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Synthesis method for lenvatinib

A synthesis method and technology of lenvatinib are applied in the field of synthesis route of thyroid cancer drug lenvatinib, which can solve the problems of low CDI activity, long synthesis steps, easy shedding of intermediates, etc., so as to avoid difficult to control low temperature and The use of diazonium salts, the effect of simplifying post-processing steps and shortening the synthesis route

Inactive Publication Date: 2018-10-16
CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main deficiency of this method is: 1) the starting material (8) needs to be synthesized in multiple steps, and the total synthetic steps are up to 7 steps
2) During the alkylation, in order to avoid competing reactions, it is necessary to protect the amino group of the intermediate (8) with di-tert-butyl dicarbonate, and the atom economy is poor
3) The protection group of di-tert-butyl dicarbonate has poor stability, and it is easy to fall off and cause the complication of intermediate (11)
4) When the final product is formed, the activity of CDI is low and the yield is moderate

Method used

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  • Synthesis method for lenvatinib
  • Synthesis method for lenvatinib
  • Synthesis method for lenvatinib

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Experimental program
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Effect test

Embodiment 1

[0013] Synthesis of 3-chloro-4-nitrophenol (3) according to literature (L-Y.Chen, et al, Arkivoc, 2014, 64-71, DOI: 10.3998 / ark.5550190.p008.587)

[0014]

Embodiment 2

[0016]

[0017] Dissolve 1.0 g of 3-chloro-4-nitrophenol (3), 1.42 g of 4-chloro-7-methoxyquinoline-6-amide (A) in 60 mL of dimethyl sulfoxide, and stir at 60°C for 36 hours , down to room temperature. The reaction solution was poured into 400mL of ice water, filtered, and the filter cake was washed with water and dried in vacuo to obtain a pale yellow solid 4 (1.14g, 52.9%).

[0018] [1HNMR (DMSO-d6) δ8.78(d, J=5.2Hz, 1H), 8.56(s, 1H), 8.25(d, J=9.0Hz, 1H), 7.88(s, 1H), 7.83(d , J=2.5Hz, 1H), 7.78(s, 1H), 7.57(s, 1H), 7.48(dd, J=9.0, 2.5Hz, 1H), 6.91(d, J=5.2Hz, 1H), 4.04 (s, 3H);

[0019] 13CNMR (DMSO-d6) δ165.71, 159.49, 158.22, 157.74, 153.46, 151.89, 144.29, 128.34, 127.60, 125.80, 124.39, 123.12, 119.84, 114.77, 108.11, 1065.795], 5

[0020] ESI-MS m / z: 374.2[m+H]+

Embodiment 3

[0022] Dissolve 1.0 g of 3-chloro-4-nitrophenol (3) and 1.70 g of 4-chloro-7-methoxyquinoline-6-amide (A) in 60 mL of chlorobenzene, stir at 120°C for 5 hours, drop to After reaching room temperature, filter, the filter cake was washed with water and toluene respectively, and then vacuum-dried to obtain light yellow solid 4 (1.50g, 69.6%).

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Abstract

The invention provides a synthesis method for lenvatinib. The synthesis method takes m-chlorophenol as a raw material and a target product, i.e., the lenvatinib, is obtained through four-step reaction. According to the synthesis method provided by the invention, steps of an original synthesis route are reduced and relatively high yield is kept; and the cost of the raw material is reduced and the atom economy is improved.

Description

technical field [0001] The invention relates to a synthesis route of lenvatinib, a drug for treating thyroid cancer, and belongs to the technical field of pharmaceutical synthesis. Background technique [0002] The chemical name of Lenvatinib (Lenvatinib, 1) is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline carboxamide, which is a Japanese health An oral multi-receptor tyrosine kinase (RTK) inhibitor developed by Eisai, which inhibits the kinase activity of vascular endothelial growth factor (VEGF) receptors VEGFR1, VEGFR2, and VEGFR3, is mainly used for the treatment of differentiated Thyroid cancer (DTC). The drug was approved for marketing by the US FDA on February 13, 2015, and the trade name is Lenvima. In July 2015, the FDA further granted lenvatinib the breakthrough drug qualification for the treatment of advanced and / or metastatic renal cell carcinoma. Its structure is as follows: [0003] [0004] The main synthetic route of lenvat...

Claims

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Application Information

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IPC IPC(8): C07D215/48
CPCC07D215/48
Inventor 郑施洋支永刚
Owner CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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