Methyl Acetate → HCID 68153908, compound

Temperature

0 °C

To a 0° C. solution of N,N-diisopropylamine (12.7 mL, 90.8 mmol) in THF (120 mL) was added n-butyllithium (2.5 M in hexanes, 35.1 mL) over ˜5 min. The resulting solution was stirred at 0° C. for 10 min, then the cooling bath was removed and the mixture stirred for an additional 10 min before it was finally cooled to −78° C. To this solution of LDA was then added via cannula a −78° C. solution of methyl acetate (6.01 mL, 75.6 mmol) in THF (30 mL) over ˜5 min. This mixture was stirred at −78° C. for 30 min, and then a mixture of chlorotriisopropoxytitanium (27.1 mL, 113 mmol) and THF (30 mL) was added via syringe. After 30 min, a RT solution of (R)-2-methyl-N-(1-(tetrahydro-2H-pyran-4-yl)ethylidene)propane-2-sulfinamide 4 (7.0 g, 30 mmol) in THF (40 mL) was added via cannula over ˜5 min. The reaction was then stirred at −78° C. for 5 h. At that time, while still at −78° C., the reaction was diluted rapidly with water (300 mL) and agitated. The reaction was allowed to gradually warm to RT overnight with stirring. At that time, the mixture was further diluted with EtOAc and water, and the mixture was filtered with copious EtOAc washes. The phases of the filtrate were separated and the aqueous layer was extracted 2× with EtOAc. The organic portions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude sample was subjected to column chromatography (ISCO, 330 g silica, 100 mL/min, 0% to 25% i-PrOH/hexanes) to give (S)-methyl 3-((R)-1,1-dimethylethylsulfinamido)-3-(tetrahydro-2H-pyran-4-yl)butanoate 5 (6.5 g, 70%). LCMS (conditions D) for 5: tR=1.90 min, m/e=306.2 (M+H, base), 328.2 (M+Na).

1. customthe cooling bath was removed
2. stirringthe mixture stirred for an additional 10 min before it
3. temperaturewas finally cooled to −78° C
4. stirringThis mixture was stirred at −78° C. for 30 min
5. additionwas added via syringe
6. waitAfter 30 min
7. stirringThe reaction was then stirred at −78° C. for 5 h
8. stirringagitated
9. temperatureto gradually warm to RT overnight
10. stirringwith stirring
11. filtrationthe mixture was filtered with copious EtOAc washes
12. customThe phases of the filtrate were separated
13. extractionthe aqueous layer was extracted 2× with EtOAc
14. washwashed with brine
15. dry with materialdried over MgSO4
16. filtrationfiltered
17. concentrationconcentrated

ORD record

ord-8d82643a77b1459c80a0ad3ff21f1043

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08569310B2