Lenvatinib mesylate

Lenvatinib mesylate (E7080 mesylate), an oral, multi-targeted tyrosine kinase inhibitor that inhibits VEGFR1-3, FGFR1-4, PDGFR, KIT, and RET, shows potent antitumor activities[1][2].

Lenvatinib mesylate is a methanesulfonate salt obtained by reaction of lenvatinib with one molar equivalent of methanesulfonic acid. A multi-kinase inhibitor and orphan drug used (as its mesylate salt) for the treatment of various types of thyroid cancer that do not respond to radioiodine. It has a role as an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor, a fibroblast growth factor receptor antagonist, an orphan drug, a vascular endothelial growth factor receptor antagonist and an antineoplastic agent. It contains a lenvatinib(1+).|Lenvatinib Mesylate is a synthetic, orally available inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2, also known as KDR/FLK-1) tyrosine kinase with potential antineoplastic activity. E7080 blocks VEGFR2 activation by VEGF, resulting in inhibition of the VEGF receptor signal transduction pathway, decreased vascular endothelial cell migration and proliferation, and vascular endothelial cell apoptosis.

4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamide methanesulfonate (0151) (0152) In a mixed solution of 20 methanesulfonic acid (5.44 kg) and 21 acetic acid (150 L) was dissolved 18 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamide (23.0 kg) at 20° C. to 35° C. Methanesulfonic acid (777 g) was further added, the solution was filtered at a temperature of 35° C. or less, and the filter paper was washed with acetic acid (11.5 L). To the filtrate, 1-propanol (46.0 L) and seed crystals (230 g) were added at 25° C. to 45° C., and 22 1-propanol (161 L) and 23 isopropyl acetate (115 L) was further added dropwise at 25° C. to 45° C. The mixed solution was cooled to 15° C. to 25° C., and subsequently, the deposited crystals were filtered and washed with a mixed solution of 1-propanol and isopropyl acetate (1-propanol concentration: 33 v/v percent). To the resulting wet crystals, ethanol (173 L) was added and stirred at 20° C. to 60° C. for three hours. After the crystals were collected by filtration and washed with ethanol, the crystals were dried under reduced pressure at a temperature of 80° C. or less to thereby obtain 24 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamide methanesulfonate (27.5 kg, yield: 94percent)Methanesulphonic acid (0.5 g) was added to a mixture of lenvatinib free base (1 g, obtained from lenvatinib hydrochloride) and isopropyl alcohol (30 mL) at 65 °C. The mixture was stirred at 60°C to 65°C for 5 hours, cooled to 25°C, and then stirred at 25°C to 26°C. The solid was filtered, washed with isopropyl alcohol (2x5 mL), and then dried in vacuum at 50°C to 55°C to obtain the title compound.100.0 g of phenyl (4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl)carbamate and 800 mL of dimethylacetamide were taken in a flask at 25-3OoC. 14.77 g of cyclopropylamine taken in 100 mL of dimethylacetamide was added to the above flask at 25C. The contents of the above flask were stirred at 25-3OoC for 1-2 hours. 2000 mL of methyl isobutyl ketone was added to the above flask and the reaction mass was maintained for 8-10 hours. The contents were filtered and washed with 500 mL of methyl isobutyl ketone. The filtered compound was dried at 70-80C for 8-10 hours. The dried material was taken in fresh flask along with 890 mL of diemethylacetamide and heated to 70-8OoC for 30- 60 minutes. The contents were then cooled to 40-50C and 1780 mL of methyl isobutyl ketone was added. The reaction mass was maintained for 3-4 hours at 40-50C and then cooled to 25-3OoC. The reaction mass was filtered and washed with methyl isobutyl ketone and then dried for 8-10 hours at 70-80 C. The dried material was taken in a fresh flask along with 720 mL of dimethylacetamide and heated to 60-70C for 30-60 minutes. The reaction mass was cooled to 25-3OoC and 24.76 g of methanesulfonic acid taken in 100 mL of methyl isobutyl ketone was added to reaction mass and stirred for 1-2 hours. 1350 mL of methyl isobutyl ketone was further added and stirred for 3-4 hours. The reaction mass was filtered under nitrogen atmosphere and dried at 5OoC under reduced pressure to afford the title compound.

E7080 (Lenvatinib) is a multi-target inhibitor of VEGFR2 and VEGFR3 with IC50 of 4 nM and 5. 2 nM, respectively.

Molecular Weight:523.0
Hydrogen Bond Donor Count:4
Hydrogen Bond Acceptor Count:8
Rotatable Bond Count:6
Exact Mass:522.0975980
Monoisotopic Mass:522.0975980
Topological Polar Surface Area:178
Heavy Atom Count:35
Complexity:727
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes