Tetrahydrofuran → 4-[2-(3,5-Difluoro-benzyloxy)-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester

HRID 2417370Notes

Reaction equation

HRID 2417370 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][OH:6].O1CCCC1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][N:34]=[C:33](Cl)[N:32]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([O:6][CH2:5][C:4]3[CH:3]=[C:2]([F:1])[CH:9]=[C:8]([F:10])[CH:7]=3)[N:32]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 24758Sodium hydrideHCID 5227213,5-Difluorobenzyl alcoholHCID 11197306Tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate

Product 1

HCID 112005874-[2-(3,5-Difluoro-benzyloxy)-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl esterYield 89.2%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

3,5-Difluorobenzyl alcohol (227.5 μL, 2.01 mmol) was dissolved into 15 mL of anhydrous tetrahydrofuran and treated with sodium hydride (80.3 mg, 60% dispersion in mineral oil, 2.01 mmol). This was stirred under nitrogen for 15 minutes at ambient temperature, then the reaction was treated with 4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (I-1a) (500 mg, 1.67 mmol) in one portion. The resultant mixture was refluxed under nitrogen for 4 hours. After cooling to room temperature, the reaction was poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (20 mL), then dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 1:1 ethyl acetate:hexanes) to afford 605.2 mg of the title product (I-1b).

Workup

  1. temperatureAfter cooling to room temperature
  2. extractionextracted with ethyl acetate (2×50 mL)
  3. washThe combined organic extracts were washed with brine (20 mL)
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by column chromatography (silica gel, 1:1 ethyl acetate:hexanes)

Sources & evidence

ORD record
ord-a62267dacb564bd58575fb50763030a5
Source dataset
uspto-grants-2004_11
Patent number
US06825198B2

Reaction notes

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