1,4-Dioxane → 3-chloro-5-(1-([3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-4-pyridinecarbonitrile

HRID 1910091Notes

Reaction equation

HRID 1910091 reaction equation
Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[C:8]#[N:9].CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28](=[O:40])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[CH2:23][CH2:22]3)O1.O1CCOCC1.C([O-])(O)=O.[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28](=[O:40])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=2)[CH2:23][CH2:22]3)[C:7]=1[C:8]#[N:9]

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 516892Sodium BicarbonateHCID 111375993,5-Dichloropyridine-4-carbonitrileHCID 668234855-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole

Product 1

HCID 668238663-chloro-5-(1-([3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-4-pyridinecarbonitrileYield 54.9%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

To 3,5-dichloro-4-pyridinecarbonitrile (300 mg, 1.74 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (823 mg, 1.908 mmol) in a 5 mL sealable vial was added 1,4-Dioxane (5 mL) and saturated NaHCO3 (2.5 mL). The mixture was then bubbled with N2 gas for 5 minutes then Pd(Ph3P)4 (200 mg, 0.173 mmol) was added. The vial was then capped and heated at 100° C. overnight. The reaction was then diluted with water (10 ml) and extracted with EtOAc (3×20 ml). The organic was combined then washed brine, dried over MgSO4, filtered and concentrated. The crude solid was then dissolved in 3 mL of DMF and loaded on to a 50 g Biotage SNAP column conditioned with hexane and purified by silica gel chromatography with 0 to 60% EtOAc in Hexane over a 30 minute gradient. The fractions with the desired product were pool and concentrated. The semi-solid oil was then treated with 20 ml of 5% DCM/Hexane to induce precipitation. The solid was isolated by filtration to give 3-chloro-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-4-pyridinecarbonitrile (421 mg, 54.9% yield) as a off yellow solid. LC/MS (ES) m/z=442.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.83 (s, 1H), 8.18 (d, J=8.34 Hz, 1H), 7.69 (s, 1H), 7.56-7.67 (m, 3H), 7.51 (d, J=8.08 Hz, 1H), 4.31 (t, J=8.59 Hz, 2H), 4.06 (s, 2H), 3.29 (t, 3H).

Workup

  1. customThe mixture was then bubbled with N2 gas for 5 minutes
  2. customThe vial was then capped
  3. extractionextracted with EtOAc (3×20 ml)
  4. dry with materialwashed brine, dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. dissolutionThe crude solid was then dissolved in 3 mL of DMF
  8. custompurified by silica gel chromatography with 0 to 60% EtOAc in Hexane over a 30 minute gradient
  9. concentrationconcentrated
  10. additionThe semi-solid oil was then treated with 20 ml of 5% DCM/Hexane
  11. customprecipitation
  12. customThe solid was isolated by filtration

Sources & evidence

ORD record
ord-1bdc757ae0414f69b3aa5fba0c9eb7a8
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

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