Cesium carbonate → [4-(4-Methyl-1,3-oxazol-5-yl)phenyl]acetic acid

HRID 254735

Reaction equation

HRID 254735 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:14]=[CH:15][O:16][C:17]=1C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:12][C:13]1[N:14]=[CH:15][O:16][C:17]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1

Participants

8

Reactant 3

HCID 10796Cesium carbonateHCID 74654Benzeneacetic acid, 4-bromo-HCID 2923114-Methyl-1,3-oxazole-5-carboxylic acid

Product 1

HCID 66893778[4-(4-Methyl-1,3-oxazol-5-yl)phenyl]acetic acidYield 24%

Reagents, catalysts & solvents 4

HCID 16212273Tetrabutylammonium chloride hydrateCatalystHCID 178418851HCID 178418851, compoundCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of 3.00 g (14.0 mmol) 4-bromophenyl acetic acid in 25.0 ml DMF was added 3.60 g (27.9 mmol) 4-methyl-1,3-oxazole-5-carboxylic acid, 6.80 g (20.9 mmol) cesium carbonate, 4.1 g (14.0 mmol) tetrabutyl ammonium chloride monohydrate, and 0.400 g (0.700 mmol) bis(tri-t-butylphosphine)palladium(0). After 3.00 h at 140° C., the reaction mixture was, diluted with CH2Cl2, washed with 10% citric acid, washed twice with water, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by preparative HPLC (5→95% CH3CN/H2O over 20 min, 0.05% added TFA, C18 50×150 mm) afforded 0.730 g (24%) [4-(4-methyl-1,3-oxazol-5-yl)phenyl]acetic acid. 1H NMR (CD3OD, 400 MHz) δ 8.14 (s, 1H); 7.61 (d, 2H, J=8.32 Hz); 7.41 (d, 2H, J=8.33 Hz); 3.65 (s, 2H); 2.41 (s, 3H). ESMS+1 for C12H11NO3: 218.1. To a solution of 0.725 g (3.34 mmol) [4-(4-methyl-1,3-oxazol-5-yl)phenyl]acetic acid in 7.00 ml CH2Cl2 was added 0.978 g (3.34 mmol) 2-[(1R)-1-ammonioethyl]-5-(2,2,2-trifluoroethoxy)pyridinium dichloride, 0.591 g (4.34 mmol) HOAT, 0.832 g (4.34 mmol) EDC, and 1.75 mL (10.0 mmol) DIEA. After 24.0 h at room temperature, the reaction mixture was diluted with CH2Cl2, washed three times with water, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 20-100% EtOAc:hexane) afforded 0.720 g (51.4%) 2-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. 1H NMR (CDCl3, 400 MHz) δ 8.22 (d, 1H, J=2.38 Hz); 7.83 (s, 1H); 7.59 (dd, 2H, J=1.83 Hz, 6.59 Hz); 7.36 (d, 2H, J=8.42 Hz); 7.22 (m, 2H); 6.72 (br d, 1H, J=7.51 Hz); 5.12 (m, 1H); 4.38 (q, 2H, J=8.06 Hz); 3.62 (s, 2H); 2.45 (s, 3H); 1.41 (d, 3H, J=6.78). HRMS (ES) exact mass calcd for C21H20F3N3O3: 420.1540, Found: 420.1530.

Workup

  1. washwashed with 10% citric acid
  2. washwashed twice with water
  3. washwashed with brine
  4. dry with materialThe organic layer was dried over NaSO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification
  8. additionby preparative HPLC (5→95% CH3CN/H2O over 20 min, 0.05% added TFA, C18 50×150 mm)

Sources & evidence

ORD record
ord-7b3c37cedb6a4c868bc2b69b619b171c
Source dataset
uspto-grants-2011_01
Patent number
US07875636B2

Linked notes

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