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Isoindoline → N-{4-[(1-Cyclobutyl-4-piperidinyl)oxy]benzoyl}isoindoline hydrochloride

HRID 268738
Notes
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Reaction equation

HRID 268738 reaction equation
Cl.[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([Cl:19])=[O:18])=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.CC[N:24]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25]C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C2C(=CC=CC=2)CN1>C(Cl)Cl>[ClH:19].[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([N:24]4[CH2:25][C:29]5[C:28](=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:27]4)=[O:18])=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 422478IsoindolineHCID 16212021N-benzyl-N-ethylethanamine;1,4-bis(ethenyl)benzene;styreneHCID 179862644-[(1-Cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride

Product 1

HCID 17986299N-{4-[(1-Cyclobutyl-4-piperidinyl)oxy]benzoyl}isoindoline hydrochlorideYield 70.4%

Reagents, catalysts & solvents 1

HCID 6344
Dichloromethane
Solvent

Procedure

A stirred mixture of 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D25) (0.25 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 1.13 g) in DCM (10 ml) at rt was treated with isoindoline (0.098 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E59) as a white powder (220 mg). MS electrospray (+ion) 377 (MH+). 1H NMR δ (DMSO-d6): 10.62 (1H, s), 7.62 (2H, m), 7.40-7.25 (4H, m), 7.08 (2H, m) 4.82 (4H, m), 4.64 (1H, m), 3.81-3.58. (1H, m), 3.45-3.20 (2H, m), 2.95 (2H, m), 2.38-1.62 (10H, m).

Workup

  1. customThe reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)]
  2. additionFractions containing the required product
  3. customwere evaporated
  4. dissolutionredissolved in DCM
  5. additiontreated with excess hydrogen chloride (1M solution in diethyl ether)
  6. concentrationconcentrated
  7. customThe residue was crystallised from acetone

Sources & evidence

ORD record
ord-7fbf65022b4d4ef0acc5a2c28b6088e8
Source dataset
uspto-grants-2008_11
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07446103B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes