4-(2-Hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid → 4-((4-chlorophenoxy)methyl)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-2(1H)-one

HRID 2059853Notes

Reaction equation

HRID 2059853 reaction equation
[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)=[CH:4][CH:3]=1.[OH:17][C:18]([CH3:33])([CH3:32])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[O:30][CH3:31]>CO.O.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][N:11]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:18]([OH:17])([CH3:33])[CH3:32])=[C:22]([O:30][CH3:31])[CH:23]=3)[C:10](=[O:14])[N:9]=2)=[CH:4][CH:3]=1

Participants

6

Reactant 2

HCID 585798634-(2-Hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acidHCID 178517840HCID 178517840, compound

Product 1

HCID 469271284-((4-chlorophenoxy)methyl)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-2(1H)-one

Reagents, catalysts & solvents 3

HCID 165397Cupric acetate monohydrateCatalystHCID 887MethanolSolventHCID 962WaterSolvent

Procedure

To a mixture of 4-((4-chlorophenoxy)methyl)pyrimidin-2(1H)-one Part C (0.2 g, 0.845 mmol), 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part D of Procedure 4 (0.304 g, 1.268 mmol), and copper (II) acetate monohydrate (0.169 g, 0.845 mmol) in MeOH (45 mL) and H2O (11 mL) was added N,N,N′N′-tetramethylethylenediamine (0.26 mL, 1.690 mmol). After stirring at RT for 45 minutes in the presence of air, the mixture was extracted with CH2Cl2 (200 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica gel/100:0 to 0:100 hexanes-ethyl acetate to 95:5 CH2Cl2/MeOH gradient). The product thus obtained was re-purified using prep HPLC (Phen Luna Axia C18 5μ 10:90 to 90:10 MeOH/H2O) to afford the desired product 4-((4-chlorophenoxy)methyl)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-2(1H)-one C-1 (16.9 mg, 0.036 mmol, 4.32% yield) as a yellow solid. 100 mg of starting material 4-((4-chlorophenoxy)methyl)pyrimidin-2(1H)-one was also recovered. LC/MS 431 (M+H)+, tR 0.81 min (method 5); 1H NMR (400 MHz, Chloroform-D) δ 7.73 (1H, d, J=6.78 Hz), 7.28-7.31 (2H, m), 6.94-7.03 (2H, m), 6.86-6.94 (3H, m), 6.66 (1H, d, J=7.03 Hz), 5.02 (2H, s), 3.87 (3H, s), 3.86 (2H, s), 1.36 (6H, s).

Workup

  1. extractionthe mixture was extracted with CH2Cl2 (200 mL)
  2. dry with materialThe organic phase was dried (Na2SO4)
  3. concentrationconcentrated
  4. customThe residue was purified by flash chromatography (silica gel/100:0 to 0:100 hexanes-ethyl acetate to 95:5 CH2Cl2/MeOH gradient)
  5. customThe product thus obtained
  6. customwas re-purified

Sources & evidence

ORD record
ord-076bb0205f2a4b4592a7e0e0c07b1758
Source dataset
uspto-grants-2012_10
Patent number
US08278316B2

Reaction notes

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