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

HRID 1261724Notes

Reaction equation

HRID 1261724 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

5% Palladium on carbon (14.21 g, 50% wet, 3.339 mmol, Aldrich 330116) was placed 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). 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) was dissolved in hot THF (360 mL), allowed to cool, added to the reaction mixture, and rinsed the residual amount of 20 with another portion of THF (124 mL). The bottle was placed on a Parr shaker and saturated with H2. After adding 45 psi H2, the bottle was shaken until consumption of 20 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. The reaction was repeated 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 the residual amount of 20 with another portion of THF (124 mL)
  4. additionAfter adding 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

Sources & evidence

ORD record
ord-5e240b1ec07a4558af42823e9bcd50e3
Source dataset
uspto-grants-2013_06
Patent number
US08471014B2

Reaction notes

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