Electric Literature of 21544-81-0, In the chemical reaction process, reaction time, type of solvent, can easily affect the result of the reaction, thereby determining the yield and properties of the reaction product. An updated downstream synthesis route of 21544-81-0 as follows.
Electric Literature of 21544-81-0, In the chemical reaction process, reaction time, type of solvent, can easily affect the result of the reaction, thereby determining the yield and properties of the reaction product. An updated downstream synthesis route of 21544-81-0 as follows.
A solution of 3,5-dimethoxyaniline (199 g, 1.30 mol) in ether (5.0 L) in a 5 L 3-necked flask was cooled to 0C. HCI gas (227 g) was bubbled through the solution over 45 min. After 45 min at 10C, the mixture was filtered, washed with isopropylacetate (4 L), and dried overnight on high vacuum at 45C to give the hydrochloride (242.3 g, 98%), as a white solid. A mixture of the hydrochloride above (20 g, 0.105 mol) and oxalyl chloride (33 mL) in a 3-necked flask equipped with a reflux condenser was heated for 2 h with stirring (170C external temperature), and the oxalyl chloride was distilled from the reaction mixture. The flask was cooled to 0C and methanol (40 mL) was added. The reaction mixture was heated to reflux for 45 min, filtered while hot, and washed with methanol (80 mL) to give the 4,6-dimethoxyisatin (17.2 g, 79%) as a yellow-green solid. To a heated solution (external temp 70C) of the isatin (162 g, 0.78 mol) in aqueous NaOH (40%, 1.5 L) was added H2O2 (35%, 405 mL) slowly over 2 h. After the addition of each portion of H2O2, the internal reaction temperature (initially 64C) increased (to a maximum temp of 80C). After the addition was complete, the foaming reaction mixture was then stirred for an additional 2 h at 70C, and the mixture was allowed to stir overnight while cooling to RT. The mixture was heated to 70C. Additional H2O2 (75 mL) was added, and the mixture was stirred at 70C for a further 2 h until the reaction was complete. After cooling to 10C (bath temperature), aqueous Na2S2O3 (150 mL, saturated) was added. The mixture was brought to pH 8 with HCI (37%, 1.6 L) and pH 6 with acetic acid (glacial, 75 mL), without allowing the reaction mixture to warm to greater than 40C. Filtration of the reaction mixture and washing with water (4 L) gave the expected amino acid as a tan solid (83.7 g, 55%). To a solution of the amino acid (82.7 g, 0.42 mol) in anhydrous THF (4.2 L) was added EDCI (89.2 g, 0.48 mol), HOBT (65 g, 0.48 rnol), and NMM (51.3 mL), and the mixture was allowed to stir at RT for 3 h. Aqueous NH3 (83 mL, 50%) was added, and the mixture was stirred at RT for 16 h. Water (1.25 L) was added, and the mixture was extracted with DCM (2×250 mL). The combined extracts were then washed with water (2×500 mL). Concentration, formation of a slurry with ether (550 mL), filtration, and drying under high vacuum gave 2-amino-4,6-dimethoxybenzamide (46.7 g,57%) as a brown solid. [0111] 2-Amino-4,6-dimethoxy-benzamide (1.06 g, 5.4 mmol), 3,5-dimethyl- 4-hydroxybenzaldehyde (0.810 g, 5.4 mmol), K2CO3 (0.747 g, 5.4 mmol) and I2 (1.645 g, 6.5 mmol) were mixed in DMF (20 ml_) and the reaction mixture was heated at 80C for 12 h. It was cooled to RT and poured into crushed ice. The solid was collected and purified by column chromatography to give 2-(4-hydroxy- 3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4<3H)-one (0.9 g, 51%) as a white solid. Selected data: MP 291-293C.
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Reference:
Patent; Resverlogix Corp.; WO2008/92231; (2008); A1;,
Indoline – Wikipedia,
Indoline | C8H9N – PubChem