Pyrazole → HCID 11568000, compound

HRID 736455Notes

Reaction equation

HRID 736455 reaction equation
[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[CH:20](CO)[C:19]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([CH2:23][CH2:24][CH2:25][O:26]C2CCCCO2)[N:18]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])[N:17]=1)C1C=CC=CC=1.N1C=CC=N1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.CCOC(C)=O.C1COCC1.CCOC(C)=O.CCO>[F:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][CH2:1][CH:20]3[C:19]([CH2:23][CH2:24][CH2:25][OH:26])([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:18]([C:39](=[O:44])[C:40]([F:42])([F:43])[F:41])[N:17]=[C:16]3[C:10]=2[CH:11]=1

Participants

10

Reactant 5

HCID 1048PyrazoleHCID 11776TriphenylphosphineHCID 521998p-Toluenesulfonic acid monohydrateHCID 5462977Diethyl azodicarboxylateHCID 57849006HCID 57849006, compound

Product 1

HCID 11568000HCID 11568000, compound

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 21584252Ethanol ethylacetateSolvent

Procedure

A solution of 6.2 g (10.1 mmol) 3-6 in 200 ml 1:1 EtOAc/EtOH was evacuated under reduced pressure and purged three times with N2 before 200 mg of 10% Pd/C was added. The solution was then evacuated and purged twice with N2, then three times with H2, and stirred at room temperature overnight under a balloon of H2. The mixture was purged with nitrogen, filtered through a pad of celite, and concentrated to give the phenolic pryazole as an amber gum. LC-MS: rt=2.8 min, m/z=441 (M−THP+1). Without further purification, 4.45 g (8.5 mmol) of the phenolic pyrazole was combined with 200 ml of THF, 3.34 g (12.7 mmol) triphenylphosphine and 2.67 ml (17 mmol) DEAD. After stirring for 1 h at room temperature, the solution was dumped into a separatory funnel with 150 ml of EtOAc and successively washed with 50 ml portions of 10% aqueous KHSO4, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, concentrated, and purified by silica gel chromatography with EtOAc/hexanes to give the THP protected tricycle as colorless gum. LC-MS: rt=3.2 min, m/z=423 (M−THP+1). To a solution of 950 mg (1.9 mmol) of the THP protected tricycle in 100 ml of MeOH was added 1 g (5.3 mmol) of p-toluenesulfonic acid monohydrate, the resulting mixture was stirred at room temperature for 1 h, and concentrated. The residue was purified by reverse phase preparative HPLC using two stacked Waters 40×100 mm PrepPak® cartridges with an 85-5% H2O/CH3CN (0.1% trifluoroacetic acid) 40 minute gradient to give 3-7 as a white solid. Data for 3-7: LC-MS: rt=2.6 min, m/z=423 (M+1).

Workup

  1. custompurged three times with N2 before 200 mg of 10% Pd/C
  2. additionwas added
  3. customThe solution was then evacuated
  4. custompurged twice with N2
  5. customThe mixture was purged with nitrogen
  6. filtrationfiltered through a pad of celite
  7. concentrationconcentrated
  8. customto give the phenolic pryazole as an amber gum
  9. customrt=2.8 min, m/z=441 (M−THP+1)
  10. stirringAfter stirring for 1 h at room temperature
  11. washsuccessively washed with 50 ml portions of 10% aqueous KHSO4, saturated aqueous NaHCO3, and brine
  12. dry with materialThe organic layer was dried over MgSO4
  13. concentrationconcentrated
  14. custompurified by silica gel chromatography with EtOAc/hexanes
  15. customto give the THP
  16. customrt=3.2 min, m/z=423 (M−THP+1)
  17. stirringthe resulting mixture was stirred at room temperature for 1 h
  18. concentrationconcentrated
  19. customThe residue was purified by reverse phase preparative HPLC
  20. customwith an 85-5% H2O/CH3CN (0.1% trifluoroacetic acid) 40 minute

Sources & evidence

ORD record
ord-1d124cdf729c478dbfcdba824db4a5ef
Source dataset
uspto-grants-2009_09
Patent number
US07595337B2

Reaction notes

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