CN109311883B - Crystal forms of FLT3 kinase inhibitor or salt thereof and preparation method thereof - Google Patents

Crystal forms of FLT3 kinase inhibitor or salt thereof and preparation method thereof Download PDF

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CN109311883B
CN109311883B CN201780017991.6A CN201780017991A CN109311883B CN 109311883 B CN109311883 B CN 109311883B CN 201780017991 A CN201780017991 A CN 201780017991A CN 109311883 B CN109311883 B CN 109311883B
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phenoxyphenyl
pyrazolo
dimethylamino
amino
pyrimidin
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CN109311883A (en
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张善春
方绪军
曹杰永
谢琼霞
程开生
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Hefei Youyuan Pharmaceutical Co.,Ltd.
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Hefei Cosource Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The invention provides a crystal form of FLT3 kinase inhibitor or salt thereof and a preparation method thereof, and particularly provides crystal forms A, B, C, D and E of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-1-yl) piperidine-1-yl) -2- (dimethylamino) ethanone or a monohalide salt or a dihalide salt thereof, and a preparation method thereof. The crystalline forms a and B of the compound according to the invention and their monohalide or dihalide salts of crystalline forms C, D and E have good stability to oxidation, light, high temperature and high humidity conditions, as well as good solubility in water.

Description

Crystal forms of FLT3 kinase inhibitor or salt thereof and preparation method thereof
Technical Field
The invention belongs to the field of chemistry, and particularly relates to a crystal form of a FLT3 kinase inhibitor or a salt thereof and a preparation method thereof.
Background
(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 (i.e., FMS-like tyrosine kinase 3(FMS-like tyrosine kinase 3)) having a molecular structure according to the following formula (I):
Figure GPA0000259861620000021
chinese patent CN105481862A describes the compound or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite, or prodrug thereof (see, compound 22), as well as pharmaceutical compositions and uses and methods thereof for preventing or treating cell proliferative disorders and or FLT 3-related disorders, particularly disorders responsive to inhibition of LT3 kinase, especially FLT3/ITD mutant kinase. In addition, the preparation method and the inhibitory activity comparison of the compound and the derivative thereof are described in detail.
However, CN105481862A simply mentions that this compound can be prepared to be used as a pharmaceutically acceptable salt, does not describe in detail the process and method of salt formation and the stability comparison of the compound after salt formation, nor does it indicate the polymorphic form of the compound, and does not even disclose the final crystallization or solvent for preparing crystals 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).
In practice, it is often desirable to form a salt of a pharmaceutical compound and obtain crystals thereof in order to improve the stability and solubility of the compound in aqueous media.
Disclosure of Invention
The object of the present invention is to provide crystalline forms of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone or its monohalide or dihalide salt, and processes for their preparation.
According to a first aspect of the present invention there is provided a crystalline form of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone or a mono-or di-halide salt thereof.
According to a second aspect of the present invention there is provided crystalline form a of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone characterized by X-ray powder diffraction peaks at about 6.1 ± 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 expressed in 2 Θ angles using Cu-ka radiation.
According to a third aspect of the present invention, there is provided a process for preparing form a as described above, characterized in that said process comprises the steps of:
(1) dissolving (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone in at least one solvent selected from the group consisting of methanol, ethanol and acetone heated to 60 to 80 ℃ with stirring;
(2) lowering the temperature of the solution obtained in step (1) to room temperature and stirring it for 12 to 16 hours;
(3) filtering the solution obtained in step (2) and drying the filter cake at a temperature of 45-55 ℃ for 6-8 hours;
(4) the crystals were collected.
According to a fourth aspect of the present invention there is provided crystalline form B of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone characterized by X-ray powder diffraction peaks at about 6.3 ± 0.2, 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, expressed in 2 Θ angles, using Cu-ka radiation.
According to a fifth aspect of the present invention, there is provided a process for preparing form B as defined above, characterized in that said process comprises the steps of:
(1) (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone is dissolved in ethyl acetate heated to 60 to 70 ℃ with stirring;
(2) lowering the temperature of the solution obtained in step (1) to room temperature and stirring it for 8 to 12 hours;
(3) filtering the solution obtained in step (2) and drying the filter cake at a temperature of 45-55 ℃ for 6-8 hours; and
(4) the crystals were collected.
According to a sixth aspect of the present invention there is provided crystalline form C of the monohydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone characterized by having diffraction peaks 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 by X-ray powder diffraction, expressed in 2 θ, using Cu-ka radiation.
According to a seventh aspect of the present invention, there is provided a process for preparing form C above, characterized in that the process comprises the steps of:
(1) reacting (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone with hydrobromic acid to prepare a monohydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone;
(2) dissolving, with stirring, a monohydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone in at least one solvent selected from the group consisting of methanol, ethanol, acetone, ethyl acetate and mixtures thereof heated to 60 to 80 ℃;
(3) lowering the temperature of the solution obtained in step (2) to room temperature and stirring it for 6 to 8 hours;
(4) filtering the solution obtained in step (3) and drying the filter cake at a temperature of 45-55 ℃ for 6-8 hours; and
(5) the crystals were collected.
According to an eighth aspect of the present invention, there is provided crystalline form D of a dihydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-D ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone characterized by having diffraction peaks 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 ± 0.2, 26.2 ± 0.2, 27.4 ± 0.2, 29.1 ± 0.2, and 29.7 ± 0.2 in an X-ray powder diffraction angle of 2 θ using Cu-ka radiation.
According to a ninth aspect of the present invention, there is provided a process for preparing form D above, characterized in that the process comprises the steps of:
(1) reacting (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone with hydrobromic acid to prepare a solution containing a dihydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone;
(2) concentrating the solution obtained in step (1) and adding ethanol thereto;
(3) lowering the temperature of the solution obtained in step (2) to room temperature and stirring it for 7 to 9 hours;
(4) filtering the solution obtained in step (3) and drying the filter cake at a temperature of 45-55 ℃ for 6-8 hours; and
(5) the crystals were collected.
According to a tenth aspect of the present invention there is provided crystalline form E of the monohydrochloride salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone characterized by an X-ray powder diffraction having diffraction peaks 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 ± 0.2, 26.2 ± 0.2, 27.4 ± 0.2, 29.8 ± 0.2, 29.1 ± 0.2 and 30.7 ± 0.2 in 2 theta angles using Cu-ka radiation.
According to an eleventh aspect of the present invention, there is provided a process for preparing the above form E, characterized in that the process comprises the steps of:
(1) reacting (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone with hydrochloric acid in a mixed solvent of ethyl acetate and ethanol in a volume ratio of 7 to 8 to prepare a solution containing a monohydrochloride salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone;
(2) lowering the temperature of the solution obtained in step (1) to room temperature and stirring it for 10 to 12 hours;
(3) filtering the solution obtained in step (2), and drying the filter cake at a temperature of 45-55 ℃ for 8-10 hours; and
(4) the crystals were collected.
The crystalline forms a and B of the compound according to the invention and their monohalide or dihalide salts of crystalline forms C, D and E have good stability to oxidation, light, high temperature and high humidity conditions, as well as good solubility in water.
Additional features and advantages of the invention will be set forth 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 a compound according to the 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 the monohydrobromide salt of the compound according to the invention;
figure 5 is a hydrogen nuclear magnetic spectrum of form C of the monohydrobromide salt of the compound according to the invention;
figure 6 is an X-powder diffraction pattern of form D of the dihydrobromide salt of the compound according to the present invention; and
figure 7 is an X-powder diffraction pattern of form E of the monohydrochloride salt of a compound according to the present invention.
Detailed Description
The inventors of the present invention have found that the compound of formula (I) according to the present invention has good crystallinity, and can be crystallized by different solvents. Furthermore, the compounds of formula (I) according to the invention belong to the class of amines, i.e. the amino group and the tertiary amine on the piperidine ring can theoretically bind one or two acid counter ions. 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 pharmaceutically acceptable acids, including inorganic and organic acids, such as hydrohalic acids, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; wherein the hydrohalic acid comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.; the organic acids include monobasic acids such as formic acid, acetic acid, propionic acid, caproic acid, methanesulfonic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, and the like; the dibasic acid is, for example, malonic acid, malic acid, succinic acid, maleic acid, tartaric acid, fumaric acid, etc. However, from the aspects of hygroscopicity and solubility in water, the crystalline forms of the monohydrobromide, dihydrobromide and monohydrochloride of the compound of formula (I) are preferably formed. Furthermore, from the viewpoint of stability, a crystalline form of the monohydrobromide salt of the compound of formula (I) is preferred.
Thus, according to one embodiment of the present invention there is provided a crystalline form of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone or a mono-or di-halide salt thereof. Preferably, the monohalide salt is selected from the group consisting of the monohydrobromide salt and the monohydrochloride salt, and the dihalochloride salt is the dihydrochloride salt.
According to another embodiment of the present invention there is provided crystalline form a of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone characterized by X-ray powder diffraction peaks at about 6.1 ± 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 expressed in terms of 2 Θ using Cu-ka radiation. In addition, the form a has a hydrogen nuclear magneto-optical spectrum as shown in fig. 2. The initial melting temperature of form a, as measured by thermogravimetry (DTG), is about 128 ℃.
According to another embodiment of the present invention, there is provided a process for preparing the above form a, characterized in that the process comprises the steps of:
(1) dissolving (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone in at least one solvent selected from the group consisting of methanol, ethanol and acetone heated to 60 to 80 ℃ with stirring;
(2) lowering the temperature of the solution obtained in step (1) to room temperature and stirring it for 12 to 16 hours;
(3) filtering the solution obtained in step (2) and drying the filter cake at a temperature of 45-55 ℃ for 6-8 hours; and
(4) the crystals were collected.
According to a preferred embodiment of the present invention, the solvent used in the above process is preferably acetone.
According to another embodiment of the present invention there is provided crystalline form B of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone characterized by X-ray powder diffraction peaks at about 6.3 ± 0.2, 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, expressed in 2 Θ angles, using Cu-ka radiation. The initial melting temperature of this form B, as measured by thermogravimetry (DTG), is about 106 ℃.
According to another embodiment of the present invention, there is provided a process for preparing the above form B, 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) piperidin-1-yl) -2- (dimethylamino) ethanone is dissolved in ethyl acetate heated to 60 to 70 ℃ with stirring;
(2) lowering the temperature of the solution obtained in step (1) to room temperature and stirring it for 10 to 12 hours;
(3) filtering the solution obtained in step (2) and drying the filter cake at a temperature of 45-55 ℃ for 6-8 hours; and
(4) the crystals were collected.
The above-mentioned crystal forms a and B are polymorphic forms of the compound of formula (I) ((R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone) according to the invention obtained under different crystallization conditions.
In addition, the invention also provides polymorphic forms of different salts (e.g., monohydrobromide, dihydrobromide, monohydrochloride, etc.) of the compound of formula (I).
According to another embodiment of the present invention, there is provided crystalline form C of the monohydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone characterized by having diffraction peaks 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 by X-ray powder diffraction, expressed in 2 θ, using Cu-ka radiation. In addition, the form C has a hydrogen nuclear magnetic spectrum as shown in fig. 5. The initial melting temperature of form C, as measured by thermogravimetry (DTG), is about 236 ℃.
According to another embodiment of the present invention, there is provided a process for preparing form C of the above-mentioned monohydrobromide salt, characterized in that the process comprises the following steps:
(1) reacting (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone with hydrobromic acid to prepare a monohydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone;
(2) dissolving, with stirring, a monohydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone in at least one solvent selected from the group consisting of methanol, ethanol, acetone, ethyl acetate and mixtures thereof heated to 60 to 80 ℃;
(3) lowering the temperature of the solution obtained in step (2) to room temperature and stirring it for 6 to 8 hours;
(4) filtering the solution obtained in step (3) and drying the filter cake at a temperature of 45-55 ℃ for 6-8 hours; and
(5) the crystals were collected.
According to certain preferred embodiments of the present invention, the solvent employed in the above process is methanol. According to certain preferred embodiments of the present invention, the solvent employed in the above process is ethanol. According to certain preferred embodiments of the present invention, the solvent employed in the above process is acetone. According to certain preferred embodiments of the present invention, the solvent employed in the above process is a mixture of ethyl acetate/methanol in a 3 to 5 volume ratio. According to certain preferred embodiments of the present invention, the solvent employed in the above process is a mixture of acetone/methanol in a volume ratio of 3 to 5.
According to another embodiment of the present invention, there is provided crystalline form D of the hydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-D ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone characterized by X-ray powder diffraction peaks 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 ± 0.2, 26.2 ± 0.2, 27.4 ± 0.2, 29.1 ± 0.2, and 29.7 ± 0.2 in 2 theta angles using Cu-ka radiation.
According to another embodiment of the present invention, there is provided a process for preparing the above crystalline form D of the dihydrobromide salt, characterized in that it comprises the steps of:
(1) reacting (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone with hydrobromic acid to prepare a solution containing a dihydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone;
(2) concentrating the solution obtained in step (1) and adding ethanol thereto;
(3) lowering the temperature of the solution obtained in step (2) to room temperature and stirring it for 7 to 9 hours;
(4) filtering the solution obtained in step (3) and drying the filter cake at a temperature of 45-55 ℃ for 6-8 hours; and
(5) the crystals were collected.
According to another embodiment of the present invention, there is provided crystalline form E of the monohydrochloride salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone characterized by an X-ray powder diffraction having diffraction peaks 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 ± 0.2, 26.2 ± 0.2, 27.4 ± 0.2, 29.8 ± 0.2, and 29.7 ± 0.2 in 2 θ degrees using Cu-ka radiation. The initial melting temperature of form E, as measured by thermogravimetry (DTG), is about 225 ℃.
According to another embodiment of the present invention, there is provided a process for preparing form E of the above-mentioned monohydrochloride characterized in that the process comprises the steps of:
(1) reacting (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone with hydrochloric acid in a mixed solvent of ethyl acetate and ethanol in a volume ratio of 7 to 8 to prepare a solution containing a monohydrochloride salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone;
(2) lowering the temperature of the solution obtained in step (1) to room temperature and stirring it for 10 to 12 hours;
(3) filtering the solution obtained in step (2), and drying the filter cake at a temperature of 45-55 ℃ for 8-10 hours; and
(4) the crystals were collected.
Examples
The following experiments are provided to illustrate the present invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof. According to the present invention, "%" indicates amounts by weight unless otherwise indicated.
Test method
X-ray powder diffraction measurements
A DX-27 miniX-powder diffractometer is utilized, a stepping test mode is adopted, 3 degrees are taken as an initial angle, 40 degrees are taken as a termination angle, 0.02 is taken as a stepping angle, the tube voltage is 35kv, the tube current is 15mA, 0.3g of sample is weighed and placed on a glass slide, and the sample is placed in the instrument in order by pressing for testing and recording atlas data.
1Hydrogen nuclear magnetic spectroscopy (HNMR) measurements
A BRUKER AV-300 type nuclear magnetic resonance spectrometer is adopted, about 5mg of sample is weighed and dissolved by using deuterated DMSO as a solvent, and a graph is tested and recorded.
Measurement of initial melting temperature according to thermogravimetry
And (3) performing melting point test by using a DTG-60A thermogravimetric analyzer, weighing about 5mg of a sample, placing the sample in an aluminum crucible, balancing and reading by using the apparatus, raising the temperature to 300 ℃ at the initial temperature of 30 ℃ and the heating rate of 10 ℃/min, starting the test, and reading and recording the map data after the test is finished.
Example 1 preparation of form A of the Compound of formula (I) Using methanol as crystallization solvent
2g of the compound of the formula (I) are weighed out and added to 14ml of methanol, stirred while heating to dissolve. Then cooling the solution to room temperature and stirring for crystallization for 12-16 h. The solution was then filtered and the filter cake was transferred to an air-blast drying oven at 50 ℃ for 6-8 h to give 1.1g of a white powdery solid. The yield of this white powdery solid was 55% by weight, and the melting point measured according to Differential Thermal Analysis (DTA) was 129 ℃ to 131 ℃. In addition, the crystal form A is shown as the generated crystal form through X-ray powder diffraction method determination, and X-ray powder diffraction data are shown in the following table 1.
TABLE 1
Peak number Diffraction angle 2 theta (°) d-spacing Relative strength% Peak number Diffraction angle 2 theta (°) d-spacing Is relatively strongDegree%
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 21 30.820 2.899 5.9
10 19.099 4.643 48.7 22 31.340 2.852 8.5
11 19.960 4.444 14.5 23 32.457 2.756 1.4
12 20.840 4.259 53.7 24 36.040 2.490 2.4
Example 2 preparation using ethanol as crystallization solventCrystalline form A of a compound of formula (I)
2g of the compound of the formula (I) are weighed out and added to 6ml of ethanol and the mixture is heated with stirring to dissolve. Then cooling the solution to room temperature and stirring for crystallization for 16-18 h. The solution was then filtered and the filter cake was transferred to an air-blast drying oven at 50 ℃ for 6-8 h to give 1.32g of a white powdery solid. The yield of this white powdery solid was 66%, and the melting point measured according to Differential Thermal Analysis (DTA) was 129 ℃ to 131 ℃. In addition, the crystal form is shown to be the crystal form A by X-ray powder diffraction method determination, and the X-ray powder diffraction pattern is shown in the following table 2.
TABLE 2
Figure GPA0000259861620000111
Figure GPA0000259861620000121
Example 3 preparation of form A of the Compound of formula (I) Using acetone as the crystallization solvent
2g of the compound of the formula (I) are weighed out and added to 10ml of acetone and the mixture is heated with stirring to dissolve it. The solution was then allowed to cool to room temperature and stirred for 16h to crystallize. The solution was then filtered and the filter cake was transferred to an air-forced drying oven at 50 ℃ for 6h to give 1.73g of a white powdery solid. The yield of the white powdery solid was 86.5%, the melting point measured according to Differential Thermal Analysis (DTA) was 129 ℃ to 131 ℃, and further, the resulting crystal form was shown to be the crystal form A as determined by X-ray powder diffraction method, and the X-ray powder diffraction pattern is shown in Table 3 below.
TABLE 3
Peak number Diffraction angle 2 theta (°) d-spacing Relative strength% Peak number Diffraction angle 2 theta (°) 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 21 31.279 2.857 7.8
11 19.100 4.643 75.8 22 35.981 2.494 3.8
Example 4 preparation of form B of the Compound of formula (I) Using Ethyl acetate as crystallization solvent
2g of the compound of the formula (I) are weighed out and added to 40ml of ethyl acetate and the mixture is heated with stirring to dissolve. The solution was then allowed to cool to room temperature and stirred for 10h to crystallize. The solution was then filtered and the filter cake was transferred to an air-forced drying oven at 50 ℃ for 6h to give 1.65g of a white powdery solid. The yield of the white powdery solid was 82.5%, the melting point measured according to Differential Thermal Analysis (DTA) was higher than 106 ℃, and further, the resulting crystal form was shown to be form B as determined by X-ray powder diffraction method, and the X-ray powder diffraction pattern is shown in table 4 below.
TABLE 4
Peak number Diffraction angle 2 theta (°) d-spacing Relative strength% Peak number Diffraction angle 2 theta (°) 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 the monohydrobromide salt of the Compound of formula (I)
30g of the compound of the formula (I) was weighed and added to 90ml of ethyl acetate, and the solution was heated to prepare a free base solution. Adding 12g of hydrobromic acid into 30ml of ethanol for dilution, and then slowly and dropwise adding the diluted hydrobromic acid solution into the free alkali solution to slowly precipitate a large amount of white solid from the system. The system was stirred for 6 hours, filtered and the filter cake was transferred to an air-blast drying oven at 50 ℃ for 8 hours to give 30.2g of a white powdery solid. The yield of this white powdery solid was 86%, the melting point measured according to Differential Thermal Analysis (DTA) being higher than 236 ℃. In the method, the content of bromide ions is titrated by silver nitrate titration solution, and potassium chromate is used as a color developing agent.
Example 6 preparation of crystalline form C of the monohydrobromide salt of the compound of formula (I) using methanol as crystallization solvent
5g of the monohydrobromide salt of the compound of formula (I) prepared in example 5 above were weighed out and added to 20ml of methanol at 60 ℃ and heated to dissolve it. Then, the temperature is slowly reduced to room temperature, the mixture is stirred and crystallized, a large amount of white solid is slowly precipitated from the system, and the mixture is stirred for 6 hours. The solution was then filtered and the filter cake was transferred to an air-blast drying oven at 50 ℃ for 8 hours to give 2.7g of a white powdery solid. The yield of this white powdery solid was 54%, the melting point measured according to Differential Thermal Analysis (DTA) being higher than 236 ℃. In addition, the crystal form is shown to be the crystal form C by X-ray powder diffraction method, and the X-ray powder diffraction pattern is shown in the following table 5.
TABLE 5
Peak number Diffraction angle 2 theta (°) d-spacing Relative strength% Peak number Diffraction angle 2 theta (°) 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 21 28.179 3.164 19.9
4 11.936 7.408 2.2 22 28.538 3.125 13.7
5 13.460 6.573 16.6 23 29.061 3.070 8.8
6 14.693 6.024 2.0 24 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 the monohydrobromide salt of the Compound of formula (I) Using ethanol as the crystallization solvent
5g of the monohydrobromide salt of the compound of formula (I) prepared in example 5 above were weighed out and added to 50ml of ethanol at 60 ℃ and heated to dissolve it. Then, the temperature is slowly reduced to room temperature, the mixture is stirred and crystallized, a large amount of white solid is slowly precipitated from the system, and the mixture is stirred for 6 hours. The solution was then filtered and the filter cake was transferred to an air-blast drying oven at 50 ℃ for 8 hours to give 4.1g of a white powdery solid. The yield of this white powdery solid was 82%, the melting point measured according to Differential Thermal Analysis (DTA) being higher than 236 ℃. In addition, the crystal form is shown to be the crystal form C by X-ray powder diffraction method, and the X-ray powder diffraction pattern is shown in the following table 6.
TABLE 6
Peak number Diffraction angle 2 theta (°) d-spacing Relative strength% Peak number Diffraction angle 2 theta (°) 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 21 25.721 3.461 14.0
4 11.820 7.481 2.4 22 26.081 3.414 9.2
5 13.299 6.652 38.1 23 26.841 3.319 16.2
6 14.945 5.923 2.1 24 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 formula (I) Using a methanol/ethyl acetate Mixed solvent as a crystallization solvent
Crystalline form C of hydrobromide
5g 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 10ml of methanol and 40ml of ethyl acetate at 60 ℃ and heated to dissolve it clearly. Then, the temperature is slowly reduced to room temperature, the mixture is stirred and crystallized, a large amount of white solid is slowly precipitated from the system, and the mixture is stirred for 6 hours. The solution was then filtered and the filter cake was transferred to an air-blast drying oven at 50 ℃ for 8 hours to give 3.8g of a white powdery solid. The yield of this white powdery solid was 76%, the melting point measured according to Differential Thermal Analysis (DTA) being higher than 236 ℃. In addition, the crystal form is shown to be the crystal form C by X-ray powder diffraction method, and the X-ray powder diffraction pattern is shown in the following table 7.
TABLE 7
Peak number Diffraction angle 2 theta (°) d-spacing Relative strength% Peak number Diffraction angle 2 theta (°) 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 21 25.823 3.447 13.6
4 11.915 7.422 2.8 22 27.142 3.283 18.3
5 13.400 6.602 25.1 23 28.121 3.171 20.7
6 15.080 5.870 3.5 24 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 Monohydrobromic acid of Compound of formula (I) Using methanol/acetone Mixed solvent as crystallization solvent Crystal form C of a salt
5g of the monohydrobromide salt of the compound of the formula (I) prepared in example 5 above was weighed and added to a mixed solvent of 10ml of methanol and 40ml of acetone at 60 ℃ and heated to dissolve it clearly. Then, the temperature is slowly reduced to room temperature, the mixture is stirred and crystallized, a large amount of white solid is slowly precipitated from the system, and the mixture is stirred for 6 hours. The solution was then filtered and the filter cake was transferred to an air-blast drying oven at 50 ℃ for 8 hours to give 4.3g of a white powdery solid. The yield of the white powdery solid was 86%, the melting point measured according to Differential Thermal Analysis (DTA) was higher than 236 ℃, and in addition, the resulting crystal form was shown to be form C as determined by X-ray powder diffraction method, and the X-ray powder diffraction pattern is shown in table 8 below.
TABLE 8
Peak number Diffraction angle 2 theta (°) d-spacing Relative strength% Peak number Diffraction angle 2 theta (°) 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 21 25.721 3.461 14.0
4 11.820 7.481 2.4 22 26.081 3.414 9.2
5 13.299 6.652 38.1 23 26.841 3.319 16.2
6 14.945 5.923 2.1 24 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 crystalline form D of the dihydrobromide salt of the Compound of formula (I)
9g of the compound of the formula (I) was weighed and added to 27ml of ethyl acetate, and the solution was heated to prepare a free base solution. Then, 7.75g of hydrobromic acid was added to 20ml of ethanol for dilution. Slowly dripping the diluted hydrobromic acid solution into the free alkali solution. The system is clear and can not separate out solids. And transferring the system to 65 ℃ for concentration, adding 200ml of ethanol for clearing, then concentrating, adding 100ml of ethanol, stirring and crystallizing for 8 hours, and slowly precipitating a large amount of white solid. The solution was then filtered and the filter cake was transferred to an air-blast drying oven at 50 ℃ for 6 hours to give 4.6g of a white powdery solid. The yield of the white powdery solid was 38%. The content of bromide ions is titrated by silver nitrate titration solution, and potassium chromate is used as a color developing agent. In addition, the crystal form is shown to be a crystal form D by X-ray powder diffraction method, and an X-ray powder diffraction pattern is shown in the following table 9.
TABLE 9
Peak number Diffraction angle 2 theta (°) d-spacing Relative strength% Peak number Diffraction angle 2 theta (°) 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 21 30.154 2.961 29.2
10 20.740 4.279 30.1 22 30.681 2.912 6.2
11 21.479 4.134 49.8 23 31.940 2.799 24.1
12 22.059 4.026 21.4 24 33.194 2.697 6.2
Example 11 preparation of crystalline form E of the monohydrochloride salt of the Compound of formula (I)
5g of the compound of formula (I) was weighed out and added to 30ml of ethanol, and the solution was heated to prepare a free base solution. A solution of 7mol/l HCl in ethyl acetate (1.3 ml) was diluted by adding to 10ml of ethyl acetate. The diluted hydrochloric acid solution was slowly added dropwise to the above free base solution, and then 1ml of water was added. The resulting solution was heated to dryness and stirred at room temperature overnight to precipitate a white solid. The solution was then filtered and the filter cake was transferred to an air-blast drying oven at 50 ℃ for 8 hours to give 3.98g of a white powdery solid. The yield of this white powdery solid was 74%, the melting point measured according to Differential Thermal Analysis (DTA) being higher than 225 ℃. The content of chloride ions is titrated by silver nitrate titration solution, and potassium chromate is used as a color developing agent. In addition, the crystal form is shown to be the crystal form E through X-ray powder diffraction method measurement, and the X-ray powder diffraction pattern is shown in the following table 10.
Watch 10
Peak number Diffraction angle 2 theta (°) d-spacing Relative strength% Peak number Diffraction angle 2 theta (°) 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 21 25.721 3.460 14.0
3 10.281 8.597 28.0 22 26.081 3.414 9.2
4 11.841 7.468 2.7 23 26.841 3.319 16.2
5 13.639 6.488 14.3 24 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
1. Stability of
The present inventors have found that the compound of formula (I) has good crystallinity and is easy to purify, but has disadvantages of poor resistance to light and oxidation, and is easy to form an oxide, thereby further degrading into other impurities. The stability of the free alkali to oxidation, illumination, high temperature and high humidity can be greatly improved after the free alkali is salified. For this reason, the stability of the compound of formula (I) and its hydrobromide salt (hereinafter, both are collectively referred to as a sample to be tested) was examined under light irradiation, oxidation, high temperature and high humidity conditions.
The light, oxidation, high temperature and high humidity tests according to the invention were carried out according to the following methods:
illumination experiment
Weighing two parts of each sample to be detected, weighing 15mg of each sample precisely, putting one part of the samples into a 50ml measuring flask, adding a proper amount of 50% acetonitrile for dissolving, then putting the two parts of samples into an SHH-150GD type medicine illumination test box (a Zoochi instrument), destroying for 10 days under the light intensity of 5000LX, and adding 50% acetonitrile for constant volume to be used as an illumination destruction sample. 20. mu.l of a photodisrupted sample was precisely measured and injected into a liquid chromatograph (LC-20AD type high performance liquid chromatograph equipped with SPD-M20A type detector SIL-20A type autosampler, Shimadzu corporation, Japan) for measurement, and a chromatogram was recorded.
Oxidation experiment
Accurately weighing 15mg of each sample to be detected, placing the samples into a 10ml measuring flask, adding 1ml of 30% hydrogen peroxide, placing the samples for 4 hours, then adding 50% acetonitrile to dissolve and dilute the samples to scale, and shaking up the samples to be detected to be used as an oxidative destruction sample solution. 0.1ml of the above-mentioned oxidative destruction sample solution was precisely transferred and placed in a 10ml measuring flask, diluted to the scale with a solvent, and shaken up to serve as a detection solution. 20. mu.l of the detection solution was measured precisely and injected into a liquid chromatograph (LC-20AD type high performance liquid chromatograph equipped with SPD-M20A type SIL-20A autosampler, Shimadzu corporation, Japan) for measurement, and a chromatogram was recorded.
High temperature experiment
200mg of each sample to be tested is weighed, placed in a weighing bottle and destroyed in a DHG-9010-2SA electric heating constant temperature air blast drying oven (Shanghai three-hair scientific instruments Co., Ltd.) at 60 ℃ for 6 hours. Then, 15mg of each sample to be measured is precisely weighed, and the sample is placed in a 50ml volumetric flask, dissolved and diluted to the scale by adding 50% acetonitrile, and used as a high-temperature destruction sample. A20. mu.l high-temperature-failure sample was precisely measured and injected into a liquid chromatograph (LC-20AD type high performance liquid chromatograph equipped with SPD-M20A type SIL-20A autosampler, Shimadzu corporation, Japan) for measurement, and a chromatogram was recorded.
High humidity experiment
8.53mg of a sample to be measured was precisely weighed and placed in a petri dish, and after being placed in a dish having a humidity of 92.5% for 7 days, dissolved and diluted to a scale with a solvent, shaken up, to serve as a high-humidity-destruction sample solution. 20. mu.l of the high-humidity-destructive sample solution was precisely measured and injected into a liquid chromatograph (LC-20AD type high performance liquid chromatograph equipped with SPD-M20A type detector SIL-20A type autosampler, Shimadzu corporation, Japan) for measurement, and a chromatogram was recorded.
The results of measurement of the compound of formula (I) and its hydrobromide according to the above method are shown in table 11 below.
TABLE 11
Figure GPA0000259861620000211
Figure GPA0000259861620000221
Remarking: "- -" indicates not suitable; "nd" indicates no detection
As is clear from the results in table 11 above, the compound of formula (I) is unstable under light and oxidation conditions, and the hydrobromide salt of the compound of formula (I) is in a more stable salt form, improving chemical stability and physicochemical properties, and suitable for long-term storage and pharmaceutical preparation.
In the present invention, the stability and dissolution residual properties of the crystalline form a and the crystalline form B of the compound of formula (I) according to the present invention were investigated according to the above-listed methods, and the results thereof are shown in table 12 below.
TABLE 12
Figure GPA0000259861620000222
As can be seen from table 12 above, a comparison is made in terms of stability: form B of the compound of formula (I) is more stable than form a; comparison in terms of dissolution residual: the compound of formula (I) in crystal form A and crystal form B can form solvates more easily and can not be removed after drying.
Various samples were also studied for hygroscopicity over a 24 hour period at different humidities, according to embodiments of the present invention. Specific results are shown in table 13 below. It was further found from the hygroscopicity data that the monohydrobromide salt was almost non-hygroscopic in the hydrohalite, the monohydrochloride salt was slightly hygroscopic, and the hydroiodide solid was very deliquescent.
Watch 13
Figure GPA0000259861620000231
From the above results, it is preferable that the hydrochloride salt and the hydrobromide salt are in a stable salt form, and it is most preferable that the hydrobromide salt is in a stable salt form. The invention provides relevant physicochemical property data of a monohydrochloride of a compound shown in a formula (I), a monohydrobromide of the compound shown in the formula (I) and a dihydrobromide of the compound shown in the formula (I), wherein the data are shown in a following table 14 by comparing the molar equivalent of acid, the pH value, the solubility and the like of solid after salification.
TABLE 14
Name (R) Amount of acida pH of solid Identification of acid numberb
The monohydrochloride salt of a compound of formula (I) 0.95 5.7 Consuming 1 equivalent of silver nitrate
The dihydrochloride of the compound of formula (I) 2.0 3.30 Consuming 2 equivalents of silver nitrate
The monohydrobromide salt of the compound of formula (I) 0.95 5.0-5.5 Consuming 1 equivalent of silver nitrate
The compound of formula (I) dihydrobromide 2.0 2.8 Consuming 2 equivalents of silver nitrate
Remarking: "a" represents the molar amount relative to the compound of formula (I); "b" represents the titration of halogen atoms using silver nitrate calibration solution.
2. Solubility in water
Taking a proper amount of a sample to be detected, respectively placing the sample in water, ethanol, methanol, ethyl acetate and acetone at 25 +/-2 ℃, strongly shaking for 30 seconds, and observing the dissolution condition. In the absence of visually detectable solute particles, complete dissolution is considered.
The results according to the above experimental method are shown in table 15 below:
watch 15
Figure GPA0000259861620000241
From table 15 above, it can be seen that the hydrochloride and hydrobromide salts of the compound of formula (I) have much higher solubility in aqueous medium than the compound of formula (I), substantially no change in methanol medium, and much lower solubility in ethyl acetate and acetone medium than the compound of formula (I).
The preferred embodiments of the present invention have been described in detail with reference to the accompanying drawings, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.

Claims (12)

  1. Crystalline form C of the monohydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone characterized by having diffraction peaks 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 by X-ray powder diffraction, expressed in terms of 2 θ, using Cu-ka radiation.
  2. 2. Crystalline form C of the monohydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone according to claim 1, characterized in that it has a hydrogen nuclear magnetic spectrum as shown in figure 5.
  3. 3. Crystalline form C of the monohydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone according to claim 1, characterized in that the initial melting temperature of form C is about 236 ℃.
  4. 4. A process for the preparation of crystalline form C of the monohydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone according to any one of claims 1 to 3, characterized in that it comprises the following steps:
    (1) reacting (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone with hydrobromic acid to prepare a monohydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone;
    (2) dissolving, with stirring, a monohydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone in at least one solvent selected from the group consisting of methanol, ethanol, acetone, ethyl acetate and mixtures thereof heated to 60 to 80 ℃;
    (3) lowering the temperature of the solution obtained in step (2) to room temperature and stirring it for 6 to 8 hours;
    (4) filtering the solution obtained in step (3) and drying the filter cake at a temperature of 45-55 ℃ for 6-8 hours; and
    (5) the crystals were collected.
  5. 5. The process of crystalline form C of the monohydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone according to claim 4, characterized in that the solvent is a mixture of ethyl acetate/methanol in a volume ratio of 7 to 8.
  6. 6. The process of crystalline form C of the monohydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone according to claim 4, characterized in that the solvent is a mixture of acetone/methanol in a volume ratio of 3 to 5.
  7. A crystalline form D of a dihydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-D ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone characterized by having diffraction peaks 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 + -0.2, 26.2 + -0.2, 27.4 + -0.2, 29.1 + -0.2, and 7 + -0.2 by X-ray powder diffraction at a 2 θ -angle using Cu-Ka radiation.
  8. 8. Crystalline form D of the dihydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-D ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone according to claim 7, characterized in that the initial melting temperature of form D is about 236 ℃.
  9. 9. A process for the preparation of crystalline form D of the dihydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-D ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone according to claim 7 or 8, characterized in that it comprises the following steps:
    (1) reacting (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone with hydrobromic acid to prepare a solution containing a dihydrobromide salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone;
    (2) concentrating the solution obtained in step (1) and adding ethanol thereto;
    (3) lowering the temperature of the solution obtained in step (2) to room temperature and stirring it for 7 to 9 hours;
    (4) filtering the solution obtained in step (3) and drying the filter cake at a temperature of 45-55 ℃ for 6-8 hours; and
    (5) the crystals were collected.
  10. A crystalline form E of the monohydrochloride salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone characterized by having diffraction peaks 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 + -0.2, 26.2 + -0.2, 27.4 + -0.2, 29.1 + -0.2, and 7 + -0.2 by X-ray powder diffraction at a 2 θ -angle using Cu-Kalpha radiation.
  11. 11. Crystalline form E of the monohydrochloride salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone according to claim 10, characterized in that the initial melting temperature of form E is about 225 ℃.
  12. 12. A process for preparing crystalline form E of the monohydrochloride salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone according to claim 10 or 11, characterized in that the process comprises the steps of:
    (1) reacting (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone with hydrochloric acid in a mixed solvent of ethyl acetate and ethanol in a volume ratio of 7 to 8 to prepare a solution containing a monohydrochloride salt of (R) -1- (3- (4-amino- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone;
    (2) lowering the temperature of the solution obtained in step (1) to room temperature and stirring it for 10 to 12 hours;
    (3) filtering the solution obtained in step (2), and drying the filter cake at a temperature of 45-55 ℃ for 8-10 hours; and
    (4) the crystals were collected.
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