Resolution of N-methylamphetamine enantiomers with tartaric acid derivatives by supercritical fluid extraction
Ildiko Kmecz, Bela Simandi, Edit Szekely and Elemer Fogassy
Tet. Asy., 2004, 15(12), 1841-1845
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Abstract: The resolution of N-methylamphetamine (MA) was carried out with the resolution agents O,O'-dibenzoyl-(2R,3R)-tartaric acid monohydrate (DBTA) and O,O'-di-p-toluoyl-(2R,3R)-tartaric acid (DPTTA). After partial diastereomeric salt formation, the unreacted enantiomers were extracted by supercritical fluid extraction (SFE). The effects of resolution agent molar ratio to the racemic mixture (mr), extraction pressure (P) and temperature (T ) on the resolution efficiency were studied. The best chiral separation was obtained at a quarter of an equivalent resolution agent molar ratio for both resolution agents. Extraction conditions [pressure (100–200 bar), temperature (33–63 °C)] did not influence the resolution efficiency, which makes the enantiomer separation robust. In one extraction step, both enantiomers can be produced with high enantiomeric excess (ee) and remarkable yield (Y ). Using DBTA as a resolution agent eeE = 83%, YE = 45% for the extract and eeR = 82%, YR = 42% for the raffinate were obtained.
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4. Experimental
4.1. Materials
Racemic N-methylamphetamine was prepared by Chinoin Pharmaceutical Ltd (Budapest). Resolution agents (O,O'-dibenzoyl-(2R,3R)-tartaric acid monohydrate = DBTA, O,O'-di-p-toluoyl-(2R,3R)-tartaric acid = DPTTA) were purchased from Merck Ltd (Budapest).
Other analytical grade reagents were obtained from Reanal Ltd (Budapest).The used CO2 was 99.5% (w/w) pure and supplied by Messer Griesheim Hungaria Ltd, (Budapest).
4.2. General methods
Enantiomeric excess values of the samples were determined by optical rotatory measurements by Perkin Elmer 241 polarimeter according to prior calibration.
The specific rotation of the optically pure (R)-N-methylamphetamine was alphaD20 = -18.9 (c 0.1, 1M HCl).19
4.3. Resolution of N-methylamphetamine with O,O'-di-ptoluoyl-(2R,3R)-tartaric acid (DPTTA)
rac-MA (1.50 g, 10.1 mmol) and 0.97 g (2.52 mmol) DPTTA (mr = 0.25) were dissolved in 40 mL methanol after which 2.0 g Perfil 100TM was added to the solution. The solvent was evaporated in vacuum (T = 40 °C, P = 20 kPa) and the sample dried at room temperature for 1 h. The solid sample was put into the extractor vessel and extracted with supercritical carbon dioxide at 150 bar 48 °C. The extract was then collected in the separator {(S)-(+)-MA, 0.72 g, YE = 48.0%, alphaD20 = +13.1 (c 0.1, 1M HCl), eeE = 69%}.
The raffinate was suspended in 15 mL 2M NaOH and 20 mL CH2Cl2 and stirred for 5 min. After filtering the support, the organic and aqueous phases were separated. The aqueous phase was extracted with 2 x 20 mL CH2Cl2. The collected organic phases were washed with 10 mL water and dried over Na2SO4. The solvent was evaporated in vacuum to give {(R)-(-)-MA, 0.58 g, YR = 38.8%, alphaD20 = -14.0 (c 0.1, 1M HCl), eeR = 74%}.
4.4. Resolution of N-methylamphetamine with O,O'-dibenzoyl-(2R,3R)-tartaric acid (DBTA)
rac-MA (1.50 g, 10.1 mmol) and 0.94 g (2.52 mmol) DBTA were dissolved in 40 mL methanol and 2.0 g Perfil 100TM then added to the solution. The solvent was evaporated in vacuum (T = 40 °C, P = 20 kPa) and the sample dried at room temperature for 1 h. The solid sample was transferred into the extractor vessel and extracted with supercritical carbon dioxide at 150 bar 48 °C. The extract was collected in the separator {(S)-(+)-MA, 0.68 g, YE = 45.3%, alphaD20 = +16.3 (c 0.1, 1M HCl), eeE = 86%}.
The raffinate was suspended in 15 mL 2M NaOH and 20 mL CH2Cl2 and stirred for 5 min. After filtering the support, the organic and aqueous phases were separated. The aqueous phase was extracted with 2 x 20 mL CH2Cl2. The collected organic phase was washed with 10 mL water and dried over Na2SO4. The solvent was evaporated in vacuum to give {(R)-(-)-MA, 0.63 g, YR = 41.9%, alphaD20 = -15.6 (c 0.1, 1M HCl), eeR = 82%}.
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References
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19. Kozma, D.; Madarasz, Z.; Acs, M.; Fogassy, E. Tetrahedron: Asymmetry 1994, 5, 193-194