Bromine → HCID 89368240, compound

Temperature

-30 °C

A solution of methyl [bis(2,2,2-trifluoroethoxy)phosphoryl]acetate (95%, 9.42 g) in tetrahydrofuran (20 mL) was slowly added to a suspension of sodium hydride (63%, 1.07 g) in tetrahydrofuran (40 mL) with stirring at −30° C. The mixture was stirred at the same temperature for 30 minutes, and bromine (1.46 mL) was then slowly added thereto. After completion of addition, the reaction solution was temporarily heated to −10° C. The reaction solution was cooled to −78° C., and sodium hydride (63%, 1.07 g) was then added thereto at once. The mixture was stirred at the same temperature for 30 minutes, and a solution of the crude product of 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3,3-dimethylbutanal (3.59 g) obtained in Step 1 in tetrahydrofuran (20 mL) was then added thereto. The mixture was stirred at −78° C. for 1 hour and then gradually heated to 10° C. over 1 hour with care to prevent foaming. The reaction mixture was further stirred at the same temperature for 1 hour, and an aqueous ammonium chloride solution was then added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the title compound (4.53 g).

1. stirringThe mixture was stirred at the same temperature for 30 minutes
2. additionAfter completion of addition
3. temperaturethe reaction solution was temporarily heated to −10° C
4. temperatureThe reaction solution was cooled to −78° C.
5. stirringThe mixture was stirred at the same temperature for 30 minutes
6. stirringThe mixture was stirred at −78° C. for 1 hour
7. temperaturegradually heated to 10° C. over 1 hour with care
8. stirringThe reaction mixture was further stirred at the same temperature for 1 hour
9. extractionfollowed by extraction with ethyl acetate
10. washThe organic layer was washed with water and saturated sodium chloride solution
11. dry with materialdried over anhydrous sodium sulfate
12. filtrationAfter filtration and concentration under reduced pressure
13. customthe obtained crude product
14. customwas purified by silica gel column chromatography

ORD record

ord-49758833f0a740a2a1476234b23a5deb

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08946443B2