反应详情

A mixture of crude 3-chloro-4-cyano-5-(3-methoxyphenyl)pyridine 1-oxide from Step 2 and phosphorus oxychloride (15 mL) in a sealed tube was placed in a 100° C. bath. After 1 h at 100° C., HPLC analysis indicated that a 2:1 mixture of products was formed. The mixture was concentrated. Recrystallization from ethyl acetate/hexanes (10 mL/10 mL) gave 2,3-dichloro-5-(3-methoxyphenyl)isonicotinonitrile as white solid (200 mg). The mother liquor was purified by reverse phase HPLC, using Sunfire S10 30×250 mm column and eluting with 80-100% solvent B (90% methanol-10% water-0.1% TFA) in solvent A (10% methanol-90% water-0.1% TFA), to give additional 2,3-dichloro-5-(3-methoxyphenyl)isonicotinonitrile (400 mg). 1H NMR (500 MHz, methanol-d4) δ ppm 8.54 (1H, s), 7.45 (1H, t, J=7.97 Hz), 6.77-7.28 (3H, m), 3.86 (3H, s); MS (ES+) m/z: 279 (M+H); LC retention time: 3.768 min (analytical HPLC Method A). No attempt was made to isolate the undesired 2,5-dichloro-3-(3-methoxyphenyl)isonicotinonitrile isomer.

1. customwas placed in a 100° C.
2. additionHPLC analysis indicated that a 2:1 mixture of products
3. customwas formed
4. concentrationThe mixture was concentrated
5. customRecrystallization from ethyl acetate/hexanes (10 mL/10 mL)