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

HRID 1404527Notes

Reaction equation

HRID 1404527 reaction equation
Br[C:2]1[CH:8]=[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[C:5]([NH2:6])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.O1CCOCC1.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+]>CCOC(C)=O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:6][C:5]1[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)=[CH:8][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+:14]([O-:16])=[O:15]

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 312751,4-DioxaneHCID 665203402-[5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-olHCID 681084754-Bromo-2-nitro-6-tetrahydrofuran-2-yl-aniline

Product 1

HCID 681081992-[5-(4-Amino-3-nitro-5-tetrahydrofuran-2-yl-phenyl)pyrimidin-2-yl]propan-2-olYield 78.8%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

4-Bromo-2-nitro-6-tetrahydrofuran-2-yl-aniline (6a) (40.40 g, 92%, 129.5 mmol), 1,4-dioxane (260 mL, Sigma-Aldrich 360481), 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (7) (41.05 g, 155.4 mmol), and aqueous 2.7 M Na2CO3 (143.9 mL, 388.5 mmol) were mixed. A stream of nitrogen was bubbled through the stirring mixture for 1 hr, followed by addition of tetrakis(triphenylphosphine)palladium (0) (7.48 g, 6.47 mmol, Strem 462150). The reaction mixture was stirred at reflux for 2 hrs (HPLC showed complete reaction), allowed to cool, and diluted with EtOAc. The mixture was washed with water, saturated aqueous NH4Cl, and brine, dried over MgSO4, and filtered through a short plug of Florisil® eluting with EtOAc. The filtrate was concentrated under reduced pressure giving dark brown oil. The oil was dissolved in CH2Cl2 and eluted through a short plug of silica gel with CH2Cl2 and then EtOAc. The desired fraction was concentrated on a rotary evaporator until a precipitate formed giving thick brown slurry, which was triturated with MTBE. The solid was collected by filtration, washed with MTBE, and dried under high vacuum giving (8) as a yellow solid (35.14 g, 99+% HPLC purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 345.00 (2.69 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. The filtrate was concentrated and purified by ISCO silica gel chromatography eluting with 0 to 80% EtOAc/hexane giving a second crop of product (8) as an amber solid (4.46 g, 88% overall yield; 88% HPLC purity).

Workup

  1. customA stream of nitrogen was bubbled through the stirring mixture for 1 hr
  2. temperatureat reflux for 2 hrs
  3. custom(HPLC showed complete reaction)
  4. temperatureto cool
  5. washThe mixture was washed with water, saturated aqueous NH4Cl, and brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered through a short plug of Florisil®
  8. washeluting with EtOAc
  9. concentrationThe filtrate was concentrated under reduced pressure
  10. customgiving dark brown oil
  11. washeluted through a short plug of silica gel with CH2Cl2
  12. concentrationThe desired fraction was concentrated on a rotary evaporator until a precipitate
  13. customformed
  14. customgiving thick brown slurry, which
  15. customwas triturated with MTBE
  16. filtrationThe solid was collected by filtration
  17. washwashed with MTBE
  18. customdried under high vacuum

Sources & evidence

ORD record
ord-c96bb4c83f6b48949b6adfe89bfa3027
Source dataset
uspto-grants-2014_12
Patent number
US08912326B2

Reaction notes

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