Dimethyl Sulfoxide → methyl 2-[[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-yl]amino]-3-oxobutanoate

HRID 566281Notes

Reaction equation

HRID 566281 reaction equation
FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)=O.CC(C)=O.CS(C)=O.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:35]=[C:34]([NH:36][CH:37]([CH:42]([OH:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39])[CH2:33][N:32]=[C:31]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[F:51])[C:30]=2[CH:52]=1>ClCCl.C(N(CC)CC)C>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:35]=[C:34]([NH:36][CH:37]([C:42](=[O:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39])[CH2:33][N:32]=[C:31]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[F:51])[C:30]=2[CH:52]=1

Participants

7

Reactant 4

HCID 679Dimethyl SulfoxideHCID 9845Trifluoroacetic anhydrideHCID 18522661Acetone cardiceHCID 178501563HCID 178501563, compound

Product 1

HCID 178501562methyl 2-[[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-yl]amino]-3-oxobutanoateYield 74.1%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent3×HCID 8471TriethylamineSolvent

Procedure

A solution of 3.8 ml of trifluoroacetic acid anhydride in 7.3 ml of dichloromethane was added dropwise to a solution, cooled with dry ice/acetone, of 2.7 ml of dimethyl sulphoxide in 18 ml of dichloromethane was added in such a manner that the temperature did not exceed −55° C. After stirring in the cold for 30 min. a solution of 7.54 g of methyl 2-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamino]-3-hydroxybutyrate in 15 ml of dichloromethane was added dropwise in a manner such that the temperature did not exceed −60° C. The mixture was stirred in a dry ice bath for 2 h., then brought to −30° C. for 5 min. and subsequently again cooled in a dry ice bath. After the slow addition of 7.5 ml of triethylamine the mixture was stirred, firstly in the cold for a further 30 min., then at room temperature for 30 min. For the working up the mixture was extracted with 30 ml of water. The organic phase was dried over magnesium sulphate, concentrated in a vacuum and purified by chromatography on 350 g of silica gel. Byproducts were eluted with dichloromethane containing 1% methanol. With dichloromethane containing 3% methanol there were isolated 5.56 g (74%) of methyl 2-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamino]-3-oxo-butyrate which was used without further purification for the step described below.

Workup

  1. additionwas added in such a manner that the temperature
  2. customdid not exceed −55° C
  3. additionwas added dropwise in a manner such that the temperature
  4. customdid not exceed −60° C
  5. waitbrought to −30° C. for 5 min.
  6. temperaturesubsequently again cooled in a dry ice bath
  7. stirringwas stirred, firstly in the cold for a further 30 min.
  8. waitat room temperature for 30 min
  9. extractionFor the working up the mixture was extracted with 30 ml of water
  10. dry with materialThe organic phase was dried over magnesium sulphate
  11. concentrationconcentrated in a vacuum
  12. custompurified by chromatography on 350 g of silica gel
  13. washByproducts were eluted with dichloromethane containing 1% methanol

Sources & evidence

ORD record
ord-718ac78c9e224dc7b1951d0652424de7
Source dataset
uspto-grants-2001_01
Patent number
US06174881B1

Reaction notes

Loading…