Calcium Carbonate → Ethyl(3-chloro-6-{[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-2,5-difluoro-4-pyridinyl)acetate

HRID 397525Notes

Reaction equation

HRID 397525 reaction equation
[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:11]([F:12])=[C:10](F)[N:9]=[C:8]([F:14])[C:7]=1[Cl:15])[CH3:2].[F:17][C:18]([F:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:19][NH2:20].C([O-])([O-])=O.[Ca+2]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:11]([F:12])=[C:10]([NH:20][CH2:19][C:18]([F:27])([F:17])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:9]=[C:8]([F:14])[C:7]=1[Cl:15])[CH3:2]

Participants

5

Reactant 3

HCID 10112Calcium CarbonateHCID 99641672,2-Difluoro-2-pyridin-2-ylethaneamineHCID 23000566Ethyl(3-chloro-2,5,6-trifluoro-4-pyridinyl)acetate

Product 1

HCID 23000565Ethyl(3-chloro-6-{[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-2,5-difluoro-4-pyridinyl)acetate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

To a solution of 5.5 g (22 mmol) ethyl(3-chloro-2,5,6-trifluoro-4-pyridinyl)acetate 1-1 in 75 mL DMF was added 3 g (19 mmol) 2,2-difluoro-2-(2-pyridinyl)ethylamine and 4 g (40 mmol) CaCO3 and the reaction mixture was heated to 70° C. for 18 hours. The reaction mixture was then cooled, diluted w. 400 mL ether, washed 2×300 mL water, and 1×300 mL brine, dried over MgSO4, filtered, and concentrated. Purification by automated flash chromatography (90 g silica cartridge, linear gradient 5-50% EtOAc/hex over 30 min, 70 mL/min flow rate.) afforded ethyl (3-chloro-6-{[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-2,5-difluoro-4-pyridinyl)acetate 1-2 as a white solid. 1H NMR (400 mHz, CDCl3) δ8.66 (br d, 1H, J=4.94 Hz); 7.84 (ddd, 1H, J=7.7, 7.7, and 1.64 Hz); 7.70 (d, 1H, J=7.88 Hz); 7.41 (dd, 1H, J=4.95, 7.14 Hz); 5.40 (br m, 1H); 4.36 (dt, 2H, J=13.9, 6.22 Hz); 4.19 (q, 2H, J=7.14 Hz); 3.77 (d, 2H, J=1.83 Hz); 1.27 (t, 3H, J=7.14 Hz). Mass Spectrum (electrospray) M+H=392.0.

Workup

  1. temperatureThe reaction mixture was then cooled
  2. additiondiluted w
  3. wash400 mL ether, washed 2×300 mL water, and 1×300 mL brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification by automated flash chromatography (90 g silica cartridge, linear gradient 5-50% EtOAc/hex over 30 min, 70 mL/min flow rate.)

Sources & evidence

ORD record
ord-3bd6a3f00e484495a141c7691e3f9692
Source dataset
uspto-grants-2003_08
Patent number
US06610701B2

Reaction notes

Loading…