CN114634446A

CN114634446A - Levatinib impurity and preparation method thereof

Info

Publication number: CN114634446A
Application number: CN202011469971.2A
Authority: CN
Inventors: 周步高; 马俊彦; 惠舰; 张明雨
Original assignee: Nanjing F&s Pharmatech Co ltd
Current assignee: Nanjing F&s Pharmatech Co ltd
Priority date: 2020-12-15
Filing date: 2020-12-15
Publication date: 2022-06-17

Abstract

The invention discloses a new impurity II of lenvatinib and a preparation method thereof. The impurity II can be used as a reference substance for detecting related substances of the lenvatinib, and is used for controlling the purity of lenvatinib intermediate and lenvatinib raw material medicines.

Description

Levatinib impurity and preparation method thereof

Technical Field

The invention belongs to the field of medicine synthesis, and particularly relates to a Levatinib impurity and a preparation method thereof.

Background

Lenvatinib is an oral multiple tyrosine kinase inhibitor developed by wakame corporation, has antitumor activity, and is preferably used for thyroid cancer that cannot be treated by radioiodine.

In 2012, 8 months, lenvatinib was awarded in japan as an orphan drug (ODD) for the treatment of thyroid cancer; us FDA orphan drug identification was obtained 2 months 2013 for the treatment of follicular, medullary, undifferentiated metastatic or locally advanced thyroid papillary carcinoma; the sanitary company filed a marketing approval application to the japan department of labor, health and welfare (MHLW), the U.S. Food and Drug Administration (FDA), and the european drug administration (EMA) in 2014. In 2015, the us FDA and european medicines agency EMA approved lenvatinib for the treatment of aggressive, locally advanced or metastatic differentiated thyroid cancer. In 2016, the U.S. FDA and european medicines agency EMA approved lenvatinib in combination with everolimus for the treatment of advanced renal cell carcinoma. In 2018, 3 months, lenvatinib was approved in japan for first-line treatment of unresectable hepatocellular carcinoma (HCC). The Levatinib-PD-1 combination also has very good small-scale clinical data on late-stage liver cancer, intrahepatic bile duct cancer, late-stage kidney cancer and late-stage endometrial cancer, and the real case that the Levatinib-PD-1 combination is used for the late-stage liver cancer and the tumor disappears in only 6 weeks is reported before.

Currently, the general synthetic route for lenvatinib is as follows:

in the lenvatinib raw material medicine prepared by the method, a plurality of unknown process impurities generated by the preparation process often exist, so that the difficulty of controlling the quality of the lenvatinib intermediate and the raw material medicine is increased.

Disclosure of Invention

The invention provides a lenvatinib impurity, and a preparation method of the impurity.

The technical scheme is as follows: the Levatinib impurity of the present invention has a structure of formula II:

in bulk drug substances obtained by the conventional preparation method of lenvatinib, the applicant found a new impurity with a very low content, and confirmed that the structure thereof is as described in formula II above. The impurities have certain influence on the purity of the lenvatinib raw material medicine, and need to be detected and monitored in the process of synthesizing the lenvatinib, so that the quality of the lenvatinib raw material medicine is controlled. The impurity II is one of the impurities generated in the synthetic process of the lenvatinib, has low content in the synthetic process of the lenvatinib and is difficult to separate, and the prior art does not report the impurity compound II and the synthetic method thereof, so people are difficult to obtain a large amount of high-purity compound II, lack corresponding reference substances and are difficult to qualitatively and quantitatively detect the impurity in the synthetic process of the lenvatinib.

The preparation method of the lenvatinib impurity compound II comprises the following steps: dissolving a compound I, dicyclopropylamine or salt thereof and alkali in an organic solvent, heating to reaction temperature, and carrying out heat preservation reaction to obtain a compound II; expressed by the reaction formula:

preferably, the dicyclopropylamine salt can be dicyclopropylamine hydrochloride, dicyclopropylamine sulfate or dicyclopropylamine phosphate, and is preferably dicyclopropylamine hydrochloride.

Preferably, the organic solvent may be DMF, DMSO or THF.

Preferably, the base may be an organic base such as triethylamine, pyridine, DMAP, or an inorganic base such as sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, more preferably an inorganic base, most preferably sodium bicarbonate or potassium bicarbonate.

Preferably, the reaction temperature is 40 to 100 ℃, more preferably 50 to 70 ℃.

Preferably, the molar ratio of the compound I to the dicyclopropylamine or the salt thereof is 1:1.2-1.5, and the molar ratio of the base to the compound I is 2-5: 1.

Has the advantages that: the invention provides a brand-new preparation method of a lenvatinib intermediate impurity II, which has the advantages of simple raw material operation, mild reaction conditions, high conversion rate and high yield of the obtained target product, and can reach the purity of more than 97 percent without adopting column chromatography purification.

Detailed Description

The present invention is further illustrated by the following examples, but the invention is not limited to the scope of the claims.

Example 1

A500 mL reaction vessel was charged with 10g (0.02 mol, 1 eq) of the compound of formula I, 100mL of DMF, 4g (0.03 mol, 1.5 eq) of dicyclopropylamine hydrochloride, 3.36g (0.04 mol) of sodium bicarbonate, and the temperature was raised to 70 ℃ for 2 h. The reaction mixture was dispersed in aqueous and ethyl acetate phases, the aqueous layer was separated off, and the organic phase was concentrated to dryness under reduced pressure to give 9.6g of a yellow solid with a purity of 97.97%.¹HNMR（DMSO-D6，400MHz）:δppm9.33(s,1H)，8.69-8.68（t,2H），8.20-8.18(d,2H)，7.87(s, 1H)，7.74（s,1H），7.57（s，1H），7.57-7.54（t，1H），7.31-7.14（m，2H），6.78-6.74（t，2H），6.55-6.54（d，1H），4.046(s，1H)，2.74（s，1H），2.64-2.61（q，1H），0.91-0.87（t，1H），0.84-0.81（t，1H）。m/z[M]⁺：467.21。

Example 2

13.9g of the compound of formula I, 150mL of DMF, 3.5g of dicyclopropylamine and 15g of potassium bicarbonate are added into a 500mL reaction kettle, and the temperature is raised to 50 ℃ for reaction for 5 h. The reaction solution was dispersed in a water phase and an ethyl acetate phase, the water layer was separated off, and the organic phase was concentrated to dryness under reduced pressure to give 12.8g of a yellow solid with a purity of 98%.

Example 3

A500 mL reaction vessel was charged with 10g of the compound of formula I, 100mL of DMSO, 4g of dicyclopropylamine hydrochloride, and 3.36g of sodium bicarbonate, and the temperature was raised to 65 ℃ for 2.5 h. The reaction solution was dispersed in aqueous phase and ethyl acetate phase, the aqueous layer was separated off, and the organic phase was concentrated to dryness under reduced pressure to give 9.5g of yellow solid with a purity of 97.8%.

Example 4

A500 mL reaction vessel was charged with 20g of the compound of formula I, 200mL of THF, 8g of dicyclopropylamine hydrochloride, and 6.72g of sodium bicarbonate, and the temperature was raised to 60 ℃ for reaction for 3 h. The reaction solution was dispersed in aqueous phase and ethyl acetate phase, the aqueous layer was separated off, and the organic phase was concentrated to dryness under reduced pressure to give 19.5g of yellow solid with a purity of 98.5%.

Example 5

A500 mL reaction vessel was charged with 30g of compound of formula I, THF250mL, 12g of dicyclopropylamine hydrochloride, and 10g of sodium bicarbonate, and the temperature was raised to 70 ℃ for 2 h. The reaction solution was dispersed in aqueous phase and ethyl acetate phase, the aqueous layer was separated off, and the organic phase was concentrated to dryness under reduced pressure to give 28.8g of yellow solid with a purity of 97.9%.

The above description is only of the preferred embodiments of the present invention, and it should be noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the invention, and such modifications and adaptations are intended to be within the scope of the invention.

Claims

1. A compound having the structure shown in formula II:

。

2. a process for the preparation of compound II according to claim 1, comprising: dissolving a compound I, dicyclopropylamine or salt thereof and alkali in an organic solvent, heating to reaction temperature, and carrying out heat preservation reaction to obtain a compound II; expressed by the reaction formula:

。

3. the method of claim 2, wherein the dicyclopropaneamine salt is dicyclopropaneamine hydrochloride, sulfate, or phosphate.

4. The process of claim 3 wherein the dicyclopropaneamine salt is dicyclopropaneamine hydrochloride.

5. The method according to claim 2, wherein the organic solvent is one or more of DMF, DMSO, THF, and the reaction temperature is 40-100 ℃.

6. The process of claim 5, wherein the reaction temperature is 50 to 70 ℃.

7. The method of claim 2, wherein the base is an inorganic base.

8. The method of claim 7, wherein the base is sodium bicarbonate, sodium carbonate, potassium bicarbonate, or potassium carbonate.

9. The method of claim 8, wherein the base is sodium bicarbonate or potassium bicarbonate.

10. The process of claim 2, wherein the molar ratio of compound I to dicyclopropylamine or the salt thereof is 1:1.2 to 1.5 and the molar ratio of base to compound I is 2 to 5: 1.