857890-39-2 Usage
Description
Lenvatinib mesylate, also known as lenvatinib, is an orally available, receptor-type tyrosine kinase inhibitor that was developed by Eisai in 2015. It is a multi-kinase inhibitor and orphan drug used for the treatment of various types of thyroid cancer that do not respond to radioiodine. Lenvatinib mesylate acts as an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor, a fibroblast growth factor receptor antagonist, a vascular endothelial growth factor receptor antagonist, and an antineoplastic agent. It is a methanesulfonate salt obtained by the reaction of lenvatinib with one molar equivalent of methanesulfonic acid and contains a lenvatinib(1+) ion.
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
Check Digit Verification of cas no
The CAS Registry Mumber 857890-39-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 8,5,7,8,9 and 0 respectively; the second part has 2 digits, 3 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 857890-39:
(8*8)+(7*5)+(6*7)+(5*8)+(4*9)+(3*0)+(2*3)+(1*9)=232
232 % 10 = 2
So 857890-39-2 is a valid CAS Registry Number.
857890-39-2Relevant articles and documents
Novel method for the synthesis of lenvatinib using 4-nitrophenyl cyclopropylcarbamate and their pharmaceutical salts
Sadineni, Ravi Kumar,Rapolu, Rajesh Kumar,Raju, V. V. N. K. V. Prasada,Srinivasu,Malladi, Sireesha,Mulakayala, Naveen
, p. 1475 - 1483 (2020/11/05)
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.
Method for refining Lenvatinib mesylate
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, (2020/03/02)
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
Preparation method of high-purity lenvatinib mesylate crystal form C
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Paragraph 0054-0072, (2020/10/04)
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