Benzoyl Peroxide → 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-5-chloro-7-iodo-2,3-dihydro-1H-isoindol-1-one

HRID 333217Notes

Reaction equation

HRID 333217 reaction equation
[Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]([C:6]([O:8]C)=O)=[C:4]([I:13])[CH:3]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.[F:47][C:48]1([F:61])[CH2:53][CH2:52][CH:51]([N:54]2[CH2:59][CH2:58][CH:57]([NH2:60])[CH2:56][CH2:55]2)[CH2:50][CH2:49]1>C(OC)(=O)C(C)(C)C.ClCCl.ClCCl.C(O)C>[F:61][C:48]1([F:47])[CH2:53][CH2:52][CH:51]([N:54]2[CH2:55][CH2:56][CH:57]([N:60]3[CH2:12][C:10]4[C:5](=[C:4]([I:13])[CH:3]=[C:2]([Cl:1])[CH:11]=4)[C:6]3=[O:8])[CH2:58][CH2:59]2)[CH2:50][CH2:49]1

Participants

9

Reactant 5

HCID 7187Benzoyl Peroxide2×HCID 8471TriethylamineHCID 67184N-bromobutanimide2×HCID 67192903Methyl 4-chloro-2-iodo-6-methylbenzoateHCID 671942361-(4,4-Difluorocyclohexyl)-piperidin-4-ylamine

Product 1

HCID 671930032-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-5-chloro-7-iodo-2,3-dihydro-1H-isoindol-1-oneYield 46.9%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 69027Methyl pivalateSolventHCID 21584144Dichloromethane ethanolSolvent

Conditions

Temperature
85 °C

Procedure

To a solution of methyl 4-chloro-2-iodo-6-methylbenzoate (175 mg, 0.56 mmol) in methyl pivalate (1 mL), N-bromosuccinimide (120 mg, 0.67 mmol) and benzoylperoxide (14 mg, 0.06 mmol) were added. The reaction mixture was stirred at 85° C. under nitrogen atmosphere for 3 hours. Additional N-bromosuccinimide (60 mg) and benzoylperoxide (7 mg) were added and stirring continued for 1 hour. Crude was filtered on Gooch and washed with toluene. Volatiles were evaporated and the residue was dissolved in acetonitrile (2 mL). Triethylamine (0.28 mL, 2 mmol) and 1-(4,4-difluorocyclohexyl)-piperidin-4-ylamine (110 mg, 0.5 mmol) were added and the reaction mixture was stirred at 90° C. for 4 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:97/3) afforded title compound (116 mg, 45% yield).

Workup

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

Sources & evidence

ORD record
ord-a44219cb4dd24fd18ca9a0809ba587a4
Source dataset
uspto-grants-2014_11
Patent number
US08877944B2

Reaction notes

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