Toluene → (2S,3S)-2-amino-N-(4-cyano-2-fluoro-phenyl)-3-phenyl-butyramide

Temperature

80 °C

To an argon degassed and dried flask was added (2S,3S)-2-amino-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-butyramide (796 mg, 1.99 mmol), zinc cyanide (352 mg, 2.99 mmol), tetrakis-triphenylphosphine palladium (0) (116 mg, 0.1 mmol) and dry tetrahydrofuran (4 mL). After heating at 80° C. for 8 hours there was no reaction. To the cooled mixture was added 2-dicylohexylphosphino-2′-6′-dimethoxybiphenyl (42 mg, 0.1 mmol) and the reaction mixture heated again to 80° C. for 90 minutes, again no reaction occurred. To the cooled mix was added triethylamine (840 μl, 5.99 mmol) and the reaction mixture heated at 80° C. for 2 hours, again no reaction occurred. To the cooled mix was added 2-dicylohexylphosphino-2′-6′-dimethoxybiphenyl (84 mg, 0.2 mmol) and still no reaction occurred after 2 hours at 85° C. To the cooled mix was added rac-2-2′-bis(diphenylphosphino)-1-1′binaphthyl (125.6 mg, 0.2 mmol) and dry toluene (2 mL). After heating at 85° C. for 40 hours the reaction mix was dissolved in ethyl acetate (50 mL) and washed with 1.5 N aqueous potassium hydrogen sulfate solution, saturated aqueous sodium bicarbonate solution and the aqueous layers were back extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The crude residue was purified by chromatography over silica gel gradient eluted from 5 to 15% v/v ethyl acetate in hexanes to give (2S,3S)-2-amino-N-(4-cyano-2-fluoro-phenyl)-3-phenyl-butyramide as a yellow residue after concentration of the product containing fractions (120 mg, 20.2% yield).

1. customTo an argon degassed
2. customdried flask
3. customno reaction
4. temperaturethe reaction mixture heated again to 80° C. for 90 minutes
5. additionTo the cooled mix
6. temperaturethe reaction mixture heated at 80° C. for 2 hours
7. additionTo the cooled mix
8. additionTo the cooled mix
9. temperatureAfter heating at 85° C. for 40 hours the reaction
10. additionmix
11. washwashed with 1.5 N aqueous potassium hydrogen sulfate solution, saturated aqueous sodium bicarbonate solution
12. extractionthe aqueous layers were back extracted with ethyl acetate (2×50 mL)
13. dry with materialThe combined organic layers were dried over sodium sulfate
14. concentrationconcentrated
15. customThe crude residue was purified by chromatography over silica gel gradient
16. washeluted from 5 to 15% v/v ethyl acetate in hexanes

ORD record

ord-4cab14f7270b4a8e83794a8dbd199c0f

Source dataset

uspto-grants-2009_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07612212B2