ChemicalBook CAS DataBase List lenvatinib Mesylate

lenvatinib Mesylate synthesis

11synthesis methods

Product Name:lenvatinib Mesylate
CAS Number:857890-39-2
Molecular formula:C22H23ClN4O7S
Molecular Weight:522.9586

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.
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417716-92-8 Synthesis

417716-92-8
446 suppliers
$5.00/10mg

75-75-2 Synthesis

75-75-2
601 suppliers
$10.00/5g

857890-39-2
359 suppliers
$29.00/5mg

Yield:857890-39-2 99%

Reaction Conditions:

in tetrahydrofuran;lithium hydroxide monohydrate at 20; for 3.66667 h;

Steps:

1 Preparation of compound 5.

Weigh compound 4 (0.33 g, 0.77 mmol) into a 50 mL eggplant-shaped flask. Add 7 mL of THF and 3 mL of water, and stir well. Prepare a mixed solution of methanesulfonic acid and water (0.4mL methanesulfonic acid, 1.6mL water), add 0.5mL of the prepared methanesulfonic acid aqueous solution dropwise to the eggplant-shaped flask, stir at room temperature for ten minutes, continue to add 0.4 mL methanesulfonic acid aqueous solution, after stirring for 30 min, continue to add 0.1 mL of methanesulfonic acid aqueous solution, and after stirring for 2 hours at room temperature, after adding 1 mL of methanesulfonic acid aqueous solution and reacting for 1 hour, after suction filtration, it was dried in a blast drying cabinet to obtain compound 5: 0.40 g, with a yield of 99%.

References:

CN111349045,2020,A Location in patent:Paragraph 0049; 0062-0064