1-[2-(4-Bromophenoxy)ethyl]piperidine → (+)-1-[3-Hydroxy-6-[4-(2-piperidin-1-yl-ethoxy)phenyl]-6h-benzo[c]chromen-8-yl]-ethanone

HRID 1359148Notes

Reaction equation

HRID 1359148 reaction equation
Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.C[O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]3[CH:38]=[CH:37][C:36]([C:39]4([CH3:44])OCC[O:40]4)=[CH:35][C:29]=3[C:30](=O)[O:31]2)=[CH:26][CH:25]=1.[Li]>C1COCC1.O>[OH:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]3[CH:38]=[CH:37][C:36]([C:39](=[O:40])[CH3:44])=[CH:35][C:29]=3[CH:30]([C:2]3[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)=[CH:4][CH:3]=3)[O:31]2)=[CH:26][CH:25]=1

Participants

7

Reactant 4

HCID 8671951-[2-(4-Bromophenoxy)ethyl]piperidine2×HCID 3028194LithiumHCID 113244043-Methoxy-8-(2-methyl-[1,3]-dioxolan-2-yl)-benzo[c]chromen-6-oneHCID 178418339Butyllithium

Product 1

HCID 11374158(+)-1-[3-Hydroxy-6-[4-(2-piperidin-1-yl-ethoxy)phenyl]-6h-benzo[c]chromen-8-yl]-ethanoneYield 48%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

1-[2-(4-bromo-phenoxy)-ethyl]-piperidine (0.76 g, 2.7 mmol) from Step F was dissolved in THF (15 ml) under Ar and cooled to −78° C. n-Butyl lithium (10.0 M, 0.26 ml, 2.6 mmol) was added and the mixture was stirred at −78° C. for 1 hour. The compound from Step E (1.11 g, 3.56 mmol) was dissolved in THF (35 ml) under Ar and cooled to −78° C. to which the freshly prepared lithium salt of 1-(2-(4-bromo-phenoxy)-ethyl)-piperidine was transferred via a cannula. The reaction was stirred for 2 h. Water (150 ml) was added and the reaction extracted three times with ethyl acetate (150 ml). After removing the solvent the crude product was chromatographed on silica gel with 7% CH3OH/CH2Cl2 to yield 0.56 g (48%) of the title compound. 1H-NMR (400 MHz, CDCl3) δH 1.44 (2H, m, NCH2CH2CH2), 1.59 (4H, m, NCH2CH2CH2) 1.61 (3H, s, CH3), 2.25 (4H, m, NCH2CH2CH2), 2.83 (2H, m, NCH2CH2O), 3.78 (2H, m, OCH2), 3.85 (3H, s, OCH3), 4.01 (2H, m, OCH2), 4.18 (2H, m, NCH2CH2O), 6.69 (1H, s, ArH), 6.73 (1H, d, ArH), 6.96 (2H, d, ArH), 7.17 (1H, s, ArH), 7.56 (1H, m, ArH), 7.60 (2H, d, ArH), 7.76 (2H, m, ArH).

Workup

  1. additionwas added
  2. stirringThe reaction was stirred for 2 h
  3. extractionthe reaction extracted three times with ethyl acetate (150 ml)
  4. customAfter removing the solvent the crude product
  5. customwas chromatographed on silica gel with 7% CH3OH/CH2Cl2

Sources & evidence

ORD record
ord-12f7047f8ecf414fa7f70b8e77c55f5a
Source dataset
uspto-grants-2003_07
Patent number
US06599921B2

Reaction notes

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