3-((Benzyloxy)methyl)cyclobutanone → 3-Benzyloxymethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutanol

HRID 1241504Notes

Reaction equation

HRID 1241504 reaction equation
Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CC(O)C.C(=O)=O.C([Li])CCC.[CH2:26]([O:33][CH2:34][CH:35]1[CH2:38][C:37](=[O:39])[CH2:36]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:26]([O:33][CH2:34][CH:35]1[CH2:38][C:37]([C:2]2[CH:13]=[CH:12][C:5]([CH2:6][N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=2)([OH:39])[CH2:36]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1

Participants

6

Reactant 4

HCID 118198503-((Benzyloxy)methyl)cyclobutanoneHCID 127380041-(4-Bromobenzyl)pyrrolidineHCID 86586944Isopropanol carbon dioxideHCID 178418339Butyllithium

Product 1

HCID 112103253-Benzyloxymethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutanolYield 71%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a stirring solution of 1-(4-bromo-benzyl)-pyrrolidine (1.9 g, 7.9 mmol) in 13 mL of tetrahydrofuran at −78 C (iPrOH/dry ice) was added slowly down the side of the flask a solution of n-butyl lithium (3.2 mL, 7.9 mmol, 2.5 M in THF). After 30 minutes a precooled −78 C (iPrOH/CO2 ice) solution of 3-benzyloxymethyl-cyclobutanone (1.0 g, 5.3 mmol, in 1 mL of THF) was added via cannula down the side of the flask (wash 1 mL). The resulting solution was stirred at −78 C for 30 minutes, then quenched with a saturated solution of aqueous NH4OH and diluted with EtOAc. The layers were separated and the organic layer was dried over magnesium sulfate, filtered through a fritted funnel and then concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a Biotage column, eluting with a gradient of 2% MeOH/CH2Cl2 w/0.1% NH4OH through 30% MeOH/CH2Cl2 w/0.1% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to yield the title compound (1.3 g, 71% yield) as a colorless oil and a 3:1 mixture of cis:trans isomers.

Workup

  1. customquenched with a saturated solution of aqueous NH4OH
  2. additiondiluted with EtOAc
  3. customThe layers were separated
  4. dry with materialthe organic layer was dried over magnesium sulfate
  5. filtrationfiltered through a fritted funnel
  6. concentrationconcentrated under reduced pressure
  7. customPurification of this material
  8. washeluting with a gradient of 2% MeOH/CH2Cl2
  9. additionThe product containing fractions
  10. customwere collected
  11. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-27646548869e4f249ad241480d8a7908
Source dataset
uspto-grants-2006_10
Patent number
US07115600B2

Reaction notes

Loading…