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Stage #1: With sodium hydrogencarbonate In water at 3℃; for 0.25 h; Stage #2: at 3 - 20℃; for 4 h;
5-Hydroxy-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl esterSolid NaHCO3 (70.35 g, 0.8375 mol, 2.5 equiv) was added slowly portion wise to a near solution of crude 2,3-Dihydro-1 H-isoindol-5-ol hydrobromide (72.02 g, 0.335 mol) in H2O (750 mL) at ~3 0C. When addition was complete, the reaction mixture was stirred for 15 min 5 then diluted with THF (500 mL). A solution of BoC2O (73.03 g, 0.335 mol) in THF (200 mL) was added over 0.5 h at 3-4 0C. The brown reaction mixture was stirred at ~3 0C for 0.5 h then allowed to warm to room temperature and stirred for 3 h. The reaction mixture was diluted with EtOAc (1.5 L) and the organic solution washed with brine, dried (Na2SO4) and the solvent removed in vacuo giving a dark brown solid. The crude product was absorbed onto 0 silica gel using DCM and added to a column of silica gel (2 kg) packed in heptane. Elution with heptane to.heptane/EtOAc (3:1) gave a light brown solid that was slurried in heptane, filtered, washed with heptane and dried to give 39.82 g (51percent) of 5-Hydroxy-1 ,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester as an off-white solid. MS: APCI: M-C4H9+1: 180.0 (179.0).
Stage #1: With borane-THF In tetrahydrofuran at -5 - 80℃; for 19 h; Stage #2: With hydrogenchloride In methanol; water at 0 - 80℃; for 3 h; Stage #3: With triethylamine In methanol; water at 22℃; for 0.5 h;
Preparation of 2,3-dihydro-5-hydroxy-1H-isoindole (7); tert-Butyl 5-hydroxy-1,3-dihydroisoindole-2-carboxylate (6): 750 ml of a 1M borane/THF solution are added dropwise to 20.4 g (125 mmol) of hydroxyisoindole-1,3-dione in 300 ml of THF (dry) at -5° C. over a period of 60 min. The mixture is subsequently stirred for 2 h at 22° C. and then for 16 h at 80° C. The mixture is then cooled to 0° C., before 100 ml of methanol (exothermic.) and 100 ml of 2M hydrochloric acid are slowly added. The resultant mixture is stirred for 3 h at 80° C., cooled to 22° C., and 100 ml of water are added. The aqueous solution is extracted three times with 150 ml of dichloromethane each time. 27.8 g (125 mmol) of di-tert-butyl dicarbonate and 12.6 g (125 mmol) of triethylamine are then added to this aqueous solution, and the mixture is then stirred for 30 min at 22° C. The mixture is subsequently extracted three times with 100 ml of dichloromethane each time, the organic phases are dried over sodium sulfate, filtered, and the filtrate is evaporated to dryness in vacuo. Trituration with petroleum ether gives 6.7 g (22percent) of pale-beige crystals; 1H-NMR (500 MHz, DMSO-d6/TFA-d1, 90° C.): δ [ppm] 7.093 (m, 1H), 6.709 (m, 2H), 4.486 (m, 4H), 1.457 (s, 9H); MW 235.3.
Stage #1: 5-hydroxy-isoindoline hydrobromide With sodium hydrogencarbonate In water at 3℃; for 0.25h;
Stage #2: di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran; water at 3 - 20℃; for 4h;
5-Hydroxy-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl esterSolid NaHCO3 (70.35 g, 0.8375 mol, 2.5 equiv) was added slowly portion wise to a near solution of crude 2,3-Dihydro-1 H-isoindol-5-ol hydrobromide (72.02 g, 0.335 mol) in H2O (750 mL) at ~3 0C. When addition was complete, the reaction mixture was stirred for 15 min 5 then diluted with THF (500 mL). A solution of BoC2O (73.03 g, 0.335 mol) in THF (200 mL) was added over 0.5 h at 3-4 0C. The brown reaction mixture was stirred at ~3 0C for 0.5 h then allowed to warm to room temperature and stirred for 3 h. The reaction mixture was diluted with EtOAc (1.5 L) and the organic solution washed with brine, dried (Na2SO4) and the solvent removed in vacuo giving a dark brown solid. The crude product was absorbed onto 0 silica gel using DCM and added to a column of silica gel (2 kg) packed in heptane. Elution with heptane to.heptane/EtOAc (3:1) gave a light brown solid that was slurried in heptane, filtered, washed with heptane and dried to give 39.82 g (51%) of 5-Hydroxy-1 ,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester as an off-white solid. MS: APCI: M-C4H9+1: 180.0 (179.0).
With hydrogenchloride In 1,4-dioxane at 22℃; for 1h;
2,3-Dihydro-5-hydroxy-1H-isoindole hydrochloride (7): 2 g (235.3 mmol) of tert-butyl 5-hydroxy-1,3-dihydroisoindole-2-carboxylate are dissolved in 20 ml of a 4 M hydrogen chloride solution in dioxane. After 1 h at 22° C., the mixture is evaporated to dryness in vacuo. The resultant white crystals (1.4 g (96%) MW 171.6) are employed in the following reactions without further purification.
A solution of tert-butyl 5-hydroxyisoindole-2-carboxylate (470 mg, 2.0 mmol, References Bioorg. Med. Chem. Lett., 2001, 11 (5), 685-688) and 1-bromo-4-trifluoromethoxybenzene (481 mg, 2.0 mmol) were dissolved in 1,4-dioxane (10 mL). Cuprous iodide (38 mg, 0.2 mmol), N,N-dimethylglycine (62 mg, 0.6 mmol) and cesium carbonate (977 mg, 3.0 mmol) were added and heated under reflux under argon for 24 h. The reaction was completed, filtered, concentrated and chromatographed (CH2Cl2 / CH3OH = 100/1). The resulting product was directly charged to the next step. The intermediate was obtained by dissolving the intermediate in methylene chloride (10 mL). The ice salt was cooled, and trifluoroacetic acid (10 mL) was added. The reaction was carried out at room temperature for 3 hours to stop the reaction and concentrate. The residue was dissolved in dichloromethane (100 mL), saturated sodium bicarbonate solution (50 mL), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was dried to give the intermediate TH-1 (312 mg, 53% in two steps).
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