Citric Acid → 3-chloro-N'-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide

HRID 1254661

Reaktionsgleichung

Reaktionsgleichung von HRID 1254661
[Cl:1][C:2]1[C:3]([CH2:18]C)=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][NH2:27])=[O:25].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.O.C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][NH:27][C:12](=[O:14])[C@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:18])[C@@H:15]([OH:17])[CH3:16])=[O:25]

Komponenten

9

Edukt 5

HCID 311Citric AcidHCID 8471TriethylamineHCID 742893-ChlorobenzohydrazideHCID 27960291-Hydroxybenzotriazole hydrateHCID 67006383(2R,3S)-2-(3-chloro-4-cyano-2-ethylphenylamino)-3-hydroxybutanoic acid

Produkt 1

HCID 670065243-chloro-N'-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazideAusbeute 68,1 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 962WaterLösungsmittelHCID 8028TetrahydrofuranLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
-15 °C

Versuchsvorschrift

(2R,3S)-2-(3-chloro-4-cyano-2-ethylphenylamino)-3-hydroxybutanoic acid (800 mg, 2.98 mmol), 3-Chlorobenzhydrazide (508 mg, 2.98 mmol) and anhydrous THF (40 mL) were placed in a 100 mL round bottomed flask and the mixture was cooled to −15° C. 1-Hydroxybenzotriazole hydrate (403 mg, 2.98 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N-ethylcarbodimide HCl (857 mg, 4.47 mmol) at −15° C. followed by triethylamine (0.62 mL, 4.47 mmol). 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. Water (40 mL) was added to the reaction mixture followed by citric acid (4 g) while stirring. EtOAc (60 mL) was then added to the mixture and the phases were partitioned. The organic phase was then washed with saturated aqueous sodium bicarbonate (40 mL) and the organic phase dried (Na2SO4). EtOAc was removed under vacuum and replaced by chloroform (60 mL). The insoluble hydrazide was then separated from the mixture by filtration and dried under reduced pressure to furnish a white solid (855 mg, 68%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.7 (br s, 2H), 7.96 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.46-7.7 (m, 2H), 6.64 (d, J=8.6 Hz, 1H), 5.3 (d, J=7 Hz, 1H), 4.19-4.03 (m, 1H), 3.98-3.87 (m, 1H), 2.35 (s, 3H) and 1.26 (d, J=6.35 Hz, 3H).

Aufarbeitung

  1. temperatureThe reaction mixture was maintained at −15° C.
  2. stirringstirring
  3. waitcontinued overnight while the mixture
  4. temperatureslowly warmed to room temperature
  5. stirringwhile stirring
  6. customthe phases were partitioned
  7. washThe organic phase was then washed with saturated aqueous sodium bicarbonate (40 mL)
  8. dry with materialthe organic phase dried (Na2SO4)
  9. customEtOAc was removed under vacuum
  10. customThe insoluble hydrazide was then separated from the mixture by filtration
  11. customdried under reduced pressure

Quellen und Nachweise

ORD-Eintrag
ord-36606e9219ac42df8bf79e4e67e88814
Quelldatensatz
uspto-grants-2013_06
Patentnummer
US08455525B2

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