Confirmation and prevention of halogen exchange: practical and highly efficient one-pot synthesis of dibromo- and dichloropyridazinones

Article abstract of DOI:10.1016/j.tetlet.2006.10.009

Commercially available anilines were converted by a two step, one-pot process to the corresponding pyridazinones in good to excellent yields. During the process research, a significant halogen exchange was confirmed and prevented which allowed the process to be scaled to multikilogram quantities.

Full text of DOI:10.1016/j.tetlet.2006.10.009

Tetrahedron Letters 47 (2006) 8733–8735
Confirmation and prevention of halogen exchange:
practical and highly efficient one-pot synthesis of
dibromo- and dichloropyridazinones
Ji Zhang,* Howard E. Morton and Jianguo Ji
Process Research Department, Abbott Laboratories, 1401 Sheridan Road, North Chicago, IL 60064, USA
Received 19 September 2006; revised 29 September 2006; accepted 2 October 2006
Available online 20 October 2006
Abstract—Commercially available anilines were converted by a two step, one-pot process to the corresponding pyridazinones in
good to excellent yields. During the process research, a significant halogen exchange was confirmed and prevented which allowed
the process to be scaled to multikilogram quantities.
Ó 2006 Elsevier Ltd. All rights reserved.
Substituted pyridazinones are useful compounds with a
broad array of biological activities.1 They have been uti-
lized as herbicides, such as Norflurazon and as insecti-
cides, like Pyridaben for crop protection.2 In drug
discovery, pyridainones were identified as selective
COX-2 inhibitors (ABT-9633 and CK-1264) and as car-
diotonic agents5 and a4 integrin receptor antagonists6
(Fig. 1). Consequently, 4,5-dihalo-3(2H)pyridazinones
1 and 2 are valuable and versatile building blocks7 for
access to these targets and mono- or poly-cyclic pyridaz-
inones because both Cl and Br atoms at the 4- and 5-
positions can be easily substituted by a wide variety of
N-, O- and C-nucleophiles, allowing introduction of dif-
ferent side chains regioselectively. In addition, 1 and 2
are electron deficient halogenated heterocycles, and they
have been successfully applied in palladium catalyzed
C–C coupling reactions, such as the Heck, Suzuki and
Sonogashira cross-coupling reactions.8 However, the
synthesis of these versatile intermediates has not been
previously reported from the commercially available
and cheap mucohalic acid precursors, and substituted
anilines in a one-pot version.9 Herein, we report the first
practical syntheses of 1 and 2 where the corresponding
hydrazine is not commercially available.
O
CF3
Cl
N
N
O
Cl
S
N
N
MeHN
Norflurazon
Pyridaben
F
F
O
O
X
X
R
N
O
N
HO
N
N
O
S
R = aryl or alkyl
1 (X=Cl) and 2 (X=Br)
O
ABT-963
Figure 1. Some important substituted pyridazinone compounds.
During our process research on ABT-963, a selective
COX-2 inhibitor, we required an efficient approach to
prepare multikilogram quantities of dibromopyridazi-
none 6. The early approach to 6 was via a two step pro-
cess (Scheme 1). A suitably substituted aniline is
diazotized with NaNO2/HCl and reduced by excess
SnCl2 (3 equiv) to the corresponding hydrazine 4, iso-
lated and subsequently reacted with mucobromic acid
in acetic acid to give 6 in 43% overall yield. This process
has several issues: (a) Sn species were precipitated when
sodium hydroxide solution was used to neutralize the
excess HCl to liberate hydrazine 4. (b) Serious emulsion
Keywords: Pyridazinone; Halogen exchange; Mucohalic acid; Muco-
chloric acid; Mucobromic acid; Water; One-pot process.
*
Corresponding author at present address: Research API, Pfizer
Global Research and Development, Ann Arbor Laboratories, Pfizer,
Inc., USA. Tel.: +1 734 6223940; fax: +1 734 6223294; e-mail:
ji.zhang@pfizer.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.009

8734
J. Zhang et al. / Tetrahedron Letters 47 (2006) 8733–8735
unfortunately it also generated a new compound (average
F
F
F
F
HCl
1. SnCl2
2. NaOH
8–15% in HPLC area at 215 nm) which proved
prohibitively difficult to remove by recrystallization.
Surprisingly, under similar conditions, 4,5-dichloro-
3(2H)pyridazinones 8 were produced in excellent yield
(85% and 90%) and high purity (96% HPLC area), with-
out the corresponding side product! (Scheme 2).
NaNO2
H2NHN
H2N
4
3
HOAc
O
F
Isolated
F
O
F
F
Br
Br
N
N
Br
Br
The analysis of crude product 6 via LC/MS gave an
unexpected peak at m/z = 321 and 323. This indicated
O
H2NHN
.HCl
6
that the side product was from halogen exchange.11
A
OH
4. HCl salt
further stepwise investigation suggested that the halogen
exchange happens at higher temperature, or in the final
step. To further prove this, a pure bromide 11 was trea-
ted with 6 N HCl for 2 h in HOAc (reflux), and indeed it
gave a molecule at m/z = 285 and 287, corresponding to
a single chlorine–bromine exchange and a purity reduc-
tion from 99% to 77% (Scheme 3).
5
Scheme 1. The original approach to dibromopyridazinone 6.
occurred when 4 was extracted with organic solvent. (c)
The crude hydrazine 4 is brown in color and unstable to
storage, making it difficult to determine the amount of
mucobromic acid to use in the next step. Finally when
a larger amount of SnCl2 was used, it was not easy to
stir well during the reaction. Accordingly, initial
improvements were realized by reducing the amount of
SnCl2 from 3 equiv to 2 equiv, and, instead of isolation
of 4, the HCl salt of 4 was separated and used directly in
the next step to make dibromopyridazinone 6. Thus, the
overall yield increased from 43% to 58%, and the prod-
uct 6 was obtained as a light yellow solid with good pur-
ity (>90%). Although the extraction and emulsion were
avoided and the yield was improved, it was found that
the 4ÆHCl salt is soluble in water, resulting in yield loss
when 4ÆHCl salt was isolated.
Finally, we decided to use HBr/NaNO2 for diazotiza-
tion, SnCl2/HBr for the reduction step and water as
the sole solvent for the whole process. After these
changes, 6 was isolated in 82% with excellent chemical
purity (96%). Without further purification, 6 was used
directly for the next step. This one-pot process has been
successfully scaled up to make 22.0 kg of bromide 6 and
utilized in the ABT-963 multikilogram synthesis.
It became clear that to prepare bromide, HBr/water
must be used as solvent and, to prepare the chloride,
HCl/water must be used as solvent.12 The generality
of this one-pot approach was then tested (Table 1).
Several dibromides and dichlorides were prepared in
high yield with high purity (>95%). If the aromatic ring
contained an electron donating group, the yield was
lower (entries 4 and 9), mostly likely due to the lower
stability of the diazonium salt and the side reaction
(denitrogenation); if the aromatic ring contained elec-
tron-withdrawing groups, the yield was higher (entries
3 and 8).
Mucobromic acid and mucochloric acid are soluble in
hot HCl solution, while the final dibromopyridazinone
6 has poor solubility in water, therefore, we anticipated
the separation of the final products 6 and 8 from excess
starting material, mucohalic acid, would be very simple.
Thus, we studied the possibility of using a telescoped
one-pot process:10 After 4ÆHCl salt formation was com-
pleted, without adding acetic acid as solvent, 1 equiv of
mucobromic acid was added directly, and the reaction
was heated to 80–90 °C. The product 6 precipitated dur-
ing the reaction. After 2 h of heating, the reaction mix-
ture was cooled to room temperature, and the dibromide
was isolated in moderate yield (between 65% and 73%),
In summary, we have developed a simple, highly efficient
one-pot process for preparing 4,5-dihalo-3(2H)pyridazi-
nones. Halogen exchange during the process was
confirmed and was prevented by careful choice of
reagents.
F
F
F
HCl
SnCl2
HCl
F
F
F
NaNO2
H2NHN
F
F
O
H2N
O
4
3
Cl
Br
Br
Cl
N
N
F
N
N
or
F
O
9
10
O
X
N
N
+ ~8% to 15% side product
(when X=Br)
X
O
O
O
O
X
Cl
Br
HCl
Br
Cl
N
N
X
Br
Br
N
N
N
N
or
OH
6 X=Br, yield: 65% to 73%
8 X=Cl (without side product), yield: 85% to 90%.
HOAc
5 X=Br
7 X=Cl
11
12
13
Scheme 2. One-pot process to dibromide and dichloride.
Scheme 3. Confirmation of halogen exchange.

J. Zhang et al. / Tetrahedron Letters 47 (2006) 8733–8735
8735
Table 1. Results of one-pot process to dibromo- and dichloro-
pyrodazinones
´
2003, 46, 1055–1059; (c) Van der Mey, M.; Bommele, K.
M.; Boss, H.; Hatzelmann, A.; Slingerland, M. V.; Sterk,
G. J.; Timmerman, H. J. Med. Chem. 2003, 46, 2008–2016;
(d) Costantino, L.; Rastelli, G.; Gamberini, C.; Giovan-
noni, M. P.; Piaz, V. D.; Vianello, P.; Barlocco, D. J. Med.
Chem. 1999, 42, 1894–1900; (e) Piaz, V. D.; Giovannoni,
M. P.; Castellana, C. J. Med. Chem. 1997, 40, 1417–1421;
(f) Costantino, L.; Rastelli, G.; Vescovini, K.; Gignarella,
G.; Vianello, P.; Corso, A. D.; Cappiello, M.; Mura,
Umberto.; Barlocco, D. J. Med. Chem. 1996, 39, 4396–
4405.
R2
R1
HX(X=Cl or Br)
NaNO2/water
1. SnCl2
HX/water
H2N
R2
80-90 °C
R1
O
O
X
X
2. Stevenson, T. M.; Crouse, B. A.; Thieu, T. V.; Gebreysus,
C.; Finkelstein, B. L.; Sethuraman, M. R.; Dubas-
Cordery, C. M.; Piotrowski, D. L. J. Heterocycl. Chem.
2005, 42, 427–435.
3. Kerdesky, F. A.; Leanna, M. R.; Zhang, J.; Li, W.;
Lallaman, J. E.; Ji, J.; Morton, H. E. Org. Process Res.
Dev. 2006, 10, 512–517.
N
N
X
X
O
X=Cl or Br
OH
Using HBr with mucobromic acid
Using HCl if mucochloric acid was used
5 X=Br
7 X=Cl
4. Chiou, G. C. Y. Drugs Future 1999, 24, 979–990.
5. (a) Moos, W. H.; Humblet, C. C.; Sircar, I.; Rithner, C.;
Weishaar, R. E.; Bristol, J. A.; McPhail, A. T. J. Med.
Chem. 1987, 30, 1963–1972; (b) Sircar, I.; Duell, B. L.;
Bobowski, G.; Bristol, J. A.; Evans, D. B. J. Med. Chem.
1985, 28, 1405–1413.
6. Gong, Y.; Barbay, J. K.; Byatkin, A. B.; Miskowski, T.
A.; Kimball, E. S.; Prouty, S. M.; Fisher, M. C.; Santulli,
R. J.; Schneider, C. R.; Wallace, N. H.; Ballentine, S. A.;
Hageman, W. E.; Masucci, J. A.; Maryanoff, B. E.;
Damiano, B. P.; Andrade-Gordon, P.; Hlasta, D. J.;
Hornby, P. J.; He, W. J. Med. Chem. 2006, 49, 3402–
3411.
Entry
R1
R2
X
Isolated
yield (%)a
1
2
3
4
5
6
7
8
9
F
H
F
OMe
H
F
H
H
OMe
F
Cl
CF3
F
H
H
F
H
CF3
H
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
87
74
90
35
88
82
78
85
34
86
10
´
´
7. (a) Matyus, P.; Maes, B. U. W.; Riedl, Z.; Hajos, G.;
a The reaction was carried out using 1 (1.0 equiv), NaNO2 (1.05 equiv),
SnCl2 (2.0 equiv) and mucobromic acid or mucochloric acid
(1.0 equiv). HX (X = Cl or Br)/water as solvent.
Lemiere, G. L. F.; Tapolcsanyl, P.; Monsieurs, K.; Elias,
ꢀ
`
´
´
O.; Dommisse, R. A.; Krajsovszky, G. Synlett 2004, 7,
´
´
1123–1139; (b) Tapolcsanyl, P.; Matyus, P.; Maes, B. U.
W. Targets Heterocycl. Syst. 2002, 6, 369–398.
8. (a) R’kyek, O.; Maes, B. U. W.; Jonckers, T. H. M.;
`
Lemiere, G. L. F.; Dommisse, R. A. Tetrahedron 2001, 57,
Acknowledgement
10009–10016; (b) Coelho, A.; Sotelo, E.; Novoa, H.;
Peeters, O. M.; Blaton, N.; Ravinˇa, E. Tetrahedron Lett.
2004, 45, 3459–3463.
We thank Dr. Jeremy Starr for proofreading of this
manuscript.
9. 4,5-Dihalo-3(2H)pyridazinones were normally synthesized
from hydrazine or arylhydrazines and mucohalic acid
(X = Cl or Br) in acetic acid medium.
10. Several issues were considered in our early study: (1) the
stability of diazonium salt and its safety profile; (2) how to
control the ratio of several reagents and how to simplify
the separation; (3) will the process work without removing
excess SnCl2? (4) Is water the best solvent for this one-pot
process?
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.10.009.
11. (a) Treating chloropyridazinones with KF in DMSO at
100 °C gave 32–82% fluoropyridazinones, see Gaodeng
Xuexiao Huaxue Xuebao, 1988, 9, 1083–1084; (b) Treat-
ment of, 4,5-dichloro-3(2H)-pyridazinones with 47% HBr
gave a mixture of 4,5-dibromo-3(H)-pyridazinone and
4-bromo-5-chloro-3(2H)-pyridazinone, see Yakugaku Zas-
shi, 1988, 108, 911–915.
12. SnCl2 was still used in the preparation of dibromide since
(1) SnCl2 is much cheaper than SnBr2; (2) the solubility of
SnBr2 in water is much lower; (3) when HBr was used as
solvent, [Br] ꢀ [Cl], therefore it will inhibit the halogen
exchange.
References and notes
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B. K.; Scapin, G.; Fitzgerals, C. E.; Kumar, S.; Nichols, E.
A.; O’Keefe, S. J.; O’Neill, E. A.; Porter, G.; Samuel, K.;
Schmatz, D. M.; Schwartz, C. D.; Shoop, W. L.; Thomp-
son, C. M.; Thompson, J. E.; Wang, R.; Woods, A.;
Zaller, D. M.; Doherty, J. B. J. Med. Chem. 2003, 46, 349–
352; (b) Giovannoni, M. P.; Vergelli, C.; Ghelardini, C.;
Galeotti, N.; Bartolini, A.; Piaz, V. D. J. Med. Chem.