4-Aminotetrahydropyran → 2-(Tetrahydro-pyran-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide

HRID 602391Notes

Reaction equation

HRID 602391 reaction equation
Br[C:2]1[CH:9]=[C:8]([N:10]2[C:18]3[CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][C:14](=[O:21])[C:13]=3[C:12]([CH3:22])=[CH:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CC(C)([O-:33])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[O:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:2]2[CH:9]=[C:8]([N:10]3[C:18]4[CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][C:14](=[O:21])[C:13]=4[C:12]([CH3:22])=[CH:11]3)[CH:7]=[CH:6][C:3]=2[C:4]([NH2:5])=[O:33])[CH2:25][CH2:26]1

Participants

7

Reactant 3

HCID 4192234-AminotetrahydropyranHCID 118539082-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrileHCID 23676156Sodium t-butoxide

Product 1

HCID 118539102-(Tetrahydro-pyran-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamideYield 36%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 1140TolueneSolvent

Conditions

Temperature
115 °C

Procedure

A “Personal Chemistry” microwave vial was charged with the title compound of Example 2 (2.858 g, 8.0 mmol), 4-aminotetrahydropyran (3.236 g, 32.0 mmol), palladium (II) acetate (89.8 mg, 5 mol %), 1,1′-bis(diphenylphosphino)ferrocene (443.6 mg, 10 mol %), and sodium tert-butoxide (1.538 g, 16.0 mmol). The reagents were suspended in toluene (40 mL) and were heated with microwave radiation to a temperature of 115° C. for fifteen minutes. After allowing the reaction vessel to cool, the suspension was filtered and the filtrate concentrated. After purifying the crude intermediate nitrile by flash chromatography, the nitrile was dissolved in 25% dimethylsulfoxide/ethanol, and 2 mL of 1 N sodium hydroxide and 2 mL of 30% aqueous hydrogen peroxide were added, followed by stirring at room temperature for 16 hours. The DMSO/ethanol mixture was then diluted with water and extracted with ethyl acetate (3×). The combined organics were washed with brine (2×), dried over Na2SO4, and evaporated. The residue was purified by column chromatography (EtOAc/MeOH) to yield 1.132 g (36%) of the title compound as an off-white powder. LCMS m/z: (M+H)=396.7.

Workup

  1. temperatureto cool
  2. filtrationthe suspension was filtered
  3. concentrationthe filtrate concentrated
  4. customAfter purifying the crude intermediate nitrile by flash chromatography
  5. dissolutionthe nitrile was dissolved in 25% dimethylsulfoxide/ethanol
  6. addition2 mL of 1 N sodium hydroxide and 2 mL of 30% aqueous hydrogen peroxide were added
  7. additionThe DMSO/ethanol mixture was then diluted with water
  8. extractionextracted with ethyl acetate (3×)
  9. washThe combined organics were washed with brine (2×)
  10. dry with materialdried over Na2SO4
  11. customevaporated
  12. customThe residue was purified by column chromatography (EtOAc/MeOH)

Sources & evidence

ORD record
ord-79cef75600e54bb6a4cf345281dadd57
Source dataset
uspto-grants-2011_03
Patent number
US07906529B2

Reaction notes

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