Triphenylphosphine → (R)-benzyl 2-(4-cyano-3-(trifluoromethyl)phenyl)-3-oxo-hexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylate

HRID 502525Notes

Reaction equation

HRID 502525 reaction equation
O[CH2:2][C@H:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)=[CH:23][C:22]=1[C:37]([F:40])([F:39])[F:38])#[N:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CC(N(C)C)=O.CCOC(C)=O>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:2][C@@H:3]3[CH2:4][N:5]([C:9]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:10])[CH2:6][CH2:7][N:8]3[C:28]2=[O:29])=[CH:23][C:22]=1[C:37]([F:38])([F:39])[F:40])#[N:20]

Participants

7

Reactant 4

HCID 11776TriphenylphosphineHCID 5363146Diisopropyl azodicarboxylateHCID 7023275(S)-Benzyl 3-(hydroxymethyl)piperazine-1-carboxylateHCID 57656744phenyl N-[4-cyano-3-(trifluoromethyl)phenyl]carbamate

Product 1

HCID 58855883(R)-benzyl 2-(4-cyano-3-(trifluoromethyl)phenyl)-3-oxo-hexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylateYield 52%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
40 °C

Procedure

To (S)-benzyl 3-(hydroxymethyl)piperazine-1-carboxylate (256 mg, 1.02 mmol) in DMA (1 mL) was added phenyl 4-cyano-3-(trifluoromethyl)phenylcarbamate (250 mg, 0.82 mmol), and the mixture was heated to 40° C. for 5 h. The reaction was cooled to RT, and PPh3 (321 mg, 1.22 mmol) followed by DIAD (241 μL, 1.22 mmol) were added to the reaction. After stirring for 15 min at RT, the reaction was diluted with EtOAc (20 mL) and washed twice with 0.5 N NaOH (10 mL), then twice with sat'd brine (10 mL). The EtOAc was dried over MgSO4 then concentrated in vacuo. The residue was taken up in CH2Cl2 (5 mL) and cooled to −10° C., and Et2O (5 mL) was added. The resulting precipitate was collected by filtration and rinsed with cold 1:1 Et2O:CH2Cl2 to give Example 1, (R)-benzyl 2-(4-cyano-3-(trifluoromethyl)phenyl)-3-oxo-hexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylate 187 mg (52%). HPLC RT: 3.253 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous MeOH over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm). (M+H)+:445.

Workup

  1. temperatureThe reaction was cooled to RT
  2. additionwere added to the reaction
  3. washwashed twice with 0.5 N NaOH (10 mL)
  4. dry with materialThe EtOAc was dried over MgSO4
  5. concentrationthen concentrated in vacuo
  6. temperaturecooled to −10° C.
  7. additionEt2O (5 mL) was added
  8. filtrationThe resulting precipitate was collected by filtration
  9. washrinsed with cold 1:1 Et2O

Sources & evidence

ORD record
ord-c7b4a5af79a34683b66bf03ad6e99a25
Source dataset
uspto-grants-2010_08
Patent number
US07776859B2

Reaction notes

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