Dimethylformamide → (R)-1-(2-chloropropanoyl)-3,3-dimethylindoline-6-carbonitrile

HRID 1475411Notes

Reaction equation

HRID 1475411 reaction equation
C(N([CH2:6][CH3:7])CC)C.[CH3:8][C:9]1([CH3:20])[C:17]2[C:12](=[CH:13][C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[NH:11][CH2:10]1.CN([CH:24]=[O:25])C.C(Cl)[Cl:27]>>[Cl:27][C@H:6]([CH3:7])[C:24]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[C:9]([CH3:20])([CH3:8])[CH2:10]1)=[O:25]

Participants

5

Reactant 4

HCID 6228DimethylformamideHCID 6344Dichloromethane2×HCID 8471TriethylamineHCID 107023412,3-dihydro-3,3-dimethyl-1H-indole-6-carbonitrile

Product 1

HCID 86724007(R)-1-(2-chloropropanoyl)-3,3-dimethylindoline-6-carbonitrile

Procedure

To a stirred solution of 2-chloro-1-propionic acid (0.11 mL, 1.16 mmol) in DCM (20 mL) was added O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (0.55 g, 1.45 mmol). The mixture was stirred for 30 minutes then triethylamine (0.48 mL, 3.44 mmol), 3,3-dimethyl-2,3-dihydro-1H-indole-6-carbonitrile (0.2 g, 1.16 mmol) and a drop of DMF was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with DCM and washed with water. The organic phases were separated, dried with Na2SO4 and concentrated. The crude product was washed with diethyl ether and the filtrate was concentrated and purified by flash column chromatography eluting with 10% EtOAc in heptane to give (R)-1-(2-chloropropanoyl)-3,3-dimethylindoline-6-carbonitrile (0.133 g) [M+H]+=263. A solution of this material, (R)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.13 g, 0.51 mmol) and potassium carbonate (0.10 g, 0.51 mmol) in acetonitrile (2.5 mL) was heated at 60° C. for 48 h. The reaction mixture was then diluted with EtOAc and washed with water. The organic phase was separated, dried with Na2SO4 and concentrated. The residue was purified by flash column chromatography eluting with 15% EtOAc in heptane to give the title compound (33.5 mg), [M+H]+=427.

Workup

  1. stirringthe resulting mixture was stirred overnight
  2. washwashed with water
  3. customThe organic phases were separated
  4. dry with materialdried with Na2SO4
  5. concentrationconcentrated
  6. washThe crude product was washed with diethyl ether
  7. concentrationthe filtrate was concentrated
  8. custompurified by flash column chromatography
  9. washeluting with 10% EtOAc in heptane

Sources & evidence

ORD record
ord-fa45342a0cc64c77aedfc7fb903040da
Source dataset
uspto-grants-2015_04
Patent number
US09018214B2

Reaction notes

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