3-Fluorobenzohydrazide → N'-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-3-fluorobenzohydrazide

HRID 563360

Reaction equation

HRID 563360 reaction equation
[Cl:1][C:2]1[C:3]([CH3:18])=[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].[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][NH2:26])=[O:24].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:26][NH:25][C:23](=[O:24])[C:22]2[CH:27]=[CH:28][CH:29]=[C:20]([F:19])[CH:21]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]

Participants

6

Reactant 4

HCID 3516403-FluorobenzohydrazideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 57908671(3-Chloro-4-cyano-2-methylphenyl)-D-threonine2×HCID 178418300HCID 178418300, compound

Product 1

HCID 67006496N'-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-3-fluorobenzohydrazideYield 91.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-15 °C

Procedure

(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (2 g, 7.44 mmol) and 3-Fluorobenzohydrazide (1.26 g, 8.19 mmol) were mixed together in THF (100 ml) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (1.0 g, 7.44 mmol), TEA (1.56 mL, 11.16 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (2.14 g, 11.16 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete based on TLC, the urea was filtered off and the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) followed by water (80 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (2.75 g, 91%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.84 (br s, 2H), 7.79-7.76 (m, 1H), 7.67-7.63 (m, 1H), 7.58-7.51 (m, 2H), 7.41-7.35 (m, 1H), 6.68 (d, J=9 Hz, 1H), 5.55 (d, J=9 Hz, 1H), 4.79 (br s, 1H), 4.42-4.36 (m, 1H), 4.14-4.10 (m, 1H), 2.36 (s, 3H) and 1.36 (d, J=6.5 Hz).

Workup

  1. customTo the pre-cooled reaction mixture
  2. customat room temperature
  3. customovernight
  4. filtrationthe urea was filtered off
  5. washthe solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL)
  6. dry with materialdried (Na2SO4)

Sources & evidence

ORD record
ord-44771002d31146fba63391bcf8f9defc
Source dataset
uspto-grants-2011_11
Patent number
US08067448B2

Linked notes

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