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Investigation of Alcaftadine using a Double Oxidation Process by Eliminating Column Chromatography
Corresponding Author(s) : Anand M. Lahoti
Asian Journal of Chemistry,
Vol. 34 No. 6 (2022): Vol 34 Issue 6
Abstract
Alcaftadine is an active pharmaceutical ingredient (API) used as an ophthalmic solution for the prevention of itching associated with allergic conjunctivitis. The originally reported synthesis uses a time-consuming column chromatography technique for the isolation of hydroxymethylated product alcohol (10). A simple yet effective double oxidation strategy is developed using oxidation grade manganese dioxide to avoid tedious chromatographic purification. Firstly, a partial oxidation of hydroxymethylated crude mass (mixture of compounds 9, 10 and 16) was carried out using a limited amount of MnO2 to get rid of critical diol impurity (16) and to allow crystallization of alcohol (10) crude, followed by its second oxidation using additional MnO2 to provide alcaftadine via a scale-up friendly process. This synthetic approach has been proven to be cost effective and commercially viable. Various impurities formed during the process were also identified and eliminated to obtain ICH guideline purity of alcaftadine API. The process was validated in plant scale and US DMF was filed to manufacture alcaftadine API.
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- F.M. Janssens, G.S.M. Diels and J.E. Leenaerts, Imidazo[2,1-b]benzazepine Derivatives, Compositions and Method of Use, US Patent 5468743 (1995).
- G. Torkildsen and A. Shedden, Curr. Med. Res. Opin., 27, 623 (2011); https://doi.org/10.1185/03007995.2010.548797
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- H.J.M. Dou and J. Metzger, Bull. Soc. Chim. Fr., 1861 (1976).
- T. Kamijo, R. Yamamoto, H. Harada and K. Iizuka, Chem. Pharm. Bull. (Tokyo), 31, 1213 (1983); https://doi.org/10.1248/cpb.31.1213.
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- A. Gupta, H.M. Schipper, M. Alaoui-Jamali, W.A. Szarek, K. Nakatsu and J.Z. Vlahakis, Compounds and Methods for Treating Cancer and Diseases of the Central Nervous System, WO Patent 20110319459A1 (2011).
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References
F.M. Janssens, G.S.M. Diels and J.E. Leenaerts, Imidazo[2,1-b]benzazepine Derivatives, Compositions and Method of Use, US Patent 5468743 (1995).
G. Torkildsen and A. Shedden, Curr. Med. Res. Opin., 27, 623 (2011); https://doi.org/10.1185/03007995.2010.548797
A.C. Gallois-Bernos and R.L. Thurmond, J. Receptor Ligand Channel Res., 5, 9 (2012); https://doi.org/10.2147/JRLCR.S39369
J.V. Greiner, K.E. Swanson and A. Ingerman, Clin. Ophthalmol., 5, 87 (2011); https://doi.org/10.2147/OPTH.S15379
S.J. Ono and K. Lane, Drug Design Develop. Ther., 5, 77 (2011); https://doi.org/10.2147/DDDT.S15788
R. Namdar and C. Valdez, Drugs Today, 47, 883 (2011); https://doi.org/10.1358/dot.2011.47.12.1709243
H. Nakatani, P. Gomes, R. Bradford, Q. Guo, E. Safyan and D.A. Hollander, Ocul. Immunol. Inflamm., 27, 622 (2019); https://doi.org/10.1080/09273948.2018.1432764)
J. Bronson, M. Dhar, W. Ewing and N. Lonberg, Annu. Rep. Med. Chem., 46, 433 (2011); https://doi.org/10.1016/B978-0-12-386009-5.00002-3
E. Wagner, H.J. Wittmann, S. Elz and A. Strasser, Naunyn Schmiedebergs Arch. Pharmacol., 387, 235 (2014); https://doi.org/10.1007/s00210-013-0926-4
M.V.R. Raju, M.A.S. Raju, A. Mantena, R.R. Suraparaju, S.S. Rao and S. Koneru, A Process for the Preparation of 4-Hydroxypiperidines, Indian Patent Appl. IN 201841041206 A 20200501 (2020).
S.B. Venkata, E.R. Kodali, G.B. Patel, S.D. Vaidya and A.P. Tripathi, Process of Preparing Alcaftadine, US20150119570A1 (2016).
M.S.P. Sarma, L. Chakrapani, M.B. Reddy, D. Yakaiah and P. Anil, Novel and Improved Process for the Preparation of Alcaftadine, Indian Patent Appl. IN 2014CH03056 A 20160205 (2016).
J.A. Parihar, K.N. Jain and M.H. Sharma, An Improved Process for Preparing Alcaftadine, Indian Patent Appl. IN 2014MU01986 A 20160101 (2016).
Y. Zhu, D. Ning, J. Pan, B. Yang and C. Chen, A Kind of Method for Oxidation for Preparing Alcaftadine, Chinese Patent CN104987337B (2015).
S.B. Venkata, E.R. Kodali, G.B. Patel, S.D. Vaidya and A.P. Tripathi, Process of Preparing Alcaftadine, US Patent US9580436B2 (2014).
L. Li, B. Liu, K. Wu, J. Bao, Y. Jiang and X. Zhang, Synthesis of Alcaftadine Intermediates and Alcaftadine by Introducing Hydroxymethyl from (1H-Imidazol-5-yl)methanol Raw Material, Chinese Patent CN 104860888 A 20150826 (2015).
K. Deo, A.Y. Merwade, M. Rafeeq, R.K. Sinha and R. Chaniyara, A Process for the Preparation of 3-(Hydroxymethyl)-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine an Intermediate of Alcaftadine or Salt Thereof, Indian Pat. Appl. IN 2013MU03105 A 20150717 (2015).
J. Li, R. Cong, D. Song, G. Shi and W. Zhuang, Novel Alcaftadine Crystal Form, CN 104710427 A 20150617 (2015).
A.L. Bonde-Larsen, J.M.I. Retuerto, F.J.G. Nieto and J.J.F. Gil, Methods for the Preparation of Alcaftadine, Eur. Patent EP2978765A1 (2014).
P.B. Pansuriya, G.E.M. Maguire and H.B. Friedrich, Spectrochim. Acta A Mol. Biomol. Spectrosc., 142, 311 (2015); https://doi.org/10.1016/j.saa.2015.01.090
T.R. Srinivasan, S. Eswaraiah and P.S.R. Sarma, Crystalline Form of 7-Chloro-1,2,3,4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolinesulfonamide and Process Thereof, Indian Patent Appl. IN 2014CH01257 A 20150918 (2015).
C. Qu, M. Ding, Y. Zhu, Y. Lu, J. Du, M. Miller, J. Tian, J. Zhu, J. Xu, M. Wen, A.G.A. Er-Bu, J. Wang, Y. Xiao, M. Wu, O.B. McManus, M. Li, J. Wu, H.-R. Luo, Z. Cao, B. Shen, H. Wang, M.X. Zhu and X. Hong, J. Med. Chem., 60, 4680 (2017); https://doi.org/10.1021/acs.jmedchem.7b00304
H.J.M. Dou and J. Metzger, Bull. Soc. Chim. Fr., 1861 (1976).
T. Kamijo, R. Yamamoto, H. Harada and K. Iizuka, Chem. Pharm. Bull. (Tokyo), 31, 1213 (1983); https://doi.org/10.1248/cpb.31.1213.
A. Sharifian, K. Parang, H. Zorrieh-Amirian, M. Nazarinia and A. Shafiee, J. Heterocycl. Chem., 31, 1421 (1994); https://doi.org/10.1002/jhet.5570310621
E.J. Kim, S.Y. Ko and E.K. Dziadulewicz, Tetrahedron Lett., 46, 631 (2005); https://doi.org/10.1016/j.tetlet.2004.11.144
A. Gupta, H.M. Schipper, M. Alaoui-Jamali, W.A. Szarek, K. Nakatsu and J.Z. Vlahakis, Compounds and Methods for Treating Cancer and Diseases of the Central Nervous System, WO Patent 20110319459A1 (2011).
J.Z. Vlahakis, C. Lazar, G. Roman, D. Vukomanovic, K. Nakatsu and W.A. Szarek, ChemMedChem, 7, 897 (2012); https://doi.org/10.1002/cmdc.201100602
G. Sravya, G.V. Zyryanov, K. Ramaseshaiah, G.M.K. Reddy, C.S. Reddy and N.B. Reddy, Asian J. Chem., 31, 2257 (2019); https://doi.org/10.14233/ajchem.2019.22059