (m, 2H, NCH2), 7.31 (t, 1H, Aromatic), 7.38 (d, 1H, Aromatic), 7.48 (t, 1H, Aromatic), 7.51 (q, 1H, Aromatic), 8.01 (brd, 1H, NH), 8.48 (brd, 1H, NH), 8.48 (brd, 1H, NH), 8.70 (brd, 1H, NH). Solvent was removed the solid residue purified by silica gel chromatography (60%-70% ethyl acetate/hexane)

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

実験手順: A solution of 1-(3-fluorophenyl)ethanone (14.0 g, 100 mmol) (Aldrich) in dioxane (250 mL) at 12-15° C. was treated with a solution of bromine (17 g, 105 mmol) in dioxane (120 mL) drop wise over 0.5 h. This was stirred for 15 min and most of the solvent removed. The residue was taken up in hexane (200 mL), washed 2× water, and dried (MgSO4). Solvent was removed to give 2-bromo-1-(3-fluorophenyl)ethanone. 1H NMR (CDCl3), 300 MHz) δ3.71 (s, 2H, CH2), 7.30-7.77(m, 4H, Aromatic). removed washed 2× water dried (MgSO4) Solvent was removed