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Determination of the Enantiomeric Purity of Methadone Using the Chiral NMR Shift Reagent Euhfc3.

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31 7/84
Determination of the Enantiomeric Purity
653
Arch. Pharm. (Weinheim) 317, 653-655 (1984)
Determination of the Enantiomeric Purity of Methadone Using
the Chiral NMR Shift Reagent Eu(hfc),
Bestimmung der enantiomeren Reinheit von Methadon mit den chiralen NMR
Verschiebungsreagens E ~ ( h f c ) ~
Nadir Biiyiiktimkin
Faculty of Pharmacy, University of Istanbul, Istanbul, Turkey
Eingegangen am 20. M a n 1984
Methadone is a stronger analgesicthan morphine and also can be given orally. In equal quantities the
depressive effect on the respiration center is lower and the side effects are rare”. The analgesic
activities of the enantiomeric forms are quantitatively different. In mice R-methadone is 1.85 to 1.95
times as active as the racemate and 11 to 13 times as active as S-methadone. The R enantiomer is
1.3-1.5 times as toxic as the racemate”.
The use of chiral lanthanide NMR shift reagents is a convenient and quick method to
differentiate and to assay chiral compounds3). In this work the shift reagent tris[3(heptafluoro-l-hydroxybutylidene)-(+)-camphorato]europium(III) (Eu(hfc),) was used
to identify and estimate methadone enantiomers.
pprn(6)lO
9
E
7
6
5
L
3
2
1
Fig. 1: ‘H-NMRSpectrum of methadone in CDCI,
0
(6 (ppm); TMS = 0)
In the NMR spectrum of methadone (fig. 1)with the continued addition of Eu(hfc),, the
proton singlet at 2.2 ppm associated with -N(CH,), protons was quickly shifted downfield
and separated distinctly in two singlets, each one corresponding to an enantiomer. The
best molar ratio of reagent to substrate (r/s) was found to be 0.14 : 1. The effect of the
europium shift reagent on the NMR spectrum of racemic methadone is illustrated in
fig. 2.
Further addition of the reagent shifted the peak signals rapidly downfield and the shift
differences between enantiomericpeak signals were greater. Beyond an rls value of 0.25 : 1
the peak broadening tended to collapse the signals completely.
036.5-6233184/0707-0653 S 02.5010
0 Verlag Chemie GmbH, Weinheim 1984
Biiyiiktimkin
654
Arch. Pharm.
The signal corresponding to each enantiomer was equally affected by broadening. In all
cases the peak signal corresponding to the S-enantiomer was moved farthest downfield.
This assignment was based on racemic samples spiked with enantiomers.
The peak heights of the singlets associated with-N(CH,), protons were large enough to
allow the determination of one enantiomer in the presence of the other. In fig. 3 induced
shift differences of -N(CH,), proton signals by the continuous addition of Eu(hfc), are
shown.
O' :[
,
,
,
0
0.1
0.2 0.3 0.4
,
,
,
0.5 0.6
r/s
Fig.3: Induced enantiomeric shifts (Hz)of -N(CH3)2
protons versus the 11s molar ratio
The peaks corresponding to the other protons were only shifted and showed marked
enhancement of resolution, no enantiomeric shifts were observed.
With the described method an enantiomeric impurity of 5 % can be successfully
detected. The peak height or the peak area ratios of enantiomers were equal to the
enantiomeric ratio.
In conclusion Eu(hfc), can be used to identify and to estimate methadone enantiomers
accurately in the presence of each other. The method utilizes low-frequency NMR and
requires less than 20 min. Several experimentally prepared enantiomeric mixtures were
tested. Their analyses agree very well with the actual amounts weighed.
The author thanks Prof. Dr. Dr. W. Schmuck for his encouragement in this work. The financial help
of the University of Maim is gratefully acknowledged.
Experimental Part
A 60 MHz NMR spectrometer Varian EM 360 A was used. Racemic methadone and R-methadone
were purchased as hydrochlorides. S-methadone was prepared using optically active tartaric acid.
31 7/84
Buchbesprechungen
655
Preparation of free bases
A 3 x 30 cm glass column was filled with anionic exchanger resin (OH@form). Approximately 0.25
mmol salt were dissolved in methanol, transferred to the column and eluted with 750 ml
methanoUethanol(1 : 1). The eluate was distilled at room temp. i. vac. The base was dissolved in 0.6
ml CDC13. For each experiment freshly prepared free bases were used.
Procedure
The CDC13 solution of free base was quantitatively transferred to an NMR tube. Then the shift
reagent was added sequentially in 5 mg increments. An NMR spectrum was taken after each
addition. To avoid any error, each sample was measured and integrated.
-
References
1 G. Erhard and H. Ruschig, Arzneimittel, Entwicklung, Wirkung, Darstellung, Vol. 1, p. 93,
Verlag Chemie, Weinheim 1972.
2 0.Schaumann, Arzneim. Forsch. 4, 115 (1954).
3 G. R. Sullivan, Chiral Lanthanide Shift Reagents, Top. Stereochem. 10, 287 (1978).
[KPh 3071
Buchbesprechungen
Arzneistoffproduktion durch Mikroorgnnismen- Grundlagen, Moglichkeiten und Grenzen - von
E. Sprecher, 11Abb., 12Tab., 111S.,PreisDM28,00(furBezieherdesDAZDM22,40),Deutscher
Apotheker Verlag, Stuttgart 1983.
Das in der Reihe ,,Paperback DAZ' erschienene Buch ist eine aktualisierte und etwas erweiterte
Fassung einer Artikelserie zum gleichen Thema. Der Autor behandelt das aktuelle Gebiet der
Arzneistoffproduktion durch Mikroorganismen unter biologischen und biotechnologischen
Aspekten und bringt insbesondere die physiologischen und genetischen Grundlagen mit Anwendungsbeispielen, wobei auch die Wirtschaftlichkeit der Verfahren mit im Blickfeld steht.
In den Kapiteln werden besprochen: Die Produktion einzelner Verbindungen des Grundstoffwechsels mit den Hauptbeispielen Glutaminsaure und Citronensaure, von Vitaminen und Enzymen;
dabei werden vor allem die biochemischen Wege, die Ausschaltung von Regulationsmechanismen
und die physiologischen Moglichkeiten zur Verbesserung der Ausbeuten dargestellt. Hauptbeispiel
fur die Sekundiirstoffproduktionsind die Antibiotica, besonders die p-Lactame, Anwendungsgebiet
verbesserter screening-Methoden und moderner Genetik (auch Protoplastenverschmehng).
Mutterkornalkaloide, Enzyminhibitoren, Polysaccharide, Impfstoffe sowie mikrobielle Stoffumwandlungen sind weitere kurzgefaate Themen. Das Schluf3kapitel handelt von zukunftsweisenden
Methoden wie Gentransfer, Genmahipulation und Gentechnik, mit denen bereits Anfangserfolgezur
bakteriellen Produktion von Insulin und Somatostatin erreicht sind.
Das Buch vermittelt wertvolle Informationen uber neue Entwicklungen in der pharmazeutischen
Mikrobiologie und fiihrt dank der Beschrinkung auf Schwerpunkte in kurz gefal3ter Form den
modernen Stand biologischer Methoden vor Augen. Die zahlreichen Literaturzitate am Schluf3jedes
Kapitels vermitteln den Zugang zur weiterfiihrenden Literatur wie zu Originalarbeiten. Das Buch ist
fur Pharmazeuten und Pharmaziestudenten, fur Chemiker, Mikrobiologen und Biotechnologen eine
empfehlenswerte aktuelle Lekture.
B. Wolters, Braunschweig
[B 601
0 Verlag Chemie GmbH, Weinheim 1984
0365-6233/84/0707-0655 $02.50/0
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chiral, using, enantiomers, euhfc3, nmr, reagents, determination, purity, shifr, methadone
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