Check patentability & draft patents in minutes with Patsnap Eureka AI!

Preparation method of lenvatinib and preparation method of lenvatinib intermediate

A solvent and compound technology, which is applied in the field of preparation of lenvatinib and intermediates, can solve the problems of single preparation method of lenvatinib, and achieve the effects of low toxicity, high yield and simple operation

Pending Publication Date: 2021-06-29
LUOXIN PHARM SHANGHAI CO LTD +1
View PDF1 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved by the present invention is aimed at the single problem of the preparation method of lenvatinib in the prior art, and provides a kind of preparation method of lenvatinib and intermediate

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of lenvatinib and preparation method of lenvatinib intermediate
  • Preparation method of lenvatinib and preparation method of lenvatinib intermediate
  • Preparation method of lenvatinib and preparation method of lenvatinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104]

[0105] In a 250mL three-necked flask equipped with a reflux condenser, add N,N'-bis-succinimide carbonate (also called: succinimide carbonate, hereinafter replaced by succinimide carbonate) (6.85 g, 26.76mmol) and add 50mL DMF to dissolve at room temperature, and replace the gas in the reaction bottle with a nitrogen balloon for 3 times, keep the nitrogen atmosphere in the bottle, and heat to an inner temperature of 40 degrees. After stirring and dissolving, 4-(4-amino-3-chlorophenyloxy)-7-methoxy-quinoline-6-carboxamide (5.00 g, 14.55 mmol) was added in batches and stirred for 1 hour. The reaction is complete (detecting 4-(4-amino-3-chlorophenyloxy)-7-methoxy-quinoline-6-carboxamide with HPLC is less than 0.2% (area normalization method). The step formed The intermediate was unstable, and during separation and purification, it was partially degraded to the starting material), cooled to room temperature, added cyclopropylamine (2.29 g, 51 mmol, 3.5 equivalents), an...

Embodiment 2

[0111] Adopt reaction conditions and method as embodiment 1, difference only is to use different solvents to replace DMF; The result is as follows:

[0112] serial number Solvent type Crude reaction yield Crude purity 1 DMF 103.2％ 99.2％ 2-1 DMSO 90％ 95.5％ 2-2 THF 70％ 45.2% (incomplete conversion of raw materials)

[0113] Adopt reaction condition and method as embodiment 1, difference only is to use different temperature to react

[0114] serial number temperature reflex Crude reaction yield Crude purity 1 40℃ 103.2％ 99.2％ 2-3 55℃ 99％ 81.2% (reaction becomes impurity) 2-4 35℃ 42％ 32.5% (incomplete conversion of raw materials)

[0115] Adopt the reaction condition and method as embodiment 1, difference only is that the equivalent number of succinimidyl carbonate is different

[0116] serial number Succinimide carbonate equivalent Crude reaction yield Crude purity 1 1.84eq...

Embodiment 3

[0118] The synthetic method of succinimide-phenol carbonate:

[0119]

[0120]N-hydroxysuccinimide (11.5g, 100mmol) and diethylaniline (16.4g, 110mmol) were dissolved in dichloromethane (115mL) at room temperature, and the temperature was lowered to -20°C, and chloroformic acid benzene was added dropwise Ester (17.2 g, 110 mmol) was added dropwise over 30 minutes. After the dropwise addition was completed, the temperature was gradually raised to room temperature, and stirred at room temperature for 1 hour. Add 50 mL of dilute hydrochloric acid (1.0 M) to wash once, brine (50 mL) once, and dry over anhydrous sodium sulfate. Concentration under reduced pressure gave a white solid. The white solid was dissolved with dichloromethane (100 mL) under reflux, and n-heptane was added dropwise to precipitate white crystals, which were stirred at room temperature for 3 hours to grow crystals. The crystals were filtered out and dried in vacuo to obtain pure 4-nitrobenzene-phenol car...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a preparation method of lenvatinib and a preparation method of a lenvatinib intermediate. The preparation method of an amide compound as shown in a formula II comprises the following step: in a solvent, carrying out amidation reaction as shown in the specification on a compound as shown in a formula I and a compound as shown in a formula V to obtain the amide compound as shown in the formula II. In the formulas, when R' is a halogen atom or R<1'>-L<1'>, R-L- is R<1>-L<1>-; when R' is R<1'>-L<1'> and R-L- is R<1>-L<1>-, L1 and L1' are the same, R<1> and R<1'> are the same; when R' is R<2>-L<2>- or 4-nitrophenyl-O-, R-L- is R<3>-O-; and L<1>, L<1'> and L<2> are independently O or S. Lenvatinib can be prepared from the amide compound as shown in the formula II. The preparation methods have the advantages of being low in toxicity of raw materials, simple to operate, high in yield and high in purity.

Description

technical field [0001] The invention relates to a preparation method of lenvatinib and an intermediate. Background technique [0002] Lenvatinib, also known as lenvatinib, is an effective liver cancer treatment drug. [0003] [0004] The prior art discloses various preparation methods of lenvatinib. For example, Eisai's recently filed Chinese patent application 201580042365.3 discloses an improved synthesis method for lenvatinib, which uses phenyl chloroformate as a reaction raw material, which can reduce the genotoxicity of the previously used method. However, this method still has the disadvantages of high genotoxicity, cumbersome operation, low yield and low purity. [0005] Therefore, need a kind of synthetic method of new lenvatinib. Contents of the invention [0006] The technical problem to be solved by the present invention is to provide a preparation method of lenvatinib and intermediates aiming at the single problem of the preparation method of lenvatinib ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48C07D401/12C07C201/12C07C205/43
CPCC07D215/48C07D401/12C07C201/12C07C205/43
Inventor 王振宇杨国胜唐伟杨文谦王铁林
Owner LUOXIN PHARM SHANGHAI CO LTD
Features
  • R&D
  • Intellectual Property
  • Life Sciences
  • Materials
  • Tech Scout
Why Patsnap Eureka
  • Unparalleled Data Quality
  • Higher Quality Content
  • 60% Fewer Hallucinations
Social media
Patsnap Eureka Blog
Learn More

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2025 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com