Trimethylsulfonium iodide → HCID 86724400, compound

Temperature

-30 °C

Into a different flask, trimethylsulfonium iodide (181.35 g, 888.65 mmol) was dissolved in THF. The solution was cooled to −30° C. Lithium hexamethyldisilazide (888.65 mL, 1 M solution in THF, 888.65 mmol) was added over 25 mins. The internal temperature went from −30° C. to −26° C. upon the addition. The reaction was stirred at −30° C. for 30 mins. To this solution was added the (S)-2-(fluoromethyl)oxirane solution (that was prepared in the previous flask). The addition was done over 5 mins at −30° C. The reaction was then allowed to warm up to RT and stirred for 3 h. It was then cooled to 3° C. (internal temperature) using an ice bath and 1-methyl-2-pyrrolidinone (100 mL) was added. The internal temperature rose to 8° C. tert-Butyl bromoacetate (131.22 mL, 888.65 mmol) in 1-methyl-2-pyrrolidinone (100 mL) was added dropwise using a dropping funnel and ensuring the temperature remained between 17-20° C. The reaction was stirred in the ice bath for 10 mins until the temperature went to 5° C. The ice bath was removed and it was stirred at RT overnight. Water (2 L) was poured into the reaction mixture and followed by Et2O (1 L). After stirring for 10 mins the two layers were separated and the aqueous layer was extracted with Et2O (4×500 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by silica gel column chromatography using hexanes initially and then 5% EtOAc in hexanes to obtain the title compound as a yellow liquid (57 g, 63%).

1. additionThe internal temperature went from −30° C. to −26° C. upon the addition
2. customwas prepared in the previous flask)
3. additionThe addition
4. waitwas done over 5 mins at −30° C
5. temperatureto warm up to RT
6. stirringstirred for 3 h
7. temperatureIt was then cooled to 3° C. (internal temperature)
8. customrose to 8° C.
9. additionwas added dropwise
10. customremained between 17-20° C
11. customwent to 5° C
12. customThe ice bath was removed
13. stirringit was stirred at RT overnight
14. additionWater (2 L) was poured into the reaction mixture
15. stirringAfter stirring for 10 mins the two layers
16. customwere separated
17. extractionthe aqueous layer was extracted with Et2O (4×500 mL)
18. dry with materialThe combined organic extracts were dried over MgSO4
19. concentrationconcentrated
20. customThe crude product was purified by silica gel column chromatography

ORD record

ord-fc29db25f4db4379899f839fcf7710aa

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09175013B2