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ChemicalBook CAS DataBase List Bosutinib
380843-75-4

Bosutinib synthesis

9synthesis methods
Bosutinib, also known as SKI-606, is a synthetic quinolone derivative and dual kinase inhibitor that targets both Abl and Src kinases with potential antineoplastic activity. Unlike imatinib, bosutinib inhibits the autophosphorylation of both Abl and Src kinases, resulting in inhibition of cell growth and apoptosis. Because of the dual mechanism of action, this agent may have activity in resistant CML disease, other myeloid malignancies and solid tumors. Abl kinase is upregulated in the presence of the abnormal Bcr-abl fusion protein which is commonly associated with chronic myeloid leukemia (CML). Overexpression of specific Src kinases is also associated with the imatinib-resistant CML phenotype. Bosutinib received US FDA and EU European Medicines Agency approval on September 4, 2012 and 27 March, 2013 respectively for the treatment of adult patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy.
Synthetic Routes
  • ROUTE 1

    • 202112070092413763.jpg

    Boschelli, Diane H.; Wang, Yanong D.; Johnson, Steve; Wu, Biqi; Ye, Fei; Sosa, Ana Carolina Barrios; Golas, Jennifer M.; Boschelli, Frank. 7-Alkoxy-4-phenylamino-3-quinolinecarbonitriles as Dual Inhibitors of Src and Abl Kinases. Journal of Medicinal Chemistry. Volume 47. Issue 7. Pages 1599-1601. Journal. (2004).

  • ROUTE 2

    • 202112073930304934.jpg

    Mao, Yongjun; Zhu, Chunping; Kong, Ziyang; Wang, Jiao; Zhu, Guoqing; Ren, Xinfeng. New Synthetic Process for Bosutinib. Synthesis. Volume 47. Issue 20. Pages 3133-3138. Journal; Online Computer File. (2015).

  • ROUTE 3

    • 202112073316734753.jpg

    Chen, Hong; Wang, Yingli; Liu, Tongbin. Synthesis of bosutinib. Zhongguo Yiyao Gongye Zazhi. Volume 44. Issue 11. Pages 1086-1088. Journal. (2013).

  • ROUTE 4

    • 202112073651608485.jpg

    Wu, Yanchao; Jiang, Hong; Lv, Chuantao; Lu, Jingjing. Preparation method of Bosutinib using active copper reagent as coupling reaction catalytic reagent. Assignee Shandong Chuangxin Pharmaceutical Research & Development Co., Ltd., Peop. Rep. China. CN 109180578. (2019).

  • ROUTE 5

    • 202112078952506518.jpg

    Xiao, Tao; Tian, Xin; Feng, Yi; Wang, Xiaoming; Li, Song. A process for preparing bosutinib. Assignee Nanjing Zhengrong Pharmaceutical Chemical Co., Ltd., Peop. Rep. China. CN 104876865. (2015).

202112070092413763.jpg

Boschelli, Diane H.; Wang, Yanong D.; Johnson, Steve; Wu, Biqi; Ye, Fei; Sosa, Ana Carolina Barrios; Golas, Jennifer M.; Boschelli, Frank. 7-Alkoxy-4-phenylamino-3-quinolinecarbonitriles as Dual Inhibitors of Src and Abl Kinases. Journal of Medicinal Chemistry. Volume 47. Issue 7. Pages 1599-1601. Journal. (2004).

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Yield:380843-75-4 75.4%

Reaction Conditions:

Stage #1:5-nitroguaiacol;1.3-chlorobromopropane with potassium carbonate in isopropyl alcohol at 75 - 80; for 6 h;
Stage #2:1-methyl-piperazine in isopropyl alcohol at 70 - 75; for 12 h;
Stage #3:2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide;orthoformic acid triethyl esterFurther stages;Solvent;Temperature;Reagent/catalyst;

Steps:

1-19 Example 1
Add SM-1 (33.83g, 0.20mol), potassium carbonate (55.28g, 0.40mol), 1-bromo-3-chloropropane (56.68g, 0.36mol) to isopropanol (350mL), and control the temperature to 75 React at 80 for 6h,After the reaction is completed, filter, the obtained filtrate is cooled to room temperature, N-methylpiperazine (40.07g, 0.40mol) is added, and the temperature is controlled at 7075 to react for 12h.After the reaction is complete, filter,The obtained filtrate was cooled to room temperature, Pd/C (3.38g) was added, hydrogen gas was introduced at normal pressure, and the temperature was controlled at 30-35°C to react for 6 hours.After the reaction is complete, filter, the obtained filtrate is cooled to room temperature, triethyl orthoformate (62.24g, 0.42mol), compound 1 (46.46 g, 0.18mol) is added, and the temperature is controlled at 7782 to react for 6h.After the reaction was completed, the reaction solution was cooled to room temperature, acetone (1400 mL) was added, and stirring was continued for 2 hours, and then suction filtered. The filter cake was rinsed with acetone (50 mL).The filter cake obtained after vacuum drying under reduced pressure is the target product II with a yield of 75.4%.The purity is 98.90%.

References:

Lunan Pharmaceutical Group Co., Ltd.;Zhang Guimin;Li Zhenyu;Sun Xiaolei CN111646955, 2020, A Location in patent:Paragraph 0041-0078

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