Sodium Carbonate → 2-[5-(4-Amino-3-nitro-5-tetrahydrofuran-2-yl-phenyl)pyrimidin-2-yl]propan-2-ol

HRID 1404530Notes

Reaction equation

HRID 1404530 reaction equation
Br[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)[C:5]([NH:13]C(=O)C(F)(F)F)=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][C:34]([C:37]([OH:40])([CH3:39])[CH3:38])=[N:35][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>CCOC(C)=O.O.ClCCl.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:13][C:5]1[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)=[CH:7][C:2]([C:31]2[CH:32]=[N:33][C:34]([C:37]([OH:40])([CH3:39])[CH3:38])=[N:35][CH:36]=2)=[CH:3][C:4]=1[N+:20]([O-:22])=[O:21]

Participants

8

Reactant 4

HCID 10340Sodium Carbonate2×HCID 312751,4-DioxaneHCID 665203402-[5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-olHCID 71551840N-(4-bromo-2-nitro-6-tetrahydrofuran-2-yl-phenyl)-2,2,2-trifluoro-acetamide

Product 1

HCID 681081992-[5-(4-Amino-3-nitro-5-tetrahydrofuran-2-yl-phenyl)pyrimidin-2-yl]propan-2-ol

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

N-(4-Bromo-2-nitro-6-tetrahydrofuran-2-yl-phenyl)-2,2,2-trifluoro-acetamide (6) (19.00 g, 49.59 mmol), 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (7) (14.41 g, 54.55 mmol), aqueous 2.7 M sodium carbonate (73.48 mL, 198.4 mmol), and 1,4-dioxane (190 mL, Sigma-Aldrich 360481) were mixed. A stream of nitrogen was bubbled through the stirring mixture for 40 minutes, followed by addition of 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium dichloromethane adduct (2.025 g, 2.480 mmol, Strem 460450). The reaction mixture was stirred at reflux under N2 for 7 hrs, added another 50 mL of saturated aqueous sodium carbonate, and refluxed for another 16 hrs. The reaction mixture was allowed to cool, then diluted with EtOAc (500 mL) and water (200 mL). The layers were separated and the aqueous phase extracted with EtOAc (200 mL). The combined organic phase was washed with water (500 mL), brine (500 mL), dried over Na2SO4, filtered through a Florisil® plug, and concentrated on a rotary evaporator to give crude (8) as an orange oil. Purified by ISCO silica gel chromatography eluting with 20-90% EtOAc/hexane to give (8) as an orange solid (15.00 g, 81-88% purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 345.35 (2.68 min). 1H NMR (300 MHz, CDCl3) δ 8.88 (s, 2H), 8.36 (d, J=2.2 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H), 7.09 (s, 2H), 4.92 (t, J=7.2 Hz, 1H), 4.62 (s, 1H), 4.20-4.11 (m, 1H), 4.03-3.94 (m, 1H), 2.39-2.26 (m, 1H), 2.23-2.08 (m, 3H), 1.64 (s, 6H) ppm.

Workup

  1. customA stream of nitrogen was bubbled through the stirring mixture for 40 minutes
  2. temperatureat reflux under N2 for 7 hrs
  3. temperaturerefluxed for another 16 hrs
  4. temperatureto cool
  5. customThe layers were separated
  6. extractionthe aqueous phase extracted with EtOAc (200 mL)
  7. washThe combined organic phase was washed with water (500 mL), brine (500 mL)
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered through a Florisil® plug
  10. concentrationconcentrated on a rotary evaporator

Sources & evidence

ORD record
ord-276a49384ffc4f308767cc6071bddde5
Source dataset
uspto-grants-2014_12
Patent number
US08912326B2

Reaction notes

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