Ethanol → HCID 71008913, compound

Zinc (5.07 g, 77.5 mmol) and cuprous chloride (2.64 g, 25.8 mmol) were stirred in a dried apparatus and heated for 1 minute with a heat gun under a flow of argon. After cooling to room temperature, tetrahydrofuran (85.1 ml) was added. The reaction mixture was stirred in a 70° C. oil bath for 30 minutes, then cooled to room temperature. A solution of ethyl bromodifluoroacetate (13.5 g, 8.54 ml, 64.6 mmol) in tetrahydrofuran (25.5 ml) was added dropwise while maintaining the temperature between 26 and 29° C. After stirring for 10 minutes at 23° C., a solution of (R,E)-N-(1-(3-(benzyloxy)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (intermediate A2.6) (8.51 g, 25.8 mmol) in tetrahydrofuran (25.5 ml) was added dropwise and stirring continued for 24 hours at room temperature. For the workup, the reaction mixture was cooled to 0° C. and ethanol (3 ml) was added dropwise. The mixture was filtered through a pad of Dicalite® and washed with ethyl acetate. The filtrate was concentrated at reduced pressure. The residue was taken in ethyl acetate (40 ml) and water was added. The emulsion was filtered again through a pad of Dicalite®. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated at reduced pressure. The crude product (13.7 g, yellow oil) was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 50:50 as the eluent. The (R)-3-(3-benzyloxy-phenyl)-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester (7.72 g, 66% yield) was obtained as a yellow oil. MS (ISP): m/z=454.2 [M+H]+.

1. temperatureheated for 1 minute with a heat gun under a flow of argon
2. temperaturecooled to room temperature
3. temperaturewhile maintaining the temperature between 26 and 29° C
4. stirringAfter stirring for 10 minutes at 23° C.
5. stirringstirring
6. waitcontinued for 24 hours at room temperature
7. temperatureFor the workup, the reaction mixture was cooled to 0° C.
8. filtrationThe mixture was filtered through a pad of Dicalite®
9. washwashed with ethyl acetate
10. concentrationThe filtrate was concentrated at reduced pressure
11. additionwater was added
12. filtrationThe emulsion was filtered again through a pad of Dicalite®
13. customThe layers were separated
14. extractionthe aqueous layer was extracted with ethyl acetate
15. dry with materialThe combined organic layers were dried over sodium sulphate
16. customevaporated at reduced pressure
17. customThe crude product (13.7 g, yellow oil) was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 50:50 as the eluent

ORD record

ord-1343a5009e3843f38c50a0936b9ddaca

Source dataset

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08785436B2