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Racemic Modification of RS-3-4-Phenyl-1-piperazinyl-12-propandiol and Melting Point Diagram.

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(R,S)-3-(CPhenyl-1-piperazinyl)-l,2-propandiol
23
Racemic Modification of (R,S)-3-(4-Phenyl-l-piperazinyl)-1,2propandiol and Melting Point Diagram
Davide Pitrk*)and Riccardo Stradi")
*) Istituto di Chimica Farmaceutica
**)
.
Istituto di Chimica Organica - Facolta di Farmacia Universith degli Studi di Milano
Wale Abruzzi, 42 - Milano 20131 - Italy
Received January 30,1989
The results of D.S.C., 1.R.- and X Ray-Diffractionstudies on (R,S)-3<4-phe-
nyl-l-piperaZinyl~l,2-pmpandiol(l)and on its S(-)enantiomer (2)are consistent with the definition of "racemic compound" for (1).The melting point
diagram has been plotted theoretically through D.S.C. data and then confirmed experimentally. In this way the calorimetricdetermindon of
tiomeric purity has a precise reference.
(R.S)J-(Cphenyl-l-piperazinyl)-l ,2-propandiol (1) is an antitussive
drug known as dropropizine'). Its recently synthesized S(-) enantiomeric
form named levodmpropizine2)(2)has been reported to display an improved ratio of antitussive versus sedative activity3'. Increased selectivity
in the pharmacological and pharmacokinetical profile could be expected
from the previous literature
using a single enantiomer.
Racemische Modiflkation von (R,S)-~(S-Phenyl-l-piperazinyl)-1,2-propandiol und sein Schmelzpunktdiagramm
Die D.S.C.7 I*R.Spekmn und die RontgendiffraktionVOn (R.S)-344phenylpipe~-l-yl>Propan-l2diol (1) und seinem S(-)-Enantiomer (2)
haben es ermiiglicht, Substanz (1) die Bezeichnung "racemische Verbindung" zuzuschreiben Besonders die Untersuchung der D.S.C hat die Erstellung des theoretischenSchlzpunktdiagramma und dessen experimentelle
Kontrolle erm6glicht, so da8 man uber einen sicheren Anhaltspunkt fiir die
kalorimetrische Bestimmung derEnantiomeren-Reinheitverfiigt
(~)-3-(4-phenyl-l-piperarinyl)-l,2-propandiol(2)
has been prepared by a
stereospecificsynthesis according to Ciani2)and after three crystallization
from ethanol it melted at 1WC.
15
[a] (tun) = -33.27 (589); -34.65 (578); -39.14 (546); -64.34(436);
-96.7 (365) (C = 1.091.0.1 N HCI)
[all5 (nm)= -26.25 (589); -27.55 (578); -31.08 (546); -50.19 (436);
-74.03 (365) (C = 1.078, CHCl3)
D.S.C.Measurement
Samples of 1-2 mg, weighed in aluminium pans. have been used, with a
scan speed of Z'C/min. Compounds 1 and 2 have been melted in vacuo in
the molar ratios 0.6, 0.7, 0.83, and 0.9. Racemization was not observed
even maintaining the samples in molten status for more than 30 min. The
results are collected in Tab. 1.
Consequently it is important to have analytical methods
for the determination of the enantiomeric purity. One of
such methods, the differential scanning calorimetry (D.S.C),
requires the knowledge of the melting point diagram of the
different mixture compositions of one enantiomer and the
racemic form.
For the determination of enantiomeric purity of levodropropizine (2) we have studied the modification of the
racemic form and we have prepared a melting point diagram.
Experimentalpart
m.p.: BUchi apparatus according to S. Tottoli. - I.R.: Perkin-Elmer spectrometer mod. 882. - D.S.C.: MettIer T.A. 3000 System. - XRay Powder
Diffraction (X.R.S): Philips Diffraction PW 1710(Tube LFF, Cu,4 KV, 40
mA). - Polarimetry: Perkin-Elmer Polarimeter 141.
Tab. 1: D.S.C. data of 1 and 2
Form
M.p.
AHf (Kj . mol-')
ASf (j . mol-')
Purity %
1
2
382.9
377
29.64
34.05
74.40
91.50
100
99.1
The knowledge of melting points and of fusion enthalpies of 1 and 2
allowed the plotting of the melting point phase diagram whose correctness
was confirmedexperimentally (Fig. 1).
In table 2 the calculated and found values of melting points for the
racemic and the enantiomericbranches are reported.
Infrared spectra
Infrared spectra of 1and 2 in Nujol are shown in Fig. 2. The spectra are
different especially in the +OH region and in the finger print region.
XRS Measurements
(RS)-3-(4-phenyl-I-liperazinyl)-l ,I-propandiol (1)has been prepared
according
- to Norren ) and was crystallized three times from ethanol; m.p.
1W C .
Arch. Pharm. (Weinheim) 323.23-25 (1990)
The spectra of 1 and 2 are also significantly different, and in particular
for values of 2 8 around 20' the S-form 2 presents peaks of high intensity
which are lacking in the racemic form 1 (Fig. 3).
OVCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1990
0365-6233/90/0101-03 $02.50/Q
24
Piu&and Suadi
Tab. 2: Calculated and found values of melting point
Molar fraction
Calculated values
tea)
1
104
0.90
0.83
0.80
0.70
0.60
0.50
100.4
97.64
96.41
-
tab)
hund values
to
XI0 3
At
Calc.-found
O
104
97.48
100.94
106.35
109.06
109.90
3.90
l.?l
1.40
_
..
100.5
97.8
-0.1
4.25
105.5
108.76
109.9
-0.85
-0.30
0
b) Calculated using
a)
by means
the simplified
of Prigogine
form
and
ofDSchrdder-VanLear
e f q equation
equation
LDropropizine
L-
_____-
__
i n
0.16
0.04
. .
3.90
5.0
-5::)
0.04
2.60
3.0
.
25.0
34.0
i*
35.0
40.0
(
5
7
50.0
55.0
----_I
60.0
.
95
-- :
0.03 .
,
,____________-_
r--
90
Fig. 3 - X-raypowder patterns of (1) and (2)
f (S/StR)
-
Fig. 1 Melting point phase diagram of 3-(4-phenyl-l-piperazinyl)-l,Zpropandiol
olooo
3000
2000
1600
1200
aon
Fig. 2 - IR spectraof (1) top and (2) bottom in Nujol
Results and discussion
The IR- and XR-spectra of the optically inactive compound 1 compared with the spectra of the enantiomere 2
show significant differences, therefore it is concluded that 1
fits the definition of "racemic compound".
This conclusion is supported by the following observations: 1 shows a melting point higher than that of 2, the SD.
lubility of 2 in ethanol is larger than that of 1, furthenno=
the melting point of a mixture of 1 with 2 is lower than the
melting point of i7).
The fusion diagram represented in Fig. 1 is characteristic
for the fundamental type assigned by Roozeboom') to
racemic compounds. The eutectic point at 98.7-C cornsponds to a molar ratio S/R of 0.83. This eutectic point is
shifted in the abscissa toward the enantiomeric form. Them
fore, the tendency for 1 to form a racemic compound is
high.
This fusion diagram permits the calorimetric determination of enantiomeric purity by direct or indirect method~~*'~).
It is worth mentioning that the indirect method can
give very precise results (* 0.1% or less) especially in the
range 99.0 to 99.9 mol%. The thermodynamic data processing gives a fusion energy AGfO = -3.07Kj: mol-' perfectly
fitting for a racemic compound.
The high purity of the enantiomer 2, determhed by calorimetric methods strengthens the value of the polarimetric
data.
References
1
2
R. Rimoldi, Le Scalpel 177.57 (1964).
R. Giani. E. Marinoni. G. Melillo, M. Borsa, and G.C. Tonon.
Ameim. Forsch. 38.1139 (1988).
Arch. Pharm. (Weinheim) 323,23-25(1990)
25
(R.S)-3-(4Phenyl-1 -piperazinyl)-1,Zpropandiol
3
4
5
S. Malandrino. G. Melillo, A. Besteai, M.Borsa, R. Guiliani, and G.C.
Tonon. A~zneii-Forsch.38,1141 (1988).
S. Pedrazzini, M. De Angelis. W. Zanaboni Muciaccia, G. Sacchi, and
A. Fordone, h e i m . Forsch.38,1130 (1988).
E.J. Ariens, "Racemates: an impediment in the use of medicins and
agrochemicals", 1st Intern. Symp. on Separation of C W molecules.
Paris, 31.5.1988.
Arch. Phann. (Weinheim)323,23-25 (1990)
H. Norren, Belg. Pat. N. 601394; C.A. 56,2460 (1 961J.
G. Hallas, Organic stereochemistry, p. 37, McGraw-Hill Publishg,
London.
8 M.W.B. Roozebmm. Z Phys. Chem. 28.494 (1 899).
9 C. Fouquey and J. Jacques, Tetrahedron 23,4009 (1 967).
10 C. Fouquey and M. Leclercq,Tetrahedron 24.5637 (1970).
6
7
[m371
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point, racemic, piperazine, melting, propandiols, diagram, phenyl, modification
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