Cesium carbonate → ethyl 2-(1-((2,2-difluorocyclopropyl)methyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylate

HRID 1882394Notes

Reaction equation

HRID 1882394 reaction equation
[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[C:16](=[O:17])[NH:15][N:14]=[CH:13]2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH:26]1[CH2:28][C:27]1([F:30])[F:29]>CN(C)C=O>[F:29][C:27]1([F:30])[CH2:28][CH:26]1[CH2:25][N:15]1[C:16](=[O:17])[N:12]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[CH:13]=[N:14]1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 27614022-(Bromomethyl)-1,1-difluorocyclopropaneHCID 57920013ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate

Product 1

HCID 57919808ethyl 2-(1-((2,2-difluorocyclopropyl)methyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylateYield 98%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate (9.36 g, 36.8 mmol) in anhydrous N,N-dimethylformamide (150 mL) was added cesium carbonate (23.90 g, 73.70 mmol). The reaction mixture was stirred at ambient temperature for 30 min, followed by the addition of bromomethyl-2,2-difluorocyclopropane (6.00 g, 35.10 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture was heated at 40° C. for 3 h and filtered. The solid was washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to dryness. The residue was triturated with ethyl acetate (50 mL) to afford the title compound as a yellow solid (10.8 g, 98%): mp 146-148° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 4.23 (t, J=7.1 Hz, 2H), 3.97-3.77 (m, 2H), 2.54 (s, 3H), 2.20-2.04 (m, 1H), 1.73-1.60 (m, 1H), 1.48-1.37 (m, 1H), 1.26 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.8, 156.6, 154.0, 149.9, 132.2, 118.2, 114.4 (t), 61.6, 42.8 (d), 20.7 (t), 17.2, 14.9 (t), 14.5; MS (ES+) m/z 345.9 (M+1).

Workup

  1. temperatureThe reaction mixture was heated at 40° C. for 3 h
  2. filtrationfiltered
  3. washThe solid was washed with ethyl acetate (100 mL)
  4. concentrationThe filtrate was concentrated in vacuo to dryness
  5. customThe residue was triturated with ethyl acetate (50 mL)

Sources & evidence

ORD record
ord-535ebc3999bd4faba10da7bc79527fc1
Source dataset
uspto-grants-2012_11
Patent number
US08318949B2

Reaction notes

Loading…