An efficient synthesis of novel 1,3-oxazolo[4,5-d]pyridazinones

Article abstract of DOI:10.1016/j.tetlet.2004.04.093

A convenient and versatile synthetic approach to substituted 1,3-oxazolo[4,5-d]pyridazinones is developed. The oxazole ring was formed upon reaction of 5-amino-4-hydroxy-3(2H)-pyridazinone with various carboxylic acid derivatives using a microwave-assisted procedure, which favors the reaction time and purity of the resulting products. The developed methodology is suitable for rapid, parallel, automated synthesis of oxazolopyridazinone libraries.

Full text of DOI:10.1016/j.tetlet.2004.04.093

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4693–4696
An efficient synthesis of novel 1,3-oxazolo[4,5-d]pyridazinones
Eugene B. Frolov, Frederick J. Lakner, Alexandre V. Khvat
and Alexandre V. Ivachtchenko*
Chemical Diversity Labs, Inc., 11558 Sorrento Valley Rd., Suite 5, San Diego, CA 92121, USA
Received 26 March 2004; revised 9 April 2004; accepted 16 April 2004
Abstract—A convenient and versatile synthetic approach to substituted 1,3-oxazolo[4,5-d]pyridazinones is developed. The oxazole
ring was formed upon reaction of 5-amino-4-hydroxy-3(2H)-pyridazinone with various carboxylic acid derivatives using a micro-
wave-assisted procedure, which favors the reaction time and purity of the resulting products. The developed methodology is suitable
for rapid, parallel, automated synthesis of oxazolopyridazinone libraries.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Synthetic 3(2H)-pyridazinones are important scaffolds
in drug discovery, with many of their analogs being used
in the treatment of various human pathological states.
They were described as nonsteroidal antiinflammatory
drugs (e.g. Emorfazone and related compounds1),
agents for therapeutic intervention of renal-urologic
(e.g. FK-8382), cardiovascular (e.g. EMD-572833),
respiratory (e.g. NIP-5024), and dermatologic diseases
(e.g. FR-1818775). According to these examples and due
to evident structural similarity to many physiologically
active heterocyclic-fused pyridazinones,6 1,3-oxazolo-
[4,5-d]pyridazinones represent promising synthetic
targets. Development of efficient synthetic approaches
to the related combinatorial scaffolds will provide a
valuable source of novel physiologically active agents.
elevated temperatures.8 Synthesis of several 2-substi-
tuted derivatives of oxazolo[4,5-d]pyridazine, such as
2-amino-7-chloroxazolo[4,5-d]pyridazine, was achieved
by the cyclization of the corresponding N-pyridazin-5-
ylformamide oximes.9 7-Chloro-2-phenyloxazolo[4,5-d]-
pyridazine10 and poly-2,6-oxazolo[4,5-d]pyridazine11
were also reported. However, the described synthetic
strategies have found limitations mainly due to lack of
versatility and low yields of the desired products.
Here we report a convenient and versatile synthetic
approach to novel 3,6-disubstituted 1,3-oxazolo[4,5-
d]pyridazine-2(3H),7(6H)-diones of general formula A
and 2,6-disubstituted 1,3-oxazolo[4,5-d]pyridazine-
7(6H)-ones of general formula B.
To the best of our knowledge, only a few oxazolo[4,5-d]-
pyridazines have previously been described. Thus,
synthesis of 4-hydroxypyridazinones from the correspond-
ing dicarboxylates has been reported.7 A synthetic
approach to oxazolo[4,5-d]pyridazin-2-ylacetamides has
also been proposed, using reaction of ortho-amino-
hydroxypyridazine with cyanoacetic acid amides at
O
O
R1
R1
O
N
O
N
N
N
N
N
R3
O
R2
B
A
5-Nitro-4-hydroxy-3(2H)-pyridazinones 6a,b were pre-
pared from the corresponding 4,5-dichloro derivatives
5a,b using a previously reported procedure12 (Scheme 1).
Solutions of 5a,b in N,N-dimethyl-formamide were
treated with water solution of sodium nitrite to afford
pure products in good yields (65–70%). The key inter-
mediates, 5-amino-4-hydroxy-3(2H)-pyridazinones 7a,b,
were then prepared using a catalytic reduction of 6a,b.
Keywords: 1,3-Oxazolo[4,5-d]pyridazinones; 5-Amino-4-hydroxy-3(2-
H)-pyridazinone; Microwave-assisted; Rapid; Parallel; Automated
synthesis.
* Corresponding author. Tel.: +1-858-794-4860; fax: +1-858-794-4931;
e-mail: av@chemdiv.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.093

4694
E. B. Frolov et al. / Tetrahedron Letters 45 (2004) 4693–4696
O
O
O
O
HO
O2N
R1
R1
Cl
Cl
R1
O
N
O
N
b
a
N
N
a
NH
N
N
N
N
N
O
O
8a
6a: R1 = H (65%)
6b: R1 = Ph (67%)
5a: R1 = H
5b: R1 = Ph
10a: R1 = Bn (67%)
10b: R1 = CH2CO2Et (62%)
9 (45%)
O
O
HO
b
Scheme 2. Reagents and conditions: (a) PhCH2Br, N-methylpyrroli-
done, Cs2CO3, 20 ꢁC, 4–6 h; (b) BnBr (10a) or ClCH2CO2Et (10b),
N-methylpyrrolidone, Cs2CO3, 50 ꢁC, 6–10 h.
O
O
c
NH
N
NH
N
6a
6b
N
H2N
H
7a (50%)
8a (42%)
All new 1,3-oxazolo[4,5-d]pyridazine-2(3H),7(6H)-
diones were characterized by 1H NMR, LCMS, and
HRMS spectral data.15
O
O
Ph
HO
Ph
O
O
e
d
N
N
N
N
N
Reaction of o-aminophenols with carboxylic acids or
their derivatives, such as acid chlorides, anhydrides,
esters, amides or nitriles, under thermal conditions is a
known method for the preparation of substituted
benzoxazoles.16 In the present work, we demonstrate
the utility of this approach to provide some substituted
H2N
H
8b (93%)
7b (99%)
Scheme 1. Synthesis of 1,3-oxazolo[4,5-d]pyridazine-2(3H),7(6H)-
diones. Reagents and conditions: (a) NaNO2, HCONMe2/H2O, reflux,
5 h; (b) H2/PtO2, EtOH/H2O, 50 ꢁC, 10% Pd/C, 80 ꢁC, reflux; (c) CDI,
1,4-dioxane, microwaves, 170 ꢁC, 15 min; (d) HCOONH4, 10% Pd/C,
EtOH, reflux, 20 min; (e) CDI, 1,4-dioxane, reflux, 30 min.
1,3-oxazolo[4,5-d]pyridazine-7(6H)-ones.
5-Amino-4-
hydroxy-3(2H)-pyridazinone 7a was used as a starting
compound for microwave-assisted formation of a series
of novel oxazolopyridazinones 11a–d (Scheme 3). A
mixture of 7a with the corresponding carboxylic acid in
N-methylpyrrolidone with addition of polyphosphoric
acid was irradiated in the microwave reactor17 at 230 ꢁC
for 15–20 min to afford a series of 2-substituted oxazolo-
pyridazinones 11a–d18 with 60–80% yields (Table 1).
There was observed clear advantage in using microwave
assistance for this reaction. The yields under microwaves
were considerable higher, compared to that observed
under traditional thermal conditions (based on LCMS
data).
A mild PtO2-catalyzed hydrogenation of 6a in 1:1 water–
ethanol solution gave amine 7a in 50% yield.13 We have
found these conditions to be optimal for synthesis of 7a.
At the same time, almost quantitative reduction of the
nitro group of 6b was achieved by using 5 equiv of
ammonium formate and a catalytic amount of palla-
dium on charcoal (10%) in ethanol for 15–20 min of
heating under reflux (95% isolated yield of 7b).
Access to 1,3-oxazolo[4,5-d]pyridazine-2(3H),7(6H)-
diones 8a,b was achieved by the reaction of 5-amino-
4-hydroxypyridazinones 7a,b with 1,10-carbonyldiimidaz-
ole (CDI) (Scheme 1). It should be noted that our
attempts to obtain 8a from 7a and CDI using traditional
(nonmicrowave) thermal conditions led to a complex
mixture of products. Only the microwave-assisted pro-
cedure afforded the desired product. The yield of the
isolated 8a was 42%. At the same time, reaction of 7b
with CDI proceeded rapidly, with higher yield (93%)
and did not require microwave assistance.
The resulting 2-substituted oxazolopyridazinones can be
alkylated with the appropriate alkylating agents under
the reaction conditions similar to those described for
Scheme 2.14 For instance, 2-bicyclo[2.2.1]hept-2-yl-
methyl derivative 11a was converted in 45–50% yields
into N6-substituted oxazolopyridazinones 12a,b upon
the treatment with benzyl bromide or ethyl chloroace-
Compounds 8a and 8b were found to be useful precur-
sors for a variety of novel N3- and N6-substituted 1,3-
oxazolo[4,5-d]pyridazine-2(3H),7(6H)-dione derivatives,
which were obtained in good yields from 8a and 8b by
reaction with appropriate electrophilic agents. As we
observed the NH-group at the position 3 in 8a is rela-
tively more active compared to NH- in the position 6.
Thus N3-benzyl derivative 9 was prepared from 8a and
stoichiometric quantity of benzyl bromide in the pres-
ence of cesium carbonate and in N-methylpyrrolidone at
the room temperature (Scheme 2).14 Subsequent reac-
tion of 9 with electrophilic agents, such as benzyl bro-
mide or ethyl chloroacetate, conducted at the same
conditions, but at a higher temperature and using some
excess of alkylating agents led to the N3,N6-disubsti-
tuted compounds 10a,b in good yields.
O
O
HO
O
N
a
NH
N
NH
N
R3
H2N
11a-d (60-80%)
7a
O
O
R1
O
O
N
b
N
NH
N
N
N
12a: R1 = Bn (45%)
12b: R1 = CH2CO2Et (48%)
11a
Scheme 3. Reagents and conditions: (a) R3-COOH, 15 wt % H3PO4 in
N-methylpyrrolidone, microwaves, 230 ꢁC, 15–20 min. (b) BnBr (12a)
or ClCH2CO2Et (12b), N-methylpyrrolidone, Cs2CO3, 30–50 ꢁC, 2 h.

E. B. Frolov et al. / Tetrahedron Letters 45 (2004) 4693–4696
4695
Table 1. Substituted 1,3-oxazolo[4,5-d]pyridazine-7(6H)-ones 11a–d
(Scheme 3)
dues by flash column chromatography (silica gel, 5–50%
THF–dichloromethane) afforded pure 11a–d in 60–80%
yields.
Compound
R
Yield (%)
75
11a
References and notes
1. Piaz, V. D.; Vergelli, C.; Giovannoni, M. P.; Scheideler,
M. A.; Petrone, G.; Zaratin, P. Farmaco 2003, 58, 1063–
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2. Akahane, A.; Katayama, H.; Mitsunaga, T.; Kato, T.;
Kinoshita, T.; Kita, Y.; Kusunoki, T.; Terai, T.; Yoshida,
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H.; Kitagawa, M. Chem. Pharm. Bull. 1998, 46, 602–609.
4. Yamamoto, A.; Iwama, T.; Takeda, H.; Nagai, H. Jpn. J.
Pharmacol. 1995, 68, 47–55.
11b
11c
11d
81
63
77
F
F
5. Tsubaki, K.; Taniguchi, K.; Tabuchi, S.; Okitsu, O.;
Hattori, K.; Seki, J.; Sakane, K.; Tanaka, H. Bioorg. Med.
Chem. Lett. 2000, 10, 2787–2790.
tate respectively, in the presence of cesium carbonate in
N-methylpyrrolidone (Scheme 3).
6. (a) Bakthavatchalam, R.; Gilligan, P. J. U.S. Patent
6271380, 2001; Chem. Abstr. 2000, 133, 074025y; (b)
Froissant, J.; Marabout, B.; Burnier, P.; Puech, F.;
Marguet, F. WO 0355884, 2003; (c) Giovannoni, M. P.;
Vergelli, C.; Chelardini, C.; Galeotti, N.; Bartolini, A.;
Dal Piaz, V. J. Med. Chem. 2003, 46, 1055–1059; (d) Dal
Piaz, V.; Giovannoni, M. P.; Castellana, C.; Palacios, J.
M.; Beleta, J.; Domenech, T.; Segarra, V. J. Med. Chem.
1997, 40, 1417–1421; (e) Ferzaz, B.; Brault, E.; Bourliaud,
G.; Robert, J. P.; Poughon, G.; Claustre, Y.; Marguet, F.;
Liere, P.; Schumacher, M.; Nowicki, J. P.; Fournier, J.;
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301, 1067–1078; (f) Bantick, J.; Perry, M.; Thorne, P.;
Cooper, M. U.S. Patent 6342601, 2002; Chem. Abstr.
1999, 131, 044836e.
In summary, we have reported a new convenient
approach to a variety of substituted 1,3-oxazolo[4,5-d]-
pyridazinones, using the reaction of 5-amino-4-hydroxy-
3(2H)-pyridazinone with various carboxylic acid deriv-
atives. Optimization of the synthetic route was achieved
by using a microwave-assisted methods, which have
received an increasing interest in organic synthesis.19
The developed methodology is suitable for rapid,
parallel, automated synthesis of oxazolopyridazinone
libraries, which are of interest as promising structural
analogs of biologically active pyridazinones.
7. Yokoyama, M.; Irie, M.; Sujino, K.; Kagemoto, T.; Togo,
H.; Funabashi, M. J. Chem. Soc., Perkin Trans. 1 1992,
2127–2134.
8. Harnisch, H. U.S. Patent 3985763, 1976; Chem. Abstr.
1976, 85, 050098p.
1. Typical procedures for the microwave-assisted
synthesis of substituted 1,3-oxazolo[4,5-d]pyridazinones
9. Merslavic, M.; Stanovnik, B.; Tisler, M. Monatsh. Chem.
1985, 116, 1447–1458.
1.1. 1,3-Oxazolo[4,5-d]pyridazine-2(3H),7(6H)-dione (8a)
10. Ruraishi, N. Chem. Pharm. Bull. 1958, 6, 641–644.
11. Kurkov, V. P. U.S. Patent 4505840, 1985, Chem. Abstr.
1984, 100, 166427c.
12. Reicheneder, F.; Dury, K. French Patent 1384304; Chem.
Abstr. 1965, 62, 16265b.
A mixture of 7a (0.541 g, 4.26 mmol), and 1,10-carbon-
yldiimidazole (0.770 g, 4.8 mmol) in 1,4-dioxane (6 mL)
was irradiated in microwave reactor at 170 ꢁC for
15 min. The reaction mixture was cooled, the precipitate
was filtered off and recrystallized (1,4-dioxane/water,
9:1) to afford 8a in 42% yield.
13. Rusting, N.; Frielink, J. G.; Van der Beek, G. F. Chem.
Abstr. 1965, 63, 11582g.
14. Alkylation was carried out using the following typical
procedure: A solution of benzyl bromide (1 mmol) in
dioxane (0.5 mL) was added to a mixture of 8a (1 mmol)
and Cs2CO3 (500 mg) in N-methylpyrrolidone (1 mL). The
reaction mixture was stirred at 20 ꢁC for 4–6 h. After that
time, the LCMS analysis of the reaction mixture indicated
the monoalkylated derivative 9 as a major product. The
di-alkylated derivative 10a was observed in trace amounts.
The reaction mixture was diluted with water (5 mL), and
then extracted with CH2Cl2 (3 · 5 mL). The combined
organic extract was dried and concentrated in vacuo.
Flash column chromatography of the residue (silica gel,
CH2Cl2–THF, 2:1) provided pure 9 (152 mg, 45%). Com-
pound 10a was obtained from the mono-alkylated deriv-
ative 9 by the reaction with 1.5 equiv of benzyl bromide at
50 ꢁC for 6–10 h using the above described procedure.
Other alkylation products described in this report were
prepared by the similar procedures.
1.2. 2-Substituted 1,3-oxazolo[4,5-d]pyridazine-7(6H)-
ones (11a–d)
A mixture of 7a (0.254 g, 2 mmol) and the corresponding
acid R3-COOH (3 mmol) in 0.5 mL of 15% polyphos-
phoric acid solution in N-methylpyrrolidone was irra-
diated in microwave reactor at 230 ꢁC for 15 min. Then,
the reaction mixtures were cooled and dissolved in a
minimal amount of dimethylsulfoxide. Water (5 mL)
was added and the mixtures were extracted with
dichloroethane (3 · 5 mL). The combined organic layers
were washed with water (2 · 5 mL) and aqueous sodium
bicarbonate (5%, 5 mL), dried, filtered, and concen-
trated in vacuo to give 11a–d. Purification of the resi-

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E. B. Frolov et al. / Tetrahedron Letters 45 (2004) 4693–4696
15. Selected data: Compound 8a: LCMS m=z 154 (M+ 1);
High resolution MS data (HRMS): determined by the
MALDI-FTMS method: M + 23þ 176.0073 (expected
176.0067). Compound 8b: 1H NMR (300 MHz, DMSO-
d6) d 7.4–7.5 (m, 5H), 8.33 (s, 1H); 13C NMR (DMSO-d6) d
126.3, 126.4, 128.7, 129.1, 131.8, 135.5, 141.5, 150.8, 153.8;
LCMS m=z 230.0 (M+ 1). Compound 9: 1H NM R
(300 MHz, DMSO-d6) d 5.04 (s, 2H), 7.28–7.44 (m, 5H),
8.31 (s, 1H), 13.46 (br s, 1H); LCMS m=z 244 (M+ 1).
HRMS: MHþ 244.0720 (expected 244.0717). Compound
17. Parallel solution-phase reactions were performed using a
laboratory synthesizer ‘CombiSyn-012-3000’ (Baru, M.;
Ivachtchenko, A. Russian Patent 2180609, 2002; Patent
PCT WO 02/087740 A1, 2002; Chem. Abstr. 2003, 138,
014907f).
18. Satisfactory analytical data (1H NMR and MS) were
obtained for compounds 11a–d. Selected data: Compound
11a: 1H NMR (300 MHz, DMSO-d6) d 1.02–1.21 (m, 4H),
1.36–1.54 (m, 4H), 1.94–2.04 (m, 2H), 2.20 (br s, 1H),
2.77–2.99 (m, 2H), 8.51 (s, 1H), 13.35 (br s, 1H); LCMS
m=z 246 (M + 1); HRMS: MHþ 246.1238 (expected
1
10a: H NMR (300 MHz, DMSO-d6) d 5.04 (s, 2H), 5.33
(s, 2H), 7.35–7.45 (m, 10H), 8.38 (s, 1H); HRMS: LCMS
1
246.1237). Compound 11b: H NMR (300 MHz, DMSO-
m=z 334 (M + 1); HRMS: MHþ 334.1183 (expected
334.1186). Compound 10b: H NMR (300 MHz, DMSO-
d6) d 7.60–7.70 (m, 2H), 7.98–8.22 (m, 4H), 8.61 (s, 1H),
8.81 (s, 1H), 13.43 (br s, 1H); LCMS m=z 264 (M+ 1);
HRMS: MHþ 264.0767 (expected 264.0767). Compound
1
d6) d 1.18 (t, J ¼ 7.5 Hz, 3H), 4.08 (q, 7.5 Hz, 2H), 4.95 (d,
J ¼ 1.7 Hz, 2H), 5.05 (s, 2H); 7.30–7.45 (m, 5H), 8.37 (s,
1H); LCMS m=z 330 (M + 1); HRMS: MHþ 330.1083
(expected 330.1084).
1
11c: H NMR (300 MHz, DMSO-d6) d 4.49 (s, 2H), 7.02–
7.11 (m, 1H), 7.21–7.30 (m, 2H), 7.35–7.45 (m, 1H); 8.51
(s, 1H), 13.45 (br s, 1H); LCMS m=z 246 (M+ 1); HRMS:
MHþ 246.0674 (expected 246.0673).
16. (a) Boyd, G. V. In Comprehensive Heterocyclic Chemis-
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