Chlorotrimethylsilane → Ethyl 3-(benzyl(3-ethoxy-3-oxopropyl)amino)-2,2-difluoropropanoate

To a suspension of activated zinc dust (4.13 g, 63.2 mmol) in dry THF (100 mL) under argon was added TMS-Cl (3.60 g, 4.24 mL, 33.2 mmol). After 10 minutes ethyl bromodifluoroacetate (7.05 g, 4.49 mL, 34.7 mmol) was added slowly, whereby the temperature was kept below 30° C. (cooling with a waterbath). Then a solution of 3-(benzotriazol-1-ylmethyl-benzyl-amino)-propionic acid ethyl ester (10.69 g, 31.6 mmol) in dry THF (100 mL) was added. The exothermic reaction was kept between 20 and 25° C. with a waterbath. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured on 5% aqueous NaHCO3 solution and filtered over dicalite. The filtrate was extracted three times with ethyl acetate. The organic layers were washed with water and 1 N HCl, then dried over Na2SO4, filtered and the solvents were evaporated. The residue was purified by flash chromatography (silica gel, 100 g, 0% to 50% EtOAc in heptane) to give the title compound as colorless liquid (10.78 g, 99%).

1. customwas kept below 30° C.
2. temperaturecooling with a waterbath)
3. customThe exothermic reaction
4. customwas kept between 20 and 25° C. with a waterbath
5. filtrationfiltered over dicalite
6. extractionThe filtrate was extracted three times with ethyl acetate
7. washThe organic layers were washed with water and 1 N HCl
8. dry with materialdried over Na2SO4
9. filtrationfiltered
10. customthe solvents were evaporated
11. customThe residue was purified by flash chromatography (silica gel, 100 g, 0% to 50% EtOAc in heptane)

ORD record

ord-3382ecc366394f04b9c4a8799eb5972f

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08486967B2