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

HRID 705557Notes

Reaction equation

HRID 705557 reaction equation
[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:13]1[N:18]=[C:17]([NH2:19])[C:16]([F:20])=[CH:15][N:14]=1>O1CCOCC1>[F:20][C:16]1[C:17]([NH2:19])=[N:18][C:13]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[N:14][CH:15]=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 2-Chloro-5-fluoropyrimidin-4-amine* (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.

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-934a1378151442d3a749451caec7c3ca
Source dataset
uspto-grants-2015_11
Patent number
US09174970B2

Reaction notes

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