Hydrochloric Acid → 5-(4-Chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid

HRID 1025980Notes

Reaction equation

HRID 1025980 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:10][CH:11]=[C:12]([CH:17]=2)[C:13]([O:15]C)=[O:14])=[CH:4][C:3]=1[CH3:24].[Li+].[OH-].C1COCC1.Cl>O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[N:10][CH:11]=[C:12]([CH:17]=2)[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[CH3:24]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 8028TetrahydrofuranHCID 66678833Methyl 5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinate

Product 1

HCID 666788365-(4-Chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acidYield 82.6%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent2×

Procedure

Methyl 5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinate (example BI; 4.8 g, 13.3 mmol) and LiOH (0.96 g, 40.0 mmol) were combined with THF (70 mL), water (14 mL) and methanol (7 mL) to give a yellow suspension. The reaction mixture was stirred for 22 h at room temperature, 15 mL water was added and the reaction mixture was heated to 45° C. and stirred for 3 h. After cooling to room temperature the reaction mixture was poured into 150 mL of 1 M HCl with ice (pH=1) and extracted with ethyl acetate (2×150 mL). The organic layers were combined, dried with Na2SO4, filtrated and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 70 g, 0% to 100% EtOAc in heptane to give 3.8 g (82%) of the title compound as a white crystalline solid; MS (ESI): 346.1 (M+H)+.

Workup

  1. customto give a yellow suspension
  2. temperaturethe reaction mixture was heated to 45° C.
  3. stirringstirred for 3 h
  4. temperatureAfter cooling to room temperature the reaction mixture
  5. extractionextracted with ethyl acetate (2×150 mL)
  6. dry with materialdried with Na2SO4
  7. filtrationfiltrated
  8. concentrationconcentrated in vacuo
  9. customThe crude material was purified by flash chromatography (silica gel, 70 g, 0% to 100% EtOAc in heptane

Sources & evidence

ORD record
ord-45d4b5913cdb4fb69281c45fa87a0829
Source dataset
uspto-grants-2014_05
Patent number
US08729105B2

Reaction notes

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