Ethyl diazoacetate → Ethyl 5-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole-3-carboxylate

Temperature

160 °C

CuCN (1.74 g, 19.4 mmol) and LiCl (4.95 g, 117.0 mmol) were dried under high vacuum with stirring at 160° C. overnight and then cooled to room temperature. To a solution of 2-(3-butynyloxy)tetrahydro-2H-pyran (3.1 mL, 19.5 mmol) in THF at −78° C. (40.0 mL) was added n-BuLi (12.2 mL, 19.4 mmol, 1.6M solution in hexane). The resulting solution was stirred at −78° C. for 1 h and then transferred to a −78° C. suspension of CuCN.6LiCl (6.70 g, 19.5 mmol, from above) in THF (60.0 mL). The resulting reaction mixture was warmed to −17° C. (dry ice/brine) and stirred for 1.5 h. A solution of ethyl diazoacetate (2.0 mL, 19.4 mmol) in THF (40.0 mL) was then added, and the reaction mixture was stirred at −17° C. for 30 min. The ice bath was removed and stirring was continued at room temperature for 4 h. The reaction mixture was quenched with sat. aq. NH4Cl solution and extracted with Et2O (3×). The combined organic extracts were washed with sat. aq. NaCl solution and then dried over MgSO4, filtered and concentrated in vacuo. The crude oil was purified using flash column chromatography to give the title compound (2.76 g, 53%). 1H NMR (DMSO-d6) δ 6.55 (br s, 1H), 4.64-4.53 (m, 1H), 4.24 (q, J=7.0 Hz, 2H), 3.83 (td, J=9.7, 6.8 Hz, 1H), 3.72-3.53 (m, 2H), 3.47-3.34 (m, 1H), 2.88 (t, J=6.3 Hz, 2H), 1.76-1.52 (m, 2H), 1.51-1.35 (m, 4H), 1.27 (t, J=7.0 Hz, 3H); MS(ESI+) m/z 269.2 (M+H)+.

1. temperaturecooled to room temperature
2. stirringThe resulting solution was stirred at −78° C. for 1 h
3. customtransferred to a −78° C.
4. customThe resulting reaction mixture
5. stirringstirred for 1.5 h
6. stirringthe reaction mixture was stirred at −17° C. for 30 min
7. customThe ice bath was removed
8. stirringstirring
9. waitwas continued at room temperature for 4 h
10. customThe reaction mixture was quenched with sat. aq. NH4Cl solution
11. extractionextracted with Et2O (3×)
12. washThe combined organic extracts were washed with sat. aq. NaCl solution
13. dry with materialdried over MgSO4
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. customThe crude oil was purified

ORD record

ord-3c3d78786cca4fbabec084d947821a0b

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09346795B2