Potassium Carbonate → 7-benzyl-3-ethyl-1-(isoxazol-5-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

HRID 2200673Notes

Reaction equation

HRID 2200673 reaction equation
[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:19][CH3:20])[C:11]=2[N:10]=[C:9]1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:34][C:35]1[O:39][N:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:34][C:35]3[O:39][N:38]=[CH:37][CH:36]=3)[C:13](=[O:18])[N:12]([CH2:19][CH3:20])[C:11]=2[N:10]=[C:9]1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:31])([F:30])[F:32])[CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 38580135-(Chloromethyl)isoxazoleHCID 904027047-benzyl-3-ethyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione2×

Product 1

HCID 904031437-benzyl-3-ethyl-1-(isoxazol-5-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dioneYield 12.6%

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 7-benzyl-3-ethyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (40 mg, 0.090 mmol, intermediate 47) in DMF (3 mL) was added 5-(chloromethyl)isoxazole (30 mg, 0.256 mmol), followed by potassium carbonate (50 mg, 0.362 mmol) and TBAI (5 mg, 0.014 mmol). The reaction was stirred at 60° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give a crude product, which was purified by preparative HPLC to give 7-benzyl-3-ethyl-1-(isoxazol-5-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (5.9 mg, 12.6% yield) as white solid. 1H-NMR (CD3OD) δ 8.33-8.32(d, 1H), 7.57-7.53(t, 1H), 7.47-7.45(d, 2H), 7.38-7.31(m, 5H), 7.25-7.23(d, 1H), 6.34-6.33(dd, 1H), 5.52(s, 2H), 5.36(s, 2H), 4.06-4.01(q, 2H), 1.27-1.24(t, 3H). LCMS retention time 3.269 min; LCMS MH+528.

Workup

  1. temperatureThe mixture was cooled
  2. custompartitioned between ethyl acetate and water
  3. washThe organic phase was washed with brine
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated
  6. customto give a crude product, which
  7. customwas purified by preparative HPLC

Sources & evidence

ORD record
ord-d3216b0d1f804fa8a9c0f4a290839641
Source dataset
uspto-grants-2016_06
Patent number
US09359359B2

Reaction notes

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