With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.37418-88-5,4-Hydroxyisobenzofuran-1,3-dione,as a common compound, the synthetic route is as follows.
7-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.55 g, 3.85 mmol) was cooled in an ice bath and then dissolved in a solution of 20 % trifluoroacetic acid/dichloromethane (15 ml). The reaction was stirred and allowed to slowly warm to ambient temperature during 3 hours. The solution was concentrated in vacuo to give crude 2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)isoindole-1,3-dione which was used directly in the following step (assumed 100 % yield). 1H-NMR (400 MHz, CDCl3): delta 9.26 (bs, 1H), 8.19 (bs, 1H), 7.78-7.75 (m, 2H), 7.74-7.71 (m, 2H), 4.11-3.98 (m, 5H), 3.90-3.79 (m, 3H), 3.26-3.17 (m, 1H), 2.10-2.00 (m, 3H), 1.92-1.88 (m, 1H). To a suspension of the above 2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)isoindole-1,3-dione (3.85 mmol) in absolute ethanol (25 ml) was added hydrazine (0.36 ml, 11.55 mmol). The reaction was stirred at 80 C (oil bath) for 6 hours, then cooled to ambient temperature and stirred for an additional 12 hours. The thick precipitate was filtered off and washed with ethanol. The filtrate was concentrated in vacuo and reconstituted in dichloromethane (20 ml), forming a small amount of a second precipitate, which was filtered off. The filtrate was evaporated in vacuo and the resulting oil was dissolved in water (10 ml) and basified with 1N sodium hydroxide until pH = 10. The aqueous layer was extracted with 20 % isopropyl alcohol/chloroform (12 x 40 ml). The combined organic extracts were dried (K2CO3), filtered and the solvent evaporated in vacuo affording 0.42 g (63 %) of (1,4-dioxa-8-aza-spiro[4.5]dec-7-yl)methylamine as an oil. 1H-NMR (300 MHz, CDCl3): delta 3.94 (bs, 4H), 3.11-3.05 (m, 1H), 2.81 (dt, 1H, J = 12 Hz and J = 3 Hz), 2.76-2.65 (m, 2H), 2.58-2.50 (m, 1H), 1.70-1.57 (m, 3H), 1.31 (t, 1H, J = 12 Hz). APCI-MS: m/z: 173.2 [M+H]+ To a solution of 4-hydroxy-isobenzofuran-1 ,3-dione (0.51 g, 3.09 mmol) in anhydrous N,N-dimethylformamide (7 ml) under nitrogen was added sodium hydride (130 mg, 3.25 mmol). Immediate evolution of gas and bright yellow color was observed. The mixture was stirred for 5 minutes after which benzyl bromide (1.8 ml, 15.45 mmol) was added. The reaction was stirred for 72 hours. Saturated sodium bicarbonate (2 ml) was added and the mixture stirred for 2 minutes, diluted in ethyl acetate (35 ml) and washed with saturated sodium bicarbonate (5 ml), 1N hydrochloric acid (5 ml), and brine (2 x 5 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo. To the crude material was added hexane and the formed precipitate was filtered off, washed further with hexane and dried in vacuo to give 0.54 g (69 %) of 4-(benzyloxy)-isobenzofuran-1,3-dione as a solid. 1H-NMR (300 MHz, CDCl3): delta 7.74 (t, 1H, J = 8 Hz), 7.54 (d, 1H, J = 8 Hz), 7.47-7.29 (m, 6H), 5.36 (s, 2H). A solution of (1,4-dioxa-8-aza-spiro[4.5]dec-7-yl)methylamine (0.19 g, 1.1 mmol) and 4-(benzyloxy)-isobenzofuran-1,3-dione (0.27 g, 1.05 mmol) was prepared in a mixture of distilled dichloromethane (3 ml) and anhydrous N,N-dimethylformamide (2.5 ml) under nitrogen. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g, 1.21 mmol) was added followed by triethylamine (0.46 ml, 3.3 mmol) and the reaction stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and the residue diluted with ethyl acetate (25 ml) and washed with water (5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The organic layer was evaporated in vacuo and the residue purified by silica gel chromatography using a mixture of 5 % methanol/dichloromethane/1 % triethylamine as eluent. Pure fractions were collected and the solvent evaporated in vacuo affording 0.22 g (50 %) of 4-benzyloxy-2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione as a semi-solid. 1H-NMR (400 MHz, CDCl3): delta 7.57 (t, 1H, J = 8 Hz), 7.48 (d, 2H, J = 7 Hz), 7.42-7.29 (m, 4H), 7.18 (d, 1H, J = 8 Hz), 5.31 (s, 2H), 3.94-3.90 (m, 4H), 3.65 (d, 2H, J = 6 Hz), 3.16-3.09 (m, 1H), 3.07-3.02 (m, 1H), 2.76 (dt, 1H, J = 13 Hz and J = 3 Hz), 1.78 (d, 1H, J = 12 Hz), 1.64-1.54 (m, 3H), 1.37 (t, 1H, J = 12 Hz), 1.08 (t, 1 H, J = 7 Hz). LC-MS: Rt=2.59 min, m/z: 409 [M+H]+ To a solution of the above 4-benzyloxy-2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione (0.22 g, 0.54 mmol) in 1,4-dioxane (4 ml) was added 4N hydrochloric acid (4 ml) and the reaction stirred in a 65 C (oil bath) for 6 hours. The mixture was basified with saturated sodium bicarbonate until pH = 8 and extracted with dichloromethane (3 x 20 ml). The combined organic extracts were dried (MgSO4), filtered, and the solvent evaporated in vacuo affording crude 4-benzyloxy-2-(4-oxo-piperidin-2-ylmethyl)-isoindole-1,3-dione as an oil. Which was used without further purification or characterization. The above crude 4-benzyloxy-2-(4-oxo-piperidin-2-ylmethyl)-isoindole-1,3-dione (0.17 g, 0.47 mmol) was dissolved in dichloromethane (4…, 37418-88-5
37418-88-5 4-Hydroxyisobenzofuran-1,3-dione 96580, abenzofuran compound, is more and more widely used in various fields.
Reference£º
Patent; NOVO NORDISK A/S; Ontogen Corporation; EP1214324; (2006); B1;,
Benzofuran – Wikipedia
Benzofuran | C8H6O – PubChem