Chlorosuccinimide → 2-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-1-methyl-1H-pyrrole-3-carboxamide

HRID 1967121Notes

Reaction equation

HRID 1967121 reaction equation
[Cl:1][C:2]1[N:3]([CH3:40])[C:4]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][CH:35]=2)=[CH:5][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])=[O:8].C1C(=O)N([Cl:48])C(=O)C1>O1CCCC1>[Cl:1][C:2]1[N:3]([CH3:40])[C:4]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][C:35]=2[Cl:48])=[CH:5][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])=[O:8]

Participants

4

Reactant 2

HCID 31398Chlorosuccinimide2×HCID 581729142-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxamide

Product 1

HCID 581729132-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-1-methyl-1H-pyrrole-3-carboxamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 2-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxamide (125 mg, 0.22 mmol) and NCS (29 mg, 0.22 mmol) in tetrahydrofuran (2.2 ml) was stirred at 70° C. in a sealed tube. LCMS showed a 1:1 mixture of two chlorination products along with starting material. Additional NCS (29 mg, 0.22 mmol) was added and the solution stirred an additional 1 h where LCMS showed complete conversion to the two chlorination products. The resulting solution was partitioned between DCM-H2O and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated, dry loaded onto silica and purified by column chromatography (2% MeOH in DCM (1% NH4OH)) affording an inseparable mixture of the desired title compound along with a chloro-regioisomer: LCMS (ES) m/e 604, 606 (M, M+2)+.

Workup

  1. additiona 1:1 mixture of two chlorination products along with starting material
  2. customThe resulting solution was partitioned between DCM-H2O
  3. washthe aqueous phase was washed several times with DCM
  4. dry with materialThe combined organic fractions were dried over Na2SO4
  5. concentrationconcentrated
  6. customdry loaded onto silica
  7. custompurified by column chromatography (2% MeOH in DCM (1% NH4OH))
  8. customaffording

Sources & evidence

ORD record
ord-84162641ed9d4d7e9c96e816b82efe39
Source dataset
uspto-grants-2013_04
Patent number
US08420690B2

Reaction notes

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