1-Methylimidazole → (+/-)-2-[3-chloro-4-[(chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione monohydrate

HRID 984050Notes

Reaction equation

HRID 984050 reaction equation
C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Cl:12][Si](CC)(CC)CC.[Cl:20][C:21]1[CH:22]=[C:23]([N:36]2[C:41](=[O:42])[NH:40][C:39](=[O:43])[CH:38]=[N:37]2)[CH:24]=[CH:25][C:26]=1[C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31](Cl)=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1>[OH2:35].[Cl:20][C:21]1[CH:22]=[C:23]([N:36]2[C:41](=[O:42])[NH:40][C:39](=[O:43])[CH:38]=[N:37]2)[CH:24]=[CH:25][C:26]=1[C:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:12])([OH:35])[C:11]1[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=1

Participants

7

Reactant 5

HCID 13901-MethylimidazoleHCID 13819ChlorotriethylsilaneHCID 25517Ammonium ChlorideHCID 161969CP 25415HCID 178418339Butyllithium2×

Product 1

HCID 22557334(+/-)-2-[3-chloro-4-[(chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione monohydrateYield 25%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-70 °C

Procedure

n-Butyllithium, 1.6M (0.0203 mol) was added dropwise at −70° C. under N2 flow to a solution of 1-methyl-1H-imidazole (0.0203 mol) in THF (60 ml). The mixture was stirred at −70° C. for 40 minutes. Chlorotriethylsilane (0.203 mol) was added quickly and the mixture was allowed to warm to 0° C. on an ice bath. The mixture was cooled to −70° C. and n-butyllithium (0.0203 mol) was added dropwise. The mixture was allowed to warm to −20° C. and cooled to −70° C. A solution of 2-[3-chloro-4-(4-chlorobenzoyl)phenyl-1,2,4-triazine-3,5(2H,4H)-dione (0.00812 mol) in THF (20 ml) was added dropwise. The mixture was allowed to warm to −5° C., then poured out into a satured NH4Cl solution and ice, and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 96/4). The pure fractions were collected and the solvent was evaporated. The residue (0.85 g) was crystallized from 2-propanone and diethyl ether. The precipitate was filtered off and dried, yielding 0.47 g (13%) of (±)-2-[3-chloro-4-[(chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione monohydrate (compound 121).

Workup

  1. temperatureto warm to 0° C. on an ice bath
  2. temperatureThe mixture was cooled to −70° C.
  3. temperatureto warm to −20° C.
  4. temperaturecooled to −70° C
  5. temperatureto warm to −5° C.
  6. extractionextracted with EtOAc
  7. customThe organic layer was separated
  8. customdried
  9. filtrationfiltered
  10. customthe solvent was evaporated
  11. customThe residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 96/4)
  12. customThe pure fractions were collected
  13. customthe solvent was evaporated
  14. customThe residue (0.85 g) was crystallized from 2-propanone and diethyl ether
  15. filtrationThe precipitate was filtered off
  16. customdried

Sources & evidence

ORD record
ord-7a792f9359204d8297970c615dcad5af
Source dataset
uspto-grants-2005_03
Patent number
US06867207B2

Reaction notes

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