2-ethylisoindole-1,3-dione

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: To a cooled (5° C.) suspension of 0.914 g (2.7 mmol) of 6-(chlorophenyl)-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-ol, 1.041 g (5.4 mmol) of N-(2-hydroxyethyl)-phthalimide, 1.43 g (5.4 mmol) of triphenylphosphine in 15 mL of 1,4-dionxane was added dropwise a solution of 0.95 g (0.86 mL, 5.4 mmol) diethylazodicarboxylate in 5 mL of 1,4-dioxane over a period of 30 min. After addition was completed, the ice-water cooling bath was removed. The suspension soon turned into a clear light brown solution. This was allowed to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on 120 g of silica gel using 90:10:0.5 ethyl acetate/dichloromethane/ammonium hydroxide to obtain 0.38 g of the N-ethylphthalimide intermediate. A mixture of 0.18 g (0.35 mmol) of this intermediate and 0.05 g (0.42 mmol) of trans-4-aminocyclohexanol in 1 mL of NMP was heated to 120° C. for 30 min. The reaction mixture was cooled, diluted with 75 mL of water and extracted with ethyl acetate (3×75 mL). The combined ethyl acetate solution was washed with water (3×75 mL), brine, dried, filtered and concentrated. The material was purified by column chromatography on 40 g of silica eluting with 5% methanol/dichloromethane affording 45 mg of compound 65. (mass spec. MH+=544, mp 208-210° C.). To a cooled After addition the ice-water cooling bath was removed The reaction mixture was concentrated under reduced pressure purified by column chromatography on 120 g of silica gel using 90:10:0.5 ethyl acetate/dichloromethane/ammonium hydroxide

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Hydroxy-2-ethyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 4.0 g of N-ethylphthalimide in 20 cm3 of methanol and 1.2 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then cooled to a temperature in the region of 0° C. and distilled water is added dropwise. The precipitate obtained is filtered off and then washed with cold water. The methanol is then partially evaporated from the filtrate under reduced pressure (2 kPa) at a temperature in the region of 35° C., and the residue is cooled to 0° C. The second precipitate thus obtained is filtered off and then washed with cold water. The two fractions of solid are dried under reduced pressure (2 kPa) at a temperature in the region of 35° C. 1.9 g of 3-hydroxy-2-ethyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a flaky white powder. (Rf=0.5, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (30/70 by volume)). 3-Hydroxy-2-ethyl-2,3-dihydroisoindol-1-one is prepared is then cooled to a temperature in the region of 0° C. distilled water is added dropwise The precipitate obtained is filtered off washed with cold water The methanol is then partially evaporated from the filtrate under reduced pressure (2 kPa) at a temperature in the region of 35° C. the residue is cooled to 0° C The second precipitate thus obtained is filtered off washed with cold water The two fractions of solid are dried under reduced pressure (2 kPa) at a temperature in the region of 35° C

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

実験手順: 80% Sodium hydride (0.155 g) was added portionwise to a solution of 2-phthalimido-ethanethiol (1.03 g) in dry dimethylformamide at 0°. After 20 mins a solution of 2-furanethanol, 4-methylbenzenesulphonate (1.33 g) in dry dimethylformamide was added dropwise and the solution stirred overnight at room temperature. The mixture was poured into ice-water and 2-[[2-furanyl)ethyl]thio]ethyl-1H-isoindole-1,3(2H)-dione isolated as a white solid (1.3 g) m.p. 53°-55°.

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: 80% Sodium hydride (0.155 g) was added portionwise to a solution of 2-phthalimido-ethanethiol (1.03 g) in dry dimethylformamide at 0°. After 20 mins a solution of 2-furanethanol, 4-methylbenzenesulphonate (1.33 g) in dry dimethylformamide was added dropwise and the solution stirred overnight at room temperature. The mixture was poured into ice-water and 2-[[2-furanyl)ethyl]thio]ethyl-1H-isoindole-1,3(2H)-dione isolated as a white solid (1.3 g) m.p. 53°-55°.

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Hydroxy-2-ethyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 4.0 g of N-ethylphthalimide in 20 cm3 of methanol and 1.2 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then cooled to a temperature in the region of 0° C. and distilled water is added dropwise. The precipitate obtained is filtered off and then washed with cold water. The methanol is then partially evaporated from the filtrate under reduced pressure (2 kPa) at a temperature in the region of 35° C., and the residue is cooled to 0° C. The second precipitate thus obtained is filtered off and then washed with cold water. The two fractions of solid are dried under reduced pressure (2 kPa) at a temperature in the region of 35° C. 1.9 g of 3-hydroxy-2-ethyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a flaky white powder. (Rf=0.5, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (30/70 by volume)). 3-Hydroxy-2-ethyl-2,3-dihydroisoindol-1-one is prepared is then cooled to a temperature in the region of 0° C. distilled water is added dropwise The precipitate obtained is filtered off washed with cold water The methanol is then partially evaporated from the filtrate under reduced pressure (2 kPa) at a temperature in the region of 35° C. the residue is cooled to 0° C The second precipitate thus obtained is filtered off washed with cold water The two fractions of solid are dried under reduced pressure (2 kPa) at a temperature in the region of 35° C

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

実験手順: To a cooled (5° C.) suspension of 0.914 g (2.7 mmol) of 6-(chlorophenyl)-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-ol, 1.041 g (5.4 mmol) of N-(2-hydroxyethyl)-phthalimide, 1.43 g (5.4 mmol) of triphenylphosphine in 15 mL of 1,4-dionxane was added dropwise a solution of 0.95 g (0.86 mL, 5.4 mmol) diethylazodicarboxylate in 5 mL of 1,4-dioxane over a period of 30 min. After addition was completed, the ice-water cooling bath was removed. The suspension soon turned into a clear light brown solution. This was allowed to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on 120 g of silica gel using 90:10:0.5 ethyl acetate/dichloromethane/ammonium hydroxide to obtain 0.38 g of the N-ethylphthalimide intermediate. A mixture of 0.18 g (0.35 mmol) of this intermediate and 0.05 g (0.42 mmol) of trans-4-aminocyclohexanol in 1 mL of NMP was heated to 120° C. for 30 min. The reaction mixture was cooled, diluted with 75 mL of water and extracted with ethyl acetate (3×75 mL). The combined ethyl acetate solution was washed with water (3×75 mL), brine, dried, filtered and concentrated. The material was purified by column chromatography on 40 g of silica eluting with 5% methanol/dichloromethane affording 45 mg of compound 65. (mass spec. MH+=544, mp 208-210° C.). To a cooled After addition the ice-water cooling bath was removed The reaction mixture was concentrated under reduced pressure purified by column chromatography on 120 g of silica gel using 90:10:0.5 ethyl acetate/dichloromethane/ammonium hydroxide

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

実験手順: To a cooled (5° C.) suspension of 0.914 g (2.7 mmol) of 6-(chlorophenyl)-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-ol, 1.041 g (5.4 mmol) of N-(2-hydroxyethyl)-phthalimide, 1.43 g (5.4 mmol) of triphenylphosphine in 15 mL of 1,4-dionxane was added dropwise a solution of 0.95 g (0.86 mL, 5.4 mmol) diethylazodicarboxylate in 5 mL of 1,4-dioxane over a period of 30 min. After addition was completed, the ice-water cooling bath was removed. The suspension soon turned into a clear light brown solution. This was allowed to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on 120 g of silica gel using 90:10:0.5 ethyl acetate/dichloromethane/ammonium hydroxide to obtain 0.38 g of the N-ethylphthalimide intermediate. A mixture of 0.18 g (0.35 mmol) of this intermediate and 0.05 g (0.42 mmol) of trans-4-aminocyclohexanol in 1 mL of NMP was heated to 120° C. for 30 min. The reaction mixture was cooled, diluted with 75 mL of water and extracted with ethyl acetate (3×75 mL). The combined ethyl acetate solution was washed with water (3×75 mL), brine, dried, filtered and concentrated. The material was purified by column chromatography on 40 g of silica eluting with 5% methanol/dichloromethane affording 45 mg of compound 65. (mass spec. MH+=544, mp 208-210° C.). To a cooled After addition the ice-water cooling bath was removed The reaction mixture was concentrated under reduced pressure purified by column chromatography on 120 g of silica gel using 90:10:0.5 ethyl acetate/dichloromethane/ammonium hydroxide

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Hydroxy-2-ethyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 4.0 g of N-ethylphthalimide in 20 cm3 of methanol and 1.2 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then cooled to a temperature in the region of 0° C. and distilled water is added dropwise. The precipitate obtained is filtered off and then washed with cold water. The methanol is then partially evaporated from the filtrate under reduced pressure (2 kPa) at a temperature in the region of 35° C., and the residue is cooled to 0° C. The second precipitate thus obtained is filtered off and then washed with cold water. The two fractions of solid are dried under reduced pressure (2 kPa) at a temperature in the region of 35° C. 1.9 g of 3-hydroxy-2-ethyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a flaky white powder. (Rf=0.5, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (30/70 by volume)). 3-Hydroxy-2-ethyl-2,3-dihydroisoindol-1-one is prepared is then cooled to a temperature in the region of 0° C. distilled water is added dropwise The precipitate obtained is filtered off washed with cold water The methanol is then partially evaporated from the filtrate under reduced pressure (2 kPa) at a temperature in the region of 35° C. the residue is cooled to 0° C The second precipitate thus obtained is filtered off washed with cold water The two fractions of solid are dried under reduced pressure (2 kPa) at a temperature in the region of 35° C