Introduction
Pentazocine, sold under the brand name Talwin among others, is a painkiller used to treat moderate to severe pain. It is believed to work by activating (agonizing) κ-opioid receptors (KOR) and μ-opioid receptors (MOR). As such, it is called an opioid, as it delivers its effects on pain by interacting with the opioid receptors. Chemically, it is classed as a benzomorphan, and it comes in two enantiomers, which are molecules that are exact (non-superimposable) mirror images of one another. It was patented in 1960 and approved for medical use in 1964. Usually, in its oral formulations, it is combined with naloxone to prevent people from crushing the tablets, dissolving them in a solvent (like water) and injecting them for a high (as orally administered naloxone produces no opioid-negating effects, whereas intravenous or intramuscular administration does).
Equipment and glassware:
- 2 L and 500 mL round bottom flasks (RBF);
- Magnetic stirrer with a heater;
- Glass rod and spatula;
- Retort stand and clamp for securing apparatus;
- Laboratory scale (0.1 — 200 g is suitable);
- Reflux condenser;
- Buchner flask and funnel (Schott filter may be used instead of Buchner funnel);
- 1 L Separatory funnel;
- Rotovap machine;
- Vacuum source;
- Pasteur pipette;
- Water bath;
- 1 L x 1, 500 mL x 1, 250 mL x2, 100 mL x2 Beakers.
Reagents:
- 42.2 g 2-Phenylchloroethane (1);
- 35.7 g of 3,4-lutidine (2);
- 36.3 g p-Methoxybenzyl magnesium chloride (4);
- 6.0 g of 1-bromo-3-methyl-2-butene (7);
- 14 g Ammonium chloride (NH4Cl);
- 200 mL Acetone;
- 1.5 L Diethyl ether (Et2O);
- ~2 L Distilled water;
- ~300 mL Ethanole (EtOH);
- 3.9 g Sodium borohydride (NaBH4);
- 17.5 g Phosphoric acid 85% (H3PO4);
- ~50 g Sodium hydroxide;
- 9.1 g Oxalic acid;
- 145 mL Acetic acid (AcOH);
- 285 mL Hydrobromic acid 62% (HBr);
- 800 mL Isopropyl alcohol (IPA; i-PrOH);
- 5.0 g Sodium bicarbonate (NaHCO3);
- 125 mL Dimethylfomamide (DMF);
- 5 mL Hydrochloric acid (HCl) (25 mL aq. Solution);
- ~50 mL Ammonium hydroxide (NH4OH).
2-Dimethylallyl-5,9-dimethyl-2′-hydroxybenzomorphan:
Boiling Point: 403,5 °C at 760 mm Hg;
Melting Point: 145.4-147.2°C;
Molecular Weight: 285.42 g/mole;
Density: 1.0±0.1 g/mL;
CAS Number: 359-83-1.
Procedure
1-Benzyl-3,4-dimethylpyridinium chloride (3)A solution of 42.2 g of 2-phenylchloroethane (1) and 35.7 g of 3,4-lutidine (2) in 100 mL of acetone was allowed to stand overnight at room temperature in a 500 mL round bottom flask (RBF). The product (3), obtained in 81-89 % yield in two crops, m.p. 196-197°С.
1-Benzyl-2-(p-methoxybenzyl)-3,4-dimethy-1,2,5,6-tetrahydropyridine (5)
The Grignard reagent from 36.3 g of p-methoxybenzyl chloride (4) (using 3 L of Et2O/mole to reduce coupling) in 600 mL was added to 32.8 g of (3) in Et2O in 2 L RBF. The mixture was stirred and refluxed for 1.5 h with reflux condenser and poured into a solution of NH4Cl 14 g in H2O. Crude bianisyl was removed by filtration, the Et2O layer separated and washed with H2O, and the dihydropyridine isolated as a crude residue (57.5 g) by removal of the Et2O. This was reduced in EtOH with 3.9 g of NaBH4 in H2O. The reaction mixture was stirred overnight at room temperature and the EtOH then removed in vacuo. The aqueous phase was extracted with Et2O and the latter extracted in several portions with a total of 17.5 g of 85% H3PO4 in 400 mL of H2O. Addition of excess 35% aqueous NaOH to the acid extracts, extraction of the resultant oil into Et2O, drying, filtration, and concentration afforded 32.5 g of crude base. This was added to 9.1 g of oxalic acid in 100 mL of acetone to precipitate 31.2 g of (5) oxalate, m.p. 153-158°С.
The Grignard reagent from 36.3 g of p-methoxybenzyl chloride (4) (using 3 L of Et2O/mole to reduce coupling) in 600 mL was added to 32.8 g of (3) in Et2O in 2 L RBF. The mixture was stirred and refluxed for 1.5 h with reflux condenser and poured into a solution of NH4Cl 14 g in H2O. Crude bianisyl was removed by filtration, the Et2O layer separated and washed with H2O, and the dihydropyridine isolated as a crude residue (57.5 g) by removal of the Et2O. This was reduced in EtOH with 3.9 g of NaBH4 in H2O. The reaction mixture was stirred overnight at room temperature and the EtOH then removed in vacuo. The aqueous phase was extracted with Et2O and the latter extracted in several portions with a total of 17.5 g of 85% H3PO4 in 400 mL of H2O. Addition of excess 35% aqueous NaOH to the acid extracts, extraction of the resultant oil into Et2O, drying, filtration, and concentration afforded 32.5 g of crude base. This was added to 9.1 g of oxalic acid in 100 mL of acetone to precipitate 31.2 g of (5) oxalate, m.p. 153-158°С.
5,9-dimethyl-2'-hydroxy-6,7-benzomorphan (6)
A mixture of 53.8 g of crude (5) oxalate, 145 mL of AcOH, and 285 mL of 62% HBr was refluxed for 22 h in 2 L RBF, concentrated in vacuo, and diluted with 800 mL of i-PrOH. The slurry was stirred, concentrated to about 250 mL, cooled, and filtered. The product was taken up in EtOH and precipitated with about an equal volume of Et2O to give 23.7 g of (5) as the hydrobromide, m.p. 259-262°С.
A mixture of 53.8 g of crude (5) oxalate, 145 mL of AcOH, and 285 mL of 62% HBr was refluxed for 22 h in 2 L RBF, concentrated in vacuo, and diluted with 800 mL of i-PrOH. The slurry was stirred, concentrated to about 250 mL, cooled, and filtered. The product was taken up in EtOH and precipitated with about an equal volume of Et2O to give 23.7 g of (5) as the hydrobromide, m.p. 259-262°С.
2-Dimethylallyl-5,9-dimethyl-2′-hydroxybenzomorphan (Pentazocine) (8)
A stirred mixture of 9.7 g. of 5,9-dimethyl-2'-hydroxy-6,7-benzomorphan (6), 6.0 g of 1-bromo-3-methyl-2-butene (7), 5.0 g of sodium bicarbonate, and 125 mL of dimethylfomamide (DMF) was refluxed for 4.5 h in 500 mL RBF with reflux condenser. The reaction mixture was filtered, and the filter cake washed with ethanol. The solvent was removed in vacuo, and the product was dissolved in ether and filtered from a small amount of insoluble material. The ether layer was extracted with 5 ml of hydrochloric acid in 20 mL of water. Addition of dilute ammonium hydroxide to the aqueous phase precipitated 10.6 g of crude product (8), m.p. 128-139°С. Two recrystallizations from aqueous methanol gave 8.2 g, m.p. 145-148°С. A second experiment on twice this scale gave 18.2 g of recrystallized material.
A stirred mixture of 9.7 g. of 5,9-dimethyl-2'-hydroxy-6,7-benzomorphan (6), 6.0 g of 1-bromo-3-methyl-2-butene (7), 5.0 g of sodium bicarbonate, and 125 mL of dimethylfomamide (DMF) was refluxed for 4.5 h in 500 mL RBF with reflux condenser. The reaction mixture was filtered, and the filter cake washed with ethanol. The solvent was removed in vacuo, and the product was dissolved in ether and filtered from a small amount of insoluble material. The ether layer was extracted with 5 ml of hydrochloric acid in 20 mL of water. Addition of dilute ammonium hydroxide to the aqueous phase precipitated 10.6 g of crude product (8), m.p. 128-139°С. Two recrystallizations from aqueous methanol gave 8.2 g, m.p. 145-148°С. A second experiment on twice this scale gave 18.2 g of recrystallized material.
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