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Optical Resolution of Methamphetamine
by O,O'-Dibenzoyl-R,R-Tartaric Acid in
Dichloroethane-Water-Methanol Solvent System

David Kozma and Elemer Fogassy
Synthetic Communications 29(24), 4315-4319 (1999)

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A new optical resolution method was developed by the use of a two phase three component solvent system and demonstrated on the example of the resolution of the N-methyl-amphetamine with O,O'-Dibenzoyl-R,R-tartaric acid. By adding methanol as an intermediate solvent to the two phase water-dichloroethane solvent system the solubility and the optical purity of the precipitated salt can be adjusted in wide ranges. By this way a highly efficient one step resolution process can be accomplished.

One of the most important problems during the development of a new optical resolution process is the selection of the appropriate solvent1,2. Usually a more polar solvent results in a more efficient resolution3. It means that water is an ideal solvent for optical resolutions via diastereomeric salt formation, since not only this is the most polar solvent, but also cheap, readily available and non toxic. The main problem with water is that most organic compound not or hardly soluble in it. Acs et al. found4 that the use of water and a water immiscible organic solvent eliminate the solubility problem of optical resolutions, since all the reactants can be dissolved in one of the phases.

The N-methyl-amphetamine (MA) is the key intermediate of the Jumex antiparkinson agent, on an industrial scale it is resolved via its hydrogen tartrates5,6. By looking for alternative processes for the resolution of MA we tried to use the O,O'-dibenzoyl-R,R-tartaric acid (DBTA) as resolving agent. The experimental results are summarised in Table 1.

Table 1
Summary of the experimental results

40 ml
11.8 g
15 ml
60 ml
15.6 g
15 ml
60 ml
3 ml
15.3 g
15 ml
60 ml
6 ml
14.9 g
15 ml
60 ml
18.8 ml
13.1 g
15 ml
18.8 ml
13.6 g

All resolution experiments were performed by using quarter molar equivalent amounts of DBTA, since in spite of the resolution with tartaric acid, with DBTA always the neutral salt precipitated. That is advantageous from practical point of view since a quarter of molar equivalent amount of resolving agent enough for the resolution. The efficiency of the resolution7 in methanol is moderate, but in water-dichloroethane solvent mixture two times higher efficiency attainable The efficiency of this resolution was already in the range of the industrial scale resolutions., but unfortunately the 82.5% optical purity of the precipitate was not high enough for a one step process. The resulted enantiomeric mixture should be enriched by at least in one further step8. We found that if some amount of methanol is added to the system the optical purity of the precipitate increases.

Simultaneously the yield decreases, but the efficiency remains practically constant. To investigate the role of the second solvent phase, the 5th experiment was repeated without dichloroethane. The decrease in the efficiency of the resolution was caused by the decrease of the optical purity of the precipitated salt. The experiment indicates that, the water immiscible organic phase has an important role to shift the equilibrium into the thermodynamically preferred direction.

By the use of the methanol as an intermediate solvent between the two liquid phases the solubility of the precipitated salt can be adjusted in wide ranges. By the adjustment of the amount of methanol in the two immiscible solvents the MA can be resolved.


All chemicals purchased from Merck. Optical rotations measured on a Perkin Elmer 241 polarimeter.
The specific rotation of the optically pure (R)-N-methylamphetamine is [α]20D = -18.90 (c 0.1; 1 N HCl).

Optical resolution of racemic N-methyl-amphetamine with O,O'-dibenzoyl-R,R-tartaric acid

15.0 g (0.1 mol) racemic base was dissolved in the mixture of 20 ml of dichloroethane and 15 ml of water. A solution of 9.4 g (0.025 mol) O,O'-dibenzoyl-2R,3R-tartaric acid in 40 ml of dichloroethane and given amount of methanol was added to the two phase solution of the racemic base in 30 minutes at room temperature. From the stirred solution the crystallization starts in 10-15 minutes. The resulted suspension was stirred at 5C overnight, then filtered. The precipitate was washed on the filter three times with 5 ml dichloroethane 5C and dried under an infrared lamp. The precipitated salts were reacted by 30 ml 2N NaOH and extracted tree times with 25 ml of dichloromethane. After drying over MgSO4, the solvent was evaporated and the specific rotation was measured. The results are summarised in Table 1.

References and Notes

  1. Newman, P. Optical Resolution Procedures for Chemical Compounds, vols. 1-3, Optical Resolution Information Center, Manhattan College, New York, 1978-84
  2. Sheldon, R. A., Chirotechnology, Marcel Dekker Inc., New York, 1993
  3. Jacques, J., Collet, A. and Wilen, S. H. Enantiomers, Racemates and Resolutions, Wiley and Sons, New York, 1981, p. 383
  4. Acs, M., Fogassy, E. and Faigl, F., Tetrahedron 41, 2465 (1985) [ Abstract ]
  5. Fogassy, E., Acs, M., Faigl, F., Simon, K., Rohonczy, J. and Ecsery, Z., J. C. S. Perkin Trans. 2., 1881 (1986)
  6. Kozma, D., Madarasz, Z., Acs, M and Fogassy, E., Tetrahedron Asymmetry 5, 193 (1994)
  7. The efficiency (0<S<1) of the optical resolution has been defined as the product of the optical purity (0<OP<1) and the yield (0<Y<1) of the precipitated salt: S=OPxY, in Fogassy, E., Lopata, A., Faigl, F., Darvas, F., Acs, M and Tike, L. Tetrahedron Lett. 21, 647 (1980) [ Abstract ]
  8. Kozma, D. and Fogassy, E.: Enantiomer 2, 51 (1997)