WO2018145280A1 - Flt3 kinase inhibitor or crystal forms of salt thereof and preparation method therefor - Google Patents

Abstract

The present invention provides an FLT3 kinase inhibitor and crystal forms of a salt thereof and a preparation method therefor, and specifically, relates to crystal forms A, B, C, D and E of (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3, 4-d]pyrimidine-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone or mono-halate or di-halate thereof and a preparation method therefor. The crystal forms A and B of the compound and the crystal forms C and D of the mono-halate or the di-halate in the present invention have good stability for oxidation, illumination, high temperature and high humidity conditions and have good solubility in water.

Description

Crystal form of FLT3 kinase inhibitor or salt thereof and preparation method thereof Technical field

The present invention belongs to the field of chemistry, and in particular to a crystal form of a FLT3 kinase inhibitor or a salt thereof and a process for the preparation thereof.

Background technique

(R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)- 2-(Dimethylamino)ethanone is a novel inhibitor of FLT3 kinase (ie, FMS-like tyrosine kinase 3) having the following formula (I) Molecular Structure:

Chinese Patent CN105481862A describes the compound or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite, or prodrug thereof (see, Compound 22), and pharmaceutical compositions thereof for use in prevention or treatment Uses and methods of cell proliferative disorders and or FLT3-related disorders, particularly those that are responsive to inhibition by LT3 kinases, particularly FLT3/ITD mutant kinases. In addition, the preparation method and inhibition activity comparison of the compound and its derivative are described in detail.

However, CN105481862A simply mentions that the compound can be made into a pharmaceutically acceptable salt, and the process, method, and stability comparison of the salt-forming compound are not described in detail, nor the polymorph of the compound is indicated. For the compound (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl -2-(Dimethylamino)ethanone (Example 22), even without revealing the solvent for its final crystallization or crystal preparation.

In practical applications, in order to improve the stability of the drug compound and the solubility in an aqueous medium, it is generally desired to salt the compound and obtain crystals thereof.

Summary of the invention

The object according to the invention is to provide (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin Crystal forms of pyridin-1-yl)-2-(dimethylamino)ethanone or its monohaloate or dihaloate, and processes for their preparation.

According to a first aspect of the invention there is provided (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl a crystalline form of piperidin-1-yl)-2-(dimethylamino)ethanone or a monohalide or dihaloate thereof.

According to a second aspect of the invention there is provided (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl Crystalline form A of piperidin-1-yl)-2-(dimethylamino)ethanone characterized by X-ray powder diffraction at a 2θ angle of about 6.1 ± 0.2 using Cu-Kα radiation. 17.6±0.2, 18.9±0.2, 20.8±0.2, 21.9±0.2, 22.1±0.2, and 22.6±0.2 have diffraction peaks.

According to a third aspect of the invention, there is provided a method of preparing the above Form A, characterized in that the method comprises the steps of:

(1) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) with stirring Piperidin-1-yl)-2-(dimethylamino)ethanone is dissolved in at least one solvent selected from the group consisting of methanol, ethanol and acetone heated to 60 to 80 ° C;

(2) reducing the temperature of the solution obtained in the step (1) to room temperature and stirring it for 12 to 16 hours;

(3) filtering the solution obtained in the step (2), and drying the filter cake at a temperature of 45-55 ° C for 6 to 8 hours;

(4) Collect crystals.

According to a fourth aspect of the present invention, there is provided (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl Crystalline Form B of piperidin-1-yl)-2-(dimethylamino)ethanone characterized by X-ray powder diffraction at a angle of 2θ of about 6.3 ± 0.2 using Cu-Kα radiation. 16.8 ± 0.2, 17.4 ± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 20.6 ± 0.2, 22.5 ± 0.2, and 22.9 ± 0.2 have diffraction peaks.

According to a fifth aspect of the invention, there is provided a method of preparing the above Form B, characterized in that the method comprises the steps of:

(1) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) with stirring Piperidin-1-yl)-2-(dimethylamino)ethanone is dissolved in ethyl acetate heated to 60 to 70 ° C;

(2) lowering the temperature of the solution obtained in the step (1) to room temperature and stirring it for 8 to 12 hours;

(3) filtering the solution obtained in the step (2), and drying the filter cake at a temperature of 45 to 55 ° C for 6 to 8 hours;

(4) Collect crystals.

According to a sixth aspect of the invention, there is provided (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl Crystalline form C of piperidin-1-yl)-2-(dimethylamino)ethanone monohydrobromide characterized by X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation At approximately 8.7 ± 0.2, 10.1 ± 0.2, 11.7 ± 0.2, 13.2 ± 0.2, 15.5 ± 0.2, 16.2 ± 0.2, 17.3 ± 0.2, 17.7 ± 0.2, 19.2 ± 0.2, 21.4 ± 0.2, 22.2 ± 0.2, 22.8 ± 0.2, There are diffraction peaks at 23.6 ± 0.2, 27.9 ± 0.2, and 30.4 ± 0.2.

According to a seventh aspect of the present invention, there is provided a method of preparing the above Form C, characterized in that the method comprises the steps of:

(1) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 -yl)-2-(dimethylamino)ethanone is reacted with hydrobromic acid to prepare (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazole a monohydrobromide salt of [3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone;

(2) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) with stirring The monohydrobromide salt of piperidin-1-yl)-2-(dimethylamino)ethanone is dissolved in at least one selected from the group consisting of methanol, ethanol, acetone, ethyl acetate and mixtures thereof heated to 60 to 80 °C. In a solvent;

(3) lowering the temperature of the solution obtained in the step (2) to room temperature and stirring it for 6 to 8 hours;

(4) filtering the solution obtained in the step (3), and drying the filter cake at a temperature of 45 to 55 ° C for 6 to 8 hours;

(5) Collect crystals.

According to an eighth aspect of the present invention, there is provided (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl Crystalline form D of piperidin-1-yl)-2-(dimethylamino)ethanone dihydrobromide characterized by X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation At approximately 10.7 ± 0.2, 11.6 ± 0.2, 13.6 ± 0.2, 14.4 ± 0.2, 15.8 ± 0.2, 16.4 ± 0.2, 17.6 ± 0.2, 19.1 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.5 ± 0.2, 22.1 ± 0.2, There are diffraction peaks at 22.7 ± 0.2, 23.8 ± 0.2, 24.5 ± 0.2, 26.2 ± 0.2, 27.4 ± 0.2, 29.1 ± 0.2, and 30.7 ± 0.2.

According to a ninth aspect of the invention, there is provided a method of preparing the above Form D, characterized in that the method comprises the steps of:

(1) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 -yl)-2-(dimethylamino)ethanone is reacted with hydrobromic acid to prepare (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazole) a solution of [3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone dihydrobromide;

(2) concentrating the solution obtained in the step (1) and adding ethanol thereto;

(3) lowering the temperature of the solution obtained in the step (2) to room temperature and stirring it for 7 to 9 hours;

(4) filtering the solution obtained in the step (3), and drying the filter cake at a temperature of 45 to 55 ° C for 6 to 8 hours;

(5) Collect crystals.

According to a tenth aspect of the present invention, there is provided (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl Form E of the monohydrochloride salt of piperidin-1-yl)-2-(dimethylamino)ethanone characterized by the use of Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angle About 10.7 ± 0.2, 11.6 ± 0.2, 13.6 ± 0.2, 14.4 ± 0.2, 15.8 ± 0.2, 16.4 ± 0.2, 17.6 ± 0.2, 19.1 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.5 ± 0.2, 22.1 ± 0.2, 22.7 There are diffraction peaks of ±0.2, 23.8±0.2, 24.5±0.2, 26.2±0.2, 27.4±0.2, 29.1±0.2, and 30.7±0.2.

According to an eleventh aspect of the present invention, there is provided a method of preparing the above Form E, characterized in that the method comprises the steps of:

(1) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazole in a mixed solvent of ethyl acetate and ethanol in a volume ratio of 7-8 And [3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone is reacted with hydrochloric acid to prepare (R)-1-(3-(4- Single of amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone a solution of the hydrochloride;

(2) lowering the temperature of the solution obtained in the step (1) to room temperature and stirring it for 10 to 12 hours;

(3) filtering the solution obtained in the step (2), and drying the filter cake at a temperature of 45 to 55 ° C for 8 to 10 hours;

(4) Collect crystals.

Forms A and B of the compound according to the invention and crystal forms C, D and E of the monohalo or dihaloate thereof have good stability to oxidation, light, high temperature and high humidity conditions, and Good solubility in water.

Other features and advantages of the invention will be described in detail in the detailed description which follows.

DRAWINGS

Figure 1 is an X powder diffraction pattern of Form A of a compound according to the present invention;

Figure 2 is a hydrogen nuclear magnetic spectrum of Form A of the compound according to the present invention;

Figure 3 is an X powder diffraction pattern of Form B of a compound according to the present invention;

Figure 4 is an X powder diffraction pattern of Form C of a monohydrobromide salt of a compound according to the present invention;

Figure 5 is a hydrogen nuclear magnetic spectrum of Form C of a monohydrobromide salt of a compound according to the present invention;

Figure 6 is an X powder diffraction pattern of Form D of the dihydrobromide salt of the compound according to the present invention;

Figure 7 is an X powder diffraction pattern of Form E of the monohydrochloride salt of the compound according to the present invention.

detailed description

The inventors of the present invention have found that the compound of the formula (I) according to the present invention has good crystallinity and can be crystallized by a different solvent. Furthermore, the compounds of the formula (I) according to the invention belong to the class of amine compounds, ie the amino groups and tertiary amines on the piperidine ring can theoretically be combined with one or two acid counterions. Types of pharmaceutically acceptable salts include, but are not limited to, acid addition salts formed by reacting the free base form of the compound with a pharmaceutically acceptable acid, including inorganic and organic acids, for example, It is a hydrohalic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; wherein the hydrohalic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.; the organic acid includes a monobasic acid and a dibasic acid, for example, formic acid, acetic acid , propionic acid, caproic acid, methanesulfonic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, etc.; dibasic acids such as malonic acid, malic acid, succinic acid, maleic acid, tartaric acid, fumaric acid Wait. However, in terms of hygroscopicity and solubility in water, it is preferred to form a crystalline form of the monohydrobromide, dihydrobromide and monohydrochloride of the compound of formula (I). Further, from the viewpoint of stability, a crystal form of the monohydrobromide salt of the compound of the formula (I) is preferred.

Thus, according to one embodiment of the invention, (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1 is provided a crystalline form of -yl)piperidin-1-yl)-2-(dimethylamino)ethanone or a monohalide or dihaloate thereof. Preferably, the monohaloate is selected from the group consisting of monohydrobromide and monohydrochloride, and the dihaloate is a dihydrochloride.

According to another embodiment of the present invention, (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- Crystalline form A of piperidin-1-yl)-2-(dimethylamino)ethanone characterized by X-ray powder diffraction at 2θ angle using Cu-Kα radiation at about 6.1 There are diffraction peaks of ±0.2, 17.6±0.2, 18.9±0.2, 20.8±0.2, 21.9±0.2, 22.1±0.2, and 22.6±0.2. Further, the crystal form A has a hydrogen nuclear magnetic spectrum as shown in FIG. 2. The initial melting temperature of this Form A as measured by thermogravimetry (DTG) was about 128 °C.

According to another embodiment of the present invention, there is provided a method of preparing the above Form A, characterized in that the method comprises the steps of:

(1) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) with stirring Piperidin-1-yl)-2-(dimethylamino)ethanone is dissolved in at least one solvent selected from the group consisting of methanol, ethanol and acetone heated to 60 to 80 ° C;

(2) reducing the temperature of the solution obtained in the step (1) to room temperature and stirring it for 12 to 16 hours;

(3) filtering the solution obtained in the step (2), and drying the filter cake at a temperature of 45 to 55 ° C for 6 to 8 hours;

(4) Collect crystals.

According to a preferred embodiment of the invention, the solvent employed in the above process is preferably acetone.

According to another embodiment of the present invention, (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- Form B of piperidin-1-yl)-2-(dimethylamino)ethanone characterized by X-ray powder diffraction at 2θ angle of about 6.3 ± 0.2 using Cu-Kα radiation There are diffraction peaks of 16.8±0.2, 17.4±0.2, 18.6±0.2, 19.4±0.2, 20.6±0.2, 22.5±0.2 and 22.9±0.2. The initial melting temperature of this Form B as measured by thermogravimetry (DTG) was about 106 °C.

According to another embodiment of the present invention, there is provided a method of preparing the above Form B, characterized in that the method comprises the steps of:

(1) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) with stirring Piperidin-1-yl)-2-(dimethylamino)ethanone is dissolved in ethyl acetate heated to 60 to 70 ° C;

(2) lowering the temperature of the solution obtained in the step (1) to room temperature and stirring it for 10 to 12 hours;

(3) filtering the solution obtained in the step (2), and drying the filter cake at a temperature of 45 to 55 ° C for 6 to 8 hours;

(4) Collect crystals.

The above crystalline forms A and B are the compounds of formula (I) according to the invention ((R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazole) [3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone) Polymorphs obtained under different crystallization conditions.

Furthermore, the present invention also provides polymorphs of different salts of the compounds of formula (I) (for example, monohydrobromide, dihydrobromide, monohydrochloride, etc.).

According to another embodiment of the present invention, (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- Form C of the monohydrobromide salt of phenylpiperidin-1-yl)-2-(dimethylamino)ethanone characterized by the use of Cu-Kα radiation, X-ray powder expressed in 2θ angle Diffraction at about 8.7 ± 0.2, 10.1 ± 0.2, 11.7 ± 0.2, 13.2 ± 0.2, 15.5 ± 0.2, 16.2 ± 0.2, 17.3 ± 0.2, 17.7 ± 0.2, 19.2 ± 0.2, 21.4 ± 0.2, 22.2 ± 0.2, 22.8 ± 0.2 23.6±0.2, 27.9±0.2, and 30.4±0.2 have diffraction peaks. Further, the crystal form C has a hydrogen nuclear magnetic spectrum as shown in FIG. The initial melting temperature of this Form C as measured by thermogravimetry (DTG) was about 236 °C.

According to another embodiment of the present invention, there is provided a process for the preparation of Form C of the above monohydrobromide salt, characterized in that the process comprises the steps of:

(1) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 -yl)-2-(dimethylamino)ethanone is reacted with hydrobromic acid to prepare (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazole a monohydrobromide salt of [3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone;

(2) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) with stirring The monohydrobromide salt of piperidin-1-yl)-2-(dimethylamino)ethanone is dissolved in at least one selected from the group consisting of methanol, ethanol, acetone, ethyl acetate and mixtures thereof heated to 60 to 80 °C. In a solvent;

(3) lowering the temperature of the solution obtained in the step (2) to room temperature and stirring it for 6 to 8 hours;

(4) filtering the solution obtained in the step (3), and drying the filter cake at a temperature of 45 to 55 ° C for 6 to 8 hours;

(5) Collect crystals.

According to certain preferred embodiments of the invention, the solvent employed in the above process is methanol. According to certain preferred embodiments of the invention, the solvent employed in the above process is ethanol. According to certain preferred embodiments of the invention, the solvent employed in the above process is acetone. According to certain preferred embodiments of the invention, the solvent employed in the above process is a mixture of 3-5 times by volume of ethyl acetate/methanol. According to certain preferred embodiments of the invention, the solvent employed in the above process is a mixture of acetone to methanol in a volume ratio of 3-5 times.

According to another embodiment of the invention, (R)-1-(3-(4-amino-(4-phenoxybenzene) is provided Form D of the dihydrobromide salt of -1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone, Characterized in that, using Cu-Kα radiation, the X-ray powder diffraction expressed in terms of 2θ angle is about 10.7±0.2, 11.6±0.2, 13.6±0.2, 14.4±0.2, 15.8±0.2, 16.4±0.2, 17.6±0.2, 19.1±0.2, 19.8±0.2, 20.7±0.2, 21.5±0.2, 22.1±0.2, 22.7±0.2, 23.8±0.2, 24.5±0.2, 26.2±0.2, 27.4±0.2, 29.1±0.2 and 30.7±0.2 have diffraction peaks .

According to another embodiment of the present invention, there is provided a process for the preparation of the crystalline form D of the above dihydrobromide salt, characterized in that the process comprises the steps of:

(1) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 -yl)-2-(dimethylamino)ethanone is reacted with hydrobromic acid to prepare (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazole) a solution of [3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone dihydrobromide;

(2) concentrating the solution obtained in the step (1) and adding ethanol thereto;

(3) lowering the temperature of the solution obtained in the step (2) to room temperature and stirring it for 7 to 9 hours;

(4) filtering the solution obtained in the step (3), and drying the filter cake at a temperature of 45 to 55 ° C for 6 to 8 hours;

(5) Collect crystals.

According to another embodiment of the present invention, (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- Form E of monohydrochloride of phenyl)piperidin-1-yl)-2-(dimethylamino)ethanone characterized by X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation At approximately 10.7 ± 0.2, 11.6 ± 0.2, 13.6 ± 0.2, 14.4 ± 0.2, 15.8 ± 0.2, 16.4 ± 0.2, 17.6 ± 0.2, 19.1 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.5 ± 0.2, 22.1 ± 0.2, There are diffraction peaks at 22.7 ± 0.2, 23.8 ± 0.2, 24.5 ± 0.2, 26.2 ± 0.2, 27.4 ± 0.2, 29.1 ± 0.2, and 30.7 ± 0.2. The initial melting temperature of this Form E as measured by thermogravimetry (DTG) was about 225 °C.

According to another embodiment of the present invention, there is provided a process for the preparation of Form E of the above monohydrochloride salt, characterized in that the process comprises the steps of:

(1) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazole in a mixed solvent of ethyl acetate and ethanol in a volume ratio of 7-8 And [3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone is reacted with hydrochloric acid to prepare (R)-1-(3-(4- Single of amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone a solution of the hydrochloride;

(2) lowering the temperature of the solution obtained in the step (1) to room temperature and stirring it for 10 to 12 hours Time;

(3) filtering the solution obtained in the step (2), and drying the filter cake at a temperature of 45 to 55 ° C for 8 to 10 hours;

(4) Collect crystals.

Example

The following experiments were provided to illustrate the invention. They should not be considered as limiting the scope of the invention, but merely as a representative thereof. According to the present invention, the amount indicated by "%" is calculated by weight unless otherwise indicated.

testing method

X-ray powder diffraction measurement

Using DX-27miniX-powder diffractometer, using step test method, starting angle of 3°, 40° is the end angle, 0.02 is the step angle, the tube voltage is 35kv, the tube current is 15mA, weigh 0.3g The sample is placed on a glass slide and placed in a neatly placed instrument for testing and mapping data.

Hydrogen nuclear magnetic spectroscopy ( ¹ HNMR) measurement

A BRUKER AV-300 nuclear magnetic resonance apparatus was used, and about 5 mg of the sample was weighed and dissolved in deuterated DMSO as a solvent, and the spectrum was tested and recorded.

Measurement of the initial melting temperature according to the thermogravimetric method

The melting point test was carried out using a DTG-60A thermogravimetric analyzer. Approximately 5 mg of the sample was placed in an aluminum crucible. The instrument was equilibrated and read. The test was started at a starting temperature of 30 ° C and a heating rate of 10 ° C / min to 300 ° C. At the end of the test, the map data is read and recorded.

Example 1 - Preparation of Form A of Compound of Formula (I) Using Methanol as Crystallization Solvent

2 g of the compound of the formula (I) was weighed and added to 14 ml of methanol, and the mixture was heated and stirred to dissolve. The solution was then cooled to room temperature and stirred for 12 to 16 h. The solution was then filtered and the filter cake was transferred to a blast oven at 50 ° C for 6 to 8 h to give 1.1 g of a white powdery solid. The yield of the white powdery solid was 55% by weight, and the melting point measured by differential thermal analysis (DTA) was 129 ° C to 131 ° C. Further, the crystal form formed by the X-ray powder diffraction method was crystal form A, and the X-ray powder diffraction data is shown in Table 1 below.

Table 1

Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%	Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%
1	6.181	14.288	100	13	22.140	4.012	63.9
2	10.480	8.434	14.5	14	22.680	3.917	40
3	11.260	7.852	16.0	15	23.159	3.838	9.8
4	12.440	7.109	7.6	16	24.058	3.696	5.7
5	13.020	6.794	6.0	17	26.339	3.381	14.1
6	13.981	6.329	6.2	18	27.361	3.257	3.3
7	14.889	5.941	13.5	19	28.121	3.171	3.5
8	16.781	5.279	31.2	20	28.761	3.102	5.3
9	17.680	5.012	47.1	twenty one	30.820	2.899	5.9
10	19.099	4.643	48.7	twenty two	31.340	2.852	8.5
11	19.960	4.444	14.5	twenty three	32.457	2.756	1.4
12	20.840	4.259	53.7	twenty four	36.040	2.490	2.4

Example 2 - Preparation of Form A of Compound of Formula (I) Using Ethanol as Crystallization Solvent

2 g of the compound of the formula (I) was weighed and added to 6 ml of ethanol, and the mixture was heated and stirred to dissolve. The solution was then cooled to room temperature and stirred for 16 to 18 h. The solution was then filtered and the filter cake was transferred to a blast oven at 50 ° C for 6 to 8 h to give 1.32 g of a white powdery solid. The yield of the white powdery solid was 66%, and the melting point measured by differential thermal analysis (DTA) was 129 ° C to 131 ° C. Further, as measured by X-ray powder diffraction, it was revealed that the crystal form formed was Form A, and the X-ray powder diffraction pattern is shown in Table 2 below.

Table 2

Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%	Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%
1	6.121	14.431	100	13	20.780	4.271	90.3
2	10.36	8.532	19.2	14	21.961	4.044	78.8
3	11.120	7.950	18.2	15	22.540	3.941	52.0
4	12.399	7.133	8.3	16	23.920	3.717	11.8
5	12.941	6.835	8.6	17	25.020	3.556	7.6

6	13.881	6.375	9.2	18	26.200	3.398	21.5
7	14.780	5.989	32.6	19	27.360	3.257	9.2
8	15.921	5.562	5.6	20	28.079	3.175	10.9
9	16.681	5.310	24.1	twenty one	28.759	3.102	8.1
10	17.580	5.040	70.8	twenty two	31.260	2.852	8.1
11	18.960	4.677	73.6	twenty three	32.323	2.767	2.1
12	19.920	4.453	26.9	twenty four	35.980	2.494	3.6

Example 3 - Preparation of Form A of Compound of Formula (I) Using Acetone as Crystallization Solvent

2 g of the compound of the formula (I) was weighed and added to 10 ml of acetone, and the mixture was heated and stirred to dissolve. The solution was then cooled to room temperature and stirred for 16 h. The solution was then filtered and the filter cake was transferred to a blast oven at 50 ° C for 6 h to give 1.73 g of a white powdery solid. The yield of the white powdery solid was 86.5%, and the melting point measured by differential thermal analysis (DTA) was 129 ° C to 131 ° C. Further, the crystal form formed by the X-ray powder diffraction method was crystal form A. The X-ray powder diffraction pattern is shown in Table 3 below.

table 3

Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%	Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%
1	6.218	14.202	100	12	20.000	4.436	30.9
2	9.220	9.584	2.3	13	20.860	4.255	97.2
3	10.460	8.451	25.1	14	22.080	4.022	83.9
4	11.259	7.852	20.1	15	22.700	3.914	58.0
5	12.459	7.098	7.2	16	23.961	3.711	11.1
6	12.980	6.815	8.9	17	26.260	3.391	14.4
7	13.979	6.330	11.2	18	27.361	3.257	3.8
8	14.840	5.965	34.9	19	28.042	3.179	5.8
9	16.781	5.279	25.9	20	28.885	3.088	3.5
10	17.700	5.007	74.8	twenty one	31.279	2.857	7.8
11	19.100	4.643	75.8	twenty two	35.981	2.494	3.8

Example 4 - Preparation of Form B of Compound of Formula (I) Using Ethyl Acetate as Crystallization Solvent

2 g of the compound of the formula (I) was weighed and added to 40 ml of ethyl acetate, and the mixture was heated and stirred to dissolve. The solution was then cooled to room temperature and stirred for 10 h. The solution was then filtered and the filter cake was transferred to a blast oven at 50 ° C for 6 h to give 1.65 g of a white powdery solid. The yield of the white powdery solid was 82.5%, and the melting point measured by differential thermal analysis (DTA) was higher than 106 ° C. Further, as determined by X-ray powder diffraction, the resulting crystal form was crystal form B, X-ray. The powder diffraction pattern is shown in Table 4 below.

Table 4

Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%	Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%
1	6.300	14.018	100	11	20.619	4.304	42.6
2	9.721	9.091	22.3	12	21.540	4.122	20.5
3	10.578	8.356	9.3	13	22.540	3.914	33.1
4	12.701	6.964	8.4	14	22.999	3.864	24.5
5	13.520	6.544	6.6	15	24.860	3.579	11.7
6	15.901	5.569	8.3	16	25.901	3.437	10.1
7	16.859	5.255	46.3	17	27.419	3.250	5.0
8	17.440	5.081	37.5	18	29.442	3.031	5.7
9	18.600	4.767	27.6	19	33.060	2.707	1.7
10	19.440	4.562	28.7	20	35.701	2.513	2.0

Example 5 - Preparation of a monohydrobromide salt of a compound of formula (I)

30 g of the compound of the formula (I) was weighed and added to 90 ml of ethyl acetate, and the solution was heated to dissolve to prepare a free base solution. 12 g of hydrobromic acid was added to 30 ml of ethanol to dilute, and then the diluted hydrobromic acid solution was slowly added dropwise to the above free alkali solution, and a large amount of white solid was gradually precipitated. The system was stirred for 6 hours, filtered, and the filter cake was transferred to a blast oven at 50 ° C for 8 hours to give 30.2 g of a white powdery solid. The yield of the white powdery solid was 86%, and the melting point measured by differential thermal analysis (DTA) was higher than 236 °C. In the above method, the content of the bromide ion is titrated with a silver nitrate titration solution, and potassium chromate is used as a color developer.

Example 6 - Preparation of Form C of Monohydrobromide Salt of Compound of Formula (I) Using Methanol as Crystallization Solvent

5 g of the monohydrobromide salt of the compound of the formula (I) prepared in the above Example 5 was weighed and added to 20 ml of methanol at 60 ° C, and dissolved by heating. Then, the mixture was slowly cooled to room temperature and stirred to crystallize, and a large amount of white solid was gradually precipitated in the system, followed by stirring for 6 hours. The solution was then filtered and the filter cake was transferred to a blast oven at 50 ° C for 8 hours to give 2.7 g of a white powdery solid. The yield of the white powdery solid was 54%, and the melting point measured by differential thermal analysis (DTA) was higher than 236 °C. Further, as measured by X-ray powder diffraction, it was revealed that the crystal form formed was Form C, and the X powder diffraction pattern is shown in Table 5 below.

table 5

Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%	Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%
1	8.202	10.772	2.9	19	25.860	3.442	10.8
2	8.961	9.861	7.5	20	27.221	3.273	20.6
3	10.378	8.516	16.8	twenty one	28.179	3.164	19.9
4	11.936	7.408	2.2	twenty two	28.538	3.125	13.7
5	13.460	6.573	16.6	twenty three	29.061	3.070	8.8
6	14.693	6.024	2.0	twenty four	29.660	3.009	4.8
7	15.777	5.612	10.6	25	30.641	2.915	30.0
8	16.400	5.401	34.4	26	31.460	2.841	18.8
9	16.736	5.293	25.8	27	32.459	2.756	13.8
10	17.500	5.063	48.0	28	34.178	2.621	8.2
11	18.520	4.787	39.4	29	34.679	2.585	3.7
12	19.360	4.581	54.2	30	35.462	2.529	3.1
13	20.801	4.267	15.3	31	36.077	2.488	2.9
14	21.580	4.115	100	32	36.680	2.448	3.9
15	22.301	3.983	55.7	33	37.200	2.415	4.2
16	23.059	3.853	55.8	34	38.239	2.352	5.7
17	23.701	3.751	32.4	35	39.256	2.293	3.2
18	25.021	3.556	9.7

Example 7 - Preparation of Form C of Monohydrobromide Salt of Compound of Formula (I) Using Ethanol as Crystallization Solvent

5 g of the monohydrobromide salt of the compound of the formula (I) prepared in the above Example 5 was weighed and added to 50 ml of ethanol at 60 ° C, and dissolved by heating. Then, the mixture was slowly cooled to room temperature and stirred to crystallize, and a large amount of white solid was gradually precipitated in the system, followed by stirring for 6 hours. The solution was then filtered and the filter cake was transferred to a blast oven at 50 ° C for 8 hours to give 4.1 g of a white powdery solid. The yield of the white powdery solid was 82%, and the melting point measured by differential thermal analysis (DTA) was higher than 236 °C. In addition,

The crystal form formed by the X-ray powder diffraction method was crystal form C, and the X powder diffraction pattern is shown in Table 6 below.

Table 6

Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%	Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%
1	8.045	10.981	4.1	19	23.561	3.773	38.3
2	8.819	10.019	20.4	20	24.899	3.573	10.6
3	10.219	8.650	28.6	twenty one	25.721	3.461	14.0
4	11.820	7.481	2.4	twenty two	26.081	3.414	9.2
5	13.299	6.652	38.1	twenty three	26.841	3.319	16.2
6	14.945	5.923	2.1	twenty four	27.360	3.257	11.3
7	15.582	5.683	11.9	25	27.982	3.186	16.6
8	16.239	5.454	38.6	26	28.398	3.140	9.9
9	16.780	5.279	24.2	27	28.922	3.081	3.8
10	17.302	5.121	53.9	28	30.481	2.930	27.3
11	17.797	4.980	49.3	29	31.310	2.855	16.3
12	18.380	4.823	45.3	30	31.640	2.826	9.4
13	19.219	4.614	72.2	31	32.301	2.769	7.9
14	20.339	4.363	7.9	32	32.640	2.743	7.6
15	20.641	4.299	11.7	33	33.621	2.664	4.3
16	21.439	4.141	100.0	34	34.000	2.635	6.4
17	22.201	4.001	58.2	35	35.282	2.542	3.5
18	22.919	3.877	50.0	36	36.445	2.463	2.4

Example 8 - Preparation of a compound of the formula (I) using a methanol/ethyl acetate mixed solvent as a crystallization solvent Form C of hydrobromide

5 g of the monohydrobromide salt of the compound of the formula (I) prepared in the above Example 5 was weighed and added to a mixed solvent of 10 ml of methanol and 40 ml of ethyl acetate at 60 ° C, and dissolved by heating. Then, the mixture was slowly cooled to room temperature and stirred to crystallize, and a large amount of white solid was gradually precipitated in the system, followed by stirring for 6 hours. The solution was then filtered and the filter cake was transferred to a blast oven at 50 ° C for 8 hours to give 3.8 g of a white powdery solid. The yield of the white powdery solid was 76%, and the melting point measured by differential thermal analysis (DTA) was higher than 236 °C. Further, as measured by X-ray powder diffraction, it was revealed that the crystal form formed was Form C, and the X powder diffraction pattern is shown in Table 7 below.

Table 7

Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%	Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%
1	8.144	10.847	5.0	19	23.681	3.754	35.5
2	8.956	9.866	11.9	20	25.021	3.556	11.3
3	10.339	8.549	23.2	twenty one	25.823	3.447	13.6
4	11.915	7.422	2.8	twenty two	27.142	3.283	18.3
5	13.400	6.602	25.1	twenty three	28.121	3.171	20.7
6	15.080	5.870	3.5	twenty four	28.579	3.121	13.6
7	15.721	5.632	11.2	25	29.061	3.070	8.7
8	16.340	5.420	36.0	26	30.640	2.915	28.5
9	16.676	5.312	27.9	27	31.400	2.847	16.1
10	17.422	5.086	50.3	28	31.798	2.812	8.8
11	17.861	4.962	35.3	29	32.381	2.763	10.4
12	18.481	4.797	41.9	30	32.798	2.728	9.2
13	19.339	4.586	59.8	31	33.758	2.653	4.0
14	20.421	4.345	10.4	32	34.101	2.627	4.8
15	20.861	4.255	14.9	33	35.422	2.532	2.8
16	21.559	4.119	100.0	34	35.955	2.493	4.2
17	22.300	3.983	58.3	35	36.617	2.452	4.6
18	23.038	3.857	59.9	36	37.120	2.463	2.4

Example 9 - Preparation of a monohydrobromo compound of the compound of formula (I) using a methanol/acetone mixed solvent as a crystallization solvent Acid crystal form C

5 g of the monohydrobromide salt of the compound of the formula (I) prepared in the above Example 5 was weighed and added to a mixed solvent of 10 ml of methanol and 40 ml of acetone at 60 ° C, and the solution was heated and dissolved. Then, the mixture was slowly cooled to room temperature and stirred to crystallize, and a large amount of white solid was gradually precipitated in the system, followed by stirring for 6 hours. The solution was then filtered and the filter cake was transferred to a blast oven at 50 ° C for 8 hours to give 4.3 g of a white powdery solid. The yield of the white powdery solid was 86%, the melting point measured by differential thermal analysis (DTA) was higher than 236 ° C, and further, the crystal form formed by the X-ray powder diffraction method was crystal form C, X. The powder diffraction pattern is shown in Table 8 below.

Table 8

Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%	Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%
1	8.045	10.981	4.1	19	23.561	3.773	38.3
2	8.819	10.019	20.4	20	24.899	3.573	10.6
3	10.219	8.650	28.6	twenty one	25.721	3.461	14.0
4	11.820	7.481	2.4	twenty two	26.081	3.414	9.2
5	13.299	6.652	38.1	twenty three	26.841	3.319	16.2
6	14.945	5.923	2.1	twenty four	27.360	3.257	11.3
7	15.582	5.683	11.9	25	27.982	3.186	16.6
8	16.239	5.454	38.6	26	28.398	3.140	9.9
9	16.780	5.279	24.2	27	28.922	3.081	3.8
10	17.302	5.121	53.9	28	30.481	2.930	27.3
11	17.797	4.980	49.3	29	31.310	2.855	16.3
12	18.380	4.823	45.3	30	31.640	2.826	9.4
13	19.219	4.614	72.2	31	32.301	2.769	7.9
14	20.339	4.363	7.9	32	32.640	2.743	7.6
15	20.641	4.299	11.7	33	33.621	2.664	4.3
16	21.439	4.141	100.0	34	34.000	2.635	6.4
17	22.201	4.001	58.2	35	35.282	2.542	3.5
18	22.919	3.877	50.0	36	36.445	2.463	2.4

Example 10 - Preparation of the crystalline form D of the dihydrobromide salt of the compound of formula (I)

9 g of the compound of the formula (I) was weighed and added to 27 ml of ethyl acetate, and the solution was heated to dissolve to prepare a free base solution. Then, 7.75 g of hydrobromic acid was added to 20 ml of ethanol for dilution. The diluted hydrobromic acid solution was slowly added dropwise to the free base solution. The system clarified that solids could not be precipitated. The system was transferred to a concentration of 65 ° C, concentrated by adding 200 ml of ethanol, and then concentrated. The mixture was stirred for 8 hours by adding 100 ml of ethanol, and a large amount of white solid was gradually precipitated. The solution was then filtered and the filter cake was transferred to a blast oven at 50 ° C for 6 hours to give 4.6 g of a white powdery solid. The yield of the white powdery solid was 38%. The content of bromide ions was titrated with a silver nitrate titration solution, and potassium chromate was used as a color developer. Further, as measured by X-ray powder diffraction, it was revealed that the crystal form formed was Form D, and the X powder diffraction pattern is shown in Table 9 below.

Table 9

Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%	Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%
1	10.761	8.215	17.6	13	22.677	3.918	41.6
2	11.560	7.649	31.7	14	23.100	3.847	32.1
3	13.641	6.486	92.0	15	23.893	3.729	42.8
4	14.359	6.163	36.4	16	24.480	3.633	32.1
5	15.840	5.590	61.2	17	26.201	3.399	42.8
6	16.439	5.388	29.0	18	27.358	3.257	60.0
7	17.621	5.029	69.7	19	28.680	3.110	98.4
8	19.120	4.638	100.0	20	29.121	3.064	11.5
9	19.820	4.476	39.9	twenty one	30.154	2.961	29.2
10	20.740	4.279	30.1	twenty two	30.681	2.912	6.2
11	21.479	4.134	49.8	twenty three	31.940	2.799	24.1
12	22.059	4.026	21.4	twenty four	33.194	2.697	6.2

Example 11 - Preparation of Form E of Monohydrochloride of Compound of Formula (I)

5 g of the compound of the formula (I) was weighed and added to 30 ml of ethanol, and dissolved by heating to prepare a free base solution. A solution of 7 mol/l of HCl in ethyl acetate (1.3 ml) was added to 10 ml of ethyl acetate for dilution. The diluted hydrochloric acid solution is slowly added dropwise to the above free alkali solution, and then added Into 1 ml of water. The obtained mixture was heated and dissolved, and stirred at room temperature overnight to precipitate a white solid. The solution was then filtered and the filter cake was transferred to a blast oven at 50 ° C for 8 hours to give 3.98 g of a white powdery solid. The yield of the white powdery solid was 74%, and the melting point measured by differential thermal analysis (DTA) was higher than 225 °C. The content of chloride ions was titrated with a silver nitrate titration solution, and potassium chromate was used as a color developer. Further, as measured by X-ray powder diffraction, it was revealed that the crystal form formed was Form E, and the X powder diffraction pattern is shown in Table 10 below.

Table 10

Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%	Peak number	Diffraction angle 2θ (°)	D-spacing	Relative Strength%
1	4.418	19.983	36.0	20	24.899	3.373	10.6
2	8.121	10.878	4.3	twenty one	25.721	3.460	14.0
3	10.281	8.597	28.0	twenty two	26.081	3.414	9.2
4	11.841	7.468	2.7	twenty three	26.841	3.319	16.2
5	13.639	6.488	14.3	twenty four	27.360	3.257	11.3
6	14.679	6.030	14.8	25	27.982	3.186	16.6
7	15.100	5.863	15.9	26	28.398	3.140	9.9
8	15.721	5.633	28.2	27	28.922	3.084	3.8
9	16.360	5.414	19.1	28	30.381	2.930	27.3
10	16.739	5.292	26.7	29	31.301	2.769	16.3
11	17.480	5.069	45.6	30	31.640	2.826	9.4
12	18.539	4.782	55.1	31	32.301	2.769	7.9
13	19.340	4.586	51.2	32	32.621	2.742	7.6
14	20.720	4.283	29.6	33	33.621	2.663	4.3
15	20.641	4.299	11.7	34	34.237	2.617	2.5
16	21.439	4.141	100.0	35	35.368	2.536	1.8
17	22.201	4.001	58.2	36	36.780	2.442	3.0
18	22.919	3.877	50.0	37	37.192	2.416	2.5
19	23.561	3.773	38.3	38	38.461	2.338	3.3

Performance Testing

Stability

The present inventors have found that the compound of the formula (I) has good crystallinity and is easy to purify, but has disadvantages in that it is poor in resistance to light and oxidation, and it is easy to form an oxide, thereby further degrading into other impurities. In the present invention, the salt can be greatly improved in stability against oxidation, light, high temperature and high humidity after being formed into a salt. For this reason, the stability of the compound of the formula (I) and its hydrobromide salt (hereinafter collectively referred to as the sample to be tested) under light, oxidation, high temperature and high humidity conditions were examined.

The illumination, oxidation, high temperature and high humidity tests according to the invention were carried out according to the following methods:

Light experiment

Weigh two samples of each sample, each 15mg, accurately weighed, put one of them in a 50ml volumetric flask, add 50% acetonitrile to dissolve, and then take two samples in SHH-150GD drug light test chamber In the instrument, it was destroyed at a light intensity of 5000 LX for 10 days, and then fixed with 50% acetonitrile to destroy the sample as a light. Precisely measure 20 μl of light to destroy the sample and inject it into a liquid chromatograph (LC-20AD high performance liquid chromatograph equipped with SPD-M20A type detector SIL-20A autosampler, Shimadzu Corporation, Japan) for measurement. Record the chromatogram.

Oxidation experiment

Weigh 15 mg of each sample to be tested, place it in a 10 ml volumetric flask, add 1 ml of 30% hydrogen peroxide solution, place for 4 hours, then add 50% acetonitrile to dissolve and dilute to the mark, shake well, and use as an oxidative destruction sample solution. Accurately transfer 0.1 ml of the above oxidative destruction sample solution, place it in a 10 ml volumetric flask, dilute to the mark with a solvent, and shake it to obtain a detection solution. Precisely measure 20μl of detection solution and inject it into liquid chromatograph (LC-20AD high performance liquid chromatograph with SPD-M20A detector SIL-20A autosampler, Shimadzu Corporation, Japan) for measurement and record chromatogram .

High temperature experiment

200 mg of each sample to be tested was weighed and placed in a weighing bottle, and destroyed in a DHG-9010-2SA electrothermal constant temperature blast drying oven (Shanghai Sanfa Scientific Instrument Co., Ltd.) at 60 ° C for 6 hours. Then, 15 mg of each sample to be tested was accurately weighed, placed in a 50 ml volumetric flask, dissolved in 50% acetonitrile and diluted to the mark to serve as a high temperature destruction sample. Precisely measure 20μl of high temperature destruction sample and inject it into liquid chromatograph (LC-20AD high performance liquid chromatograph with SPD-M20A detector SIL-20A autosampler, Shimadzu Corporation, Japan) for measurement and recording. Chromatogram.

High humidity experiment

8.35 mg of the sample to be tested was accurately weighed and placed in a petri dish, and placed in a vessel having a humidity of 92.5% for 7 days, dissolved in a solvent and diluted to a mark, and shaken to destroy the sample solution as a high humidity. Precisely measure 20μl of high-humidity damage sample solution and inject it into liquid chromatograph (LC-20AD high performance liquid chromatograph with SPD-M20A detector SIL-20A autosampler, Shimadzu Corporation, Japan) , record the chromatogram.

The results of the measurement of the compound of the formula (I) and its hydrobromide salt according to the above method are shown in Table 11 below.

Table 11

Remarks: "--" means not suitable; "nd" means not checked out

From the results in Table 11 above, it is known that the compound of the formula (I) is unstable under light and oxidation conditions, and the hydrobromide salt of the compound of the formula (I) is a more stable salt type, which improves chemical stability and physicochemical properties. Suitable for long-term storage and manufacture of pharmaceuticals.

In the present invention, the stability and dissolution residual of the crystalline form A and the crystalline form B of the compound of the formula (I) according to the present invention were investigated according to the methods listed above, and the results are shown in Table 12 below.

Table 12

As can be seen from the above Table 12, the comparison is made in terms of stability: the crystal form B of the compound of the formula (I) is more stable than the crystal form A; compared with the solubility residue: the crystal form A and the crystal form B of the compound of the formula (I) The solvate is more easily formed and the drying is not removed.

According to an embodiment of the present invention, the hygroscopicity of various samples subjected to 24 hours under different humidity was also investigated. The specific results are shown in Table 13 below. It was further found by the wettability data that the monohydrobromide salt in the hydrohalide salt has almost no hygroscopicity, the monohydrochloride salt is slightly hygroscopic, and the hydroiodide solid is extremely deliquescent.

Table 13

From the above results, it is preferred that the hydrochloride, hydrobromide salt be a stable salt form, and most preferably the hydrobromide salt is a stable salt form. The present invention provides data on the related physical and chemical properties of the compound monohydrochloride of the formula (I), the monohydrobromide salt of the compound of the formula (I), the dihydrobromide salt of the compound of the formula (I), wherein the salt is formed by the molar equivalent of the acid. The pH, solubility, etc. of the post solids were compared. The specific data are shown in Table 14 below.

Table 14

name	Amount of acid a	Solid pH	Acid number identification b
Compound of formula (I) monohydrochloride	0.95	5.7	Consume 1 equivalent of silver nitrate
Compound dihydrochloride of formula (I)	2.0	3.30	Consume 2 equivalents of silver nitrate
Compound (I) compound monohydrobromide	0.95	5.0-5.5	Consume 1 equivalent of silver nitrate
Compound dihydrobromide salt of formula (I)	2.0	2.8	Consume 2 equivalents of silver nitrate

Remarks: "a" represents the molar amount relative to the compound of formula (I); "b" represents the titration of the halogen atom using a silver nitrate calibration solution.

2. Solubility

The appropriate amount of the sample to be tested was placed in water, ethanol, methanol, ethyl acetate and acetone at 25 + 2 ° C and shaken vigorously for 30 seconds while observing the dissolution. When there are no visible solute particles, It is considered to be completely dissolved.

The results according to the above experimental methods are shown in Table 15 below:

Table 15

As can be seen from Table 15 above, the solubility of the hydrochloride salt of the compound of the formula (I) and the hydrobromide salt in the aqueous medium is greatly improved as compared with the compound of the formula (I), and substantially unchanged in the methanol medium, in the ethyl acetate and acetone medium. The solubility in the medium is much lower than that of the compound of formula (I).

The preferred embodiments of the present invention have been described in detail above with reference to the accompanying drawings, but the invention is not limited In the specific details of the above-described embodiments, various simple modifications can be made to the technical solutions of the present invention within the scope of the technical idea of the present invention, and these simple modifications are all within the scope of the present invention.

It should be further noted that the specific technical features described in the above specific embodiments may be combined in any suitable manner without contradiction. To avoid unnecessary repetition, the present invention has various possibilities. The combination method will not be described separately.

In addition, any combination of various embodiments of the invention may be made as long as it does not deviate from the idea of the invention, and it should be regarded as the disclosure of the invention.

Claims (22)

1. (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)- Crystal form of 2-(dimethylamino)ethanone or its monohaloate or dihaloate.
2. (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)peridine according to claim 1. a crystalline form of pyridin-1-yl)-2-(dimethylamino)ethanone or a monohalide or dihalide thereof, characterized in that the monohaloate is selected from the group consisting of monohydrobromide salts and Monohydrochloride salt, and the dihaloate salt is a dihydrochloride salt.
3. (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)- Form A of 2-(dimethylamino)ethanone characterized by X-ray powder diffraction at 2θ angles of about 6.1 ± 0.2, 17.6 ± 0.2, 18.9 ± 0.2, 20.8 using Cu-Kα radiation. There are diffraction peaks of ±0.2, 21.9±0.2, 22.1±0.2, and 22.6±0.2.
4. (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)peridine according to claim 3 Form A of pyridin-1-yl)-2-(dimethylamino)ethanone, characterized in that the crystal form A has a hydrogen nuclear magnetic spectrum as shown in FIG.
5. (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)peridine according to claim 3 Form A of pyridin-1-yl)-2-(dimethylamino)ethanone, characterized in that the initial melting temperature of the crystalline form A is about 128 °C.
6. A preparation of (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-] according to any one of claims 3 to 5. Process for the preparation of Form A of pyrimido-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone, characterized in that the process comprises the steps of:

   (1) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) with stirring Piperidin-1-yl)-2-(dimethylamino)ethanone is dissolved in at least one solvent selected from the group consisting of methanol, ethanol and acetone heated to 60 to 80 ° C;

   (2) reducing the temperature of the solution obtained in the step (1) to room temperature and stirring it for 12 to 16 hours;

   (3) filtering the solution obtained in the step (2), and drying the filter cake at a temperature of 45 to 55 ° C for 6 to 8 hours;

   (4) Collect crystals.
7. Preparation of (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) according to claim 6 Method for crystal form A of piperidin-1-yl)-2-(dimethylamino)ethanone, characterized In that the solvent is acetone.
8. (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)- Form B of 2-(dimethylamino)ethanone characterized by X-ray powder diffraction at 2θ angles of about 6.3 ± 0.2, 16.8 ± 0.2, 17.4 ± 0.2, 18.6 using Cu-Kα radiation. There are diffraction peaks of ±0.2, 19.4±0.2, 20.6±0.2, 22.5±0.2, and 22.9±0.2.
9. (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)peridine according to claim Form B of pyridin-1-yl)-2-(dimethylamino)ethanone, characterized in that the initial melting temperature of Form B is about 106 °C.
10. A preparation of (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine according to claim 8 or 9 - Process for the crystalline form B of 1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone, characterized in that the process comprises the steps of:

    (1) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) with stirring Piperidin-1-yl)-2-(dimethylamino)ethanone is dissolved in ethyl acetate heated to 60 to 70 ° C;

    (2) lowering the temperature of the solution obtained in the step (1) to room temperature and stirring it for 8 to 12 hours;

    (3) filtering the solution obtained in the step (2), and drying the filter cake at a temperature of 45 to 55 ° C for 6 to 8 hours;

    (4) Collect crystals.
11. (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)- Form C of monohydrobromide salt of 2-(dimethylamino)ethanone characterized by X-ray powder diffraction at 2θ angle using Cu-Kα radiation at about 8.7 ± 0.2, 10.1 ± 0.2 11.7±0.2, 13.2±0.2, 15.5±0.2, 16.2±0.2, 17.3±0.2, 17.7±0.2, 19.2±0.2, 21.4±0.2, 22.2±0.2, 22.8±0.2, 23.6±0.2, 27.9±0.2 and 30.4 ±0.2 has a diffraction peak.
12. (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)peridine according to claim 11 Form C of the monohydrobromide salt of pyridin-1-yl)-2-(dimethylamino)ethanone, characterized in that the crystal form C has a hydrogen nuclear magnetic spectrum as shown in FIG.
13. (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)peridine according to claim 11 Form C of the monohydrobromide salt of pyridin-1-yl)-2-(dimethylamino)ethanone, characterized in that the initial melting temperature of the Form C is about 236 °C.
14. A preparation of (R)-1-(3-(4-amino-(4-) according to any one of claims 11 to 13 Monohydrobromide salt of phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone A method of Form C, characterized in that the method comprises the following steps:

    (1) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 -yl)-2-(dimethylamino)ethanone is reacted with hydrobromic acid to prepare (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazole a monohydrobromide salt of [3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone;

    (2) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) with stirring The monohydrobromide salt of piperidin-1-yl)-2-(dimethylamino)ethanone is dissolved in at least one selected from the group consisting of methanol, ethanol, acetone, ethyl acetate and mixtures thereof heated to 60 to 80 °C. In a solvent;

    (3) lowering the temperature of the solution obtained in the step (2) to room temperature and stirring it for 6 to 8 hours;

    (4) filtering the solution obtained in the step (3), and drying the filter cake at a temperature of 45 to 55 ° C for 6 to 8 hours;

    (5) Collect crystals.
15. (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)peridine according to claim Process for crystal form C of monohydrobromide salt of pyridin-1-yl)-2-(dimethylamino)ethanone, characterized in that the solvent is ethyl acetate/methanol in a volume ratio of 7-8 mixture.
16. (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)peridine according to claim Process for crystal form C of monohydrobromide salt of pyridin-1-yl)-2-(dimethylamino)ethanone, characterized in that the solvent is a mixture of acetone/methanol in a volume ratio of 3-5 .
17. (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)- Form D of the dihydrobromide salt of 2-(dimethylamino)ethanone characterized by X-ray powder diffraction at 2θ angle using Cu-Kα radiation at about 10.7 ± 0.2, 11.6 ± 0.2 13.6±0.2, 14.4±0.2, 15.8±0.2, 16.4±0.2, 17.6±0.2, 19.1±0.2, 19.8±0.2, 20.7±0.2, 21.5±0.2, 22.1±0.2, 22.7±0.2, 23.8±0.2, 24.5 There are diffraction peaks of ±0.2, 26.2±0.2, 27.4±0.2, 29.1±0.2, and 30.7±0.2.
18. (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)peridine according to claim 17 Form D of the dihydrobromide salt of pyridin-1-yl)-2-(dimethylamino)ethanone, characterized in that the initial melting temperature of the crystalline form D is about 236 °C.
19. A preparation of (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine according to claim 17 or 18 - A method of crystal form D of a dihydrobromide salt of 1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone, characterized in that the method comprises the steps of:

    (1) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 -yl)-2-(dimethylamino)ethanone is reacted with hydrobromic acid to prepare (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazole) a solution of [3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone dihydrobromide;

    (2) concentrating the solution obtained in the step (1) and adding ethanol thereto;

    (3) lowering the temperature of the solution obtained in the step (2) to room temperature and stirring it for 7 to 9 hours;

    (4) filtering the solution obtained in the step (3), and drying the filter cake at a temperature of 45 to 55 ° C for 6 to 8 hours;

    (5) Collect crystals.
20. (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)- Form E of monohydrochloride of 2-(dimethylamino)ethanone characterized by X-ray powder diffraction at 2θ angles of about 10.7 ± 0.2, 11.6 ± 0.2 using Cu-Kα radiation. 13.6±0.2, 14.4±0.2, 15.8±0.2, 16.4±0.2, 17.6±0.2, 19.1±0.2, 19.8±0.2, 20.7±0.2, 21.5±0.2, 22.1±0.2, 22.7±0.2, 23.8±0.2, 24.5± 0.2, 26.2 ± 0.2, 27.4 ± 0.2, 29.1 ± 0.2, and 30.7 ± 0.2 have diffraction peaks.
21. (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidyl according to claim 20. Form E of the monohydrochloride salt of pyridin-1-yl)-2-(dimethylamino)ethanone, characterized in that the initial melting temperature of the Form E is about 225 °C.
22. A preparation of (R)-1-(3-(4-amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine according to claim 20 or 21 - Process for the crystal form E of monohydrochloride of 1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone, characterized in that the process comprises the steps of:

    (1) (R)-1-(3-(4-Amino-(4-phenoxyphenyl)-1H-pyrazole in a mixed solvent of ethyl acetate and ethanol in a volume ratio of 7-8 And [3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone is reacted with hydrochloric acid to prepare (R)-1-(3-(4- Single of amino-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone a solution of the hydrochloride;

    (2) lowering the temperature of the solution obtained in the step (1) to room temperature and stirring it for 10 to 12 hours;

    (3) filtering the solution obtained in the step (2), and drying the filter cake at a temperature of 45 to 55 ° C for 8 to 10 hours;

    (4) Collect crystals.

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