Water → (R)-1-(6-bromo-2-methylpyridin-3-yl)-3-hydroxypyrrolidin-2-one

Beteiligte Stoffe

Reaktionsbedingungen

Reaktionsschritte

To a jacketed 5.0 liter glass reactor was added 2.150 liter of acetonitrile and 250 mL of water (10%, 27.78 moles, ˜87 molar equivalent to acetate). The temperature was set to 25° C. Then, to the same reactor was added 1-(6-bromo-2-methylpyridin-3-yl)-2-oxopyrrolidin-3-yl acetate (50 g, 0.160 moles, 20 g/L), followed by 100 mL of acetonitrile The reaction mixture was stirred for 10 min at 90 rpm until complete dissolution. To the reaction mixture added 12.5 g of Novozym 435 (Enzyme to substrate 1:4) with continuous stirring under same reaction conditions. The temperature of the reaction was maintained at 25° C. during the course of the reaction. The reaction was stopped after 28 h, and the Novozym 435 was filtered. The reaction mixture was concentrated to dryness 30° C. to yield a viscous brownish liquid. The reaction mixture was taken out in 75 ml dichloromethane and stirred it at room temperature for 1 h. To the reaction mixture was added 100 g of silica gel, and slurry was then allowed to dry under pressure. A Column was packed with ˜400 g of silica gel in heptanes and slurry was loaded into column with heptane. The column was run using 50% ethyl acetate-heptane until all the undesired chiral acetate was recovered. After the removal of acetate, the column was eluted with pure ethyl acetate and the (R)-1-(6-bromo-2-methylpyridin-3-yl)-3-hydroxypyrrolidin-2-one containing fractions were combined. The mixture was concentrated down to 50 mL under pressure at 20° C., stirred for 30 min, filtered, and washed with heptane. 16.042 g of (R)-1-(6-bromo-2-methylpyridin-3-yl)-3-hydroxypyrrolidin-2-one was obtained, as off-white solid, AP 99.4, ee 99.9% in 37% yield.

Herkunft & Nachweise