Diethyl chlorophosphate → tert-Butyl 6-Fluoro4,5-dihydro-5-[(pyrrolidino)carbonyl]imidazo[1,5-a]quinoxaline-3-carboxylate

HRID 1736686Notes

Reaction equation

HRID 1736686 reaction equation
CC(C)([O-])C.[K+].[F:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[N:10]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:11][C:12](=O)[NH:13]2.C(OP(Cl)(OCC)=O)C.[N+:35]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])#[C-:36]>C1COCC1>[F:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[N:10]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:11][C:12]1[N:13]2[CH:36]=[N:35][C:37]=1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]

Participants

6

Reactant 4

HCID 13139Diethyl chlorophosphateHCID 2759404tert-Butyl isocyanoacetateHCID 229128415-Fluoro-1,2,3,4-tetrahydro4-[(pyrrolidino)carbonyl]quinoxalin-2-oneHCID 23665647Potassium tert-butoxide2×

Product 1

HCID 22912915tert-Butyl 6-Fluoro4,5-dihydro-5-[(pyrrolidino)carbonyl]imidazo[1,5-a]quinoxaline-3-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Potassium tert-butoxide (1M, 3.8 ml) is added to 5-fluoro-1,2,3,4-tetrahydro-4-[(pyrrolidino)carbonyl]quinoxalin-2-one (XXXII, EXAMPLE 29, 0.908 g) at 0° in THF (20 ml). The mixture is stirred for 30 min and then diethylchlorophosphate (0.55 ml) is added. The reaction is stirred for 1 hr at 0°, then cooled at -78°. tert-butyl isocyanoacetate (0.58 g) is added, followed by potassium tert-butoxide (1 M, 4.14 ml). The reaction is stirred at -78° for 4 hr, then allowed to warm to 20°-25° over 1 hr. The mixture is then partitioned between ethyl acetate, water, and saline. The organic layers are dried over magnesium sulfate and concentrated. The crude product is chromatographed on silica gel (250 ml) eluting with a gradient of ethyl acetate/dichloromethane (20/80 to 40/60). The appropriate fractions are pooled, concentrated and crystallized from dichloromethane/hexane to give the title compound; mp 213.5-214.5°; MS (m/z) at 386; IR (mineral oil) 1689, 1677, 1217, 1363 and 1157 cm-1 ; NMR (CDCl3) 1.63, 1.88, 3.36, 5.08, 7.08, 7.20, 7.33 and 8.00 δ.

Workup

  1. stirringThe reaction is stirred for 1 hr at 0°
  2. temperaturecooled at -78°
  3. stirringThe reaction is stirred at -78° for 4 hr
  4. temperatureto warm to 20°-25° over 1 hr
  5. customThe mixture is then partitioned between ethyl acetate, water, and saline
  6. dry with materialThe organic layers are dried over magnesium sulfate
  7. concentrationconcentrated
  8. customThe crude product is chromatographed on silica gel (250 ml)
  9. washeluting with a gradient of ethyl acetate/dichloromethane (20/80 to 40/60)
  10. concentrationconcentrated
  11. customcrystallized from dichloromethane/hexane

Sources & evidence

ORD record
ord-93d1938e5a284794adfefb6c5f985fa4
Source dataset
uspto-grants-1996_07
Patent number
US05541324

Reaction notes

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