Benzylamine → 4-(Benzylamino)-3,3-difluoro-4-oxobutanoic acid

Temperature

50 °C

To a solution of 2,2-difluorosuccinic acid (2.15 g, 14.0 mmol) in iPrOAc (23 mL) was added trifluoroacetic anhydride (2.34 mL, 16.7 mmol) in one portion at ambient temperature. The reaction solution was stirred at 50° C. for 2 hr. The reaction solution was allowed to cool to 5° C. in an ice bath. Benzyl amine (2.29 mL, 20.9 mmol) was added dropwise while the reaction temperature was maintained below 20° C. The solution was stirred at ambient temperature for 2 hr. The reaction was quenched with water (10 mL) followed by saturated Na2CO3 to pH 8-9. The separated organic phase was discarded. The aqueous phase was acidified with 6 N HCl to pH 1 and extracted with EtOAc (2×100 mL). The combined organic phase was washed with 2 N HCl, brine (100 mL), dried over MgSO4 filtered and concentrated. The intermediate was carried forward without further purification (2.89 g, 56.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.42 (m, 5 H) 7.14-7.21 (m, 1 H) 6.77 (br. s., 1 H) 4.54 (d, J=5.87 Hz, 2 H) 3.39 (t, J=14.18 Hz, 2 H).

1. temperatureto cool to 5° C. in an ice bath
2. temperaturewas maintained below 20° C
3. stirringThe solution was stirred at ambient temperature for 2 hr
4. customThe reaction was quenched with water (10 mL)
5. extractionextracted with EtOAc (2×100 mL)
6. washThe combined organic phase was washed with 2 N HCl, brine (100 mL)
7. dry with materialdried over MgSO4
8. filtrationfiltered
9. concentrationconcentrated
10. customThe intermediate was carried forward without further purification (2.89 g, 56.8% yield)

ORD record

ord-4c82e8c3342c448ebc51a180f7196b88

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09290496B2