Potassium Carbonate → 4-chloro-1-(3-hydroxy-2,3-dimethylbutan-2-yl)-1H-indole-5-carbonitrile

HRID 1851125Notes

Reaction equation

HRID 1851125 reaction equation
[NH2:1][C:2]([CH3:8])([CH3:7])[C:3]([CH3:6])([OH:5])[CH3:4].[Cl:9][C:10]1[C:17]([C:18]#[C:19][Si](C)(C)C)=[C:16](F)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>O.CCOC(C)=O>[Cl:9][C:10]1[C:11]([C:12]#[N:13])=[CH:14][CH:15]=[C:16]2[C:17]=1[CH:18]=[CH:19][N:1]2[C:2]([CH3:8])([C:3]([OH:5])([CH3:6])[CH3:4])[CH3:7]

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 13387N-methyl-2-pyrrolidoneHCID 157085323-Amino-2,3-dimethylbutan-2-olHCID 86709177HCID 86709177, compound

Product 1

HCID 867091814-chloro-1-(3-hydroxy-2,3-dimethylbutan-2-yl)-1H-indole-5-carbonitrileYield 5.3%

Reagents, catalysts & solvents 1

HCID 22728543Water ethylacetateSolvent

Conditions

Temperature
60 °C

Procedure

An oven-dried vial was charged with 3-amino-2,3-dimethylbutan-2-ol (0.063 g, 0.539 mmol), 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (Example 32B) (0.113 g, 0.449 mmol), and K2CO3 (0.137 g, 0.988 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 1 h, the vial was sealed with a PTFE-faced crimp top and subjected to microwave heating; 1 h at 140° C. followed by 45 min at 160° C. (with air cooling). The mixture was poured into water/EtOAc and the whole was filtered through a pad of Celite. Layers of the filtrate were separated and the aqueous layer was extracted with EtOAc (×2). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (C18 stationary phase, MeCN/water gradient with 0.1% TFA additive) affording 4-chloro-1-(3-hydroxy-2,3-dimethylbutan-2-yl)-1H-indole-5-carbonitrile (0.0066 g, 5% yield) as a tan solid (ca. 85% purity): 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J=9.0 Hz, 1H), 7.49 (d, J=3.5 Hz, 1H), 7.32 (d, J=8.9 Hz, 1H), 6.71 (d, J=3.4 Hz, 1H), 1.87 (s, 6H), 1.20 (s, 6H); MS (LCMS ES+) m/z 277 ([M+H]+, 65%), 318 ({[M+H]+MeCN}+, 100%).

Workup

  1. customsealed with a rubber septum
  2. temperatureto microwave heating
  3. wait1 h at 140° C. followed by 45 min at 160° C.
  4. temperature(with air cooling)
  5. filtrationthe whole was filtered through a pad of Celite
  6. customLayers of the filtrate were separated
  7. extractionthe aqueous layer was extracted with EtOAc (×2)
  8. washCombined organics were washed (water, brine)
  9. dry with materialdried over Na2SO4
  10. concentrationconcentrated in vacuo
  11. customThe residue was purified by preparative HPLC (C18 stationary phase, MeCN/water gradient with 0.1% TFA additive)

Sources & evidence

ORD record
ord-5c509493fb4344a987388a3f529460ba
Source dataset
uspto-grants-2015_02
Patent number
US08957104B2

Reaction notes

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