New Synthetic Process for Bosutinib

Abstract

A new and improved synthetic route to bosutinib is described on a hectogram scale. The key step is the intramolecular cyclization of a 3-(2-aminophenyl)-3-oxopropanenitrile with N,N-dimethylformamide dimethyl acetal to form the 3-cyano-4-hydroxyquinoline ring of 7-(3-chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile. A practical synthetic method to 2,4-dichloro-5-methoxyaniline is also established. Bosutinib is obtained in 18.0% yield over nine steps from acetovanillone with 98.9% purity (HPLC).

Key Words

bosutinib - synthetic process - intramolecular cyclization - antitumor agents - green chemistry

• References

• 1a Puttini M, Coluccia AM, Boschelli F, Cleris L, Marchesi E, Donella-Deana A, Ahmed S, Redaelli S, Piazza R, Magistroni V, Andreoni F, Scapozza L, Formelli F, Gambacorti-Passerini C. Cancer Res. 2006; 66: 11314
• 1b Vultur A, Buettner R, Kowolik C, Liang W, Smith D, Boschelli F, Jove R. Mol. Cancer Ther. 2008; 7: 1185
• 2a Cortes JE, Kantarjian HM, Brummendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C. Blood 2013; 118: 4567
• 2b Cortes JE, Kim DW, Kantarjian HM, Brummendorf TH, Dyagil I, Griskevicus L, Malhotra H, Powell C, Gogat K, Countouriotis AM, Gambacorti-Passerini C. J. Clin. Oncol. 2012; 30: 3486
• 2c Daud AI, Krishnamurthi SS, Saleh MN, Gitlitz BJ, Borad MJ, Gold PJ, Chiorean EG, Springett GM, Abbas R, Agarwal S, Bardy-Bouxin N, Hsyu PH, Leip E, Turnbull K, Zacharchuk C, Messersmith WA. Clin. Cancer Res. 2012; 18: 1092
• 3a Berger D, Boschelli D, Johnson S, Wang Y. US 2003,0212,276, 2003
• 3b Arndt KT, Boschelli DH, Boschelli FC, Zaleska MM. WO 2004,075,898, 2004
• 3c Boschelli DH, Wang YD, Johnson S, Wu B, Ye F, Barrios Sosa AC, Golas JM, Boschelli F. J. Med. Chem. 2004; 47: 1599
• 4a Withbroe GJ, Seadeek C, Girard KP, Guinness SM, Vanderplas BC, Vaidyanathan R. Org. Process Res. Dev. 2013; 17: 500
• 4b Olszewski JD, May MK, Berger DM. US 2007,0208,164 A1, 2007
• 4c Sutherland KW, Feigelson GB, Boschelli DH, Blum DM, Strong HL. US 2005,043,537, 2005
• 5a Yin X, Xu G, Sun X, Peng Y, Ji X, Jiang K, Li F. Molecules 2010; 15: 4261 ; http://www.mdpi.com/journal/molecules
• 5b Li F, Yin X, Jiang K, Sun X, Xu G. CN 101,792,416, 2010
• 6 Wang H, Zhu C, Zhu G, Tian X, Shen Y, Mao Y. Heterocycles 2014; 89: 2806
• 7a Walsh DA, Franzyshen SK, Yanni JM. J. Med. Chem. 1989; 32: 105
• 7b Solanki PV, Uppelli SB, Pandit BS, Mathad VT. Org. Process Res. Dev. 2014; 18: 342
• 8a Tang Q, Zhang G, Du X, Zhu W, Li R, Lin H, Li P, Cheng M, Gong P, Zhao Y. Bioorg. Med. Chem. 2014; 22: 1236
• 8b Zhou S, Liao H, He C, Dou Y, Jiang M, Ren L, Zhao Y, Gong P. Eur. J. Med. Chem. 2014; 83: 581
• 9 Cai L, Cuevas J, Temme S, Herman MM, Dagostin C, Widdowson DA, Innis RB, Pike VW. J. Med. Chem. 2007; 50: 4746
• 10 Ma W, Mao Y, Xie K, Zhu Q, Zhang R, Shen J, Jiang X. J. Heterocycl. Chem. 2014; 51: 866
• 11 Mao Y, Qin J, He H, Liu G, Gao B, Wang H. Heterocycles 2014; 89: 1885
• 12 Wang Y, Ji Z, Shi W, Liu X. CN 102,617,358, 2012
• 13 Mao Y, Tian X, Jiang L, Zhu G, Wang H. Org. Prep. Proced. Int. 2015; 47: 207
• 14 Jacobs WA, Heidelberger M, Rolf IP. J. Am. Chem. Soc. 1919; 41: 458