4-Bromobutyryl chloride → N-[4-(3-Piperidin-1-ylpropoxy)-benzoyl]-5-(2-oxo-pyrrolidin-1-yl)-isoindoline hydrochloride

HRID 268731Notes

Reaction equation

HRID 268731 reaction equation
CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.Cl.[N:32]1([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:59]=[CH:58][C:45]([C:46]([N:48]3[CH2:56][C:55]4[C:50](=[CH:51][CH:52]=[C:53]([NH2:57])[CH:54]=4)[CH2:49]3)=[O:47])=[CH:44][CH:43]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.Br[CH2:61][CH2:62][CH2:63][C:64]([Cl:66])=[O:65]>C(Cl)Cl>[ClH:66].[N:32]1([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:43]=[CH:44][C:45]([C:46]([N:48]3[CH2:56][C:55]4[C:50](=[CH:51][CH:52]=[C:53]([N:57]5[CH2:61][CH2:62][CH2:63][C:64]5=[O:65])[CH:54]=4)[CH2:49]3)=[O:47])=[CH:58][CH:59]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1

Participants

5

Reactant 3

HCID 702254-Bromobutyryl chlorideHCID 16212021N-benzyl-N-ethylethanamine;1,4-bis(ethenyl)benzene;styreneHCID 68963025HCID 68963025, compound

Product 1

HCID 17986260N-[4-(3-Piperidin-1-ylpropoxy)-benzoyl]-5-(2-oxo-pyrrolidin-1-yl)-isoindoline hydrochloride

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A stirred mixture of diethylaminomethyl polystyrene (247 mg, 3.2 mmol/g) and N-[4-(3-piperidin-1-ylpropoxy)-benzoyl]-5-aminoisoindoline hydrochloride (E13) (150 mg) in DCM (5 ml) at rt was treated with 4-bromobutanoyl chloride (0.05 ml) for 30 mins. The mixture was filtered and evaporated. The residue was redissolved in DMF (5 ml) and treated with sodium hydride (18 mg of a 60% suspension in mineral oil) and stirred for 2 h. A further portion of sodium hydride (18 mg) was added and the mixture stirred for 1 h. The reaction was partitioned between EtOAc (10 ml) and saturated sodium hydrogen carbonate solution (10 ml). The organic layer was washed with water (2×10 ml), brine (10 ml), dried (MgSO4) and evaporated. After chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)] fractions containing the required product were evaporated, then redissolved in DCM, treated with excess 4M HCl in dioxan and evaporated. Crystallisation from EtOH/diethyl ether afforded the title compound (E15) (77 mg). MS electrospray (+ion) 448 (MH+). 1H NMR δ (DMSO-d6): 10.15 (1H, s), 7.60 (4H, m), 7.34 (1H, m), 7.0 (2H, d, J=8.5 Hz), 4.80 (4H, m), 4.13. (2H, t, J=6 Hz), 3.80 (2H, m), 3.05-3.58 (6H, m), 2.91 (2H, m), 2.21 (2H, m), 2.06 (2H, m), 1.28-1.90 (6H, m).

Workup

  1. filtrationThe mixture was filtered
  2. customevaporated
  3. dissolutionThe residue was redissolved in DMF (5 ml)
  4. additiontreated with sodium hydride (18 mg of a 60% suspension in mineral oil) and
  5. additionA further portion of sodium hydride (18 mg) was added
  6. stirringthe mixture stirred for 1 h
  7. customThe reaction was partitioned between EtOAc (10 ml) and saturated sodium hydrogen carbonate solution (10 ml)
  8. washThe organic layer was washed with water (2×10 ml), brine (10 ml)
  9. dry with materialdried (MgSO4)
  10. customevaporated
  11. additionAfter chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)] fractions containing the required product
  12. customwere evaporated
  13. dissolutionredissolved in DCM
  14. additiontreated with excess 4M HCl in dioxan
  15. customevaporated
  16. customCrystallisation from EtOH/diethyl ether

Sources & evidence

ORD record
ord-bc3da3cc08de4021ac8b8bb783f5dd58
Source dataset
uspto-grants-2008_11
Patent number
US07446103B2

Reaction notes

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