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Bull. SOC. Chim. B e l g . vo1.94/n0 8 / 1 9 8 5
PROTON
MUR
AND
HASS
SPECTROMETRIC
STUDY
OF
TRIAZOLOBENZODIAZEPINES
M.A. Fernandez-Arciniega, L. Hernandez, A.H.R. Habeeb
Department of Analytical Chemistry, Universidad Autonoma, 28049 M d r i d , Spain
R.M. Alone0 and R.M. Jimenez
Department of Chemistry, Universidad del Pais Vasco, Bilbao, Spain
Received : 03/06/1985
- Accepted :
07/08/1965
SUM(ARY
The proton NHR and the high-resolution electron impact mass spectra of alp r a l o l m and triazolam, two new triazolo [4,3-aJ-11,41-benzodiazapines were
studied.
One o€ the most important groups of psicotropic drugs is that of benzodiazepines. Since the discovery of the potentialities of chordlazapoxide in
the clinical and pharmaceutical field, many compounds of this family have been
tested for their activity. Those studies developed drugs such as diazepam,
nitrazepam, fluorazepam, atc., that have been used succesfully for many years.
Among the newer benzodiazepine derivatives are those containing heterocyclic groups and compounds such as thienodiazepines and triazolobenzodiazepines.
Host of the analytical properties of these new compounds are atill unknown,
since most of the studies have clinical and p h A ~ c o l o g i c & l aspects. Some of
the present authors have recently undertaken the study of the spectroscopic
properties of this new group of benzodiazepine derivatives with heterocyclic
ring. fused to the diazepine ring (1-4).
The aim of this paper is to study proton NMR and mass spectrometric characteristics of triazilobenzodiazepines, a group of substances recently introduced cammercially.
We have chosen for this study two of the most important drugs of this
group, alprazolam and triazolam.
33
Alprazolam
Triazo1.m
X-H
X=Cl
CI
__
~~~
-
The chemical names and numbers in the Chemical Abstracts are
1. 8-Chloro-l-methyl-6-phenyl-4H- I1,2,41 -triazolo- [4,3-al- Il,41 -benzodiazapine;
CANr (28981-97-11 for alprazolam.
2. 8-Chloro-6-(2-chlorophenyl)-l-methyl-4H- 11,2,4J -triazolo- [4,3-aI [l,4l
benzodiazepine; CANr [28911-01-5] for triazolam.
-
-
585
-
-
APPARATUS AND REAGENTS
Proton NMR spectra were obtained in CDC13 (TMS reference standard) on a
200 MHz Bruker WE(-200-SY spectrometer at concentrations of 30 mg 0.4 ml of solvent.
High resolution electron impact mass spectra were obtained on a Kratos
MS 80 mass spectrometer with a coupled data system DS-55. ThB ionization voltage was 70 eV and the acceleration voltage 4000 V. The sunple was introduced
in the solid state and the temperature of the ion source and the sample probe
for triazolam.
were respectively 200 and 300'C for alprazolam and 250 and 350'C
Perfluorokerosene was used for providing reference masses.
RESULTS AND DISCUSSION
The 'H NMR spectra of alprazolam and triazolam are simple And present
three types of signals :
1. The M
e singlets appearing respectively at 2.65 p p and at 2.63 p p €or alprazolam and triazolam.
2. An AE system due to the methylene grouping of the benzodiazepine system
(Table 1 ) .
TABLE 1
Parameters calculated for the AB system
Compound
A
Alprazolam
I
Triazolam
(PP)
(Ppm)
5.49
I
J
4.10
I
5.52
4.17
(HZ)
12.8
1
13.0
I
3. Multiplets in the arcaratic region 7.2 to 7.8 ppm.
The high resolution electron impact mass spectra of alprazolam and triazolam are shown in FIG. l.
The molecular ion M+=342 i s quite intense (47.48) in the mass spectrum of
triazolam. This ion undergoes three types of fragmentation :
One leading to the base peak, m/e 313, M+-29 [C15H7N4C121. This fragmentation must involve a complex process most probably due to the loss of m e t h y l
group fran the methyltriazole group after transposition of two hydrogens
from other part of the molecule yielding a very stable ion.
The second fragmentation process involves the loms of a chlorine at- M+-35
m/e 307, which appears in the spectrum with a low intensity.
The third fragmentation of the molecular ion consists in the loss of a nitrogen molecule yielding M+-28-314 [C17H12N2C121. This peak m/e 314 is also
partly f o m e d by the isotopic peak of m/e 313, but its intensity, 37.1%,
indicate8 the presence of the ion C17H12N2C12.
From the base peak m/e 313 no logical mass losses are observed; this confirms a180 the high stability of thin ion.
The other two ions above mentioned can undergo different fragmentation
patterns. For example ion m/e 314 l o o m s a chlorine atom yielding m/e 279
[C,7H,2#2Cll and the ion m/o 307 undergoes two fragmentations : one with the
loss of N2 (m/e 279) and the second of acetonitrile (m/e 266; C1SHgN3Cl).
-
506
-
3
8'9"''
w
0
IJ
u
806F
g
082
L92-
0
5'71
6C2
-
2
s
m
N
74oz
LLl
i
a
Q:
-
507
-
The ion m/e 238, w i t h a composition C15HgNCl in formed then by the lone of acetonitrile from ion m/e 279 and from a Ion8 of a nitrogen molecule from ion m/e
266.
The ion m/e 238 is the second in intennity (92.3%), and it undergoe8 succesnive losnen that yield the most important peak8 of the low mass region of
tha 8pectrum, 0.9. m/e 203 (m/e 238-Cl; C15XgN) and m/e 177 (m/e 238-C1,-HCtCHi
C13H7U)
From ion m/e 177 peaks m/e 102 (m/e 177-C6B3; C7H4N) and m/e 163 (m/e 177NZ; C13H7) are formed. Succen8lve losnen of acetylene from thle ion yield the
peaks m/e 131 (CllH5) and m/e 111 (CgH3).
Ion m/e 75 (C6H3) is alno quite intense.
Similar fragmentation patterns are obnerved in the case of alprazolam,
where the molecular ion forms the ba8e peak of the npectrum, while the [M-291’
peak prenentn an intensity of 89.19.
In alprazolam a fourth fragmentation from the molecular ion i8 obnerved,
the lorn of acetonitrile to yield m/e 267 IC15H10N3ClI. This ion undergoen a
further fragmentation to yield m/e 239 of composition Cl5HlONCl that by l08E of
a chlorine atom yields m/e 204, the third ion in intensity of the spectrum, a
77.21.
If we consider the analogous fragmentation procens in triazolam the loss
of acetonitrile from the molecular ion would give m/e 301 that in not observed,
but the nuccesnive losnen of N2 and C1 from it would glve ions m/e 273 and m/e
238 which are both obnerved.
In alprazolam the peaks m/e 75 and m/e 77 of composition CsXj and C6H5
renpectively are also quite intenne.
The fragmentation procenmen for alprazolam can then be summarized according to ncheme.
An the conclu8ionn we can summarize the mass spectrometric bahaviour of
alprazolam and triazolam in the three following pQints :
1. Lon8 of 29 mass units (-CH2CH3) from the molecular ion.
2. The nuccessive losses of 35 (-Cl), 28 (-N2) and 41 (-CH3QJ) in different
order. produce the most important ion. of the high mass region of the spectra.
3. In the low masn region of the spectra several losses of acetylene (-C2H2)
are noticed.
1
-
588
-
C15H8N4C1
*-CH 3CH2
-CH2CN
17 H 1jNqC1
M+ 3 0 8
m/e 279
-C1/
1
' gH1ON jC1
m/e 2 6 7
\N2
-N2
m/e 2 7 3
- c H 3 d
m/e 239
/-Cl
\N2
C15H10N3
1
,/
'1 7H13N2
m / e 2515H10?;
245
-C1
m/e 204
'lSHgN
.
m/e 203
-C6H3
C7HqN
m/e
102
-N
C13H7N
C13H17
m/e 177
m/e 1 6 3
1
-C2H2
c1 l H 5
m/e 1 3 7
1
-C2H2
C9H3
m / e 111
The a u t h o r s thank Upjohn L a b o r a t o r i e s f o r k i n d l y providing t h e drugs used
i n t h i s work and to t h e Department of Chemistry of t h e U n i v e r s i t y o f Technology
of Loughborough, England, f o r t h e f a c i l i t i e s provided f o r t h e r e a l i z a t i o n of
t h i s work.
R.M.A. and A.H.R.H.
thank t h e P a t r o n a t o de la Universidad do1 Pais Vasco
and t h e M i n i s t e r y of Education of I r a k r e s p e c t i v e l y for t h e award o f a r e s e a r c h
grant.
REFERENCES
Rosas J. and
57-65, 1 9 8 4
CA-100-145065t.
2. Fernandez-Arciniega M.A., Hernandez L.
365-370, 1 9 8 4
CA-101-21632%.
3. F e r n h d e z - A r c i n i e g a M.A., H e r n h d e z L.
275-279, 1 9 8 4
CA-102-50778e.
4. Fernandez-hrciniega H.A., Rooas J. and
124-130
1985
CA-102-225958t.
1. Fernbndez-Arciniega M.A.,
,
-
589
Hernandez L . ,
2,
P rat. 2,
Farmaco Ed. P r a t .
and Fogg A.G.,
Farrnaco Ed.
and Fogg A.G.,
Bull. Chim. Farm.
Hernandez L . ,
-
FarMCO Ed. P r a t .
123,
40,
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