Efficient synthesis of 2,6-disubstituted-5-hydroxy-3-oxo-2,3-dihydro-pyridazine-4-carboxylic acid ethyl esters

Article abstract of DOI:10.1016/j.tetlet.2007.11.187

A general procedure is described for the preparation of 6-substituted-5-hydroxy-3-oxo-2,3-dihydro-pyridazine-4-carboxylic acid ethyl esters (6-substituted-5-hydroxy-3(2H)-pyridazinone-4-carboxylic acid ethyl esters). These compounds are shown to undergo s

Full text of DOI:10.1016/j.tetlet.2007.11.187

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 811–815
Efficient synthesis of 2,6-disubstituted-5-hydroxy-3-oxo-
2,3-dihydro-pyridazine-4-carboxylic acid ethyl esters
Douglas E. Murphy *, Peter S. Dragovich, Benjamin K. Ayida, Thomas M. Bertolini,
Lian-Sheng Li, Frank Ruebsam, Nebojsa S. Stankovic, Zhongxiang Sun,
Jingjing Zhao, Yuefen Zhou
Anadys Pharmaceuticals, 3115 Merryfield Row, San Diego, CA 92121, United States
Received 16 October 2007; revised 29 November 2007; accepted 29 November 2007
Available online 4 December 2007
Abstract
A general procedure is described for the preparation of 6-substituted-5-hydroxy-3-oxo-2,3-dihydro-pyridazine-4-carboxylic acid ethyl
esters (6-substituted-5-hydroxy-3(2H)-pyridazinone-4-carboxylic acid ethyl esters). These compounds are shown to undergo selective
alkylation at the 2-position in moderate to good yields (19–77%) to afford 2,6-disubstituted-5-hydroxy-3-oxo-2,3-dihydro-pyridazine-
4-carboxylic acid ethyl esters (2,6-disubstituted-5-hydroxy-3(2H)-pyridazinone-4-carboxylic acid ethyl esters).
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Pyridazinone; Dieckmann cyclization; Selective alkylation; a-Keto-ester; a-Hydrazono-ester
3(2H)-Pyridazinones
(3-oxo-2,3-dihydro-pyridazines)
acid ethyl esters (3). We envisioned the di-anions of these
cyclized intermediates undergoing selective alkylation with
electrophiles at the 2-position to provide the title
compounds (4) (Scheme 1). Similar N-alkylations of
are an important class of biologically active molecules with
many potential therapeutic applications. For example,
these molecules have been previously reported to be plate-
let aggregation inhibitors,1 a-adrenoceptor antagonists,2
and antisecretory/antiulcer agents.3 We previously
reported a versatile synthesis to prepare 2,6-disubstituted-
5-hydroxy-3-oxo-2,3-dihydro-pyridazine-4-carboxylic acid
ethyl esters (4),4 in which the 2-substituent was introduced
in the first step of the synthetic sequence. Herein we report
a novel synthesis of the same heterocycles that regioselec-
tively introduces the 2-substituent in the final step, allowing
facile variation at this position.
Our retrosynthetic strategy employed the condensation
of a variety of a-keto-esters with commercially available
hydrazinocarbonyl-acetic acid ethyl ester followed by an
intramolecular Dieckmann cyclization to afford 6-substi-
tuted-5-hydroxy-3-oxo-2,3-dihydro-pyridazine-4-carboxylic
O
O
R1
(i)
O
R1
O
N
O
NH
O
O
O
1
2
(ii)
OH
O
OH
O
O
5
R1
1 N
(iii)
R1
O
O
3
N
N
R2
O
N
H
4
3
Scheme 1. Reagents and conditions: (i) Hydrazinocarbonyl-acetic acid
ethyl ester, DMSO, 0.4% TFA (v/v), 70 °C, 16 h; (ii) NaOAc, DMF,
150 °C, 30 min, À2 h; (iii) NaH, DMF, 25 °C, 10 min followed by addition
of electrophiles, then heating (if needed).
*
Corresponding author. Tel./fax: +1 858 676 1837.
E-mail address: douglasmurphy@hotmail.com (D. E. Murphy).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.187

812
D. E. Murphy et al. / Tetrahedron Letters 49 (2008) 811–815
3(2H)-pyridazinones have been reported to proceed in the
presence of KOH under phase transfer conditions,5 with
metallic sodium in absolute ethanol,6 and with NaH in
DMF.7 However, to the best of our knowledge, there are
no reported examples of the regioselective alkylation of
3(2H)-pyridazinones containing unprotected hydroxyl
groups at the 5-position.
We initially evaluated the feasibility of forming the
cyclized intermediates (3). The condensation of aryl- and
alkyl-a-keto-esters (1) with hydrazinocarbonyl-acetic acid
ethyl ester proceeded in DMSO containing 0.4% TFA (v/v)
at 70 °C overnight to afford the hydrazone intermediates
2a–h (Table 1). In all cases, analysis of the reaction mix-
tures by LC–MS indicated two distinct products with the
desired mass, presumably the E and Z hydrazone isomers.
Purification by flash column chromatography yielded
either a major hydrazone product (P10:1 mixture of iso-
mers; suggesting isomerization on silica gel) or an insepara-
ble, near-equal mixture of isomers.12 Heating the purified
hydrazones, either as inseparable mixtures or major iso-
mers, in the presence of 2 equiv of NaOAc in DMF at
150 °C, afforded the desired cyclized intermediates 3a–h
in less than 2 h (Table 1). In cases where near-equal mix-
tures of hydrazone isomers were cyclized, the disappear-
ance of both isomers was observed suggesting their
in situ isomerization under the reaction conditions. In most
cases, the products could be isolated in pure form by addi-
tion of aqueous 1 M HCl to the cooled reaction mixture
followed by filtration of the resulting precipitate.
With the cyclized intermediates (3) in hand, we investi-
gated methods that would afford selective derivatization
of the 2-position. Initial attempts to alkylate 3a with iso-
amyl bromide using KOH and TBAB in benzene5 failed
to give any desired product. Alternatively, treatment of
3a with 2.2 equiv of NaH in DMF followed by 1.1 equiv
of isoamyl bromide and heating at 80 °C for 3 h afforded
the N-alkylated product in 74% yield. The site of alkylation
was confirmed by matching the 13C NMR spectral data for
the isolated product with the corresponding data for the
identical 3(2H)-pyridazinone that was prepared through
an unambiguous, independent synthesis.13
Table 1
Synthesis of 6-substituted-5-hydroxy-3-oxo-2,3-dihydro-pyridazine-4-carb-
Encouraged by this result, we explored the ability of this
method to selectively derivatize cyclized pyridazinones 3a–
h with a variety of alkylating agents (Table 2). The use of
primary and secondary alkyl halides typically afforded
the desired products in good yields, regardless of the R1
substituent present on the pyridazinone ring (entries
1–12). A double alkylation product, presumably the enol
ether, was observed (estimated yield of 80% based on
LC–MS of the crude reaction mixture) from the alkylation
of 3f at 80 °C, contributing to the lower yield of the mono-
alkylated pyridazinone (entry 6). However, the formation
of this di-alkylated product was suppressed by performing
the reaction at room temperature (entry 7). Utilizing the
same conditions, the alkylation of 3g, 3h, and 3a proceeded
at room temperature in moderate yields (entries 8–10).
Neopentyl iodide (entry 13) required a higher temperature
and longer reaction time to give the coupled product and
did so in reduced yield. Tosylates were tolerated as electro-
philes (entries 14 and 15) with yields comparable to those
obtained for similar alkyl halides. Pyridyl and benzyl bro-
mides (entries 16–19) coupled, but with lower yields.
Again, a double alkylation product, presumably the enol
ether, was obtained during the alkylation of 3e with benzyl
bromide (entry 20), contributing to the lower yield of the
mono-alkylated pyridazinone. The formation of this di-
alkylated product was suppressed by utilizing benzyl chlo-
ride as the electrophile (entry 21).
oxylic acid ethyl esters (3)17,18
Entry
1
R1
Products 2a (Isolated
Products 3 (Isolated
yield, %)b
yield, %)c
2a (85)
2b (84)
2c (86)
2d (20)d
2e (73)
2f (33)d
2g (65)
2h (68)
3a (80)
3b (82)
3c (74)
3d (60)
3e (51)
3f (85)
3g (95)e
3h (38)
S
N
S
28
3
49
510
6
711
89
In summary, we have discovered an efficient method for
the synthesis of 2,6-substituted-5-hydroxy-3-oxo-2,3-dihy-
dro-pyridazine-4-carboxylic acid ethyl esters. Variation of
substituents at the 6-position is achieved via the use of
readily accessible a-keto-esters. Variation of the 2-position
substituents, introduced in the last step by selective alkyl-
ation, allows significant diversification of the pyridazinone
products due to the widely accessible set of available
a
P10:1 Mixture of E and Z-isomers unless otherwise noted.
Isolated yields after flash column chromatography.
Isolated yields after precipitation from the crude reaction mixtures
b
c
unless otherwise noted.
d
Near-equal mixture of E and Z-isomers.
Purified by concentrating the cooled reaction mixture and passing the
e
residue through a plug of silica gel, eluting with 100% EtOAc, followed by
concentration in vacuo to afford a brown solid.

D. E. Murphy et al. / Tetrahedron Letters 49 (2008) 811–815
813
Table 2
Alkylation of pyridazinones 3 with various electrophiles19
OH
O
O
OH
R1
O
O
R1
1. NaH, DMF
2. X-R2
O
O
N
N
N
H
N
R2
3
4
Entry
1
R1
R2
X
Temperature (°C)
Time (h)
3
Yielda (%)
74
Br
Br
Br
Br
Br
Br
Br
Br
80
S
N
S
2
3
4
5
6
7
8
80
80
80
80
80
25
25
3
3
1
1
1
6
3
76
73
61
77
20b
61
41
9
Br
I
25
25
2
53
87
10
16
S
S
S
11
12
Br
Br
80
80
5
5
73
61
13
14
I
110
80
16
5
25
52
S
S
OTs14
F
F
15
16
OTs15
80
80
7
5
35
F
S
S
Brc
46
N
(continued on next page)

814
D. E. Murphy et al. / Tetrahedron Letters 49 (2008) 811–815
Table 2 (continued)
Entry
R1
R2
X
Temperature (°C)
Time (h)
5
Yielda (%)
47
17
18
19
20
Br
80
S
N
S
Br
Br
80
80
3
3
59
61
Br
Cl
80
80
3
3
19
66
21
a
Isolated yield unless otherwise noted.
Estimated yield based on LC–MS of the crude reaction mixture.
The hydrobromide salt of the alkylating agent, 2-bromomethyl-pyridine, was employed, necessitating the use of 3.2 equiv of NaH.
b
c
combined with CuI (1.2 mmol) in THF (3 mL) at À25 °C and stirred
at 0 °C for 20 min. The mixture was cooled to À20 °C and chloro-
oxo-acetic acid ethyl ester (1 mmol) was added. The mixture was
warmed to 25 °C over 1 h. The reaction was quenched by the addition
of saturated NH4Cl and the product was extracted into Et2O.
Concentration in vacuo followed by flash column chromatography
afforded the desired a-keto-ester.
alkylating agents. Over-alkylation was observed in two
cases but could be suppressed by either reducing the reac-
tion temperature or using a weaker electrophile.
Acknowledgment
10. The required a-keto-ester was obtained in 53% yield by following the
procedure described by Babudri, F.; Fiandanese, V.; Marchese, G.;
Punzi, A. Tetrahedron 1996, 52, 13513 (replacing chloro-oxo-acetic
acid methyl ester with chloro-oxo-acetic acid ethyl ester).
We would like to thank Dr. Stephen Webber for his con-
tinued support throughout the course of this work.
11. The required a-keto-ester was obtained by following the procedure
described in Graham, D. W.; Ashton, W. T.; Barash, L.; Brown, J. E.;
Brown, R. D.; Canning, L. F.; Chen, A.; Springer, J.; Rogers, E. F.
J. Med. Chem. 1987, 30, 1074.
12. No attempt was made to assign the hydrazone products as either the
E or Z-isomers.
13. Dragovich, P. S.; Bertolini, T. M.; Ayida, B. K.; Li, L.-S.; Murphy, D.
E.; Ruebsam, F.; Sun, Z.; Zhou, Y. Tetrahedron 2007, 63, 1154.
14. The required tosylate was obtained by treatment of 2-cyclopentyl-
ethanol with tosyl chloride (1.1 equiv), Et3N (1.3 equiv) and DMAP
(0.1 equiv) in CH2Cl2 (5 mL/mmol of the alcohol) at room temper-
ature for 16 h. The mixture was washed with 1 M HCl and the organic
phase passed through a plug of silica gel, eluting with 100% CH2Cl2.
Concentration in vacuo afforded the desired tosylate.
15. The required tosylate was obtained from (1-trifluoromethyl-cyclo-
propyl)-methanol16 under the same conditions described above.14
However, it was necessary to heat the reaction mixture to 45 °C for
16 h.
16. Wolniewicz, A.; Dmowski, W. J. Fluorine Chem. 2001, 109, 95.
17. Representative procedure for the preparation of compounds 2. [(2-
Ethoxycarbonyl-acetyl)-hydrazono]-thiophen-2-yl-acetic acid ethyl
ester (2a): Oxo-thiophen-2-yl-acetic acid ethyl ester (2 g, 10.86 mmol)
was dissolved in anhydrous DMSO (54.3 mL). Hydrazinocarbonyl-
acetic acid ethyl ester (1.75 g, 11.95 mmol) was added followed by
TFA (0.2 mL). The flask was evacuated and filled with nitrogen. The
mixture was heated at 70 °C for 16 h. Upon cooling to 25 °C, the
mixture was diluted with EtOAc and washed with 0.1 M HCl (three
times). The organic phase was further washed with brine, dried over
MgSO4, and concentrated in vacuo. Purification of the residue by
flash column chromatography (10–15% EtOAc/hexanes) afforded 2a
References and notes
1. Corsano, S.; Vezza, R.; Scapicchi, R.; Foresi, S.; Strappaghetti, G.;
Nenci, G. G.; Gresele, P. Eur. J. Med. Chem. 1995, 30, 627.
2. Betti, L.; Zanelli, M.; Giannaccini, G.; Manetti, F.; Schenone, S.;
Strappaghetti, G. Bioorg. Med. Chem. 2006, 14, 2828; and references
cited therein.
3. Yamada, T.; Nobuhara, Y.; Shimamura, H.; Tsukamoto, Y.;
Yoshihara, K.; Yamaguchi, A.; Ohki, M. J. Med. Chem. 1983, 26,
373.
4. Li, L.-S.; Zhou, Y.; Zhao, J.; Dragovich, P. S.; Stankovic, N.;
Bertolini, T. M.; Murphy, D. E.; Sun, Z.; Tran, C. V.; Ayida, B. K.;
Ruebsam, F.; Webber, S. E. Synthesis 2007, 21, 3301.
5. Yamada, T.; Ohki, M. Synthesis 1981, 8, 631.
6. King, J.; McMillan, F. J. Am. Chem. Soc. 1952, 74, 3222; McMillan,
F.; Kun, K.; McMillan, C.; Schwartz, B.; King, J. J. Am. Chem. Soc.
1956, 78, 407; Nitta, Y.; Yoneda, F.; Ohtaka, T.; Kato, T. Chem.
Pharm. Bull. 1964, 12, 69.
7. Holava, H. M.; Partyka, R. A. J. Med. Chem. 1971, 14, 262.
8. The required a-keto-ester was obtained in 51% yield following a
modified procedure from Dondoni, A.; Fantin, G.; Fogagnolo, M.;
Medici, A.; Pedrini, P. J. Org. Chem. 1988, 53, 1748. A neat mixture
of 5-trimethylsilanyl-thiazole (1 equiv) and chloro-oxo-acetic acid
ethyl ester (2 equiv) was heated at 80 °C for 1.75 h. After cooling to
25 °C, flash column chromatography (10–25% EtOAc/hexanes)
afforded the a-keto-ester.
9. The required a-keto-esters were obtained following
a modified
procedure from Zhu, L.; Wehmeyer, R.; Rieke, R. J. Org. Chem.
1991, 56, 1445. The corresponding alkyl zinc halide (1.2 mmol) was

D. E. Murphy et al. / Tetrahedron Letters 49 (2008) 811–815
815
(2.89 g, 9.25 mmol, 85% yield) as a faintly yellow oil that crystallized
to a beige, waxy solid upon standing. 1H NMR (400 MHz, CDCl3,
10:1 mixture of isomers observed, data for major isomer reported):
d = 1.28 (t, 3H, J = 6.9 Hz), 1.47 (t, 3H, J = 7.1 Hz), 3.80 (s, 2H),
4.22 (q, 2H, J = 7.1 Hz), 4.47 (q, 2H, J = 7.1 Hz), 7.03 (t, 1H,
J = 4.2 Hz), 7.33 (d, 1H, J = 4.4 Hz), 7.60 (d, 1H, J = 3.7 Hz), 11.80
(br s, 1H). 13C NMR (100 MHz, CDCl3): d = 14.2, 14.3, 40.7, 61.5,
62.9, 127.5, 128.1, 129.0, 130.9, 138.2, 160.5, 166.9, 168.5. MS (ESI):
m/z = 313.1 [M+H+] (100%). Anal. Calcd for C13H16N2O5S: C,
49.99; H, 5.16; N, 8.97. Found: C, 49.83; H, 5.38; N, 9.01.
(100%), 533.2 [2M+H+] (25%). Anal. Calcd for C11H10N2O4S: C,
49.62; H, 3.79; N, 10.52. Found: C, 49.48; H, 4.09; N, 10.67.
19. Representative procedure for the preparation of compounds 4.
5-Hydroxy-2-(3-methyl-butyl)-3-oxo-6-thiophen-2-yl-2,3-dihydro-pyr-
idazine-4-carboxylic acid ethyl ester (Table 2, entry 1): 5-Hydroxy-3-
oxo-6-thiophen-2-yl-2,3-dihydro-pyridazine-4-carboxylic acid ethyl
ester (3a) (0.2 g, 0.751 mmol) was suspended in anhydrous DMF
(3.75 mL). A 60% suspension of NaH in mineral oil (0.066 g,
1.65 mmol) was added. The mixture was stirred in a sealed vial for
10 min with occasional venting. 1-Bromo-3-methyl-butane (0.125 g,
0.826 mmol) was added and the mixture stirred at 80 °C for 3 h. Upon
cooling to 25 °C, the mixture was diluted with EtOAc and washed
with 1 M HCl (three times). The organic phase was further washed
with brine, dried over MgSO4, and concentrated in vacuo. Purifica-
tion of the residue by flash column chromatography (100% CH2Cl2)
afforded the desired product (Table 2, entry 1, 0.186 g, 0.553 mmol,
74% yield), as a yellow waxy solid. 1H NMR (400 MHz, CDCl3):
d = 0.99 (d, 6H, J = 6.2 Hz), 1.50 (t, 3H, J = 7.1 Hz), 1.64–1.76 (m,
3H), 4.22 (t, 2H, J = 7.1 Hz), 4.53 (q, 2H, J = 7.0 Hz), 7.10 (dd, 1H,
J = 4.9, 3.6 Hz), 7.38 (d, 1H, J = 4.0 Hz), 7.88 (d, 1H, J = 4.6 Hz),
13.87 (s, 1H). 13C NMR (100 MHz, CDCl3): d = 14.3, 22.6, 25.9, 37.3,
50.8, 63.1, 103.2, 127.3, 127.6, 128.2, 134.8, 135.8, 156.5, 163.7, 171.4.
MS (ESI): m/z = 337.2 [M+H+] (100%). Anal. Calcd for
C16H20N2O4S: C, 57.12; H, 5.99; N, 8.33. Found: C, 57.13; H, 6.38;
N, 8.49.
18. Representative procedure for the preparation of compounds 3. 5-
Hydroxy-3-oxo-6-thiophen-2-yl-2,3-dihydro-pyridazine-4-carboxylic
acid ethyl ester (3a): [(2-Ethoxycarbonyl-acetyl)-hydrazono]-thio-
phen-2-yl-acetic acid ethyl ester (2a) (1 g, 3.2 mmol) was dissolved
in DMF (16 mL) and NaOAc (0.525 g, 2.55 mmol) was added. The
flask was evacuated and filled with nitrogen. The mixture was heated
at 150 °C for 30 min. Upon cooling to 25 °C, 1 M HCl (32 mL) was
added and the product precipitated. After stirring for 5 min, the solid
was collected by filtration, washed with 1 M HCl and dried in vacuo
for 16 h to afford 3a as a light beige powder (0.68 g, 2.55 mmol, 80%
1
yield). H NMR (400 MHz, DMSO-d6): d = 1.29 (t, 3H, J = 7.3 Hz),
4.30 (q, 2H, J = 7.3 Hz), 7.12 (dd, 1H, J = 5.4, 3.8 Hz), 7.62 (d, 1H,
J = 3.8 Hz), 7.80 (d, 1H, J = 4.6 Hz), 13.00 (br s, 1H). 13C NMR
(100 MHz, DMSO-d6): d = 14.0, 61.6, 107.6, 127.5, 127.8, 127.8,
135.7, 137.1, 158.3, 158.5, 166.2. MS (ESI): m/z = 267.1 [M+H+]