4-iodobenzenesulfonamide

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 1,3-dipropyl-8-(1-prop-2-ynyl-1H-pyrazol-4-yl)-3,7-dihydro-purine-2,6-dione (200 mg, 0.59 mmol), 4-iodo-benzenesulfonamide (166 mg, 0.59 mmol), copper iodide (10 mg, 0.059 mmol), dichlorobis (triphenylphosphine)-palladium (II) (21 mg, 0.03 mmol), triethylamine (2 ml), DMF (2 ml) was degassed for 10 min. and stirred for 20 hrs at room temperature. The reaction mixture was diluted with water (10 ml) and extracted with DCM (3×10 ml). Organic layer was washed with brine (2×15 ml) and dried over Na2SO4. The organic volatile solvent was evaporated and the crude product was purified using HPLC to obtain pure 4-{3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-pyrazol-1-yl]-prop-1-ynyl}-benzenesulfonamide (4.2 mg, 2%). was degassed for 10 min. The reaction mixture was diluted with water (10 ml) extracted with DCM (3×10 ml) Organic layer was washed with brine (2×15 ml) dried over Na2SO4 The organic volatile solvent was evaporated the crude product was purified

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

実験手順: The compound 2-2 (58 mg) prepared in Step 1 was dissolved in dimethylformamide (2 ml) and to the solution were added zinc cyanide [Zn(CN)2] (58 mg) and tetrakistriphenylphosphine palladium (10 mg), followed by stirring at 80° C. for 12 hours. The resulting mixture was basified with aqueous sodium bicarbonate solution, diluted with ethyl acetate (30 ml), washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was chromatographed on silica gel column eluting with ethyl acetate/hexane (1/2) to yield the compound 2-3 (30 mg, 80%). washed with water and saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate concentrated under reduced pressure The obtained residue was chromatographed on silica gel column eluting with ethyl acetate/hexane (1/2)

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

実験手順: Pipsylchloride (100 mg) was dissolved in 28% ammonia solution (4 ml) and the solution was stirred at room temperature for 1 hours. The resulting mixture was extracted with ethyl acetate (20 ml), washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was chromatographed on column eluting with ethyl acetate/hexane (1/2) to yield the compound 2-2 (89 mg, 100%). The resulting mixture was extracted with ethyl acetate (20 ml) washed with water and saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was chromatographed on column eluting with ethyl acetate/hexane (1/2)

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

実験手順: Pipsylchloride (100 mg) was dissolved in 28% ammonia solution (4 ml) and the solution was stirred at room temperature for 1 hours. The resulting mixture was extracted with ethyl acetate (20 ml), washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was chromatographed on column eluting with ethyl acetate/hexane (1/2) to yield the compound 2-2 (89 mg, 100%). The resulting mixture was extracted with ethyl acetate (20 ml) washed with water and saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was chromatographed on column eluting with ethyl acetate/hexane (1/2)

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: As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 4-iodobenzenesulphonamide instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 120 mg, 71%) which was obtained as a white solid. MS: m/e=339.2 [M+H]+.

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 5 starting from 4-iodo-benzenesulfonamide (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.90 (s, 3H), 4.95 (s, 2H), 5.02 (s, 2H), 6.41 (d, 1H), 6.65-6.71 (m, 2H), 7.09 (t, 1H), 7.26-7.33 (m, 2H), 7.35-7.42 (m, 6H), 7.58-7.60 (m, 3H), 7.99 (d, 1H), 8.07 (s, 1H).

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

実験手順: A mixture of 4-iodobenzenesulphonamide (651 mg); dipinacoldiborane (495 mg)2; potassium acetate (860 mg); and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex:dichloromethane (1:1) (50 mg); in DMF (5 ml) was heated under nitrogen at 80° for 1.5 h. To the cooled reaction mixture was added 3-bromo-2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridine (330 mg, 0.919 mmol), 2N Na2CO3 (4 ml) and tetrakis(triphenylphosphine)palladium(0) (40 mg) and the mixture heated at reflux under nitrogen for 18 hours. The cooled reaction mixture was poured into water (30 ml) and the suspension extracted with ethyl acetate (3×20 ml). The organic extracts were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by SPE chromatography eluting with a gradient of cyclohexane:ethyl acetate (100:0 to 0:100, 10% step). Trituration of the concentrated fractions containing product with diethyl ether gave the title compound as a white solid (139 mg, 35%). MH+ 436 To the cooled reaction mixture the mixture heated at reflux under nitrogen for 18 hours The cooled reaction mixture the suspension extracted with ethyl acetate (3×20 ml) dried (Na2SO4) concentrated in vacuo The residue was purified by SPE chromatography eluting with a gradient of cyclohexane:ethyl acetate (100:0 to 0:100, 10% step) Trituration of the concentrated fractions containing product with diethyl ether

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

実験手順: A mixture of 1,3-dipropyl-8-(1-prop-2-ynyl-1H-pyrazol-4-yl)-3,7-dihydro-purine-2,6-dione (200 mg, 0.59 mmol), 4-iodo-benzenesulfonamide (166 mg, 0.59 mmol), copper iodide (10 mg, 0.059 mmol), dichlorobis (triphenylphosphine)-palladium (II) (21 mg, 0.03 mmol), triethylamine (2 ml), DMF (2 ml) was degassed for 10 min. and stirred for 20 hrs at room temperature. The reaction mixture was diluted with water (10 ml) and extracted with DCM (3×10 ml). Organic layer was washed with brine (2×15 ml) and dried over Na2SO4. The organic volatile solvent was evaporated and the crude product was purified using HPLC to obtain pure 4-{3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-pyrazol-1-yl]-prop-1-ynyl}-benzenesulfonamide (4.2 mg, 2%). was degassed for 10 min. The reaction mixture was diluted with water (10 ml) extracted with DCM (3×10 ml) Organic layer was washed with brine (2×15 ml) dried over Na2SO4 The organic volatile solvent was evaporated the crude product was purified

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

実験手順: The compound 2-2 (58 mg) prepared in Step 1 was dissolved in dimethylformamide (2 ml) and to the solution were added zinc cyanide [Zn(CN)2] (58 mg) and tetrakistriphenylphosphine palladium (10 mg), followed by stirring at 80° C. for 12 hours. The resulting mixture was basified with aqueous sodium bicarbonate solution, diluted with ethyl acetate (30 ml), washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was chromatographed on silica gel column eluting with ethyl acetate/hexane (1/2) to yield the compound 2-3 (30 mg, 80%). washed with water and saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate concentrated under reduced pressure The obtained residue was chromatographed on silica gel column eluting with ethyl acetate/hexane (1/2)

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

実験手順: Pipsylchloride (100 mg) was dissolved in 28% ammonia solution (4 ml) and the solution was stirred at room temperature for 1 hours. The resulting mixture was extracted with ethyl acetate (20 ml), washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was chromatographed on column eluting with ethyl acetate/hexane (1/2) to yield the compound 2-2 (89 mg, 100%). The resulting mixture was extracted with ethyl acetate (20 ml) washed with water and saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was chromatographed on column eluting with ethyl acetate/hexane (1/2)