5,6,7,8-Tetrahydropyrido[4,3- c ]pyridazine: A lead-oriented scaffold with two diversity points

Article abstract of DOI:10.1055/s-0033-1339325

An approach to the derivatives of 5,6,7,8-tetrahydropyrido[4,3-c] pyridazine, a lead-oriented scaffold with two diversity points, was developed. The method included five steps starting from the readily available 4-piperidone derivatives and allowed for the preparation of the target compounds in 32-35% overall yields. The key step of the sequence included one-pot solvent-free reaction of the corresponding 4-piperidone derivative, glyoxylic acid, and hydrazine.

Full text of DOI:10.1055/s-0033-1339325

PAPER
▌2413
p5a,p6er,7,8-Tetrahydropyrido[4,3-c]pyridazine: A Lead-Oriented Scaffold with
Two Diversity Points
Tetrahydropyrido[4,3-c]pyridazines
Alexander V. Borisov,a Volodymyr V. Voloshchuk,a,b Maxim A. Nechayev,c Oleksandr O. Grygorenko*d
a
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
b
National Technical University of Ukraine ‘Kyiv Politechnic Institute’, Peremogy Avenue 37, Kyiv 03056, Ukraine
c
National University of Pharmacy, Pushkinska Street 53, Kharkiv 61002, Ukraine
d
National Taras Shevchenko University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine
Fax +380(44)5732643; E-mail: gregor@univ.kiev.ua
Received: 17.04.2013; Accepted after revision: 07.06.2013
O
R2
O
Abstract: An approach to the derivatives of 5,6,7,8-tetrahydropyr-
ido[4,3-c]pyridazine, a lead-oriented scaffold with two diversity
points, was developed. The method included five steps starting from
the readily available 4-piperidone derivatives and allowed for the
preparation of the target compounds in 32–35% overall yields. The
key step of the sequence included one-pot solvent-free reaction of
the corresponding 4-piperidone derivative, glyoxylic acid, and hy-
drazine.
NH
N
N
N
N
R1
N
N
2
4
1
3
R2
R1
H
N
N
Ph
H2N
N
N
N
N
Key words: nitrogen heterocycles, pyridazine, piperidine, nucleo-
philic substitution, lead-oriented synthesis
Figure 1
Derivatives of 1 have already proven their efficiency in
drug discovery: in the 1970s, endralazine (4) was intro-
duced as an antihypertensive agent.10 Surprisingly, almost
no attention has since been paid to the synthesis of deriv-
atives of general formula 2 or 3. The known approach
commenced from the 4-piperidone derivative 5;11 it was
transformed into compound 6 in four steps (Scheme 1).
Further modifications of 6 were limited to the synthesis of
endralazine (4) or its analogues, which were prepared via
reaction of the chloride 7 with hydrazine.
Pyridazine derivatives have attracted much interest in the
search for new drugs.1 In a recent review by Wermuth,
they were recognized as privileged structures for drug dis-
covery.2 Recently, pyridazine-based scaffolds were pro-
posed as possible analogues of nucleobases3 and α-helix
mimetics.4
Recent tendencies in drug discovery are shifting towards
using sp3-enriched conformationally restricted low-
molecular-weight templates as starting points in the design
of potential lead compounds.5 Fusion of the pyridazine
ring with a saturated heterocycle (e.g., piperidine) can
generate scaffolds of enhanced interest to drug discovery.
In this work, we propose an example of such a scaffold,
namely, 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine (1)
(Figure 1). It is important to note that apart from the sec-
ondary amine function of the piperidine ring, which can
be easily modified using the methods of combinatorial
chemistry, 1 contains an additional hidden diversity point
related to the pyridazine fragment. In particular, libraries
of compounds of general formula 2 or 3 can be designed.
Moreover, the values of relevant physicochemical proper-
ties of 1 (MW 135.2; Fsp3 0.43; cLogP –0.60; TPSA
37.81 Å2)6 are well below the common limits for the mo-
lecular fragments, such as ‘rule of three’.7 Therefore, 1
represents an example of a bifunctional conformationally
restricted scaffold8 potentially useful for lead-oriented
synthesis.9
O
COOEt
O
N
N
H
Br
COOEt
N
N
N
COOEt
N2H4
COOEt
5
COOEt
H
N
H
N
Cl
O
O
N
N
N
N
N
N
Br2
POCl3
N
COOEt
COOEt
COOEt
7a
6a
Scheme 1 Synthesis of 5,6,7,8-tetrahydropyrido[4,3-c]pyridazines
reported in the literature
SYNTHESIS 2013, 45, 2413–2416
Advanced online publication: 10.07.2013
DOI: 10.1055/s-0033-1339325; Art ID: SS-2013-Z0293-OP
© Georg Thieme Verlag Stuttgart · New York
Instead of using the four-step sequence reported in the lit-
erature,10,11 we have developed a simple one-pot proce-
dure for the preparation of the pyridazinone 6. The
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

2414
A. V. Borisov et al.
PAPER
The solvents were purified according to standard procedures. All
starting materials were purchased from Acros, Merck, Fluka, or
UORSY. Analytical TLC was performed using Polychrom SI F254
plates. Column chromatography was performed using Kieselgel
Merck 60 (230–400 mesh) as the stationary phase. 1H and 13C NMR
spectra were recorded on a Bruker 170 Avance 500 spectrometer
[500 MHz (1H) and 125 MHz (13C)], downfield from TMS (1H, 13C)
as an internal standard. Mass spectra were recorded on an Agilent
1100 LCMSD SL instrument [chemical ionization (APCI) and
Agilent 5890 Series II 5972 GCMS instrument [electron impact ion-
ization (EI)].
method commenced from 5a or 5b, which can be easily
obtained by derivatization of commercially available 4-
piperidone hydrochloride with the corresponding chloro-
formate.12 The key step in the synthesis included heating
of 5 with glyoxylic acid monohydrate in the presence of a
catalytic amount of potassium acetate without solvent at
80 °C, followed by careful addition of hydrazine hydrate
(Scheme 2).13 Although the yield of 6a and 6b was mod-
erate (55–72%), the robustness of the synthetic operations
as well as the availability of the starting materials made
this method preferable.
Alkyl 3-Oxo-3,5,7,8-tetrahydropyrido[4,3-c]pyridazine-6(2H)-
carboxylates 6a,b; General Procedure
Glyoxalic acid monohydrate (47 g), KOAc (2 g), and piperidone 5
(0.5 mol) were added to a 1-L reactor equipped with a mechanical
stirrer. The resulting mixture was heated at 80 °C (internal temper-
ature control) for 3 h. Hydrazine hydrate (27.5 mL) was added por-
tionwise with stirring (CAUTION! Very exothermic reaction).
After the vigorous reaction had ceased, the mixture was stirred for
an additional 10 min, diluted with MeOH (400 mL), and cooled to
r.t. The precipitate was filtered off and washed with MeOH (40 mL)
to give pure 6.
H
N
Cl
O
N
O
N
N
1. (HO)2CHCOOH,
KOAc (cat.)
POCl3
Et3N (cat.)
2. N2H4⋅xH2O
N
N
N
COOR
COOR
COOR
5a R = Et
5b R = Bn
6a R = Et, 55%
6b R = Bn, 72%
7a R = Et, 92%
7b R = Bn, 87%
Ethyl 3-Oxo-3,5,7,8-tetrahydropyrido[4,3-c]pyridazine-6(2H)-
Scheme 2 Synthesis of intermediates 6 and 7
carboxylate (6a)
White powder; yield: 207 g (55%); mp 174–176 °C (Lit.11 165–168
°C).
Reaction of 6a or 6b with phosphoryl chloride in the pres-
ence of a catalytic amount of triethylamine gave chlorides
7a and 7b in 92% and 87% yields, respectively. The reac-
tivity of 7 towards nucleophilic substitution of the chlo-
rine atom was low. In particular, reaction of 7a with N-
nucleophiles (such as aliphatic amines and hydrazine) was
accomplished only by heating in an autoclave at 120 °C or
by microwave irradiation (Scheme 3). Nevertheless, the
corresponding derivatives 8a–d were obtained in 60–95%
yields. Reaction of 7 and liquid ammonia or its aqueous
solution did not give satisfactory results under any condi-
tions studied; nevertheless, compound 8e was easily ob-
tained from 8d in 78% yield using catalytic
hydrogenation. Deprotection of 8 by acidic hydrolysis
gave the corresponding amines 9a–e (73–77% yields).
1H NMR (400 MHz, DMSO-d6): δ = 12.81 (br s, 1 H), 6.78 (s, 1 H),
4.50 (s, 2 H), 4.09 (q, J = 7.0 Hz, 2 H), 3.64 (t, J = 6.0 Hz, 2 H), 2.72
(t, J = 6.0 Hz, 2 H), 1.21 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 160.4, 154.6, 142.4, 140.2,
124.9, 61.1, 43.8, 40.9, 28.0, 14.6.
Anal. Calcd for C10H13N3O3: C, 53.81; H, 5.87; N, 18.82. Found:
C, 53.97; H, 5.60; N, 18.74.
Benzyl 3-Oxo-3,5,7,8-tetrahydropyrido[4,3-c]pyridazine-
6(2H)-carboxylate (6b)
White powder; yield: 42 g (72%); mp 187–189 °C .
1H NMR (500 MHz, DMSO-d6): δ = 12.33 (s, 1 H), 7.06–6.72 (m,
J = 14.0 Hz, 5 H), 6.28 (s, 1 H), 4.61 (s, 2 H), 4.02 (s, 2 H), 3.15 (s,
2 H), 2.22 (s, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 160.39, 154.45, 142.36,
136.65, 128.39, 127.87, 127.60, 124.92, 66.52, 43.86, 27.97.
MS (CI): m/z = 286 (M + H+).
R1
R1
N
Cl
N
N
Anal. Calcd for C15H15N3O3: C, 63.15; H, 5.30; N, 14.73. Found:
C, 63.20; H, 5.34; N, 14.74.
N
H
N
R2
N
N
N
R2
N
R2
R1
1. aq HBr
2. NaOMe
Alkyl 3-Chloro-7,8-dihydropyrido[4,3-c]pyridazine-6(5H)-car-
boxylates 7a,b; General Procedure
H2O, 120 °C
N
N
N
H
POCl3 (150 mL) and Et3N (0.5 mL) were added to 6 (0.2 mol). The
resulting mixture was heated under an argon atmosphere at 80 °C
for 3 h, and then cooled. Most of the POCl3 was removed in vacuo,
and the residue was poured into a mixture of ice (1 kg) and 25% aq
NH3 (1 L). The product was extracted with CHCl3 (500 mL). The
extract was dried (Na2SO4) and evaporated in vacuo. The brownish
residue contained >98% of the target compound. After purification
of the crude product by flash chromatography (CHCl3), pure 7 was
obtained. Alternatively, 7 can be purified by recrystallization
(MeOH).
COOEt
COOEt
9a R1 = H, R2 = Me, 77%
9b R1 = H, R2 = Et, 76%
9c R1 = R2 = Me, 73%
9e R1 = R2 = H, 74%
7a
8a R1 = H, R2 = Me, 90%
8b R1 = H, R2 = Et, 83%
8c R1 = R2 = Me, 93%
H2, RaNi
8d R1 = H, R2 = NH2, 61%
87%
8e R1 = R2 = H
Scheme 3
Ethyl 3-Chloro-7,8-dihydropyrido[4,3-c]pyridazine-6(5H)-car-
In conclusion, a convenient five-step reaction sequence
was developed for the synthesis of 3-substituted 5,6,7,8-
tetrahydropyrido[4,3-c]pyridazine derivatives, starting
from readily available 4-piperidones, in 32–35% overall
yields.
boxylate (7a)
White solid; yield: 48 g (92%); mp 109–111 °C (MeOH) (Lit.11
105–107 °C).
1H NMR (500 MHz, DMSO-d6): δ = 7.83 (s, 1 H), 4.66 (s, 2 H), 4.10
(q, J = 7.0 Hz, 2 H), 3.74 (t, J = 6.0 Hz, 2 H), 3.09 (t, J = 6.0 Hz, 2
H), 1.23 (t, J = 7.0 Hz, 3 H).
Synthesis 2013, 45, 2413–2416
© Georg Thieme Verlag Stuttgart · New York

PAPER
Tetrahydropyrido[4,3-c]pyridazines
2415
13C NMR (125 MHz, DMSO-d6): δ = 157.4, 154.6, 153.7, 137.1,
125.3, 61.2, 43.5, 40.2, 28.8, 14.5.
13C NMR (125 MHz, DMSO-d6): δ = 160.0, 155.2, 148.0, 134.2,
110.4, 61.5, 44.4, 41.7, 29.0, 15.1.
MS (CI): m/z = 242/244 (M + H+).
MS (CI): m/z = 223 (M + H+).
Anal. Calcd for C10H12ClN3O2: C, 49.70; H, 5.00; Cl, 14.67;
N, 17.39. Found: C, 49.91; H, 4.69; Cl, 14.73; N, 17.05.
Anal. Calcd for C10H14N4O2: C, 54.04; H, 6.35; N, 25.21. Found:
C, 54.30; H, 6.06; N, 25.39.
Benzyl 3-Chloro-7,8-dihydropyrido[4,3-c]pyridazine-6(5H)-
carboxylate (7b)
5,6,7,8-Tetrahydropyrido[4,3-c]pyridazin-3-amines 9; General
Procedure
White solid; yield: 27 g (87%); mp 95–97 °C (MeOH).
Pyridazine 8 (0.5 mol) was dissolved in 47% aq HBr (230 mL,
2 mol). The resulting mixture was refluxed under argon atmosphere
for 12 h, then cooled and evaporated in vacuo. The residue was trit-
urated with i-PrOH (300 mL), the solid was filtered, washed with
i-PrOH (100 mL) and dried in vacuo to give 9·2 HBr as the hydro-
bromide. Unlike the corresponding hydrochlorides, 9·2 HBr were
not hygroscopic. Characterization of 9b–d·2 HBr is given in the
Supporting Information.
1H NMR (500 MHz, DMSO-d6): δ = 7.85 (s, 1 H), 7.39 (s, 5 H), 5.15
(s, 2 H), 4.72 (s, 2 H), 3.79 (s, 2 H), 3.11 (s, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 157.88, 154.94, 154.23,
137.55, 137.08, 134.68, 128.91, 128.42, 128.16, 125.93, 79.66,
67.16, 44.08, 40.92, 29.31.
MS (CI): m/z = 304/306 (M + H+).
To obtain 9 as a free base, 9·2 HBr (0.1 mol) was treated with 1 M
NaOMe in MeOH (0.2 mol). The precipitate was filtered, and the
filtrate was evaporated in vacuo. The solid residue was extracted
with CHCl3 (3 × 100 mL), and the combined extracts were evapo-
rated in vacuo to give 9. Characterization of 9b–d is given in the
Supporting Information.
Anal. Calcd for C15H14ClN3O2: C, 59.31; H, 4.65; Cl, 11.67;
N, 13.83. Found: C, 49.91; H, 4.69; Cl, 14.73; N, 17.05.
Ethyl 3-Amino-7,8-dihydropyrido[4,3-c]pyridazine-6(5H)-car-
boxylates 8a–d; General Procedure Method A
Compound 7a 1.21 g (5 mmol), the corresponding amine (15 mmol,
concd in H2O), and LiCl (30 mg) were sealed in a 5-mL MW vial
and irradiated in a Emrys Creator™ microwave oven at 120 °C and
normal absorption level for 10 min. Then the vial was unsealed, and
the mixture was diluted with 5% aq NaHCO3 (10 mL). The precip-
itate formed was filtered, washed with H2O (1 mL), and dried. The
crude product 8 was of >95% purity. Analytical samples were ob-
tained by flash chromatography (gradient CHCl3–EtOAc). Charac-
terization of 8b–d is given in the supplementary information.
N-Methyl-5,6,7,8-tetrahydropyrido[4,3-c]pyridazin-3-amine
(9a)
Yellowish crystals; yield: 67 g (77%); mp 150–152 °C.
1H NMR (500 MHz, DMSO-d6): δ = 6.48 (s, 1 H), 6.44 (s, 1 H), 3.72
(s, 2 H), 2.97 (d, J = 4.7 Hz, 2 H), 2.81 (d, J = 4.7 Hz, 3 H), 2.75 (d,
J = 5.5 Hz, 2 H), 2.43 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 152.9, 146.7, 137.6, 119.3,
95.9, 43.2, 29.3, 25.2.
MS (CI): m/z = 165 (M + H+).
Ethyl 3-Amino-7,8-dihydropyrido[4,3-c]pyridazine-6(5H)-car-
boxylates 8a–d; General Procedure Method B
Chloride 7a (121 g, 0.5 mol), the corresponding amine (1.5 mol,
concd in H2O), and LiCl (1 g) were sealed in an autoclave and heat-
ed with stirring at 120 °C for 5 h. The mixture was cooled, diluted
with a soln of K2CO3 (35 g) in H2O (200 mL), and the product was
extracted with CHCl3 (3 × 100 mL). The combined extracts were
dried (K2CO3) and evaporated in vacuo. The residue was purified by
flash chromatography (gradient CHCl3–EtOAc) to give 8. Charac-
terization of 8b–d is given in the Supporting Information.
Anal. Calcd for C8H12N4: C, 58.52; H, 7.37; N, 34.12. Found:
C, 58.25; H, 7.19; N, 34.43.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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boxylate (8e)
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2413–2416

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PAPER
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© Georg Thieme Verlag Stuttgart · New York