Imidazole → 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1R)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide

HRID 20574Notes

Reaction equation

HRID 20574 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[F:28][C:29]1[CH:30]=[C:31]([CH:38]=[CH:39][C:40]=1F)[C:32]([N:34]1[CH2:37][CH2:36][CH2:35]1)=[O:33].N1C=CN=C1.[Si](Cl)(C(C)(C)C)(C)C>CC(N(C)C)=O.CN(C=O)C.O>[N:34]1([C:32]([C:31]2[CH:38]=[CH:39][C:40]([O:7][C:8]3[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=3)[C:11]([NH:13][C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)=[O:12])=[C:29]([F:28])[CH:30]=2)=[O:33])[CH2:37][CH2:36][CH2:35]1

Participants

9

Reactant 5

HCID 795ImidazoleHCID 10796Cesium carbonateHCID 28928tert-Butyldimethylsilyl chlorideHCID 593468591-(3,4-Difluorobenzoyl)azetidineHCID 593468763-hydroxy-5-[(1R)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide

Product 1

HCID 116771093-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1R)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
160 °C

Procedure

Cesium carbonate (780 mg, 2.40 mmol) was added to a mixture of 3-hydroxy-5-[(1R)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (350 mg, 1.2 mmol) and 1-(3,4-difluorobenzoyl)azetidine (235 mg, 1.2 mmol) in dimethylacetamide (5.0 mL) and the stirred-mixture heated at 160° C. in a ‘Smith Creator Microwave’ for 2 hours. The mixture was allowed to return to ambient temperature and pressure and was partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate layer was separated, washed with water (5×50 mL) brine (50 mL), dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-10% methanol in DCM, and then chromatographed by preparative HPLC on C18 reversed phase using 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA) as eluant. A 10% impurity remained. This mixture (0.12 g, 0.26 mmol) was dissolved in DMF (3 mL) and imidazole (0.123 g, 1.79 mmol) and tert-butyldimethylsilylchloride (77 mg, 0.51 mmol) were added. After stirring at RT for 24 hours water (30 mL) was added and the material extracted into diethyl ether (2×50 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-10% methanol in chloroform, and then chromatographed by preparative HPLC on C18 reversed phase using 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA) as eluant. The chromatography fractions were allowed to stand overnight and the acetonitrile removed in vacuo. The aqueous residue was basified with saturated aqueous sodium bicarbonate solution and extracted into ethyl acetate (2×50 mL) and the combined extracts reduced in vacuo to give the desired compound. (30 mg)

Workup

  1. customto return to ambient temperature
  2. custompressure and was partitioned between ethyl acetate (50 mL) and water (50 mL)
  3. customThe ethyl acetate layer was separated
  4. washwashed with water (5×50 mL) brine (50 mL)
  5. dry with materialdried (MgSO4)
  6. customevaporated to a residue which
  7. customwas chromatographed on silica
  8. washeluting with a gradient of 0-10% methanol in DCM
  9. customchromatographed by preparative HPLC on C18 reversed phase
  10. additionwas added
  11. extractionthe material extracted into diethyl ether (2×50 mL)
  12. washThe combined extracts were washed with brine (50 mL)
  13. dry with materialdried (MgSO4)
  14. customevaporated to a residue which
  15. customwas chromatographed on silica
  16. washeluting with a gradient of 0-10% methanol in chloroform
  17. customchromatographed by preparative HPLC on C18 reversed phase
  18. customthe acetonitrile removed in vacuo
  19. extractionextracted into ethyl acetate (2×50 mL)

Sources & evidence

ORD record
ord-1c4a36d62ff6410892de933d3756f90b
Source dataset
uspto-grants-2010_06
Patent number
US07745475B2

Reaction notes

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