mavatrep synthesis

Yield: 36.5%

Reaction Conditions:

with sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride in 1,2-dimethoxyethane;water for 18 h;Product distribution / selectivity;Heating / reflux;

Steps:

10.1.E
A 5-L 4-neck flask equipped with a thermocouple controller, condenser, overhead mechanical stirrer, Firestone valve and a nitrogen inlet/outlet was charged with dimethoxyethane (2 L), Dl water (1 L) and sodium carbonate (230.9 g, 2.18 mol). The solution was degassed and purged with N₂ three times. Compound 10e (71.7 g, 0.35 mol) and Compound 10c (100.0 g, 0.27 mol) were added to the degassed solution. The solution was degassed and purged with N₂ three times. PdCl₂(dppf) (44.48 g, 54.4 mmol) was added to the solution, and the solution was degassed and purged with N₂ three times. The resulting two-phase suspension was heated to reflux for 18 h, and then cooled to room temperature. The reaction mixture was transferred to a 12-L seatory funnel, and the layers were separated. The organic layer was washed with brine (1 L). The two aqueous layers were combined and extracted with EtOAc (1 L). The combined organic layers were dried (Na₂SO₄), filtered, and the filtrate was concentrated to an oil. Two seate 100 g coupling reactions were combined and purified by chromatography in 10 successive chromatography runs on an ISCO preparative chromatography system (10×1.5 Kg SiO2, 5 column volumes of EtOAc, 250 mL/min flow rate). The combined fractions were transferred to two 22 L 4-neck round bottom flasks, and Silicycle Si-thiol functionalized silica gel (2 g) was added to each solution. The solutions were warmed to 40° C. and aged for 1 h. The solutions were filtered thru a medium glass funnel and washed with EtOAc (4 L) and combined. The filtrate was evaporated to a semi solid, which was transferred to a 2 L round bottom flask, to which EtOAc (0.4 L) was added. The resulting white precipitate slurry was cooled to -5° C. and stirred for 1 h. The slurry was filtered and washed twice with cold EtOAc (100 mL). The solids were dried in a vacuum oven at 40° C. for 40 h to afford 84.0 g (36.5% yield, 98.8 area % purity) of the title Compound 18 as a white solid. Anal. Calcd for C₂₅H₂₁N₂OF₃ 0.04% H₂O 0.15 mol MeOH: C, 70.48; H, 5.14: N, 6.42; F, 13.06 Found: C, 70.54; H, 4.83: N, 6.18; F, 13.33

References:

Location in patent:Page/Page column 172