Synthesis of Tenidap: An improved process for the preparation of 5-chloro-2-oxindole-1-carboxamide

Article abstract of DOI:10.1021/op000082b

An industrially viable, robust, and economic process is developed for Tenidap sodium and its important intermediate 5-chloro-2-oxindole-1-carboxamide. Use of inorganic cyanates, in place of organic isocyanates, makes the process simple and commercially vi

Full text of DOI:10.1021/op000082b

Organic Process Research & Development 2001, 5, 61−64
Synthesis of Tenidap: An Improved Process for the Preparation of
5-Chloro-2-oxindole-1-carboxamide†
P. Rajender Kumar, P. Satish Goud, S. Raju, M. Sailaja, M. R. Sarma, and G. Om Reddy*
Process Chemistry R&D, Dr. Reddy’s Research Foundation, Bollaram road, Miyapur Hyderabad, India 500 050
Abstract:
An industrially viable, robust, and economic process is devel-
oped for Tenidap sodium and its important intermediate
5-chloro-2-oxindole-1-carboxamide. Use of inorganic cyanates,
in place of organic isocyanates, makes the process simple and
commercially viable. The advantage of using acetic anhydride
and sodium acetate over reported reagents such as trifluoro-
acetic acid and its anhydride on industrial scale is described.
Figure 1.
Drastic reduction of DMAP in the final step and overall
improvement of yields makes the process economical.
drolysis with aqueous acetic acid gave 5-chloro-2-oxindole-
1-carboxamide (4) as shown in Scheme 1.
(b)Reaction of 5-chloro-2-oxidnole (2) with isobutyryl
isocyanate and cyclohexyl carbonyl isocyanate in toluene
gave the intermediate (5). Hydrolysis of (5) in potassium
hydroxide yielded 2-(5-chloro-2-ureidophenyl)acetic acid10
(6), which was cyclised with a mixture of trifluoroacetic acid
and trifluoroacetic anhydride to give the desired 5-chloro-
2-oxidnole-1-carboxamide (4) (Scheme 2).
(c)Reaction of 5-chloro-2-oxindole (2) with trichloroacetyl
isocyanate11 in toluene followed by warming the reaction
mixture to 80 °C to give 5-chloro-2-oxindole-1-carboxamide
(4) in one step (Scheme 3).
It is evident from the literature that the preparation of
the key intermediate (4) of tenidap sodium (1) is uneconomi-
cal and employs hazardous organic isocyanates. Further, the
reported process for condensation of thiophene-2-carbonyl
chloride with 5-chloro-2-oxindole-1-carboxamide (4) to
prepare tenidap (7) (Scheme 4) employs an excess of the
expensive base N,N-dimethylaminopyridine (DMAP), thereby
making the process cost-ineffective.
Therefore, it was felt necessary to develop an improved
process for the preparation of tenidap sodium (1) by
employing nonhazardous, inexpensive, and easy-to-handle
chemicals on large scale.
Introduction
Oxindole-1-carboxamide derivatives, particularly 5-chloro-
3-(2-thenoyl)-2-oxindole-1-carboxamide sodium salt, tenidap
sodium (1) (Figure 1), are for the treatment of rheumatoid
arthritis1 and osteoarthritis2. Tenidap is an inhibitor of
prostaglandin3 and interleukin-14 production in the body. It
inhibits both the enzymes cycloxygenase and 5-lypoxyge-
nase,5 which convert arachidonic acid into prostaglandin and
leukotrienes3, and exhibits superior activity compared to other
nonsteroidal antiinflammatory drugs (NSAIDs) such as
naproxen,6 piroxicam,7 diclofenac sodium,8 indomethacin,9
and so forth, currently available in the market. Tenidap
sodium has not been launched in the market because of toxic
effects found in clinical trials.
Introduction
5-Chloro-2-oxindole-1-carboxamide10 (4) is an important
intermediate in the preparation of tenidap sodium (1), which
is commonly prepared by one of the following methods.
(a)N-acylation of 5-chloro-2-oxindole (2) with chlorosul-
fonyl isocyanate produced intermediate (3) which on hy-
† DRF publication No. 99.
(1) Johnson, J. A.; Loeser, R.; Smith, D. M.; Turner, R. A. Agent Action 1990,
31, (1-2), 102.
Results and Discussion
The synthetic route discussed in this paper is presented
in Scheme 5. The salient features are discussed below.
(a) Expensive and highly reactive organic isocyanates are
substituted by inorganic cyanates which are not only
inexpensive but also easy to handle even at large scale
operations for the preparation of 2-(5-chloro-2-ureidophenyl)-
acetic acid (6).
(b) The cyclisation of 2-(5-chloro-2-ureidophenyl)acetic
acid (6) to 5-chloro-2-oxindole-1-carboxamide (4) is carried
out with acetic anhydride and sodium acetate, thereby
avoiding the expensive trifluoroacetic acid and trifluoroacetic
anhydride mixture. The above cyclisation can also be carried
(2) (a)Fernandes, J.; Martel-Pelletier, J.; Mineau, F.; Otterness, I.; Pelleteir, J.
P. Can. J. Physiol. Pharmacol. 1994, 72 (1), Abstr. P 10.1.47. (b) Fernandes,
J. C.; Lopez-Anaya A.; Martel-Pelletier, J.; Mineau, F.; Otternes, I. G.;
Pelletier, J. P. Arthritis Rheum. 1994, 37 (9), Abstr. 1205.
(3) Carty, T..J.; Showell, H. J.; Loose, L. D.; Kadin, S. B. Arthritis Rheum.
1988, 31 (4), S 89.
(4) McDonald, B.; Loose, L.; Rosenwasser, L. J. Arthritis Rheum. 1988, 31
(4), S 17.
(5) Moilanen, E.; Alanko, J.; Asmawi, M. Z.; Vepaatalo, H. Eicosanoids 1988,
1, 35-39.
(6) Cavanaugh, M. J.; Finman, J. S.; Kirby, D. S.; Loose, L. D.; Ting, N.;
Weiner, E. S. Rheumatol. Eur. 1995, 24 (3), D35.
(7) Krasaka, A. R.; Kirby, D. S.; Loose, L. D.; Shanahan, W. R.; Ting, N.;
Weiner, E. S. ReV. Esp. Reumatol. 1993, 20(1), Th80.
(8) Wylie, G. ReV. Esp. Reumatol. 1993, 20(1), 306.
(9) Granger, D. N.; Panes, J.; Wallace, J. L.; Wolf, R. E. Arthritis Rheum. 1994,
37 (9), 1053.
(10) Kadin, S. B. U.S. Patent 4,556,672, 1985.
(11) Kelly, S. E. U.S. Patent 4,952,703, 1990.
10.1021/op000082b CCC: $20.00 © 2001 American Chemical Society and The Royal Society of Chemistry
Published on Web 12/07/2000
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Scheme 1
Scheme 2
Scheme 3
The cyclisation of compound 6 was accomplished by using
acetic anhydride and sodium acetate to give 5-chloro-2-
oxindole-1-carboxamide (4) in good yield. The above cy-
clisation can also be carried out with thionyl chloride and/
or p-toluene sulfonic acid. The 1H NMR spectrum of
compound (4) in CDCl3 has two broad peaks resonating at
δ 5.4 and 8.5 which are due to exchangeable amidic protons.
It is interesting to note that they resonate at different
frequencies. This could be rationalised in terms of restricted
C-N- bond rotation due to the strong intramolecular
hydrogen bonding with one of the amidic proton with C2-
carbonyl as showed in Figure 2. Tenidap (7) is obtained by
condensation of above carboxamide (4) with thiophene-2-
carbonyl chloride by using a mixture of triethylamine and a
catalytic amount of DMAP.
The pharma grade tenidap sodium (1) is obtained by
known methods10 by first converting tenidap (7) into its
sodium salt using ethanolamine and sodium methoxide in
methanol and finally recrystallising the product from glacial
acetic acid. The 1H NMR spectrum of the compound 7 and
compound 1 showed the same pattern of amidic protons as
in compound 4.
out with thionyl chloride or p-toluene sulfonic acid in
moderate yields.
(c) The condensation of 5-chloro-2-oxindole-1-carbox-
amide (4) with thiophene-2-carbonyl chloride is accom-
plished by using inexpensive trialkylamines and a catalytic
amount of N,N-dimethylaminopyridine (DMAP). The reduc-
tion of expensive DMAP from 2 M equiv10 to a catalytic
amount (0.2 M equiv) greatly reduces the cost of the final
compound.
(d) The cost benefits are also due to the improved yields
in the synthesis of the two intermediates 4 and 7.
Many procedures are reported in the literature12 for the
preparation of 5-chloro-2-oxindole (2). Keeping in view
scale-up and process convenience, compound 2 is prepared
from 5-chloroisatin10 under Wolff-Kishner reduction condi-
tions. 5-Chloro-2-oxindole (2) (Scheme 5) on hydrolysis with
aqueous sodium hydroxide followed by acidification gave
an unstable 2-amino-5-chlorophenylacetic acid which without
isolation on reaction with in situ generated isocyanic acid
(from the reaction of potassium cyanate with acetic acid)
gave 2-(5-chloro-2-ureidophenyl)acetic acid (6) in good yield.
Scale-Up Trials. The process mentioned in Scheme 5 is
fully optimized and the scale-up trials were performed on 1
to 2 kg scale. This route performed routinely and reliably,
affording the expected yields and purities in all stages of
the synthesis, thus demonstrating the robustness and viability
of the process.
Experimental Section
(12) (a)Gessmann, P. G.; Gillbert, D. P.; Luh, T. Y. J. Org. Chem. 1977, 42,
1340. (b) Fogila, T. A.; Swern, D. J. Org. Chem. 1968, 33, 4440. (c) Coffey,
S. Rodds Chemistry of Carbon Compounds, 2nd ed.; Elsevier: Amsterdam,
The Netherlands, 1973; Vol. IV, Part A, pp 448-450.
Solvents and reagents are obtained from commercial
sources and are not purified unless specified. Proton NMR
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Scheme 4
Scheme 5
IR (KBr) 1234, 1350, 1540, 1575, 1657, 1702, 3272, 3340,
3486 cm-1. Mass m/z 265, 228, 211, 185, 168, 140, 112.
Preparation of 5-chloro-2-oxindole-1-carboxamide (4).
(a) A solution of 2-(5-chloro-2-uridophenyl)acetic acid (6)
(10 g, 0.47 M) dissolved in dichloroethane (150 mL) was
cooled to 10 °C. Thionyl chloride (4.5 mL) was added slowly
to the reaction mixture with stirring over a period of 20 min.
The temperature was raised to 30 °C, and the mixture was
stirred for 4 h more. The reaction mixture was evaporated
to dryness under vacuum. The residue was washed first with
sodium bicarbonate solution and then with water. The crude
product was purified by column chromatography packed with
silica gel to give 5-chloro-2-oxindole-1-carboxamide: yield
3.8 g (41%).
(b) 2-(5-Chloro-2-uridophenyl)acetic acid (6) (10 g) was
dissolved in 300 mL of toluene and p-toluenesulfonic acid
(2.5 g) in a flask arranged for azeotropic reflux. The reaction
mixture was refluxed for 8 h and then washed with water.
The toluene layer was dried over sodium sulfate and
evaporated. The crude product thus obtained was chromato-
graphed over silica gel to give 5-chloro-2-oxindole-1-
carboxamide (4): yield 9.03 g (35%).
(c) To cooled (0 °C) acetic anhydride (60 mL, freshly
distilled over sodium acetate), anhydrous sodium acetate (2
g) was added. To the above solution, 2-(5-chloro-2-uridophe-
nyl)acetic acid (6) (10 g) was added slowly, while maintain-
ing the temperature between 0 and 5 °C; stirring was
continued for 1 h more at the same temperature. The white
precipitate which formed was filtered, washed with 10%
sodium bicarbonate solution followed by water, and dried
under vacuum. The first crop yield was 5 g. The filtrate was
Figure 2.
data was obtained on a Varian Gemini 200 MHz FT NMR
spectrometer. Infrared spectra (IR) were recorded on a
Perkin-Elmer 1650 FT-IR spectrophotometer. Mass spectra
were recorded on an HP-5989A quadrapole mass spectrom-
eter. All of the melting points are uncorrected.
Preparation of 2-(5-chloro-2-uridophenyl)acetic acid
(6). 5-Chloro-2-oxindole (2) (20 g, 0.12M) and sodium
hydroxide (200 mL, 10% solution) were refluxed for 7 h.
The reaction mixture was cooled to 0° C, neutralized with
concentrated sulfuric acid while maintaining the temperature
between 0 and 5° C, and filtered. To the filtrate, acetic acid
(36 mL) was added slowly while stirring to obtain a white
precipitate. A freshly prepared solution of potassium cyanate
(19.5 g in 50 mL water) was added dropwise to the above
reaction mixture at room temperature. Stirring was continued
for 1 h. The precipitate was filtered and dissolved in 5%
sodium bicarbonate solution (250 mL). After removal of
undissolved matter by filtration, the solution was extracted
with ethyl acetate (2 × 100 mL) to remove soluble
impurities; the organic layer was discarded. The bicarbonate
solution was acidified with sulfuric acid, and the precipitated
material was filtered and dried under vacuum: mp 180-
182° C (lit. mp ) 187.5 °C),10 purity 98.5%, yield 18.6 g
1
(68%). H NMR (CD3OD) δ 3.5 (s, 2H), 7.2-7.5 (m, 3H).
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poured onto crushed ice and set aside for 2 h; the separated
material was filtered, washed with 10% sodium bicarbonate
solution and water, and dried under vacuum to yield 2.7 g
of additional 5-chloro-2-oxindole-1-carboxamide (4). The
yield from the two crops was 7.7 g (83%). This compound
can be used in the next step without further purification. The
crude product (1 g) was recrystallised from acetonitrile to
give 300 mg of pure product: mp 210-211 °C (lit. mp 211
°C), HPLC purity 98%. 1H NMR (CDCl3) δ 3.8 (s, 2H), 5.3
(1H, D2O exchangeable), 7.3 (d, 2H), 8.1 (d, 1H), 8.4 (s,
D2O exchangeable). IR (KBr) 1093, 1166, 1290, 1370, 1471,
5585, 1710, 1749, 3212, 3367 cm-1. Mass m/z (70 ev) 210,
167, 138, 112, 102.
Preparation of 5-chloro-3-(2-thenoyl)-2-oxindole-1-
carboxamide (Tenidap) (7). To a solution of 5-chloro-2-
oxindole-1-carboxamide (4) (10 g) dissolved in dimethyl-
formamide (90 mL), N,N-dimethylaminopyridine (1.45 g,
0.01 M) and triethylamine (1.96 mL, 0.14 M) were added
and cooled to 8 °C. Thiophene-2-carbonyl chloride (5.6 mL,
0.052 M) in dimethylformamide (18 mL) was added to the
above mixture slowly while maintaining the temperature
between 8 and 15 °C. Dilute hydrochloric acid (8 mL,
concentrated HCl in 200 mL of water) was added to the
above reaction mass and kept for 2 h at room temperature.
The precipitate was washed with water followed by metha-
nol. The above crude material was refluxed in methanol (200
mL) for 1 h. Ethanolamine (3 mL) and active carbon (2 g)
were added to the above methanolic solution and refluxed
for 30 min and filtered. The filtrate was cooled to room
temperature and acidified with hydrochloric acid. The yellow
solid was filtered and dried to obtain tenidap (7): yield 13.4
g, (88.1%), mp 226-229 °C (lit. mp 229-231 °C)10 (dec).
Preparation of Sodium Salt of 5-Chloro-3-(2-thenoyl)-
2-oxindole-1-carboxamide. (Tenidap Sodium) (1). 5-Chloro-
3-(2-thenoyl)-2-oxindole-1-carboxamide (10 g, 0.031M) was
dissolved in a mixture of methanol (200 mL) and ethanol-
amine (3 mL) and filtered to remove any insoluble matter.
To the above solution, sodium methoxide (3.7 g) in methanol
(10 mL) was added and refluxed for 1 h. The reaction
mixture was maintained at room temperature for 10 h while
stirring. The crystallised yellow material was filtered and
washed with methanol (3 mL) and dried under vacuum to
yield 8.7 g of tenidap sodium (1). The filtrate was concen-
trated to half its volume to obtain a second crop of tenidap
sodium (1.2 g): the total yield (two crops) was 96%, mp
232-233 °C (lit. mp 236-238 °C),10 purity 99%. 1H NMR
(CDCl3) δ 6.5 (s, 1H, exchangeable), 6.8 (dd, 1H), 7.1 (d,
1H), 7.5 (d, 1H), 8.1 (t, 1H), 8.4 (d, 1H), 9.6 (s, 1H,
exchangeable). IR (KBr) 722, 787, 1039, 1075, 1177, 1374,
1421, 1642, 1673, 1698, 3043, 3668 cm-1. Mass m/z (20
ev) 277, 193, 167, 137, 127, 111.
Acknowledgment
We thank the management of Dr. Reddy’s Research
foundation in general and Dr. A. Venkateswarlu in particular
for permission to publish this work. Cooperation extended
by all the colleagues of analytical and structure elucidation
group is highly appreciated.
Received for review July 25, 2000.
OP000082B
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