1-Bromo-2,4-difluorobenzene → (2S,4S)-1-Boc-4-[(2,4-difluorophenyl)amino]-2-[(4-methylpiperazin-1-yl)carbonyl]pyrrolidine

HRID 1927565Notes

Reaction equation

HRID 1927565 reaction equation
[C:1]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.Br[C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][C:52]=1[F:58]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:8]1[CH2:12][C@@H:11]([NH:13][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][C:52]=2[F:58])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]

Participants

7

Reactant 4

HCID 676741-Bromo-2,4-difluorobenzeneHCID 27342152-(Di-tert-butylphosphino)biphenylHCID 23676156Sodium t-butoxideHCID 67358152(2S,4S)-1-Boc-4-amino-2-[(4-methylpiperazin-1-yl)carbonyl]pyrrolidine

Product 1

HCID 67358440(2S,4S)-1-Boc-4-[(2,4-difluorophenyl)amino]-2-[(4-methylpiperazin-1-yl)carbonyl]pyrrolidineYield 78%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

(2S,4S)-1-Boc-4-amino-2-[(4-methylpiperazin-1-yl)carbonyl]pyrrolidine (10.61 g, 33.96 mmol) obtained in Step C was dissolved in toluene (100 mL). Sodium t-butoxide (3.73 g, 38.81 mmol), 2-(di-t-butylphosphino)biphenyl (863 mg, 2.89 mmol), Tris(dibenzylideneacetone)-dipalladium(0) (1.73 g, 1.93 mmol) and 1-bromo-2,4-difluorobenzene (7.48 g, 38.81 mmol) were added thereto and the reaction solution was stirred for 10 hours at 110° C. After the reaction was completed, solid like material was filtered using the Cellite from the reaction solution. The reaction solution was diluted with EtOAc and washed with water. The extracted organic solution was dried over MgSO4, concentrated in vacuo and purified by column chromatography (eluent: MC:MeOH=10/1) to give the title compound (11.24 g, 78%).

Workup

  1. filtrationsolid like material was filtered
  2. additionThe reaction solution was diluted with EtOAc
  3. washwashed with water
  4. dry with materialThe extracted organic solution was dried over MgSO4
  5. concentrationconcentrated in vacuo
  6. custompurified by column chromatography (eluent: MC:MeOH=10/1)

Sources & evidence

ORD record
ord-e56434fa315b47b5b5134825a7861fa7
Source dataset
uspto-grants-2012_05
Patent number
US08183243B2

Reaction notes

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