KR20200020471A - Sorafenib hemicamsylate and processes for preparation thereof - Google Patents

Abstract

The present invention relates to: novel sorafenib hemi camsylate salt for treating cancer (chemical formula III); a novel crystalline form thereof; and a method for manufacturing the same. More specifically, the present invention relates to: hemi camsylate salt having high stability, solubility, and purity; a crystalline form thereof; and a method for manufacturing the same. The problem to be solved by the present invention is to provide novel sorafenib salt which is easy to make various preparations, and the method for manufacturing novel salt.

Description

Sorafenib hemicamyl acid salt and its preparation method {Sorafenib hemicamsylate and processes for preparation according}

The present invention relates to novel hemicamyl acid salts and methods for their preparation, which are difficult to prepare with conventional salt preparation procedures. The present invention also relates to novel hemicamyl acid salts having various advantages in terms of stability, solubility and bioavailability, high purity, and crystalline forms thereof and methods of preparing such novel hemicamyl acid salts.

Sorafenib is an inhibitor of the enzyme raf kinase, known from International Patent Application Publication No. WO 00/42012. Sorafenib is 4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carbox amide, Has the structure of formula (I).

[Formula I]

The conch penip are sold as tosylate product (Nexavar ^®), such as the formula II.

[Formula II]

International patent application publication number WO 00/42012 published July 20, 2000

The problem to be solved by the present invention is a novel salt of sorafenib, in particular a novel sorafenib salt with improved physicochemical and / or pharmaceutical properties such as solubility, stability (dissolution stability, storage stability, etc.) and a process for preparing such salts. To provide.

Another problem to be solved by the present invention is to provide new sorafenib novel salts and methods for preparing such new salts, which are improved in pharmaceutical properties and are easy to prepare various formulations.

For this purpose, the present invention provides 4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N represented by the following general formula (III): -Methylpyridine-2-carbox amide hemicamyl acid salt, preferably such novel salt is in crystalline form.

[Formula III]

The novel salts according to the invention exhibit good physical properties in various aspects such as stability, solubility, in particular solubility of the solvent, bioavailability, etc., which are preferred for the preparation of various formulations.

The hemicamyl crystalline form of the present invention has a 2Θ (theta) angle of 4.79 ± 0.2, 8.02 ± 0.2, 9.57 ± 0.2, 11.88 ± 0.2, 14.37 ± 0.2, 14.77 ± 0.2, and 2θ in the powder X-ray diffraction analysis (PXRD) graph. Diffraction peaks are present at 18.13 ± 0.2 degrees, preferably 4.79 ± 0.2, 7.08 ± 0.2, 8.02 ± 0.2, 9.57 ± 0.2, 10.58 ± 0.2, 11.88 ± 0.2, 12.08 ± 0.2, 14.37 ± 0.2, Diffraction peaks are characterized in the presence of 14.77 ± 0.2, 16.21 ± 0.2, 18.13 ± 0.2, 19.36 ± 0.2, 21.29 ± 0.2, 21.87 ± 0.2, 25.42 ± 0.2 and 27.55 ± 0.2 degrees.

Hemicamyl crystalline form of the present invention is characterized by having an endothermic transition peak value at 200 to 230 ℃ in the differential scanning calorimetry (DSC) graph, preferably having an endothermic transition peak value at 214 ± 2 ℃ It is done.

The present invention also comprises the steps of (1) dissolving a compound represented by the following formula (I) in a single organic solvent or a mixed solvent and reacting with camphorsulfonic acid

[Formula I]

; 및

; And

(2) cooling the mixture, removing the solvent and then drying;

Provided is a method for preparing the hemicamyl acid salt represented by the following formula (III).

[Formula III]

In the preparation method of the present invention, the single organic solvent comprises methanol, ethanol, isopropanol, normal propanol, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran and acetonitrile It is preferable that it is 1 type selected from the group, and it is more preferable that the said single organic solvent is 1 type chosen from the group which consists of methanol, ethanol, isopropanol, and normal propanol for preparing a hemi form.

In the production method of the present invention, the mixed solvent is (a) methanol, ethanol, isopropanol, normal propanol, acetone, methyl ethyl ketone, acetonitrile, methyl acetate, ethyl acetate, tetrahydrofuran, and 2-methyl tetrahydro A mixed solvent of at least one solvent selected from the group consisting of furans and (b) at least one solvent selected from the group consisting of normal heptane, normal hexane, and diisopropyl ether.

The mixing ratio of the mixed solvent may be 1: 1 to 1:20 in volume ratio.

In the production method of the present invention, preferably, the step (1) is carried out at a temperature of 20 to 70 ℃, the mixture in the step (2) is cooled to a temperature of 0 to 30 ℃, (2) After cooling in the step the mixture is dried at a temperature of 30 to 70 ° C.

The present invention provides a sorafenib hemicamyl acid salt, a sorafenib novel salt having advantages in several aspects such as solubility, stability, bioavailability, and a method for preparing such a novel salt. The present invention also provides novel crystalline forms of sorafenib hemicamyl acid salts and methods for preparing such crystalline forms.

The following drawings, which are attached to this specification, illustrate exemplary embodiments of the present invention, and together with the contents of the present invention serve to further understand the technical spirit of the present invention, the present invention is limited to the matters described in such drawings. It should not be construed as limited.
1 is a PXRD (powder X-ray diffraction analysis) graph of the compound prepared in Example 1 of the present invention.
Figure 2 is a differential scanning calorimetry (DSC) graph of the compound prepared in Example 1 of the present invention.
3 is a graph showing the results of solubility test in methanol, ethanol, isopropanol and acetonitrile of the compound prepared in Comparative Examples 1 to 3 and the compound prepared in Example 1.
FIG. 4 shows pharmacokinetics in beagle dogs for tablets containing a sorafenib tosylate salt such as the compound prepared in Comparative Example 3 (Table C of Tablet No. 9737488) and the compound-containing tablet prepared in Comparative Example 1. FIG. A graph showing comparative test results.
FIG. 5 shows pharmacokinetics in beagle dogs for tablets containing Sorafenib tosylate salt as a compound prepared in Comparative Example 3 as a main component (Tablet C of US Pat. No. 9737488) and tablets containing compound prepared in Example 1. FIG. A graph showing comparative test results.

The present invention provides a novel 4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine represented by the following general formula (III): To a hemicamyl acid salt of 2-carboxamide (sorafenib), the inventors of the present invention provide 4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl in the form of a conventional free base. ] Amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide compound has superior solubility and bioavailability, and is more stable and solubilized than other pharmaceutically acceptable salt compounds of the compound. And the sorafenib hemicamyl acid salt having excellent bioavailability and high purity to complete the present invention.

[Formula III]

Unlike the (mono) camsylic acid salts, the hemicamyl acid salts are absent from most of the compounds that form the salts. For example, among salts of compounds that are commercially available with FDA approval, hemicamic acid has not been published yet. In other words, hemicamyl acid salts that are not mono-camsylate salts of certain compounds are generally not selectable salts. The inventors of the present invention, while studying sorafenib, have found that sorafenib hemicamyl acid salts are specifically produced by specific methods of preparation, and the hemicamyl acid salts of these novel sorafenib compounds are pharmaceutically acceptable salt compounds. It was confirmed that it is excellent in a variety of aspects, such as stability, solubility, bioavailability, high purity, and also easy to prepare a large amount of such sorafenib hemicamyl acid salt, which is the manufacturing method of the present invention. .

In particular, in order to prepare a variety of formulations, it was intended to develop new salts with high solubility in organic solvents such as ethanol, which have been found to be relatively safe for the human body. For example, when preparing a solid dispersion to improve solubility, it is necessary to prepare a solution in which both a hydrophilic polymer and a drug are dissolved. In this case, ethanol solubility is very important. In addition, ethanol is also very advantageous for later permitting processes.

In addition, given the dosage of existing sorafenib formulations with a recommended dosage of about 400 mg, it is desirable to develop salts with as low molecular weight as possible, in this respect hemiform salts are preferred over monoform salts.

In one aspect of the invention, the novel salt represented by the general formula (III) is characterized in that the crystalline form, which also belongs to the scope of the present invention. Given that crystalline forms are typically safer than amorphous forms, crystalline forms of pharmaceutical compounds may be important in connection with the development of suitable formulations.

In one aspect of the invention, the crystalline form of the compound represented by Formula III (hereinafter referred to herein as crystalline form (I)) is 2θ (theta) angle in the PXRD graph 4.79 ± 0.2, 8.02 ± 0.2, 9.57 ± 0.2, 11.88 ± 0.2, 14.37 ± 0.2, 14.77 ± 0.2, and 18.13 ± 0.2 degrees, more preferably 4.79 ± 0.2, 7.08 ± 0.2, 8.02 ± 0.2, 9.57 ± 0.2, 10.58 ± 0.2, 11.88 ± 0.2, 12.08 Diffraction peaks exist where ± 0.2, 14.37 ± 0.2, 14.77 ± 0.2, 16.21 ± 0.2, 18.13 ± 0.2, 19.36 ± 0.2, 21.29 ± 0.2, 21.87 ± 0.2, 25.42 ± 0.2 and 27.55 ± 0.2 degrees.

In another aspect of the present invention, Form (I) of the compound represented by Formula III has an endothermic transition peak value at 200 to 230 ℃, preferably 214 ± 2 ℃ in the DSC (differential scanning calorimetry) graph It is also preferable that the starting point (Onset) is 212 ± 2 ° C.

The present invention also relates to a method for preparing a compound represented by the following general formula (III), comprising the steps of: (1) reacting a compound represented by the following general formula (I) with a camsylic acid in a single organic solvent or a mixed solvent;

[Formula I]

; 및

; And

(2) cooling the mixture, removing the solvent, and then drying the method. A crystal form (I) of a compound represented by the following Chemical Formula III may be prepared by the present manufacturing method, but is not limited thereto. It doesn't work.

In one aspect of the present invention, the single organic solvent is not particularly limited as long as it is suitable for the present invention, methanol, ethanol, isopropanol, normal propanol, 2-methoxy-2-methylpropane, acetone, methyl ethyl ketone, methyl acetate , Ethyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran and acetonitrile are preferably one selected from the group consisting of methanol, ethanol, isopropanol, and normal propanol. . In the case of using a single organic solvent, in particular, an alcoholic solvent which is a preferred single organic solvent, hemicampxate can be stably formed instead of the mono form of chamlate, regardless of the reaction equivalent, and the crystalline form of the compound represented by Formula III There is an advantage that (I) can be manufactured stably.

In another aspect of the present invention, the mixed solvent may be a mixed solvent of a suitable organic solvent, (a) methanol, ethanol, isopropanol, normal propanol, acetone, methyl ethyl ketone, acetonitrile, methyl acetate, ethyl acetate, At least one selected from the group consisting of tetrahydrofuran and 2-methyl tetrahydrofuran, and (b) at least one mixed solvent selected from the group consisting of normal heptane, normal hexane, and diisopropyl ether is preferable. When using the mixed solvent, there is an advantage that the crystalline form (I) of the compound represented by Formula 1 can be stably prepared.

In another aspect of the invention, the mixing ratio of the organic solvent may be 1: 1 to 1:20 ((a) :( b)) in volume ratio, preferably 1: 1 to 1: 5 days Can be. When mixed in the above ratio, there is an advantage that the reduction of the yield of the crystalline form (I) of the compound represented by the formula (1) can be minimized.

In one aspect of the invention, the step (1) may be carried out at a temperature of 20 to 70 ℃, preferably at a temperature of 30 to 60 ℃, it is carried out within the temperature range There is an advantage that it is advantageous to improve the quality of Form (I) of the compound represented by the formula (1).

In another aspect of the invention, in the step (2) the mixture may be cooled to a temperature of 0 to 30 ℃, preferably to a temperature of 0 to 20 ℃, it is cooled to the temperature range It is advantageous to minimize the reduction in the yield of the crystalline form (I) of the compound represented by the above formula (III).

In another aspect of the invention, the mixture after cooling in the step (2) may be dried to a temperature of 30 to 70 ℃, glass in that drying in the temperature range can effectively remove the residual solvent Do.

Hereinafter, examples and the like will be described in detail to help the understanding of the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. Embodiments of the present invention are provided to more fully explain the present invention to those skilled in the art.

Example 1: 4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carbox amide hemicam Preparation of Sulfates

4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carbox amide (100.0 g, 215.14 mmol ) And ethanol (1.0 L) were charged to the reactor. (+)-10-camphorsulfonic acid (52.48 g, 225.89 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was stirred at 50 ° C for 30 minutes or more, cooled to 20-30 ° C and stirred for 2 hours or more. After the reaction mixture was filtered under reduced pressure, the wet cake was washed with ethanol (100 mL), and the obtained solid was dried in vacuo at 50 to 60 ° C. to obtain 104.36 g of the compound prepared in Example 1 (yield: 83.5%).

The compound prepared in Example 1 was measured by ¹ H-NMR (400 MHz, DMSO-d ₆ ) as follows.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (s, 1H), 9.12 (s, 1H), 8.84 (s, 1H), 8.52 (d, 1H), 8.11 (d, 1H), 7.60- 7.70 (m, 4H), 7.45 (s, 1H), 7.17 (m, 3H), 2.95-2.99 (d, 0.5H), 2.79 (m, 3H), 2.65 (m, 0.5H), 2.22-2.26 ( d, 0.5H), 1.79-1.95 (m, 1.5H), 1.28-1.34 (m, 1H), 1.05 (s, 1.5H), 0.75 (s, 1.5H)

The compound prepared in Example 1 was measured by differential scanning calorimetry (DSC), and showed an endothermic transition peak at about 214 ° C in the DSC graph. The DSC was measured using a Mettler Toledo DSC 1 STAR (sample container: sealed aluminum pan, 99% nitrogen condition, temperature rising from 30 ° C to 300 ° C per minute at 10 ° C per minute).

As a result of measuring PXRD of the compound prepared in Example 1, 2Θ angles in the PXRD graph were 4.79, 7.08, 8.02, 9.57, 10.58, 11.88, 12.08, 14.37, 14.77, 16.21, 18.13, 19.36, 21.29, 21.87, 25.42 And a diffraction peak at 27.55 degrees (see FIG. 1). The PXRD spectrum of the compound was measured using Bruker D8 advance (X-ray source: CuKα, tube voltage: 40 kV / tube current: 40 mA, diverging slit: 0.3 and scattering slit: 0.3). .

Example 2: 4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carbox amide hemicam Preparation of Sulfates

4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carbox amide (10.0 g, 215.14 mmol ) And isopropanol (1.0 L) were charged to the reactor. (+)-10-camphorsulfonic acid (4.00 g, 17.21 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was stirred at 50 ° C for 30 minutes or more, cooled to 20-30 ° C and stirred for 2 hours or more. After the reaction mixture was filtered under reduced pressure, the wet cake was washed with ethanol (10 mL), and the obtained solid was dried in vacuo at 50 to 60 ° C. to obtain 10.55 g of the compound prepared in Example 2 (yield: 84.4%).

Example 3: 4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carbox amide hemicam Preparation of Sulfates

4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carbox amide (10.0 g, 21.51 mmol ), And 2-methoxy-2-methylpropane (200 mL) were charged to the reactor. (+)-10-camphorsulfonic acid (5.25 g, 22.59 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was stirred at 50 ° C for 30 minutes or more, cooled to 15-25 ° C and stirred for 2 hours or more. After the reaction mixture was filtered under reduced pressure, the wet cake was washed with 2-methoxy-2-methylpropane (30 mL), and the obtained solid was dried in vacuo at 50 to 60 ° C. to prepare in Example 3. 49.80 g of compound were obtained (yield: 99.4%).

Example 4: 4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carbox amide hemicam Preparation of Sulfates

4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carbox amide (10.0 g, 21.51 mmol ), And ethanol (100 mL) were added to the reactor. (-)-10-camphorsulfonic acid (5.25 g, 22.59 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was stirred at 50 ° C for 30 minutes or more, cooled to 20-30 ° C and stirred for 2 hours or more. After the reaction mixture was filtered under reduced pressure, the wet cake was washed with ethanol (10 mL), and the obtained solid was dried in vacuo at 50 to 60 ° C. to obtain 9.98 g of the compound prepared in Example 4 (yield: 79.8%).

Example 5: 4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carbox amide hemicam Preparation of Sulfates

4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carbox amide (10.0 g, 21.51 mmol ), And ethanol (100 mL) were added to the reactor. (±) -10-camphorsulfonic acid (5.25 g, 22.59 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was stirred at 50 ° C for 30 minutes or more, cooled to 20-30 ° C and stirred for 2 hours or more. After the reaction mixture was filtered under reduced pressure, the wet cake was washed with ethanol (10 mL), and the obtained solid was dried in vacuo at 50 to 60 ° C. to obtain 10.32 g of the compound prepared in Example 5 (yield: 82.6%).

Comparative Example 1. Preparation of 4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide

A solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (14.60 g, 65.90 mmol) in dichloromethane (35 mL) was added to 4- (2- (N-methylcarbamoyl) in dichloromethane (35 mL). To a suspension of -4-pyridyloxy) aniline (16.0 g, 65.77 mmol) was added at 0 ° C. The resulting mixture was stirred at rt for 22 h. After the reaction mixture was filtered under reduced pressure, the wet cake was washed with dichloromethane (30 mL), and the obtained solid was dried under vacuum at 50 ° C. to give a grayish white solid 4- {4-[({[4 28.5 g of -chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide were obtained (yield: 93%).

The compound prepared in Comparative Example 1 was measured by ¹ H-NMR (400 MHz, DMSO-d ₆ ) under the same conditions as in Example 1. Results are as follows.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.99 (s, 1H), 8.77 (br d, 1H), 8.49 (d, 1H), 8.11 (d, 1H), 7.62 (m, 4H), 7.37 (d, 1H), 7.16 (m, 3H), 2.77 (d, 3H).

Comparative Example 2. 4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide besylic acid Preparation of Salt

4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carbox amide (25.0 g, 53.78 mmol ), And ethyl acetate (500 mL) were charged to the reactor. Benzenesulfonic acid (12.76 g, 80.66 mmol) was added thereto, followed by stirring at 15-25 ° C. for at least 4 hours. After the reaction mixture was filtered under reduced pressure, the wet cake was washed with ethyl acetate (50 mL), and the obtained solid was dried under vacuum at 50 ° C. to obtain 4- {4-[({[4-chloro-3- 31.97 g of (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide besylic acid salt were obtained (yield: 95.4%).

The compound prepared in Comparative Example 2 was measured by ¹ H-NMR (400 MHz, DMSO-d ₆ ) under the same conditions as in Example 1, as follows.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.38 (s, 1H), 9.19 (s, 1H), 8.98 (s, 1H), 8.56 (d, 1H), 8.13 (d, 1H), 7.60- 7.68 (m, 6H), 7.34 (m, 3H), 7.20-7.26 (m, 1H), 7.18 (m, 3H), 2.81 (t, 3H)

Comparative Example 3. 4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide tosyl acid Preparation of salt

4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carbox amide (25.0 g, 53.78 mmol ), And ethyl acetate (500 mL) were charged to the reactor. p-toluenesulfonic acid (13.89 g, 80.66 mmol) was added thereto, followed by stirring at 20-30 ° C. for at least 4 hours. After the reaction mixture was filtered under reduced pressure, the wet cake was washed with ethyl acetate (50 mL), and the obtained solid was dried under vacuum at 50 ° C. to obtain 4- {4-[({[4-chloro-3- 28.34 g of (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide tosylic acid salt were obtained (yield: 82.7%).

The compound prepared in Comparative Example 3 was measured by ¹ H-NMR (400 MHz, DMSO-d ₆ ) under the same conditions as in Example 1. Results are as follows.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.23 (s, 1H), 9.07 (s, 1H), 9.22 (s, 1H), 8.84 (s, 1H), 8.52 (d, 1H), 8.11 ( d, 1H), 7.59-7.67 (m, 4H), 7.49 (m, 3H), 7.11-7.19 (m, 5H), 2.80 (d, 3H), 2.29 (s, 3H)

Test Example 1. Solubility Test

For the salt compounds prepared in Example 1, Comparative Example 1, Comparative Example 2 and Comparative Example 3, solubility according to pH and solubility in artificial gastric juice, artificial intestinal fluid, water, methanol, ethanol, isopropanol, acetonitrile were compared. Solubility was measured by high performance liquid chromatography (HPLC) analysis by adding until the compounds prepared in Example 1, Comparative Example 1, Comparative Example 2 and Comparative Example 3 became a supersaturated solution and sample. In the case of an aqueous solvent, the solubility was measured while stirring for 3 hours under a 37 ℃ water bath, the organic solvent solubility was measured after stirring for 24 hours at room temperature. The results are shown in Figure 3 and Table 1 below.

Figure 3 is a result of comparing the solubility of the hemicamic acid salt in the alcoholic solvent according to the present invention with the comparative examples of sorafenib free base, tosylate salt and besylate salt, that the somicamyl acid salt according to the present invention is excellent Shows.

The solubility measurement results (60 minutes) in various aqueous solutions are summarized in Table 1 below. The solubility of the hemicamyl acid salt according to the invention was relatively high compared to the free base and other salts.

Unit: μg / ml Sorafenib
Free base Sorafenib
Hemicamyl acid salts Sorafenib
Tosylate salt Sorafenib
Besylate Salt (VI) water 0.04 0.06 0.04 0.04 Artificial Gastric Fluid (FaSSGF) 0.05 0.09 0.03 0 Artificial Serum (FaSSIF) 5.05 13.62 7.49 9.06

Test Example 2 Test Method of Forced Decomposition

Forced degradation tests were performed on the compounds of Example 1 and Comparative Examples 1-3. In order to perform a forced decomposition test under acid, base, and oxidization conditions with respect to the four compounds, 3M HCl, 3M NaOH, and 5% H ₂ O ₂ were each exposed at 60 ° C. for 24 hours, and then a high performance liquid. The forced decomposition test was performed by chromatography (HPLC), and the results are shown in Table 2 in detail.

division Condition Comparative Example 1
Sorafenib
Free base Comparative Example 2
Sorafenib
Besylate Salt (VI) Comparative Example 3
Sorafenib
Tosylate salt Example 1
Sorafenib
Hemicamyl acid salts water(%) start 99.86 99.88 99.88 99.82 acid 99.74 99.77 99.81 99.44 base 99.84 99.86 99.87 99.83 oxidation 99.73 99.85 99.83 99.78 content(%) start 100.1 99.2 100.5 100.1 acid 99.6 99.6 99.7 99.3 base 99.6 98.6 100.2 99.4 oxidation 98.8 98.9 100.5 98.8

Test Example 3 Light Stability Test Method

Forced degradation tests were performed on the compounds of Example 1 and Comparative Examples 1-3. The four compounds were subjected to photostability testing by high performance liquid chromatography (HPLC) by exposure to light conditions of visible light (VIS) 1,200,000 Lux · hr and ultraviolet (UV) 200 W · hr / m ² . The results are shown in Table 3 in detail.

division Condition Comparative Example 1
Sorafenib
Free base Comparative Example 2
Sorafenib
Besylate Salt (VI) Comparative Example 3
Sorafenib
Tosylate salt Example 1
Sorafenib
Hemicamyl acid salts content(%) Shading 98.1 96.9 97.8 97.5 exposure 98.0 96.9 98.1 96.8 Leading material (%) Shading 0.20 0.13 0.19 0.16 exposure 0.20 0.14 0.20 0.17

Test Example 4 Stability Test Method

Stability tests were performed on the compounds of Example 1 and Comparative Example 2. Stability tests were performed on the two compounds under long term. And accelerated conditions. The two conditions are shown in Table 3 below and the long term stability conditions shown in Table 4 and The stability of the compound was tested under accelerated conditions and the results are shown in detail in Tables 5 and 6.

division Long term stability condition Acceleration conditions Temperature 25 ± 2 ℃ 40 ± 2 ℃ Humidity 60 ± 5% (relative humidity) 75 ± 5% (relative humidity) Container Polyethylene double bag, HDPE bottle Polyethylene double bag,
High Density Polyethylene (HDPE) Bottles Sampling time 3 months at the start 3 months at the start

Classification (long term stability condition) Comparative Example 2
Sorafenib Besylate Salt (VI) Example 1
Sorafenib Hemicamyl Acid start 3 months start 3 months Constellation Off-white powder Off-white powder White powder White powder moisture 0.08% 0.08% 0.07% 0.04% PXRD Pattern - Same pattern - Same pattern content(%) 100.7  98.5 99.3 99.7

Classification (acceleration condition) Comparative Example 2
Sorafenib Besylate Salt (VI) Example 1
Sorafenib Hemicamyl Acid start 3 months start 3 months Constellation Off-white powder Off-white powder White powder White powder moisture 0.08% 0.07% 0.07% 0.05% PXRD Pattern - Same pattern - Same pattern content(%) 100.7  98.1 99.3 99.0

From the results of the stability test, the compound prepared in Example 1 had a slight change in purity and moisture content at the start and end of the stability test, no change in the PXRD pattern, and excellent stability.

Test Example 5 Comparative Study of Pharmacokinetics in Beagle Dogs on Sorafenib Tosylate Tablet (200 mg) and the Compound-Containing Tablet Prepared in Comparative Example 1

The pharmacokinetics of beagle dogs were determined using a tablet containing a sorafenib tosylate salt as a main ingredient (Comparative Example 3) (Tablet C in US Pat. No. 9737488) and a tablet containing the compound prepared in Comparative Example 1. Compared. The main ingredient in each tablet was 200 mg of sorafenib. Tablets containing sorafenib free base were prepared by granulation by wet granulation using conventional fillers, binders, and the like, and then further mixed with a disintegrant and a lubricant, followed by compression. The components and contents of each sample are shown in Table 7 below.

Composition (mg / tablet) Tablet C
(US Patent No. 9737488) Comparative Example 1
Sorafenib Free Base
refine Example 1
Sorafenib Hemicamylate
refine Sorafenib tosylate salt (as sorafenib) 274.0
(200) - - Sorafenib Free Base - 200 - Sorafenib hemicamyl acid salt (as sorafenib) - - 250.0
(200) Microcrystalline cellulose 16.0 16.0 16.0 Croscarmellose sodium 36.4 36.4 36.4 Hypromellose 10.2 10.2 10.2 Magnesium stearate 2.55 2.55 2.55 Sodium lauryl sulfate 1.7 1.7 1.7

Each tablet was made and orally administered to beagle dogs, and the results are shown in FIG. 4 and Table 8 below.

Tablet C
(US Patent No. 9737488) Comparative Example 1
Sorafenib Free Base
refine Maximum blood concentration (Cmax, ng / mL) 2207.7 379.8 Area under the blood concentration curve (AUC _{0 ~ 24hr} , ng · hr / mL) 22870.3 3593.0

Test Example 6 Comparative Study of Pharmacokinetics in Beagle Dogs on Sorafenib Tosylate Tablets (200 mg) and Compound-Containing Tablets Prepared in Example 1

A beagle dog using a tablet containing a sorafenib tosylate salt as a main component (Comparative Tablet No. 9737488) and a compound prepared in Example 1 of Table 7 above The pharmacokinetics were compared at. Tablets were prepared in the same manner as in Test Example 5. 200 mg tablets were made orally administered to beagle dogs as sorafenib, and the results are shown in FIG. 5 and Table 9 below.

Tablet C
(US Patent No. 9737488) Example 1
Sorafenib Hemicamyl Acid
refine Maximum blood concentration (Cmax, ng / mL) 1706.8 1851.3 Area under the blood concentration curve (AUC _{0 ~ 24hr} , ng · hr / mL) 18735.1 21636.5

As mentioned above, although an embodiment of the present invention has been described, those of ordinary skill in the art may add, change, delete or add elements within the scope not departing from the spirit of the present invention described in the claims. The present invention may be modified and changed in various ways, etc., which will also be included within the scope of the present invention.

Claims (14)

4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carbox represented by the following general formula (III): Amide hemicamyl acid salts.
[Formula III]

The hemicamic acid salt according to claim 1, wherein the hemicamyl acid salt is in crystalline form. The method according to claim 2, wherein the crystal form has a 2Θ (theta) angle of 4.79 ± 0.2, 8.02 ± 0.2, 9.57 ± 0.2, 11.88 ± 0.2, 14.37 ± 0.2, 14.77 ± 0.2, and in the powder X-ray diffraction analysis (PXRD) graph Hemicamyl acid salt, characterized by the presence of diffraction peaks at 18.13 ± 0.2 degrees. The method according to claim 3, wherein the crystal form has a 2Θ (theta) angle of 4.79 ± 0.2, 7.08 ± 0.2, 8.02 ± 0.2, 9.57 ± 0.2, 10.58 ± 0.2, 11.88 ± 0.2, 12.08 in powder X-ray diffraction analysis (PXRD) graph Characterized in that diffraction peaks are present at ± 0.2, 14.37 ± 0.2, 14.77 ± 0.2, 16.21 ± 0.2, 18.13 ± 0.2, 19.36 ± 0.2, 21.29 ± 0.2, 21.87 ± 0.2, 25.42 ± 0.2 and 27.55 ± 0.2 degrees, Hemicamyl acid salts. According to claim 2, wherein the crystalline form is characterized in that the endothermic transition peak value at 200 to 230 ℃ in the differential scanning calorimetry (DSC) graph, hemicamyl acid salt. 6. The hemicamic acid salt of claim 5, wherein the crystalline form has an endothermic transition peak at 214 ± 2 ° C. in a DSC graph. (1) dissolving the compound represented by the following formula (I) in a single organic solvent or mixed solvent and reacting with camphorsulfonic acid
[Formula I]

; And
(2) cooling the mixture, removing the solvent and then drying;
A method for preparing the hemicamyl acid salt represented by the following general formula (III).
[Formula III]

8. The method of claim 7, wherein the single organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, normal propanol, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran and acetonitrile. The method characterized by the above-mentioned. The method according to claim 8, wherein the single organic solvent is one selected from the group consisting of methanol, ethanol, isopropanol, and normal propanol. The method of claim 7, wherein the mixed solvent
At least one solvent selected from the group consisting of methanol, ethanol, isopropanol, normal propanol, acetone, methyl ethyl ketone, acetonitrile, methyl acetate, ethyl acetate, tetrahydrofuran, and 2-methyl tetrahydrofuran
At least one solvent selected from the group consisting of normal heptane, normal hexane, and diisopropyl ether
It is a mixed solvent, The method characterized by the above-mentioned. The method of claim 9, wherein the mixing ratio of the organic solvent is 1: 1 to 1:20 by volume ratio. 8. The method of claim 7, wherein step (1) is performed at a temperature of 20 to 70 ° C. 8. The method of claim 7, wherein the mixture in step (2) is cooled to a temperature of 0 to 30 ° C. 8. The method according to claim 7, wherein after the cooling in the step (2), the mixture is dried at a temperature of 30 to 70 ℃.

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