CELECOXIB
169590-42-5
4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (Celecoxib)
SYNTHESIS
4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (Celecoxib)
SYNTHESIS
PAPER
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
Org. Process Res. Dev., 2009, 13 (1), pp 98–101
DOI: 10.1021/op800158w
E-mail: prataprp@ drreddys.com. Fax: 914044346285. Telephone: 9989997176
E-mail: prataprp@ drreddys.com. Fax: 914044346285. Telephone: 9989997176
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); 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.
An improved, scalable and commercially viable process is developed for an active pharmaceutical ingredient, celecoxib.
HPLC Conditions:
Column: Kromasil 100 C18, 250 mm × 4.6 mm × 5 μm
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
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
29.2 min
Retention time of regioisomer: 30.9 min
30.9 min
http://newdrugapprovals.org/2013/04/07/drug-spotlight-celecoxib-from-g-d-searle-company/
Celecoxib extraction
Celecoxib was extracted from Celebra™ 100
mg and 200 mg capsules. Ten capsules were
crushed to fine powder, using agate mortar and
pestle, transferred to a 50 ml volumetric flask
and diluted to volume with methanol. The solution
was shaked for 5 min and filtered. The
residue was recrystallized from acetonitrile after
evaporation of the solvent in a water bath at 50
°C, under a stream of nitrogen.
Thin layer Chromatography (TLC) In this procedure it was used silica gel 60 F254 plates (20 x 20 cm) with a thickness of 0.25 mm. All plates used were commercially prepared by MERCK (lot # 040422153). The mobile phase used to develop the system consisted of chloroform-ethyl acetate-ether (10:5:1, v/v/v). Just in order to verify the selectivity of the proposed system, another COX-2 inhibitor (rofecoxib) with similar properties was used. 20 µl of celecoxib reference substance and extracted from tablets and rofecoxib solutions (50 µg.ml–1) were spotted on the TLC plates, and transferred to a developing tank containing the mobile phase. The plate was then examined under UV light (254 and 365 nm).
Thin-layer chromatography One of the most effective screening methods is the thin-layer chromatography (TLC), which is the simplest of all the widely used chromatographic methods to perform. In the determination of this method, different chromatography systems were tested and analyzed according to the classification proposed by Moffat 13, which divide the drugs in three categories: acid, basic and neutrals based on their polarity and acid characteristics. This procedure is important in
order to increase the information obtained only by changing the mobile phase, and thus resulting in a significant change in selectivity. These chromatographic systems consisted of mixtures of the following solvents: chloroformacetonitrile, ethyl acetate, acetone and methanol, in different concentrations. Nevertheless, all the mobile phases tested were not adequate for the proper identification of the drug. With the objective to develop more reliable chromatographic method, a modification in the system tested was proposed, in order to improve the chromatographic resolution. The mobile phase used consisted of chloroform-ethyl acetate-ether (10:5:1 v/v/v). The system was chosen due to its sensitivity, simplicity and efficacy
The preference to use commercially prepared silica gel plates was due to its durability and homogeneity of the absorbent layer. A sample solution of the working standard and the drug sample (50 (µg ml–1) were spotted onto a silica gel plate with a micropipette and the chromatogram was developed by placing the plate in a tank containing the mobile phase. Following development the individual solute spots were identified under UV lamp (254 and 365 nm). The spots in the drug sample and the working standard presented similar Rf values. The Rf value obtained for drug sample and the working standard were 0.45 and for rofecoxib 0.32.
NMR
The spectrum shown in Figure 3 possesses two characteristic sharp singlet peaks at 2.3 and3.3 ppm that belong to the methyl and sulfonamide protons of celecoxib. The spectrum also reveals peaks from 7.3 to 7.9, which is due to the protons of aromatic groups. The characteristics peaks from the working standard agree well with those observed in the samples, considering the fact that a constant shift is observed in all peaks 11, 12.
UV
IR
1150 - 1350 S = O stretching (sulfonamide group)
1550 - 1600 N - H stretching
3300 - 3500 NH2 stretching
1H NMR PREDICT
13 C NMR
(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.
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 Substances 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.
SYNTHESIS
+
GIVES........CELECOXIB
EUCLISES PHARMACEUTICALS, INC.; MARTINEZ, Eduardo, J.; TALLEY, John, J.; JEROME, Kevin, D.; BOEHM, Terri, L. Patent: WO2014/12074 A2, 2014 ; Location in patent: Paragraph 00209; 00210
2
+
+
Reddy, Anumula Raghupathi; Sampath, Alla; Goverdhan, Gilla; Yakambaram, Bojja; Mukkanti, Kagga; Reddy, Padi Pratap Organic Process Research and Development, 2009 , vol. 13, # 1 p. 98 - 101
3
Prabhakaran, Jaya; Underwood, Mark D.; Parsey, Ramin V.; Arango, Victoria; Majo, Vattoly J.; Simpson, Norman R.; Van Heertum, Ronald; Mann, J. John; Kumar, J.S. Dileep Bioorganic and Medicinal Chemistry, 2007 , vol. 15, # 4 p. 1802 -
4
Li, Feng; Nie, Jing; Sun, Long; Zheng, Yan; Ma, Jun-An Angewandte Chemie - International Edition, 2013 , vol. 52, # 24 p. 6255 - 6258
5
Synlett, , vol. 1997, # 4 p. 375 - 377
6Tetrahedron Letters, , vol. 52, # 45 p. 6000 - 6002
7
Bioorganic and Medicinal Chemistry Letters, , vol. 21, # 22 p. 6636 - 6640
COCK WILL TEACH YOU NMR
COCK SAYS MOM CAN TEACH YOU NMR
Celecoxib extraction
Celecoxib was extracted from Celebra™ 100
mg and 200 mg capsules. Ten capsules were
crushed to fine powder, using agate mortar and
pestle, transferred to a 50 ml volumetric flask
and diluted to volume with methanol. The solution
was shaked for 5 min and filtered. The
residue was recrystallized from acetonitrile after
evaporation of the solvent in a water bath at 50
°C, under a stream of nitrogen.
Thin layer Chromatography (TLC) In this procedure it was used silica gel 60 F254 plates (20 x 20 cm) with a thickness of 0.25 mm. All plates used were commercially prepared by MERCK (lot # 040422153). The mobile phase used to develop the system consisted of chloroform-ethyl acetate-ether (10:5:1, v/v/v). Just in order to verify the selectivity of the proposed system, another COX-2 inhibitor (rofecoxib) with similar properties was used. 20 µl of celecoxib reference substance and extracted from tablets and rofecoxib solutions (50 µg.ml–1) were spotted on the TLC plates, and transferred to a developing tank containing the mobile phase. The plate was then examined under UV light (254 and 365 nm).
Thin-layer chromatography One of the most effective screening methods is the thin-layer chromatography (TLC), which is the simplest of all the widely used chromatographic methods to perform. In the determination of this method, different chromatography systems were tested and analyzed according to the classification proposed by Moffat 13, which divide the drugs in three categories: acid, basic and neutrals based on their polarity and acid characteristics. This procedure is important in
order to increase the information obtained only by changing the mobile phase, and thus resulting in a significant change in selectivity. These chromatographic systems consisted of mixtures of the following solvents: chloroformacetonitrile, ethyl acetate, acetone and methanol, in different concentrations. Nevertheless, all the mobile phases tested were not adequate for the proper identification of the drug. With the objective to develop more reliable chromatographic method, a modification in the system tested was proposed, in order to improve the chromatographic resolution. The mobile phase used consisted of chloroform-ethyl acetate-ether (10:5:1 v/v/v). The system was chosen due to its sensitivity, simplicity and efficacy
The preference to use commercially prepared silica gel plates was due to its durability and homogeneity of the absorbent layer. A sample solution of the working standard and the drug sample (50 (µg ml–1) were spotted onto a silica gel plate with a micropipette and the chromatogram was developed by placing the plate in a tank containing the mobile phase. Following development the individual solute spots were identified under UV lamp (254 and 365 nm). The spots in the drug sample and the working standard presented similar Rf values. The Rf value obtained for drug sample and the working standard were 0.45 and for rofecoxib 0.32.
NMR
The spectrum shown in Figure 3 possesses two characteristic sharp singlet peaks at 2.3 and3.3 ppm that belong to the methyl and sulfonamide protons of celecoxib. The spectrum also reveals peaks from 7.3 to 7.9, which is due to the protons of aromatic groups. The characteristics peaks from the working standard agree well with those observed in the samples, considering the fact that a constant shift is observed in all peaks 11, 12.
UV
IR
1150 - 1350 S = O stretching (sulfonamide group)
1550 - 1600 N - H stretching
3300 - 3500 NH2 stretching
1H NMR PREDICT
13 C NMR
(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.
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 Substances 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.
SYNTHESIS
+GIVES........CELECOXIBEUCLISES PHARMACEUTICALS, INC.; MARTINEZ, Eduardo, J.; TALLEY, John, J.; JEROME, Kevin, D.; BOEHM, Terri, L. Patent: WO2014/12074 A2, 2014 ; Location in patent: Paragraph 00209; 00210
2
++Reddy, Anumula Raghupathi; Sampath, Alla; Goverdhan, Gilla; Yakambaram, Bojja; Mukkanti, Kagga; Reddy, Padi Pratap Organic Process Research and Development, 2009 , vol. 13, # 1 p. 98 - 101
3
Prabhakaran, Jaya; Underwood, Mark D.; Parsey, Ramin V.; Arango, Victoria; Majo, Vattoly J.; Simpson, Norman R.; Van Heertum, Ronald; Mann, J. John; Kumar, J.S. Dileep Bioorganic and Medicinal Chemistry, 2007 , vol. 15, # 4 p. 1802 -
4
Li, Feng; Nie, Jing; Sun, Long; Zheng, Yan; Ma, Jun-An Angewandte Chemie - International Edition, 2013 , vol. 52, # 24 p. 6255 - 6258
5
Synlett, , vol. 1997, # 4 p. 375 - 377
6Tetrahedron Letters, , vol. 52, # 45 p. 6000 - 6002
7
Bioorganic and Medicinal Chemistry Letters, , vol. 21, # 22 p. 6636 - 6640
COCK WILL TEACH YOU NMRCOCK SAYS MOM CAN TEACH YOU NMR
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE
