Trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)benzoyl]-naphthalen-2-yl ester → [2-(4-Fluoro-benzyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone

HRID 1243898Notes

Reaction equation

HRID 1243898 reaction equation
[Cl-].[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Zn+])=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([C:23](=[O:39])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:26][CH:25]=1)=[C:18](OS(C(F)(F)F)(=O)=O)[CH:17]=[CH:16]2>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C1COCC1.CN1C(=O)CCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH3:11])[CH:14]=3)[C:19]=2[C:23]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:26][CH:25]=2)=[O:39])=[CH:5][CH:4]=1

Participants

7

Reactant 2

HCID 11685250Trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)benzoyl]-naphthalen-2-yl esterHCID 178505764HCID 178505764, compound

Product 1

HCID 10481006[2-(4-Fluoro-benzyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanoneYield 78%

Reagents, catalysts & solvents 4

HCID 67553Tetrabutylammonium IodideCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalystHCID 22156051tetrahydrofuran N-methylpyrrolidinoneSolvent

Procedure

Add 4-fluorobenzylzinc chloride (4 mL of 0.5 M/THF) to a stirred solution of trifluoro-methanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (525 mg), Pd(dba)2 (68 mg), dppf (66 mg) and Bu4NI (1.1 g) in THF/NMP (2 mL/1.5 mL) at room temperature. Heat the mixture to reflux for 2 h and quench with water. Dilute the mixture with CH2Cl2 and wash with water and brine, dry over MgSO4, filter and concentrate. Load the crude product on an SCX cartridge, wash with MeOH and elute the product with 2M NH3/MeOH. Purify the product by flash chromatography (0–5% (2M NH3 in MeOH/CH2Cl2) to afford [2-(4-fluoro-benzyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (380 mg, 78%)

Workup

  1. temperatureHeat the mixture
  2. temperatureto reflux for 2 h
  3. customquench with water
  4. additionDilute the mixture with CH2Cl2
  5. washwash with water and brine
  6. dry with materialdry over MgSO4
  7. filtrationfilter
  8. concentrationconcentrate
  9. washLoad the crude product on an SCX cartridge, wash with MeOH
  10. washelute the product with 2M NH3/MeOH
  11. customPurify the product by flash chromatography (0–5% (2M NH3 in MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-2d5e7b27f2e94b53a9fa0fd7dd229beb
Source dataset
uspto-grants-2006_10
Patent number
US07119206B2

Reaction notes

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