Cesium carbonate → Methyl 3-[(9-chloro-4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]-5-[(phenylmethyl)oxy]benzoate

HRID 548760Notes

Reaction equation

HRID 548760 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].[Cl:26][C:27]1[C:28](F)=[C:29]([CH:37]=[CH:38][C:39]=1F)[C:30]([N:32]([CH2:34][CH2:35][OH:36])[CH3:33])=[O:31].S(Cl)(Cl)=O>C(#N)C.CO>[Cl:26][C:27]1[C:28]2[O:36][CH2:35][CH2:34][N:32]([CH3:33])[C:30](=[O:31])[C:29]=2[CH:37]=[CH:38][C:39]=1[O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 24386Thionyl ChlorideHCID 7472028Methyl 3-(benzyloxy)-5-hydroxybenzoateHCID 576632133-chloro-2,4-difluoro-N-(2-hydroxyethyl)-N-methylbenzamide

Product 1

HCID 57663169Methyl 3-[(9-chloro-4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]-5-[(phenylmethyl)oxy]benzoateYield 44.5%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
160 °C

Procedure

Cesium carbonate (41.2 g, 126.4 mmol) was added to a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (10.9 g, 42.25 mmol) and 3-chloro-2,4-difluoro-N-(2-hydroxyethyl)-N-methylbenzamide (11.6 g, 46.4 mmol) in acetonitrile (210 mL) and the stirred mixture heated at 160° C. in a microwave reactor for 8 hours. The mixture was cooled to RT and pressure, the acetonitrile evaporated in vacuo, and the residue partitioned between water (500 mL) and ethyl acetate (300 mL). The mixture was adjusted to pH 2, the organic layer washed with brine, dried (MgSO4) and evaporated to a residue (shown to contain a large amount of acid). The mixture was added to a solution of thionyl chloride (11.7 mL, 160 mmol) in methanol (120 mL) at −35° C., the solution stirred at −35° C. for 1 hour then allowed to come to RT and stirred for 18 hours. The methanol was evaporated in vacuo to a residue which was partitioned between ethyl acetate (250 mL) and a saturated sodium hydrogen carbonate solution (175 mL). The organic layer was washed with a saturated sodium hydrogen carbonate solution (3×75 mL), brine, dried (MgSO4) and evaporated in vacuo to a residue which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound (8.8 g).

Workup

  1. temperatureThe mixture was cooled to RT
  2. custompressure, the acetonitrile evaporated in vacuo
  3. customthe residue partitioned between water (500 mL) and ethyl acetate (300 mL)
  4. washthe organic layer washed with brine
  5. dry with materialdried (MgSO4)
  6. customevaporated to a residue (
  7. customto come to RT
  8. stirringstirred for 18 hours
  9. customThe methanol was evaporated in vacuo to a residue which
  10. customwas partitioned between ethyl acetate (250 mL)
  11. washThe organic layer was washed with a saturated sodium hydrogen carbonate solution (3×75 mL), brine
  12. dry with materialdried (MgSO4)
  13. customevaporated in vacuo to a residue which
  14. customwas chromatographed on silica
  15. washeluting with 50% ethyl acetate in isohexane

Sources & evidence

ORD record
ord-d35a8fccbf2e496494925f8f8f2fb54e
Source dataset
uspto-grants-2011_05
Patent number
US07943607B2

Reaction notes

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