Triethylamine → N'-((2R,3S)-2-(3-Chloro-4-cyano-2-ethylphenylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide

Temperature

-15 °C

(2R,3S)-2-(3-chloro-4-cyano-2-ethylphenylamino)-3-hydroxybutanoic acid (700 mg, 2.48 mmol), 4-cyanobenzohydrazide (439 mg, 2.73 mmol) and anhydrous THF (20 mL) were placed in a 50 mL round bottomed flask and the mixture was cooled to −15° C. 1-Hydroxybenzotriazole hydrate (335 mg, 2.48 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (589 mg, 3.07 mmol) at −15° C. followed by triethylamine (0.43 mL, 3.07 mmol). The reaction mixture was maintained −15° C. and stirred for 1 h, after which stirring continued overnight while the mixture slowly warmed to room temperature. After 18 h, the mixture was filtered under vacuum and the residue washed with THF (30 mL). The THF solution was concentrated to ca. 10 mL, whereupon EtOAc (200 mL) was added followed by extraction with 5% citric acid (3×100 mL). The phases were partitioned and the organic phase washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated to furnish a light yellow solid (920 mg, 87% yield). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.80 (br s, 2H), 8.09 (d, J=8.6 Hz, 2H), 7.94 (d, =8.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 1H), 6.72 (d, J=8.6 Hz, 1H), 5.65 (d, J=6.7 Hz, 1H), 4.76 (br s, 1H), 4.43-4.35 (m, 1H), 4.15 (dd, J=3.7 Hz, 6.7 Hz, 1H), 2.94-2.79 (m, 2H) 1.38 (d, J=6.8 Hz, 3H) and 1.18 (t, J=7.6 Hz, 3H).

1. temperatureThe reaction mixture was maintained −15° C.
2. stirringafter which stirring
3. waitcontinued overnight while the mixture
4. temperatureslowly warmed to room temperature
5. waitAfter 18 h
6. filtrationthe mixture was filtered under vacuum
7. washthe residue washed with THF (30 mL)
8. concentrationThe THF solution was concentrated to ca. 10 mL, whereupon EtOAc (200 mL)
9. additionwas added
10. extractionfollowed by extraction with 5% citric acid (3×100 mL)
11. customThe phases were partitioned
12. washthe organic phase washed with water (100 mL), brine (100 mL)
13. dry with materialdried (Na2SO4)
14. filtrationfiltered
15. concentrationconcentrated

ORD record

ord-98232c45c1d74e1f8fcd9306557d7714

Source dataset

uspto-grants-2014_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08629167B2