Phenazocine (Prinadol, Narphen) synthesis


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Jul 5, 2021
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Phenazocine (brand names Prinadol, Narphen) is an opioid analgesic drug, which is related to pentazocine and has a similar profile of effects. Effects of phenazocine include analgesia and euphoria, also may include dysphoria and hallucinations at high doses, most likely due to action at κ-opioid and σ receptors. Phenazocine appears to be a much stronger analgesic with fewer side effects than pentazocine, probably due to a more favorable μ/κ binding ratio. Phenazocine is a much more potent analgesic than pentazocine and other drugs in the benzomorphan series, most likely due to the presence of an N-phenethyl substitution, which is known to boost μ-opioid activity in many classes of opioid analgesics. Consequently, phenazocine is some 4x the potency of morphine as an analgesic.
Equipment and glassware:
  • 250 and 100 mL Round bottom flask;
  • 50 mL Two necked round bottom flasks;
  • Magnetic stirrer;
  • Buchner flask and funnel (Schott filter may be used instead of Buchner funnel) 100-500 ml;
  • Glass rod and spatula;
  • Retort stand and clamp for securing apparatus;
  • Laboratory scale (0.01 — 100 g is suitable);
  • 500 mL x 1, 250 ml x2; 100 ml x2 Beakers;
  • Ice water bath;
  • Pasteur pipette;
  • Reflux condenser;
  • Separatory funnel, 500 ml;
  • Septum cap;
  • Nitrogen bubbler with ballon ~10-20 L (1 atm);
  • Laboratory grade thermometer (-20 °C to 200 °C) with three-necked flask adapter;
  • Dewar bath (for -78 deg making) and Dry ice (CO2);
  • Flash chromatography kit (column and silica gel);
  • Rotovap machine;
  • Vacuum source.


  • 3,4-lutidine (1) 5 mL, 4.7 g, 44.5 mmol;
  • Diethyl ether (Et2O) 450 mL;
  • 2-Phenylethyl bromide (2) 8.25 g, 44.5 mmol;
  • Sodium borohydride (NaBH4) 2.98 g, 80 mmol;
  • Methanol (MeOH) 100 mL;
  • Distilled water (H2O) 300 mL;
  • Sodium sulphate (Na2SO4) anhydrous ~100 g;
  • Sodium chloride ~50 g;
  • Boron trifluoride etherate (BF3*OEt2 0.35 g) 0.33 mL, 4.91 mmol;
  • sec-Butyllithium (s-BuLi) 1.8 mL, 2.6 N, 4.70 mmol;
  • p-Methoxybenzyl chloride 0.72 g, 0.62 mL, 4.7 mmol;
  • Hydrochloric acid 5% (HCl);
  • Sodium carbonate (Na2CO3);
  • Chloroform (CHCl3) 140 mL;
  • Hexane ~200 mL;
  • Ethyl acetate (EtOAc) ~200 mL;
  • Hydrobromic acid 48% (HBr) 10 mL;
  • Ammonium hydroxide (NH4OH);
  • Triethylamine ~10 ml;

Boiling Point: 461.0±45.0 °C at 760 mm Hg;
Melting Point: 181–182 °C;
Molecular Weight: 321.46 g/mole;
Density: 1.1±0.1 g/mL;
CAS Number: 127-35-5.


N-(2-Phenylethyl)-3,4-dimethyl-1,2,5,6-tetrahydropyridine (3)
To an ice cooled stirred solution of 3,4-lutidine (1) (5 mL, 4.7 g, 44.5 mmol) in dry diethyl ether (100 mL), 2-phenylethyl bromide (2) (8.25 g, 44.5 mmol) was added, and the resulting solution was stirred for 24 h at ambient temperature in 250 ml round bottom flask. The pyridinium salt that precipitated out was filtered and washed thoroughly with diethyl ether. To an ice cooled solution of this salt (10 g, 40.1 mmol) in 80% aqueous methanol (100 mL) was added sodium borohydride (2.98 g, 80 mmol) in small portions. After the completion of addition, the solution was heated under reflux for 1 hour. Metanol was removed under reduced pressure and water (50 mL) was added to the residual mass. It was extracted with diethyl ether (5 x 40 mL) and the combined organic layer was washed with brine and dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was distilled under reduced pressure to give (3) as a pale yellow liquid (6.5 g, 70 %), bp 110–115°С/4 Torr.

N-(2-Phenylethyl)-2-(4’-methoxybenzyl)-3,4-dimethyl-1,2,5,6-tetrahydropyridine (4)
Into a flame dried 50 mL two necked round bottom flasks equipped with a stir bar, septum cap and nitrogen bubbler, a solution of the amine (3) (0.5 g, 2.35 mmol) was cooled to -78°С under nitrogen atmosphere and BF3*OEt2 (0.35 g, 0.33 mL, 4.91 mmol) was added. The contents were stirred for 10 min and s-BuLi (1.8 mL, 2.6 N, 4.70 mmol) was added and stirring was continued for 30 min. The reaction mixture was quenched with p-methoxybenzyl chloride (0.72 g, 0.62 mL, 4.7 mmol). After 10 min stirring at -78°С, the temperature was allowed to rise to -30°С over a period of 30 min. The contents were then poured into diethyl ether (50 mL) and extracted with 5% HCl (4 x 10 mL). The combined acidic layer was made basic with solid Na2CO3 and extracted with chloroform (3 x 20 mL). The combined organic layer was washed with water, brine and dried over anhydrous sodium sulphate. The solvent was evaporated in vacuo and residual oil was subjected to column chromatography over silica gel. Elution with hexane-ethyl acetate (6:4) gave a-alkylated amine (3) (0.49 g, 64 %) as a viscous liquid.

(+/-)-Phenazocine (5)
Reaction of amine (4) (0.3 g, 8.9 mmol) with 48% HBr (10 mL) was heated at 135°С for 24 h in 100 mL round bottom flask. The cooled solution was diluted with water (20 mL) and made basic with ammonium hydroxide. The mixture was extracted with chloroform (4 x 20 mL) and the combined organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvent was removed in vacuo and residue was purified by column chromatography over silica gel. Elution with hexane-ethylacetate-triethylamine (60:35:5) gave (+/-)-Phenazocine (5) (0.16 g, 59 %), mp 179–181°С, lit. mp 181–182°С.
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New member
Oct 29, 2022
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This might actually be a good synth as reagent look easily sourced hmmm
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