Dichloromethane → 2-((1S)-1-(5-chloro-3-(2-(methylthio)phenyl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dione

HRID 75375Notes

Reaction equation

HRID 75375 reaction equation
Cl[C:2]1[C:3]([C@@H:13]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][CH:6]=2.[CH3:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[Cl:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:2]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:27][CH3:26])[C:3]([C@@H:13]([N:15]1[C:16](=[O:25])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]1=[O:24])[CH3:14])=[N:4]2

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 27735432-(Methylthio)benzeneboronic acidHCID 86698514(S)-2-(1-(3,5-dichloroquinoxalin-2-yl)ethyl)isoindoline-1,3-dione

Product 1

HCID 866985132-((1S)-1-(5-chloro-3-(2-(methylthio)phenyl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dioneYield 95%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A 5 L three-necked round-bottomed flask equipped with a mechanical stirrer, a condenser, a nitrogen gas inlet and a temperature probe was charged with DMF (2.16 L), (S)-2-(1-(3,5-dichloroquinoxalin-2-yl)ethyl)isoindoline-1,3-dione (273 g, 733 mmol) and 2-(methylthio)phenylboronic acid (136 g, 807 mmol). To the mixture, was added potassium carbonate (203 g, 147 mmol) and [1,1-bis(di-phenylphosphino)ferrocene]palladium(ii) chloride, complex with DCM (29.9 g, 36.7 mmol). The mixture was vacuum purged with N2 (2×), and heated to 100° C. The reaction was monitored by LC-MS, and deemed complete after 4 h. The reaction was cooled to rt (21° C.), and then divided into two batches. Each batch was partitioned between EtOAc (1.08 L) and water (1.35 L) in a 4 L separatory funnel After phase separation, the organic layer was washed with brine (2×500 mL) and concentrated to afford the crude product. The combined batches of crude material were loaded on silica gel and purified by flash chromatography (ISCO/RediSep™) (hexane:EtOAc=10:0 to 6:4) to provide the product as a light brown solid 320 g with 98% LC purity and 95% yield.

Workup

  1. customA 5 L three-necked round-bottomed flask equipped with a mechanical stirrer, a condenser, a nitrogen gas inlet
  2. custompurged with N2 (2×)
  3. temperatureThe reaction was cooled to rt (21° C.)
  4. customEach batch was partitioned between EtOAc (1.08 L) and water (1.35 L) in a 4 L separatory funnel
  5. customAfter phase separation
  6. washthe organic layer was washed with brine (2×500 mL)
  7. concentrationconcentrated
  8. customto afford the crude product
  9. custompurified by flash chromatography (ISCO/RediSep™) (hexane:EtOAc=10:0 to 6:4)

Sources & evidence

ORD record
ord-7db32352842945b3838c5700b5b98b05
Source dataset
uspto-grants-2014_09
Patent number
US08835432B2

Reaction notes

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