2,6-Lutidine → 1-Methyl-5-(5-methyl-6,8-dioxaspiro[2.5]octan-7-yl)-4-nitro-pyrazole

To a solution of 1-(2-hydroxypropyl)cyclopropanol (2.0 g, 17.2 mmol) in DCM (35 mL) at 0° C. was added 2,6-lutidine (5 mL, 42.9 mmol) followed by trimethylsilyl trifluoromethanesulfonate (6 mL, 32.9 mmol). The reaction mixture was warmed to room temperature and stirred for 18 hr. Additional amounts of 2,6-lutidine (5 mL, 42.9 mmol) and trimethylsilyl trifluoromethanesulfonate (6 mL, 32.9 mmol) were added at 0° C. The mixture was stirred for 1 hr and quenched with saturated aqueous NaHCO3 (30 mL). The mixture was extracted with DCM (50 mL) and the organic layer was washed with aqueous 0.1 M HCl (2×15 mL) and passed through a phase separation cartridge. To this solution was added 2-methyl-4-nitro-pyrazole-3-carbaldehyde (1.40 g, 9.03 mmol) and the resulting solution was cooled to −78° C. and trimethylsilyl trifluoromethanesulfonate (4.11 mL, 22.6 mmol) added. The mixture was warmed to 0° C., stirred for 3 hr, cooled to −78° C. and additional trimethylsilyl trifluoromethanesulfonate (4.11 mL, 22.6 mmol) added. The mixture was warmed to 0° C. and stirred for 1 hr and solid sodium carbonate (2.5 g) added. The reaction mixture was stirred for 10 min before saturated aqueous NaHCO3 (100 mL) was added. The organic layer was washed with water (100 mL) and brine (100 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 1-methyl-5-(5-methyl-6,8-dioxaspiro[2.5]octan-7-yl)-4-nitro-pyrazole as a colourless solid (1.0 g, 44% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 6.59 (s, 1H), 4.29-4.02 (m, 4H), 2.33-2.23 (m, 1H), 1.33 (d, J=6.2 Hz, 3H), 1.17-1.12 (m, 1H), 1.02-0.89 (m, 2H), 0.70-0.52 (m, 2H).

1. stirringThe mixture was stirred for 1 hr
2. customquenched with saturated aqueous NaHCO3 (30 mL)
3. extractionThe mixture was extracted with DCM (50 mL)
4. washthe organic layer was washed with aqueous 0.1 M HCl (2×15 mL)
5. custompassed through a phase separation cartridge
6. temperaturethe resulting solution was cooled to −78° C.
7. temperatureThe mixture was warmed to 0° C.
8. stirringstirred for 3 hr
9. temperaturecooled to −78° C.
10. temperatureThe mixture was warmed to 0° C.
11. stirringstirred for 1 hr
12. additionwas added
13. washThe organic layer was washed with water (100 mL) and brine (100 mL)
14. customseparated
15. dry with materialdried over Na2SO4
16. concentrationconcentrated under reduced pressure
17. customPurification via silica gel column chromatography (0-100% EtOAc/isohexane)

ORDレコード

ord-6a27fc45a7df40ce8f8ef0d2b98ab484

出典データセット

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09328106B2