Hydrochloric Acid → 3-(3-chloro-1H-pyrazol-1-yl)pyridine

Temperature

0 °C

To a 3-neck round bottomed flask (250 mL) was charged 3-(3-amino-1H-pyrazol-1-yl)pyridine (5.00 g, 31.2 mmol) and hydrogen chloride (37 wt %, 15 mL). The mixture was cooled to 0° C. A solution of sodium nitrite (4.31 g, 62.4 mmol) in water (15 mL) was added in portions at <1° C. over 20 minutes and the resulting brown solution was stirred at <0° C. for 2 hours. To a separate 3-neck round bottomed flask (250 mL) was charged copper(II) chloride (5.04 g, 37.5 mmol) and toluene (30 mL). It was cooled to 0° C. and the yellow solution was added in portions at <1° C. over 15 minutes. The resulting mixture was allowed to warm up, off-gassing was observed when the reaction temperature reached 18° C. The reaction was stirred at 20° C. for 18 hours. The reaction was basified with 50 wt % sodium hydroxide to pH ˜10. Celite® (10 g) was added and the resulting suspension was stirred for 10 minutes. The suspension was filtered through a Celite® pad (10 g) and the filter cake was rinsed with ethyl acetate (2×50 mL). The layers of the filtrates were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were concentrated to dryness and the residue was purified by flash column chromatography using 0-60% ethyl acetate/hexanes as eluent. The fractions containing the desired product were concentrated to give the title compound as a white solid (3.80 g, 68%): mp 104-106° C.; 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=2.7 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. temperatureIt was cooled to 0° C.
2. additionthe yellow solution was added in portions at <1° C. over 15 minutes
3. temperatureto warm up
4. customreached 18° C
5. stirringThe reaction was stirred at 20° C. for 18 hours
6. additionCelite® (10 g) was added
7. stirringthe resulting suspension was stirred for 10 minutes
8. filtrationThe suspension was filtered through a Celite® pad (10 g)
9. washthe filter cake was rinsed with ethyl acetate (2×50 mL)
10. customThe layers of the filtrates were separated
11. extractionthe aqueous layer was extracted with ethyl acetate (100 mL)
12. concentrationThe organic layers were concentrated to dryness
13. customthe residue was purified by flash column chromatography
14. additionThe fractions containing the desired product
15. concentrationwere concentrated

ORD record

ord-63a151d966b645599dda9cefb9e8b148

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09199964B1