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Step 46.1: 1-(2-hydroxy-3-methylphenyl)ethanone To a colorless solution of 3-methyl-salicylic acid (1 g, 6.57 mmol) in Et2O (50 mL) under argon and cooled down to 0° C. was added dropwise methyllithium 1.6M in Et2O (12.32 mL, 19.72 mmol) over 20 min. The resulting mixture was stirred at this temperature for 30 min then allowed to warm up and stir overnight at RT. The reaction mixture was slowly poured into a stirred mixture of 100 g of ice and HCl 4N (50 mL) and extracted twice with EtOAc. The combined organic layers were washed with 10percent NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title product (920 mg, 5.94 mmol, 90percent yield) as a pale yellow oil. tR: 0.91 min (LC-MS 2); ESI-MS: 481/483 [M+H]+, ESI-MS: 479/501 [M−H]− (LC-MS 2); Rf=0.55 (hexane/EtOAc 3:1).
90%
at 0 - 20℃; Inert atmosphere
To a colorless solution of 3-methyl-salicylic acid (1 g, 6.57 mmol) in Et20 (50 mL) under argon and cooled down to 000 was added dropwise methyllithium 1.6M in Et20 (12.32 mL, 19.72mmol) over 20 mm. The resulting mixture was stirred at this temperature for 30 mm then allowed to warm up and stir overnight at RT. The reaction mixture was slowly poured into a stirred mixture of 100 g of ice and HCI 4N (50 mL) and extracted twice with EtOAc. The combined organic layers were washed with 10percent NaHCO3 solution and brine, dried over Mg504, filtered and concentrated under reduced pressure to afford the title product (920 mg, 5.94 mmol, 90percentyield) as a pale yellow oil. tR: 0.91 mm (LC-MS 2); ESl-MS: 481/483 [M+H], ESl-MS: 479/501 [M-H] (LC-MS 2); R = 0.55 (hexane/EtOAc 3:1).
49%
at 0 - 20℃; Inert atmosphere
To a colorless solution of 3-methyl-salicylic acid (10 g, 65.7 mmol) in Et20 (350 mL) under Ar and cooled down to 0 0 was added dropwise methyllithium 1.6M in Et20 (123 mL, 197 mmol) over 30 mm. The resulting mixture was stirred at this temperature for 30 mm then allowed to warm up and stir overnight at RT. The reaction mixture was poured onto a cold 2N HCI and the product was extracted with EtOAc. Combined extracts were washed with 10 percent NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title product (5.14 g, 32.5 mmol, 49 percent yield) as a pale yellow oil. tR: 0.99 mm (LC-MS 2); ESI-MS: no ionisation [M+H] (LC-MS 2); TLC (hexane/EtOAc 3:1) Rf = 0.55.
With phosphorus pentoxide-methanesulfonic acid; at 80℃; for 3h;
General procedure: To a mixture of commercially available phloroglucinol (1.2 equiv) and an appropriate substituted salicylic acid (1 equiv), 20 mL of Eaton's reagent (P2O5-CH3SO3H) was added slowly. The mixture was stirred for 3 h at 80 C, cooled to rt, and poured onto ice. After vigorous stirring at rt for 2 h, a brown solid was precipitated. The solid was collected by filtration, washed with water (pH ? 6), and dried at 60 C. In most instances, this intermediate 1,3-dihydroxy-9H-xanthen-9-one was used without further purification.
With phosphorus pentoxide-methanesulfonic acid; at 80℃; for 2h;
General procedure: 2,6-dihydroxybenzoic acid (5.0 g, 32.4 mmol) andphloroglucinol (4.09 g, 32.4 mmol) were added to Eaton?s reagent (20 mL) and heated on an 80 Coil bath for 2 h. After cooling to r.t., the dark-brown solution was transferred slowly to crushedice while being vigorously stirred. The mixture was filtered and the filter cake was washed withwater, dried, and purified by flash column chromatography to afford xanthone 3 as a yellow solid(2.3 g, yield: 29%).
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