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

HRID 1851136Notes

Reaction equation

HRID 1851136 reaction equation
F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[C:14]#[C:15][Si](C)(C)C.[NH2:20][C@@H:21]([C:24]1[CH:25]=[N:26][CH:27]=[C:28]([CH:31]=1)[C:29]#[N:30])[CH2:22][CH3:23].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:29]([C:28]1[CH:31]=[C:24]([C@H:21]([N:20]2[C:2]3[C:3](=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([C:6]#[N:7])=[CH:8][CH:9]=3)[CH:14]=[CH:15]2)[CH2:22][CH3:23])[CH:25]=[N:26][CH:27]=1)#[N:30]

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 516892Sodium BicarbonateHCID 55262634(R)-5-(1-aminopropyl)nicotinonitrileHCID 867091684-Fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile

Product 1

HCID 86709193(R)-1-(1-(5-cyanopyridin-3-yl)propyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrileYield 36%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
60 °C

Procedure

An oven-dried vial was charged with 4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile (Example 21D), (0.171 g, 0.598 mmol), commercially available (R)-5-(1-aminopropyl)nicotinonitrile (0.106 g, 0.658 mmol) and K2CO3 (0.091 g, 0.658 mmol) and sealed with a rubber septum. Anhydrous NMP (3 mL) was added via syringe and the mixture was stirred in a heating block at 60° C. under N2. After 22 h the mixture was cooled, poured into satd NaHCO3 and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (R)-1-(1-(5-cyanopyridin-3-yl)propyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.0758 g, 36% yield) as a tan gum: 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.69 (br. s., 1H), 7.64 (br. s., 1H), 7.60-7.43 (m, 3H), 7.00 (br. s., 1H), 5.49 (t, J=7.5 Hz, 1H), 2.42 (sxt, J=7.1 Hz, 2H), 1.04 (t, J=7.1 Hz, 3H); MS (LCMS ES+) m/z 355 ([M+H]+, 62%), 396 ({[M+H]+MeCN}+, 100%).

Workup

  1. customsealed with a rubber septum
  2. temperatureAfter 22 h the mixture was cooled
  3. extractionextracted with EtOAc (×3)
  4. washCombined organics were washed (water, brine)
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution)

Sources & evidence

ORD record
ord-347e1c6dce7c4eeb8a3e0dbf72e4dbba
Source dataset
uspto-grants-2015_02
Patent number
US08957104B2

Reaction notes

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