Cesium carbonate → 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]benzoic acid

HRID 20523

Reaction equation

HRID 20523 reaction equation
[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:16])[CH2:14][OH:15])[CH:11]=1)[C:5]([O:7]C)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[F:23][C:24]1[CH:25]=[C:26]([CH:33]=[CH:34][C:35]=1F)[C:27]([N:29]1[CH2:32][CH2:31][CH2:30]1)=[O:28].O.[OH-].[Li+]>CC(N(C)C)=O.O.C(OCC)C.C(OCC)(=O)C>[N:29]1([C:27]([C:26]2[CH:33]=[CH:34][C:35]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:16])[CH2:14][OH:15])[CH:11]=3)[C:5]([OH:7])=[O:6])=[C:24]([F:23])[CH:25]=2)=[O:28])[CH2:32][CH2:31][CH2:30]1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 168937Lithium hydroxide, monohydrateHCID 59127187methyl 3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoateHCID 593468591-(3,4-Difluorobenzoyl)azetidine

Product 1

HCID 593468833-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]benzoic acid

Reagents, catalysts & solvents 3

HCID 962WaterSolvent3×HCID 31374DimethylacetamideSolventHCID 21584169Diethylether ethylacetateSolvent

Conditions

Temperature
120 °C

Procedure

A suspension of methyl 3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate (10.65 g, 0.047 mmol), cesium carbonate (30.71 g, 0.094 mol) and 1-(3,4-difluorobenzoyl)azetidine (9.28 g, 0.047 mol) in dimethylacetamide (80 mL) was heated at 120° C. for 22 hours. The reaction mixture was cooled and water (60 mL) added followed by lithium hydroxide monohydrate (1.97 g, 0.047 mol) in water (45 mL). The reaction was stirred for a further 24 hours. Water (100 mL) was added and the mixture extracted with ethyl acetate (3×50 mL) to remove any ester. The aqueous layer was acidified and extracted into ethyl acetate (5×50 mL). The extracts were combined and washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered, and evaporated in vacuo to give a yellow liquid. A diethyl ether/ethyl acetate mixture (3:1) was added and the solution washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and evaporated in vacuo to give the desired compound. (9.8 g)

Workup

  1. temperatureThe reaction mixture was cooled
  2. extractionthe mixture extracted with ethyl acetate (3×50 mL)
  3. customto remove any ester
  4. extractionextracted into ethyl acetate (5×50 mL)
  5. washwashed with water (100 mL), brine (100 mL)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. customevaporated in vacuo
  9. customto give a yellow liquid
  10. washthe solution washed with water (100 mL), brine (100 mL)
  11. dry with materialdried (MgSO4)
  12. filtrationfiltered
  13. customevaporated in vacuo

Sources & evidence

ORD record
ord-fb96a22953a74262a19670280383b308
Source dataset
uspto-grants-2010_06
Patent number
US07745475B2

Linked notes

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