TRAMADOL, EP1077923

TRAMADOL

http://www.google.com/patents/EP1077923B1?cl=en

Neile A. Grayson, Robert E. Halvachs, Esa T. Jarvi
Applicant	Mallinckrodt Inc.

Example 2

Synthesis of Tramadol in the Presence of the Additive 1-methylimidazole

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  The Mannich reaction was run to give Mannich hydrochloride in water. This was adjusted to pH 10.8 and extracted with toluene and then dried with magnesium sulfate. A 200 mL solution containing 98 g of the Mannich base B in toluene was thus obtained.
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  To 24 g of magnesium turnings under 425 mL of dry THF was added 177 g of meta-bromoanisole at such a rate as to keep the reaction at reflux. After the addition, reflux was continued for one hour. At a temperature of 60°C, 77 g of 1-methylimidazole was added. A precipitate formed. The mixture was stirred until all of the precipitate dissolved.
  
  The temperature was allowed to fall to 28°C, and then the solution of Mannich base B in toluene (above) was added over 15 min, while a temperature rise to 60°C was observed. During 2 hours, the reaction mixture was stirred and allowed to cool to room temperature. The mixture was cooled to 15°C and 420 mL of 4 M ammonium chloride in water was slowly added, keeping the temperature under 30°C. To the mixture was added 350 mL of water.
  
  The mixture was cooled while 215 mL of concentrated hydrochloric acid was added, giving a pH of 1.0. The top, organic layer was separated and discarded. The aqueous layer was washed with 150 mL toluene and the toluene discarded. The aqueous mixture was cooled in an ice bath and taken to pH 9.5 with 355 mL of concentrated ammonium hydroxide. The mixture was extracted with 140 mL of toluene.
  
  The two phase mixture was filtered before separation to remove insolubles. The aqueous layer was extracted with a second 140 mL of toluene, and the toluene extracts were combined. Small amounts of toluene were added for transfer. Approximately 90 mL of toluene was distilled out to remove water. The toluene solution was assayed to show there is 106 g of a mixture of trans/cis isomers of C there, in a 90.3/9.7 ratio (HPLC).
  
  A simple assay of the solution is to remove solvent from a few milliliters of sample by rotary evaporation followed by drying in high vacuum. The solution can be used as such in Example 8 type experiments, or concentrated further. An additional extraction of the original aqueous layer with toluene gave 5.4 g more of the desired product.