Dimethyl-1,3-thiazole-5-carboxylic acid → 2-{2-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-2-hydroxy-ethyl}-4-methyl-thiazole-5-carboxylic acid

HRID 2365229Notes

Reaction equation

HRID 2365229 reaction equation
[CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Li]CCCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]=[N:26][N:25]([CH3:28])[C:24]=2[CH:29]=[O:30])=[CH:19][CH:18]=1>C1COCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:27]=[N:26][N:25]([CH3:28])[C:24]=2[CH:29]([OH:30])[CH2:1][C:2]2[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=2)=[CH:21][CH:22]=1

Participants

5

Reactant 3

HCID 736488Dimethyl-1,3-thiazole-5-carboxylic acidHCID 86664764HCID 86664764, compoundHCID 178418339Butyllithium

Product 1

HCID 674976492-{2-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-2-hydroxy-ethyl}-4-methyl-thiazole-5-carboxylic acidYield 77%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-75 °C

Procedure

To a suspension of 2,4-dimethylthiazole-5-carboxylic acid (236 mg, 1.5 mmol) in THF (12 mL) was added dropwise n-BuLi (1.6 M in hexanes, 1.88 mL, 3.0 mmol) under Ar at −75° C. The brown suspension was stirred at −75° C. for 2 h and then a solution of 5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazole-4-carbaldehyde (308 mg, 1.50 mmol) in THF (4.5 mL) was added at −75° C. and the brown suspension was stirred at −75° C. for 2 h. The mixture was then quenched with an aqueous solution of citric acid (5%, 15 mL), allowed to warm to room temperature. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 30% methanol in dichloromethane) afforded 2-{2-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-2-hydroxy-ethyl}-4-methyl-thiazole-5-carboxylic acid (417 mg, 77%) as a yellow foam. The acid was then dissolved in methanol (4 mL) and diethylether (2 mL) and trimethylsilyldiazomethane (2M in diethylether, 5×0.38 mL, 3.75 mmol) added dropwise. The reaction was quenched with a few drops of AcOH and evaporated. To the brown oil was added sodium hydroxide (1 N, 20 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, 0 to 30% methanol in dichloromethane) afforded the title compound (214 mg, 38%) as a light brown foam.

Workup

  1. stirringthe brown suspension was stirred at −75° C. for 2 h
  2. customThe mixture was then quenched with an aqueous solution of citric acid (5%, 15 mL)
  3. temperatureto warm to room temperature
  4. additionThe mixture was then poured into saturated ammonium chloride solution
  5. extractionextracted with ethyl acetate
  6. washthe combined organic extracts washed with brine
  7. dry with materialdried over sodium sulphate
  8. filtrationfiltered
  9. customevaporated
  10. customPurification by chromatography (silica, 0 to 30% methanol in dichloromethane)

Sources & evidence

ORD record
ord-c39ed4d8915846e8b516dfe8357845e9
Source dataset
uspto-grants-2014_04
Patent number
US08697696B2

Reaction notes

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