Methyl iodide → HCID 71116591, compound

Temperature

-78 °C

LHMDS (2.2 mL, 2.16 mmol, 1.0 equiv, 1.0 M in THF) was added to an oven-dried flask under N2 and cooled to −78° C. A solution of 2-(4-methoxyphenyl)-2-azabicyclo-[2.2.2]octan-5-one (2-1, 500 mg, 2.16 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (8.6 mL) was added dropwise via cannula, and the resulting mixture was allowed to stir for 20 min at −78° C. Following this duration, the enolate mixture was added via cannula to a solution of iodomethane (0.68 mL, 10.8 mmol, 5.0 equiv) in anhydrous tetrahydrofuran (2.2 mL). After 1 h, the reaction contents were removed from the −78° C. bath and allowed to gradually warm to RT. After 18 h, LCMS showed complete consumption of starting material. The reaction was quenched with saturated NH4Cl (15 mL), added to ethyl acetate (20 mL) and diluted with water (5 mL). The layers were separated and the aqueous layer was back-extracted with ethyl acetate (3×10 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give an orange solid. Purification by normal-phase HPLC (0-40% CH3CN:0.1% TFA in H2O) provided 7-1 as a pale yellow solid (inconsequential 1:1 mixture of diastereomers).

1. waitAfter 1 h
2. customthe reaction contents
3. customwere removed from the −78° C. bath
4. temperatureto gradually warm to RT
5. waitAfter 18 h
6. customconsumption of starting material
7. customThe reaction was quenched with saturated NH4Cl (15 mL)
8. additionadded to ethyl acetate (20 mL)
9. additiondiluted with water (5 mL)
10. customThe layers were separated
11. extractionthe aqueous layer was back-extracted with ethyl acetate (3×10 mL)
12. dry with materialThe combined organics were dried over Na2SO4
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. customto give an orange solid
16. customPurification by normal-phase HPLC (0-40% CH3CN:0.1% TFA in H2O)

ORD record

ord-a6800a6cb920473e89aa211a41b0d470

Source dataset

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09315518B2