Ammonium Chloride → 5-Chloropyrazinamide

Temperature

0 °C

Suspend ammonium chloride (0.465 g, 8.69 mmol) in toluene (14 mL). Cool to 0° C. and slowly add 2.0 M Al(CH3)3 in toluene (4.3 mL, 8.69 mmol). After the gas stops evolving, add 5-chloropyrazine-2-carboxylic acid methyl ester (0.500 g, 2.89 mmol). Heat at 50° C. overnight. Cool the reaction mixture to room temperature, then slowly pour into a slurry of silica gel (10 g) in CHCl3 (50 mL). Stir for 10 minutes before filtering. Wash the silica plug with methanol (2×100 mL) before concentrating. Take the resulting solid up in dichloromethane and wash with water (30 mL) and brine (40 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 50% ethyl acetate in hexanes to give the title compound (0.155 g, 34.0%): TOF MS EI+ 157.0 (M+), HRMS calcd for C5H4N3OCl 157.0043 (M+H)+, found 157.0047, time 4.19 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min. 5-95% over 19 min], tR=7.1 min, 100% purity.

1. temperatureHeat at 50° C. overnight
2. temperatureCool the reaction mixture to room temperature
3. filtrationbefore filtering
4. washWash the silica plug with methanol (2×100 mL)
5. concentrationbefore concentrating
6. washwash with water (30 mL) and brine (40 mL)
7. dry with materialDry the organic layer over Na2SO4
8. filtrationfilter
9. concentrationconcentrate
10. customPurify by flash chromatography
11. washeluting with 50% ethyl acetate in hexanes

ORD record

ord-f1902f65c0ef4e5489d9b8f5743aee32

Source dataset

uspto-grants-2009_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07560463B2