Reaction #6660

Reaction equation

(−)-tramadol

potassium hydride

thiophenol

→

O-desmethyl tramadol

Solvents

diethylene glycol

Diethylene glycol

diethylene glycol

Conditions

Workup

1. 1
   Temperaturebeing maintained at <50° C
2. 2
   OtherThe final reaction mixture
3. 3
   Temperaturewas heated slowly
4. 4
   Temperatureto reflux for 45 minutes
5. 5
   TemperatureThe mixture was cooled
6. 6
   Otherquenched into water
7. 7
   Extractionthe mixture was extracted with ethyl ether
8. 8
   Extractionthe resulting mixture was extracted 5 more times with methylene chloride
9. 9
   OtherThe extract was dried
10. 10
    Otherthe methylene chloride was evaporated

Procedure

First, O-desmethyl tramadol was prepared as set forth hereinafter. Diethylene glycol (125 mL) was added with cooling to potassium hydride (9.5 g) with the temperature being maintained at <50° C. To the solution was added thiophenol (10 mL) dissolved in diethylene glycol (25 mL), and then (−)-tramadol as the free base (9.3 g) in diethylene glycol (50 mL) was added. The final reaction mixture was heated slowly to reflux for 45 minutes. The mixture was cooled and then quenched into water. The pH was adjusted to about 3, and the mixture was extracted with ethyl ether. The pH was readjusted to about 8 and the resulting mixture was extracted 5 more times with methylene chloride. The extract was dried and the methylene chloride was evaporated to yield 4.6 g of the title compound as an oil. The oil was distilled (Kugelrohr), dissolved in tetrahydrofuran, treated with an ethanol/HCl solution to give 2.3 g of the salt. The salt was recrystallized from ethanol/ethyl ether and dried to yield 1.80 g of the salt of the (−) enantiomer of O-desmethyl tramadol (mp. 242°-3° C.), [α]D25=−32.9 (C=1, EtOH).

Source