Hydrogen Bromide → HCID 39254711, compound

HRID 581635Notes

Reaction equation

HRID 581635 reaction equation
[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.ClC(OCC1C=CC=CC=1)=O.[C:22]([N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1)(N1C=CN=C1)=O.C(OC(N1CCNCC1)=O)C.Br>C1COCC1.CN(C=O)C.C1COCC1.C(O)(=O)C.N1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:29]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:22]2)=[O:8])=[CH:9][CH:10]=1

Participants

10

Reactant 5

HCID 260Hydrogen BromideHCID 9784-Aminobenzoic AcidHCID 84311-Piperazinecarboxylic acid, ethyl esterHCID 10387Benzyl chloroformateHCID 682631,1'-Carbonyldiimidazole

Product 1

HCID 39254711HCID 39254711, compoundYield 50%

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolventHCID 1049PyridineSolventHCID 8028TetrahydrofuranSolvent2×HCID 21974620tetrahydrofuran N,N-dimethylformamideSolvent

Conditions

Temperature
75 °C

Procedure

4-aminobenzoic acid (Aldrich 99%) was reacted stoichiometrically with benzyl chloroformate (Aldrich 95%) in THF solvent in the presence of pyridine acid acceptor initially at 2-25° C. for 1 hour then refluxed 75° C. for 2 hours. After evaporation of solvent, washing the solids in water, filtering and drying, the resulting N-CBZ-protected product was obtained in 85% yield. This compound was first reacted with a stoichiometric quantity of 1,1'-carbonyl diimidazole at room temperature for 2 hours in DMF/THF solvent. A stoichiometric amount of ethyl-1-piperazine carboxylate (Lancaster 99%) in THF was then added to this mix, kept at room temperature for 1 hour, then refluxed at 80° C. for 8 hours. The reaction solution was evaporated to a solid residue, washed with water, filtered and finally dried to obtain the solid diprotected product in 90% yield. This solid was deprotected in excess 5N hydrobromic acid in acetic acid at 48° C. for 10 hours. After evaporation of acidic fluids, the solid residue was washed with acetone then ether, filtered and dried as the dihydrobromide salt. Dissolution of this salt in a stirred aqueous suspension of 2× equivalents of strong base anion exchange resin (Amberlite IRA-400-OH) followed by filtration and washing of resin, evaporation of filtrates and azeotropic drying in anhydrous ethanol then in 1,2-dichloroethane, gave dry 4-aminobenzoyl piperazine (4ABP) solid in 50% yield. 3ABP was prepared in the same manner as above but starting with 3-aminobenzoic acid.

Workup

  1. customAfter evaporation of solvent
  2. washwashing the solids in water
  3. filtrationfiltering
  4. customdrying
  5. customwas obtained in 85% yield
  6. temperaturerefluxed at 80° C. for 8 hours
  7. customThe reaction solution was evaporated to a solid residue
  8. washwashed with water
  9. filtrationfiltered
  10. customfinally dried
  11. customto obtain the solid diprotected product in 90% yield
  12. customAfter evaporation of acidic fluids
  13. washthe solid residue was washed with acetone
  14. filtrationether, filtered
  15. dry with materialdried as the dihydrobromide salt
  16. dissolutionDissolution of this salt
  17. additionin a stirred aqueous suspension of 2× equivalents of strong base anion exchange resin (Amberlite IRA-400-OH)
  18. filtrationfollowed by filtration
  19. washwashing of resin, evaporation of filtrates
  20. dry with materialazeotropic drying in anhydrous ethanol

Sources & evidence

ORD record
ord-00d8c53e51ee425382a27b6347a9ac54
Source dataset
uspto-grants-1999_07
Patent number
US05922203

Reaction notes

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