Sodium hydride → 5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-amine

HRID 1500004Notes

Reaction equation

HRID 1500004 reaction equation
[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].[NH2:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=1>O1CCOCC1>[F:19][C:18]1[C:13]([NH2:12])=[N:14][C:15]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[N:16][CH:17]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 680224-Fluorobenzylic alcoholHCID 2543722-Chloro-5-fluoropyrimidin-4-amine

Product 1

HCID 578185745-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-amineYield 52%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

To a solution of 4-fluorobenzyl alcohol (2.56 g, 20.3 mmol) in 1,4-dioxane (20 mL) was added 60% NaH (0.813 g, 20.3 mmol) in several portions over a period of 10 min. To the magnetically stirred solution was added 4-amino-2-chloro-5-fluoropyrimidine* (2.00 g, 13.6 mmol) and the mixture was stirred at room temperature until gas evolution subsided. The reaction mixture was then heated in a CEM Discover microwave reactor at 120° C. for 90 min. The cooled reaction mixture was partitioned between ethyl acetate and water, the organic phase was concentrated, and the product was purified by column chromatography (hexane/ethyl acetate gradient) to yield 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-amine (1.66 g, 52% yield) as a white solid: mp 129-131° C.; 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J=2.6 Hz, 1H), 7.42 (m, 2H), 7.03 (m, 2H), 5.27 (s, 2H), 5.05 (br s, 2H); MS (ESI) m/z 238 (M+H)+. *4-Amino-2-chloro-5-fluoropyrimidine can be purchased commercially or can be prepared through known literature methods. 1. Hayashi, T.; Kawakami, T. JP Patent 2005126389 2. Durr, G. J. J. Med. Chem. 1965, 8(2), 253.

Workup

  1. temperatureThe reaction mixture was then heated in a CEM Discover microwave reactor at 120° C. for 90 min
  2. customThe cooled reaction mixture
  3. customwas partitioned between ethyl acetate and water
  4. concentrationthe organic phase was concentrated
  5. customthe product was purified by column chromatography (hexane/ethyl acetate gradient)

Sources & evidence

ORD record
ord-2d48ea80ff044d1fa47f77348bf9d7ba
Source dataset
uspto-grants-2015_12
Patent number
US09204653B2

Reaction notes

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