Hydrochloric Acid → (5R)-3-{4-[(3-chloro-5-fluorophenyl)oxy]phenyl}-5-methyl-2,4-imidazolidinedione

HRID 1023593Notes

Reaction equation

HRID 1023593 reaction equation
ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[C:16]([O:21][C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH:17]=[C:18]([F:20])[CH:19]=1.[NH2:29][C@@H:30]([C:32](O)=[O:33])[CH3:31].Cl>C1(C)C=CC=CC=1.CN(C)C=O.O.C(N(CC)CC)C>[Cl:13][C:14]1[CH:15]=[C:16]([O:21][C:22]2[CH:28]=[CH:27][C:25]([N:26]3[C:32](=[O:33])[C@@H:30]([CH3:31])[NH:29][C:5]3=[O:11])=[CH:24][CH:23]=2)[CH:17]=[C:18]([F:20])[CH:19]=1

Participants

9

Reactant 4

HCID 313Hydrochloric Acid2×HCID 71080D-AlanineHCID 94429TriphosgeneHCID 672366794-[(3-Chloro-5-fluorophenyl)oxy]aniline2×

Product 1

HCID 53241609(5R)-3-{4-[(3-chloro-5-fluorophenyl)oxy]phenyl}-5-methyl-2,4-imidazolidinedioneYield 11.8%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1140TolueneSolvent2×HCID 6228DimethylformamideSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
100 °C

Procedure

To triphosgene (0.052 g, 0.177 mmol) was added a solution of 4-[(3-chloro-5-fluorophenyl)oxy]aniline (Intermediate 6, 0.12 g) in toluene (1 mL) and triethylamine (0.16 g) with shaking. A thick slurry immediately formed and additional toluene (1 mL) was added. The mixture was stirred for 3 hours at room temperature and then D-alanine (0.067 g, 0.757 mmol) in N,N-dimethylformamide (2 mL) and water (ca. 2 mL) (barely dissolved) was rapidly added via pipette. A two-layer system formed that was vigorously stirred for 2 hours and kept overnight at room temperature. Volatiles were evaporated, hydrochloric acid (2 mL, 24.35 mmol) added and the heterogeneous mixture heated at 100° C. for 2 hours, then allowed to cool to room temperature. After cooling to room temperature the aqueous HCl was pipetted off and the residue dried under vacuum. The residue was purified by silica gel chromatography (Biotage instrument, 10 g column) eluting with 0-100% EtOAc/cHex to give the title compound as colourless solid (7 mg).

Workup

  1. customA thick slurry immediately formed
  2. stirringThe mixture was stirred for 3 hours at room temperature
  3. additionwas rapidly added via pipette
  4. customA two-layer system formed
  5. stirringthat was vigorously stirred for 2 hours
  6. customVolatiles were evaporated
  7. temperatureto cool to room temperature
  8. customthe residue dried under vacuum
  9. customThe residue was purified by silica gel chromatography (Biotage instrument, 10 g column)
  10. washeluting with 0-100% EtOAc/cHex

Sources & evidence

ORD record
ord-8f159bd6faa74bb7ad01744a0703a865
Source dataset
uspto-grants-2014_05
Patent number
US08722695B2

Reaction notes

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