Phosphorus oxychloride → 3-(3-chloro-1H-pyrazol-1-yl)pyridine

A 250 mL, 3-neck round bottom flask was charged with methyl 2-acetamidoacrylate (4.91 g, 34.3 mmol) and ethanol (40 mL). 3-Hydrazinopyridine dihydrochloride (5 g, 27.5 mmol) was added, followed by sodium ethoxide (7.48 g, 110 mmol) and the reaction was stirred at 60° C. for 6 hours, at which point thin layer chromatography analysis [Eluent: 10% methanol/dichloromethane] indicated that the starting material had disappeared and a major product had formed: ESIMS m/z 221 ([M+H]+). The reaction was allowed to cool to room temperature and concentrated to afford a yellow solid. The resulting solid was slowly charged with phosphoryl chloride (29.2 g, 191 mmol). The reaction was stirred at 60° C. for 3 hours, at which point a sample of the reaction mixture was diluted with water and basified with 50 wt % sodium hydroxide solution. The resulting solution was extracted with ethyl acetate and the organic layer was analyzed by thin layer chromatography [Eluent: ethyl acetate], which indicated that the reaction was complete. The reaction mixture was concentrated at 40° C. to remove phosphoryl chloride and the residue was slowly quenched with water (40 mL) at <30° C. The resulting solution was basified with 50 wt % sodium hydroxide solution and the resulting suspension was extracted with ethyl acetate (3×50 mL). The organic layers were concentrated to dryness and the residue was purified by flash column chromatography using 40-50% ethyl acetate/hexanes. The fractions containing the pure product were concentrated to dryness to afford a white solid, which was further dried under vacuum at room temperature to afford the desired product as a white solid (2.4 g, 49%): mp 104-106° C.; 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=27 Hz, 1H), 8.57 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.47-7.34 (m, 1H), 6.45 (d, J=2.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 148.01, 142.72, 140.12, 135.99, 128.64, 126.41, 124.01, 108.08; EIMS m/z 179 ([M]+).

1. customa major product had formed
2. concentrationconcentrated
3. customto afford a yellow solid
4. extractionThe resulting solution was extracted with ethyl acetate
5. concentrationThe reaction mixture was concentrated at 40° C.
6. customto remove phosphoryl chloride
7. customthe residue was slowly quenched with water (40 mL) at <30° C
8. extractionthe resulting suspension was extracted with ethyl acetate (3×50 mL)
9. concentrationThe organic layers were concentrated to dryness
10. customthe residue was purified by flash column chromatography
11. additionThe fractions containing the pure product
12. concentrationwere concentrated to dryness
13. customto afford a white solid, which
14. customwas further dried under vacuum at room temperature

ORD record

ord-8af7caab302642b994091a73d8abf4de

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09414594B2