COMPOUNDS INTERACTING WITH THE NEUROEXCITATORY AMINO ACIDS: SYNTHESIS OF 2-(4-ARALKYLPIPERAZINE-1-YL)-1-ARYLETHANOLS

Article abstract of DOI:10.1135/cccc19940658

Amino ketones Ia - If and III were synthesized.Their reduction gave corresponding alcohols IIa - IIf, IVa and IVb.These were evaluated by methods of biochemical and behavioural pharmacology.

Full text of DOI:10.1135/cccc19940658

6
58
Silhankova, Dobrovsky, Krejci, Polivka:
COMPOUNDS INTERACTING WITH THE NEUROEXCITATORY
AMINO ACIDS: SYNTHESIS OF
2
-(4-ARALKYLPIPERAZINE-1-YL)-1-ARYLETHANOLS
Alexandra SILHANKOVA, Karel DOBROVSKY, Ivan KREJCI and Zdenek POLIVKA
Research Institute for Pharmacy and Biochemistry,
1
30 60 Prague 3, The Czech Republic
Received July 15, 1993
Accepted September 29, 1993
Amino ketones Ia – If and III were synthesized. Their reduction gave corresponding alcohols IIa – IIf,
IVa and IVb. These were evaluated by methods of biochemical and behavioural pharmacology.
Within the program of synthesis of agents with neuroprotective action, the work was
concentrated to compounds interacting selectively with the individual subtypes of
neuroexcitatory amino acid receptors. In addition to substances with affinity to the
quisqualate receptor, for which neurotropic effects against consequences of ischemia
1
are assumed , also compounds having affinity to the glycine binding site on the NMDA
receptor complex were searched after. For the last type of compounds one could expect
anticonvulsant activity, a positive influence on memory and learning processes, and
2
,3,4
even antipsychotic effects . In connection with a broader program of preparation of
agents of this type, 2-(4-aralkylpiperazine-1-yl)-1-arylethanols were investigated which
are the object of this communication.
The amino ketones Ia – If and III were obtained by alkylation reactions of 1-benzyl-
5
,6
piperazine, 1-benzhydrylpiperazine and 1-(6,11-dichydrodibenzo[b,e]thiepin-11-yl)-
7
piperazine with 4-fluorophenacyl chloride, 4-chloro- and 4-bromophenacyl bromide in
tetrahydrofuran in the presence of triethylamine. Their reduction with sodium borohy-
dride in ethanol resulted in the desired amino alcohols IIa – IIf, IVa and IVb obtained
in yields of 71 – 93%. For pharmacological testing, the bases were transformed into
water-soluble salts with pharmacologically acceptable acids (hydrochlorides, methane-
sulfonates, fumarates) and these were evaluated by methods of biochemical and beha-
vioural pharmacology.
3
The following biochemical methods were used: (i) inhibition of binding of [ H]5,7-
dichlorokynurenic acid in rat brain cortex membrane protein (the glycine binding site
3
of the NMDA receptor complex), (ii) inhibition of binding of [ H]MK-801 in the rat
brain cortex (the ionic channel coupled with the NMDA receptor), and (iii) inhibition
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

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-(4-Aralkylpiperazine-1-yl)-1-arylethanols
659
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

6
60
Silhankova, Dobrovsky, Krejci, Polivka:
3
of binding of [ H]mepyramine in the guinea pig cerebellum (interaction with the H
1
receptor).
3
The following results were obtained: Inhibition of binding of 3.5 nM [ H]5,7-di-
chlorokynurenic acid (100 µg of the membrane protein from the rat brain cortex, the
compounds used in a concentration of 100 nM; inhibition of the original binding in %
is given): IIa, 42; IIb, 33; IIc, 19; IIf, 25; the remaining compounds were inactive.
3
Inhibition of binding of 1 nM [ H]MK-801 in the rat brain cortex (compounds used in
a concentration of 1 000 nM; inhibition of the original binding in % or the IC50 values
in µM given): IIb, 51; IIc, 89; IId, IC50 = 52.7; IIe, IC50 = 73.7; IIf, IC50 = 43.9; IVa,
IC50 = 35; IVb, IC = 43; the remaining compounds were inactive. Inhibition of binding
50
3
of 2 nM [ H]mepyramine in the guinea pig cerebellum (IC values in µM given): IIb,
5
0
8
.7; IIc, 15.5; IId, 0.17; IIf, 0.04; IVb, 1.3.
Pharmacological tests in vivo evaluated the neuroprotective effect in the state of
acute ischemia in mice (gasping reflex) where in the i.p. doses of 20 mg/kg compounds
IIa – IId proved significant activity, and further in the state of histotoxic anoxia (KCN)
in mice where in the same doses compounds IIe, IIf, IVa and IVb were significantly
active. Anticonvulsant effect (test of electroshock in mice) was observed with com-
pound IIa in the dose of 20 mg/kg. The general anaesthetic effect (potentiation of the
barbiturate sleep) did not achieve with any of the compounds the level of the effect of
ketamine.
Acute toxicity of the compounds in mice (approximate LD50 values in mg/kg): IIa,
IIb, IIc, 45 – 50 i.v.; IId, IIe, > 75 i.p.; IIf, 80 i.v.; IVa, > 150 i.p.; IVb, > 75 i.p.
EXPERIMENTAL
The melting points of analytical samples were determined in the Kofler block and they are not cor-
rected; the samples were dried in vacuo of about 40 Pa at room temperature or at a suitably elevated
temperature. UV spectra (in methanol), λmax in nm (log ε) were recorded with the Unicam SP 8000
−1
spectrophotometer; IR spectra (Nujol, wavenumbers in cm ) with Unicam SP 2000 or Perkin–Elmer
1
2
1
98 spectrophotometers; NMR spectra (in CDCl unless stated otherwise) on a Tesla BS 567A ( H at
3
1
3
00 MHz, C at 25.14 MHz; chemical shifts are given in ppm (δ-scale), coupling constants (J) in
Hz); mass spectra (m/z, %) were measured on a Varian-MAT 44S (GC-MS) spectrometer. The homo-
geneity of the products and composition of the mixtures were checked by thin-layer chromatography
(
TLC) on silica gel (Silufol UV254). Preparative chromatographic separations were carried out on a
columns of silica gel (Fluka 60).
1
-Benzyl-4-(4-fluorophenacyl)piperazine (Ia)
A solution of 1-benzylpiperazine (7.04 g, 0.04 mol), 4-fluorophenacyl chloride (6.9 g, 0.04 mol) and
triethylamine (5.3 ml, 0.04 mol) in tetrahydrofuran (100 ml) was stirred for 5 h at room temperature
and allowed to stand overnight. The precipitated triethylamine hydrochloride was filtered off and
washed with tetrahydrofuran. The filtrate was evaporated in vacuo; the oily residue (13.5 g) crystal-
lized after cooling. Crystallization from pentane afforded 10.9 g (88%) of Ia as a slightly yellowish
1
crystalline substance melting at 50 – 52 °C, unstable on air. H NMR spectrum: 2.60 bs, 8 H (4 × H-2,
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

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-(4-Aralkylpiperazine-1-yl)-1-arylethanols
661
4
7
× H-3); 3.52 s, 2 H (N−CH −Ar); 3.75 s, 2 H (N−CH −CO); 7.10 t, 2 H (2 × H-3′, J(HH) = J(HF) = 8.5);
.30 s, 5 H (2 × H-2″, 2 × H-3″, H-4″); 8.02 dd, 2 H (2 H-2′, J(HH) = 8.5, J(HF) = 6.0). For
2
2
C H FN O (312.4) calculated: 73.05% C, 6.78% H, 6.08% F, 8.97% N; found: 72.75% C, 6.79% H,
1
9
21
2
6
.26% F, 8.65% N.
Dihydrochloride hemihydrate, m. p. 216 – 219 °C (ethanol–water 9 : 1). IR spectrum: 700, 746
(
(
(
5 adjacent Ar−H); 831, 841 (2 adjacent Ar−H); 1 235 (Ar−F); 1 509, 1 596, 3 015 (Ar); 1 700
+
13
COAr); 1 627, 3 100, 3 280 (H O); 2 200, 2 240, 2 430, 2 530 (NH ). C NMR spectrum: 190.85 s
2
CO), 165.11 s (C-4′, J(FC) = 256), 136.00 (C-1″), 131.02 d (C-3″), 130.78 d (C-2′, J(FC) = 7.5),
1
5
1
29.22 s (C-1′), 129.00 d (C-4″), 128.25 d (C-2″), 115.03 d (C-3′, J(FC) = 21), 59.76 t (Ar−CH −N),
2
+
8.11 t (N−CH -CO), 48.25 t and 47.13 (C-2 and C-3). Mass spectrum: 312 (M , C H FN O, 3),
2
19 21
2
89 (80), 146 (14), 98 (14), 91 (100), 70 (57), 42 (29). For C H Cl FN O + 0.5 H O (394.3) cal-
1
9
23
2
2
2
culated: 57.87% C, 6.14% H, 17.98% Cl, 4.82% F, 7.10% N; found: 57.97% C, 5.97% H, 18.24% Cl,
.21% F, 6.88% N.
5
2
-(4-Benzylpiperazine-1-yl)-1-(4-fluorophenyl)-ethanol (IIa)
A stirred solution of Ia (10.9 g, 0.035 mol) in ethanol (150 ml) was treated over 30 min with a
suspension of NaBH (2.64 g, 0.07 mol) in ethanol (100 ml) at 10 – 15 °C. The clear solution ob-
4
tained was stirred for 2 h at room temperature and allowed to stand overnight. Ethanol was evap-
orated in vacuo, the residue was diluted with water and extracted with chloroform (3 × 100 ml). The
extract was dried with MgSO ; processing afforded IIa (10.0 g, 91%) as colourless crystals, m.p.
4
1
1
23 °C (ethanol). IR spectrum: 698, 741 (5 adjacent Ar−H); 833 (2 adjacent Ar−H); 1 090 (CH−OH);
1
223 (Ar−F); 1 509, 1 600, 3 028, 3 060 (Ar); 2 778, 2 820 (N−CH ); 3 100 (OH). H NMR spec-
2
trum: 7.30 m, 7 H (2 × H-2′, 2 × H-2″, 2 × H-3″, H-4″); 7.00 t, 2 H (2 × H-3′, J(HH) = J(HF) = 8.5);
4
4
.65 dd, 1 H (CH−O); 4.04 bs, 1 H (OH); 3.52 s, 2 H (Ar−CH −N); 2.40 – 2.80 m, 10 H (N−CH −CH,
2 2
× H-2, 4 × H-3). C NMR spectrum: 162.39 s (C-4′, J(FC) = 250), 138.19 s (C-1″), 138.04 s
1
3
(
C-1′), 129.30 d (C-3″), 128.33 d (C-2″), 127.73 d (C-4″), 127.32 d (C-2′, J(FC) = 6), 115.25 d (C-3′,
J(FC) = 24), 68.27 d (CH−OH), 66.25 t (N−CH −CH−OH), 63.12 t (Ar−CH −N), 53.26 t (C-2, C-3).
2
2
For C H FN O (314.4) calculated: 72.58% C, 7.37% H, 6.04% F, 8.91% N; found: 72.90% C, 7.54%
1
9
23
2
H, 6.06% F, 9.31% N.
Dihydrochloride, m.p. 221 – 223 °C (ethanol–water 9 : 1). IR spectrum: 702, 760 (5 adjacent Ar−H);
8
2
2
2
35 (2 adjacent Ar−H); 1 075 (CH−OH); 1 212 (Ar−F); 1 510, 1 603, 3 010, 3 060 (Ar); 2 265,
+
1
450, 2 540, 2 630 (NH ); 3 300 (OH). H NMR spectrum (CD SOCD ): 7.40 – 7.80 m, 7 H (2 × H-2′,
3
3
× H-2″, 2 × H-3″, H-4″); 7.24 t, 2 H (2 × H-3′, J(HF) = J(HH) = 9.0); 5.20 m, 1 H (CH−O); 4.40 s,
H (Ar−CH −N); 3.50 bm, 10 H (4 × H-2, 4 × H-3, N−CH −CH). For C H ClFN O (387.3) cal-
2
2
19 24
2
culated: 58.92% C, 6.50% H, 18.31% Cl, 4.91% F, 7.23% N; found: 59.12% C, 6.61% H, 18.34% Cl,
.16% F, 7.23% N.
5
1
-Benzyl-4-(chlorophenacyl)piperazine (Ib)
Title compound was prepared similarly like Ia but the reaction mixture was heated for 2 h to 50 – 60 °C
8
(
bath temperature); yield 80%, m.p. 61 – 62 °C (pentane). Reference described the preparation of Ib
by a similar reaction in ether in the presence of K CO ; the base was isolated as an oil and charac-
2
3
1
terized in the form of dihydrochloride. H NMR spectrum: 7.94 d, 2 H (2 × H-2′, J = 8.5); 7.40 d, 2 H
(
2 × H-3′, J = 8.5); 7.38 s, 5 H (2 × H-2″, 2 × H-3″, H-4″); 3.74 s, 2 H (N−CH −Ar); 3.54 s, 2 H
2
(
N−CH −CO); 2.60 s, 8 H (4 × H-2, 4 × H-3). For C H ClN O (328.8) calculated: 69.40% C,
2
19 21
2
6
.44% H, 10.78% Cl, 8.52% N; found: 69.51% C, 6.38% H, 11.02% Cl, 8.46% N.
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Silhankova, Dobrovsky, Krejci, Polivka:
2
-(4-Benzylpiperazine-1-yl)-1-(4-chlorophenyl)ethanol (IIb)
8
Title compound was prepared similarly like IIa; yield 92%, m.p. 148 – 151 °C. Reference described
the preparation from the corresponding ketone by reduction with aluminum isopropoxide, m.p.
1
1
3
52 °C. H NMR spectrum: 7.35 s, 9 H (Ar−H); 4.68 dd, 1 H (CH−O); 3.52 s, 2 H (N−CH −Ar);
2
.40 flat band (OH); 2.20 – 2.80 m, 10 H (4 × H-2, 4 × H-3, N−CH −CHOH).
2
Reduction of the ketone Ib with LiAlH in ether at 0 °C gave IIb in the yield of 91%; it was
4
necessary to isolate the product by extraction from the precipitated hydroxides in the Soxhlet
apparatus.
Dihydrochloride, m.p. 209 – 213 °C (ethanol–water 19 : 1). IR spectrum: 696, 743 (5 adjacent
Ar−H); 813 (2 adjacent Ar−H); 1 070 (CHOH); 1 490, 1 577, 1 596, 3 040 (Ar); 2 300, 2 435, 2 500,
+
2
2
605, 2 630 (NH ); 3 270 (OH). For C H Cl N O (403.8) calculated: 56.52% C, 6.24% H,
1
9
25
3
2
6.34% Cl, 6.94% N; found: 56.99% C, 6.31% H, 26.16% Cl, 6.68% N.
1
-Benzyl-4-(4-bromophenacyl)piperazine (Ic)
The preparation was similar like with Ia, yield 73% of title compound Ic, m.p. 94 – 95 °C (cyclo-
1
hexane); the compound was unstable on air. H NMR spectrum: 7.88 d, 2 H (2 × H-2′, J = 8.5);
7
3
6
.56 d, 2 H (2 × H-3′, J = 8.5); 7.28 s, 5 H (2 × H-2″, 2 × H-3″, H-4″); 3.73 s, 2 H (N−CH −CO);
2
.52 s, 2 H (N−CH −Ar); 2.58 bs, 8 H (4 × H-2, 4 × H-3). For C H BrN O (373.3) calculated:
2
19 21
2
1.13% C, 5.67% H, 21.41% Br, 7.50% N; found: 61.20% C, 5.69% H, 21.47% Br, 7.14% N.
Dihydrochloride, m.p. 214 – 216 °C (ethanol–water 10 : 1). For C H BrCl N O (446.2)
1
9
23
2
2
calculated: 51.14% C, 5.20% H, 17.91% Br, 15.89% Cl, 6.28% N; found: 50.95% C, 5.09% H,
7.94% Br, 15.91% Cl, 6.56% N.
1
2
-(4-Benzylpiperazine-1-yl)-1-(4-bromophenyl)ethanol (IIc)
The preparation was similar like with IIa, yield 93% of title compound IIc, m.p. 158.5 – 159 °C
1
(
ethanol). H NMR spectrum: 7.45 d, 2 H (2 × H-3′, J = 8.5); 7.35 s, 5 H (2 × H-2″, 2 × H-3″,
H-4″); 7.23 d, 2 H (2 × H-2′, J = 8.5); 4.66 dd, 1 H (Ar−CH−OH); 4.02 bs, 1 H (OH); 3.54 s, 2 H
1
3
(
Ar−CH −N); 2.30 – 2.80 m, 10 H (4 × H-2, 4 × H-3, N−CH −CHOH). C NMR spectrum: 141.32 s
2 2
(
(
C-1′), 138.11 s (C-1″), 131.46 d (C-3′), 129.22 d (C-3″), 128.33 d (C-2″), 127.65 d (C-2′), 127.21 d
C-4″), 121.23 d (C-4′), 68.20 d (CH−OH), 65.96 t (N−CH −CHOH), 63.04 t (N−CH −Ar), 53.11 t
2
2
(
C-2, C-3). For C H BrN O (375.3) calculated: 60.80% C, 6.18% H, 21.19% Br, 7.46% N; found:
19 23 2
6
0.69% C, 6.13% H, 21.28% Br, 7.61% N.
Dihydrochloride, m.p. unsharp till 224 °C (ethanol–water 7 : 1). For C H BrCl N O (448.3)
1
9
25
2
2
calculated: 50.91% C, 5.62% H, 17.83% Br, 15.82% Cl, 6.25% N; found: 50.80% C, 5.60% H,
8.00% Br, 15.97% Cl, 6.64% N.
1
1
-Benzhydryl-4-(4-fluorophenacyl)piperazine (Id)
The preparation was similar like with Ia, yield 76.7% of title compound Id, m.p. 101 – 103 °C
(
2-propanol). IR spectrum: 705, 750 (5 adjacent Ar−H); 828, 831 (2 adjacent Ar−H); 1 223 (Ar−F);
1
491, 1 501, 1 597, 3 005, 3 050 (Ar); 1 689 (ArCOR); 2 753, 2 795 (N−CH ). UV spectrum: 225
2
1
(4.18), 240 (4.11). H NMR spectrum: 8.05 dd, 2 H (2 × H-2′); 7.10 – 7.60 m, 10 H (4 × H-2″, 4 × H-3″,
2
× H-4″); 7.10 t, 2 H (2 H-3′); 4.24 s, 1 H (N−CHAr ); 3.76 s, 2 H (N−CH CO); 2.20 – 3.80 m, 8 H
2 2
(
4 × H-2, 4 × H-3). For C H FN O (388.5) calculated: 77.29% C, 6.49% H, 4.89% F, 7.21% N;
25 25 2
found: 77.12% C, 6.72% H, 4.73% F, 6.93% N.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

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-(4-Aralkylpiperazine-1-yl)-1-arylethanols
663
Dihydrochloride, m.p. 199 – 202 °C (ethanol). For C H Cl FN O (461.4) calculated: 65.08% C,
2
5
27
2
2
5
5
.90% H, 15.37% Cl, 4.12% F, 6.07% N; found: 64.82% C, 5.92% H, 15.35% Cl, 4.02% F,
.69% N.
2
-(4-Benzhydrylpiperazine-1-yl)-1-(4-fluorophenyl)ethanol (IId)
The preparation was similar like with IIa, yield 71% of title compound IId, m.p. 110 – 111 °C
(
(
3
7
2
7
2-propanol). IR spectrum: 705, 748, 757 (5 adjacent Ar−H); 836 (2 adjacent Ar−H); 1 065, 1 095
CH−OH); 1 221 (Ar−F); 1 490, 1 509, 1 600, 3 020, 3 056, 3 075 (Ar); 2 755, 2 805 (CH −N);
2
1
350 (OH). H NMR spectrum: 7.30 – 7.50 m, 12 H (2 × H-2′, 4 × H-2″, 4 × H-3″, 2 × H-4″);
.00 t, 2 H (2 × H-3′); 4.68 dd, 1 H (CH–OH); 4.22 s, 1 H (CHAr ); 2.80 m, 2 H (N−CH −CH);
2
2
.50 m, 8 H (4 × H-2, 4 × H-3). For C H FN O (390.5) calculated: 76.89% C, 6.69% H, 4.87% F,
2
5
27
2
.17% N; found: 76.72% C, 7.06% H, 4.67% F, 6.95% N.
Fumarate hemihydrate, m.p. 199 – 202 °C (ethanol). Mass spectrum: 390 (<0.1), 372 (0.1), 265
(
26), 167 (100), 152 (10). For C H FN O + 0.5 H O (515.6) calculated: 67.55% C, 6.26% H,
29 31 2 5 2
3
.69% F, 5.43% N; found: 67.62% C, 6.20% H, 3.63% F, 5.34% N.
1
-Benzhydryl-4-(4-chlorophenacyl)piperazine (Ie)
The preparation was similar like with Ia, yield 83% of title compound Ie, m.p. 99 – 102 °C
(
2-propanol). IR spectrum: 705, 745, 759 (5 adjacent Ar−H); 819 (2 adjacent Ar−H); 1 483, 1 590,
3
020, 3 060 (Ar); 1 684 (ArCOR); 2 655, 2 700 (N−CH ). UV spectrum: 224 infl. (4.13), 254
2
1
(
4.25). H NMR spectrum: 7.94 d, 2 H (2 × H-2′); 7.00 – 7.50 m, 12 H (2 × H-3′, 4 × H-2″,
4
× H-3″, 2 × H-4″); 4.22 s, 1 H (N−CHAr ); 3.72 s, 2 H (N−CH CO); 2.30 – 2.80 bm, 8 H
2 2
+
(
4 × H-2, 4 × H-3). Mass spectrum: 404 (M , C H ClN O, 0.6), 265 (24), 237 (6), 167 (100), 152
25 25 2
(
12), 139 (4). For C H ClN O + 0.25 H O (409.4) calculated: 73.36% C, 6.27% H, 8.66% Cl,
25 25 2 2
6
.84% N; found: 73.19% C, 6.28% H, 9.00% Cl, 6.59% N.
2
-(4-Benzhydrylpiperazine-1-yl)-1-(4-chlorophenyl)ethanol (IIe)
The preparation was similar like with IIa, yield 93% of title compound IIe, m.p. 138.5 – 140 °C
1
(
ethanol). H NMR spectrum: 7.30 s, 4 H (2 × H-2′, 2 × H-3′); 7.00 – 7.50 m, 10 H (4 × H-2″,
× H-3″, 2 × H-4″); 4.70 dd, 1 H (CH−OH); 4.24 s, 1 H (N−CHAr ); 2.80 m, 2 H (N−CH −
4
2
2
CHOH); 2.50 m, 8 H (4 × H-2, 4 × H-3). For C H ClN O (407.0) calculated: 73.78% C, 6.69% H,
2
5
27
2
8
.71% Cl, 6.88% N; found: 73.44% C, 6.72% H, 8.87% Cl, 7.22% N.
Dihydrochloride hemihydrate, m.p. 234 – 236 °C (ethanol). Mass spectrum: 388 (0.2), 265 (25),
67 (100), 152 (8). The mass M 406 was confirmed by chemical ionization. For C H N Cl O + 0.5
1
2
5
29
2
3
H O (488.9) calculated: 61.41% C, 6.19% H, 5.73% N; found: 61.36% C, 6.25% H, 5.64% N.
2
1
Dimethanesulfonate, m.p. 181 – 182 °C (2-propanol–ether). H NMR spectrum: 7.20 – 7.60 m,
1
4 H (Ar−H); 5.10 dd, 1 H (CH−OH); 4.76 s, 1 H (CHAr ); 3.48 bm, 4 H (4 × H-3); 3.30 m, 2 H
2
(
N−CH CH); 2.80 bm, 4 H (4 × H-2); 2.50 s, 6 H (2 × CH SO H). For C H ClN O S (599.2)
2 3 3 27 35 2 7 2
calculated: 54.12% C, 5.89% H, 5.92% Cl, 4.68% N, 10.70% S; found: 53.75% C, 5.85% H,
6
.04% Cl, 4.94% N, 10.74% S.
Methanesulfonate hemihydrate was formed by crystallization of the dimethanesulfonate from
water, m.p. 215 – 217 °C. For C H ClN O S + 0.5 H O (512.1) calculated: 60.98% C, 6.30% H,
2
6
31
2
4
2
6
.92% Cl, 5.47% N, 6.26% S; found: 61.19% C, 6.24% H, 7.09% Cl, 5.55% N, 6.19% S.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

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64
Silhankova, Dobrovsky, Krejci, Polivka:
1
-Benzhydryl-4-(4-bromophenacyl)piperazine (If)
The preparation was similar like with Ia, yield 68% of title compound If, m.p. 102 – 104 °C
9
1
9
(
2-propanol). Reference gave the m.p. of 93 – 94 °C. H NMR spectrum in accord with ref. . IR
spectrum: 703, 749, 755 (5 Ar−H in C H ); 1 490, 1 581, 3 015, 3 015, 3 050 (Ar); 1 699 (ArCOR).
6
5
1
3
UV spectrum: 225 infl. (4.12), 253 (4.08). C NMR spectrum: 195.78 s (CO), 142.67 s (C-1″),
1
1
34.83 s (C-1′), 131.76 d (C-3′), 129.82 d (C-2′), 128.85 s (C-4′), 128.48 d (C-3″), 127.95 d (C-2″),
26.91 d (C-4″), 76.11 d (N−CHAr ), 64.69 t (N−CH −CO), 53.71 t (C-2), 51.69 t (C-3).
2
2
Dihydrochloride hemihydrate, m.p. 171 – 174 °C (ethanol). For C H BrCl N O + 0.5 H O
2
5
27
2
2
2
(
531.3) calculated: 55.70% C, 5.41% H, 5.18% N; found: 55.42% C, 5.67% H, 4.80% N.
2
-(4-Benzhydrylpiperazine-1-yl)-1-(4-bromophenyl)ethanol (IIf)
The preparation was similar like with IIa; yield 78% of title compound IIf, m.p. 147 – 151 °C
1
(
(
ethanol). H NMR spectrum: 7.00 – 7.60 m, 14 H (Ar−H); 4.63 dd, 1 H (CH−OH); 4.22 s, 1 H
N−CHAr ); 4.00 bs, 1 H (OH); 2.75 m, 2 H (N−CH −CH); 2.44 bs, 8 H (4 × H-2, 4 × H-3). For
2
2
C H BrN O (451.4) calculated: 66.52% C, 6.03% H, 17.70% Br, 6.21% N; found: 66.43% C,
2
5
27
2
6
.03% H, 18.11% Br, 6.21% N.
Dihydrochloride monohydrate, m.p. 233 – 237 °C (ethanol–water 20 : 1). For C H BrCl N O +
2
5
29
2
2
H O (542.4) calculated: 55.36% C, 5.76% H, 14.73% Br, 13.07% Cl, 5.17% N; found: 55.37% C,
2
5
.76% H, 15.01% Br, 13.30% Cl, 4.88% N.
Dimethanesulfonate, m.p. 187 – 189 °C (2-propanol–ether). For C H BrN O S (643.6) calcu-
2
7
35
2
7
lated: 50.38% C, 5.48% H, 12.42% Br, 4.35% N, 9.96% S; found: 50.20% C, 5.53% H, 12.43% Br,
.29% N, 9.74% S.
4
1
-(6,11-Dihydrodibenzo[b,e]thiepin-11-yl)-4-(4-fluorophenacyl)piperazine (III)
The preparation of title compound III was similar like with Ia. The product obtained, which was
not homogeneous (TLC), was separated by chromatography on silica gel (elution with chloroform
and chloroform shaken with aqueous ammonia). There were obtained 72% of III, m.p. 82 – 84 °C
(
1
7
methanol–ethanol 1 : 1). IR spectrum: 751 (4 adjacent Ar−H); 835 (2 adjacent Ar−H); 1 223 (Ar−F);
501, 1 595, 1 611, 3 050 (Ar); 1 688 (COAr). H NMR spectrum: 8.05 m, 2 H (2 × H-2′);
.00 – 7.40 m, 10 H (2 × H-3′ and Ar−H of dibenzothiepin); 4.05 s, 1 H (N−CH); 3.72 s, 2 H
1
(
N−CH −CO); 2.50 bm, 8 H (4 × H-2, 4 × H-3); flat band belonging to S−CH (shifting with tem-
2 2
+
perature changes). Mass spectrum: 432 (M , C H FN OS, 1), 309 (0.5), 221 (4), 211 (38), 210
2
6
25
2
(
100), 178 (44), 165 (6), 123 (8), 99 (7), 56 (14). For C H FN OS + CH OH + 0.5 H O (473.6)
26 25 2 3 2
calculated: 68.47% C, 6.38% H, 4.01% F, 5.91% N, 6.77% S; found: 68.72% C, 6.34% H, 4.15% F,
.79% N, 6.83% S.
5
2
-[4-(6,11-Dihydrodibenzo[b,e]thiepin-11-yl)-piperazine-1-yl]-1-(4-fluorophenyl)ethanol (IVa)
The preparation of title compound IVa was similar like with IIa. The crude product, which was ob-
tained by extraction with chloroform, was triturated with cyclohexane and filtered after crystal-
lization; 81% of IVa, m.p. 99 – 103 °C (ethanol). IR spectrum: 752 (4 adjacent Ar−H); 831
(
3
2 adjacent Ar−H); 1 065 (CHOH); 1 212 (Ar−F); 1 504, 1 590, 1 613, 3 000, 3 010, 3 055 (Ar);
340 (OH). UV spectrum: 260 (4.88), 289 infl. (3.11). H NMR spectrum: 7.00 – 7.50 m, 12 H
1
(
Ar−H); 4.70 m, 1 H (CH−OH); 4.12 s, 1 H (CH−N). For C H FN OS (434.6) calculated: 4.37% F,
2
6
27
2
7
.38% S; found: 4.15% F, 7.41% s.
Fumarate hemihydrate, m.p. 177 – 180 °C (ethanol–water 10 : 1). IR spectrum: 755 (4 adjacent
−
Ar−H); 835 (2 adjacent Ar−H); 1 105 (CHOH); 1 360, 1 565 (COO ); 1 220 (Ar−F); 1 455, 1 510,
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2
1
-(4-Aralkylpiperazine-1-yl)-1-arylethanols
665
+
+
600 (Ar); 2 640 (NH ); infl. 3 070 (OH). Mass spectrum: 434 (M , C H FN OS, 1) 309 (6), 211
2
6
27
2
(
84), 210 (100), 178 (47), 99 (19), 56 (20). For C H FN O S + 0.5 H O (501.6) calculated:
28 29 2 3 2
6
7.04% C, 6.03% H, 5.58% N, 6.39% S; found: 67.37% C, 5.97% H, 5.42% N, 6.52% S.
1
-(4-Chlorophenyl)-2-[4-(6,11-dihydrodibenzo[b,e]-thiepin-11-yl)piperazine-1-yl]ethanol (IVb)
7
A stirred solution of 1-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)piperazine (14.8 g, 0.05 mol) in tetra-
hydrofuran (100 ml) was treated with a solution of 4-chlorophenacyl bromide (11.7 g, 0.05 mol) in
tetrahydrofuran (50 ml) and with triethylamine (7.0 ml, 0.05 mol). The mixture was stirred for 10 h
at room temperature, the precipitated triethylamine hydrochloride was filtered off, the filtrate was
evaporated in vacuo and the oily residue was dried in vacuo. The remaining solid (22.6 g,
m.p. 64 – 70 °C) could not be crystallized and was used in crude state.
Similarly like in the preparation of IIb, the above mentioned solid (10 g) was reduced with
NaBH4 (1.6 g) in ethanol. The oily residue, obtained after evaporation of the chloroform extract,
was dissolved in ether. The solution was treated with HCl in ether, the suspension was diluted with
2
-propanol, the hydrochloride was filtered and crystallized. The base was released by means of a
solution of Na CO , extracted with ether and the extract was dried with MgSO . Evaporation of the
2
3
4
solvent in vacuo gave a solid which was crystallized from a mixture of cyclohexane and hexane
1 : 1), m.p. 102 – 106 °C. Even drying in vacuo for 10 h did not remove cyclohexane completely.
IR spectrum: 750 (4 adjacent Ar−H); 817 (2 adjacent Ar−H); 1 090 (CHOH); 1 489, 1 589, 3 050
(
1
(
(
(
Ar), 3 340 (OH). UV spectrum: 260 (3.55), 290 (2.77). H NMR spectrum: 7.00 – 7.40 m, 12 H
Ar−H); 4.65 m, 1 H (CH−OH); 4.10 s, 1 H (CH−N); 2.75 bm, 2 H (N−CH −CH); 2.44 bm, 8 H
4 × H-2, 4 × H-3); 6.00 and 3.42, flat bands shifting with temperature changes (CH S). Mass
spectrum: 450 (M − 1, C H ClN OS, 1), 309 (6.5), 211 (82), 210 (100), 178 (46), 99 (17), 77 (9),
2
2
+
2
6
27
2
5
6 (20).
Hydrochloride, m.p. 237 – 239 °C (aqueous ethanol). IR spectrum: 754 (4 adjacent Ar−H); 821,
+
8
41 (2 adjacent Ar−H); 1 090 (CHOH); 1 490, 1 590 (Ar); 2 444, 2 560, 2 635 (NH ); 3 220 (OH).
+
Mass spectrum: 450 (M − 1, C H ClN OS, 0.1), 432 (0.3), 212 (15), 211 (22), 210 (26), 197 (6),
2
6
27
2
1
6
79 (21), 178 (34), 44 (100). For C H Cl N OS (487.5) calculated: 64.06% C, 5.79% H, 5.75% N,
26 28 2 2
.58% S; found: 64.18% C, 5.74% H, 5.65% N, 6.75% S.
The authors thank the following colleagues for co-operation: Mr M. Cech, Mrs R. Svatosova and Mrs
A. Svatonova (elemental analyses), Dr J. Holubek (NMR spectra), Dr M. Ryska and Dr I. Koruna (mass
spectra), Dr E. Svatek and Mrs R. Hanusova (IR spectra), and Dr I. Lapka (determination of inhibition
of binding of labelled mepyramine).
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1
2
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2, 1 (1989).
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66
Silhankova, Dobrovsky, Krejci, Polivka:
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1987).
Translated by M. Protiva.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)