Ethyl bromoacetate → HCID 117837235, compound

Temperature

130 °C

In a dry flask under an inert atmosphere copper(I) chloride (2.74 g, 27.7 mmol) and activated zinc powder (14.5 g, 221 mmol) were mixed and heated to 130° C. After cooling to r.t. dry THF (80 ml) was added and under stirring the dispersion was heated to reflux for 30 min. The external heating was removed and a solution of ethyl 2-bromoacetate (11.5 g, 7.65 ml, 69.1 mmol) in dry THF (40 ml) was added dropwise in a manner that the temperature was maintained at 55° C. After complete addition stirring at 55° C. was continued for 30 min. Thereafter, the mixture was cooled to 5° C. and a solution of the (S,Z)—N-(2,2-difluoro-1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (7.67 g, 27.7 mmol) in dry THF (40 ml) was added dropwise within 10 min while the temperature was kept below 5° C. In order to complete the reaction stirring was continued at 0° C. for 1 h. For the workup, the reaction mixture was filtered through a layer of Dicalite® which was washed with TBME. The filtrate was extracted with a saturated solution of NH4Cl, the organic layer was dried over MgSO4 and evaporated at reduced pressure. The crude product was purified by 2 consecutive chromatographies on silica gel (eluent: heptane/AcOEt 4:1, then 3:1 for the mixture of isomers) to give the (R)-ethyl 3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluoro-3-(2-fluorophenyl)butanoate (XV-1) (yellow oil, 5.17 g, 51.2% yield) as the first eluting isomer and the (S)-ethyl 3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluoro-3-(2-fluorophenyl)butanoate (XV-2) (orange solid, 2.59 g, 25.7% yield) as the second eluting isomer.

1. additionwas added
2. temperaturewas heated
3. temperatureto reflux for 30 min
4. temperatureThe external heating
5. customwas removed
6. temperaturewas maintained at 55° C
7. additionAfter complete addition
8. stirringstirring at 55° C.
9. temperatureThereafter, the mixture was cooled to 5° C.
10. customwas kept below 5° C
11. stirringstirring
12. waitwas continued at 0° C. for 1 h
13. filtrationFor the workup, the reaction mixture was filtered through a layer of Dicalite® which
14. washwas washed with TBME
15. extractionThe filtrate was extracted with a saturated solution of NH4Cl
16. dry with materialthe organic layer was dried over MgSO4
17. customevaporated at reduced pressure
18. customThe crude product was purified by 2 consecutive chromatographies on silica gel (eluent
19. additionheptane/AcOEt 4:1, then 3:1 for the mixture of isomers)

ORD record

ord-7304db698a654a51ad7ac44c9fad2ba0

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09067926B2