Hydrochloric Acid → 2-Methyl-2-(5-(trifluoromethyl)pyridin-2-yloxy)propanoic acid

HRID 2354506Notes

Reaction equation

HRID 2354506 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[K+].C([O:13][C:14](=[O:19])[C:15]([OH:18])([CH3:17])[CH3:16])C.Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1.Cl>O1CCCC1>[CH3:17][C:15]([O:18][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1)([CH3:16])[C:14]([OH:13])=[O:19]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 6653Ethyl 2-hydroxyisobutyrateHCID 923422-Chloro-5-(trifluoromethyl)pyridineHCID 3251421Potassium bis(trimethylsilyl)amide

Product 1

HCID 160983422-Methyl-2-(5-(trifluoromethyl)pyridin-2-yloxy)propanoic acid

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (0.91 M, 275 mL) at −70° C. under nitrogen and was added ethyl-2-hydroxyisobutyrate (36 mL, 34.7 g, 0.263 mol) over 12 min. After stirring for additional 10 min, 2-chloro-5-trifluormethylpyridine was added in one portion. The cooling bath was removed and the reaction was allowed to warm to room temperature overnight. Sodium hydroxide (105 mL, 5N) was added, and the reaction was refluxed overnight. The reaction mixture was partially concentrated on a rotary evaporator, diluted with water (150 mL), and extracted with hexane (2×150 L). The aqueous layer was separated and acidified with 2N HCl (350 mL, 0.7 mol), and the resulting suspension was cooled to 0° C. After aging for 20 min, the precipitate was collected by filtration, which was washed with water (4×150 mL) and air-dried to afford 38.0 g of a tan solid. (85.5%). Treatment with Darco KB and recrystallization in 3:1 heptane/isopropyl acetate provided the title compound as a white crystalline material. 1H NMR (500 MHz, CD3OD): δ 8.38 (br s, 1H), 7.93 (dd, 1H), 7.13 (d, 1H), 1.70 (s, 6H). LC-MS: m/e 250 (M+H)+ (2.6 min).

Workup

  1. customThe cooling bath was removed
  2. additionSodium hydroxide (105 mL, 5N) was added
  3. temperaturethe reaction was refluxed overnight
  4. concentrationThe reaction mixture was partially concentrated on a rotary evaporator
  5. additiondiluted with water (150 mL)
  6. extractionextracted with hexane (2×150 L)
  7. customThe aqueous layer was separated
  8. temperaturethe resulting suspension was cooled to 0° C
  9. waitAfter aging for 20 min
  10. filtrationthe precipitate was collected by filtration, which
  11. washwas washed with water (4×150 mL)
  12. customair-dried

Sources & evidence

ORD record
ord-1f8e43190be549f9b3b77b47c61a0f7d
Source dataset
uspto-grants-2010_07
Patent number
US07754188B2

Reaction notes

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