Sodium hydride → 4-Tert-butoxycarbonylamino-4-(4-chloro-benzyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester

HRID 2406006Notes

Reaction equation

HRID 2406006 reaction equation
[H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH2:16][OH:17])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH2:16][O:17][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][CH:29]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:5])([CH3:6])[CH3:4]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 693291-(Bromomethyl)-4-chlorobenzeneHCID 45139438Tert-butyl 4-{[(tert-butoxy)carbonyl]amino}-4-(hydroxymethyl)piperidine-1-carboxylate

Product 1

HCID 668728604-Tert-butoxycarbonylamino-4-(4-chloro-benzyloxymethyl)-piperidine-1-carboxylic acid tert-butyl esterYield 22.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

Sodium hydride (60% suspension in oil, 4.9 mg, 0.11 mmol) was added in small portions to a cooled (0° C.) solution of 4-tert-butoxycarbonylamino-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (19 mg, 0.057 mmol) in dry DMF (0.2 mL). The suspension was stirred vigorously at 0° C. for 15 min followed by addition of 4-chlorobenzyl bromide (14 mg, 0.066 mmol). After stirring for 45 min at 0° C., the reaction mixture was warmed to rt. When TLC showed complete consumption of the starting material, the reaction mixture was partioned between ethyl acetate (5 mL) and water (2 mL). The aqueous phase was further extracted with ethyl acetate (5 mL). The combined organic layers were dried (Mg2SO4), filtered and concentrated. Flash column chromatography on silica, eluting with 1% methanol in dichloromethane, gave 4-tert-butoxycarbonylamino-4-(4-chloro-benzyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (6 mg, 0.013 mmol, 22%). LC-MS (LCT2) m/z 477 [M+Na+], Rt 8.74 min.

Workup

  1. stirringAfter stirring for 45 min at 0° C.
  2. temperaturethe reaction mixture was warmed to rt
  3. customconsumption of the starting material
  4. extractionThe aqueous phase was further extracted with ethyl acetate (5 mL)
  5. dry with materialThe combined organic layers were dried (Mg2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. washFlash column chromatography on silica, eluting with 1% methanol in dichloromethane

Sources & evidence

ORD record
ord-7c73f116665c40299331ee7bf3427215
Source dataset
uspto-grants-2014_08
Patent number
US08809336B2

Reaction notes

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