(4-fluorophenyl)thiourea

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

実験手順: 18 mg (0.10 mmol) of 4-fluorophenylthiourea and 13 mg (0.10 mmol) of 1,3-dichloroacetone are dissolved in 2 ml of DMF, and the reaction solution is stirred at 80° C. for 3 h. After cooling, 89 mg (0.09 mmol, 33% pure) of the compound from example 4A and 32 mg (0.38 mmol) of sodium bicarbonate are added, and the mixture is stirred at RT for a further 20 h. The mixture is then filtered through a paper filter, and the filtrate is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). Sat. sodium bicarbonate solution (5 ml) is added to the product fraction obtained, and the mixture is extracted with ethyl acetate (three times, 5 ml each). The combined organic phases are dried over magnesium sulphate, and the solvent is removed on a rotary evaporator. After cooling the mixture is stirred at RT for a further 20 h The mixture is then filtered through a paper filter the filtrate is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5) Sat. sodium bicarbonate solution (5 ml) is added to the product fraction obtained the mixture is extracted with ethyl acetate (three times, 5 ml each) The combined organic phases are dried over magnesium sulphate the solvent is removed on a rotary evaporator

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

実験手順: 18 mg (0.10 mmol) of 4-fluorophenylthiourea and 13 mg (0.10 mmol) of 1,3-dichloroacetone are dissolved in 2 ml of DMF, and the reaction solution is stirred at 80° C. for 3 h. After cooling, 89 mg (0.09 mmol, 33% pure) of the compound from example 4A and 32 mg (0.38 mmol) of sodium bicarbonate are added, and the mixture is stirred at RT for a further 20 h. The mixture is then filtered through a paper filter, and the filtrate is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). Sat. sodium bicarbonate solution (5 ml) is added to the product fraction obtained, and the mixture is extracted with ethyl acetate (three times, 5 ml each). The combined organic phases are dried over magnesium sulphate, and the solvent is removed on a rotary evaporator. After cooling the mixture is stirred at RT for a further 20 h The mixture is then filtered through a paper filter the filtrate is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5) Sat. sodium bicarbonate solution (5 ml) is added to the product fraction obtained the mixture is extracted with ethyl acetate (three times, 5 ml each) The combined organic phases are dried over magnesium sulphate the solvent is removed on a rotary evaporator

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

実験手順: 1-(4-fluorophenyl)thiourea (2.00 g, 11.7 mmol) and 2-chloroacetaldehyde(3.72 mL, 58.6 mmol) in anhydrous ethanol (5 mL) were added to a microwave vial. The reaction mixture was heated to 80° C. in a microwave reactor for 20 min. On cooling, ethyl acetate (2 mL) was added to the crude product reaction mixture and pure product crystallized out. This filtered off, washed with hexane and air-dried to afford the title compound as a crystalline brown solid, 1.568 g. MS (M+H)+ 195. On cooling crystallized out This filtered off washed with hexane air-dried

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

実験手順: 1-(4-fluorophenyl)thiourea (2.00 g, 11.7 mmol) and 2-chloroacetaldehyde(3.72 mL, 58.6 mmol) in anhydrous ethanol (5 mL) were added to a microwave vial. The reaction mixture was heated to 80° C. in a microwave reactor for 20 min. On cooling, ethyl acetate (2 mL) was added to the crude product reaction mixture and pure product crystallized out. This filtered off, washed with hexane and air-dried to afford the title compound as a crystalline brown solid, 1.568 g. MS (M+H)+ 195. On cooling crystallized out This filtered off washed with hexane air-dried

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

実験手順: 18 mg (0.10 mmol) of 4-fluorophenylthiourea and 13 mg (0.10 mmol) of 1,3-dichloroacetone are dissolved in 2 ml of DMF, and the reaction solution is stirred at 80° C. for 3 h. After cooling, 89 mg (0.09 mmol, 33% pure) of the compound from example 4A and 32 mg (0.38 mmol) of sodium bicarbonate are added, and the mixture is stirred at RT for a further 20 h. The mixture is then filtered through a paper filter, and the filtrate is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). Sat. sodium bicarbonate solution (5 ml) is added to the product fraction obtained, and the mixture is extracted with ethyl acetate (three times, 5 ml each). The combined organic phases are dried over magnesium sulphate, and the solvent is removed on a rotary evaporator. After cooling the mixture is stirred at RT for a further 20 h The mixture is then filtered through a paper filter the filtrate is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5) Sat. sodium bicarbonate solution (5 ml) is added to the product fraction obtained the mixture is extracted with ethyl acetate (three times, 5 ml each) The combined organic phases are dried over magnesium sulphate the solvent is removed on a rotary evaporator

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

実験手順: 244 mg (1.92 mmol) of 1,3-dichloroacetone are added to a solution of 327 mg (1.92 mmol) of 4-fluorophenylthiourea in 8 ml of ethanol, and the mixture is stirred under reflux for 1 h. The mixture is concentrated, the residue is dissolved in 4 ml of DMF, 429 mg (1.37 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-mercaptopyridine-3,5-dicarbonitrile (preparation see WO 03/053441, Example 6/Method 1, Step 1) and 346 mg (4.1 mmol) of sodium bicarbonate are added and the mixture is stirred at RT overnight. After addition of water, the precipitate is decanted off and the residue is triturated with dichloromethane. After chromatography on silica gel (mobile phase dichloromethane/methanol 50:1), the title compound is obtained as a yellowish solid. under reflux for 1 h The mixture is concentrated the residue is dissolved in 4 ml of DMF the mixture is stirred at RT overnight the precipitate is decanted off the residue is triturated with dichloromethane

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

実験手順: A solution of 78.6 mg (0.46 mmol) of 4-fluorophenylthiourea and 56.0 mg (0.44 mmol) of 1,3-dichloroacetone in 2 ml of dry DMF is stirred at +80° C. for 3 h. After cooling to RT, 370 mg (0.42 mmol) of the compound from Example 42A are added, and the mixture is then stirred at RT for 20 h. The reaction mixture is purified directly by two preparative HPLCs (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). The reaction mixture is purified directly by two preparative HPLCs (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5)

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

実験手順: A solution of 78.6 mg (0.46 mmol) of 4-fluorophenylthiourea and 56.0 mg (0.44 mmol) of 1,3-dichloroacetone in 2 ml of dry DMF is stirred at +80° C. for 3 h. After cooling to RT, 370 mg (0.42 mmol) of the compound from Example 42A are added, and the mixture is then stirred at RT for 20 h. The reaction mixture is purified directly by two preparative HPLCs (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). The reaction mixture is purified directly by two preparative HPLCs (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5)

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

実験手順: A solution of 74 mg (0.44 mmol) of 4-fluorophenylthiourea and 55 mg (0.44 mmol) of 1,3-dichloroacetone in 5 ml of ethanol is stirred at +85° C. for 60 min. After removal of the solvent on a rotary evaporator, the residue is taken up in 5 ml of DMF, 105 mg (0.31 mmol) of the compound from Example 38A and 78 mg (0.93 mmol) of sodium bicarbonate are added and the mixture is then stirred at RT for 20 h. The mixture is then added to 15 ml of saturated sodium bicarbonate solution. The mixture is extracted with ethyl acetate (three times, 15 ml each) and the combined organic phases are dried over magnesium sulphate. After removal of the solvent on a rotary evaporator, the crude product is purified chromatographically on silica gel 60 (mobile phase gradient dichloromethane/ethanol 200:1→20:1). After removal of the solvent on a rotary evaporator The mixture is extracted with ethyl acetate (three times, 15 ml each) the combined organic phases are dried over magnesium sulphate After removal of the solvent on a rotary evaporator the crude product is purified chromatographically on silica gel 60 (mobile phase gradient dichloromethane/ethanol 200:1→20:1)

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

実験手順: A solution of 74 mg (0.44 mmol) of 4-fluorophenylthiourea and 55 mg (0.44 mmol) of 1,3-dichloroacetone in 5 ml of ethanol is stirred at +85° C. for 60 min. After removal of the solvent on a rotary evaporator, the residue is taken up in 5 ml of DMF, 105 mg (0.31 mmol) of the compound from Example 38A and 78 mg (0.93 mmol) of sodium bicarbonate are added and the mixture is then stirred at RT for 20 h. The mixture is then added to 15 ml of saturated sodium bicarbonate solution. The mixture is extracted with ethyl acetate (three times, 15 ml each) and the combined organic phases are dried over magnesium sulphate. After removal of the solvent on a rotary evaporator, the crude product is purified chromatographically on silica gel 60 (mobile phase gradient dichloromethane/ethanol 200:1→20:1). After removal of the solvent on a rotary evaporator The mixture is extracted with ethyl acetate (three times, 15 ml each) the combined organic phases are dried over magnesium sulphate After removal of the solvent on a rotary evaporator the crude product is purified chromatographically on silica gel 60 (mobile phase gradient dichloromethane/ethanol 200:1→20:1)

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

実験手順: 102 mg (0.6 mmol) of 4-fluorophenylthiourea and 73.6 mg (0.58 mmol) of 1,3-dichloroacetone are dissolved in 2.5 ml of ethanol, and the mixture is stirred under reflux for 60 min. The mixture is allowed to cool and concentrated using a rotary evaporator. The residue is taken up in 1.5 ml of DMF, 153 mg (0.4 mmol) of the compound from Example 3A and 101 mg (1.2 mmol) of sodium bicarbonate are added and the reaction solution is stirred at RT for a further 16 h. The reaction mixture is purified directly by preparative HPLC chromatography (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). under reflux for 60 min to cool concentrated a rotary evaporator the reaction solution is stirred at RT for a further 16 h The reaction mixture is purified directly by preparative HPLC chromatography (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5)

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

実験手順: 102 mg (0.6 mmol) of 4-fluorophenylthiourea and 73.6 mg (0.58 mmol) of 1,3-dichloroacetone are dissolved in 2.5 ml of ethanol, and the mixture is stirred under reflux for 60 min. The mixture is allowed to cool and concentrated using a rotary evaporator. The residue is taken up in 1.5 ml of DMF, 153 mg (0.4 mmol) of the compound from Example 3A and 101 mg (1.2 mmol) of sodium bicarbonate are added and the reaction solution is stirred at RT for a further 16 h. The reaction mixture is purified directly by preparative HPLC chromatography (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). under reflux for 60 min to cool concentrated a rotary evaporator the reaction solution is stirred at RT for a further 16 h The reaction mixture is purified directly by preparative HPLC chromatography (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5)