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Lenvatinib intermediate, preparation thereof and preparation of lenvatinib

A technology of lenvatinib and intermediates, applied in the field of pharmaceutical chemical synthesis, to achieve the effects of cheap and easy-to-obtain reaction raw materials, avoid the use of organic solvents, and simplify the process route

Inactive Publication Date: 2018-12-14
CHENGDU DIAO PHARMA GROUP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0022] In view of the deficiencies and defects existing in the prior art, seek a kind of process step is simple, environmental pollution is little, and cost is low, especially the key intermediate 1-(2-chloro-4-hydroxybenzene of lenvatinib that does not use organic solvent Base)-3-cyclopropylurea new aqueous phase preparation method, and its application in the preparation of lenvatinib has very important practical significance, and will greatly reduce the environmental pollution of raw materials

Method used

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  • Lenvatinib intermediate, preparation thereof and preparation of lenvatinib
  • Lenvatinib intermediate, preparation thereof and preparation of lenvatinib
  • Lenvatinib intermediate, preparation thereof and preparation of lenvatinib

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preparation example Construction

[0065] (1) Compared with the reagent phenyl chloroformate used in the preparation of the existing lenvatinib intermediate 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (compound E), the present invention The reagent CDI (N,N'-carbonyldiimidazole) used is more environmentally friendly and cheap and easy to obtain. And it is also possible to directly use water as a solvent, and directly precipitate 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea with a purity greater than 98.5% from the water phase after the reaction, avoiding the reaction process and after-treatment The use of a large amount of organic solvents in the treatment process is more environmentally friendly.

[0066] (2) react with compound CDI earlier by cyclopropylamine and then react with 4-amino-3-chlorophenol to obtain key intermediate E, and then react with 4-chloro-7-methoxyquinoline-6-formamide (compound F) Condensation can greatly reduce the side reactions caused by the fact that 4-amino-3-chlorophenol has ...

Embodiment 1

[0074] Example 1: Synthesis of 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (compound E)

[0075] Step 1: Synthesis of N-cyclopropyl-1H-imidazole-1-carboxamide (Compound I)

[0076]

[0077] In a 250ml round-bottomed flask, add cyclopropylamine (10g, 0.175mol) and 50ml of water as a solvent, place it in an ice bath, add CDI (51.08g, 0.315mol) in three batches, after the addition is complete, continue at 0°C After reacting for 1 h, TLC monitored that the reaction was complete, and the reaction mixture was directly carried out to the next reaction without any post-treatment.

[0078] Step 2: Synthesis of 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (compound E)

[0079]

[0080] To the untreated N-cyclopropyl-1H-imidazole-1-carboxamide (Compound I) aqueous solution obtained in Step 1, directly add raw material 4-amino-3-chlorophenol (Compound A) (17.7g, 0.123mol) , the reaction mixture was heated in an oil bath at 78°C, and after 4 hours, TLC monitored that the react...

Embodiment 2

[0081]Example 2: Synthesis of 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (compound E)

[0082] Step 1: Synthesis of N-cyclopropyl-1H-imidazole-1-carboxamide (Compound I)

[0083]

[0084] In a 250ml round-bottomed flask, add cyclopropylamine (10g, 0.175mol) and 30ml of water as a solvent, place it in an ice bath, add CDI (51.08g, 0.315mol) in three batches, after the addition is complete, continue at 25°C After reacting for 1 h, TLC monitored that the reaction was complete, and the reaction mixture was directly carried out to the next reaction without any post-treatment.

[0085] Step 2: Synthesis of 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (compound E)

[0086]

[0087] To the untreated N-cyclopropyl-1H-imidazole-1-carboxamide (Compound I) aqueous solution obtained in Step 1, directly add raw material 4-amino-3-chlorophenol (Compound A) (17.7g, 0.123mol) , the reaction mixture was heated in an oil bath at 78°C, and after 4 hours, TLC monitored that the react...

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Abstract

The invention relates to the field of drug synthesis and discloses a lenvatinib key intermediate 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea, preparation thereof and preparation of lenvatinib. Thelenvatinib intermediate has purity higher than 99% and is prepared by the following steps: (1) cyclopropylamine is subjected to reaction with a compound N,N'-carbonyldiimidazole in a solvent, and N-cyclopropyl-1H-imidazole-1-formamide is obtained; (2) N-cyclopropyl-1H-imidazole-1-formamide and 4-amino-3-chlorophenol are subjected to reaction, and 1-(2-chloro-hydroxyphenyl)-cyclopropylurea is obtained. The intermediate 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea and 4-chloro-7-methoxyquinoline-6-carboxamide are subjected to reaction, and a final product lenvatinib is obtained. The preparation methods are simple to operate, raw materials are cheap and easily available, few difficult-to-remove impurities are produced, water is directly used as a solvent, an organic solvent is not needed, the purity of the product can be higher than 99% with low environmental pollution and simple post-processing, and the methods are green, environmentally friendly, economic and suitable for large-scaleindustrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to an aqueous phase preparation method of a key intermediate of lenvatinib and its application in the synthesis of lenvatinib. Background technique [0002] Lenvatinib (lenvatinib) is an oral multi-receptor tyrosine kinase inhibitor developed by Japan's Eisai Company, which has a novel binding mode and targets vascular endothelial growth factor receptor (VEGFR) 1-3 , fibroblast growth factor receptor (FGFR) 1-3, platelet-derived growth factor receptor (PDGFR) of the stem cell growth factor receptor beta type. On February 13, 2015, the FDA approved its listing for the treatment of locally recurrent or metastatic, aggressive, radioactive iodine-refractory differentiated thyroid cancer; on May 13, 2016, the FDA approved the combination of lenvatinib and everolimus For the treatment of advanced metastatic renal cell carcinoma. In addition, Eisai i...

Claims

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Application Information

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IPC IPC(8): C07D215/48C07C275/34C07C273/18
CPCC07C273/1836C07D215/48C07C2601/02C07C275/34
Inventor 何鹏王学超邓塔何倩
Owner CHENGDU DIAO PHARMA GROUP
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