Acetic Acid → methyl 2,2-dimethyl-3-[4-(7-methyl-2-(methylsulfanyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-propanoate

HRID 1877803Notes

Reaction equation

HRID 1877803 reaction equation
[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[C:9]1[C:15](OC)=O.C(O)(=O)C.Cl.Cl.[CH3:29][C:30]([CH3:42])([CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:31]([O:33][CH3:34])=[O:32]>O.[Fe]>[CH3:29][C:30]([CH3:42])([CH2:35][N:36]1[CH2:41][CH2:40][N:39]([C:15]2[C:9]3=[CH:10][C:11]([S:13][CH3:14])=[CH:12][N:8]3[CH2:7][C:6]3[CH:19]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[N:20]=2)[CH2:38][CH2:37]1)[C:31]([O:33][CH3:34])=[O:32]

Participants

6

Reactant 3

HCID 176Acetic AcidHCID 68155874methyl 1-(5-methyl-2-nitrobenzyl)-4-(methylsulfanyl)-1H-pyrrole-2-carboxylateHCID 68155933Methyl 2,2-dimethyl-3-(piperazin-1-yl)propanoate dihydrochloride

Product 1

HCID 68156150methyl 2,2-dimethyl-3-[4-(7-methyl-2-(methylsulfanyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-propanoateYield 27.2%

Reagents, catalysts & solvents 2

HCID 23925IronCatalystHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

Treat methyl 1-(5-methyl-2-nitrobenzyl)-4-(methylsulfanyl)-1H-pyrrole-2-carboxylate (3.49 mmoles; 1.12 g) with acetic acid (15 mL) then treat with iron, powder (10.5 mmoles; 585 mg) then slowly heat in an oil bath at 80° C. After a few hours increase the oil bath temperature to 90° C. Then leave the reaction at 60° C. for 2 days. Then concentrate to dryness to remove acetic acid then treat with EtOAc and wash through a pad of silica with more EtOAc until the orange colour stops coming off. Concentrate the red eluant to dryness then treat with methanol then re-concentrate and dissolve in DCM (20 mL) and treat with phosphoryl chloride (1.0 mL). Heat the reaction in an oil bath at 50° C. overnight. Then cool the reaction to RT and treat with ice then wash with water twice and then NaHCO3 (aq). Dry the organic layer over MgSO4, filter and concentrate to a tar. Meanwhile dissolve methyl 2,2-dimethyl-3-(piperazin-1-yl)-propanoate dihydrochloride (1.60 g, 5.86 mmoles) in water then load on to a SCX-2 cartridge (2×10 g) and wash with methanol and then elute with ammonia in methanol. Concentrate the basic solution to dryness to an oil. Then dissolve this oil in acetonitrile (50 mL) and add to a mixture of the tar and potassium carbonate (1.0 g) then heat to reflux. After 2 hours, microwave the reaction to 140° C. for 2 hours. Then filter the reaction and extract with acetonitrile and acetone. Combine and concentrate the mother liquors to dryness onto silica then purify by flash chromatography silica (40 g) (10-50% EtOAc in hexane). Take the fractions which contain clean product, combine and concentrate to yield methyl 2,2-dimethyl-3-[4-(7-methyl-2-(methylsulfanyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-propanoate (418 mg; 27% yield). MS (m/z): 441.18 (M+1).

Workup

  1. temperatureAfter a few hours increase the oil bath temperature to 90° C
  2. customThen leave
  3. customthe reaction at 60° C. for 2 days
  4. concentrationThen concentrate to dryness
  5. customto remove acetic acid
  6. additionthen treat with EtOAc
  7. washwash through a pad of silica with more EtOAc until the orange colour
  8. concentrationConcentrate the red eluant to dryness
  9. additionthen treat with methanol
  10. concentrationthen re-concentrate
  11. dissolutiondissolve in DCM (20 mL)
  12. additiontreat with phosphoryl chloride (1.0 mL)
  13. temperatureHeat
  14. customthe reaction in an oil bath at 50° C. overnight
  15. temperatureThen cool
  16. customthe reaction to RT
  17. additiontreat with ice
  18. washthen wash with water twice
  19. dry with materialDry the organic layer over MgSO4
  20. filtrationfilter
  21. concentrationconcentrate to a tar
  22. washwash with methanol
  23. washelute with ammonia in methanol
  24. concentrationConcentrate the basic solution to dryness to an oil
  25. dissolutionThen dissolve this oil in acetonitrile (50 mL)
  26. additionadd to a mixture of the tar and potassium carbonate (1.0 g)
  27. temperaturethen heat to reflux
  28. customthe reaction to 140° C. for 2 hours
  29. filtrationThen filter
  30. customthe reaction
  31. extractionextract with acetonitrile and acetone
  32. concentrationCombine and concentrate the mother liquors to dryness onto silica
  33. customthen purify by flash chromatography silica (40 g) (10-50% EtOAc in hexane)
  34. concentrationconcentrate

Sources & evidence

ORD record
ord-6c80b974a198436fb8c9e0f01af005af
Source dataset
uspto-grants-2012_11
Patent number
US08314092B2

Reaction notes

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