N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-(t-butoxycarbonylamino)ethyl]-4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid amide → 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-2-(methylthio)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin

HRID 1829641Notes

Reaction equation

HRID 1829641 reaction equation
[F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH2:20][CH2:21][NH:22]C(OC(C)(C)C)=O)[C:8]([C:10]1[C:11](Cl)=[N:12][C:13]([S:17][CH3:18])=[N:14][C:15]=1[Cl:16])=[O:9]>C(OCC)(=O)C.Cl>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:6][N:7]1[C:8](=[O:9])[C:10]2[C:15]([Cl:16])=[N:14][C:13]([S:17][CH3:18])=[N:12][C:11]=2[NH:22][CH2:21][CH2:20]1

Participants

3

Reactant 1

HCID 21030673N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-(t-butoxycarbonylamino)ethyl]-4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid amide

Product 1

HCID 220535646-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-2-(methylthio)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepinYield 68%

Reagents, catalysts & solvents 1

HCID 21866389Hydrogen chloride-ethyl acetateSolvent

Procedure

3 mol/L hydrogen chloride-ethyl acetate (30 mL) was added to N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-(t-butoxycarbonylamino)ethyl]-4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid amide (Compound of Reference Example 5; 11.8 g) while the solution was chilled on an ice bath. The reaction mixture was stirred for 1 hour and then additional 1 hour at room temperature. The solvent was removed and the resulting residue was dissolved in N,N-dimethylformamide (20 mL). To this solution, potassium carbonate (5.37 g) was added and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, was sequentially washed with water and a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. Following removal of the solvent, the residue was purified on a silica gel column chromatography (ethyl acetate:hexane=2:1) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-2-(methylthio)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin (6.22 g, 68%).

Workup

  1. temperaturewas chilled on an ice bath
  2. customadditional 1 hour
  3. customat room temperature
  4. customThe solvent was removed
  5. dissolutionthe resulting residue was dissolved in N,N-dimethylformamide (20 mL)
  6. additionTo this solution, potassium carbonate (5.37 g) was added
  7. stirringthe mixture was stirred at 100° C. for 1 hour
  8. additionThe reaction mixture was diluted with ethyl acetate
  9. washwas sequentially washed with water
  10. dry with materiala saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate
  11. customremoval of the solvent
  12. customthe residue was purified on a silica gel column chromatography (ethyl acetate:hexane=2:1)

Sources & evidence

ORD record
ord-37510f94e1814e1eb4aca1918ddeb8e5
Source dataset
uspto-grants-2006_06
Patent number
US07064119B2

Reaction notes

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