AZD-9291 synthesis

Osimertinib, also known as AZD-9291 and Mereletinib, is a third-generation EGFR inhibitor, showed promise in preclinical studies and provides hope for patients with advanced lung cancers that have become resistant to existing EGFR inhibitors. AZD9291 is highly active in preclinical models and is well tolerated in animal models. It inhibits both activating and resistant EGFR mutations while sparing the normal form of EGFR that is present in normal skin and gut cells, thereby reducing the side effects encountered with currently available medicines. Osimertinib was approved in Nov. 2015 by FDA. Synthetic Description Reference: Finlay MR, Anderton M, Ashton S, Ballard P, Bethel PA, Box MR, Bradbury RH, Brown SJ, Butterworth S, Campbell A, Chorley C, Colclough N, Cross DA, Currie GS, Grist M, Hassall L, Hill GB, James D, James M, Kemmitt P, Klinowska T, Lamont G, Lamont SG, Martin N, McFarland HL, Mellor MJ, Orme JP, Perkins D, Perkins P, Richmond G, Smith P, Ward RA, Waring MJ, Whittaker D, Wells S, Wrigley GL. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem. 2014 Oct 23;57(20):8249-67. doi: 10.1021/jm500973a. Epub 2014 Oct 1. PubMed PMID: 25271963. Synthetic Description Reference: Liu, H., Lv, Y., Li, Y., Cai, J., Chen, J., Qin, Y., & Ji, M. (2015). A Novel and Efficient Synthesis of Anti-Cancer Agent, Mereletinib. Journal of Chemical Research, 39(6), 318–320. https://doi.org/10.3184/174751915X14320297505570 Synthetic Description Reference: Zhang H, Wu W, Feng C, Liu Z, Bai E, Wang X, Lei M, Cheng H, Feng H, Shi J, Wang J, Zhang Z, Jin T, Chen S, Hu S, Zhu Y. Design, synthesis, SAR discussion, in vitro and in vivo evaluation of novel selective EGFR modulator to inhibit L858R/T790M double mutants. Eur J Med Chem. 2017 Jul 28;135:12-23. doi: 10.1016/j.ejmech.2017.04.036. Epub 2017 Apr 14. PubMed PMID: 28426996. Synthetic Description Reference: Zhu, G., Wang, X., Wang, F., Mao, Y., and Wang, H. ( 2017) New and Convergent Synthesis of Osimertinib. J. Heterocyclic Chem., 54: 2898– 2901. doi: 10.1002/jhet.2898. Synthetic Description Reference: Boyd, Alistair John; Telford, Alexander. Improved process for the preparation of osimertinib (AZD9291) or a salt thereof, and "AZD9291 aniline" or a salt thereof. WO 2017134051 A1. (Assignee AstraZeneca AB, Swed.; 2017) Synthetic Description Reference: Anon. (2016) Process for the preparation of N-[2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide, or a salt thereof and intermediates thereof. Volume 17. Issue 1A. Pages 1-10. Synthetic Description Reference: Huang, Wei-Sheng; Gong, Yongjin; Li, Feng; Bencivenga, Nicholas E.; Dalgarno, David C.; Kohlmann, Anna; Shakespeare, William C.; Thomas, Ranny M.; Zhu, Xiaotian; West, Angela V.; Youngsaye, Willmen; Zhang, Yun; Zhou, Tianjun. Preparation of heteroaryl compounds for kinase inhibition. WO 2015195228. (Assignee ARIAD Pharmaceuticals, Inc., USA) Synthetic Description Reference: Qiu, Renhua; Li, Dingzhong; Fu, Lihua; Zhang, Dejiang; Kanbe, Nobuaki. Process for preparation of osimertinib AZD9291. CN 109134435. (Assignee Hunan University, Peop. Rep. China) Synthetic Description Reference: Zhang, Shuilong; Wang, Yubin; Zhang, Qineng. Method for preparing Osimertinib. CN 108623567. (Assignee Shanghai Sinochemtech Co., Ltd., Peop. Rep. China) Synthetic Description Reference: Liu, Keke; Chen, Ao; Li, Minghai; He, Jian; Chen, Zhengyi. Preparation of antitumor drug AZD9291. CN 108218839. (Assignee Shangyao Kony (Changzhou) Pharmaceutical Co., Ltd., Peop. Rep. China)

• ROUTE 1



Reference: Finlay MR, Anderton M, Ashton S, Ballard P, Bethel PA, Box MR, Bradbury RH, Brown SJ, Butterworth S, Campbell A, Chorley C, Colclough N, Cross DA, Currie GS, Grist M, Hassall L, Hill GB, James D, James M, Kemmitt P, Klinowska T, Lamont G, Lamont SG, Martin N, McFarland HL, Mellor MJ, Orme JP, Perkins D, Perkins P, Richmond G, Smith P, Ward RA, Waring MJ, Whittaker D, Wells S, Wrigley GL. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem. 2014 Oct 23;57(20):8249-67. doi: 10.1021/jm500973a. Epub 2014 Oct 1. PubMed PMID: 25271963.

• ROUTE 2



Reference: Liu, H., Lv, Y., Li, Y., Cai, J., Chen, J., Qin, Y., & Ji, M. (2015). A Novel and Efficient Synthesis of Anti-Cancer Agent, Mereletinib. Journal of Chemical Research, 39(6), 318–320. https://doi.org/10.3184/174751915X14320297505570

• ROUTE 3



Reference: Zhang H, Wu W, Feng C, Liu Z, Bai E, Wang X, Lei M, Cheng H, Feng H, Shi J, Wang J, Zhang Z, Jin T, Chen S, Hu S, Zhu Y. Design, synthesis, SAR discussion, in vitro and in vivo evaluation of novel selective EGFR modulator to inhibit L858R/T790M double mutants. Eur J Med Chem. 2017 Jul 28;135:12-23. doi: 10.1016/j.ejmech.2017.04.036. Epub 2017 Apr 14. PubMed PMID: 28426996.

• ROUTE 4



Reference: Zhu, G., Wang, X., Wang, F., Mao, Y., and Wang, H. ( 2017) New and Convergent Synthesis of Osimertinib. J. Heterocyclic Chem., 54: 2898– 2901. doi: 10.1002/jhet.2898.

• ROUTE 5



Reference: Boyd, Alistair John; Telford, Alexander. Improved process for the preparation of osimertinib (AZD9291) or a salt thereof, and "AZD9291 aniline" or a salt thereof. WO 2017134051 A1. (Assignee AstraZeneca AB, Swed.; 2017)

• ROUTE 6



Reference: Anon. (2016) Process for the preparation of N-[2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide, or a salt thereof and intermediates thereof. Volume 17. Issue 1A. Pages 1-10.

• ROUTE 7



Reference: Huang, Wei-Sheng; Gong, Yongjin; Li, Feng; Bencivenga, Nicholas E.; Dalgarno, David C.; Kohlmann, Anna; Shakespeare, William C.; Thomas, Ranny M.; Zhu, Xiaotian; West, Angela V.; Youngsaye, Willmen; Zhang, Yun; Zhou, Tianjun. Preparation of heteroaryl compounds for kinase inhibition. WO 2015195228. (Assignee ARIAD Pharmaceuticals, Inc., USA)

• ROUTE 8



Reference: Qiu, Renhua; Li, Dingzhong; Fu, Lihua; Zhang, Dejiang; Kanbe, Nobuaki. Process for preparation of osimertinib AZD9291. CN 109134435. (Assignee Hunan University, Peop. Rep. China)

• ROUTE 9



Reference: Zhang, Shuilong; Wang, Yubin; Zhang, Qineng. Method for preparing Osimertinib. CN 108623567. (Assignee Shanghai Sinochemtech Co., Ltd., Peop. Rep. China)

• ROUTE 10



Reference: Liu, Keke; Chen, Ao; Li, Minghai; He, Jian; Chen, Zhengyi. Preparation of antitumor drug AZD9291. CN 108218839. (Assignee Shangyao Kony (Changzhou) Pharmaceutical Co., Ltd., Peop. Rep. China)

• ROUTE 11



Preparation of 2-(2,4,5-substituted-anilino)pyrimidine derivatives as EGFR modulators useful for treating cancer; Butterworth, Sam; Finlay, Maurice Raymond Verschoyle; Ward, Richard Andrew; Kadambar, Vasantha Krishna; Chandrashekar, Reddy C.; Murugan, Andiappan; Redfearn, Heather Marie; Assignee AstraZeneca AB, Swed.; AstraZeneca UK Limited; 2013; Patent Information; Jan 31, 2013; WO 2013014448 A1

• ROUTE 12



Intermediate N-[2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-carboxamidine]phenyl-2-acrylamide for preparing Azd9291, and its preparation method; Xu, Xuenong; Assignee Suzhou Miracpharma Technology Co., Ltd., Peop. Rep. China; 2016; Patent Information; Dec 22, 2016; WO 2016202125 A1