2-Chloropropane → (4-Cyano-3-fluorophenyl)boronic acid

Temperature

16 °C

A solution of 2-fluoro-4-bromobenzonitrile (18, 12.5 Kg, 62.5 mol) in anhydrous tetrahydrofuran (THF, 30 L) was treated with a solution of isopropylmagnesium chloride generated from magnesium (Mg, 1.8 Kg, 150 mol, 1,2 equiv) an 2-chloropropane (7.2 Kg, 92 mol, 1.47 equiv) in THF (20 L) and 2-(2-(dimethylamino)ethoxy)-N,N-dimethylethanamine (11 Kg, 69 mol, 1.1 equiv) at room temperature. The resulting mixture was then stirred at 12-20° C. for an additional 2 h before being treated with trimethylborate (9 Kg, 86.7 mol, 1.4 equiv) at 10-15° C. The reaction mixture was stirred at 7-16° C. for 40 min. When TLC and LC/MS showed that the reaction was deemed complete, the reaction mixture was quenched with 1 N aqueous hydrochloric acid (HCl, 35 Kg) at room temperature. The quenched aqueous reaction mixture was then extracted with ethyl acetate (EtOAc, 4×35 L). The combined organic extracts were washed with water (50 L), dried over magnesium sulfate (MgSO4), and concentrated under the reduced pressure. The residual solids were then recrystallized from acetonitrile (20 L) and hexanes (45 L) to afford the corresponding crude 3-fluoro-4-cyanophenyl boronic acid (5.0 Kg, 48% yield).

1. customat room temperature
2. stirringThe reaction mixture was stirred at 7-16° C. for 40 min
3. customthe reaction mixture was quenched with 1 N aqueous hydrochloric acid (HCl, 35 Kg) at room temperature
4. extractionThe quenched aqueous reaction mixture was then extracted with ethyl acetate (EtOAc, 4×35 L)
5. washThe combined organic extracts were washed with water (50 L)
6. dry with materialdried over magnesium sulfate (MgSO4)
7. concentrationconcentrated under the reduced pressure
8. customThe residual solids were then recrystallized from acetonitrile (20 L) and hexanes (45 L)

ORD record

ord-fc6079666ebd4f19ae248b96723689b9

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08420645B2