Cesium carbonate → Methyl 5-chloro-2-methyl-3-((1-(pyrimidin-4-yl)piperidin-4-yl)oxy)benzoate

HRID 1050452Notes

Reaction equation

HRID 1050452 reaction equation
CS([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)(=O)=O.[Cl:18][C:19]1[CH:20]=[C:21](O)[C:22]([CH3:29])=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Cl:18][C:19]1[CH:20]=[C:21]([O:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)[CH2:8][CH2:7]2)[C:22]([CH3:29])=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25]

Participants

5

Reactant 3

HCID 10796Cesium carbonate2×HCID 70904667Methyl 5-chloro-3-hydroxy-2-methylbenzoateHCID 902730741-(Pyrimidin-4-yl)piperidin-4-yl methanesulfonate

Product 1

HCID 90272838Methyl 5-chloro-2-methyl-3-((1-(pyrimidin-4-yl)piperidin-4-yl)oxy)benzoateYield 41.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

A 250 mL round bottom flask was charged with 1-(pyrimidin-4-yl)piperidin-4-yl methanesulfonate (713 mg, 2.77 mmol), methyl 5-chloro-3-hydroxy-2-methylbenzoate (0.301 mL, 2.218 mmol), Cs2CO3 (867 mg, 2.66 mmol) and N,N-dimethylformamide (6 mL). The flask was equipped with a reflux condenser and heated at 60° C. for 3 days, at which time the solvent was removed in vacuo. The residue was diluted with EtOAc (120 mL) and mixture filtered. LCMS showed some starting chlorophenol remained, so the EtOAc was removed in vacuo and the residue dissolved in N,N-dimethylformamide (6 mL). Cs2CO3 (867 mg, 2.66 mmol) was added and the reaction was heated to 80° C. overnight, at which time the solvent was removed in vacuo. The residue was diluted with EtOAc (120 mL) and mixture was filtered. The EtOAc was removed in vacuo and crude residue was purified by reverse phase HPLC (Column: Phenomenex Gemini-NX, 30×100, 5μ, C18. Gradient: 7 min, 30-60% acetonitrile/0.1% formic acid in water). Two additional HPLC purifications using the same column (Gradient: 7 min, 10-90% acetonitrile/0.1% formic acid in water; and Gradient: 7 min, 10-90% acetonitrile/0.1% TFA in water) were performed to provide methyl 5-chloro-2-methyl-3-((1-(pyrimidin-4-yl)piperidin-4-yl)oxy)benzoate (335 mg, 0.926 mmol, 41.7% yield) as a yellow viscous oil. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.34 (dd, J=1.52, 7.58 Hz, 1H), 7.44 (d, J=2.02 Hz, 1H), 7.34 (d, J=2.02 Hz, 1H), 7.27 (d, J=7.58 Hz, 1H), 4.85-4.96 (m, 1H), 4.05 (br. s., 2H), 3.91 (br. s., 2H), 3.83 (s, 3H), 2.30 (s, 3H), 2.01-2.13 (m, 2H), 1.71-1.87 (m, J=3.92, 7.03, 7.03, 13.61Hz, 2H). MS(ES) [M+H]+ 362.1.

Workup

  1. customThe flask was equipped with a reflux condenser
  2. customwas removed in vacuo
  3. additionThe residue was diluted with EtOAc (120 mL) and mixture
  4. filtrationfiltered
  5. customwas removed in vacuo
  6. dissolutionthe residue dissolved in N,N-dimethylformamide (6 mL)
  7. temperaturethe reaction was heated to 80° C. overnight, at which time the solvent
  8. customwas removed in vacuo
  9. additionThe residue was diluted with EtOAc (120 mL) and mixture
  10. filtrationwas filtered
  11. customThe EtOAc was removed in vacuo and crude residue
  12. customwas purified by reverse phase HPLC (Column: Phenomenex Gemini-NX, 30×100, 5μ, C18. Gradient: 7 min, 30-60% acetonitrile/0.1% formic acid in water)
  13. customthe same column (Gradient: 7 min, 10-90% acetonitrile/0.1% formic acid in water; and Gradient: 7 min, 10-90% acetonitrile/0.1% TFA in water)

Sources & evidence

ORD record
ord-09c2c98214f942cf88ea74a3cd72e405
Source dataset
uspto-grants-2016_07
Patent number
US09382234B2

Reaction notes

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