Chlorosulfonyl isocyanate → 1-Cyclopropyl-6-fluoro-7-methylsulfanyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione

HRID 10324

Reaction equation

HRID 10324 reaction equation
[CH:1]1([NH:4][C:5]2[N:15]=[C:14]([S:16][CH3:17])[C:13]([F:18])=[CH:12][C:6]=2[C:7]([O:9]CC)=O)[CH2:3][CH2:2]1.ClS([N:23]=[C:24]=[O:25])(=O)=O.C([O-])(=O)C.[Na+].CC(C)([O-])C.[Na+]>ClCCl>[CH:1]1([N:4]2[C:5]3[N:15]=[C:14]([S:16][CH3:17])[C:13]([F:18])=[CH:12][C:6]=3[C:7](=[O:9])[NH:23][C:24]2=[O:25])[CH2:2][CH2:3]1

Participants

6

Reactant 4

HCID 70918Chlorosulfonyl isocyanateHCID 517045Sodium AcetateHCID 21979206Ethyl 2-cyclopropylamino-5-fluoro-6-methylsulfanylnicotinateHCID 23676156Sodium t-butoxide

Product 1

HCID 219794201-Cyclopropyl-6-fluoro-7-methylsulfanyl-1H-pyrido[2,3-d]pyrimidine-2,4-dioneYield 18.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
-20 °C

Procedure

A solution of 4.1 g (15.2 mmol) of ethyl 2-cyclopropylamino-5-fluoro-6-methylsulfanylnicotinate (Example 34) in 125 mL of dichloromethane is cooled to −20° C. and treated dropwise with 5.24 g (37 mmol) of chlorosulfonyl isocyanate. The reaction is stirred at −20° C. for 3 hours and allowed to come to room temperature overnight. The mixture is recooled to −20° C. and treated with 6.8 g (80 mmol) of solid sodium acetate. After stirring for 1 hour without cooling, the solvent is removed in vacuo without heating. The residue is triturated with a saturated solution of sodium acetate in brine and extracted with ethyl acetate (3×75 mL). The combined organic layers are dried (MgSO4), filtered and evaporated in vacuo. The residue is suspended in 100 mL of tetrahydrofuran and treated with 3.6 g (32 mmol) of solid sodium tert-butoxide and stirred at room temperature for 36 hours. The solvent is removed in vacuo, the residue triturated with 100 mL of 0.1 M formic acid and extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water, dried (MgSO4), filtered and evaporated in vacuo to give a residue which is chromatographed over flash grade silica gel (230–400 mesh) eluting with dichloromethane to give 0.75 g of the title compound, mp 220–222° C.

Workup

  1. waitto come to room temperature overnight
  2. customis recooled to −20° C.
  3. stirringAfter stirring for 1 hour
  4. temperaturewithout cooling
  5. customthe solvent is removed in vacuo
  6. temperaturewithout heating
  7. customThe residue is triturated with a saturated solution of sodium acetate in brine
  8. extractionextracted with ethyl acetate (3×75 mL)
  9. dry with materialThe combined organic layers are dried (MgSO4)
  10. filtrationfiltered
  11. customevaporated in vacuo
  12. stirringstirred at room temperature for 36 hours
  13. customThe solvent is removed in vacuo
  14. customthe residue triturated with 100 mL of 0.1 M formic acid
  15. extractionextracted with ethyl acetate (3×100 mL)
  16. washThe combined organic layers are washed with water
  17. dry with materialdried (MgSO4)
  18. filtrationfiltered
  19. customevaporated in vacuo
  20. customto give a residue which
  21. customis chromatographed over flash grade silica gel (230–400 mesh)
  22. washeluting with dichloromethane

Sources & evidence

ORD record
ord-296269dc43554704b3f2db025bb12e66
Source dataset
uspto-grants-2006_08
Patent number
US07094780B1

Linked notes

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