Potassium Carbonate → (R)-4-chloro-1-(1-(5-cyanopyridin-3-yl)propyl)-1H-indole-5-carbonitrile

HRID 1851137Notes

Reaction equation

HRID 1851137 reaction equation
[NH2:1][C@@H:2]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH:12]=1)[C:10]#[N:11])[CH2:3][CH3:4].[Cl:13][C:14]1[C:21]([C:22]#[C:23][Si](C)(C)C)=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[Cl:13][C:14]1[C:15]([C:16]#[N:17])=[CH:18][CH:19]=[C:20]2[C:21]=1[CH:22]=[CH:23][N:1]2[C@@H:2]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:10]#[N:11])[CH:12]=1)[CH2:3][CH3:4]

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 516892Sodium BicarbonateHCID 55262634(R)-5-(1-aminopropyl)nicotinonitrileHCID 86709177HCID 86709177, compound

Product 1

HCID 86709194(R)-4-chloro-1-(1-(5-cyanopyridin-3-yl)propyl)-1H-indole-5-carbonitrileYield 34.3%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
60 °C

Procedure

An oven-dried vial was charged with commercially available (R)-5-(1-aminopropyl)nicotinonitrile (0.165 g, 1.023 mmol), 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (Example 32B) (0.234 g, 0.93 mmol), and K2CO3 (0.141 g, 1.023 mmol) and sealed with a rubber septum. Anhyd NMP (3 mL) was added via syringe and the mixture was stirred in a heating block at 60° C. under N2. After 18 h, the septum was replaced with a PTFE-faced crimp top and the mixture was subjected to microwave heating (140° C.) for 15 min. Upon cooling the mixture was poured into satd NaHCO3 and extracted with EtOAc (×3). Combined organics were washed (water, brine), the combined washes were filtered (Whatman #2) and re-extracted with EtOAc (×1). Combined organics were dried over Na2SO4, filtered through a short pad of silica and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (R)-4-chloro-1-(1-(5-cyanopyridin-3-yl)propyl)-1H-indole-5-carbonitrile (0.1024 g, 34% yield) as a gum which formed a tan solid upon trituration with Et2O/hexanes: 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J=1.1 Hz, 1H), 8.68 (d, J=1.8 Hz, 1H), 7.66-7.58 (m, 1H), 7.44 (d, J=3.4 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 6.88 (d, J=3.1 Hz, 1H), 5.43 (dd, J=8.5, 6.9 Hz, 1H), 2.50-2.30 (m, 2H), 1.03 (t, J=7.3 Hz, 3H); MS (LCMS ES+) m/z 321 ([M+H]+, 55%), 362 ({[M+H]+MeCN}+, 100%).

Workup

  1. customsealed with a rubber septum
  2. temperatureheating (140° C.) for 15 min
  3. temperatureUpon cooling the mixture
  4. extractionextracted with EtOAc (×3)
  5. washCombined organics were washed (water, brine)
  6. filtrationthe combined washes were filtered (Whatman #2)
  7. extractionre-extracted with EtOAc (×1)
  8. dry with materialCombined organics were dried over Na2SO4
  9. filtrationfiltered through a short pad of silica
  10. concentrationconcentrated in vacuo
  11. customThe residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution)

Sources & evidence

ORD record
ord-1858620bd371456da1587ef0c05da36a
Source dataset
uspto-grants-2015_02
Patent number
US08957104B2

Reaction notes

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