Tributylphosphine → (4-(Difluoromethyl)-6-((2,6-dimethylpyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetic acid

HRID 591523Notes

Reaction equation

HRID 591523 reaction equation
C[O:2][C:3](=[O:18])[CH2:4][C:5]1[C:9]2[C:10]([CH:15]([F:17])[F:16])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:19][C:20]1[C:25]([CH2:26]O)=[CH:24][CH:23]=[C:22]([CH3:28])[N:21]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[F:16][CH:15]([F:17])[C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:2])=[O:18])=[CH:6][S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:26][C:25]2[C:20]([CH3:19])=[N:21][C:22]([CH3:28])=[CH:23][CH:24]=2)[CH:11]=1

Participants

6

Reactant 4

HCID 13831Tributylphosphine2×HCID 730421,1'-(Azodicarbonyl)dipiperidine2×HCID 2784752(2,6-Dimethylpyridin-3-yl)methanolHCID 131734529Methyl(4-(difluoromethyl)-6-hydroxy-1-benzothiophen-3-yl)acetate

Product 1

HCID 89767948(4-(Difluoromethyl)-6-((2,6-dimethylpyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetic acidYield 26.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a mixture of methyl(4-(difluoromethyl)-6-hydroxy-1-benzothiophen-3-yl)acetate (78 mg) and THF (dry) (2 mL) were added (2,6-dimethylpyridin-3-yl)methanol (43.2 mg), tri-n-butylphosphine (0.212 mL) and ADDP (94 mg) at room temperature. The mixture was stirred at room temperature for 2 h. To the mixture were added ADDP (94 mg) and tri-n-butylphosphine (0.212 mL), and the mixture was stirred at room temperature for 30 min. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by short pad of silica gel (EtOAc/hexane). To a mixture of the residue and THF (2 mL) was added 1N NaOH (1 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was neutralized with 1N HCl at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by preparative HPLC (C18, H2O/CH3CN (including 10 mM NH4HCO3)). The fraction was extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was crystallized from EtOAc-hexane to give the title compound (29.1 mg).

Workup

  1. stirringthe mixture was stirred at room temperature for 30 min
  2. customThe insoluble material was removed by filtration
  3. concentrationthe filtrate was concentrated in vacuo
  4. customThe residue was purified by short pad of silica gel (EtOAc/hexane)
  5. additionTo a mixture of the residue and THF (2 mL)
  6. additionwas added 1N NaOH (1 mL) at room temperature
  7. stirringThe mixture was stirred at room temperature for 16 h
  8. customwas neutralized with 1N HCl at room temperature
  9. extractionextracted with EtOAc
  10. customThe organic layer was separated
  11. washwashed successively with water and brine
  12. dry with materialdried over MgSO4
  13. concentrationconcentrated in vacuo
  14. customThe crude product was purified by preparative HPLC (C18, H2O/CH3CN (including 10 mM NH4HCO3))
  15. extractionThe fraction was extracted with EtOAc
  16. customThe organic layer was separated
  17. washwashed successively with water and brine
  18. dry with materialdried over MgSO4
  19. concentrationconcentrated in vacuo
  20. customThe residue was crystallized from EtOAc-hexane

Sources & evidence

ORD record
ord-f17ae11a8bc64cf9952405942b3ed55f
Source dataset
uspto-grants-2016_01
Patent number
US09238639B2

Reaction notes

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