Acetone Cyanohydrin → 3-[2-(2-Methoxy-ethoxymethyl)-6-trifluoromethyl-pyridine-3-carbonyl]-1,5-dimethyl-8-oxa-bicyclo[3.2.1]oct-6-ene-2,4-dione

HRID 502919Notes

Reaction equation

HRID 502919 reaction equation
[CH3:1][C:2]12[O:9][C:6]([CH3:10])([CH:7]=[CH:8]1)[C:5](=[O:11])[CH2:4][C:3]2=[O:12].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C>[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]1[C:20]([C:21]([CH:4]2[C:3](=[O:12])[C:2]3([CH3:1])[O:9][C:6]([CH3:10])([CH:7]=[CH:8]3)[C:5]2=[O:11])=[O:22])=[CH:24][CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[N:27]=1

Participants

7

Reactant 5

HCID 6406Acetone CyanohydrinHCID 8471TriethylamineHCID 10868DicyclohexylcarbodiimideHCID 113349532-(2-Methoxy-ethoxymethyl)-6-trifluoromethyl-nicotinic acidHCID 586095231,5-Dimethyl-8-oxa-bicyclo[3.2.1]oct-6-ene-2,4-dione

Product 1

HCID 586095343-[2-(2-Methoxy-ethoxymethyl)-6-trifluoromethyl-pyridine-3-carbonyl]-1,5-dimethyl-8-oxa-bicyclo[3.2.1]oct-6-ene-2,4-dione

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

146 mg (0.879 mmol) of 1,5-dimethyl-8-oxa-bicyclo[3.2.1]oct-6-ene-2,4-dione and 245 mg (0.879 mmol) of 2-(2-methoxy-ethoxymethyl)-6-trifluoromethyl-nicotinic acid (preparation as described in WO 01/94339) are dissolved in 29 ml of acetonitrile and treated at ambient temperature with 199 mg (0.966 mmol) of dicyclohexylcarbodiimide. The reaction mixture is stirred for 2 hours and then 0.184 ml (1.318 mmol) of triethylamine and 0.08 ml (0.879 mmol) of acetone cyanohydrin are added. Stirring is carried out for a further 16 hours at ambient temperature, followed by concentration under reduced pressure. The residue that remains behind is chromatographed over silica gel (eluant: toluene/ethanol/dioxane/triethylamine/water 20:8:4:4:1). The product-containing fraction is concentrated. The oily residue is again dissolved in fresh ethyl acetate and washed with 10 ml of dilute hydrochloric acid (pH 1), and then with water (2×) and sodium chloride solution (2×). After the solution has been dried over sodium sulfate and concentrated by evaporation under reduced pressure, 128 mg (34%) of 3-[2-(2-methoxy-ethoxymethyl)-6-trifluoromethyl-pyridine-3-carbonyl]-1,5-dimethyl-8-oxa-bicyclo[3.2.1]oct-6-ene-2,4-dione are obtained in the form of a yellow oil.

Workup

  1. stirringStirring
  2. waitis carried out for a further 16 hours at ambient temperature
  3. concentrationfollowed by concentration under reduced pressure
  4. customThe residue that remains behind is chromatographed over silica gel (eluant: toluene/ethanol/dioxane/triethylamine/water 20:8:4:4:1)
  5. concentrationThe product-containing fraction is concentrated
  6. dissolutionThe oily residue is again dissolved in fresh ethyl acetate
  7. washwashed with 10 ml of dilute hydrochloric acid (pH 1)
  8. dry with materialAfter the solution has been dried over sodium sulfate
  9. concentrationconcentrated by evaporation under reduced pressure, 128 mg (34%) of 3-[2-(2-methoxy-ethoxymethyl)-6-trifluoromethyl-pyridine-3-carbonyl]-1,5-dimethyl-8-oxa-bicyclo[3.2.1]oct-6-ene-2,4-dione
  10. customare obtained in the form of a yellow oil

Sources & evidence

ORD record
ord-3526f4b4621e487fa6875796ccc6831b
Source dataset
uspto-grants-2010_08
Patent number
US07776888B2

Reaction notes

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