Lithium diisopropylamide → HCID 178455347, compound

HRID 2235305Notes

Reaction equation

HRID 2235305 reaction equation
[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.Br[CH2:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:39]>C1COCC1>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[CH2:31][CH:15]1[CH2:16][CH2:17][CH2:18][N:13]([C@H:10]2[CH2:9][CH2:8][C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:21])[CH3:20])[CH2:12][CH2:11]2)[C:14]1=[O:19]

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 27736252-Chloro-6-fluorobenzyl bromideHCID 178455338HCID 178455338, compound

Product 1

HCID 178455347HCID 178455347, compoundYield 45.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

Dissolve trans-1-(4-[tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-piperidin-2-one (0.3 g, 0.96 mmol) in anhydrous THF (6 mL) under nitrogen, cool to −78° C. and add LDA (2M solution in THF) (0.72 mL, 1.44 mmol) dropwise. Stir the reaction mixture for 5 minutes and add 2-bromomethyl-1-chloro-3-fluoro-benzene (0.3 g, 1.44 mmol) in anhydrous THF (2 mL) dropwise. Stir the reaction mixture at −78° C. for 3 hours, slowly warm to room temperature, quench with saturated aqueous NH4Cl (5 mL) and extract with DCM (3×10 mL). Dry the organic layer over Na2SO4, remove the solvent and purify the residue by chromatography over silica gel (eluting with 0 to 20% EtOAc in hexane) to obtain trans-3-(-2-chloro-6-fluoro-benzyl)-1-(4-[tert-butyl-dimethyl-silanyloxy]-cyclohexyl)-piperidin-2-one as a white solid (0.2 g). Dissolve the trans-3-(-2-chloro-6-fluoro-benzyl)-1-(4-[tert-butyl-dimethyl-silanyloxy]-cyclohexyl)-piperedin-2-one in methanol containing concentrated hydrochloric acid (5% v/v) and heat at 40° C. for 1 hour. Evaporate the solvent, dissolve the residue in DCM (10 mL) and wash with saturated aqueous NaHCO3 (5 mL). Dry the organic layer over anhydrous Na2SO4, remove the solvent and purify the residue by chromatography over silica gel (eluting with 0 to 50% EtOAc in hexane) to obtain the title compound as a clear oil (110 mg, 34%): MS (ES+) m/z=340 (M+H)+.

Workup

  1. stirringStir the reaction mixture at −78° C. for 3 hours
  2. temperatureslowly warm to room temperature
  3. customquench with saturated aqueous NH4Cl (5 mL)
  4. extractionextract with DCM (3×10 mL)
  5. dry with materialDry the organic layer over Na2SO4
  6. customremove the solvent
  7. custompurify the residue by chromatography over silica gel (eluting with 0 to 20% EtOAc in hexane)

Sources & evidence

ORD record
ord-7cde30b03a9041c99355267b86097f13
Source dataset
uspto-grants-2010_05
Patent number
US07713979B2

Reaction notes

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