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

HRID 10342Notes

Reaction equation

HRID 10342 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-2f6822f4b3d84e5c8faab5b8723b6257
Source dataset
uspto-grants-2006_08
Patent number
US07094780B1

Reaction notes

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