5-Fluoro-2,3-dihydro-1H-isoindole → N-{4-[(1-Cyclobutyl-4-piperidinyl)oxy]benzoyl}-5-fluoro-isoindoline hydrochloride

HRID 268739Notes

Reaction equation

HRID 268739 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.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[F:52][C:53]1[CH:54]=[C:55]2[C:59](=[CH:60][CH:61]=1)[CH2:58][NH:57][CH2:56]2>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:57]4[CH2:56][C:55]5[C:59](=[CH:60][CH:61]=[C:53]([F:52])[CH:54]=5)[CH2:58]4)=[O:18])=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1

Participants

5

Reactant 3

HCID 147958695-Fluoro-2,3-dihydro-1H-isoindoleHCID 16212021N-benzyl-N-ethylethanamine;1,4-bis(ethenyl)benzene;styreneHCID 179862644-[(1-Cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride

Product 1

HCID 17986310N-{4-[(1-Cyclobutyl-4-piperidinyl)oxy]benzoyl}-5-fluoro-isoindoline hydrochlorideYield 57.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A stirred mixture of 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D25) (0.20 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 0.80 g) in DCM (10 ml) at rt was treated with 5-fluoroisoindoline (0.101 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 (1 M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E60) as a white powder (150 mg). MS electrospray (+ion) 395 (MH+). 1H NMR δ (DMSO-d6): 10.60 (1H, s), 7.62 (2H, m), 7.42-7.06 (5H, m), 4.85 (4H, m), 4.66 (1H, m), 3.75-3.55 (1H, m), 3.45-3.20 (2H, m), 2.90 (2H, m), 2.41-1.62 (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 (1 M solution in diethyl ether)
  6. concentrationconcentrated
  7. customThe residue was crystallised from acetone

Sources & evidence

ORD record
ord-94208afcb80a42f295381d8f9018ce1b
Source dataset
uspto-grants-2008_11
Patent number
US07446103B2

Reaction notes

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