4-(Bromoacetyl)benzonitrile → HCID 13102050, compound

Following the procedure of Corey et al. (Angew. Chem. Int. Ed., 37:1986-2012 (1998)), a solution of 4-(2-bromoacetyl)benzonitrile (10.00 g, 44.6 mmol) in THF (50 mL) was cooled to 0° C. and treated with (S)-methyl oxazaborolidine (1.0 M in toluene) (8.93 mL, 8.93 mmol) followed by borane-methyl sulfide complex (2.0 M in THF) (13.01 mL, 26.0 mmol) over 10 minutes. The reaction was stirred for 1.5 hours and then quenched by adding MeOH. The reaction was concentrated on a rotary evaporator and then extracted from 1 M HCl using DCM×3 followed by drying over MgSO4, and filtering. The crude material was concentrated in vacuo and purified on a 220 g SiO2 cartridge using 20-80% EtOAc/hexanes gradient over 10 column volumes. The product eluted in fractions 46-60 to afford 9.8 g of 4-(2-bromo-1-hydroxyethyl)-benzonitrile as a clear oil. Chiral HPLC conditions showed 80% e.e. favoring the (S) stereoisomer based on the Corey precedent. The minor (R) stereoisomer was removed by chiral HPLC using multiple runs on a Thar 350 Preparative SFC instrument equipped with a CHIRALPAK® AD-H (25×5 cm, 5 μM). Temp: 35° C.; Flow rate: 280 mL/min; Mobile phase: CO2/iPrOH in 88:12 ratio; Runtime 7.7 min; Retention time=5.1 min to give (S)-4-(2-bromo-1-hydroxyethyl)-benzonitrile in 99.8% d.e. 1H NMR (400 MHz, CDCl3) δ ppm 7.76 (2H, d), 7.56 (2H, d), 5.02 (1H, dd), 3.68 (1H, dd), 3.55 (1H, dd), 3.53 (1H, s).

1. customquenched
2. additionby adding MeOH
3. concentrationThe reaction was concentrated on a rotary evaporator
4. extractionextracted from 1 M HCl
5. dry with materialby drying over MgSO4
6. filtrationfiltering
7. concentrationThe crude material was concentrated in vacuo
8. custompurified on a 220 g SiO2 cartridge
9. washThe product eluted in fractions 46-60

ORD record

ord-fdbda5e1a4ec4ec9a5030b0e676e6944

Source dataset

uspto-grants-2013_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08399451B2