This application is a U.S. national stage of PCT/EP2019/073442 filed on 3 Sep. 2019, which claims priority to and the benefit of European Application No. 18193196.5 filed on 7 Sep. 2018, the contents of which are incorporated herein by reference in their entireties.

The present invention relates to a process for the preparation of Lenvatinib of formula (I) from 4-amino-3-chloro-phenol and 4-chloro-7-methoxyquinoline-6-carboxamide.



BACKGROUND OF THE INVENTION

Lenvatinib of formula (I), disclosed for the first time in WO0232872, is used as mesylate salt to treat differentiated thyroid carcinoma not responding to treatment with radioactive iodine. Lenvatinib (I) is also active against advanced renal cell carcinoma.

U.S. Pat. No. 7,683,172 discloses a process for the preparation of Lenvatinib (I) from 4-amino-3-chloro-phenol and 4-chloro-7-methoxyquinoline-6-carboxamide which comprises:

1) conversion of 4-amino-3-chloro-phenol (II) into the corresponding phenyl carbamate derivative (III);



2) reaction of derivative (III) obtained in step (1) with cyclopropylamine to provide a compound of formula (V);



3) coupling reaction between compound (V) obtained in step (2) with 4-chloro-7-methoxyquinoline-6-carboxamide of formula (VI) to provide Lenvatinib (I);



4) crystallization of Lenvatinib (I).

The main drawback of this process lies in step (3) that is performed by mixing 1 eq. of 4-chloro-7-methoxyquinoline-6-carboxamide (VI), 1.2 eq. of the urea derivative (V) obtained in step 2), 2 eq. of cesium carbonate or in alternative 1.2 eq. of sodium tert-butoxide in dimethylsulfoxide at 65-70° C. for 23 h. At the end of the reaction, the product is isolated by crystallization. In these conditions, the precipitate turned out to be contaminated by 1.8% of impurity (VII), 0.5% of impurity (VIII) and 1.7% of impurity (IX). Impurities (VIII) and (IX) are described in CN 107266363. The high amounts of said impurities require an impracticable number of crystallizations with a detrimental effect to the process yield. Therefore, there is still the need for an improved process for the preparation of Lenvatinib (I) which overcomes the above mentioned drawbacks.



