2-Bromo-4-chloroaniline → 2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-5-chlorobromobenzene

HRID 988622

Reaction equation

HRID 988622 reaction equation
Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:15]=1[NH2:16].C(N(CC)C(C)C)(C)C.[C:31]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>ClCCl>[C:31]([N:38]1[CH2:39][CH2:40][N:41]([C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:14]=2[Br:13])=[O:4])[CH2:42][CH2:43]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]

Participants

6

Reactant 4

HCID 701102-Bromo-4-chloroanilineHCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 143452tert-Butyl piperazine-1-carboxylate

Product 1

HCID 219065382-[(4-Boc-piperazin-1-ylcarbonyl)amino]-5-chlorobromobenzeneYield 191.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

To a stirring solution of triphosgene (2.7 g, 9.0 mmol) in dichloromethane (100 mL) was added, dropwise via an addition funnel, a solution of 2-bromo-4-chloroaniline (5 g, 24.2 mmol) and N,N-diisopropylethylamine (6.9 g, 53.2 mmol) in dichloromethane (50 mL). After complete addition and an additional hour, a solution of N-Boc-piperazine (5 g, 26.6 mmol) in dichloromethane (50 mL) was added. After stirring overnight, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was separated and washed consecutively with 1 M citric acid, brine, sat. aq sodium bicarbonate and finally with brine, then dried with MgSO4, filtered and concentrated in vacuo. The residue was then dissolved in a minimal amount of chloroform and chromatographed over silica gel, eluting with 20% ethyl acetate in hexanes followed by 30% ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo and the resulting solid was suspended in diethyl ether, sonicated and then filtered and dried in vacuo to give 7.2 g (71%) of a white powder.

Workup

  1. additionAfter complete addition
  2. customthe solvent was removed in vacuo
  3. customthe residue was partitioned between ethyl acetate and water
  4. customThe organic phase was separated
  5. washwashed consecutively with 1 M citric acid, brine, sat. aq sodium bicarbonate and finally with brine
  6. dry with materialdried with MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. dissolutionThe residue was then dissolved in a minimal amount of chloroform
  10. customchromatographed over silica gel
  11. washeluting with 20% ethyl acetate in hexanes
  12. additionThe product containing fractions
  13. concentrationconcentrated in vacuo
  14. customsonicated
  15. filtrationfiltered
  16. customdried in vacuo

Sources & evidence

ORD record
ord-d7e4e3d9262843f78eda677a727a6669
Source dataset
uspto-grants-2003_10
Patent number
US06635657B1

Linked notes

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