Morpholine → HCID 57657217, compound

HRID 244832Notes

Reaction equation

HRID 244832 reaction equation
[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:20][CH2:21][C:22]([OH:24])=O)=[CH:5][C:4]=2[N:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CN(C)C=O>[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:20][CH2:21][C:22]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[O:24])=[CH:5][C:4]=2[N:3]=1

Participants

6

Reactant 4

HCID 8083Morpholine2×HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide2×HCID 757711-Hydroxybenzotriazole2×HCID 69080347HCID 69080347, compound

Product 1

HCID 57657217HCID 57657217, compoundYield 56.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

3-[4-Amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoic acid (500 mg, 1.5 mmol), anhydrous N,N-dimethylformamide (25 mL), and 1-hydroxybenzotriazole (250 mg, 1.8 mmol) were combined and the reaction was stirred for 15 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (350 mg, 1.8 mmol) was added and the reaction mixture was stirred for an additional 30 minutes. Morpholine (400 mg, 2.3 mmol) was added to the reaction slurry. After five hours 1-hydroxybenzotriazole (250 mg, 1.8 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (350 mg, 1.8 mmol), and morpholine (400 mg, 2.3 mmol) were added and the mixture was heated at 70° C. for 2 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure and the residue was partitioned between chloroform (100 ml) and 1% aqueous sodium carbonate (50 mL). The fractions were separated and organic fraction was washed 1% aqueous sodium carbonate (2×50 mL). The combined aqueous fractions were back extracted with chloroform (50 mL). The combined organic fractions were dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting off-white solid was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-5% CMA over 75 mL, 5-35% over 1500 mL, and 35% for 600 mL) followed by recrystallization from acetonitrile to provide 335 mg of 3-[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-1-(morpholin-4-yl)propan-1-one as an off-white solid, mp 217-218° C.

Workup

  1. stirringthe reaction mixture was stirred for an additional 30 minutes
  2. temperatureAfter cooling to ambient temperature
  3. customthe solvent was removed under reduced pressure
  4. customthe residue was partitioned between chloroform (100 ml) and 1% aqueous sodium carbonate (50 mL)
  5. customThe fractions were separated
  6. washorganic fraction was washed 1% aqueous sodium carbonate (2×50 mL)
  7. extractionThe combined aqueous fractions were back extracted with chloroform (50 mL)
  8. dry with materialThe combined organic fractions were dried (MgSO4)
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe resulting off-white solid was purified by chromatography
  12. washeluting with a CMA
  13. custom0-5% CMA over 75 mL, 5-35% over 1500 mL, and 35% for 600 mL) followed by recrystallization from acetonitrile

Sources & evidence

ORD record
ord-c373f197d858464b8f2bee5281397fe9
Source dataset
uspto-grants-2014_02
Patent number
US08658666B2

Reaction notes

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