Triethylamine → 3,4-dichloro-N'-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenyl-amino)-3-hydroxybutanoyl)benzohydrazide

Temperatur

-15 °C

(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (1.0 g, 3.7 mmol), 3,4-dichlorobenzohydrazide (CAS 28036-91-1, 763 mg, 3.7 mmol) and anhydrous THF (100 mL) were placed in a 500 mL round bottomed flask and the mixture was cooled to −15° C., 1-Hydroxybenzotriazole hydrate (502.8 mg, 3.7 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (1.4 g, 7.4 mmol) and triethylamine (1.03 mL, 7.4 mmol) at −15° C. The reaction mixture was maintained at −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 (50 mL). The THF solution was concentrated to ca. 10 mL, whereupon ethyl acetate (200 mL) was added followed by water (100 mL). The phases were partitioned and the organic phase washed with water (50 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated to furnish a light brown solid. 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.10 (d, J=2.1 Hz, 1H), 7.90 (dd, J=2.2 Hz, 8.3 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 5.57 (d, J=6.8 Hz, 1H), 4.44-4.36 (m, 1H), 4.16-4.10 (m, 1H), 2.88-2.80 (m, 1H), 2.37 (s, 3H), 1.37 (d, J=6.3 Hz, 3H).

1. temperatureThe reaction mixture was maintained at −15° C.
2. stirringstirring
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 (50 mL)
8. concentrationThe THF solution was concentrated to ca. 10 mL, whereupon ethyl acetate (200 mL)
9. additionwas added
10. customThe phases were partitioned
11. washthe organic phase washed with water (50 mL), brine (50 mL)
12. dry with materialdried (Na2SO4)
13. filtrationfiltered
14. concentrationconcentrated
15. customto furnish a light brown solid

ORD-Eintrag

ord-85412756abb047d6a1e4c62ca968664c

Quelldatensatz

uspto-grants-2014_01

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08629167B2