Diazepam → Ethyl 5-chloro-3-phenyl-2H-isoindole-1-carboxylate

HRID 1973285Notes

Reaction equation

HRID 1973285 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2N(C)C(=O)[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[H-].[Na+].C(O[C:26](=[O:30])[O:27][CH2:28][CH3:29])C.[Cl-].[Na+]>CN(C)C=O>[CH2:28]([O:27][C:26]([C:9]1[NH:8][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:6]2[C:5]=1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20]2)=[O:30])[CH3:29]

Participants

6

Reactant 4

HCID 3016DiazepamHCID 5234Sodium ChlorideHCID 7766Diethyl CarbonateHCID 24758Sodium hydride

Product 1

HCID 54174784Ethyl 5-chloro-3-phenyl-2H-isoindole-1-carboxylate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

A solution of 28.5 g. of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one in 400 ml. of dimethylformamide is treated under nitrogen at -10° C. with 0.25 mol. of sodium hydride (11.0 g. of a 55% dispersion in mineral oil) and stirred at the same temperature for 15 minutes. The suspension is then treated at -10° C. to -5° C. with a solution of 35.5 g. of diethylcarbonate in 50 ml. of dimethylformamide. The mixture is stirred firstly for 1 hour at 20° C., then for an additional 4 hours at 60° C. and finally poured onto a mixture of 100 g. of sodium chloride and 2.5 kg. of ice. The precipitate is removed by filtration, washed with water and dissolved in methylene chloride. The organic solution, shielded from daylight, is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The crystalline residue is heated to reflux with 500 ml. of ethanol for 10 minutes and then cooled in an ice-bath. After filtering and washing with ethanol and ether, there is obtained 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in the form of greenish crystals; melting point 208°-210° C. (decomposition). Crystallization from acetonitrile does not increase the melting point.

Workup

  1. additionThe suspension is then treated at -10° C. to -5° C. with a solution of 35.5 g
  2. stirringThe mixture is stirred firstly for 1 hour at 20° C.
  3. waitfor an additional 4 hours at 60° C.
  4. additionfinally poured onto a mixture of 100 g
  5. customThe precipitate is removed by filtration
  6. washwashed with water
  7. dissolutiondissolved in methylene chloride
  8. washis washed with a saturated aqueous solution of sodium chloride
  9. dry with materialdried over sodium sulfate
  10. concentrationconcentrated to dryness
  11. temperatureThe crystalline residue is heated
  12. temperatureto reflux with 500 ml
  13. waitof ethanol for 10 minutes
  14. temperaturecooled in an ice-bath
  15. filtrationAfter filtering
  16. washwashing with ethanol and ether

Sources & evidence

ORD record
ord-f80f6c8d62d84a6583784418842f3ddf
Source dataset
uspto-grants-1976_12
Patent number
US03996374

Reaction notes

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