Betrixaban synthesis

Betrixaban, also known as PRT054021, MK-4448; PRT-021; PRT-054021; MLN-1021, is a potent, orally active and highly selective factor Xa inhibitor undergone human clinical trials for prevention of embolism after knee surgery, and prevention of stroke following atrial fibrillation. Betrixaban is currently being studied in a human clinical trial for extended duration thromboprophylaxis to prevent venous thromboembolism in acute medically ill patients. Synthetic Description Reference: Zhang P, Huang W, Wang L, Bao L, Jia ZJ, Bauer SM, Goldman EA, Probst GD, Song Y, Su T, Fan J, Wu Y, Li W, Woolfrey J, Sinha U, Wong PW, Edwards ST, Arfsten AE, Clizbe LA, Kanter J, Pandey A, Park G, Hutchaleelaha A, Lambing JL, Hollenbach SJ, Scarborough RM, Zhu BY. Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenz amide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2179-85. doi: 10.1016/j.bmcl.2009.02.111. Epub 2009 Mar 3. PubMed PMID: 19297154. Synthetic Description Reference: Chen, Dafeng; Hui, Shuai; Hu, Zhipeng; Gao, Bingkun; Cheng, Rui; Jia, Xiaoman; Liu, Xiaofeng; Luo, Jie; Xiang, Zhixiang. Method for preparation of betrixaban. CN 104693114. (Assignee Sichuan Haisco Pharmaceutical Co., Ltd., Peop. Rep. China) Synthetic Description Reference: Yuan, Jianyong; Li, Yanwu; Li, Lun. A kind of preparation method of betrixaban. CN 105732490. (Assignee Chongqing University of Medical Sciences, Peop. Rep. China) Synthetic Description Reference: Wang, Haibo; Li, Ting; Jin, Hui; Mei, Guangyao; Ouyang, Xiaohui; Feng, Shangjun; Zheng, Haicheng; Xu, Caie. Preparing method and application of betrixaban intermediate. CN 107382897. (Assignee Zhejiang Hongyuan Pharmaceutical Co., Ltd., Peop. Rep. China) Synthetic Description Reference: Li, Jianye; Chen, Ligong; Yan, Xilong; Li, Yang; Wei, Daiyan; Wang, Donghua. A facile method for the synthesis of Betrixaban Journal of Chemical Research (School of Pharmaceutical Science and Technology) Synthetic Description Reference: Sinha, Uma; Hollenbach, Stanley J.; Andre, Patrick. Combination anticoagulant therapy with a compound that acts as a factor Xa inhibitor for treatment of thrombotic disease. US 20080254036. (Assignee Millennium Pharmaceuticals, Inc., USA) Synthetic Description Reference: Scarborough, Robert M.; Kanter, James P.; Sujino, Keiko; Zuberi, Sharique Sami. Methods for preparing pharmaceutical salts of a factor Xa inhibitor. WO 2008057972. (Assignee Millennium Pharmaceuticals, Inc., USA; Scarborough, Carroll) Synthetic Description Reference: Pandey, Anjali; Leitao, Emilia P. T.; Rato, Jose; Song, Zhiguo Jake. Process for preparation of Betrixaban and maleate salt as factor Xa inhibitors. WO 2011084519. (Assignee Millennium Pharmaceuticals, Inc., USA; Merck Sharp & Dohme Corp) Synthetic Description Reference: Zhao, Hua; Chu, Qian-qian; Wang, Hui; Shang, Zhen-hua. Synthetic process of betrixaban. Hebei University of Science and Technology, Shijiazhuang, Peop. Rep. China 050018. (Zhongguo Xinyao Zazhi)

• ROUTE 1



Reference: Zhang P, Huang W, Wang L, Bao L, Jia ZJ, Bauer SM, Goldman EA, Probst GD, Song Y, Su T, Fan J, Wu Y, Li W, Woolfrey J, Sinha U, Wong PW, Edwards ST, Arfsten AE, Clizbe LA, Kanter J, Pandey A, Park G, Hutchaleelaha A, Lambing JL, Hollenbach SJ, Scarborough RM, Zhu BY. Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenz amide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2179-85. doi: 10.1016/j.bmcl.2009.02.111. Epub 2009 Mar 3. PubMed PMID: 19297154.

• ROUTE 2



Reference: Chen, Dafeng; Hui, Shuai; Hu, Zhipeng; Gao, Bingkun; Cheng, Rui; Jia, Xiaoman; Liu, Xiaofeng; Luo, Jie; Xiang, Zhixiang. Method for preparation of betrixaban. CN 104693114. (Assignee Sichuan Haisco Pharmaceutical Co., Ltd., Peop. Rep. China)

• ROUTE 3



Reference: Yuan, Jianyong; Li, Yanwu; Li, Lun. A kind of preparation method of betrixaban. CN 105732490. (Assignee Chongqing University of Medical Sciences, Peop. Rep. China)

• ROUTE 4



Reference: Wang, Haibo; Li, Ting; Jin, Hui; Mei, Guangyao; Ouyang, Xiaohui; Feng, Shangjun; Zheng, Haicheng; Xu, Caie. Preparing method and application of betrixaban intermediate. CN 107382897. (Assignee Zhejiang Hongyuan Pharmaceutical Co., Ltd., Peop. Rep. China)

• ROUTE 5



Reference: Li, Jianye; Chen, Ligong; Yan, Xilong; Li, Yang; Wei, Daiyan; Wang, Donghua. A facile method for the synthesis of Betrixaban Journal of Chemical Research (School of Pharmaceutical Science and Technology)

• ROUTE 6



Reference: Sinha, Uma; Hollenbach, Stanley J.; Andre, Patrick. Combination anticoagulant therapy with a compound that acts as a factor Xa inhibitor for treatment of thrombotic disease. US 20080254036. (Assignee Millennium Pharmaceuticals, Inc., USA)

• ROUTE 7



Reference: Scarborough, Robert M.; Kanter, James P.; Sujino, Keiko; Zuberi, Sharique Sami. Methods for preparing pharmaceutical salts of a factor Xa inhibitor. WO 2008057972. (Assignee Millennium Pharmaceuticals, Inc., USA; Scarborough, Carroll)

• ROUTE 8



Reference: Pandey, Anjali; Leitao, Emilia P. T.; Rato, Jose; Song, Zhiguo Jake. Process for preparation of Betrixaban and maleate salt as factor Xa inhibitors. WO 2011084519. (Assignee Millennium Pharmaceuticals, Inc., USA; Merck Sharp & Dohme Corp)

• ROUTE 9



Reference: Zhao, Hua; Chu, Qian-qian; Wang, Hui; Shang, Zhen-hua. Synthetic process of betrixaban. Hebei University of Science and Technology, Shijiazhuang, Peop. Rep. China 050018. (Zhongguo Xinyao Zazhi)

• ROUTE 10



Conley, Pamela B.; Andre, Patrick; Sinha, Uma. Combination antithrombotic therapy with a sulfonylurea compound acting as a platelet ADP receptor inhibitor. Assignee Portola Pharmaceuticals, Inc., USA. WO 2008137787. 2008.