Benzoyl Peroxide → 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-5-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile

HRID 333221Notes

Reaction equation

HRID 333221 reaction equation
[C:1]([C:3]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([CH3:14])[C:4]=1[C:5]([O:7]C)=O)#[N:2].BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.[F:48][C:49]1([F:62])[CH2:54][CH2:53][CH:52]([N:55]2[CH2:60][CH2:59][CH:58]([NH2:61])[CH2:57][CH2:56]2)[CH2:51][CH2:50]1>C(OC)(=O)C(C)(C)C.ClCCl.ClCCl.C(O)C>[F:62][C:49]1([F:48])[CH2:54][CH2:53][CH:52]([N:55]2[CH2:56][CH2:57][CH:58]([N:61]3[C:5](=[O:7])[C:4]4[C:3]([C:1]#[N:2])=[C:12]([F:13])[CH:11]=[CH:10][C:9]=4[CH2:14]3)[CH2:59][CH2:60]2)[CH2:51][CH2:50]1

Participants

9

Reactant 5

HCID 7187Benzoyl PeroxideHCID 8471TriethylamineHCID 67184N-bromobutanimideHCID 67192265Methyl 2-cyano-3-fluoro-6-methylbenzoateHCID 671942361-(4,4-Difluorocyclohexyl)-piperidin-4-ylamine

Product 1

HCID 696741452-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-5-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carbonitrileYield 60.6%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 69027Methyl pivalateSolventHCID 21584144Dichloromethane ethanolSolvent

Conditions

Temperature
85 °C

Procedure

To a solution of methyl 2-cyano-3-fluoro-6-methylbenzoate (208 mg, 1.07 mmol) in methyl pivalate (2 mL), N-bromosuccinimide (310 mg, 1.74 mmol) and benzoylperoxide (20 mg, 0.097 mmol) were added. The reaction mixture was stirred at 85° C. under nitrogen atmosphere for 3 hours. Crude was filtered on Gooch and washed with toluene. Volatiles were evaporated and the residue was dissolved in acetonitrile (3 mL). Triethylamine (0.41 mL, 2.9 mmol) and 1-(4,4-difluorocyclohexyl)-piperidin-4-ylamine (280 mg, 0.97 mmol) were added and the reaction mixture was stirred at 90° C. for 3 hours. Crude was diluted with dichloromethane and washed with 15% ammonium hydroxide Organic phase was dried over sodium sulfate, filtered and evaporated. Column chromatography (dichloromethane/ethanol:95/5) afforded title compound (222 mg, 60% yield).

Workup

  1. filtrationCrude was filtered on Gooch
  2. washwashed with toluene
  3. customVolatiles were evaporated
  4. dissolutionthe residue was dissolved in acetonitrile (3 mL)
  5. stirringthe reaction mixture was stirred at 90° C. for 3 hours
  6. washwashed with 15% ammonium hydroxide Organic phase
  7. dry with materialwas dried over sodium sulfate
  8. filtrationfiltered
  9. customevaporated

Sources & evidence

ORD record
ord-fe41265c19794c67b35eb10316e5112e
Source dataset
uspto-grants-2014_11
Patent number
US08877944B2

Reaction notes

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