Hydrochloric Acid → HCID 59715050, compound

Temperature

-78 °C

To an ice-cooled solution of diisopropylamine (1.68 mL) in tetrahydrofuran (10 mL) was added 1.57 M n-butyllithium/hexane (7.0 mL) dropwise over 10 minutes. After stirring the reaction solution under ice cooling for additional 30 minutes, it was cooled to −78° C. and a solution of 2-(cyclobutylidene)ethyl acetate (1.96 g) in tetrahydrofuran (2 mL) was added thereto dropwise over 10 minutes. After stirring the reaction solution at that temperature for 1 hour, chiorotrimethylsilane (1.52 mL) was added dropwise over 5 minutes. The reaction solution was stirred at room temperature for 1 hour, and then, heated under reflux for 4.5 hours. The reaction solution was ice-cooled and methanol (5 mL) and a 3N aqueous sodium hydroxide solution (8 ml) were added. The solution was stirred for 30 minutes. Then, conc. hydrochloric acid (4 mL) was added to the solution and it was stirred for additional 30 minutes. The reaction solution was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (20 mL), to which potassium carbonate (8.29 g) and methyl iodide (1.87 mL) were added. The solution was stirred at room temperature for 3 hours. The reaction solution was filtered with Celite and insolubles on Celite were washed with ethyl acetate. The filtrate was combined with the wash and washed in turn with 2N hydrochloric acid and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, hexane-ethyl acetate (97:3)] to give the title compound (1.33 g).

1. waitdropwise over 10 minutes
2. stirringAfter stirring the reaction solution at that temperature for 1 hour
3. stirringThe reaction solution was stirred at room temperature for 1 hour
4. temperatureheated
5. temperatureunder reflux for 4.5 hours
6. temperaturecooled
7. stirringThe solution was stirred for 30 minutes
8. stirringwas stirred for additional 30 minutes
9. extractionThe reaction solution was extracted with chloroform
10. dry with materialThe organic layer was dried over anhydrous sodium sulfate
11. concentrationconcentrated under reduced pressure
12. dissolutionThe resulting residue was dissolved in N,N-dimethylformamide (20 mL), to which potassium carbonate (8.29 g) and methyl iodide (1.87 mL)
13. additionwere added
14. stirringThe solution was stirred at room temperature for 3 hours
15. filtrationThe reaction solution was filtered with Celite and insolubles on Celite
16. washwere washed with ethyl acetate
17. washwash
18. washwashed in turn with 2N hydrochloric acid and saturated aqueous sodium chloride solution
19. dry with materialThe organic layer was dried over anhydrous sodium sulfate
20. concentrationconcentrated under reduced pressure
21. customThe resulting residue was purified by chromatography [silica gel, hexane-ethyl acetate (97:3)]

ORD record

ord-50744b39fc02465f83d7c2676372b794

Source dataset

uspto-grants-2008_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07375115B2