Methanol → (R)-4-((R)-1-(5-hydroxybenz o[d]thiazol-7-yloxy)ethyl)-1-((R)-1-(4-hydroxyphenyl)ethyl)pyrrolidin-2-one

Temperature

-78 °C

(R)-4-((R)-1-(5-(benzyloxy)benzo[d]thiazol-7-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (500 mg, 1.0 mmol) was dissolved in DCM (10 mL) under Ar and the resulting solution was cooled to −78° C. A 1.0 M solution of BBr3 (10 mL, 10 mmol) was added dropwise over 5 min, and the resulting mixture was warmed to r.t. After 45 additional min, the reaction mixture was cooled in an ice water bath and MeOH (4 mL. 99 mmol) was added over 2 min. Et3N (5.6 mL, 40 mmol) was added followed by Et2NH (0.25 mL, 2.4 mmol) and the resulting mixture was warmed to r.t. After stirring an additional 30 min, the reaction mixture was concentrated, dissolved in MeOH (20 mL), and concentrated again. The resulting concentrate was partitioned between EtOAc (100 mL) and water (75 mL), and the phases were separated. The aqueous phase was extracted with EtOAc (30 mL), and the combined organic phase was washed with a mixture of 0.2 M aqueous HCl (30 mL) and brine (30 mL) followed by a mixture of saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to afford (R)-4-((R)-1-(5-hydroxybenzo[d]thiazol-7-yloxy)ethyl)-1-((R)-1-(4-hydroxyphenyl)ethyl)pyrrolidin-2-one that was used without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C21H23N2O4S: 399.1; found 399.2.

1. temperaturethe resulting mixture was warmed to r.t
2. temperatureAfter 45 additional min, the reaction mixture was cooled in an ice water bath
3. temperaturethe resulting mixture was warmed to r.t
4. concentrationthe reaction mixture was concentrated
5. dissolutiondissolved in MeOH (20 mL)
6. concentrationconcentrated again
7. concentrationThe resulting concentrate
8. customwas partitioned between EtOAc (100 mL) and water (75 mL)
9. customthe phases were separated
10. extractionThe aqueous phase was extracted with EtOAc (30 mL)
11. washthe combined organic phase was washed with a mixture of 0.2 M aqueous HCl (30 mL) and brine (30 mL)
12. additionfollowed by a mixture of saturated aqueous NaHCO3 (20 mL) and brine (20 mL)
13. dry with materialThe organic phase was dried over Na2SO4
14. filtrationfiltered
15. concentrationconcentrated

ORD record

ord-204c5fd57a514b38b2a4f9595a258d15

Source dataset

uspto-grants-2016_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09376441B2