4-Methylmorpholine → HCID 11192388, compound

HRID 394461Notes

Reaction equation

HRID 394461 reaction equation
[CH2:1]([N:8]1[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[C@@H:13]([OH:20])[C@H:12]([Br:21])[CH2:11][N:10]3[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:30][C@H:31]([C:44](O)=[O:45])[C:32]1[CH:33]=[CH:34][C:35]2[CH:36]=[C:37]([O:42][CH3:43])[CH:38]=[CH:39][C:40]=2[CH:41]=1.[Cl-].C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[CH3:43][O:42][C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[CH:41]=[C:32]([C@@H:31]([CH3:30])[C:44]([O:20][C@H:13]1[C:14]3[C:19]4=[C:18]([N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:9](=[O:22])[N:10]4[CH2:11][C@@H:12]1[Br:21])[CH:17]=[CH:16][CH:15]=3)=[O:45])[CH:33]=[CH:34]2

Participants

8

Reactant 4

HCID 79724-MethylmorpholineHCID 11430Potassium CarbonateHCID 15547193HCID 15547193, compoundHCID 86584140(2S)-2-(6-methoxynaphthalen-2-yl)propanoic acid chloride

Product 1

HCID 11192388HCID 11192388, compound

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

(5R,6R)-1-Benzyl-5-bromo-6-hydroxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (III, EXAMPLE 2, 143 g), methylene chloride (3,136 g), N-methyl morpholine (100.2 g) and 4-dimethylaminopyridine (497 mg) are added to the reactor and the mixture is cooled to 0 to 5°. (R)-Naproxen chloride (PREPARATION 1, 118.5 g) dissolved in methylene chloride (694 ml) is added to the reactor over about 1 hr and the mixture is stirred at 0 to 5° to complete the reaction. If necessary, additional naproxen chloride is added to complete the reaction. Potassium carbonate solution diluted with water is added to the mixture. The aqueous phase is extracted with methylene chloride and the combined methylene chloride phase is washed with water. The washed mixture is concentrated by vacuum distillation and solvent exchange with ethyl acetate is performed. The concentrate is cooled to −10° and stirred. The crystal slurry is filtered and the crystal cake is washed with precooled methyl t-butyl ether and dried at 50° to give the title compound in solid form, (5S,6S)-1-benzyl-5-bromo-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-6-yl (2R)-2-(6-methoxy-2-naphthyl)propanoate (IVA), CMR (CDCl3) δ 173.2, 157.8, 153.4, 136.1, 134.6, 133.7, 129.2, 128.8, 127.8, 127.8, 127.6, 127.2, 125.9, 125.9, 125.6, 121.5, 121.4, 119.1, 113.2, 109.0, 105, 105.6, 69.2, 55.3, 45.4, 45.2, 42.5, 41.7 and 18.3.

Workup

  1. temperaturethe mixture is cooled to 0 to 5°
  2. additionis added to the reactor over about 1 hr
  3. customthe reaction
  4. customthe reaction
  5. additionis added to the mixture
  6. extractionThe aqueous phase is extracted with methylene chloride
  7. washthe combined methylene chloride phase is washed with water
  8. concentrationThe washed mixture is concentrated by vacuum distillation and solvent exchange with ethyl acetate
  9. temperatureThe concentrate is cooled to −10°
  10. stirringstirred
  11. filtrationThe crystal slurry is filtered
  12. washthe crystal cake is washed with precooled methyl t-butyl ether
  13. customdried at 50°

Sources & evidence

ORD record
ord-7c88d521ff284228901a9e4a4c136112
Source dataset
uspto-grants-2003_08
Patent number
US06602868B2

Reaction notes

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