An improved and scalable process for celecoxib: A selective cyclooxygenase-2 inhibitor

Article abstract of DOI:10.1021/op800158w

An improved, scalable and commercially viable process is developed for an active pharmaceutical ingredient, celecoxib.

Full text of DOI:10.1021/op800158w

Organic Process Research & Development 2009, 13, 98–101
Technical Notes
An Improved and Scalable Process for Celecoxib: A Selective Cyclooxygenase-2
Inhibitor§
Anumula Raghupathi Reddy, Alla Sampath, Gilla Goverdhan, Bojja Yakambaram, Kagga Mukkanti,‡ and Padi Pratap Reddy*
Department of Research and DeVelopment, Integrated Product DeVelopment, InnoVation Plaza, Dr. Reddy’s Laboratories Ltd.,
SurVey Nos. 42, 45, 46, and 54, Bachupally, Qutubullapur, R R Dist-500 072, A.P., India
Abstract:
An improved, scalable and commercially viable process is devel-
oped for an active pharmaceutical ingredient, celecoxib.
Introduction
Figure 1. Chemical structure of celecoxib.
Scheme 1. Synthetic scheme of celecoxib
Pyrazoles have been widely described as pharmaceutical
therapeutic agents, including antiinflammatories and antidia-
betics. Celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-
1H-pyrazol-1-yl] benzene sulfonamide, Figure 1) was the first
cyclooxygenase-2 (COX-2) inhibitor approved for the treatment
of rheumatism and osteoarthritis.1,2 This drug was devoid of
the usual adverse effects associated with conventional nonste-
roidal antiinflammatory agents.3 Celecoxib was developed by
GD Searle, currently available in the market under the brand
name of Celebrex.
The preparation of pyrazoles from the condensation of
diketones with hydrazines is well documented4 in the literature.
The first reported synthetic method5-7 for the preparation of
celecoxib involved condensation of diketone 2 with phenyl
§ Dr. Reddy’s Communication no. IPDOIPM-00139.
* To whom correspondence should be addressed. E-mail: prataprp@
drreddys.com. Fax: 914044346285. Telephone: 9989997176.
‡ Institute of Science and Technology, Center for Environmental Science,
J.N.T. University, Kukatpally, Hyderabad-500 072, A.P., India.
(1) Simon, L. S.; Lanza, F. L.; Lipsky, P. E.; Hubbard, R. C.; Talwalker,
S.; Schwartz, B. D.; Isakson, P. C.; Geis, G. S. Arthritis Rheum 1998,
41, 1591.
hydrazine hydrochloride 3 in refluxing ethanol, and this reaction
yielded celecoxib 1 along with regioisomer 4 in the ratio of
99.5:0.5 with a yield of around 46% (Scheme 1). O’Shea and
co-workers8 described a two-step process for the preparation
of celecoxib from a similar condensation of a diketone 2 and
phenyl hydrazine hydrochloride 3 in an amide solvent. The
celecoxib was obtained as a solvate of the amide solvent and
was subsequently isolated and recrystallised from isopropanol
and water to produce an unsolvated celecoxib. Usage of
multisolvent system and repeated crystallizations made this
process less attractive. Zhi and co-workers9 synthesized cele-
coxib by reacting diketone 2 with phenyl hydrazine hydrochlo-
ride 3 in a mixture of 90% ethanol and methyl tert-butyl ether
(2) (a) Goldstien, J. L.; Silverstein, F. E.; Agrawal, N. M.; Hubbard, R. C.;
Kaiser, J.; Maurath, C. I.; Verburg, K. M.; Geis, G. S. Am. J.
Gastroenterol 2000, 95, 1681. (b) Daily Drug News.com (Daily
Essentials) January 4, 1999.
(3) Drug Data Rep, 1997 19 (2), 161.
(4) (a) Matsuo, M.; Tsuji, K.; Konishi, N.; Nakamura, K. EP patent
0,418,845, A1, 1990. (b) Matsuo, M.; Tsuji, K.; Konishi, N.; Ogino,
T. EP patent 0,554,829, A1, 1993. (c) Nishiwaki, T. Bull. Chem. Soc.
Jpn. 1969, 42, 3024. (d) Soliman, R.; Feid-allah, H. J. Pharm. Sci.
1980, 70, 602. (e) Wright, J. B.; Dulin, W. E.; Markillie, J. H. J. Med.
Chem. 1963, 7, 102. (f) Habeeb, A. G.; Rao, P. N. P.; Knaus, E. E.
J. Med. Chem. 2001, 44, 3039. (g) Szabo, G.; Fischer, J.; Kis-Varga,
A.; Gyires, K. J. Med. Chem. 2008, 51, 142. (h) Oh, L. M. Tetrehedron
Lett. 2006, 47, 7943.
(5) Talley, J. J.; Penning, T. D.; Collins, P. W.; Rogier, D. J.; Malecha,
J. W.; Miyashiro, J. M.; Bertenshaw, S. R.; Khanna, I. K.; Graneto,
M. J.; Rogers, R. S.; Carter, J. S. US patent 5,466,823, 1995.
(6) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins,
P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson,
G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.;
Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson,
P. C. J. Med. Chem. 1997, 40, 1347.
(7) Talley, J. J.; Penning, T. D.; Collins, P. W.; Rogier, D. J.; Malecha,
J. W.; Miyashiro, J. M.; Bertenshaw, S. R.; Khanna, I. K.; Graneto,
M. J.; Rogers, R. S.; Carter, J. S.; Docter, S. H.; Yu, S. S. US patent
6,586,603, B1, 2003.
(8) (a) O′ Shea, P. ; Tillyer, R. D. ; Wang, X. ; Clas, S. D. ; Dalton, C.
US patent 6,150,534, 2000. (b) O′ Shea, P. ; Tillyer, R. D. ; Wang,
X. ; Clas, S. D. ; Dalton, C. US patent 6,232,472, 2001.
(9) (a) Zhi, B. ; Newaz, M. US patent 5,892,053, 1999. (b) Zhi, B. ; Newaz,
M. US patent 5,910,597, 1999.
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10.1021/op800158w CCC: $40.75
2009 American Chemical Society
Published on Web 11/26/2008

Table 1. Optimization of solvent in the condensation
(MTBE). Concentration of the reaction mass followed by
dilution with water provided celecoxib in 73% yield.
In an alternative process,10 the condensation was performed
in the presence of trifluoroacetic acid (0.5-1.5 equiv) in
isopropyl alcohol. The yield and quality were good, but the
work-up process was laborious, involving repeated pH adjust-
ment and 12-14 h maintenance for isolation. Furthermore, as
the isopropyl alcohol is miscible in water, it can not be recovered
through normal distillation.
Thus, the reported processes suffer from several
disadvantages such as (a) lengthy reaction time (20 h),
(b) purification using a mixture of solvents, (c) a relatively
higher content of regioisomer impurity (0.5%), and (d)
usage of a multisolvent system, making the processes less
viable for commercial production. Herein we describe an
improved, economic, simple and scalable process for the
preparation of celecoxib that meets the regulatory quality
requirements.11 Our process involves condensation of
diketone 26,12 and phenyl hydrazine hydrochloride 312,13
in a mixture of ethyl acetate and water to provide
celecoxib in a yield of 84% after recrystallisation from
toluene.
reaction of compounds 2 and 3
celecoxib regioisomer yield
entry
solvent
1 (%)
4 (%)
(%)b
1
2
3
4
5
6
7
8
methanol
97.0
98.0
98.2
-
3.0
2.0
1.8
-
80
77
85
-
ethanol
isopropanol
ethyl acetatea
toluenea
-
-
-
water
96.7
97.0
98.5
3.3
3.0
1.5
97
87
95
water and toluene
water and ethyl acetate
a Reaction was not initiated. b Isolated yield.
Table 2. Optimization of solvent mixture in the
condensation reaction of compounds 2 & 3
water:EAa
ratio
celecoxib
1 (%)
regioisomer
yield
(%)c
entry
4 (%)
1
2
3
4
5
0:1b
1:0
1:1
1:2
1:3
-
-
-
96.76
98.56
99.46
99.83
3.10
1.36
0.41
0.12
97
95
79
71
a Ethyl acetate. b Reaction was not initiated. c Isolated yield.
Results and Discussion
Table 3. Impact of reaction temperature on the yield of
Condensation of 4,4,4-trifluoro-1-[4-(methyl)phenyl]-butane-
1,3-dione (2) and 4-sulfonamidophenyl hydrazine hydrochloride
(3) in a mixture of ethyl acetate and water, followed by usual
work-up furnished crude celecoxib containing <0.5% of 4-[3-
(4-methylphenyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide (4), a regioisomer of celecoxib (specification limit
is not more than 0.15%). Recrystallisation of this crude material
from toluene afforded celecoxib in 84% yield with more than
99.97% purity and e0.03% of regioisomer 4.
celecoxib
temperature
reaction celecoxib regioisomer yield
entry
(°C)
time (h)
1 (%)
4 (%)
(%)c
1
2
3
reflux (75-85)
55-65
2
7a
99.31
99.26
98.46
0.5
0.7
1.5
95
88
66
25-35
14b
a 90% reaction was completed. b 70% reaction was completed. c Isolated yield.
Different solvent media such as methanol, ethanol, isopro-
panol, ethyl acetate, toluene, water, a mixture of water and
toluene, and a mixture of water and ethyl acetate were explored
to obtain celecoxib in high yields from the condensation of
diketone 2 and phenyl hydrazine derivative 3. A mixture of
water and ethyl acetate was found to be the best solvent system
in terms of yield of 1 (Table 1). When reaction was conducted
in simple aqueous medium, the yield of the resulting celecoxib
was comparable to that obtained from aqueous ethyl acetate,
but regioisomer 4 was formed at a slightly higher level; hence,
a mixture of water and ethyl acetate medium was selected for
further optimization. By increasing the ethyl acetate ratio in
the solvent mixture, the yield of celecoxib was decreased
because of its high solubility in ethyl acetate. On the other hand,
increasing the water content in the solvent mixture led to a
higher amount of regioisomer 4 in the product. The 1:1 ratio
of the mixture of water and ethyl acetate was found to be
suitable to obtain celecoxib in quantitative yield with good purity
(Table 2).
To study the impact of reaction temperature on reaction time
and content of regiosiomer, experiments were conducted at
different temperatures. The results clearly indicated that the
reaction temperature plays a major role. While the reaction was
completed within 2 h at reflux temperature, the reaction got
slowed down, and the regioisomer content increased by
decreasing the reaction temperature (Table 3).
Enhanced formation of regioisomer 4 at lower reaction
temperatures may be attributed to the formation of diketone
hydrate 5 resulting from the attack of nucleophile (H2O) at the
more electropositive carbonyl carbon. Subsequent reaction of
hydrazine function at the aroyl carbonyl leads to regioisomer 4
(Scheme 2).10
Celecoxib was isolated through a simple work-up process
by cooling the reaction mixture to 0-5 °C and subsequent
filtration after 1-1.5 h stirring. Isolation temperature and time
did not have any significant impact on the quality and yield of
the product.
The crude clecoxib containing <0.5% of regioisomer was
subjected to further purification to meet the regulatory require-
ments.11 The reported purification process for celecoxib involved
a mixture of isopropanol and water,4h a mixture of ethyl acetate
and isooctane/5,6dichloromethane and hexane.7 We have ex-
plored the methanol, isopropanol, toluene, and ethyl acetate to
use a single solvent for the recrystallisation process. Yield and
quality were excellent when celecoxib was recrystallised from
(10) (a) Letendre, L. J.; McGhee, W. D.; Snoddy, C.; Klemm, G.; Graud,
H. T. US patent 7,141,678, 2006. (b) Letendre, L. J.; McGhee, W. D.;
Snoddy, C.; Klemm, G.; Graud, H. T. US patent 2007/0,004, 924 A1,
2007.
(11) ICH harmonized tripartite guideline, Impurities in New Drug Sub-
stances Q3A (R2), current step 4 version dated 25 October2006.
(12) Ahlstrom, M. M.; Ridderstrom, M.; Zamora, I.; Luthman, K. J. Med.
Chem. 2007, 50, 4444.
(13) Soliman, R. J. Med. Chem. 1979, 22, 321.
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Scheme 2. Pathway for the formation of diketone hydrate 5
Table 7. Experimental results of celecoxib recrystallisation
from recovered toluene
celecoxib
1 (%)
regioisomer
yield
(%)a
entry
toluene
4 (%)
1
2
fresh
recovered
99.9
99.9
0.1
0.1
95
95
a Isolated yield.
Table 8. Experimental results of final optimized process
entry
celecoxib 1 (%)
regioisomer 4 (%)
yield (%)a
1
2
3
99.97
99.98
99.97
0.03
0.02
0.03
84
83
84
a Isolated yield.
Table 4. Optimization of solvents for recrystallisation of
celecoxib
celecoxib
1 (%)
regioisomer
yield
(%)a
recovered ethyl acetate, and no significant impact was observed
on the yield and quality of celecoxib.
The quality of recovered toluene matches that of fresh
solvent.
In the final optimized process, celecoxib was obtained with
consistent quality with a yield of around 84% (Table 8).
entry
solvent
methanol
isopropyl alcohol
toluene
ethyl acetate
4 (%)
1
2
3
4
99.80
99.95
99.92
99.70
0.12
0.05
0.06
0.27
50
72
92
28
a Isolated yield.
Conclusion
Table 5. Experimental results of different isolation
temperatures
In conclusion, we have developed an improved, scalable,
and commercially viable manufacturing process for the prepara-
tion of celecoxib with a yield of around 84%, and this active
pharmaceutical ingredient is substantially free of impurities and
meets the regulatory requirements.
celecoxib
1 (%)
regioisomer
yield
(%)a
entry
temperature (°C)
4 (%)
1
2
3
4
0-5
99.89
99.88
99.91
99.94
0.06
0.07
0.04
0.03
95
95
90
84
10-15
25-35
40-45
Experimental Section
a Isolated yield.
A liquid chromatograph equipped with a variable
wavelength UV detector and integrator was used in
recording HPLC. Mass spectra were obtained using a
4000-Q-trap LC/MS/MS mass spectrometer. 1H NMR and
13C NMR were recorded in DMSO-d6 at 400 and 100
MHz, respectively, on a Mercury Plus (Varian 400 MHz)
FT NMR spectrometer; the chemical shifts are reported
in δ ppm relative to TMS (δ 0.00 ppm) and DMSO-d6 (δ
39.5 ppm) as internal standards, respectively.
Table 6. Experimental results of celecoxib by using
recovered ethyl acetate
ethyl
acetate
celecoxib
1 (%)
regioisomer
yield
(%)a
entry
4 (%)
1
2
fresh
recovered
99.3
99.2
0.7
0.8
95
93
a Isolated yield.
4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]ben-
zenesulfonamide (Celecoxib). A mixture of 4,4,4-trifluoro-1-
[4-(methyl) phenyl]-butane-1,3-dione (17.0 kg, 73.91 mol),
4-sulfonamidophenyl hydrazine hydrochloride (17.85 kg, 79.86
mol), water (85 L, 1.15 L/mol) and ethyl acetate (85 L, 1.15
L/mol) was heated to reflux for 2 h. The reaction mixture was
cooled to 0-5 °C and stirred for 1-1.5 h. The obtained solid
was filtered under reduced pressure and washed with water (34
L, 0.46 L/mol). Wet material was taken into toluene (375 L,
5.07 L/mol) and heated to 80-85 °C, and the aqueous layer
was separated. The organic layer was cooled to 10-15 °C and
stirred for 1-1.5 h. The isolated solid was filtered, washed with
toluene (25 L, 0.34 L/mol), and dried at 75-85 °C for 6-8 h
under reduced pressure to give the title compound. Yield 23.7
kg (84%); purity by HPLC 99.97%; regioisomer 0.03%; DSC
162.14 °C; Heavy metals <10 ppm; M/S m/z 382 M+ + H; IR
(KBr) cm-1 3341, 3235 (N-H); 1H NMR, (DMSO-d6) δ 7.89
(d, J ) 8.8 Hz, 2H), 7.55 (d, J ) 8.8 Hz, 2H); 7.52 (s, NH2);
toluene (Table 4). Hence, further optimization was carried out
by using toluene.
In the recrystallisation of crude celecoxib, isolation
temperature was impacting the yield of the product. Thus,
no significant change was observed by isolating the
celecoxib at 0-5 °C and 10-15 °C, but further increases
in the temperature led to lower yields due to the enhanced
solubility of the product in ethyl acetate at the higher
temperatures (Table 5).
Solvents used for the condensation reaction and recrystal-
lisation were recovered (65% of ethyl acetate and 85% of
toluene) by simple distillation and were reused in the preparation
of celecoxib (Tables 6 and 7).
In the recovered ethyl acetate ∼25% of ethanol and ∼5%
of acetic acid were observed. Experiments were conducted with
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7.22 (m, 4H); 7.17 (s, 1H); 2.32 (s, 3H); 13C NMR (DMSO-
d6) δ 20.7, 37.4, 106.1, 121.5, 125.3, 125.9, 126.8, 128.7, 129.4,
139.1, 141.1, 142.2, 144.0, 145.2, 267.4; Anal. Calcd for
C17H14F3N3O2S: C 53.53, H 3.69, N 11.01, S 8.39. Found: C
53.50, H 3.70, N 11.01, S 8.44.
Gradient program: time (min): 0 8 20 30 42 45 60
% of mobile phase A: 50 50 10 5 5 50 50
% of mobile phase B: 50 50 90 95 95 50 50
Retention time of celecoxib: ∼29.2 min
Retention time of regioisomer: ∼30.9 min
HPLC Conditions: Column: Kromasil 100 C18, 250 mm
× 4.6 mm × 5 µm
Acknowledgment
We thank the management of Dr. Reddy’s Laboratories Ltd.
for supporting this work. Co-operation from the project col-
leagues of analytical research and development department and
process research and development department of active phar-
maceutical ingredients, IPDO, Dr. Reddy’s Laboratories Ltd.
is highly appreciated.
Wavelength: 258 nm
Flow: 0.8 mL/min
Temperature: 25 °C
Injection load: 10 µL
Run time: 60 min
Mobile phase A: buffer (1.36 g potassium dihydrogen
phosphate and 0.22 g octane-1-sulfonic acid sodium salt in 1 L
of milli-Q water. pH adjusted to 3.3 with dilute H3PO4)
Mobile phase B: acetonitrile and water in the ratio of
7:3
Received for review July 3, 2008.
OP800158W
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