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

HRID 2063963
Notes
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Reaction equation

HRID 2063963 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]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

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]pyrrolidine
Yield 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-0a2abd93ce724ef1911944e00612ee9e
Source dataset
uspto-grants-2012_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08288386B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes