Potassium Phosphate, Tribasic → 5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one

HRID 2204360Notes

Reaction equation

HRID 2204360 reaction equation
Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[CH3:29])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[F:21])[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[C:15]([F:21])=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][CH3:30])[N:6]([CH:7]([CH3:8])[CH3:9])[C:5]=3[CH:10]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[CH3:29])[CH:19]=[CH:18][CH:17]=1

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27339582-Methoxyphenylboronic acidHCID 867030922-Bromo-5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one2×

Product 1

HCID 722057255-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A degassed mixture of 2-bromo-5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate A) (0.392 mmol), 2-methoxyphenylboronic acid [5720-06-9] (0.549 mmol), (Ph3P)2PdCl2 (0.039 mmol) and K3PO4 (1.569 mmol) in DMF (4 mL) was heated at 100° C. for 8 h. After cooling to rt, the reaction mixture was concentrated. The residue was diluted with a saturated aqueous solution of NaHCO3 and extracted with EtOAc (3×). The combined organic phases were successively washed with water and brine, dried (Na2SO4) and concentrated. The residue was dissolved in MeOH and filtered through a PL-thiol MP SPE cartridge (StratoSpheres), washing through with additional MeOH. The filtrate was re-concentrated and the residue purified using a RediSep® silica gel column to afford the title compound as a light yellow solid. tR: 8.55 min (HPLC 2); ESI-MS: tR=1.43 min, [M+H]+523/525 (LC-MS 1); TLC: Rf=0.41 (98:2 CH2Cl2/MeOH); 1H-NMR (d6-DMSO, 600 MHz): (rotamers) 7.56 (d, 0.5H), 7.50-7.56 (m, 1.5H), 7.45-7.49 (m, 1.5H), 7.30 (d, 1H), 7.27 (m, 1H), 7.19-7.25 (m, 2H), 7.14 (d, 1H), 7.05 (m, 1H), 6.92 (d, 0.5H), 6.51/6.67 (s, 1H), 6.25/6.27 (s, 1H), 3.93/3.97 (m, 1H), 3.77 (s, 3H), 1.87/2.36 (s, 3H), 1.27 (m, 3H), 0.48 (m, 3H).

Workup

  1. temperatureAfter cooling to rt
  2. concentrationthe reaction mixture was concentrated
  3. additionThe residue was diluted with a saturated aqueous solution of NaHCO3
  4. extractionextracted with EtOAc (3×)
  5. washThe combined organic phases were successively washed with water and brine
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated
  8. dissolutionThe residue was dissolved in MeOH
  9. filtrationfiltered through a PL-thiol MP SPE cartridge (StratoSpheres)
  10. washwashing through with additional MeOH
  11. concentrationThe filtrate was re-concentrated
  12. customthe residue purified

Sources & evidence

ORD record
ord-e159eaada0194f9794e96a995019aa65
Source dataset
uspto-grants-2016_06
Patent number
US09365576B2

Reaction notes

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