3-Isocyanatobenzonitrile → (+/-)-3-[7-chloro-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile

HRID 1247639Notes

Reaction equation

HRID 1247639 reaction equation
[Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH3:10])=[CH:4][N:3]=1.[C:20]([C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1)#[N:21].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[N:28]([C:24]3[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=3)[C:20]#[N:21])[C:29](=[O:30])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:9]([CH3:10])[C:5]2=[CH:4][N:3]=1

Participants

5

Reactant 3

HCID 27333153-IsocyanatobenzonitrileHCID 10086026(+/-)-[1-(2,4-Dichloro-pyrimidin-5-yl)-ethyl]-(4-methoxy-phenyl)-amineHCID 23665647Potassium tert-butoxide

Product 1

HCID 10363933(+/-)-3-[7-chloro-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of (±)-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-(4-methoxy-phenyl)-amine (0.10 g; 0.34 mmol) (from Example 1d supra) in toluene (1 mL) was added 3-cyanophenyl isocyanate (66.6 mg; 0.46 mmol) (Aldrich). The mixture was heated in an oil bath at 110° C. for two hours. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was triturated with hexanes and dried briefly. The solid residue (intermediate urea) was taken up in freshly distilled tetrahydrofuran (1.5 mL), cooled in an ice-brine bath and treated with potassium tert-butoxide (1.0 M in tetrahydrofuran; 370 μL; 0.37 mmol) (Aldrich). After 15 minutes in the cold the reaction was complete by TLC analysis and was filtered through a silica gel pad (0.5 g) and washed with ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography (Biotage, 12M, 40:60 ethyl acetate-hexanes) to give (±)-3-[7-chloro-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile as a solid. (Yield 0.13 g; 85.6%).

Workup

  1. temperatureAfter cooling to room temperature
  2. concentrationthe reaction was concentrated under reduced pressure
  3. customThe residue was triturated with hexanes
  4. customdried briefly
  5. temperaturecooled in an ice-brine bath
  6. filtrationwas filtered through a silica gel pad (0.5 g)
  7. washwashed with ethyl acetate
  8. concentrationThe filtrate was concentrated
  9. customthe residue was purified by flash chromatography (Biotage, 12M, 40:60 ethyl acetate-hexanes)

Sources & evidence

ORD record
ord-478705a1f4614625904e93431126771c
Source dataset
uspto-grants-2006_10
Patent number
US07129351B2

Reaction notes

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