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Tri-o-tolylphosphine → 2-ethyl-7-[(1E)-3-morpholin-4-yl-3-oxoprop-1-enyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine

HRID 244883
Notes
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Reaction equation

HRID 244883 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:14]([CH2:23][CH3:24])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:47]([N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)(=[O:50])[CH:48]=[CH2:49]>CN(C)C=O.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:23]([C:14]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:6]2[C:5]3[CH:4]=[CH:3][C:2](/[CH:49]=[CH:48]/[C:47]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[O:50])=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH3:24]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

HCID 80271Tri-o-tolylphosphineHCID 98723AcryloylmorpholineHCID 690807877-bromo-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine

Product 1

HCID 576572262-ethyl-7-[(1E)-3-morpholin-4-yl-3-oxoprop-1-enyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amineYield 51.2%

Reagents, catalysts & solvents 3

HCID 167845
palladium(II) acetate
Catalyst
HCID 6228DimethylformamideSolvent3×
HCID 8471TriethylamineSolvent

Conditions

Temperature
120 °C

Procedure

A thick walled glass vessel, equipped with a stir bar, was charged with a warmed solution of 7-bromo-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (584 mg, 1.5 mmol) in N,N-dimethylformamide (10 mL). To the solution was added in succession, a solution of palladium acetate (37 mg, 0.15 mmol) and tri-ortho-tolylphosphine (91 mg, 0.3 mmol) in N,N-dimethylformamide (5 mL), triethylamine (0.6 mL), and a solution of 4-acryloylmorpholine (254 mg 1.8 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was purged with nitrogen. The vessel was sealed and heated at 120° C. for 18 hours. The reaction was cooled to ambient temperature and then concentrated to dryness under reduced pressure. The resulting solid was dissolved in dichloromethane (100 mL) and washed with saturated aqueous potassium carbonate (50 mL). The fractions were separated and the organic fraction was concentrated to dryness under reduced pressure. The resulting solid was purified by chromatography using a HORIZON HPFC system (silica cartridge, 0-15% CMA/chloroform). A final recrystallization from acetonitrile provided 345 mg of 2-ethyl-7-[(1E)-3-morpholin-4-yl-3-oxoprop-1-enyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white crystalline solid, mp>260° C.

Workup

  1. customA thick walled glass vessel, equipped with a stir bar
  2. additionTo the solution was added in succession
  3. customThe reaction mixture was purged with nitrogen
  4. customThe vessel was sealed
  5. temperatureThe reaction was cooled to ambient temperature
  6. concentrationconcentrated to dryness under reduced pressure
  7. dissolutionThe resulting solid was dissolved in dichloromethane (100 mL)
  8. washwashed with saturated aqueous potassium carbonate (50 mL)
  9. customThe fractions were separated
  10. concentrationthe organic fraction was concentrated to dryness under reduced pressure
  11. customThe resulting solid was purified by chromatography
  12. customA final recrystallization from acetonitrile

Sources & evidence

ORD record
ord-7c10b0bc18064690817dd3b4b19d37b3
Source dataset
uspto-grants-2014_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08658666B2

Reaction notes

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