Benzoxazinone Intermediate for the Synthesis of Deferasirox. Preparation of Deferasirox

Full text of DOI:10.1080/00304948.2015.1088759

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: http://www.tandfonline.com/loi/uopp20
Benzoxazinone Intermediate for the Synthesis of
Deferasirox. Preparation of Deferasirox
Suwatchai Jarussophon, Pawinee Pongwan & Onsiri Srikun
To cite this article: Suwatchai Jarussophon, Pawinee Pongwan & Onsiri Srikun
(
2015) Benzoxazinone Intermediate for the Synthesis of Deferasirox. Preparation of
Deferasirox, Organic Preparations and Procedures International, 47:6, 483-489, DOI:
0.1080/00304948.2015.1088759
1
To link to this article: http://dx.doi.org/10.1080/00304948.2015.1088759
Published online: 30 Oct 2015.
Submit your article to this journal
Article views: 24
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=uopp20
Download by: [Tulane University]
Date: 02 December 2015, At: 21:24

Organic Preparations and Procedures International, 47:483–489, 2015
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2015.1088759
Benzoxazinone Intermediate for the Synthesis
of Deferasirox. Preparation of Deferasirox
1
Suwatchai Jarussophon, Pawinee Pongwan, and Onsiri Srikun
1
2
1
National Nanotechnology Center, National Science and Technology
Development Agency. 111 Thailand Science Park, Phahonyothin Road, Klong 1,
Klong Luang, Pathumthani 12120, Thailand
2
Research and Development Institute, Government Pharmaceutical
Organization. 75/1 Rama 6 Road, Ratchathewi, Bangkok 10400, Thailand
Deferasirox (Exjade, ICL-670A), 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]ben-
zoic acid (6), is an iron chelator developed for the treatment of chronic iron overload in
patients who are receiving long-term blood transfusions for conditions such as beta-thal-
1
–7
assemia and other chronic anemias.
It is the first orally administered medication
8
approved for this purpose by USFDA in November 2005. Its pharmacokinetic profile
shows deferasirox to be effective in convenient, once-daily oral administration schedule,
as it can provide 24 h chelation coverage in patients with transfusion-dependent anemias.
Deferasirox (Figure 1) contains two phenolic oxygens and triazole nitrogens acting as a
9
–12
tridentate ligand that chelate Fe(III).
cules to bind one iron atom.
Tridentate chelators require two ligand mole-
Figure 1 Structure of Deferasirox (6)
Received May 27, 2015; in final form July 20, 2015.
Address correspondence to Suwatchai Jarussophon, National Nanotechnology Center, National
Science and Technology Development Agency. 111 Thailand Science Park, Phahonyothin Road,
Klong 1, Klong Luang, Pathumthani 12120, Thailand. E-mail: suwatchai@nanotec.or.th
4
83

4
84
Jarussophona et al.
The 1,2,4-triazole ring substituted with three aryl groups is the key structural motif of
1
deferasirox. Although a number of efficient triazole syntheses have been described,
3–18
direct access to appropriately functionalized 1,2,4-triazole rings is a difficult challenge as the
nature of the substituents limits the availability of readily accessible starting materials and
typically requires multi-step sequences. Staben and Blaquiere reported a four-component
condensation of fully substituted 5-aryl-1,2,4-triazoles by carbonylative heterocyclization of
1
9
aryl halides. This route allows regioselective access to a 5-triazolyl heterobiaryl linkage
without the need to use organometallic reagents and through reactive acylamidine intermedi-
ates. Paulvannan et al. investigated the four-step synthesis of 1,3,5-trisubstituted 1,2,4-tria-
zole via a silver carbonate-mediated cyclization of a triazole as the key step. This approach
proved to be compatible with a wide range of functional groups and amenable to scale-up as
2
0
well. Recently, Staben et.al developed a highly regioselective one-pot process for the prep-
aration of 1,3,5-trisubstituted 1,2,4-triazoles from the reaction of carboxylic acids, primary
2
1
amidines, and mono substituted hydrazines in moderate yields.
To the best of our knowledge, the most commonly employed route for the production of
9,22–24
deferasirox is the two-step procedure that has been reported by several research groups.
The first step involves the condensation of inexpensive substrates, namely salicylic acid (1)
with salicylamide (2) using thionyl chloride in the presence of pyridine at reflux in xylene to
give 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one (4) as a solid in yield (50–55%). In a sec-
ond step, compound 4 is treated with 4-hydrazinobenzoic acid (5) in boiling ethanol to afford
deferasirox in high yield (80%). Although this method seems to be the most efficient procedure
in terms of readily available and inexpensive starting materials and its suitability to scale-up,
the major problem for the larger-scale production lies in the fact that the preparation of interme-
diate 4 utilizes highly corrosive thionyl chloride at high temperatures making this process
extremely dangerous and difficult to use on an industrial scale.
The great demand for pure benzoxazinone 4 has prompted us to investigate other
effective chlorinating agents. In addition of thionyl chloride, there are a number of chlori-
nating agents that could be applied for this process, such as AlCl CSOCl , PCl , PCl ,
3
2
3
5
2
5–27
oxalyl chloride and DMF, Ph P and CCl , phosgene and triphosgene.
However, those
3
4
reagents are also toxic and the purification of the crude products is often problematic,
time-consuming, tedious and inconvenient.
Recently, cyanuric chloride (2,4,6-trichloro-1,3,5-triazine, 3) has been used exten-
2
8–38
sively as a highly efficient chlorinating agent in a number of reactions. It is a rela-
tively inexpensive and easily handled solid compared to all of the chlorinating reagents
Scheme 1 Synthetic Route to deferasirox (6) Using Cyanuric Chloride.

Benzoxazinone Intermediate for the Synthesis of Deferasirox
485
Table 1
Optimization Reaction Conditions for the Synthesis of 2-(2-Hydroxyphenyl)benz[e][1,3]
oxazin-4-one
Entry 1 (equiv.) 2 (equiv.) 3 (equiv.) Time (hr.) Solvent Base Isolated yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
1.0
1.0
1.0
1.0
0.85
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
3
16
3
Xylene
CH Cl
Toluene Et N
Et N
15
<10
22
23
20
<10
11
27
30
36
35
30
26
38
42
54
21
13
41
37
3
Et N
3
2
2
1.0
1.0
1.0
3
0.85
1.0
3
Toluene Et N
3
1.0
3
Toluene Et N
3
0.85
0.85
0.85
0.85
0.85
0.85
0.85
0.85
0.85
0.85
0.85
0.85
1.0
0.33
0.4
3
Toluene Et N
3
3
Toluene Et N
3
0.5
0.6
3
Toluene Et N
3
3
Toluene Et N
3
0
1
2
3
4
5
6
7
8
9
0
0.67
0.7
3
Toluene Et N
3
3
Toluene Et N
3
0.8
0.9
3
Toluene Et N
3
3
Toluene Et N
3
a)
Toluene Et N
0.67
0.67
0.67
0.67
1.0
3
3
a)
Toluene Et N
6
3
a)
Toluene Et N
16
16
16
16
16
3
a)
Toluene DIPEA
a)
Toluene DIPEA
a)
Toluene DBU
0.85
1.0
0.67
1.0
a)
Toluene DBU
a)
Using a Dean-Stark trap to remove water.
mentioned above. Thus, an alternative process utilizing mild reaction conditions using
cyanuric chloride was devised for this purpose as shown in Scheme 1. Compound 4 was
characterized using infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR),
mass spectroscopy (MS) and the purity of the product was confirmed using high perfor-
mance liquid chromatography (HPLC).
Table 1 (Entries 1–13) shows the results of our initial investigation of reaction condi-
tions for the preparation of compound 4. The proper selection of non-polar solvents was
one of the most important factors since it could help in the isolation of the product 4 from
the relatively less toxic, bio-degradable by-product, i. e. cyanuric acid derivatives in the
purification step after the completion of the reaction. Toluene was found to be the solvent
of choice. Exactly 0.67 equiv. of cyanuric chloride (with respect to the acid) was required
to obtain the highest yield (36%) of 4 (Entry 10). The yield was not significantly
improved either by increasing or decreasing the amount of cyanuric chloride. However,
the yield was improved to 54% by carrying out the reaction at higher temperatures for

4
86
Jarussophona et al.
1
6 h with the use of a Dean-Stark trap for the removal of water formed (Table 1, Entries
4–20). Other hindered bases (N,N-diisopropylethylamine, DIPEA and 1,8-diazabicy-
1
cloundec-7-ene, DBU) were tested but the best results were obtained with triethylamine
as the base (Table 1).
The purification of the products can often be problematic in organic chemistry. The
most efficient method for the purification of solids is by recrystallization from a suitable
solvent system. In our case, the product 4 was isolated as a pale-yellow solid with precipi-
tation occurring after a short period of time. The crude product may be recrystallized from
3
9
ethanol, with the optimal crystallization depending on the amount of ethanol used.
The resulting pure compound 4 was then treated with 4-hydrazinobenzoic acid in eth-
anol at reflux for 3 h. using a procedure modified and improved from that reported in the
2
4
literature. The reaction mixture was then cooled to room temperature, and the precipi-
tated material was collected and dried under vacuum overnight. The resulting compound
was recrystallized from ethanol and decolorized using charcoal to give 6 in 86% yields as
a white solid.
The likely role of cyanuric chloride is to convert salicylic acid to its acid chlo-
ride which then reacted with salicylamide to give the bis-salicylimide 7 (Figure 2);
the reaction does not proceed without triethylamine. In this case, there are two com-
petitive reactions generating both the anhydride of salicylic acid and the acid-amide
coupling product 7 that could initially be detected during the progress of the reac-
tion. The condensation between salicyloyl chloride and salicylamide has also been
ꢀ
22
carried out at higher temperature (170 C) in xylene with the higher yield of 4.
However, salicyloyl choride is a highly unstable and difficult to handle and makes
this method less attractive on a commercial scale. The use of the reaction conditions
reported here minimizes the formation of 7 and thus leads to increased purity of
final product (deferasirox) compared to the original procedure reported in the
2
4
patent.
Figure 2 Structure of Uncyclized Product 7
In summary, we have developed a milder process for preparation of 2-(2-
hydroxyphenyl)benz[e][1,3]oxazin-4-one (4) using cyanuric chloride as chlorinating
agent to give the desired product with high purity in satisfactory yield (54%). There
is no requirement for chromatography in the purification steps, i. e. the product can
be easily isolated by simple filtration. We anticipate that our approach should help
facilitate the large scale synthesis of deferasirox. The industrial-scale production is
currently being evaluated and optimized at The Government Pharmaceutical Organi-
zation in Thailand. The operational simplicity and ease of manipulation makes our
method a less dangerous and more attractive protocol and amenable for scale-up for
the chemical industry.

Benzoxazinone Intermediate for the Synthesis of Deferasirox
487
Experimental Section
All reagents were purchased from commercial available sources such as Aldrich or Fisher
1
13
and used without further purification. H and C magnetic resonance spectra were
recorded on a Bruker Avance 500 (500 MHz) spectrometer. Chemical shifts are reported
in d (ppm) from tetramethylsilane with the solvent resonance as an internal standard.
Data are listed as follows: chemical shifts, multiplicity (s D singlet, d D doublet, t D trip-
let, m D multiplet), coupling constant (Hz). FT-IR spectra were obtained on a Perkin
Elmer RXI spectrometer. High resolution ESIMS data were recorded on a Bruker MicrO-
TOF mass spectrometer. Melting points were determined on a Mettler Toledo MP 90.
Synthesis of 2-(2-hydroxyphenyl)-benz[e][1,3]oxazin-4-one (4)
In a round bottom flask fitted a reflux condenser and a Dean-Stark trap, a suspension of
salicylic acid (27.6 g, 0.2 mol), salicylamide (23.3 g, 0.17 mol) and 2,4,6-trichloro-
1
,3,5-triazine (24.8 g, 0.134 mol) in 600 mL toluene was heated under a nitrogen atmo-
ꢀ
sphere for 30 minutes at 80 C. Then triethylamine (28.08 mL, 0.2 mol) was added slowly
to the solution and the resulting mixture was heat to reflux for 16 h. Precipitation of some
ꢀ
solid began to occur during the reaction; the reaction mixture was cooled to about 80 C
and then filtered hot (by suction) as quickly as possible to remove the solid mixture of
triethylamine hydrochloride, cyanuric acid and other solids. The filtrate was then evapo-
3
9
rated and the resulting crude solid was recrystallized from ethanol (600 mL) to give
1.9 g (54% yield) of benzoxazinone 4 in better than 98% purity as a very pale yellow
solid. All spectroscopic data of product 4 matched those of an authentic sample.
2
ꢀ
22
ꢀ
Compound 4, mp 202.5–204.2 C, (lit. mp. 203–204 C); FTIR (KBr): 1704, 1614,
¡
1 1
540, 1355, 1245, 765, 696 cm ; H NMR (CDCl ): d 6.96 (t, J D 7.5 Hz, 1H), 7.05 (d,
1
3
J D 8.0 Hz, 1H), 7.48–7.52 (m, 3H), 7.75–7.79 (m, 1H), 8.08 (d, J D 8.0 Hz, 1H), 8.17 (t,
1
3
J D 7.0 Hz, 1H), 12.68 (s, 1H); C NMR (CDCl ): d 113.9, 119.7, 120.9, 121.5, 122.2,
3
1
29.9, 130.5, 131.4, 138.4, 139.5, 156.8, 165.8, 166.6, 167.8; HRMS: Calcd for
C
C H NO Na (MCNa ) 262.0475. Found: 262.0476.
1
4
9
3
Synthesis of Deferasirox (6)
A solution of compound 4 (2.39 g, 10 mmol) and 4-hydrazinobenzoic acid (1.67g,
1
1 mmol) was heated with stirring in 30 mL ethanol for 3 h at reflux. The reaction mix-
ture was then cooled to room temperature; the precipitated solid was collected and dried
under vacuum overnight. Recrystallization and decolorization with activated charcoal in
ethanol afforded 3.21 g (86% yield) of deferasirox (6) as a white solid. All spectroscopic
data of product 6 matched those of an authentic sample.
ꢀ
40
ꢀ
1
Compound 6, mp. 261–263 C, (lit. mp. 259–261 C); H NMR (DMSO-d ): d 6.81
6
(
d, J D 8.0 Hz, 1H), 6.91–6.98 (m, 3H), 7.30–7.35 (m, 2H), 7.50 (d, J D 8.5 Hz, 3H),
7
.94 (d, J D 8.0 Hz, 2H), 7.99 (d, J D 6.5 Hz, 1H), 9.99 (s, 1H), 10.75 (s, 1H), 13.15
C
(s, 1H); HRMS: Calcd. for C H N O (MCH ): 374.1135. Found: 374.1132.
2
1 16 3 4
Acknowledgements
The authors wish to acknowledge the financial supports from the Research, Development
and Engineering (RD&E) through the National Nanotechnology Center (NANOTEC),
National Science and Technology Development Agency (NSTDA), Thailand (Project

4
88
Jarussophona et al.
No. P-11-00892) and technical supports from Research and Development Institute, the
Government Pharmaceutical Organization. Additionally, we thank Dr. Nongpanga
Jarussophon from the Natural Products and Cosmetics Research Unit, Department of
Chemistry, Faculty of Liberal Arts and Sciences, Kasetsart University, Kamphaeng Saen
Campus for her collaboration and useful supports in this project.
References
1
2
3
4
5
. D. S. Kalinowski and D. R. Richardson, Pharmacol. Rev., 57, 547 (2005).
. J. A. McIntyre, J. Casta ~n er, N. E. Mealy and M. Bay ꢀe s, Drug Future, 29, 331 (2004).
. M. D. Cappellini and L. Zanaboni, US Hematology, 68 (2009).
. L. P. Yang, S. J. Keam and G. M. Keating, Drugs, 67, 2211 (2007).
. D. Chirnomas, A. L. Smith, J. Braunstein, Y. Finkelstein, L. Pereira, A. K. Bergmann, F. D.
Grant, C. Paley, M. Shannon and E. J. Neufeld, Blood, 114, 4009 (2009).
6. J. C. Wood, B. P. Kang, A. Thompson, P. Giardina, P. Harmatz, T. Glynos, C. Paley and T. D.
Coates, Blood, 116, 537 (2010).
7. M. B. Agarwal, Indian J. Pediatr., 77, 185 (2010).
8. http://www.fda.gov/newsevents/newsroom/pressannouncements/2005/ucm108514.htm. United
States Food and Drug Administration, November, 9, (2005).
9
. S. Steinhauser, U. Heinz, M. Bartholom €a , T. Weyherm €u ller, H. Nick and K. Hegetschweiler,
Eur. J. Inorg. Chem., 21, 4177 (2004).
1
1
0. J. B. Porter, Drugs Today, 42, 623 (2006).
1. K. Miyazawa, K. Ohyashiki, A. Urabe, T. Hata, S. Nakao, K. Ozawa, T. Ishikawa, J. Kato, Y.
Tatsumi, H. Mori, M. Kondo, J. Taniguchi, H. Tanii, L. Rojkjaer and M. Omine, Int. J. Hema-
tol., 88, 73 (2008).
12. U. Heinz, K. Hegetschweiler, P. Acklin, B. Faller, R. Lattmann and H. P. Schnebli, Angew.
Chem., Int. Edit., 38, 2568 (1999).
1
1
1
3. C. Liu and E. J. Iwanowicz, Tetrahedron Lett., 44, 1409 (2003).
4. S. Hussain, J. Sharma and M. Amir, E-Journal Chem., 5, 963 (2008).
5. Y. A. Al-Soud, N. A. Al-Masoudi and A. E.-R. S. Ferwanah Bioorgan. Med. Chem., 11, 1701
(
2003).
1
1
6. O. Bekircan and H. Bektas, Molecules, 11, 469 (2006).
7. A. R. Katritzky, M. Qi, D. Feng, G. Zhang, M. C. Griffith and K. Watson, Org. Lett., 1, 1189
(
1999).
1
1
2
2
8. M. J. Stocks, D. R. Cheshire and R. Reynolds, Org. Lett., 6, 2969 (2004).
9. S.T. Staben and N. Blaquiere, Angew. Chem., Int. Edit., 49, 325 (2010).
0. K. Paulvannan, T. Chen and R. Hale, Tetrahedron, 56, 8071 (2000).
1. G. M. Castanedo, P. S. Seng, N. Blaquiere, S. Trapp and S. T. Staben, J. Org. Chem., 76, 1177
(
2001).
22. H. Brunetti and C. E. Luthi, Helv. Chem. Acta, 55, 1566 (1972)

Benzoxazinone Intermediate for the Synthesis of Deferasirox
489
23. M. Mizhiritskii, E. Marom and S. Rubnov, PCT Int. Appl. WO2011070560 A1, 2011.
24. M. S. Reddy, S. Eswaraiah, G. V. Reddy and G. Shanmugam, PCT Int. Appl. WO2011021218
A2., 2011.
2
2
2
2
2
3
3
3
3
3
3
3
5. S.-Y. Han and Y.-A. Kim, Tetrahedron, 60, 2447 (2004).
6. T.-C. Lin and J.-M. Fang, Tetrahedron Lett., 52, 2232 (2011).
7. B. Thern, J. Rudolph and G. Jung, Tetrahedron Lett., 43, 5013 (2002).
8. G. Blotny, Tetrahedron, 62, 9507 (2006).
9. F. Hamon, G. G. Prie, F. Lecornue and S. Papot, Tetrahedron Lett. 50, 6800 (2009).
0. K. Venkataraman and D. R. Wagle. Tetrahedron Lett., 20, 3037 (1979).
1. C. O. Kangani and B. W. Day, Org. Lett., 10, 2645 (2008).
2. H. L. Rayle and L. Fellmeth, Org. Process Res. Dev., 3, 172 (1999).
3. T. C. Lin and J. -M. Fang, Tetrahedron Lett., 52, 2232 (2011).
4. M. Falorni, A. Porcheddu and M. Taddei, Tetrahedron Lett. 40, 4395 (1999).
5. B. P. Bandgar and S. S. Pandit, Tetrahedron Lett., 43, 3413 (2002).
6. B. P. Bandgar, N. S. Joshi, V. T. Kamble and S. S. Sawant, Australian. J. Chem., 61, 231
(
2008).
3
3
3
7. C. O. Kangani and B. W. Day. Tetrahedron Lett., 50, 5332 (2009).
8. Z. Yan, W.-L. Xue, Z.-X. Zeng and M.-R. Gu, Ind. Eng. Chem. Res., 47, 5318 (2008).
9. While the purification of 4 may be performed by the normal procedure to determine the “ideal”
volume of solvent, we have determined that the ideal volume of ethanol to be used for crystalli-
zation of 4 should be based on the amount of the starting salicylamide used. In our present
reported procedure, it is 0.28 M of salicylamide (600 mL of ethanol). A concentration higher
than 0.28 M leads to less pure material while lower number gives lower yields.
40. M. Mizhiritskii, E. Marom and S. Rubnov, US patent Appl. US 20120245361A1, 2012.