HCID 12152438, compound → 54513-59-6

Temperature

0 °C

Methyllithium in diethyl ether (1.6M, 218 mL, 349 mmol) was added in ˜10 mL portions over 20 min to a stirred slurry of copper(I) iodide (44.3 g, 233 mmol) in diethyl ether (350 mL) cooled to 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 30 min and then (R)-2-methyl-2H-pyran-4(3H)-one (13.5 g, 116 mmol) in diethyl ether (150 mL) was added dropwise over 30 min. The cold bath was removed and the reaction mixture was allowed to warm to rt and stirred for 3 h. The reaction mixture was slowly added (over ˜5 min) to a stirred solution of sat. NH4Cl (aq) (˜750 mL) and ice. Additional diethyl ether (˜500 mL) and water (˜150 mL) were added and the solution, which contained a grey precipitate, was stirred overnight. The layers were separated and the aqueous layer was extracted with diethyl ether (500 mL) and DCM (500 mL). The combined organic phase was dried (MgSO4), filtered and concentrated (the rotary evaporator bath temperature was held at or below ambient temperature) to an orange oil. The crude oil was purified with a Biotage® Horizon (240 g SiO2, 1-4% diethyl ether in DCM, column was pre-equilibrated with DCM) to yield (2R,6R)-2,6-dimethyldihydro-2H-pyran-4(3H)-one (13.4 g, 86% pure by 1H-NMR) as a light yellow oil. [Note: The material was carefully concentrated and contained 10% w/w DCM by 1H-NMR. 1H-NMR analysis also indicated that the material was contaminated with ˜2.5% TBDMSOH carried over from a previous reaction and 1.6% of (2R,6S)-2,6-dimethyldihydro-2H-pyran-4(3H)-one]. The analytical data of the product complied with the data reported in the literature, and the material was used without additional purification. 1H-NMR (400 MHz, CDCl3) δ 4.41-4.25 (m, 2H), 2.55 (ddd, J=14.1, 4.8, 1.4 Hz, 2H), 2.24 (ddd, J=14.1, 6.5, 1.5 Hz, 2H), 1.28 (d, J=6.5 Hz, 6H).

1. customThe cold bath was removed
2. temperatureto warm to rt
3. stirringstirred for 3 h
4. additionThe reaction mixture was slowly added (over ˜5 min) to a stirred solution of sat. NH4Cl (aq) (˜750 mL) and ice
5. additionAdditional diethyl ether (˜500 mL) and water (˜150 mL) were added
6. stirringwas stirred overnight
7. customThe layers were separated
8. extractionthe aqueous layer was extracted with diethyl ether (500 mL) and DCM (500 mL)
9. dry with materialThe combined organic phase was dried (MgSO4)
10. filtrationfiltered
11. concentrationconcentrated (the rotary evaporator bath temperature
12. custombelow ambient temperature
13. customThe crude oil was purified with a Biotage® Horizon (240 g SiO2, 1-4% diethyl ether in DCM, column was pre-equilibrated with DCM)

ORD record

ord-96b43d217c674976ab21868d412f1ca1

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09340520B2