Dimethylformamide → (+)-(S)-2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one (S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate

HRID 1699346Notes

Reaction equation

HRID 1699346 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].CN(C)C=O.[CH3:34][C@@H:35](O)[CH2:36]C.Br[C:40]1[CH:45]=C[C:43]([S:46]([O-:49])(=[O:48])=[O:47])=[CH:42][CH:41]=1>O>[CH3:34][C:35]1([CH3:36])[CH:5]2[CH2:6][CH2:7][C@@:8]1([CH2:43][S:46]([OH:49])(=[O:48])=[O:47])[C:3](=[O:2])[CH2:4]2.[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]([C@@H:40]([CH3:45])[CH2:41][CH3:42])[C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 42465972,4-Dihydro-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-3H-1,2,4-triazol-3-oneHCID 131721473(R)-2-butanol 4-bromobenzenesulfonate2×

Product 1

HCID 131721474(+)-(S)-2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one (S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonateYield 37.7%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 3.5 g of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl ]-phenyl]-3H-1,2,4-triazol-3-one, 0.6 g of a sodium hydride dispersion 50% and 100 ml of N,N-dimethylformarnide was stirred for 3 hours at 80° C. After the addition of 3.5 g of (R)-2-butanol 4-bromobenzenesulfonate (ester) (intermediate (3)), stirring was continued for 6 hours at this temperature. After cooling, water was added The crystallized product was filtered off and taken up in trichloromethane. The undissolved part was filtered off. The remaining solution was dried and purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4methyl-2-pentanone. The product was filtered off and converted into the (S)-7,7dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate salt in 2-propanone. The salt was filtered off and recrystallized from 1-butanol. The product was filtered off and dried, yielding 1.2 g (13.7%) of (+)-(S)-2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one (S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate (1:2); mp. 192.0° C.; [α]D20=+28.410° (conc.=1% in ethanol) (interm. 5).

Workup

  1. stirringstirring
  2. waitwas continued for 6 hours at this temperature
  3. temperatureAfter cooling
  4. filtrationwas filtered off
  5. filtrationThe undissolved part was filtered off
  6. customThe remaining solution was dried
  7. custompurified by column chromatography over silica gel
  8. customThe pure fractions were collected
  9. customthe eluent was evaporated
  10. customThe residue was crystallized from 4methyl-2-pentanone
  11. filtrationThe product was filtered off
  12. filtrationThe salt was filtered off
  13. customrecrystallized from 1-butanol
  14. filtrationThe product was filtered off
  15. customdried

Sources & evidence

ORD record
ord-4b387a8d8f6742abb4e132b3c7ab75c2
Source dataset
uspto-grants-2002_02
Patent number
US06346518B1

Reaction notes

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