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Determination of the Enantiomeric Purity of Levamisole and Dexamisole Using a Lanthanide Shift Reagent.

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Buyiiktimkin und Schunack
1042
Arch. Pharm.
Kurzmitteilungen
Arch. Pharm. (Weinheim) 316, 1042-1045 (1983)
Determination of the Enantiomeric Purity of Levamisole and
Dexamisole Using a Lanthanide Shift Reagent
Beslimmung der enantiomeren Reinheit von Levamisol Md DexPmisol mil ehem LanthanidenShiftrengens
Nadir Biiyiiktimkin* und Walter Schunack
Institut fiir Pharmazie der Johannes Gutenberg-Universitat, Saarstrak 21, D-6500 Maim 1
Eingegangen am 19.Juli 1983
The determination of the enantiomeric purity is very important especially when the
enantiomers have qualitatively and quantitatively different pharmacological activities.
The racemic tetramisoleis widely used as an anthelminthic. Levamisole, the S-(-)-isomer,
is claimed to be more effective as an anthelminthic in man and to cause fewer
side-effects','). Dexamisole, the R-( +)-isomer, is an antidepressant?. Tetramisole and
levamisole both, are immuno~timulants~).
The use of chiral lanthanide NMR shift reagents is a convenient and quick method to
differentiate and to assay chiral compoundss). In this work the shift reagent tris[3(heptafluoro-l-hydroxybutyliden)-(+)-camphorato]europium(III) (Eu(hfc),) was utilized to identify and estimate tetramisole enantiomers.
2
i
7
6
5
6
3
2
1
Oppm
KF!aa
Fii.1:'H-NMR Spectrum of tetramisole in CDCI, (6 (ppm); TMS = 0)
The NMR spectral shifts of each proton signal accompanying incremental rises in shift reagent
Selected spectra of the
concentration were plotted against the molar ratio of reagent to substrate (h).
effect of the europium shift reagent on the NMR spectrum of tetramisole are illustrated in fig. 2.
r n m ~ 3 / ~ 3 / i 2 1 2 - 1 s~ m.wm
2
0 Verlag Chemie GmbH, Weinbeim 1983
Determination of Enantiomeric Purity by Shift Reagent
316183
18 16
jKPh1
1L
12
10
8
6
4
2
1043
0 ppm
Fig. 2: A) ‘H-NMR-Spectrumof tetramisolein the presence of Eu(hfc), at a reagenusubstrateratio of
0.4 : 1.
B) A mixture of levamisole and dexamisole 9 : 1 at the same reagenusubstrate ratio.
The utility of the method is demonstrated by the marked enhancement of resolution in
heterocyclic and aromatic region and by the induced enantiomeric shifts of different
protons. In lower rls values (0.28 : 1) the triplet at 5,4 ppm due to chiral center proton was
completelyseparated in two distinct triplets. Continued addition of the reagent shifted the
signal rapidly downfield. This suggests that the adjacent nitrogen atom is probably the
pseudocontact point between substrate and reagent. The maximum resolution of the
signals occurred at a rls value of 0.4 : 1. Further addition of shift reagent caused a greater
resolution of the multiplet groups and facilitated the assignment of the peak signals. The
nonequivalent C-5 protons located in the multiplet at 6 = 3.3 ppm were shifted downfield
and completely separated above a rls value of 0.8 : 1. The C-2’ and C-6’ protons of the
phenyl ring were also shifted downfield forming two doublets at 6 = 10.3 pprn each
corresponding to one enantiomer.
In all cases the peaks corresponding to the R-enantiomers were moved farthest
downfield. This assignment was based on racemic samples spiked with enantiomers. The
signals corresponding to each enantiomer were equally affected by peak broadening. The
addition of different quantities of lanthanide shift reagent causes dramatic shift
differences. At rls values greater than 0.95 : 1the peaks correspondingto the asymmetrical
center proton overlap.
The peak broadening with imidazole ring protons was not convenient for the assay of
enantiomers, although an identification was possible. The peak heights of the doublets
associated with C-2’ and C-6’ protons of phenyl ring were great enough to allow the
determination of one enantiomer at the presence of the other. In fig. 3 the shifts of some
signals caused by the continuous addition of Eu(hfc), are shown.
According to these results it may be assumed that a second point of pseudocontact of
reagent and substrate is the N-4atom, thus facilitatingthe resolution of imidazoleprotons.
The protons of the thiazole part of the ring system formed a broad multiplet and could not
be resolved under experimental conditions. With the described method an enantiomeric
Buyuktimkin und Schunack
1044
Arch. Pharm.
nz 900
800
700
500
LOO
1
30 1,
,
200
0
,
0.2 0.4 0.6
kmm
,
0.8 1.0
.
1.2
~
mol shiftr.
rnd substr.
Fig.3: Induced chemical shifts (Hz)of some signals of tetramisole versus the rls molar ratio
impurity of 8 % can be detected, using a 60 MHz NMR spectrometer. In all cases the peak
height ratios of the enantiomers were equal to the enantiomeric ratio.
In conclusion, Eu(hfc), can be used to identify and to estimate tetramisole enantiomers
in the presence of each other. The method utilizes low-frequency N M R and requires less
than 30 min. Several experimentally prepared enantiomeric mixtures were tested. Their
analyses agree very well with the actual amounts weighed in.
We thank the Verband der ChemischenIndustrie, Fonds der ChemischenIndustrie, and the Deutsche
Forschungsgemeinschafl who supported this work by grants.
Experimental Part
A 60 MHz NMR spectrometer Varian EM 360 A was used. Tetramisole and levamisole were
purchased as hydrochlorides. Dexamisole was prepared according to6).
Preparation of free bases
A 3 x 30 cm glass column was filled with anionic exchanger resin (OHeform). Approximately 0.25
mmol salt were dissolved in methanol, transferred to the column and eluted with 750 ml
methanoYethanol(1: 1). The eluate was distillated at room temp. i. vac. The base was dissolvedin 0.6
ml CDCl,. For each experiment freshly prepared free bases were used.
Procedure
The CDCI, 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 twice.
316183
Gehaltsbestimmung des Nikotinsaurechlorids
1045
References
A. H.M.Raeymaekers, L.F. C. Roevens and P. A. J. Janssen, Tetrahedron Lett. 1967, 1467.
H.van den Bossche and P. A. J. Janssen, Biochem. Phannacol. 18, 35 (1969).
E. Przegalinski, K.Bigajska and J. Siwanowicz, Pol. J. Pharmacol. Pharm. 32, 21 (1980).
J. Brugmans, V. Schuermans, W. De Cock, D.Thienpont, P. Janssen, H.Verhaegen, L. van
Nimmen, A. C. Louwagie and E. Stevens, Life Sci. 13, 1499 (1973).
5 G.R.Sullivan, Chiral Lanthanide Shift Reagents, Top. Stereochem. 10, 287 (1978).
6 E. Fogassy, M. Acs,J. Fehneri and Z. Aracs, Period. Polytech. Chem. Eng. 20, 247 (1976).
1
2
3
4
[KPh 2761
Arch. Pharm. (Weinheim) 316, 1045-1048 (1983)
Gehaltsbestimmung des Nikotinsaurechlorids
Detennioatioo of q.ridiaed-carbonyl Cbloride
Herbert Oelschlager* und Dietrich Rothley
Institut fiir Pharmazeutische Chemie der Johann Wolfgang Goethe-Universitat,
Georg-Voigt-Str. 14,6OOOFrankfurt a. M.
Eingegangen am 25. Juli 1983
Nikotinsaurechlorid (1)wird iiberwiegend durch Einwirkung von Phosphorpentachlorid oder Thionylchlorid auf Alkalisalze der Nikotinsaure unter variierten Bedingungen
hergestellt und anschlieI3end durch Vakuumdestillation gereinigt. Diese unbequemen
Verfahren liefern oft unbefriedigende Ausbeuten'). Eine Verbesserung stellt die Methode
von Wingfield et a1.l) dar, bei der eine Suspension von Kaliumnikotinat in Benzol mit
Oxalylchlorid reagiert. Das entstehende gemischte Anhydrid zerfiillt zu 1 unter
Entwicklung von CO, und CO. Die benzolische LGsung ist lagerfahig. Die Ausbeute nach
Fraktionierung wird mit 85 % d. Th. und besser angegeben. Das bei 90" (13 Torr)siedende
1 bildet ein Hydrochlorid vom Schmp. 156".
1wird u.a. auch fir die Synthese des Lipidsenkers Etofibrat*) benotigt, die nach der
Deutschen Patentschrift 1941217 vom 14.8.19692) in der Weise erfolgt, daD 2.B. 1 mol
2-(p-Chlorphenoxy)-2-methylpropionsauremit 2 mol Ethylenglykol in Anwesenheit von
geringen Mengen 85proz. Phosphorsaure und p-Toluolsulfonsaure nahezu quantitativ
zum Halbester umgesetzt werden, der dann z.B. in THF mit 1zum Etofibrat-HC1 vom
Schmp. 100" in guter Ausbeute weiter reagiert. Infolge der bekannten Hydrolyseempfindlichkeit von 1,das bereits durch die Luftfeuchtigkeit sehr schnell zu Nikotinsaure-HC1
(2) verseift wird, ist die Reinheit von 1f i r die Ausbeute an Etofibrat und dessen moghche
*)
Hersteller in der BRD: M e n + Co.GmbH & Co.,Frankfurt a. M., Warenzeichen: Lipo-Men@
und L i p - M e n @retard.
0365423YBu1212-1045 S 02.MIO
0 Vcrlag Chcmie GmbH, Weinheim 1983
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using, enantiomers, dexamisole, reagents, determination, purity, lanthanides, levamisole, shifr
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