Trifluoroacetic acid → HCID 90026716, compound

N,N-Diisopropylethylamine (900 mg, 1.22 ml, 6.97 mmol, Eq: 2.00) was added to 3,3-difluoropyrrolidine hydrochloride (500 mg, 3.5 mmol, Eq: 1.00) in diethyl ether (10 ml). A solution of cyanic bromide (369 mg, 3.5 mmol, Eq: 1.00) in diethyl ether (2 mL) was added at 0° C. The mixture was stirred over night at room temperature, filtered and concentrated on a rotatory evaporator at 40° C., keeping the pressure above 100 mbar (product is volatile). 2,2-Dichloroacetyl chloride (510 mg, 0.336 ml, 3.5 mmol, Eq: 1.00) was added to the crude intermediate at 0° C. The mixture was stirred for 15 min. Dichloromethane (6 ml) was added, followed by N,N-diisopropylethylamine (452 mg, 0.61 ml, 3.5 mmol, Eq: 1.00). tert-Butyl 1-methylhydrazinecarboxylate (555 mg, 0.62 ml, 3.8 mmol, Eq: 1.09) was added dropwise at 0° C. The reaction mixture was stirred for 1 h at room temperature. Trifluoroacetic acid (4 g, 2.7 ml, 35 mmol, Eq: 10) was added. The reaction mixture was heated under refluxed for 1.5 h and then concentrated to an oil. The mixture was partitioned between a saturated sodium bicarbonate solution and ethyl acetate. The combined organic layers were washed with a saturated ammonium chloride solution and then dried over sodium sulfate and concentrated to an oil. Ethanol (12 ml) and water (24 ml) were added, followed by sodium acetate (717 m g, 8.75 mmol, Eq: 2.5). The reaction mixture was heated to 60° C. for 1 h. The mixture was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the desired product (699 mg, 92%) as a white powder. MS: m/z=217.3 (M+H+)

1. filtrationfiltered
2. concentrationconcentrated on a rotatory evaporator at 40° C.
3. stirringThe mixture was stirred for 15 min
4. stirringThe reaction mixture was stirred for 1 h at room temperature
5. temperatureThe reaction mixture was heated
6. temperatureunder refluxed for 1.5 h
7. concentrationconcentrated to an oil
8. customThe mixture was partitioned between a saturated sodium bicarbonate solution and ethyl acetate
9. washThe combined organic layers were washed with a saturated ammonium chloride solution
10. dry with materialdried over sodium sulfate
11. concentrationconcentrated to an oil
12. additionEthanol (12 ml) and water (24 ml) were added
13. temperatureThe reaction mixture was heated to 60° C. for 1 h
14. extractionThe mixture was extracted with ethyl acetate
15. dry with materialThe combined organic layers were dried over Na2SO4
16. filtrationfiltered
17. concentrationconcentrated in vacuo

ORD record

ord-398b46ea45b54c6da35a2af5918db857

Source dataset

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09394311B2