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c) Synthesis of 2-[(E)-2-phenylethenyl] -3-[(phenylm- ethyl)oxy]-4H-pyran-4-one (compound P-4). To a solution of 882 g of compound P-3 (1.0 eq.) in 8.82 L of THF were added 416 g of Et3N (1.5 eq.) and 408 g ofmethanesulfonyl chloride (1.3 eq.) at less than 30 C. After 5 confirmation of disappearance of compound P-3, 440mE of NMP and 1167 g of DI3U (2.8 eq.) were added to the reaction mixture at less than 30 C. and the reaction mixture was aged for 30 mm. The mixture was neutralized with 1.76 E of 16% sulthric acid and the organic ?0 layer was washed with 1.76 E of 2% Na2SO3aq. After concentration of the organic layer, 4.41 E of toluene was added and the mixture was concentrated (three times). Afier addition of 4.67 E of hexane, the mixture was cooled with ice bath. Filtration, washing with 1.77 E of 15 hexane and drying provided 780 g of compound P-4 (94% yield) as a solid. ?H NMR (300 MHz, CDC13) oe 7.69 (d, J=5.7 Hz, 1H), 7.50-7.25 (m, 1OH), 7.22 (d, J=16.2 Hz, 1H), 7.03 (d, J=16.2 Hz, 1H), 6.41 (d, J=5.7Hz, 1H), 5.27 (s, 2H). 20
93.6%
Example 1.2; 3-Benzyloxy-2-(2-hydroxy-2-phenyl-ethyl)-pyran-4-one 3a to 3-Benzyloxy-2-((E)- styryl)-pyran-4-one 4a; 3a [MW=322.35] 882.3g THF 8.8L (10V)TEA [MW=I 01.19] 415.5g (1.5eq) MsCI [MW=114.54] 407.5g (1.3eq) NMP 44OmLDBU [MW=152.24] 1166.8g (2.8eq)To the solution of 3a and TEA in THF (8.8L) was added dropwise MsCI at room temperature. (22.8C-29C) and stirred for 30min. (TLC check). After addition of NMP to this reaction mixture, DBU was added dropwise over 1hr. (25-27C), followed by dropwise addition of 1.76L solution: 1 :4 mixture of 62% H2SO4:13%NaCI. (16-27C) The reaction mixture was extracted with AcOEt, and the extracts was washed with 2%Na2S03aq. The organic layer was evaporated in vaccuo and 5V of toluene was added, again evaporated. Evaporation was stopped when volume was reduced to ca 2V. After crystalline appears (seeding is preferred), 6V of hexane was added and cooled with an ice bath. Crystalline solid was collected by filtration and washed with 2V of hexane. A second lot was conducted and 1559.6g of compound 4a was obtained (93.6% yield).
87%
Step C - Synthesis of Intermediate Compound Id Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-(benzyloxy)-2-(2-hydroxy-2-phenylethyl)-4H-pyran-4-one lc (900 g, 2.79 mol, 1.00 equiv), dichloromethane (4.5 L), TEA (423.8 g, 4.19 mol, 1.50 equiv). This was followed by the addition of MsCl (419.0 g, 3.66mol, 1.31 equiv) dropwise with stirring at -30C. The resulting solution was stirred for 2 h at -30C. To this was added DBU (1.698 kg, 11.15mol, 4.00 equiv) dropwise with stirring at 0C. The resulting solution was stirred for an additional 20 min at 0C. The pH of the solution was adjusted to 5 with hydrogen chloride (cone). The combined organic layer was washed with 3x3 L of Na2S03, dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 3-(benzyloxy)-2-[(E)-2- phenylethenyl]-4H-pyran-4-one (740 g, 87% yield) Id as a yellow solid.