Benzonitrile, 3-(bromomethyl)- → 3-[3-(4-Pyrrolidin-1-ylmethyl-phenyl)-cyclobutylmethoxymethyl]-benzonitrile

HRID 1241508Notes

Reaction equation

HRID 1241508 reaction equation
[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:16][CH:15]([CH2:17][OH:18])[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>O1CCCC1>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:14][CH:15]([CH2:17][O:18][CH2:20][C:21]4[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=4)[C:24]#[N:25])[CH2:16]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

4

Reactant 2

HCID 97249Benzonitrile, 3-(bromomethyl)-HCID 21934866[3-(4-Pyrrolidin-1-ylmethyl-phenyl)-cyclobutyl]-methanol

Product 1

HCID 219348423-[3-(4-Pyrrolidin-1-ylmethyl-phenyl)-cyclobutylmethoxymethyl]-benzonitrileYield 40.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
40 °C

Procedure

To a stirring solution of [3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutyl]-methanol (50.0 mg, 0.20 mmol) prepared above (Step F) in 3 mL of tetrahydrofuran was added a solution of KotBu (0.42 mL, 0.41 mmol, 1M THF). After 30 minutes 3-(bromomethyl)-benzonitrile (42.0 mg, 0.21 mmol), in 1 mL of THF was added and then the reaction was heated to 40° C. (oil bath). After 3 hours the reaction was quenched with water and diluted with EtOAc. The layers were separated and the organic layer was dried over MgSO4, filtered through a fitted funnel and concentrated under reduced pressure. This material was purified by flash chromatography using a 4 g ISCO column, eluting with a gradient of 2%, 4%, 8% MeOH/CH2Cl2 w/0.1% NH4OH. The product containing fractions were collected and concentrated to give the title compound (29.0 mg, 39% yield) as a colorless oil and a mixture of cis:trans isomers.

Workup

  1. customAfter 3 hours the reaction was quenched with water
  2. additiondiluted with EtOAc
  3. customThe layers were separated
  4. dry with materialthe organic layer was dried over MgSO4
  5. filtrationfiltered through a fitted funnel
  6. concentrationconcentrated under reduced pressure
  7. customThis material was purified by flash chromatography
  8. washeluting with a gradient of 2%, 4%, 8% MeOH/CH2Cl2
  9. additionThe product containing fractions
  10. customwere collected
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-cde90cc9d98440fea7ec58e3ca8d3a7b
Source dataset
uspto-grants-2006_10
Patent number
US07115600B2

Reaction notes

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