Piperazine → 4-(3-Carboxy4-chloro-benzenesulfonyl)-piperazine-1-carboxylic acid ethyl ester

HRID 1365023

Reaction equation

HRID 1365023 reaction equation
[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](F)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C.N1CCNCC1.S(F)(F)(=O)=O>C(OCC)(=O)C>[CH2:24]([O:23][C:21]([N:15]1[CH2:16][CH2:17][N:18]([S:11]([C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([C:4]([OH:6])=[O:5])[CH:7]=2)(=[O:13])=[O:12])[CH2:19][CH2:20]1)=[O:22])[CH3:25]

Participants

7

Reactant 5

HCID 4837Piperazine3×HCID 84311-Piperazinecarboxylic acid, ethyl esterHCID 17607Sulfuryl fluorideHCID 81531Diisopropylethylamine2×HCID 888732-Chloro-5-(fluorosulpho)benzoic acid

Product 1

HCID 454642314-(3-Carboxy4-chloro-benzenesulfonyl)-piperazine-1-carboxylic acid ethyl esterYield 80.8%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

2-Chloro-5-fluorosulfonylbenzoic acid (Acros Organics, 105 mg, 440 μmol, 1.0 eq) was placed in a vial and the vial was flushed with nitrogen and a positive pressure was maintained. Anhydrous dichloromethane (1.4 mL) was added, followed by ethyl 1-piperazine carboxylate (80 μL, 528 μmol, 1.2 eq) and ethyldiisopropylamine (redistilled, 80 μL, 440 μmol, 1.0 eq). The mixture was stirred for 1.5 h after which time additional piperazine was added (60 μL, 352 μmol, 0.8 eq). After 14 h the mixture was analyzed by reverse-phase HPLC-MS in negative ionization mode. The sulfonyl fluoride starting material was present, as well as a less polar compound showing (M−1) ion in about 35:65 ratio. An additional 0.35 eq of piperazine and ethyldiisopropylamine each (154 μmol, 30 μl) were added and the mixture was stirred for 4 h. HPLC-MS at this time indicated little progress and an additional 0.25 eq of piperazine (100 μmol, 20 μL) was added. After stirring for 14 h HPLC-MS indicated the reaction was complete. The reaction mixture was diluted with 2 mL of ethyl acetate, washed with 1M HCl solution (2×1 mL) and dried over anhydrous sodium sulfate. The solution was filtered, the solvents removed on a rotary evaporator and vacuum pump to afford 134 mg of a white solid, 81%. NOTE: Addition of excess nucleophilic amine at the beginning of the reaction results in significant bis addition, giving sulfonamide and carboxamide product. Stepwise addition of nucleophilic amine as needed suppresses formation of this side product.

Workup

  1. customwas flushed with nitrogen
  2. temperaturea positive pressure was maintained
  3. additionAnhydrous dichloromethane (1.4 mL) was added
  4. additionwas added (60 μL, 352 μmol, 0.8 eq)
  5. stirringAfter stirring for 14 h HPLC-MS
  6. washwashed with 1M HCl solution (2×1 mL)
  7. dry with materialdried over anhydrous sodium sulfate
  8. filtrationThe solution was filtered
  9. customthe solvents removed on a rotary evaporator and vacuum pump

Sources & evidence

ORD record
ord-4aa2c85ebd1c4aafbc44aaf17919ddfa
Source dataset
uspto-grants-2011_02
Patent number
US07888373B2

Linked notes

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