Synthesis of some unsymmetrical ester derivatives of γ-(4-Substituted piperazin-1-yl)-α-phenyl propanols with antispasmodic activity

Article abstract of DOI:10.1211/146080800128735539

Six new ester derivatives of γ-(4-substituted piperazinyl)-α-phenyl propanol were prepared by esterification of the γ-piperazinyl propanols. The derivatives were methyl, ethyl, phenyl and benzyl esters, and they were obtained in good yields using a solid-

Full text of DOI:10.1211/146080800128735539

Pharm. Pharmacol. Commun. 2000, 6: 471±475
Received March 27, 2000
Accepted July 10, 2000
# 2000 Pharm. Pharmacol. Commun.
Synthesis of Some Unsymmetrical Ester Derivatives of
g-(4-Substituted piperazin-1-yl)-a-phenyl propanols
with Antispasmodic Activity
P. O. OSADEBE, P. A. AKAH*, C. O. OKAFOR{ AND L. NATOVA{
Department of Pharmaceutical Chemistry, *Department of Pharmacology & Toxicology,
and {Department of Pure and Industrial Chemistry, University of Nigeria, Nsukka, Nigeria and
{Higher Institute of Chemical Technology, So®a, Bulgaria
Abstract
Six new ester derivatives of g-(4-substituted piperazinyl)-a-phenyl propanol were prepared
by esteri®cation of the g-piperazinyl propanols.
The derivatives were methyl, ethyl, phenyl and benzyl esters, and they were obtained in
good yields using a solid±liquid phase transfer catalysed esteri®cation method. The
nitrogen content of the new derivatives was also determined. Studies using isolated guinea-
pig ileum showed that the derivatives possessed varying degrees of antispasmodic activity.
Of the compounds evaluated, the ethyl ester of g-(4-benzyl piperazin-1-yl)-a-phenyl
propanol showed the greatest antispasmodic activity.
It is known that very small changes in the structure of
a given drug molecule can lead to radical changes in
its elicited biological activity (Janssen & Jageneal
1957; Daniels & Jorgensen 1977). Several groups
have reported that drugs containing the g-amino
alcohol moiety in their molecules usually possess
antispasmodic effects (Denton et al 1949a, b; Katz et
al 1954; Janssen & Jageneal 1957). Atropine, a tropic
acid ester of tropine (g-amino alcohol), represents a
cyclic ester. Atropine possesses some antispasmodic
properties, however its usefulness is limited because
of the numerous other effects of the drug. As a result
several open chain g-amino alcohols have been syn-
thesized (Katz et al 1954; Zaugg et al 1958; Natova &
Zhelyazkov 1973). Attention has been directed
towards the piperazine derivatives (i.e. where the
amino group is a piperazine nucleus. It has been
reported that g-amino alcohols containing a piper-
azine nucleus as the amino portion retained anti-
spasmodic properties (Cymmerman & Harrison
1956; Zaugg et al 1958; Natova & Zhelyazkov 1973;
Osadebe 1992). We therefore proposed to synthesize
a series of open chain g-piperazinyl propanols esters
in which the piperazine nucleus is substituted at N4
with benzyl and benzhydryl groups (R1), and R2
represents methyl, ethyl, phenyl and benzyl groups
(Figure 1). Six new ester derivatives of g-piperazinyl
propanol were prepared using standard esteri®cation
procedures (Szeja 1980) and also a phase-transfer
catalysed esteri®cation procedure (Dehmlow &
Dehmlow, 1980; Osadebe 1993) (Figure 2). The
antispasmodic activity of the series was evaluated
using isolated guinea-pig ileum.
Materials and Methods
Melting points were determined on a Thiele's
apparatus or Gallenkamp melting point apparatus,
and are uncorrected. H NMR spectra were recor-
1
ded on a Jeol YNM-C 100 spectrophotometer
(100 MHz) using CDCl3 as solvent. Chemical shifts
(d ppm) refer to tetramethylsilane which was used
as an internal standard. The samples were dried at
temperatures not greater than 60ꢀC. Elemental
analyses were carried out at the Leuven Linkage
Laboratory of the Department of Soil Science,
University of Nigeria. IR spectra were recorded as
100% thin ®lms (for oily products) or as
3 mg=300 mg concentration of the substance in KBr
(for solids). UV spectra were recorded on a Spec-
tronic 1201 (Milton Roy).
Correspondence: P. O. Osadebe, Department of Pharmaceu-
tical Chemistry, University of Nigeria, Nsukka, Nigeria.

472
P. O. OSADEBE ET AL
had been made alkaline (pH 10) with 5 M NaOH,
was added in portions with stirring and the mixture
was boiled for 2 h. The ethanol was distilled off, the
residue diluted with 80±90 mL water, extracted
with benzene or chloroform and dried with anhy-
drous Na2SO4 for 2 days. After distilling off the
solvent, the crude base of the piperazinyl alcohol
was obtained. Yield ˆ 14Á0 g (98Á7%); mp of the
base ˆ 75ꢀC (from petroleum ether); lit. mp ˆ 65±
75ꢀC (Zikolova & Ninov 1972); mp of the oxalate
salt ˆ 225±226ꢀC; Rf ˆ 0Á59 (butanol 100%).
Figure 1. Structure of proposed open chain g-piperazinyl
propanols esters. The piperazine nucleus is substituted at N4
with benzyl and benzhydryl groups (R1), and R2 represents
methyl, ethyl, phenyl and benzyl groups.
Preparation of g-(4-benzhydryl piperazin-1-yl)-a-
phenyl propanol. The preparation of g-(4-diphenyl-
methyl piperazinyl)a-phenyl propanol followed the
same procedure as above. After decanting and
distilling the solvent, the raw base of the piperazi-
nyl alcohol was obtained. Yield ˆ 13Á8 g (99%);
mp ˆ 149±151ꢀC (from ethanol); lit. mp ˆ 148±
1
150ꢀC (Valenta et al 1981). H NMR (d ppm):
7Á28(M, 15H, 3Ph); 4Á84 (t, 1H, CHO); 4Á18(s, 1H
1
Ph2CH); 2Á50 (M, 10H, NCH2). IR (cm ): 711,
750±775 (C6H5), 3200(OH) 1135 (C OH, KBr
®lm) 2760, 2810(NH2) 1465, 1500, 1600, 2975,
3025, 3075 (Ar); lmax ˆ 220 (in octanol); Rf ˆ 0Á51
(benzene±ethylacetate, 7 : 3)
Preparation of g-(4-benzyl piperazin-1-yl)-a-phenyl
propanol acetate. A mixture of the alcohol (20 g,
0Á047 mol), the phase-transfer catalyst, benzyl-
triethyl ammonium chloride (2Á14 g, 0Á01 mol),
and anhydrous sodium carbonate (15 g) in 35±
40 mL dichloromethane was treated with a solution
of acetyl chloride (4Á89 mL, 0Á069 mol) in 5 mL of
the same solvent for 15±20 min. The inorganic
salts were then ®ltered off and the residue washed
3- or 4- times with 25 mL water, and dried over
anhydrous sodium sulphate for 48 h. The solvent
was then evaporated. The dry oily base of the ester
was obtained (yield 91Á5%). The dihydrochloride
(SHCl) salt of the ester was obtained by redissol-
ving the oily base in chloroform or ether and
treating with excess of a saturated solution of
dry hydrogen chloride gas in ether. The yield
of the SHCl salt was 91%; mp ˆ 206±207ꢀC
(dec) (from isopropanol); Rf ˆ 0Á31 (silica gel;
benzene±ethylacetate, 7 : 3). Calculated for
C22H30H2O2Cl2: N, 6Á59; found: N, 6Á50. 1H
NMR (d ppm): 7Á30 (s, 10H, ph); 5Á76 (t, 1H,
HCO); 3Á44 (s, 2H, PhCH2) 1Á90 (s, 3H, CH3);
Figure 2. Schematic representation of the phase-transfer
catalysed esteri®cation procedure. BTAC, benzyltriethyl
ammonium chloride; RCOCl, acyl chloride.
Synthesis
Preparation of g-(4-benzyl piperazin-1-yl)-a-phenyl
propanol. The dihydrochloride salt of 1-benzyl-
4(b-benzoylethyl) piperazine (Natova & Zhelyakov
1973; Osadebe 1993; Valenta et al 1981) (13Á9 g,
0Á045 mol), was dissolved in ethanol and made
alkaline with 20±25 mL 5 M NaOH. A solution of
0Á12 mol NaBH4 (4Á5 g) in 60±70 mL water, which
1
2Á30 (M, 12H CH2). IR (cm ): 711, 750, 775
(C6H5), 2760 2810, (NH2) 1405, 1500, 2975,
3025 3078 (Ar) 1745 (CO, ester).
Preparation of g-(4-benzyl piperazin-1-yl)-a-phenyl
propanol propanoate.
A
mixture of g-(4-

ANTISPASMODIC UNSYMMETRICAL ESTERS
473
benzyl piperazin-1-yl)-a-phenyl propanol (20 g,
0Á046 mol), benzyltriethyl ammonium chloride
(2Á14 g, 0Á01 mol) and anhydrous sodium carbonate
(15 g) in dichloromethane (35±40 mL) was treated
with a solution of propanoyl chloride (6Á82 mL,
0Á078 mol) in 5 mL of the same solvent for 15±
20 min. The mixture was boiled under re¯ux for
3Á5 h and then cooled. The inorganic salts were then
®ltered off and the residue washed with the organic
solvent. The organic layer was washed 3- or 4-
times with 25 mL water in a separatory funnel and
dried over anhydrous sodium sulphate for 48 h. The
solvent was then evaporated in-vacuo. A dry oily
base was obtained. It was redissolved in chloroform
and treated with excess of a saturated solution of
dry hydrogen chloride gas in ether to give the 2HCl
salt (yield 20Á8 g, 86%); mp ˆ 228ꢀC (dec) (from
isopropanol); Rf ˆ 0Á45 (silica gel; benzene±
ethylacetate, 7 : 3). Calculated for C23H32N2Cl2: N,
6Á38; found: N, 6Á31. 1H NMR (d ppm): 7Á28 (m, 10H,
2Ph);5Á78(t, 1H, CH-O): 3Á40(s, 2H, pHCH2) 2Á12(m,
(4-benzyl piperazin-1-yl)-a-phenyl propanol (20 g,
0Á046 mol), benzyltriethyl ammonium chloride
(2Á14 g, 0Á01 mol) and anhydrous sodium carbonate
(15 g) in chloroform (35±40 mL) was treated with
phenylacetyl chloride (10Á33 mL, 0Á078 mol) in
5 mL of the same solvent for 15±20 min. The
mixture was boiled under re¯ux for 1Á5 h and then
cooled. The inorganic salts were then ®ltered off
and the residue washed with the organic solvent.
The organic layer was washed 3 times with 25 mL
water in a separatory funnel and then dried over
anhydrous sodium sulphate for 48 h, after which the
solvent was evaporated in-vacuo. A dry oily base of
the ester was obtained which crystallized at room
temperature. Yield ˆ 25Á8 g, (98Á5%); mp ˆ 79±
80ꢀC (recrystallized from ethanol); Rf ˆ 0Á49
(chloroform, 100%). Calculated for C34H36N2O2:
1
N, 5Á50; found: N, 5Á41. H NMR (d ppm) of the
base: 7Á20(m, 10H, Ph); 5Á74(t, 1H, HC-O) 4Á12(s,
1
1H, Ph2CH) 3Á45(s, 2H, CH2CO). IR (cm ): 711,
750, 775 (C6H5), 2760, 2810 (NH2), 1465, 1500
2975, 3025, 3075 (Ar), 1745 (CO, ester).
1
14H, CH2); 1Á00 (t, 3H, CH3). IR (cm ): 711, 750,
775 (C H) 2760, 2810 (NH2) 1465, 1500, 2975, 3025,
3075 (Ar), 1745 (Co, ester).
Preparation of g-(4-benzhydryl piperazin-1-yl)-a-
phenyl propanol benzoate. Anhydrous Na2CO3
(7 g) was suspended in dry chloroform (40 mL)
and stirred well until a stable suspension formed.
The solution of the alcohol (20 g, 0Á046 mol) in
chloroform (5±6 mL) was added to the reaction
vessel and stirred for approximately 10 min, after
which a solution of benzoyl chloride (13Á4 mL,
0Á12 mol) in chloroform (8 mL) was added in por-
tions from a dropping funnel (®tted with CaCl2
tube). The mixture was boiled under re¯ux for
3Á5 h. After cooling, the inorganic salts were ®ltered
off and the solid residue washed with chloroform.
The organic layer was washed 3 times with 25 mL
water and dried over anhydrous sodium sulphate.
The sodium sulphate layer was decanted and, after
washing with more of the dry solvent, the solvent
was evaporated in-vacuo. An oily base of the ester
was obtained which solidi®ed at room temperature.
Yield ˆ 4Á6 g (97%); mp ˆ 151ꢀC (recrystallized
from acetone); Rf ˆ 0Á87 (benzene=ethylacetate).
Calculated for C33H34N2O2: N, 5Á62; found: N,
Preparation of g-(4-benzyl piperazin-1-yl)-a-phenyl
propanol benzoate. A mixture of g-(4-benzyl piper-
azin-1-yl)-a-phenyl propanol (20 g, 0Á046 mol),
benzyltriethyl ammonium chloride (2Á14 g,
0Á01 mol) in chloroform was treated with a solution
of benzoyl chloride (9Á01 mL, 0Á0669 mol) in 5 mL
of the same solvent for 20 min. The mixture was
boiled under re¯ux for 1Á5 h and then cooled. After
cooling, the inorganic salts were ®ltered off and the
residue washed with the organic solvent. The
organic layer was washed 3 times with 25 mL
water in a separatory funnel and dried over anhy-
drous sodium sulphate for 48 h. After ®ltration, the
solvent was evaporated in-vacuo. A dry oily base of
the ester was obtained. The 2HCl salt was obtained
by redissolving the oily base in ether and treating
with excess of a saturated solution of dry hydro-
gen chloride in ether. Yield ˆ 24Á0 g (76Á4%);
mp ˆ 218ꢀC (dec) (recrystallized from ethanol);
Rf ˆ 0Á72 (benzene±ethylacetate, 7 : 3). Calculated
1
5Á50. H NMR (d ppm): 8Á08 (d, 2H, Ortho H
1
for C27H32N2O2Cl2: N, 5Á75; found: N, 5Á76. H
of Ph); 7Á30(m, 18H, Ph); 2Á10(m, 12H,
5NCH2 ‡ C CH2 C); 6Á10 (t, 1H, HC O) 4Á20
NMR (d ppm) of the base: 8Á00(d, 2H, OH of Ph)
7Á24 (m, 13H, Ph); 2Á10 (m, 12H, 5NCH2 ‡
CˆCH2 C), 6Á00(t, 1H, CH O) 3Á44(s, 2H,
1
(s, 1H, Ph2CHN). IR (cm ): 711, 750, 775 (C6H5)
270, 2810 (NH2, 1465, 1500, 2975, 3025 (Ar),
1745, (CO, ester).
1
NCH2Ph). IR (cm ): 711, 750, 775, (C6H5),
2760, 2810 (NH2) 1465, 1500, 2975, 3025, 3075
(Ar), 1745 (CO, ester).
Preparation of g-(4-benzhydryl piperazin-1-yl)-a-
phenyl propanol phenylacetate. A mixture of g-
(4-benzhydryl piperazin-1-yl)-a-phenyl propanol
(20 g, 0Á046 mol), benzyltriethyl ammonium
Preparation of g-(4-benzyl piperazin-1-yl)-a-
phenyl propanol phenylacetate. A mixture of g-

474
P. O. OSADEBE ET AL
chloride (2Á14 g, 0Á01 mol) and anhydrous sodium
carbonate (15 g) in chloroform (40 mL) was treated
with a solution of phenylacetyl chloride (12Á8 g,
0Á078 mol) in 5 mL of the same solvent for 15±
20 min. The mixture was boiled under re¯ux for 2 h
and then cooled. The inorganic salts were then
®ltered off and the residue washed with organic
solvent. The organic layer was washed 3 times with
25 mL water in a separatory funnel and then dried
over anhydrous sodium sulphate for 48 h. After
®ltering and washing with dry chloroform, the
solvent was evaporated to dryness in-vacuo. A
dry oily base was obtained which crystallized
at room temperature. Yield ˆ 25Á8 g (98Á5%);
mp ˆ 79±80ꢀC (recrystallized from ethanol);
Rf ˆ 0Á49 (chloroform, 100%). Calculated for
propanol benzoate was prepared using the standard
esteri®cation procedure (without the catalyst). The
g-(4-benzyl piperazin-l-yl)-a-phenyl propanol and
g-(4-benzhydryl piperazin-l-yl)-a-phenyl propanol
used in the esteri®cation were prepared by reduc-
tion of their corresponding b-ketopiperazines
(Mannich bases) using an alcoholic solution of
NaBH4 at room temperature. The optimum dura-
tion of each experiment was determined by
removing samples from the reaction vessel and
subjecting them to routine thin-layer chromato-
graphy (Osadebe 1993). For the IR spectra of the
esters, there was a disappearance of the OH
1
absorption at 3200±3350 cm , and the emergence
of the strong carbonyl band of the esteric group at
1
1745 cm .
1
C34H36N2O2: N, 5Á50; found: N, 5Á41. H NMR
The results of the antispasmodic evaluation of the
esters, based on the inhibition of acetylcholine-
induced contractions of guinea-pig ileum (ID50)
are shown in Table 1. Compounds that were soluble
in distilled water or 0Á1 M HCl were tested quanti-
tatively. Quantitative evaluation of the two benz-
hydryl propanol esters was hindered by their
insolubility. All the esters showed an inhibitory
effect against acetylcholine-induced contractions.
Of the three esters evaluated, the most potent
antispasmodic effect was exhibited by the g-(4-
benzyl piperazin-l-yl)-a-phenyl propanol propano-
ate (ID50 ˆ 149Á42 ng). When R1 was changed
from an ethyl group to a phenyl group, there was a
sharp reduction in potency from 149Á42 to
1949Á84 ng. Replacement of the phenyl group by a
benzyl group increased antispasmodic activity
(ID50 646Á51 ng). The antispasmodic activity of the
esters may therefore be related to their polarity or
aqueous solubility since the order of polarity for the
R2 substitutent is C2H5, C6H5CH2, C6H5. These
(d ppm) of the base: 7Á20(m, 10H, Ph); 5Á74(t, 1H,
HC O) 4Á12 (s, 1H, Ph2CH) 3Á45 (s, 2H, CH2CO).
1
IR (cm ): 711, 750, 775 (C6H5), 2760, 2810
(NH2), 1465, 1500, 2975, 3025, 3075 (Ar), 1745
(CO, ester).
Antispasmodic activity
Mature guinea-pigs of either sex (350±400 g), were
purchased locally. The guinea-pigs were fasted for
24 h before the experiment and then killed by
stunning. A segment of the ileum (approx. 3 cm)
was suspended in an organ bath containing Tyrode
solution of the following composition (mM): 137
NaCl; 2Á4 KCl; 1Á8 CaCl2; 1Á0 MgCl2; 0Á2 NaHPO4;
11Á9 NaHCO3 and 5Á5 glucose. The solution was
maintained at 32ꢀC and aerated using an automatic
electric aerator. After an equilibration period of
approximately 60 min at a resting tension of 0Á5 g, a
full dose±response relationship was established for
acetylcholine. The effects of increasing concentra-
tions of each derivative on the contractions induced
by a submaximal (80%) concentration of acetyl-
8
Table 1. Inhibitory effect of some g-piperazinyl esters
against acetylcholine-induced contractions of isolated guinea-
pig ileum.
choline (1Á35 6 10 M) were investigated. The
effects were recorded on an Ugo-Basile universal
oscillograph through an isotonic transducer. The
dose that produced 50% inhibition of acetylcholine-
induced contraction (ID50) was estimated for each
derivative (Van Rossum 1949).
Compound Product
R1
R2
ID50 (ng)
Results and Discussion
1
2
3
4
5
E98 : 2HCl C6H5CH2
E99 : 2HCl C6H5CH2
E96 : 2HCl C6H5CH2
E102 : base (C6H5)2 CH C2H5
E95 : base (C6H5)2 CH C2H5CH2
C2H5
C2H5
C2H5CH2
149Á42
1947Á84
646Á51
±
The derivatives were obtained in good yields (92±
99%) by reacting g-(4-benzyl piperazin-l-yl)-a-
phenyl propanol and g-(4-benzhydryl piperazin-l-
yl) propanol, respectively, with acyl chloride in the
presence of benzyltriethyl ammonium chloride.
Only g-(4-benzhydryl piperazin-l-yl)-a-phenyl
±
ID50 is the dose that produced 50% inhibition of acetyl-
choline-induced contractions.

ANTISPASMODIC UNSYMMETRICAL ESTERS
475
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gamma-amino alcohols and amino ketones. J. Org. Chem.
19: 1225±1230
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complete inhibition at microgram concentrations.
Natova, L., Zhelyazkov, L. (1973) Preparation of secondary
g-amino alcohol with probable biological activities. God.
Vissh. Khim. Teknol. Inst. So®a 21: 203±210
Osadebe, P. O. (1992) Preparation of some piperazine series
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Pharm. Pharmacol. Sci. 22: 202±208
Acknowledgements
We are grateful to the University of Nigeria Senate
(grants no. 89=69 and 94=37) for ®nancial assis-
tance.
Osadebe, P. O. (1993) Application of phase-transfer catalysis
in the synthesis of esters of some spasmolytically active
g-piperazinyl propanols. J. Univ. Sci. Technol. Kumasi
(Ghana) 13: 45±48
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