ChemicalBook CAS DataBase List Lenvatinib

Lenvatinib synthesis

5synthesis methods

Product Name:Lenvatinib
CAS Number:417716-92-8
Molecular formula:C21H19ClN4O4
Molecular Weight:426.85

Lenvatinib, also known as E7080, is a synthetic, orally available inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2, also known as KDR/FLK-1) tyrosine kinase with potential antineoplastic activity. E7080 blocks VEGFR2 activation by VEGF, resulting in inhibition of the VEGF receptor signal transduction pathway, decreased vascular endothelial cell migration and proliferation, and vascular endothelial cell apoptosis. Synthetic Description Reference: Naito, Toshihiko; Yoshizawa, Kazuhiro. Preparation of urea moiety-containing quinolinecarboxamide derivatives. WO 2005044788. (Assignee Eisai Co., Ltd., Japan) Synthetic Description Reference: Oruganti, Srinivas; Kandagatla, Bhaskar. Improved process for the preparation of lenvatinib using dimethylformamide as a solvent. IN 201641011188. (Assignee Dr. Reddy's Laboratories Limited, India) Synthetic Description Reference: Shah, Dharmesh Mahendrabhai; Wader, Guruprasad Ramchandra; Mehta, Tushar Bharatkumar; Chavda, Rajendra Gokalbhai; Kathrotiya, Harshad Ghanshyambhai; Patel, Arpit Kiritbhai. Improved process for the preparation of lenvatinib. WO 2019016664. (Assignee BDR Lifesciences Private Limited, India) Synthetic Description Reference: Funahashi, Yasuhiro; Tsuruoka, Akihiko; Matsukura, Masayuki; Haneda, Toru; Fukuda, Yoshio; Kamata, Junichi; Takahashi, Keiko; Matsushima, Tomohiro; Miyazaki, Kazuki; Nomoto, Ken-Ichi; Watanabe, Tatsuo; Obaishi, Hiroshi; Yamaguchi, Atsumi; Suzuki, Sachi; Nakamura, Katsuji; Mimura, Fusayo; Yamamoto, Yuji; Matsui, Junji; Matsui, Kenji; Yoshiba, Takako; Suzuki, Yasuyuki; Arimoto, Itaru. Preparation of urea derivatives containing nitrogenous aromatic ring compounds as inhibitors of angiogenesis. US 7253286. (Assignee Eisai Co., Ltd, Japan) Synthetic Description Reference: He, Peng; Wang, Xuechao; Deng, Ta; He, Qian. Method for preparing lenvatinib intermediate. CN 108997214. (Assignee Chengdu Diao Pharmaceutical Group Co., Ltd., Peop. Rep. China) Synthetic Description Reference: Zheng, Shiyang; Zhi, Yonggang. Method for preparation of lenvatinib. CN 108658859. (Assignee Chengdu Organic Chemicals Co., Ltd., Chinese Academy of Sciences, Peop. Rep. China) Synthetic Description Reference: Ge, Wenlei; Gao, Junlong; Liu, Kai; Guo, Dapeng. Process for preparation of lenvatinib impurity 4,4'-(((carbonylbis(azanediyl))bis(3-chloro-4,1-phenylene))bis(oxy))bis(7-methoxyquinoline-6-carboxamide) or its salt. CN 108299294. (Assignee Jiangsu Hengrui Medicine Co., Ltd., Peop. Rep. China) Synthetic Description Reference: Dong, Lichun; Hu, Geng; Li, Qi; Liu, Dianqing; Wang, Haoyuan. Synthesis method of anticancer drug lenvatinib. CN 107629001. (Assignee Chongqing University, Peop. Rep. China) Synthetic Description Reference: Jia, Huijuan; Chen, Yan; Zhang, Fan; He, Xuemin. Synthesis method of lenvatinib mesylate impurities. CN 107266363. (Assignee Hangzhou Huadong Medicine Group New Drug Research Institute Co., Ltd., Peop. Rep. China; Hangzhou Zhuyangxin Pharmaceutical Co., Ltd.; Zhejiang Huayi Pharmaceutical Co., Ltd.) Synthetic Description Reference: Nakamura, Taiju; Abe, Taichi; Miyashita, Yusuke; Kuroda, Hirofumi; Ayata, Yusuke; Akao, Atsushi. Highly pure quinoline derivative and method for the preparation thereof. WO 2016031841. (Assignee Eisai R&D Management Co., Ltd., Japan)

Synthetic Routes

ROUTE 1

ROUTE 2

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ROUTE 8

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ROUTE 10

Reference: Naito, Toshihiko; Yoshizawa, Kazuhiro. Preparation of urea moiety-containing quinolinecarboxamide derivatives. WO 2005044788. (Assignee Eisai Co., Ltd., Japan)

4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide

417722-93-1
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1885-14-9 Synthesis

1885-14-9
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765-30-0
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Yield:417716-92-8 90%

Reaction Conditions:

Stage #1: 4?(4?amino?3?chlorophenoxy)?7?methoxyquinoline?6?carboxamide;phenyl chloroformatewith pyridine in water;N,N-dimethyl-formamide at -20; for 3 h;Inert atmosphere;
Stage #2: Cyclopropylamine in water;N,N-dimethyl-formamide at 8; for 15 h;Inert atmosphere;Time;

Steps:

2 Example 2 4-[3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamide

Example 2 4-[3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamide (0148) (0149) To a mixture of 26.0 kg of 4-(4-amino-3-chlorophenoxy)-7-methoxy-quinoline-6-carboxamide, 13.2 kg of pyridine, 1.36 kg of water and 196.0 L of N,N-dimethylformamide there was added 26.6 kg of phenyl chloroformate at -20° C. under a nitrogen atmosphere, and the mixture was stirred for 3 hours. Next, 19.4 kg of cyclopropylamine was further added at 8° C. and the mixture was stirred for 15 hours. After adding 13.0 L of water and 261.0 L of acetone to the reaction mixture, the deposited precipitate was filtered. The precipitate was rinsed with acetone, and the obtained solid was dried under reduced pressure to obtain 28.7 kg of a crude product of the title compound (89% yield). This was crystallized from 359.6 L of 1,3-dimethyl-2-imidazolidinone and 575.0 L of 2-propanol, to obtain 25.7 kg of compound (IV) (90% yield).

References:

US2017/233344,2017,A1 Location in patent:Paragraph 0148; 0149

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