WO2021037185A1

WO2021037185A1 - Tyrosine kinase inhibitor having low impurity content

Info

Publication number: WO2021037185A1
Application number: PCT/CN2020/111995
Authority: WO
Inventors: 张全良; 邱振均; 曹永兴; 韦艳丽
Original assignee: 江苏恒瑞医药股份有限公司
Priority date: 2019-08-30
Filing date: 2020-08-28
Publication date: 2021-03-04
Also published as: TW202115027A

Abstract

The present disclosure relates to a tyrosine kinase inhibitor having a low impurity content. In particular, the present disclosure relates to a compound as shown in formula I or a pharmaceutically acceptable salt thereof, the impurity content of which being less than 0.2%.

Description

A tyrosine kinase inhibitor with low impurity content

This application claims the priority of the Chinese patent application CN201910812526.2 whose filing date is August 30, 2019. This application quotes the full text of the aforementioned Chinese patent application.

Technical field

The present disclosure belongs to the field of medicine, and relates to tyrosine kinase inhibitors with low impurity content, pharmaceutical compositions and preparation methods.

Background technique

Receptor tyrosine kinases are a class of transmembrane proteins involved in signal transduction. They are expressed in a variety of cells and regulate cell growth, differentiation and angiogenesis. Studies have shown that more than 50% of proto-oncogenes and oncogene products have tyrosine kinase activity, and their abnormal expression will lead to tumorigenesis. In addition, they are also resistant to tumor invasion and metastasis, tumor angiogenesis, and tumor chemotherapy. Sex is closely related. WO2011029265 discloses an effective tyrosine kinase inhibitor and a preparation method thereof, the structure of which is shown in formula I,

The compound has obvious pharmacodynamic advantages. CN102933574A describes the dimaleate salt form of the compound, which has improved physicochemical properties, pharmacokinetic properties, and good bioavailability. CN103974949A describes the crystalline form I of the dimaleate salt of this compound. WO2017186140 describes the preparation method of this compound.

Studies have found that the existing preparation process of the compound represented by formula I will produce a variety of impurities, and the compound represented by formula I will also produce a variety of impurities such as degradation impurities during the placing process, and the number of possible impurities exceeds 20. And most of them are difficult to remove. In the industrial production process, it is often necessary to invest a large amount of raw materials at a time to prepare products to reduce costs, and the input amount of raw materials at a time can reach several hundred grams, several kilograms or even tens of hundreds of kilograms. If the impurities in the product cannot be effectively removed, it is very easy to cause problems such as the impurity content of the product easily exceeding the standard during mass production. If the scale of production is reduced, production efficiency will be seriously affected.

Summary of the invention

The present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof,

Its impurity content is less than 0.2%.

In some embodiments, the impurity content of the compound may be less than 0.19%, 0.18%, 0.17%, 0.16%, 0.15%, 0.14%, 0.13%, 0.12%, 0.11%, 0.10%, 0.09%, 0.08% %, 0.07%, 0.06%, 0.05% or less, preferably less than 0.18%, more preferably less than 0.15%, most preferably less than 0.1%.

In certain embodiments, among the compounds represented by formula I or pharmaceutically acceptable salts thereof described in the present disclosure, the pharmaceutically acceptable salt of the compound represented by formula I is maleate, preferably dimaleate.

In some embodiments, the particle size D90 of the compound described in the present disclosure is less than 20 μm, for example, less than 15 μm, or less than 14 μm, or less than 13 μm, or less than 12 μm, or less than 10 μm, or less than 9 μm, or less than 8 μm, or less than 7 μm , Or less than 6μm, or less than 5μm, or less than 4μm, or less than 3μm.

In some embodiments, the particle size D50 of the compound is less than 5 μm, preferably less than 4 μm, or less than 3 μm, or less than 2 μm, or less than 1 μm.

Another aspect of the present disclosure also provides a method for preparing the compound represented by formula I or a pharmaceutically acceptable salt thereof, which comprises the step of recrystallizing the compound represented by formula I or a pharmaceutically acceptable salt thereof using a solvent. The solvent may be A mixed solvent of methanol and other solvents, the other solvents are selected from one or more of acetone, ethyl acetate and tetrahydrofuran, preferably acetone and/or tetrahydrofuran.

In some embodiments, the impurity content of the compound is less than 0.2%, for example, it can be less than 0.19%, 0.18%, 0.17%, 0.16%, 0.15%, 0.14%, 0.13%, 0.12%, 0.11%, 0.10%. %, 0.09%, 0.08%, 0.07%, 0.06%, 0.05% or less, preferably less than 0.18%, more preferably less than 0.15%, most preferably less than 0.1%.

In some embodiments, the volume ratio of methanol to other solvents may be 1:1 to 1:50, preferably 1:3 to 1:20.

In some embodiments, the volume ratio of the compound represented by formula I or its pharmaceutically acceptable salt to the solvent may range from 1:5 to 1:200.

The method of recrystallization is not particularly limited, and it can be performed by a usual recrystallization operation method. For example, the raw materials can be heated and dissolved in an organic solvent and then slowly cooled and allowed to stand for crystallization, or stirring and crystallization can be adopted. After the crystallization is completed, the desired crystals can be obtained by filtering and drying. By adopting the method of recrystallization containing methanol solvent, the recrystallization process can be carried out at room temperature without heating, which largely avoids the degradation of the compound represented by formula I and ensures that the compound represented by formula I or its pharmaceutically acceptable salt And the stability of the pharmaceutical composition and the operability of the production process. In addition, the prepared salt of the compound represented by formula I has a small particle size, which is convenient for preparation of the formulation. Although the compound represented by formula I is relatively soluble in other solvents, for example, ethanol or isopropanol, it can basically only be completely dissolved under heating conditions, which can easily cause degradation of the compound represented by formula I, resulting in purity reduce.

During the recrystallization process, seed crystals can optionally be added to accelerate the speed of crystallization.

In certain embodiments, the compound represented by formula I or a pharmaceutically acceptable salt thereof is the maleate salt of the compound represented by formula I, and the method further comprises combining the compound represented by formula I or a pharmaceutically acceptable salt thereof with The step of mixing maleic acid and solvent.

In some embodiments, the compound represented by formula I or a pharmaceutically acceptable salt thereof is the dimaleate salt of the compound represented by formula I.

In some embodiments, the solvent in the mixing step is selected from one or more of methanol, ethanol, isopropanol, acetone, ethyl acetate, or tetrahydrofuran, preferably methanol. The compound represented by the formula I has high solubility in methanol, and the dissolution rate is relatively fast, and the dissolved compound represented by the formula I is not easy to precipitate in methanol, which is beneficial to industrial production.

In some embodiments, the preparation method includes:

(1) Mixing the compound represented by formula I or its pharmaceutically acceptable salt with maleic acid and methanol to prepare the dimaleate salt of the compound represented by formula I;

(2) Using a solvent to recrystallize the dimaleate salt of the compound represented by formula I, wherein the solvent is selected from a mixed solvent of methanol and other solvents, and the other solvent is selected from one of acetone, ethyl acetate and tetrahydrofuran. One or more, preferably acetone and/or tetrahydrofuran.

In some embodiments, the method further includes the step of separating crystals of the compound represented by formula I or its pharmaceutically acceptable salt. Preferably, the isolated compound represented by formula I or its pharmaceutically acceptable salt has an impurity content of less than 0.2%, For example, it can be less than 0.19%, 0.18%, 0.17%, 0.16%, 0.15%, 0.14%, 0.13%, 0.12%, 0.11%, 0.10%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05% or more Low, preferably less than 0.18%, more preferably less than 0.15%, most preferably less than 0.1%.

In some embodiments, the methanol solution containing the dimaleate salt of the compound represented by formula I in the step (1) is mixed with other solvents in the step (2) for recrystallization. In some embodiments, the step (1) does not include the operation of removing the methanol solvent.

The method for separating the compound represented by formula I or its pharmaceutically acceptable salt described in the present disclosure is a conventional separation method in the art, such as centrifugation, filtration and the like.

Another aspect of the present disclosure also provides a pharmaceutical composition comprising the compound of formula I described in the present disclosure or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may also contain other pharmaceutically acceptable excipients.

Another aspect of the present disclosure also provides a pharmaceutical composition. The compound of formula I or a pharmaceutically acceptable salt thereof prepared by the method described in the present disclosure or the method described in the present disclosure is combined with one or more pharmaceutically acceptable salts. It is made by mixing acceptable excipients.

The content of impurities or substances described in the present disclosure can be obtained through HPLC detection.

HPLC method (Chinese Pharmacopoeia 2015 Edition Four General Rules 0512) detection conditions: octadecyl silane bonded silica as filler (Waters symmetry C18, specification: 4.6*250mm, 5μm), with sodium dihydrogen phosphate solution and acetonitrile solution as the flow Phase is eluted, and the system adaptability solution, test solution and 1% control solution are measured respectively, and the percentage of impurities is calculated by the following formula:

Among them, the relative retention time of each impurity is: impurity-A 0.31min; impurity-B 1.08min; impurity-C 0.86min.

The ratio of the impurities described in the present disclosure to the compound represented by formula I or a pharmaceutically acceptable salt thereof is a weight ratio. The "D10" mentioned in the present disclosure refers to the particle size corresponding to the cumulative particle size distribution percentage of a sample reaching 10%. "D50" refers to the particle size when the cumulative particle size distribution percentage of a sample reaches 50%. "D90" refers to the particle size when the cumulative particle size distribution percentage of a sample reaches 90%.

detailed description

Example 1

Take 2kg of free alkali compound of formula I (prepared according to the method in Example 3 of WO2017186140) and 800g of maleic acid in a 50L batching tank, add 6L of anhydrous methanol, stir to dissolve, filter to remove insolubles, transfer the filtrate to a glass reactor and add 30L of acetone, stir evenly, add 2g of compound of formula I dimaleate salt I crystal seed crystals, stir to crystallize, filter with suction, wash the filter cake with acetone, and dry the filter cake under reduced pressure at 40°C for 24 hours to obtain the compound of formula I dimaleate The total lysate was 2.408 kg, and the yield was 86.0%.

Example 2

According to the method of Example 1, 0.5 kg of compound of formula I was added to obtain a total of 601.8 g of compound of formula I dimaleate, with a yield of 86%.

Example 3

Take 5.0 g of the compound of formula I and 2.0 g of maleic acid in a reaction flask, add 15 ml of anhydrous methanol, stir to dissolve, add 75 ml of tetrahydrofuran, and stir to crystallize. After suction filtration, the filter cake was vacuum dried at 40°C to obtain 6.384 g of solid, with a yield of 91.2%.

Example 4

Add 11.78kg of free base of formula I compound and 65.00kg of anhydrous methanol into the reaction kettle, then add 4.68kg of maleic acid, stir to dissolve, filter to remove insoluble materials, and concentrate the filtrate at 45°C under reduced pressure until there is no obvious droplet flow. Add 93.00kg of isopropanol and 46.00kg of acetone, and heat to reflux until all is dissolved. After dissolving, add 4.7g of seed crystals, continue to reflux for 0.5h, cool and crystallize under stirring, filter, wash the filter cake with acetone, and dry under reduced pressure at 40°C to obtain the compound of formula I dimaleate with a total yield of 13.60kg. It is 82.58%.

Example 5

Take the dimaleate product of the compound of formula I prepared in each example and determine its impurity content, as shown in Table 1 below.

Table 1

The impurity content of the dimaleate product of the formula I compound recrystallized with methanol solvent is significantly lower than that of products prepared from other solvents.

Example 6

Take the dimaleate product of the compound of formula I prepared in each of Examples 1 and 2, and measure its particle size, as shown in Table 2 below.

Table 2

Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to these embodiments without departing from the principle and essence of the present invention. modify. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims

A compound represented by formula I or a pharmaceutically acceptable salt thereof,

Its impurity content is less than 0.2%, preferably less than 0.18%, more preferably less than 0.15%, most preferably less than 0.1%.
The compound according to claim 1, wherein the pharmaceutically acceptable salt of the compound represented by formula I is maleate, preferably dimaleate.
A method for preparing a compound represented by formula I or a pharmaceutically acceptable salt thereof, which comprises the step of recrystallizing the compound represented by formula I or a pharmaceutically acceptable salt thereof using a solvent, the solvent being a mixed solvent of methanol and other solvents, The other solvent is selected from one or more of acetone, ethyl acetate and tetrahydrofuran, preferably acetone and/or tetrahydrofuran.
The preparation method according to claim 3, wherein the volume ratio of methanol to other solvents is 1:1 to 1:50, preferably 1:3 to 1:20.
The preparation method according to claim 3, wherein the pharmaceutically acceptable salt of the compound represented by formula I is the maleate salt of the compound represented by formula I, and the method further comprises combining the compound represented by formula I or its pharmaceutically acceptable salt The step of mixing salt with maleic acid and solvent.
The preparation method according to claim 5, wherein the solvent in the mixing step is selected from one or more of methanol, ethanol, isopropanol, acetone, ethyl acetate or tetrahydrofuran, preferably methanol.
The preparation method according to claim 3, which comprises:

(1) Mixing the compound represented by formula I with maleic acid and methanol to prepare the dimaleate salt of the compound represented by formula I;

(2) Using a solvent to recrystallize the dimaleate salt of the compound represented by formula I, the solvent is selected from a mixed solvent of methanol and other solvents, and the other solvent is selected from one of acetone, ethyl acetate and tetrahydrofuran Or more, preferably acetone and/or tetrahydrofuran.
The preparation method according to claim 7, wherein the methanol solution of the dimaleate salt containing the compound shown in I in the step (1) is mixed with other solvents in the step (2) for recrystallization.
The preparation method according to claim 7, wherein the step (1) does not include the operation of removing the methanol solvent.
The preparation method according to any one of claims 3-9, which further comprises the step of separating the crystals of the compound represented by formula I or its pharmaceutically acceptable salt, preferably the isolated compound represented by formula I or its pharmaceutically acceptable salt The impurity content of is less than 0.2%, preferably less than 0.18%, more preferably less than 0.15%, most preferably less than 0.1%.
A pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2 or prepared according to any one of claims 3-10, and one or more A pharmaceutically acceptable excipient.
A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof prepared according to claim 1 or 2 or a method according to any one of claims 3-10, and one or more It is prepared by mixing a variety of pharmaceutically acceptable excipients.