857890-39-2

Basic information

• Product Name: lenvatinib Mesylate
• Synonyms: lenvatinib Methanesulfonate;E7080 Mesylate;4-[3-Chloro-4-[[(cyclopropylamino)carbonyl]amino]phenoxy]-7-methoxy-6-quinolinecarboxamide monomethanesulfonate;4-[3chloro-4-(N'-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate;lenvatinib Mesylate
• CAS NO: 857890-39-2
• Molecular Formula: CH₄O₃S*C₂₁H₁₉ClN₄O₄
• Molecular Weight: 522.95862
• EINECS: 1592732-453-0
• Product Categories: FGF receptor antagonist
• Mol File: 857890-39-2.mol

Chemical Properties

• Appearance: /
• Storage Temp.: -20°C Freezer
• Solubility: DMSO (Slightly), Methanol (Slightly)
• CAS DataBase Reference: lenvatinib Mesylate(CAS DataBase Reference)
• NIST Chemistry Reference: lenvatinib Mesylate(857890-39-2)
• EPA Substance Registry System: lenvatinib Mesylate(857890-39-2)

Safety Data

• Hazardous Substances Data: 857890-39-2(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
Lenvatinib mesylate is used as an antineoplastic agent for the treatment of differentiated thyroid cancer that is either locally recurrent, metastatic, or progressive and did not respond to radioactive iodine treatment. It was approved by the FDA in 2015 for this application.
Used in Combination Therapy for Renal Cell Carcinoma:
In May 2016, the FDA approved lenvatinib mesylate as a combination therapy with everolimus for the treatment of advanced renal cell carcinoma. This combination therapy aims to provide a more effective treatment option for patients with advanced renal cell carcinoma.
Used in Preparation of Anti-Human CTLA4xPD-1 Bispecific Antibodies:
Lenvatinib mesylate is also used in the preparation of anti-human CTLA4xPD-1 bispecific antibodies, which are employed for the diagnosis, prevention, and treatment of tumor or anemia. This application highlights the versatility of lenvatinib mesylate in various cancer treatments and its potential role in developing novel therapeutic strategies.
The primary side effect of lenvatinib mesylate is hypertension, which is thought to be due to the inhibition of VEGF2R and FGFR, as these growth factors are believed to play a role in cardiovascular signaling pathways.

Synthesis

Starting from commercial aniline 193, a substitution reaction under neutral conditions in warm isopropyl alcohol with a commercial vinyl methoxy derivative of Meldrum’s acid (194) produced enamine 195 in good yield. Next, subjection of 195 to DOWTHERM A at 190 °C affected an intramolecular cyclizative substitution reaction, followed by loss of acetone, and a decarboxylation reaction to furnish quinolone 196. This cyclization reaction, which is a variant of the Conrad-Limpach reaction, is particularly noteworthy given the temperature and pH at which it takes place. Conrad- Limpach cyclizations typically proceed under basic conditions at temperatures well above 240 °C. However, a process was developed by Zeneca in 2004 which involved subjecting 195 to the DOWTHERM heat transfer fluid (commercially available from Dow and Sigma-Aldrich, consisting of a eutectic mixture of biphenyl and diphenyl oxide) allowed the team to lower the temperature required for the reaction, clearly observe bubbling of gas indicating the progress of the reaction, and simple cooling and treatment with ether to facilitated precipitate formation. The resulting solid could be collected by filtration and required no additional purification on scale in 80% yield. Quinoline 196 was then converted to the corresponding chloride using thionyl chloride in refluxing DMF, and the resulting ester 197 was converted to the corresponding amide through the use of 28% aqueous ammonia in warm ethanol, which ultimately produced the key chloroquinoline lenvatinib subunit 198 in 80% yield from 197. Commercial aminophenol 199 was converted to the corresponding carbamate through the use of phenyl chloroformate in essentially quantitative yield prior to subjection to cyclopropylamine in chilled DMF, which ultimately furnished urea 201 in 77% overall yield from 200. Next, exposure of phenol 201 to chloroquinoline 198 in the presence of potassium t-butoxide followed by treatment with methanesulfonic acid and acetic acid resulted in clean formation of lenvatinib mesylate (XXV) in 96% yield across the two-step sequence.

Metabolism

Lenvatinib is metabolised by CYP3A and aldehyde oxidase. Following administration of radiolabelled lenvatinib to 6 patients with solid tumours, approximately two-thirds and one-fourth of the radiolabel were eliminated in the faeces and urine, respectively

Upstream product

• 417716-92-8 lenvatinib 
• 75-75-2 methanesulfonic acid 
• 17609-80-2 4-amino-3-chlorophenol 
• 1882873-21-3 1-{2-chloro-4-[(6-cyano-7-methoxy-quinolin-4-yl)oxy]phenyl}-3-cyclopropylurea 
• 205448-64-2 methyl 4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)-amino)-2-methoxybenzoate 
• 27492-84-8 Methyl 4-amino-2-methoxybenzoate 
• 205448-66-4 methyl 4-chloro-7-methoxyquinoline-6-carboxylate 
• 205448-65-3 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid methyl ester 
• 417722-95-3 {4-[(6-carbamoyl-7-methoxy-4-quinolyl)oxy]-2-chlorophenyl}amino-carboxylic acid phenyl ester 
• 765-30-0 Cyclopropylamine 
• 417721-36-9 4‐chloro‐7‐methoxyquinoline‐6‐carboxamide 
• 52671-64-4 4-Amino-3-chlorophenol hydrochloride 
• 417722-93-1 4?(4?amino?3?chlorophenoxy)?7?methoxyquinoline?6?carboxamide 

Relevant articles and documents

Novel method for the synthesis of lenvatinib using 4-nitrophenyl cyclopropylcarbamate and their pharmaceutical salts

4-Nitrophenyl cyclopropylcarbamate was deployed as a novel synthon for the synthesis of anticancer drug lenvatinib. 4-Nitrophenyl cyclopropylcarbamate was prepared by the reaction of 4-nitrophenyl chloroformate and cyclopropyl amine in acetonitrile at room temperature. Furthermore, lenvatinib was synthesized by reacting 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide with 4-nitrophenyl cyclopropylcarbamate in good yields. Apart from the synthesis of lenvatinib, citrate, phosphate, malate and oxalate salts of?lenvatinib were also reported in good yields.

Preparation method of lenvatinib mesylate

The invention relates to a preparation method of lenvatinib mesylate, in particular to a method for efficiently synthesizing lenvatinib mesylate by taking 4-chloro-6-cyano-7-methoxy quinoline and 2-chloro-4-hydroxy aniline formic acid cyclopropanamide as raw materials through two steps of substitution reaction and hydrolysis reaction. The preparation method of lenvatinib mesylate provided by the invention is a preparation method which is short in steps, high in yield, low in cost, less in three wastes, good in product purity and suitable for industrialization.

Synthesis method of lenvatinib and new intermediate

The invention discloses a synthesis method of lenvatinib and a new intermediate. The method comprises the following steps: step 1, taking 4-amino-3-chlorophenol hydrochloride and 4-chloro-7-methoxy-6-amido quinoline as initial raw materials, and carrying

Preparation method of high-purity lenvatinib mesylate crystal form C

The invention belongs to the technical field of pharmaceutical chemicals and especially relates to a preparation method of a lenvatinib mesylate crystal form C. According to the method, the conditions of high temperature, acid serving as a solvent and the

Method for refining Lenvatinib mesylate

The invention discloses a method for refining Lenvatinib mesylate. The method for refining the Lenvatinib mesylate, provided by the invention, comprises the following step: subjecting a solution formed by an organic solvent and crude Lenvatinib mesylate t

NOVEL POLYMORPHS OF 4-[3-CHLORO-4-(N'-CYCLOPROPYL UREIDO)PHENOXY]-7-METHOXYQUINOLINE-6-CARBOXAMIDE, ITS SALTS AND PROCESS FOR THE PREPARATION THEREOF

The present invention relates to novel polymorphs of 4-[3-chloro-4-(N'- cyclopropyl ureido) phenoxy]-7- methoxyquinoline- 6- carboxamide methanesulfonate represented by following structural formula-1a and process for preparation thereof. Further, the pres

AN IMPROVED PROCESS FOR THE PREPARATION OF LENVATINIB

The present invention relates to an improved and economic industrial process for the preparation of Lenvatinib and salt thereof. The present invention also relates to method and novel use of a reagent for preparing an amorphous form of Lenvatinib mesylate

PROCESS FOR THE PREPARATION OF LENVATINIB OR ITS SALTS THEREOF

The present invention provides a process for the preparation of Lenvatinib or its salts thereof. The present invention also provides a crystalline form of Lenvatinib, which is characterized by the PXRD pattern as shown in figure 1. The present invention a

Preparation method of lenvatinib and its salts

The invention discloses a preparation method of lenvatinib and its salts, wherein N-methylpyrrolidone is used as a reaction solvent in the step of condensation with phenyl chloroformate. The preparation method has the advantages that the danger is success

Preparation method of lenvatinib mesylate crystal form B

The present invention relates to a preparation method of a lenvatinib mesylate crystal form B. The method includes: reacting 4-(3-chloro-4-(cyclopropyl amino carbonyl)aminophenoxy)-7-methoxy-6-quinoline carboxamide with methanesulfonic acid in a specific