Alpha1-adrenoceptor antagonists. 6. Structural optimization of pyridazinone-arylpiperazines. Study of the influence on affinity and selectivity of cyclic substituents at the pyridazinone ring and alkoxy groups at the arylpiperazine moiety.

Article abstract of DOI:10.1021/jm0307842

In continuing our search for selective alpha(1)-adrenoceptor (AR) antagonists, we have synthesized new alkoxyarylpiperazinylalkylpyridazinone derivatives. The new compounds were tested for their affinity toward alpha(1)- and alpha(2)-AR and toward the 5-HT(1A) receptor. alpha(1)-AR affinity data are in the subnanomolar range, with 3 showing an affinity of 0.052 nM, about 5-fold higher than prazosin. None of the studied compounds was found to be alpha(1)/alpha(2) selective, but 8 showed an interesting 5-HT(1A)/alpha(1) affinity ratio of 119.

Full text of DOI:10.1021/jm0307842

J . Med. Chem. 2003, 46, 3555-3558
3555
Brief Articles
r1-Ad r en ocep tor An ta gon ists. 6.1 Str u ctu r a l Op tim iza tion of
P yr id a zin on e-Ar ylp ip er a zin es. Stu d y of th e In flu en ce on Affin ity a n d
Selectivity of Cyclic Su bstitu en ts a t th e P yr id a zin on e Rin g a n d Alk oxy Gr ou p s
a t th e Ar ylp ip er a zin e Moiety
Laura Betti,† Federico Corelli,‡ Monia Floridi,§ Gino Giannaccini,† Laura Maccari,‡ Fabrizio Manetti,‡
Giovannella Strappaghetti,*,§ and Maurizio Botta*,‡
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Universita` di Pisa, Via Bonanno 6,
56126 Pisa, Italy, Dipartimento Farmaco Chimico Tecnologico, Universita` degli Studi di Siena, Via Aldo Moro,
53100 Siena, Italy, and Istituto di Chimica e Tecnologia del Farmaco, Universita` di Perugia, Via del Liceo 1,
06123 Perugia, Italy
Received J anuary 20, 2003
In continuing our search for selective R1-adrenoceptor (AR) antagonists, we have synthesized
new alkoxyarylpiperazinylalkylpyridazinone derivatives. The new compounds were tested for
their affinity toward R1- and R2-AR and toward the 5-HT1A receptor. R1-AR affinity data are in
the subnanomolar range, with 3 showing an affinity of 0.052 nM, about 5-fold higher than
prazosin. None of the studied compounds was found to be R1/R2 selective, but 8 showed an
interesting 5-HT1A/R1 affinity ratio of 119.
In tr od u ction
and (3) a (hetero)cyclic fragment bigger than an aro-
matic five-membered ring is required as the terminal
molecular portion for best R1-AR affinity.
In continued attempts to identify potent and selective
R1-AR antagonists, we have previously published SAR
and 3D QSAR studies on arylpiperazinylalkylpyridazi-
none derivatives designed on the basis of a pharma-
cophoric model2 suggesting the following three-dimen-
sional structural properties for an ideal R1-AR antagonist
(Table 1). (1) A positively ionizable group, corresponding
to the more basic nitrogen atom of the piperazine ring,
and (2) an ortho- or meta substituted phenyl ring, both
of them constituting the arylpiperazine system, satisfy
three (namely, PI HY1-HY2, respectively) of the five
features of the pharmacophoric hypothesis. Moreover,
(3) a polar group (corresponding to the pyridazinone
ring) able to provide a hydrogen bond acceptor feature
filling the HBA portion of the pharmacophore is re-
quired at the edge of the molecule opposite the arylpip-
erazine moiety. Finally, (4) a third hydrophobic moiety,
corresponding to the terminal molecular portions di-
rectly linked to the pyridazinone ring, was hypothesized
to fit the HY3 feature of the model.
On the basis of these suggestions, 1, derived from our
previous work in this field and bearing the terminal
furoylpiperazinyl moiety similarly to the reference
compound prazosin, was chosen as a hit compound to
be structurally optimized for improving affinity and
selectivity toward R1-AR. With the length of the alkyl
chain fixed on a seven-carbon atom sequence, the new
compounds have been obtained by variation of (i) the
bulkiness of the ortho substituent on the phenyl ring of
the arylpiperazine moiety, (ii) the terminal molecular
portion opposite the arylpiperazine moiety (i.e., the
furoyl group of 1), and (iii) substituents and substitution
pattern on the central pyridazinone nucleus.
All of them were evaluated for their affinity toward
R1-AR, R2-AR, and 5-HT1A serotoninergic receptors, and
SAR studies are reported here.
Ch em istr y
The pharmacophoric model also suggested2,3 that (1)
the hydrophobic region accommodating the substituted
phenyl ring is able to locate substituents larger than a
methoxy group, (2) both affinity and selectivity are
dependent on the length of the polymethylene chain
connecting the pyridazinone and the arylpiperazine
moieties, being a heptyl spacer optimal for R1 affinity,
Compounds 2-16 were synthesized as outlined in
Scheme 1. In detail, a mixture of 4,5-dichloropyridazin-
3(2H)-one (18) and the appropriate 1-substituted pip-
erazine (19) was refluxed for 15 h in ethanol and Et3N
to afford intermediates 20a -d (method A). Next, 4-chlo-
ro-5-[4-(2-furoyl)piperazin-1-yl]pyridazin-3(2H)-one (20a),
4-chloro-5-{[4-[2-(1,4-benzodioxan)methyl]piperazin-1-
yl}pyridazin-3(2H)-one (20b), 4-chloro-5-{[4-[2-(2-meth-
oxyphenoxy)ethyl]piperazin-1-yl}pyridazin-3(2H)-one
(20c), and 4-chloro-5-{[4-[2-(2-ethoxyphenoxy)ethyl]pip-
erazin-1-yl}pyridazin-3(2H)-one (20d) were in turn trans-
formed into intermediates 21a -d by treating with 1,7-
dibromoheptane in acetone and potassium carbonate
* To whom correspondence should be addressed. For G.S.: phone,
+39 075 5855136; fax, +39 075 5855129; e-mail, noemi@unipg.it. For
M.B.: phone, +39 0577 234306; fax, +39 0577 234333; e-mail,
botta@unisi.it.
† Universita` di Pisa.
‡ Universita` degli Studi di Siena.
§ Universita` di Perugia.
10.1021/jm0307842 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/11/2003

3556 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 16
Ta ble 1. R1-AR, R2-AR, and 5-HT1A Affinities for 1-17
Brief Articles
while reaction between 24a and 22a -c afforded 4-6,
respectively, 10-12 were obtained by treating 24b with
the same arylpiperazines 22a -c, respectively.
Biology
The pharmacological profile of 2-16 was evaluated
for their affinities toward R1-AR, R2-AR, and 5-HT1A
serotoninergic receptor by determining for each com-
pound the ability to displace [3H]prazosin, [3H]rauwols-
cine, and [3H]8-OH-DPAT, respectively, from specific
binding sites on rat cerebral cortex. Ki values were
determined on the basis of three competition binding
experiments in which seven drug concentrations, run
in triplicate, were used.2,3
Moreover, to determine the intrinsic activity of com-
pounds with the best affinity profile toward R1-AR
(namely, 3, 9, and 15), competition studies were per-
formed in the presence and in the absence of 1 mM GTP
using the radiolabeled antagonist [3H]prazosin. In Table
2, the GTP shift values of the selected compounds and
the antagonist reference compound prazosin were re-
ported.
Ki c (nM)
compda Rb
R1
-OMe 1.9 ( 0.1
-OEt 0.5 ( 0.02
R1-AR
R2-AR
5-HT1A
NDe
NDe
1d
2f
a
a
a
a
a
a
b
b
b
b
b
b
d
d
d
c
c
520 ( 0.2
4.0 ( 0.2
3f
-OiPr 0.052 ( 0.007 0.56 ( 0.19 0.90 ( 0.09
4
5
6
7
8
9
10
11
12
13f
14f
15f
16f
17d
P
-OMe 0.37 ( 0.09
1.23 ( 0.14 0.42 ( 0.16
0.80 ( 0.07 0.35 ( 0.10
0.66 ( 0.05 1.16 ( 0.72
0.85 ( 0.16 11.1 ( 5.5
2.16 ( 0.08 49.8 ( 16.7
3.34 ( 0.22 2.47 ( 0.91
1.45 ( 0.21 0.40 ( 0.29
2.40 ( 0.42 1.02 ( 0.51
-OEt
0.23 ( 0.03
-OiPr 0.08 ( 0.01
-OMe 1.68 ( 0.50
-OEt
0.42 ( 0.01
-OiPr 0.31 ( 0.08
-OMe 0.54 ( 0.10
-OEt
0.43 ( 0.08
-OiPr 0.32 ( 0.02
-OMe 0.55 ( 0.17
13.4 ( 3.2
1.52 ( 0.80
At the R1 receptor, the selected compounds displayed
no significant GTP shift, suggesting that they elicited
an antagonist profile such as prazosin.
1.59 ( 0.15 0.82 ( 0.31
2.04 ( 0.24 1.32 ( 0.62
3.21 ( 0.13 2.54 ( 1.02
8.22 ( 0.34 NDe
-OEt
0.43 ( 0.08
-OiPr 0.26 ( 0.04
-OEt
0.58 ( 0.09
Resu lts a n d Discu ssion
-OMe 1.45 ( 0.14
0.24 ( 0.05
4.64 ( 0.49 NDe
Affinity data reported in Table 1 clearly showed that
all the new compounds were characterized by a very
interesting biological profile. In fact, with the exception
of 7 (Ki ) 1.68 nM), affinity values toward R1-AR were
all in the subnanomolar range (comparable to that of
the reference compound prazosin) or lower. On the basis
of both R1-AR affinity data and structural properties of
the studied compounds, some suggestions can be ruled
out. (i) As expected, increasing the size of the ortho
alkoxy substituent on the phenyl ring of the arylpip-
erazine moiety afforded compounds with enhanced
affinity toward R1-AR. In fact, without any exception,
the largest isopropoxy group led to the best R1-AR
affinity profile. Very interestingly, a couple of com-
pounds (namely, 3 and 6) showed an affinity (0.05 and
0.08 nM, respectively) significantly higher than the
reference compound prazosin. (ii) The substitution pat-
tern on the pyridazinone ring is not important for
defining affinity toward R1-AR, affinities being compa-
rable to each other among various subclasses of com-
pounds (1-3 versus 4-6, respectively, and 7-9 versus
10-12, respectively). (iii) Comparison between the
furoyl class and the remaining series suggested that the
terminal fragment was not a fundamental key in
influencing R1 affinity in compounds bearing an o-
methoxy and o-ethoxy substituent (1,2 versus 7,8 and
13,14, respectively, and 4,5 versus 10,11, respectively).
On the contrary, among the isopropoxy derivatives,
compounds belonging to the furoyl series showed affinity
values of about 6-fold (3 versus 9) and 4-fold (6 versus
12) lower than the corresponding benzodioxane deriva-
tives. Similarly, 3 was 5-fold more active than 15.
Regarding the R2 affinity values, while in the furoyl
series higher affinity was associated with a larger
substituent (as for R1-AR affinity), both the benzodiox-
ane and alkoxyphenoxyethyl derivatives showed lower
affinity with bulkier substituents. Moreover, the inter-
R
D
4.0 ( 0.3
2.0 ( 0.2
Compounds 2-15 have been submitted to an Italian patent.4
a
b a, 2-furoyl; b, 1,4-benzodioxan-2-yl; c, 2-(2-methoxyphenoxy)ethyl;
d, 2-(2-ethoxyphenoxy)ethyl. c The Ki binding data were calculated
as described in the Experimental Section. The Ki values are the
mean ( SD of a series of separate assays, each performed in
triplicate. Inhibition constants (Ki) were calculated according to
the equation of Cheng and Prusoff:5 Ki ) IC50/(1 + [L]/Kd) where
[L] is the radiolabeled ligand concentration and Kd its dissociation
constant. Kd of [3H]prazosin (P ) binding to rat cortex membranes
was 0.24 nM (R1), Kd of [3H]rauwolscine (R) binding to rat cortex
membranes was 4 nM (R2), and Kd of [3H]8-OH-DPAT (D) binding
d
to rat cortex membranes was 2 nM (5-HT1A). Compounds re-
ported elsewhere by our research group.2 e ND: not determined.
f Compounds reported elsewhere by our research group.1
(method B). Compounds 2 and 3 were obtained from 21a
with 1-(2-ethoxyphenyl)piperazine (22b) and 1-(2-iso-
propoxyphenyl)piperazine (22c), respectively, in isoamyl
alcohol and sodium carbonate (method C). Following
method C, while 16 was prepared from 21c by reaction
with 22b, compounds 13, 14, and 15 were obtained by
reaction between 21d and 1-(2-methoxyphenyl)pipera-
zine (22a ), 22b, and 22c, respectively. Finally, 7-9 were
obtained from the reaction between the intermediate
21b and 22a -c, respectively.
When the reaction between 18 and the piperazines
19a ,b was performed in an apolar aprotic solvent such
as dry dioxane instead of a polar protic solvent like ethyl
alcohol, the usual 4-chloro-5-substituted pyridazinones
20a ,b were obtained together with the corresponding
4-substituted-5-chloro isomers (23a ,b). Isomers were
easily separated by chromatography on a silica gel
column, eluting with EtOH/CH2Cl2. In particular, in-
termediates 23a ,b obtained in dry 1,4-dioxane and dry
KHCO3 (method D) starting from 19a ,b were in turn
alkylated following method B to give the corresponding
bromoalkyl derivatives 24a ,b. Following method C,

Brief Articles
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 16 3557
Sch em e 1a
a
Compounds: 1, R ) a, R1 ) OMe; 2, R ) a, R1 ) OEt; 3, R ) a, R1 ) OiPr; 4, R ) a, R1 ) OMe; 5, R ) a, R1 ) OEt; 6, R ) a, R1
)
OiPr; 7, R ) b, R1 ) OMe; 8, R ) b, R1 ) OEt; 9, R ) b, R1 ) OiPr; 10, R ) b, R1 ) OMe; 11, R ) b, R1 ) OEt; 12, R ) b, R1 ) OiPr; 13,
R ) d, R1 ) OMe; 14, R ) d, R1 ) OEt; 15, R ) d, R1 ) OiPr; 16, R ) c, R1 ) OEt; 17, R ) c, R1 ) OMe; 19a , R ) a; 19b, R ) b; 19c,
R ) c; 19d , R ) d; 20a , R ) a; 20b, R ) b; 20c, R ) c; 20d , R ) d; 21a , R ) a; 21b, R ) b; 21c, R ) c; 21d , R ) d; 23a , R ) a; 23b, R
) b; 24a , R ) a; 24b, R ) b. Reagents: (a) EtOH, Et3N; (b) Br(CH2)7Br, acetone, K2CO3; (c) 22a , 22b, or 22c, isoamyl alcohol, Na2CO3;
(d) dry 1,4-dioxane, KHCO3.
Ta ble 2. Intrinsic Activity of Compounds 3, 9, and 15 toward
R1-AR
designed, synthesized, and evaluated for their biological
properties. As a result, each of them was found to have
a
Ki toward R1 (nM)
a high affinity for R1-AR comparable to or higher (up to
4- to 5-fold higher) than the affinity of the reference
compound prazosin. Moreover, 8, belonging to the
benzodioxane class and retaining an R1-AR affinity in
the subnanomolar range (0.42 nM), was characterized
by a marked decrease in 5-HT1A affinity, thus leading
to an interesting 5-HT1A/R1 selectivity of about 120. As
a consequence, this compound has been chosen as a lead
to pursue R1 selectivity with respect to serotoninergic
5-HT1A affinity.
compd
-GTP
+GTP
GTP shift
3
9
15
0.047 ( 0.003
0.23 ( 0.03
0.28 ( 0.04
0.26 ( 0.05
0.081 ( 0.005
0.33 ( 0.05
0.22 ( 0.02
0.32 ( 0.06
1.7
1.4
0.8
1.2
prazosin
a
Displacement of [3H]prazosin from rat cerebral cortex mem-
branes in the absence and in the presence of 1 nM GTP. Values
are taken from three experiments, expressed as the mean ( SEM.
esting selectivity of 1 (R2/R1 ) 274) was lost mainly
because of an improvement of the R2 affinity profile, and
none of the studied compounds showed appreciable
selectivity, 42 being the highest R2/R1 ratio found for
12.
In summary, bulky alkoxy groups at the phenylpip-
erazine moiety in conjunction with larger (with respect
to the furoyl moiety) or conformationally flexible ter-
minal fragments are required for selectivity toward R1-
AR.
As far as 5-HT1A affinity was concerned, 8 was found
with an appreciable R1-AR selectivity (5-HT1A/R1 ratio
of 119), suggesting that the new pyridazinone-arylpip-
erazines can be good templates for the development of
novel R1 selective ligands with respect to the 5-HT1A
receptor.
Exp er im en ta l Section
Ch em istr y. Melting points were determined using a Kofler
hot-stage apparatus and are uncorrected. 1H NMR spectra
were recorded on a Bruker AC 200 MHz instrument in the
solvent indicated below. Chemical shift values (parts per
million) are relative to that for tetramethylsilane used as an
internal reference standard. Elemental analyses are within
(0.4% of theorical values. Precoated Kiesegel 60 F254 plates
(Merck) were used for TLC. The corresponding hydrochloride
derivatives were prepared by bubbling dry HCl into the dry
solution of the compound.
Syn th esis. Specific examples presented below illustrate the
general synthetic methods A-D.
Meth od A Exam ple. 4-Ch lor o-5-{4-[2-(2-eth oxyph en oxy)-
eth yl]p ip er a zin -1-yl}p yr id a zin -3(2H)-on e (20d ). A mixture
of 4,5-dichloropyridazin-3(2H)-one 18 (4.45 g, 27 mmol) and
1-[2-(2-ethoxyphenoxy)ethyl]piperazine 19d (7.30 g, 30 mmol)
in dry ethanol and Et3N was refluxed under stirring for 15 h.
The mixture was evaporated under reduced pressure and
purified by chromatography on a silica gel column, eluting with
a EtOH/CH2Cl2 mixture (6:94) to give a 50% yield of a white
Con clu sion s
On the basis of suggestions derived from our previous
work in the field of R1-AR antagonists, a number of novel
arylpiperazine-pyridazinone-containing compounds were
1
solid: mp 140-143 °C. H NMR (CDCl3) δ: 1.42 (t, 3H, J ) 6

3558 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 16
Brief Articles
Hz, CH3), 2.80 (m, 4H, H-pip), 2.95 (m, 2H, CH2), 3.45-3.50
(m, 4H, H-pip), 4.10 (quart 2H, CH2-CH3), 4.25 (t, 2H, J ) 6
Hz, CH2), 6.80-6.95 (m, 4H, H-arom), 7.68 (s, 1H, H6-pyrid),
11.82 (s, 1H, NH-pyrid).
1H NMR (CDCl3) δ: 2.60-2.79 (m, 6H, 4H-pip, CH2), 3.54-
3.59 (m, 4H, H-pip), 3.96-4.05 (m, 1H, CH-benzodioxan-),
4.28-4.42 (m, 2H, CH2-benzodioxan-), 6.75-6.90 (m, 4H,
H-arom), 7.60 (s, 1H, H6-pyrid), 11.29 (s, 1H, NH-pyrid).
Meth od B Exa m p le. 2-(7-Br om oh ep tyl)-4-ch lor o-5-{4-
[2-(2-e t h oxyp h e n oxy)e t h yl]p ip e r a zin -1-yl}p yr id a zin -
3(2H)-on e (21d ). A mixture of 20d (7.60 g, 20 mmol), 1,7-
dibromoheptane (7.75 g, 30 mmol), and dry potassium carbonate
(4.15 g, 30 mmol) in 70 mL of acetone was refluxed under
stirring for 22 h. The mixture was evaporated under reduced
pressure and purified by chromatography on a silica gel
column, eluting with a EtOH/CH2Cl2 mixture (3:97) to give
30% yield of dense oil. 1H NMR (CDCl3) δ: 1.25-1.45 (m, 9H,
3CH2, CH3), 1.76-1.85 (m, 4H, 2CH2), 2.75-2.80 (m, 4H,
H-pip), 2.89-2.93 (m, 2H, CH2), 3.35-3.45 (m, 6H, CH2, 4H-
pip), 4.00-4.20 (m, 6H, 3CH2), 6.88-6.95 (m, 4H, H-arom),
7.59 (s, 1H, H6-pyrid).
Meth od C Exa m p le. 2-{7-[4-(2-Meth oxyp h en yl)p ip er -
a zin -1-yl]h ep tyl}-4-ch lor o-5-{4-[2-(1,4-ben zod ioxa n yl)m -
eth yl]p ip er a zin -1-yl}p yr id a zin -3(2H)-on e (7). This com-
pound was obtained from 21b and 1-(2-methoxyphenyl)-
piperazine 22a following the same synthetic procedure applied
for 2. The mixture was refluxed under stirring for 6 h, and
the compound was purified by chromatography on a silica gel
column, eluting with a EtOH/CH2Cl2 mixture (5:95) to give a
50% yield of a dense oil. 1H NMR (CDCl3) δ: 1.25-1.47 (m,
6H, 3CH2), 1.76-1.79 (m, 2H, CH2), 2.30-2.42 (m, 2H, CH2),
2.58-2.78 (m, 10H, 8H-pip, CH2), 3.09-3.15 (m, 4H, H-pip),
3.37-3.41 (m, 4H, H-pip), 3.84 (s, 3H, OCH3), 3.95-4.11 (m,
5H, CH2-benzodioxan-, CH-benzodioxan-, CH2), 4.15-4.33 (m,
2H, CH2-benzodioxan-,), 6.80-6.90 (m, 8H, H-arom), 7.58 (s,
1H, H6-pyrid). For the corresponding hydrochloride: mp 62-
68 °C. Anal. (C35H47ClN6O4‚3HCl) C, H, N.
The corresponding 5-substituted isomer 20b was eluted with
EtOH/CH2Cl2 (5:95) to give 35% yield of a solid product.
Ack n ow led gm en t. Financial support provided by
the Italian MIUR (“Progettazione e Sintesi di Agenti
Neuroprotettivi”) is gratefully acknowledged. M.B. thanks
the Merck Research Laboratories for the 2002 Academic
Development Program Chemistry Award.
Su p p or tin g In for m a tion Ava ila ble: Details of the syn-
thesis and spectral data of some representative compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Refer en ces
(1) A portion of our research in this field was previously reported
in the following. Betti, L.; Floridi, M.; Giannaccini, G.; Manetti,
F.; Strappaghetti, G.; Tafi, A.; Botta, M. Bioorg. Med. Chem. Lett.
2003, 13, 171-173.
(2) Barbaro, R.; Betti, L.; Botta, M.; Corelli, F.; Giannaccini, G.;
Maccari, L.; Manetti, F.; Strappaghetti, G.; Corsano, S. Synthe-
sis, Biological Evaluation, and Pharmacophore Generation of
New Pyridazinone Derivatives with Affinity toward R1- and R2-
Adrenoreceptors. J . Med. Chem. 2001, 44, 2118-2132.
(3) Betti, L.; Botta, M.; Corelli, F.; Floridi, M.; Giannaccini, G.;
Maccari, L.; Manetti, F.; Strappaghetti, G.; Tafi, A.; Corsano,
S. R1-Adrenoceptor Antagonists. 4. Pharmacophore-Based De-
sign, Synthesis and Biological Evaluation of New Imidazo-,
Benzimidazo-, and Indolo-arylpiperazine Derivatives. J . Med.
Chem. 2002, 45, 3603-3611.
(4) Betti, L.; Botta, M.; Floridi, M.; Giannaccini, G.; Manetti, F.;
Strappaghetti, G. Pyridazinone Derivatives as R1-Adrenoceptor
Antagonists. Synthesis and their Application in the Field of
Health. Italian Patent RM2002A000362, J uly 5, 2002.
(5) Cheng, Y.-C.; Prusoff, W. H. Relationship between the Inhibition
Constant (Ki) and the Concentration of Inhibitor Which Causes
50 Per Cent Inhibition (IC50) of an Enzymatic Reaction. Biochem.
Pharmacol. 1973, 22, 3099-3108.
Meth od D Exa m p le. 4-{4-[(1,4-Ben zod ioxa n yl)-2-m e-
th yl]p ip er a zin -1-yl}-5-ch lor op yr id a zin -3(2H)-on e (23b).
A mixture of 1-[2-(1,4-benzodioxan)methyl]piperazine 19b
(0.989 g, 4.23 mmol), 18 (0.70 g, 4.23 mmol), and dry KHCO3
(0.42 g, 4 mmol) in 50 mL of dry 1,4-dioxane was refluxed
under stirring for 24 h. The mixture was filtered, and the
filtrate was evaporaed under reduced pressure. In particular,
the 4-substituted isomer 23b was eluted with EtOH/ CH2Cl2
(3:97) to give 62% yield of a solid product: mp 136-139 °C.
J M0307842