(S)-2-(1-(5-chloro-3-(2-(methylsulfonyl)phenyl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dione → 2-((S)-1-(1,3-dioxoisoindolin-2-yl)ethyl)-3-(2-(methylsulfonyl)phenyl)quinoxaline-5-carbonitrile

HRID 1019815Notes

Reaction equation

HRID 1019815 reaction equation
Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH3:34])(=[O:33])=[O:32])[C:6]([C@@H:12]([N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH3:13])=[N:7]2.[C:35]([Zn]C#N)#[N:36]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[C@H:12]([C:6]1[C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:32])=[O:33])=[N:4][C:3]2[C:2]([C:35]#[N:36])=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1)[CH3:13]

Participants

5

Reactant 2

HCID 86698515(S)-2-(1-(5-chloro-3-(2-(methylsulfonyl)phenyl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dioneHCID 178514179HCID 178514179, compound

Product 1

HCID 866985172-((S)-1-(1,3-dioxoisoindolin-2-yl)ethyl)-3-(2-(methylsulfonyl)phenyl)quinoxaline-5-carbonitrileYield 51.4%

Reagents, catalysts & solvents 2

HCID 54751079XPhos PalladacycleCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A 5 L three-necked round-bottomed flask equipped with a condenser, nitrogen inlet, overhead stirrer and thermocouple was charged with 2-((1S)-1-(5-chloro-3-(2-(methylsulfonyl)phenyl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dione (400 g, 813 mmol), dicyanozinc (143 g, 1.22 mol) and 1,4-dioxane (4.0 L). The solution was stirred vigorously and degassed with Ar for 1 h. To the solution was then added XPhos precatalyst (66.1 g, 89 mmol). The mixture was then degassed with Ar for 1 h and heated to 90° C. The reaction was monitored by LC, and deemed complete after 8 h. The reaction was cooled to rt (20-21° C.) and divided into two batches. For each batch, EtOAc (2.0 L), NaHCO3 (400 mL) and water (400 mL) were added. The mixture was stirred for 10 min and a precipitate formed. The precipitates were filtered to afford the pure product as a white solid 201.5 g. The mother liquor was washed with brine (800 mL) and the organic layer concentrated to afford the crude product ˜400 g. The crude material was then slurried in EtOAc (1.2 L) for 30 min at rt. The solid was filtered, washed with EtOAc (2×400 mL) and dried to afford the product as a tan solid 220 g. All the solids were combined, dried on a glass frit under mild vacuum and a stream of N2 for 2 days to afford the product as white solid 378 g with 99.6% LC purity and 96% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47-8.68 (m, 2H), 7.66-8.19 (m, 7H), 7.52 (dd, J=5.5, 3.0 Hz, 1H), 7.22-7.40 (m, 1H), 5.61-5.95 (m, 1H), 3.11-3.27 (m, 3H), 1.68-1.93 (m, 3H) Mass Spectrum (ESI) m/z=483.0 (M+1).

Workup

  1. customA 5 L three-necked round-bottomed flask equipped with a condenser, nitrogen inlet
  2. customdegassed with Ar for 1 h
  3. customThe mixture was then degassed with Ar for 1 h
  4. temperatureThe reaction was cooled to rt (20-21° C.)
  5. additionFor each batch, EtOAc (2.0 L), NaHCO3 (400 mL) and water (400 mL) were added
  6. stirringThe mixture was stirred for 10 min
  7. customa precipitate formed
  8. filtrationThe precipitates were filtered

Sources & evidence

ORD record
ord-fc2be69700e84ac090b8440024485ab6
Source dataset
uspto-grants-2014_05
Patent number
US08716290B2

Reaction notes

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