Synthesis of New 4,5-Dihydro-3(2H)-pyridazinone Derivatives

Article abstract of DOI:10.1081/SCC-120028351

A novel series of compounds structurally related to nonpeptide angiotensin II (AII) receptor antagonists derived from 4,5-dihydro-3(2H)-pyridazinones has been prepared. In these compounds, the spacer is linked to the C4 of the heterocyclic ring.

Full text of DOI:10.1081/SCC-120028351

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Synthesis of New 4,5‐Dihydro‐3(2H)‐pyridazinone
Derivatives
E. Meyer a , A. C. Joussef a , H. Gallardo a & L. de B. P. de Souza a
a Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis,
SC–88040‐900, Brazil
Version of record first published: 20 Aug 2006.
To cite this article: E. Meyer, A. C. Joussef, H. Gallardo & L. de B. P. de Souza (2004): Synthesis of New
4,5‐Dihydro‐3(2H)‐pyridazinone Derivatives, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 34:5, 783-793
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 5, pp. 783–793, 2004
Synthesis of New 4,5-Dihydro-3(2H)-
pyridazinone Derivatives
*
E. Meyer, A. C. Joussef, H. Gallardo, and L. de B. P. de Souza
´
Departamento de Quımica, Universidade Federal de Santa Catarina,
´
Florianopolis, Brazil
ABSTRACT
A novel series of compounds structurally related to nonpeptide angio-
tensin II (AII) receptor antagonists derived from 4,5-dihydro-3(2H)-
pyridazinones has been prepared. In these compounds, the spacer is
linked to the C4 of the heterocyclic ring.
Key Words: Pyridazinone; Angiotensin II; Renin-angiotensin system;
Blood pressure.
The renin-angiotensin system (RAS) plays an important role in the
regulation of blood pressure through the actions of angiotensin II (AII) and
thus is an appropriate target for therapeutic intervention in hypertension. AII,
an octapeptide that is formed within the RAS from angiotensin I (AI) by the
*
´
Correspondence: H. Gallardo, Departamento de Quımica, Universidade Federal de
´
Santa Catarina, Florianopolis, SC–88040-900, Brazil; E-mail: hugo@qmc.ufsc.br.
783
DOI: 10.1081/SCC-120028351
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Meyer et al.
angiotensin-converting enzyme (ACE) is one of the most powerful vaso-
constrictors known. On the basis of the success of ACE inhibitors, such as
captopril and enalapril as antihypertensive drugs, considerable efforts have
been devoted to exploring novel ways to interfere with the renin-angiotensin
cascade. AII exerts its actions through specific receptors on the cell surface,
which can be blocked by selective receptor antagonists. Two major receptor
subtypes, designated AT1 and AT2, have been identified in a variety of human
and animal tissues. The AT1 receptor mediates most of the known physio-
logical effects of AII, including the maintenance of blood pressure.[1,2]
The discovery by DuPont of the first potent and orally active nonpeptide
AII antagonist, losartan (Cozaar) opened a new phase of research to
investigate AT1-selective agents for the treatment of hypertension. Since then,
several nonpeptide AII receptor antagonists have been reported.[3–6] In the
great majority of these compounds, the spacer is linked to a nitrogen atom of
five- or six-membered heterocycles (the so called “northern moiety”)
(e.g., Eprosartan, Fig. 1).[7] Only few examples are known in which the
spacer is linked to a carbon atom of the northern moiety (e.g., SL 910102,
Fig. 1).[3]
With the aim of discovering new AII receptor antagonists,[8,9] we became
interested in synthesizing a series of C-linked spacer 6-aryl-4,5-dihydro-
3(2H)-pyridazinones of general formula 1 (Fig. 1), in which the spacer is
linked to the C4 of the heterocyclic ring. Herein we describe the synthesis of
these compounds.
The synthesis of the target dihydropyridazinones was successfully
accomplished by applying the Toth methodology[10,11] (Sch. 1). In this proto-
´
col, the key-step consists of the reductive condensation of 2,2-dimethyl-1,3-
dioxane-4,6-dione (Meldrum’s acid) (4)[12] with aromatic aldehydes in
triethylammonium formate (TEAF), to furnish the monoalkylated derivative
(3). According to this approach, the aldehyde used in the first step determines
Figure 1. Eprosartan and SL 910102.

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Synthesis of New 4,5-Dihydro-3(2H)-pyridazinone Derivatives
785
Scheme 1.
the structure of the spacer. Regarding the synthesis, the choice of this
methodology was based primarily on its mildness, along with the availability
or ease of preparation of the aldehydes to form the spacer moiety, allowing the
introduction of a variety of substituents.
In order to prepare a model compound possessing a phenoxyphenylacetic
acid moiety (enhanced AT2 binding potency has been reported in AT1-selective
antagonists in which the biphenyltetrazole moiety is replaced by a phenoxy-
phenylacetic acid element),[13] the commercially available 4-hydroxybenzalde-
hyde was alkylated with methyl a-bromophenylacetate (6) (prepared by
benzylic bromination of methyl phenylacetate (5) with N-bromosuccinimide
(NBS) in the presence of dibenzoylperoxide as the radical initiator) under
phase-transfer catalysis conditions,[14] to furnish 7 in 71% yield. Reductive
condensation of the aldehyde 7 with Meldrum’s acid (4) in TEAF afforded the
monoalkylated derivative 8. Alkylation of 8 with 40-bromophenacyl bromide
led to the dialkylated derivative 9, which upon treatment with hydrazine
provided the dihydropyridazinone 10. Saponification of the methyl ester in 10 in
aqueous methanolic NaOH gave the acid 11 (Sch. 2).
Two other pyridazinone derivatives bearing a phenyl spacer were
synthesized using the same methodology, as outlined in Sch. 3. Alkylation of
4-formylbenzoic acid (12) with CH3I in the presence of 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) furnished the ester 13, which by condensation
with Meldrum’s acid in TEAF yielded the monoalkylated derivative 14.
Alkylation of 14 with 40-bromophenacyl bromide and phenacyl bromide
afforded the desired dialkylated products 15a and 15b, respectively.
Treatment of 15a and 15b with hydrazine in DMF followed by hydrolysis
of the esters provided the acids 17a and 17b, respectively (Sch. 3, Table 1).
The dihydropyridazinone derivatives 11, 17a, and 17b are currently under
pharmacological evaluation and the results will be published elsewhere.
Melting points were measured using a Kofler hot-stage apparatus
´
(Microquımica APF-301) and are uncorrected. Each analytical sample was
homogeneous as confirmed by TLC performed on silica gel (Kieselgel 60 F

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Meyer et al.
Scheme 2.
254-Merck) plates, which were visualized with UV light. Flash chromatog-
1
raphy was performed with Merck silica gel 60 (230–400 mesh). H NMR
spectra were determined on a Bruker AW-200 (200 MHz) instrument, with
tetramethylsilane (TMS) as the internal standard and 13C NMR spectra were
recorded on a Bruker (50.3 MHz) spectrometer. Elemental analyses were
Scheme 3.

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Synthesis of New 4,5-Dihydro-3(2H)-pyridazinone Derivatives
Table 1. Compounds 15–17 prepared.
787
Product
X
Yield (%)
15a
15b
16a
16b
17a
17b
Br
H
73
68
75
75
98
95
Br
H
Br
H
within +0.4% of theoretical values and were determined on a Perkin-Elmer
2400 instrument.
Methyl a-Bromophenylacetate (6)
To a solution of methyl phenylacetate (3.00 g, 19.98 mmol) in CCl4
(50 mL) NBS (3.56 g, 19.98 mmol) and benzoyl peroxide (484 mg, 2.00 mmol)
were added. The solution was heated under reflux for 4 hr. The resultant
suspension was allowed to cool to r.t., the succinimide was filtered off and
washed with CCl4. The filtrate was evaporated to afford the crude product as
an oil (4.58 g, quantitative, 86% purity by 1H NMR), suitable for use without
further purification. 1H NMR (CDCl3): d ¼ 3.73 (s, 3H), 5.36 (s, 1H), 7.31–
7.54 (m, 5H).
Methyl 4-Formylphenoxyphenylacetate (7)
To a mixture of 4-hydroxybenzaldehyde (2.00 g, 16.38 mmol), methyl
a-bromophenylacetate (6) (4.13 g, 18.02 mmol) and tetrabutylammonium
bromide (TBAB) (529 mg, 1.64 mmol) in CH2Cl2 (70 mL), a solution of
NaOH (721 mg, 18.02 mmol) in H2O (5 mL) was added. The biphasic mixture
was agitated with a vibromixer at room temperature for 16 hr. The organic
layer was separated and the aqueous phase was extracted twice with 20 mL
portions of CH2Cl2. The combined organic extracts were washed with brine
(3 ꢀ 30 mL) and dried (MgSO4). The solvent was removed under vacuum and
the residue was flash chromatographed on SiO2 (hexane-EtOAc, 9 : 1) to
furnish the product as an oil, which upon trituration with Et2O-hexane
solidified as a white powder. Yield: 3.14 g (71%); mp 878C. IR (KBr): 2836,
2750, 1754, 1690, 1252, 1216 cm21. 1H NMR (CDCl3): d ¼ 3.75 (s, 3H), 5.73
(s, 1H), 7.05 (d, J ¼ 8.8 Hz, 2H), 7.39–7.58 (m, 5H), 7.83 (d, J ¼ 8.8 Hz, 2H),

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788
Meyer et al.
9.88 (s, 1H). Anal. Calcd. for C16H14O4: C, 71.10; H, 5.22. Found: C, 71.15;
H, 5.23.
Methyl [4-(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-
ylmethyl)phenoxy]phenylacetate (8)
To an ice cooled solution of aldehyde 7 (2.50 g, 9.25 mmol) in triethyl-
ammonium formate (TEAF) (15 mL), Meldrum’s acid (1.33 g, 9.25 mmol)
was added. The cooling bath was removed and the mixture was stirred at r.t.
until the evolution of CO2 ceased (about 3 days). The reaction mixture was
poured into ice/water and acidified with aqueous HCl (6 N) until pH 2. The
resulting precipitate was collected by filtration, washed with H2O and
recrystallized from EtOAc/hexane to afford the product as a white powder.
Yield: 2.36 g (64%); mp 112.5–1138C. IR (KBr): 3002, 1792, 1754,
1212 cm21
.
1H NMR (CDCl3): d ¼ 1.43 (s, 3H), 1.71 (s, 3H), 3.41
(d, J ¼ 4.8 Hz, 2H), 3.71 (t, J ¼ 4.8 Hz, 1H), 3.72 (s, 3H), 5.60 (s, 1H), 6.85
(d, J ¼ 8.6 Hz, 2H), 7.20–7.57 (m, 7H). Anal. Calcd. for C22H22O7: C, 66.32;
H, 5.57. Found: C, 66.37; H, 5.45.
Methyl f4-[5-[2-(4-Bromophenyl)-2-oxoethyl]-2,2-dimethyl-
4,6-dioxo-1,3-dioxan-5-ylmethyl]phenoxygphenylacetate (9)
To a solution of 8 (2.00 g; 5.02 mmol) in dry DMF (20 mL), anhydrous
sodium acetate (432 mg, 5.27 mmol), acetic acid (0.1 mL) and 40-bromo-
phenacyl bromide (1.46 g, 5.27 mmol) were added. The resulting mixture was
stirred at room temperature for 24 hr and then poured into a mixture of ice/
water and saturated aqueous solution of Na2CO3 (20 mL). The resulting
precipitate was filtered off, washed with cold water and recrystallized from
EtOAc/hexane to give 9 as a white solid. Yield: 2.06 g (69%); mp 221–
1
2228C. IR (KBr): 1758, 1738, 1680, 1274, 1234 cm21. H NMR (CDCl3):
d ¼ 0.66 (s, 3H), 1.93 (s, 3H), 3.23 (s, 2H), 3.73 (s, 3H), 3.97 (s, 2H), 5.64
.
(s, 1H), 6.86–7.82 (m, 13H). Anal. Calcd. for C30H27BrO8 0.2C6H14: 61.17;
H, 4.90. Found: C, 61.31; H, 4.85.
Methyl f4-[6-(4-Bromophenyl)-3-oxo-4,5-dihydro-2H-
pyridazin-4-ylmethyl] phenoxygphenylacetate (10)
To a stirred solution of 9 (1.90 g, 3.19 mmol) in DMF (15 mL) at 08C,
hydrazine monohydrate (0.62 mL, 12.76 mmol) was added dropwise. The

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Synthesis of New 4,5-Dihydro-3(2H)-pyridazinone Derivatives
789
reaction was left to reach r.t., while stirring was continued for 24 hr. The
reaction mixture was poured into ice/water and acidified with aq. HCl (6 N) to
pH 4–5. The precipitated solid was recovered by filtration and purified by
column chromatography (silica gel; hexane/EtOAc, 3 : 2) to furnish the
product as a white solid. Yield: 1.44 g (89%); mp 161.5–162.58C. IR (KBr):
1
3228, 1762, 1664, 1244 cm21. H NMR (CDCl3): d ¼ 2.49–2.84 (m, 4H),
3.13–3.30 (m, 1H), 3.75 (s, 3H), 5.61 (s, 1H), 6.87 (d, J ¼ 8.6 Hz, 2H), 7.04
(d, J ¼ 8.6 Hz, 2H), 7.38–7.56 (m, 9H), 8.73 (bs, 1H). 13C NMR (CDCl3):
d ¼ 26.86, 35.09, 38.40, 53.34, 79.34, 116.36, 124.92, 127.73, 128.02, 129.49,
129.72, 130.96, 131.50, 132.43, 135.07, 135.96, 150.07, 156.93, 169.98,
171.01. Anal. Calcd. for C26H23BrN2O4: C, 61.55; H, 4.57; N, 5.52. Found: C,
61.43; H, 4.50; N, 5.60.
f4-[6-(4-Bromophenyl)-3-oxo-4,5-dihydro-2H-pyridazin-4-
ylmethyl]phenoxyg phenylacetic acid (11)
To a solution of the methyl ester 10 (1.30 g, 2.56 mmol) in MeOH
(20 mL), a solution of NaOH (307 mg, 7.68 mmol) in H2O (2 mL) was added,
and the resulting mixture was stirred at 708C for 1 hr. After cooling, the
solvents were removed under vacuum, and the residue was dissolved in H2O
(20 mL). The solution was adjusted to pH 3 with aqueous HCl (6 N), and the
resulting precipitate was recovered by filtration, washed with H2O and dried
under vacuum to provide the acid 11 as a white powder. Yield: 1.11 g (88%);
mp 105.5–106.58C. IR (KBr): 3247, 1726, 1670, 1233 cm21 1H NMR
.
(DMSO-d6): d ¼ 2.51–3.04 (m, 5H), 5.76 (s, 1H), 6.87 (d, J ¼ 8.5 Hz, 2H),
7.11 (d, J ¼ 8.5 Hz, 2H), 7.38–7.61 (m, 9H), 11.06 (s, 1H). 13C NMR
(DMSO-d6): d ¼ 26.09, 33.80, 36.53, 77.35, 115.02, 122.67, 127.33, 127.50,
128.56, 130.21, 130.94, 131.47, 135.23, 136.31, 148.26, 155.73, 168.88,
170.98. Anal. Calcd. for C25H21BrN2O4: C, 60.86; H, 4.29; N, 5.68. Found:
C, 60.75; H, 4.21; N, 5.75.
Methyl 4-Formylbenzoate (13)
To a suspension of 4-formylbenzoic acid (12) (2.00 g, 13.32 mmol) in dry
CH3CN (40 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2.21 mL,
14.65 mmol) and CH3I (1.08 mL, 17.32 mmol) were added. The mixture
was stirred at r.t. for 1 hr (TLC) and then concentrated under vacuum. The
residue was dissolved in EtOAc (50 mL) and this solution was washed with
H2O (3 ꢀ 20 mL), aqueous HCl (0.4 N) (3 ꢀ 20 mL), saturated aqueous
NaHCO3 (3 ꢀ 20 mL) and brine (3 ꢀ 10 mL) and then dried (MgSO4). The

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Meyer et al.
solvent was removed under vacuum to afford 13 as a white solid. Yield: 1.92 g
(88%); mp 57–598C [lit. 59–638C (15)].
Methyl 4-(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-
ylmethyl)benzoate (14)
The title compound was prepared from 13 by the same procedure
described for the preparation of 8. Yield: 73%; mp 137–138.58C (acetone/
H2O). IR (KBr): 1787, 1750, 1720 cm21. 1H NMR (CDCl3): d ¼ 1.59 (s, 3H),
1.76 (s, 3H), 3.53 (d, J ¼ 5.0 Hz, 2H), 3.79 (t, J ¼ 5.0 Hz, 1H), 3.90 (s, 3H),
7.40 (d, J ¼ 8.2 Hz, 2H), 7.96 (d, J ¼ 8.2 Hz, 2H). Anal. Calcd. for C15H16O6:
C, 61.64; H, 5.52. Found: C, 61.72; H, 5.52.
The compounds 15a and 15b were prepared by a procedure similar to that
described for 9, starting from 14 and the appropriate a-haloketone.
Methyl 4-f5-[2-(4-Bromophenyl)-2-oxoethyl]-2,2-dimethyl-
4,6-dioxo-1,3-dioxan-5-ylmethylgbenzoate (15a)
Yield: 73%; mp 171–1728C (EtOAc/hexane). IR (KBr): 1764, 1727,
1
1684, 1277 cm21. H NMR (CDCl3): d ¼ 0.74 (s, 3H), 1.97 (s, 3H), 3.33
(s, 2H), 3.92 (s, 3H), 4.01 (s, 2H), 7.27 (d, J ¼ 8.1 Hz, 2H), 7.63 (d, J ¼ 8.5 Hz,
2H), 7.81 (d, J ¼ 8.5 Hz, 2H), 8.01 (d, J ¼ 8.1 Hz, 2H). Anal. Calcd. for
C23H21BrO7: C, 56.46; H, 4.33. Found: C, 56.47; H, 4.27.
Methyl 4-[2,2-Dimethyl-4,6-dioxo-5-(2-oxo-2-phenylethyl)-
1,3-dioxan-5-ylmethyl]benzoate (15b)
Yield: 68%; mp 152–1538C (EtOAc/hexane). IR (KBr): 1761, 1718,
1
1678, 1280 cm21. H NMR (CDCl3): d ¼ 0.75 (s, 3H), 1.99 (s, 3H), 3.35
(s, 2H), 3.92 (s, 3H), 4.07 (s, 2H), 7.26–8.03 (m, 9H). Anal. Calcd. for
C23H22O7: C, 67.31; H, 5.40. Found: C, 67.25; H, 5.20.
The dihydropyridazinones 16a and 16b were prepared in a manner
analogous to that used for 10, starting from 15a and 15b, respectively.

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791
Methyl 4-[6-(4-Bromophenyl)-3-oxo-4,5-dihydro-2H-
pyridazin-4-ylmethyl]benzoate (16a)
Yield: 75%; mp 203–2048C (MeOH/H2O). IR (KBr): 3226, 1714, 1661,
1
1282 cm21. H NMR (CDCl3): d ¼ 2.50–2.86 (m, 4H), 3.36–3.41 (m, 1H),
3.91 (s, 3H), 7.25 (d, J ¼ 8.0 Hz, 2H), 7.44–7.49 (s, 4H), 7.98 (d, J ¼ 8.0 Hz,
2H), 8.85 (s, 1H). Anal. Calcd. for C19H17BrN2O3: C, 56.87; H, 4.27; N, 6.98.
Found: C, 56.58; H, 4.23; N, 6.89.
Methyl 4-(3-Oxo-6-phenyl-4,5-dihydro-2H-pyridazin-4-
ylmethyl)benzoate (16b)
Yield: 75%; mp 163.5–1648C (MeOH/H2O). IR (KBr): 3217, 1720,
1
1662, 1280 cm21. H NMR (DMSO-d6): d ¼ 2.56–3.00 (m, 4H), 3.16–3.20
(m, 1H), 3.83 (s, 3H), 7.36–7.88 (m, 9H), 11.03 (s, 1H). Anal. Calcd. for
C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C, 70.58; H, 5.64; N, 8.63.
The acids 17a and 17b were synthesized by the same procedure described
for the preparation of 11.
4-[6-(4-Bromophenyl)-3-oxo-4,5-dihydro-2H-pyridazin-4-
ylmethyl]benzoic Acid (17a)
Yield: 98%; mp .2108C (gradual). IR (KBr): 3213, 1693, 1655 cm21. 1H
NMR (DMSO-d6): d ¼ 2.50–3.20 (m, 5H), 7.35 (d, J ¼ 8.1 Hz, 2H), 7.58
(s, 4H), 7.85 (d, J ¼ 8.1 Hz, 2H), 11.10 (s, 1H). Anal. Calcd. for
C18H15BrN2O3: C, 55.83; H, 3.90; N, 7.23. Found: C, 55.84; H, 4.04; N, 7.02.
4-(3-Oxo-6-phenyl-4,5-dihydro-2H-pyridazin-4-
ylmethyl)benzoic Acid (17b)
Yield: 95%; mp 247–2508C. IR (KBr): 3187, 1688, 1654 cm21. 1H NMR
(DMSO-d6): d ¼ 2.50–3.21 (m, 5H), 7.33–7.86 (m, 9H), 11.03 (s, 1H). Anal.
Calcd. for C18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C, 69.93; H, 5.20;
N, 9.04.

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ACKNOWLEDGMENTS
The authors are indebted to PRONEX (Brazil) and CNPq for financial
support of this work.
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