Sodium hydride → (R)-tert-butyl 3-(6-chloropyrazin-2-yloxy)piperidine-1-carboxylate

HRID 2177657Notes

Reaction equation

HRID 2177657 reaction equation
[H-].[Na+].[OH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.[Cl:17][C:18]1[CH:23]=[N:22][CH:21]=[C:20](Cl)[N:19]=1>C1COCC1.O>[Cl:17][C:18]1[N:19]=[C:20]([O:3][C@@H:4]2[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:21]=[N:22][CH:23]=1

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 785042,6-DichloropyrazineHCID 1514398(R)-1-Boc-3-hydroxypiperidine

Product 1

HCID 57502428(R)-tert-butyl 3-(6-chloropyrazin-2-yloxy)piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
2.5 °C

Procedure

Sodium hydride (225.6 g, 5.64 mol) is dispersed into THF (3 L) and the temperature is lowered to 0-5° C. A solution of (R)-3-hydroxy-1-boc piperidine (891.6 g, 4.43 mol) in THF (3 L) is added over 1 h while maintaining the temperature between 0-5° C. The reaction is stirred for 1 h. 2,6-Dichloropyrazine (600 g, 4.03 mol) as a solution in THE (3 L) is added dropwise over 1.5 h maintaining the same temperature. The reaction is stirred for 2 h at 25-30° C., and then poured onto ice. The mixture is diluted with water and extracted with ethyl acetate. The extracts are dried over anhydrous sodium sulfate, filtered, and concentrated. The residual oil is triturated with 5% dichloromethane in hexane to give the product as a white solid. The solid is collected by filtration and dried, to give 1538 g crude material. The crude product is retriturated with 5% dichloromethane in hexanes to give a white solid in quantitative yield. ES/MS m/z 314.1 [M+H]+.

Workup

  1. customis lowered to 0-5° C
  2. temperaturemaintaining the same temperature
  3. stirringThe reaction is stirred for 2 h at 25-30° C.
  4. additionpoured onto ice
  5. extractionextracted with ethyl acetate
  6. dry with materialThe extracts are dried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residual oil is triturated with 5% dichloromethane in hexane

Sources & evidence

ORD record
ord-f8c61b842ea94157805b83a93949f3e0
Source dataset
uspto-grants-2015_06
Patent number
US09067920B2

Reaction notes

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