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

Temperatur

25 °C

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.

1. customwas set to 25° C
2. additionTo the reaction mixture added 12.5 g of Novozym 435 (Enzyme to substrate 1:4)
3. stirringwith continuous stirring under same reaction conditions
4. waitThe reaction was stopped after 28 h
5. filtrationthe Novozym 435 was filtered
6. concentrationThe reaction mixture was concentrated to dryness 30° C.
7. customto yield a viscous brownish liquid
8. stirringstirred it at room temperature for 1 h
9. additionTo the reaction mixture was added 100 g of silica gel, and slurry
10. customto dry under pressure
11. customwas recovered
12. customAfter the removal of acetate
13. washthe column was eluted with pure ethyl acetate
14. concentrationThe mixture was concentrated down to 50 mL under pressure at 20° C.
15. stirringstirred for 30 min
16. filtrationfiltered
17. washwashed with heptane

ORD-Eintrag

ord-1d2ad356658049a19277f1e9daae2cb2

Quelldatensatz

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09174965B2