Methyl triflate → 4-Cyclopropyl-6-methyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester

HRID 1692379Notes

Reaction equation

HRID 1692379 reaction equation
[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:9]([CH:11]1[CH2:13][CH2:12]1)=O)[C:6](=O)[CH3:7])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].COS(C(F)(F)F)(=O)=O.Cl.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([NH2:38])=[NH:37].CC(C)([O-])C.[Na+]>C(#N)C.CCOC(C)=O.C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:9]([CH:11]2[CH2:13][CH2:12]2)=[N:37][C:36]([C:35]2[CH:39]=[CH:40][CH:41]=[C:33]([C:32]([F:31])([F:42])[F:43])[CH:34]=2)=[N:38][C:6]=1[CH3:7])=[O:14])[CH3:2]

Participants

9

Reactant 5

HCID 9526Methyl triflateHCID 10796Cesium carbonateHCID 27302433-(Trifluoromethyl)benzene-1-carboximidamide hydrochlorideHCID 23676156Sodium t-butoxideHCID 669015882-Cyclopropanecarbonyl-3-oxo-butyric acid ethyl ester

Product 1

HCID 669015814-Cyclopropyl-6-methyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl esterYield 42%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

2-Cyclopropanecarbonyl-3-oxo-butyric acid ethyl ester [Jung, J.-C.; Watkins, E. B.; Avery, M. A. Tetrahedron (2002), 58(18), 3639-3646] (4.7 g, 24 mmol) was dissolved in acetonitrile (40 ml) and cooled to 0° C. Cesium carbonate (7.8 g, 24 mmol) was added and the reaction stirred for 0.5 h before the addition of trifluoro-methanesulfonic acid methyl ester (2.6 ml, 24 mmol) and the reaction stirred for a further 2 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried (Na2SO4) and concentrated to afford a crude mixture of (E,Z)-2-cyclopropanecarbonyl-3-methoxy-but-2-enoic acid ethyl ester and/or 2-[1-cyclopropyl-1-methoxy-meth-(E,Z)-ylidene]-3-oxo-butyric acid ethyl ester (6.3 g, quant). A third of this material (2.1 g, 8 mmol) was dissolved in ethanol (10 ml) and added dropwise to a solution of 3-trifluoromethyl-benzamidine hydrochloride (1.8 g, 8 mmol) and sodium tert-butoxide (0.8 g, 8 mmol) and the mixture stirred overnight. The reaction was concentrated, re-dissolved in EtOAc, washed with 1N hydrochloric acid solution, dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc/Heptane 1:9) afforded the title product (1.2 g, 42%) as clear oil. MS: 351.2 (MH+).

Workup

  1. washwashed with water, brine
  2. dry with materialdried (Na2SO4)
  3. concentrationconcentrated
  4. customto afford a crude
  5. stirringthe mixture stirred overnight
  6. concentrationThe reaction was concentrated
  7. dissolutionre-dissolved in EtOAc
  8. washwashed with 1N hydrochloric acid solution
  9. dry with materialdried (Na2SO4)
  10. concentrationconcentrated
  11. customPurification by flash column chromatography (EtOAc/Heptane 1:9)

Sources & evidence

ORD record
ord-e325ba8ff28244779c726c6eb862c3b5
Source dataset
uspto-grants-2012_04
Patent number
US08153805B2

Reaction notes

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