Water → 3-[(8-chloro-2,3-dimethyl-4-oxo-3,4-dihydro-2h-1,3-benzoxazin-7-yl)oxy]-5-{[(1S)-1-(hydroxymethyl)propyl]oxy}-n-(1-methyl-1h-pyrazol-3-yl)benzamide

HRID 548696Notes

Reaction equation

HRID 548696 reaction equation
[OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]([CH2:21][OH:22])[CH2:19][CH3:20])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[Si](O[CH2:31][CH2:32][N:33]([CH3:45])[C:34](=[O:44])[C:35]1[CH:40]=[CH:39][C:38](F)=[C:37]([Cl:42])[C:36]=1F)(C(C)(C)C)(C)C.C(=O)([O-])[O-:47].[K+].[K+].O>CC(N(C)C)=O>[Cl:42][C:37]1[C:36]2[O:47][CH:32]([CH3:31])[N:33]([CH3:45])[C:34](=[O:44])[C:35]=2[CH:40]=[CH:39][C:38]=1[O:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]([CH2:21][OH:22])[CH2:19][CH3:20])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6]

Participants

6

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 57663164N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-2,4-difluoro-N-methylbenzamideHCID 591271493-hydroxy-5-{[(1S)-1-(hydroxymethyl)propyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

Product 1

HCID 159494963-[(8-chloro-2,3-dimethyl-4-oxo-3,4-dihydro-2h-1,3-benzoxazin-7-yl)oxy]-5-{[(1S)-1-(hydroxymethyl)propyl]oxy}-n-(1-methyl-1h-pyrazol-3-yl)benzamideYield 159.5%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Procedure

A solution of 3-hydroxy-5-{[(1S)-1-(hydroxymethyl)propyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (200 mg, 0.66 mmol), N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-2,4-difluoro-N-methylbenzamide (239 mg, 0.66 mmol) and potassium carbonate (181 mg, 1.31 mmol) in DMA (3 mL) was heated in a microwave reactor at 160° C. for 6 hours. Water (20 mL) was added and the reaction mixture extracted with ethyl acetate. The organic layer was washed with brine (20 mL), dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 2% methanol in ethyl acetate, and then chromatographed by preparative HPLC on C18 reversed phase, eluting with 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA), to give the required product (542 mg).

Workup

  1. extractionthe reaction mixture extracted with ethyl acetate
  2. washThe organic layer was washed with brine (20 mL)
  3. dry with materialdried (MgSO4)
  4. customevaporated to a residue which
  5. customwas chromatographed on silica
  6. washeluting with 2% methanol in ethyl acetate
  7. customchromatographed by preparative HPLC on C18 reversed phase
  8. washeluting with 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA)

Sources & evidence

ORD record
ord-140cbb0bf8274483a33c587fb88554d2
Source dataset
uspto-grants-2011_05
Patent number
US07943607B2

Reaction notes

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