(2S)-1,1,1-Trifluoropropan-2-ol → 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid

HRID 1480129Notes

Reaction equation

HRID 1480129 reaction equation
Cl[C:2]1[C:7]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=1.[F:14][C:15]([F:20])([F:19])[C@@H:16]([OH:18])[CH3:17].CC(C)([O-])C.[K+]>CN(C=O)C>[CH:8]1([C:7]2[C:2]([O:18][C@@H:16]([CH3:17])[C:15]([F:20])([F:19])[F:14])=[CH:3][C:4]([C:11]([OH:13])=[O:12])=[N:5][CH:6]=2)[CH2:10][CH2:9]1

Participants

5

Reactant 3

HCID 6999971(2S)-1,1,1-Trifluoropropan-2-olHCID 23665647Potassium tert-butoxideHCID 902035204-Chloro-5-cyclopropylpicolinic acid

Product 1

HCID 902045735-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acidYield 41.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 4-Chloro-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48b, 0.87 g, 4.4 mmol) in dry DMF (12.0 ml) under an argon atmosphere were added (S)-1,1,1-trifluoropropan-2-ol (CAN 3539-97-7, 1.00 g, 8.8 mmol) and potassium tert-butoxide (1.48 g, 13.2 mmol). The reaction mixture was stirred at room temperature for 30 minutes and stirred at 120° C. for one hour under microwave radiation. DMF was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was extracted with 20 mL of an 2.0M aqueous solution of hydrochloric acid. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/(3% solution formic acid in methanol) gradient to yield the title compound (505 mg, 33%) as a light brown solid. MS (ESI, m/z): 276.4 (M+H+).

Workup

  1. stirringstirred at 120° C. for one hour under microwave radiation
  2. customDMF was removed in vacuo
  3. dissolutionthe residue was dissolved in ethyl acetate
  4. extractionThe solution was extracted with 20 mL of an 2.0M aqueous solution of hydrochloric acid
  5. customThe organic phase was collected
  6. extractionthe aqueous phase was back-extracted with ethyl acetate
  7. dry with materialdried over sodium sulfate
  8. customevaporated down to dryness
  9. customThe crude material was purified by flash chromatography on silica eluting with a dichloromethane/(3% solution formic acid in methanol) gradient

Sources & evidence

ORD record
ord-2bb9bb390297450bb15dcdca5aaf023e
Source dataset
uspto-grants-2016_08
Patent number
US09409866B2

Reaction notes

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