Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

HPLC method for analyzing lenvatinib mesylate and preparation impurity thereof and application of impurity as reference standard

A lenvatinib and impurity technology, applied in the field of drug synthesis, can solve the problems that cannot truly reflect the quality of the drug, cannot accurately determine the true content of impurities, and has no qualitative analysis of impurities, etc.

Active Publication Date: 2017-10-31
BEIJING CREATRON INST OF PHARMA RES CO LTD
View PDF5 Cites 8 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] (3) The impurity calculation method of this method is the area normalization method. Due to the different structure of each impurity, the ultraviolet absorption is different under the proposed detection wavelength. Therefore, the area normalization method cannot accurately measure each impurity. The true content in the marketed drugs
[0009] (4) No qualitative analysis of specific impurities in lenvatinib mesylate
[0010] In summary, the detection results of the prior art cannot truly reflect the quality of the drug

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
  • HPLC method for analyzing lenvatinib mesylate and preparation impurity thereof and application of impurity as reference standard
  • HPLC method for analyzing lenvatinib mesylate and preparation impurity thereof and application of impurity as reference standard
  • HPLC method for analyzing lenvatinib mesylate and preparation impurity thereof and application of impurity as reference standard

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] Example 1: Synthesis of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxylic acid amide (LVTN-1).

[0144] Under the protection of nitrogen, add 200mL dimethyl sulfoxide to a 500mL three-necked flask, start stirring, and add 20.00g 4-chloro-7-methoxyquinoline-6-carboxylic acid amide (SM1), 18.20g 4 - Amino-3-chlorophenol (SM2) and 14.22 g potassium tert-butoxide. After the addition, the temperature was raised to 65° C., and the mixture was kept stirring for 19 hours. The above reaction system was poured into pure water, a large amount of solids precipitated, filtered, the filter cake was rinsed with pure water, and air-dried at 60°C for 1 to 2 hours to obtain 25.07 g of brown solid 4-(4-amino- 3-Chlorophenoxy)-7-methoxyquinoline-6-carboxylic acid amide (LVTN-1), yield: 86.32%. Intermediate-1 1 H-NMR and high-resolution mass spectrometry see respectively image 3 and Figure 4 .

[0145] 1 H-NMR (400Mz, DMSO) δ: 8.685(s, 1H), 8.653(d, J=3.6Hz, 1H), 7.754-7....

Embodiment 2

[0146] Example 2: 4-(3-chloro-4-(N'-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxylic acid amide (LVTN-3) lenvatinib Synthesis

[0147] Add 250mL of N-methylpyrrolidone to a 500mL three-necked flask, start stirring, and then add 11.50g of pyridine and 25.00g of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6- Carboxylic acid amide (LVTN-1). Under an ice-water bath, 4.94 g of phenyl chloroformate was added dropwise to the system. After the dropwise addition, the system was warmed up to room temperature. Add pure water dropwise to the reaction system, add dropwise for 1 to 2 hours, filter, rinse, and blow dry at 60°C for 2 hours to obtain 33.74g (4-((6-carboxycarboxamido-7 -Methoxyquinolin-4-yl)oxy)-2-chlorophenyl)phenylcarbamate (LVTN-2) brown powder. Yield: 81.26%.

[0148] Add 300mL N-methylpyrrolidone to a 1000mL three-necked flask, start stirring, and then add 30.00g (4-((6-carboxyformamido-7-methoxyquinolin-4-yl)oxy)-2- Chlorophenyl) phenyl carbamate (LVTN-2...

Embodiment 3

[0149] Example 3: Preparation of lenvatinib mesylate, 4-(3-chloro-4-(N'-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxylic acid Preparation of amide mesylate and preparation of lenvatinib mesylate capsules

[0150] Under the protection of nitrogen, add 100mL of acetic acid and 2.70g of methanesulfonic acid to a 250mL three-necked flask in sequence, and then add 10.00g of LVTN-3 to the system under temperature control at 40°C, stir for 1 to 2 hours, filter, collect the mother liquor, and The mother liquor was transferred to a 500mL three-neck flask, and under nitrogen protection, the temperature was controlled at 40°C, and 170mL of n-propanol was added dropwise to the system, and the dropping time was controlled for 1 to 2 hours. After filtering, the filter cake was rinsed with 70 mL of n-propanol to obtain the acetate compound of lenvatinib mesylate. Under nitrogen protection, add 100mL ethanol to a 250mL three-necked flask, start stirring, and add lenvatinib mesylate...

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

PropertyMeasurementUnit
wavelengthaaaaaaaaaa
concentrationaaaaaaaaaa
Login to View More

Abstract

The invention relates to a method for analyzing lenvatinib (4-(3-chloro-4-(N'-cyclopropylurea) phenoxy)-7-methoxyquinoline-6- carboxamide) or a preparation containing lenvatinib. The method comprises the step of determining an impurity in a sample through a chromatography, wherein the impurity is selected from one or more of compounds A-I and LVTN-1. The method comprises the following steps of (1) dissolving lenvatinib mesylate or a drug containing the lenvatinib mesylate into a solvent to prepare a sample solution; (2) dissolving one or more of the compounds A-I and a midbody-1 (LVTN-1) into the solvent to prepare a reference standard solution or a reference solution; (3) implementing a chromatography on the sample solution and the reference standard solution; and (4) determining presence of any one or more of the compounds A-I and the midbody-1 (LVTN-1) in the lenvatinib mesylate or a drug containing the lenvatinib mesylate through referring to one or more of the compounds A-I and the midbody-1 (LVTN-1) in the reference standard solution.

Description

technical field [0001] The invention belongs to the field of medicine synthesis. Specifically, the present invention relates to the preparation of lenvatinib (4-(3-chloro-4-(N'-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxylic acid amide) Impurities occurring during the process and methods for analysis of formulations containing lenvatinib. Background technique [0002] Lenvatinib was researched and developed by Eisai Company, and there is no standard Chinese translation name at present, so the applicant hereby transliterates it as "Lenvatinib". The drug was approved by the US FDA in February 2015 for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer, with the trade name LENVIMA. In March 2015, Lenvatinib was approved for marketing by the Japanese Ministry of Health and Welfare, becoming the first molecular targeted therapy drug for the treatment of unresectable thyroid cancer (...

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): G01N30/02G01N30/06C07D215/48
CPCC07D215/48G01N30/02G01N30/06G01N2030/027
Inventor 贾慧娟何学敏
Owner BEIJING CREATRON INST OF PHARMA RES CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com