Dichloromethane → 887781-62-6

Temperature

0 °C

The boronate ester of step 3 of example 1 (20 g, 40 mmoles) and the aryl bromide of step 2 of example 1 (11.4 g, 48 mmoles) were dissolved in dimethylformamide (400 mL) followed by an aqueous solution of sodium bicarbonate (60 mL, 120 mmoles). Nitrogen was then bubbled through a pipette for 15 minutes. [1,1-Bis(diphenylphosphine)ferrocene]dichloropalladium(II), 1:1 complex with dichloromethane (PdCl2dppf.CH2Cl2, 2.4 g, 3 mmoles) was added and the reaction mixture immersed in an oil bath at 80° C. for 16 hours under a nitrogen atmosphere. Most of the dimethylformamide was removed under the rotovap at low pressure (45° C., approx 1-5 mm Hg). The residue was dissolved in ethyl acetate (400 mL) and filtered onto a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was taken-up in approx 10 mL of dichloromethane and separated by flash chromatography. The most pure fractions were swished in hexanes (100 mL) at 0° C. overnight three times and flashed again (90% hexanes; 10% ethyl acetate to 45 hexanes; 55% ethyl acetate). After evaporation of the volatiles under reduced pressure, the solid was stirred in hexanes for 2 days. The product still contained 4% of pinacol so the batch was divided in two. Fraction A was dissolved in a minimum of isopropyl alcohol with gentle warming. Hexanes were added until the solution was a bit cloudy and let cool down. White crystals appeared and the reaction was further cooled to 0° C. for 15 minutes. The solids were collected by filtration to obtain the product not contaminated with pinacol. Fraction B was stirred in 20% diethyl ether; 1% ethyl acetate; 79% hexanes (100 mL) for 3 hours at room temperature. The solids were collected by filtration was contaminated with only approximately 1% pinacol by 1H NMR. The enantiomeric excess was verified chiral AD-RH using 32% acetonitrile; 68% water; 0.1% formic acid; isocratic (24 min for enantiomer and 27 minutes for desired molecule). (MH)+ ESI=528.0.

1. customNitrogen was then bubbled through a pipette for 15 minutes
2. customMost of the dimethylformamide was removed under the rotovap at low pressure (45° C., approx 1-5 mm Hg)
3. dissolutionThe residue was dissolved in ethyl acetate (400 mL)
4. filtrationfiltered onto a pad of Celite
5. concentrationThe filtrate was concentrated under reduced pressure
6. customseparated by flash chromatography
7. waitThe most pure fractions were swished in hexanes (100 mL) at 0° C. overnight
8. customAfter evaporation of the volatiles under reduced pressure
9. dissolutionFraction A was dissolved in a minimum of isopropyl alcohol with gentle warming
10. additionHexanes were added until the solution
11. temperaturelet cool down
12. filtrationThe solids were collected by filtration
13. customto obtain the product not
14. filtrationThe solids were collected by filtration
15. custom24 min
16. customfor enantiomer and 27 minutes

ORD record

ord-6101aa5ade41469e862f6fe9f552cfce

Source dataset

uspto-grants-2008_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07407959B2