4-amino-2-methylisoindole-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:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared using the procedure for Example 102 with diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 4-amino-2-methyl-1H-isoindole-1,3(2H)-dione. MS (ES+): m/z 594.34 (100) [MH+]; HPLC: tR=1.17 min (UPLC, purity).

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 using the procedure for Example 102 with diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 4-amino-2-methyl-1H-isoindole-1,3(2H)-dione. MS (ES+): m/z 594.34 (100) [MH+]; HPLC: tR=1.17 min (UPLC, purity).

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

実験手順: A 5-L flask was set up with an overhead stirrer, temperature probe, and 500-mL addition funnel. The flask was charged with lithium aluminum hydride (100 g) and anhydrous tetrahydrofuran (1.5 L). The resulting suspension was treated with 4-amino-2-methyl-1H-isoindole-1,3(2H)-dione (100 g, 0.56 mol) at a rate such that the reaction did not become too vigorous. The resulting suspension was heated at reflux for 18 hours. The reaction vessel was cooled, placed in an ice bath, and cautiously quenched with 100 mL water, 100 mL 1N NaOH, and 300 mL water. The resulting suspension was treated with chloroform (1.5 L) and the pH of the suspension adjusted to 12 with 50% aqueous sodium hydroxide solution. The resulting suspension was treated with acetic anhydride (300 mL) while maintaining the pH at approximately 12. The reaction mixture was treated with sodium sulfate (800 g) and potassium carbonate (200 g), and the reaction mixture was filtered. The filter cake was washed with additional chloroform, and the combined filtrates were concentrated. The residue was crystallized from ethyl acetate to give 71 g (66%) of the desired product, mp 157° C. A 5-L flask was set up with an overhead stirrer temperature probe, and 500-mL addition funnel The resulting suspension was heated at reflux for 18 hours The reaction vessel was cooled placed in an ice bath cautiously quenched with 100 mL water, 100 mL 1N NaOH, and 300 mL water The resulting suspension was treated with chloroform (1.5 L) The resulting suspension was treated with acetic anhydride (300 mL) while maintaining the pH at approximately 12 The reaction mixture was treated with sodium sulfate (800 g) and potassium carbonate (200 g) the reaction mixture was filtered The filter cake was washed with additional chloroform the combined filtrates were concentrated The residue was crystallized from ethyl acetate

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

実験手順: A pressure reactor was charged with 2-methyl-4-nitro-1H-isoindole-1,3(2H)-dione (59.0 g, 0.286 mol), 1 L acetic acid, and 2 q 5% Pd/C. The reactor was pressurized to 48 psi hydrogen, and the exothermic reaction was complete in 2 hours. The catalyst was removed with hot filtration, and the filtrate combined with the contents of another reactor which contained 53.2 g of 3-nitrophthalimide under the same conditions. The acetic acid was removed at the rotovap, then the salt was cracked by adding 2 M ammonium hydroxide. The slurry was stirred 30 minutes; then filtered; washed with water, ethanol, and ether; and dried at the pump to give 91.4 g, 95% of the product. the exothermic reaction The catalyst was removed with hot filtration the filtrate combined with the contents of another reactor The acetic acid was removed at the rotovap by adding 2 M ammonium hydroxide then filtered washed with water, ethanol, and ether and dried at the pump

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 5-L flask was set up with an overhead stirrer, temperature probe, and 500-mL addition funnel. The flask was charged with lithium aluminum hydride (100 g) and anhydrous tetrahydrofuran (1.5 L). The resulting suspension was treated with 4-amino-2-methyl-1H-isoindole-1,3(2H)-dione (100 g, 0.56 mol) at a rate such that the reaction did not become too vigorous. The resulting suspension was heated at reflux for 18 hours. The reaction vessel was cooled, placed in an ice bath, and cautiously quenched with 100 mL water, 100 mL 1N NaOH, and 300 mL water. The resulting suspension was treated with chloroform (1.5 L) and the pH of the suspension adjusted to 12 with 50% aqueous sodium hydroxide solution. The resulting suspension was treated with acetic anhydride (300 mL) while maintaining the pH at approximately 12. The reaction mixture was treated with sodium sulfate (800 g) and potassium carbonate (200 g), and the reaction mixture was filtered. The filter cake was washed with additional chloroform, and the combined filtrates were concentrated. The residue was crystallized from ethyl acetate to give 71 g (66%) of the desired product, mp 157° C. A 5-L flask was set up with an overhead stirrer temperature probe, and 500-mL addition funnel The resulting suspension was heated at reflux for 18 hours The reaction vessel was cooled placed in an ice bath cautiously quenched with 100 mL water, 100 mL 1N NaOH, and 300 mL water The resulting suspension was treated with chloroform (1.5 L) The resulting suspension was treated with acetic anhydride (300 mL) while maintaining the pH at approximately 12 The reaction mixture was treated with sodium sulfate (800 g) and potassium carbonate (200 g) the reaction mixture was filtered The filter cake was washed with additional chloroform the combined filtrates were concentrated The residue was crystallized from ethyl acetate

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

実験手順: A pressure reactor was charged with 2-methyl-4-nitro-1H-isoindole-1,3(2H)-dione (59.0 g, 0.286 mol), 1 L acetic acid, and 2 q 5% Pd/C. The reactor was pressurized to 48 psi hydrogen, and the exothermic reaction was complete in 2 hours. The catalyst was removed with hot filtration, and the filtrate combined with the contents of another reactor which contained 53.2 g of 3-nitrophthalimide under the same conditions. The acetic acid was removed at the rotovap, then the salt was cracked by adding 2 M ammonium hydroxide. The slurry was stirred 30 minutes; then filtered; washed with water, ethanol, and ether; and dried at the pump to give 91.4 g, 95% of the product. the exothermic reaction The catalyst was removed with hot filtration the filtrate combined with the contents of another reactor The acetic acid was removed at the rotovap by adding 2 M ammonium hydroxide then filtered washed with water, ethanol, and ether and dried at the pump

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 using the procedure for Example 102 with diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 4-amino-2-methyl-1H-isoindole-1,3(2H)-dione. MS (ES+): m/z 594.34 (100) [MH+]; HPLC: tR=1.17 min (UPLC, purity).

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 using the procedure for Example 102 with diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 4-amino-2-methyl-1H-isoindole-1,3(2H)-dione. MS (ES+): m/z 594.34 (100) [MH+]; HPLC: tR=1.17 min (UPLC, purity).

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 5-L flask was set up with an overhead stirrer, temperature probe, and 500-mL addition funnel. The flask was charged with lithium aluminum hydride (100 g) and anhydrous tetrahydrofuran (1.5 L). The resulting suspension was treated with 4-amino-2-methyl-1H-isoindole-1,3(2H)-dione (100 g, 0.56 mol) at a rate such that the reaction did not become too vigorous. The resulting suspension was heated at reflux for 18 hours. The reaction vessel was cooled, placed in an ice bath, and cautiously quenched with 100 mL water, 100 mL 1N NaOH, and 300 mL water. The resulting suspension was treated with chloroform (1.5 L) and the pH of the suspension adjusted to 12 with 50% aqueous sodium hydroxide solution. The resulting suspension was treated with acetic anhydride (300 mL) while maintaining the pH at approximately 12. The reaction mixture was treated with sodium sulfate (800 g) and potassium carbonate (200 g), and the reaction mixture was filtered. The filter cake was washed with additional chloroform, and the combined filtrates were concentrated. The residue was crystallized from ethyl acetate to give 71 g (66%) of the desired product, mp 157° C. A 5-L flask was set up with an overhead stirrer temperature probe, and 500-mL addition funnel The resulting suspension was heated at reflux for 18 hours The reaction vessel was cooled placed in an ice bath cautiously quenched with 100 mL water, 100 mL 1N NaOH, and 300 mL water The resulting suspension was treated with chloroform (1.5 L) The resulting suspension was treated with acetic anhydride (300 mL) while maintaining the pH at approximately 12 The reaction mixture was treated with sodium sulfate (800 g) and potassium carbonate (200 g) the reaction mixture was filtered The filter cake was washed with additional chloroform the combined filtrates were concentrated The residue was crystallized from ethyl acetate