Potassium Phosphate, Tribasic → 1-(4-(2-Isopropyl-1-oxoisoindolin-5-yl)benzyl)-3-methylimidazolidine-2,4-dione

HRID 1891262Notes

Reaction equation

HRID 1891262 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH:12]([CH3:14])[CH3:13])[CH2:5]2.[CH3:15][N:16]1[C:20](=[O:21])[CH2:19][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[C:17]1=[O:38].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)(Cl)Cl.[Pd].[Pd].C(Cl)Cl>[CH:12]([N:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([CH2:22][N:18]4[CH2:19][C:20](=[O:21])[N:16]([CH3:15])[C:17]4=[O:38])=[CH:24][CH:25]=3)[CH:3]=2)[C:7]1=[O:11])([CH3:14])[CH3:13]

Participants

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 117086345-Bromo-2-isopropylisoindolin-1-oneHCID 671722823-Methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]imidazolidine-2,4-dione

Product 1

HCID 529320281-(4-(2-Isopropyl-1-oxoisoindolin-5-yl)benzyl)-3-methylimidazolidine-2,4-dioneYield 31.2%

Reagents, catalysts & solvents 4

HCID 86615680Dipalladium chloroformCatalystHCID 962WaterSolvent2×HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

5-bromo-2-isopropylisoindolin-1-one (4A4) (0.418 mmol, 106 mg) was mixed with 3-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)imidazolidine-2,4-dione (4E1) (0.418 mmol, 138 mg), tricyclohexylphosphine (0.050 mmol, 14 mg), tris(dibenzylidineacetone) dipalladium chloroform adduct (0.021 mmol, 22 mg) and potassium phosphate (0.710 mmol, 151 mg) in dioxane (2 ml) and water (1 ml). The mixture was heated to 130° C. for 15 minutes in the microwave before addition of DCM (2 ml) and water (2 ml). The reaction was stirred vigorously for 30 minutes before collection of the organic layer using a hydrophobic fritted tube followed by concentration. Purification was achieved using basic HPLC and the desired fractions concentrated to give 1-(4-(2-isopropyl-1-oxoisoindolin-5-yl)benzyl)-3-methylimidazolidine-2,4-dione (Example 4a) 49.2 mg (31.2%); 1H NMR (400 MHz, CDCl3) δ 7.91 (d, 1H) 7.67-7.59 (m, 4H) 7.37 (d, 2H) 4.7 (sept, 1H) 4.62 (s, 2H) 4.4 (s, 2H) 3.79 (s, 2H) 3.07 (s, 3H) 1.31 (d, 6H) LCMS m/z (M+H) 378.2.

Workup

  1. concentrationfollowed by concentration
  2. customPurification
  3. concentrationthe desired fractions concentrated

Sources & evidence

ORD record
ord-fafb9362cb0247ac9ef2e137cf126f6b
Source dataset
uspto-grants-2013_08
Patent number
US08507521B2

Reaction notes

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