Cyclopropylamine → Ethyl 2-cyclopropylamino-5-fluoro-6-methylsulfanylnicotinate

HRID 729428Notes

Reaction equation

HRID 729428 reaction equation
[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([S:12][CH3:13])=[N:7][C:6]=1Cl)[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([S:12][CH3:13])=[N:7][C:6]=1[NH:19][CH:16]1[CH2:18][CH2:17]1)[CH3:2]

Participants

4

Reactant 2

HCID 69828Cyclopropylamine2×HCID 15657956Ethyl 2-chloro-5-fluoro-6-(methylsulfanyl)pyridine-3-carboxylate

Product 1

HCID 21979206Ethyl 2-cyclopropylamino-5-fluoro-6-methylsulfanylnicotinateYield 69.1%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A solution of 8.7 g (34.8 mmol) of 2-chloro-5-fluoro-6-methylsulfanylnicotinic acid ethyl ester (J. Med. Chem., 1993; 36:2676) and 5.7 g (100 mmol) of cyclopropylamine in 100 mL of acetonitrile is heated at reflux for 18 hours. After TLC showed the presence of unreacted starting material, 4.12 g (72 mmol) of cyclopropylamine is added and the reaction mixture is refluxed for 48 hours. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (250 mL) and water (100 mL). The organic layer is washed with water, dried (MgSO4), filtered, and concentrated in vacuo. The residue is chromatographed over flash grade silica gel (230-400 mesh) eluting with dichloromethane to give 6.5 g of the title compound, mp 67-69° C.

Workup

  1. temperatureat reflux for 18 hours
  2. additionis added
  3. temperaturethe reaction mixture is refluxed for 48 hours
  4. customThe solvent is removed in vacuo
  5. customthe residue is partitioned between dichloromethane (250 mL) and water (100 mL)
  6. washThe organic layer is washed with water
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe residue is chromatographed over flash grade silica gel (230-400 mesh)
  11. washeluting with dichloromethane

Sources & evidence

ORD record
ord-b2ab1bace85c49ee92af25f8b0bdae98
Source dataset
uspto-grants-2009_09
Patent number
US07582627B2

Reaction notes

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