Acetonitrile → HCID 66934476, compound

Temperature

-78 °C

At −78° C. in a 3 neck flask under argon atmosphere, anhydrous acetonitrile (0.150 g, 3.68 mmol) was added to dry ether (2 mL) followed by dropwise addition of LDA (1.84 mL, 3.68 mmol, 2.0M solution in cyclohexanes). The solution was stirred at −78° C. for 20 min. In a separate flask at 0° C. under argon, BF3Et2O (0.260 g, 0.19 mmol) was added to a solution of (S)-N-((5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methylene)-2-methylpropane-2-sulfinamide (0.750 g, 1.84 mmol) in dry ether (10 mL). The pre-complexed sulfinylimine solution was transferred to the anion solution via syringe dropwise at −78° C. After 30 min the orange solution was quenched by the addition of 1.0M HCl (ca. 10 mL) and the reaction mixture transferred to a separation funnel and extracted with EtOAc (3×20 mL). The combined organic portions were dried over Na2SO4, decanted, concentrated and the diastereomers purified by silica gel ISCO chromatography on 120 g column, 0-90% EtOAc/hexanes. (S)-N-((R)-1-(5-chloropyridin-2-yl)-2-cyano-1-(3-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide eluted next and was isolated as the major product (0.23 mg, 28% yield). Rf0.8 (Hexane:EtOAc 1:1) LCMS: 1.84 min [M+1] 448.1 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.58 min (4 min gradient, MeOH/H2O 0.2% PPA); Purity 99%; NMR: 400 MHz 1H (CDCl3) 8.62 ppm, d, J=2.6 Hz; 7.73 ppm, dd, J=2.6 and J=8.8 Hz; 7.38, 1H, s; 7.32 ppm, 1H, d, J=7.9 Hz; 7.20 ppm, 2H, d, J=8.8 Hz; 5.87 ppm, 1H, s; 3.76 ppm, 1H, d, J=16.7 Hz; 3.67 ppm, 1H, d, J=16.7 Hz; 1.36 ppm, 3H, s. (S)-N-((S)-1-(5-chloropyridin-2-yl)-2-cyano-1-(3-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide eluted last and was isolated as the a pale yellow oil (0.088 mg, 11% yield). Rf0.7 (Hexane:EtOAc 1:1) LCMS: 1.90 min [M+1] 448.1 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.65 min (4 min gradient, MeOH/H2O 0.2% PPA); Purity 99%.

1. customAfter 30 min the orange solution was quenched by the addition of 1.0M HCl (ca. 10 mL)
2. customthe reaction mixture transferred to a separation funnel
3. extractionextracted with EtOAc (3×20 mL)
4. dry with materialThe combined organic portions were dried over Na2SO4
5. customdecanted
6. concentrationconcentrated
7. customthe diastereomers purified by silica gel ISCO chromatography on 120 g column, 0-90% EtOAc/hexanes

ORD record

ord-be58406373df46c0b43df65fc245b38e

Source dataset

uspto-grants-2011_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07888376B2