Methanol → 2-(5-(4,5-Diamino-2-fluoro-3-(tetrahydrofuran-2-yl)phenyl)pyrimidin-2-yl)propan-2-ol

HRID 1474055Notes

Reaction equation

HRID 1474055 reaction equation
CO.CCN(CC)CC.[NH2:10][C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][C:14]([C:20]2[CH:21]=[N:22][C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[N:24][CH:25]=2)=[C:13]([F:30])[C:12]=1[CH:31]1[CH2:35][CH2:34][CH2:33][O:32]1>[Pd].C1COCC1>[NH2:10][C:11]1[C:16]([NH2:17])=[CH:15][C:14]([C:20]2[CH:21]=[N:22][C:23]([C:26]([OH:29])([CH3:27])[CH3:28])=[N:24][CH:25]=2)=[C:13]([F:30])[C:12]=1[CH:31]1[CH2:35][CH2:34][CH2:33][O:32]1

Participants

6

Reactant 3

HCID 887MethanolHCID 8471TriethylamineHCID 866681032-{5-[4-Amino-2-fluoro-5-nitro-3-(oxolan-2-yl)phenyl]pyrimidin-2-yl}propan-2-ol

Product 1

HCID 866679372-(5-(4,5-Diamino-2-fluoro-3-(tetrahydrofuran-2-yl)phenyl)pyrimidin-2-yl)propan-2-olYield 402.8%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 8028TetrahydrofuranSolvent

Procedure

Placed 5% palladium on carbon (14.21 g, 50% wet, 3.339 mmol, Aldrich 330116) in a Parr bottle under nitrogen, followed by MeOH (242 mL, JT-Baker 909333) and NEt3 (46.54 mL, 333.9 mmol, Sigma-Aldrich 471283). Dissolved 2-[5-(4-amino-2-fluoro-5-nitro-3-tetrahydrofuran-2-yl-phenyl)pyrimidin-2-yl]propan-2-ol (20) (121.0 g, 333.9 mmol) in hot THF (360 mL), allowed to cool, added to the reaction mixture, and rinsed with another portion of THF (124 mL). Placed the vessel on a Parr shaker and saturated with H2. Added 45 psi H2 and shook until consumption was complete (HPLC and LCMS showed complete reaction). The reaction mixture was purged with nitrogen, filtered through Celite™ and rinsed with EtOAc. It was re-filtered through paper (glass microfibre) and the filtrate concentrated in vacuo. Repeated the reaction three more times on the same scale and the batches were combined giving 21 as a brown solid (447 g, 99% yield; 93% HPLC purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 333.46 (1.79 min) 1H NMR (300 MHz, CDCl3) δ 8.81 (d, J=1.4 Hz, 2H), 6.69 (d, J=7.3 Hz, 1H), 5.27-5.20 (m, 1H), 4.73 (s, 1H), 4.70 (s, 2H), 4.23-4.14 (m, 1H), 3.94-3.86 (m, 1H), 3.22 (s, 2H), 2.32-2.22 (m, 1H), 2.18-1.99 (m, 3H), 1.63 (s, 6H) ppm.

Workup

  1. temperatureto cool
  2. additionadded to the reaction mixture
  3. washrinsed with another portion of THF (124 mL)
  4. additionAdded 45 psi H2
  5. custom(HPLC and LCMS showed complete reaction)
  6. customThe reaction mixture was purged with nitrogen
  7. filtrationfiltered through Celite™
  8. washrinsed with EtOAc
  9. filtrationIt was re-filtered through paper (glass microfibre)
  10. concentrationthe filtrate concentrated in vacuo
  11. customthe reaction three more times on the same scale

Sources & evidence

ORD record
ord-ecccd2ef248d40d6a0369d216eb96fbb
Source dataset
uspto-grants-2015_04
Patent number
US09018216B2

Reaction notes

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