CN117327066A

CN117327066A - Novel polymorphic form, preparation method thereof and application of novel polymorphic form in preparation of medicines

Info

Publication number: CN117327066A
Application number: CN202310790605.4A
Authority: CN
Inventors: 李晶; 姜伟明; 姜秀召
Original assignee: Shanghai Jiyu Pharmaceutical Technology Co ltd
Current assignee: Shanghai Jiyun Biotechnology Co ltd
Priority date: 2022-06-30
Filing date: 2023-06-29
Publication date: 2024-01-02

Abstract

本发明涉及一种新多晶型、其制备方法及其用于制备药物的用途，涉及N‑[[7‑羟基‑5‑(2‑苯乙基)[1,2,4]三唑并[1,5‑a]吡啶‑8‑基]羰基]甘氨酸(式(I))的新多晶型，具体地，包含新晶型A1，晶型K，晶型H，晶型J，晶型I和晶型AA。本发明还涉及式(I)化合物的多晶型的制备方法。本发明进一步还涉及包含所述晶型的药物组合物，以及所述晶型用于制备治疗非透析患者肾性贫血、腹膜透析患者肾性贫血和血液透析患者的肾性贫血药物中的用途。 The present invention relates to a new polymorph, a method for its preparation and its use for the preparation of medicaments, involving N-[[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo New polymorphic forms of [1,5-a]pyridin-8-yl]carbonyl]glycine (formula (I)), specifically, include new crystalline form A1, crystalline form K, crystalline form H, crystalline form J, crystalline form Form I and Form AA. The present invention also relates to methods for the preparation of polymorphic forms of compounds of formula (I). The present invention further relates to a pharmaceutical composition comprising the crystalline form, and the use of the crystalline form for preparing a medicament for treating renal anemia in non-dialysis patients, renal anemia in peritoneal dialysis patients and hemodialysis patients.

Description

Novel polymorphic form, preparation method thereof and application of novel polymorphic form in preparation of medicines

Technical Field

The invention belongs to the field of pharmaceutical crystal forms, and particularly relates to a novel polymorphism of N- [ [ 7-hydroxy-5- (2-phenethyl) [1,2,4] triazolo [1,5-a ] pyridin-8-yl ] carbonyl ] glycine, and a preparation method and application of the polymorphism.

Background

The incidence rate of Chronic Kidney Disease (CKD) of adults in China is as high as 10.8%, and about 1.2 hundred million patients exist. Anemia is one of the major complications of CKD during renal decompensation. More than 50% of CKD patients in our country have combined anemia. The incidence rate of chronic anemia in dialysis and non-dialysis patients is up to 98.2% and 52.1%, respectively, while the treatment standard rate of anemia in dialysis and non-dialysis patients is only 21.3% and 8.2%.

N- [ [ 7-hydroxy-5- (2-phenethyl) [1,2,4] triazolo [1,5-a ] pyridin-8-yl ] carbonyl ] glycine (formula (I)) is an orally active hypoxia inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that, by inhibiting the action of Prolyl Hydroxylase (PH), immobilizes HIF in the kidney and liver, increases endogenous erythropoiesis, upregulates expression of transferrin receptor, increases iron uptake by erythrocytes, and promotes hemoglobin-rich erythrocyte maturation. Can be used for treating renal anemia of non-dialysis patient, renal anemia of peritoneal dialysis patient, renal anemia of hemodialysis patient, etc. The structural formula of the formula (I) is shown as follows:

patent CN102471337B discloses compounds of formula (I) and a process for their preparation. Patent application US2020/0017492A1 discloses a crystalline form of formula (I), but its physicochemical properties are not investigated.

The polymorphs of the same drug may alter its physicochemical properties such as solubility, dissolution rate, melting point and stability, which in turn may affect the efficacy of the drug in humans. Therefore, the comprehensive and systematic crystal form screening of the formula (I) is necessary, and the crystal form with small hygroscopicity and high stability is developed, so that more and better choices are provided for the subsequent development of medicines.

Disclosure of Invention

The crystal forms of the compounds shown in the formula (I) are disclosed, but the preparation method, the advantages and the application value of the compounds are not disclosed. Based on the above, the inventors have conducted comprehensive crystal form screening on the compound of formula (I), and provided crystal forms A1, K, H, J, I and AA of the compound of formula (I), a method for preparing the foregoing crystal forms, and a pharmaceutical composition comprising the same, which can greatly improve the application value of the compound of formula (I).

In one aspect of the invention, the invention provides crystalline form A1 of the compound of formula (I), the X-ray powder diffraction pattern of form A1 having characteristic diffraction peaks at the following 2Θ angles: 7.0 ° ± 0.2 °, 18.5 ° ± 0.2 °, 21.3 ° ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of form A1 has characteristic diffraction peaks at the following 2θ angles: 7.0 ° ± 0.2 °, 18.5 ° ± 0.2 °, 19.4 ° ± 0.2 °, 21.3 ° ± 0.2 °, 26.6 ° ± 0.2 °, 27.5 ° ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of form A1 has characteristic diffraction peaks at the following 2θ angles: 7.0 ° ± 0.2 °, 9.8 ° ± 0.2 °, 16.4 ° ± 0.2 °, 18.5 ° ± 0.2 °, 19.4 ° ± 0.2 °, 21.3 ° ± 0.2 °, 25.1 ° ± 0.2 °, 26.6 ° ± 0.2 °, 27.5 ° ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of form A1 has an X-ray powder diffraction pattern substantially as shown in figure 1.

According to the invention, the crystal form A1 is an anhydrous crystal form.

According to the invention, the differential scanning calorimetric DSC curve of the crystal form A1 contains 1 endothermic peak at the position of 183.9 ℃ + -3 ℃ (initial temperature).

Preferably, the differential scanning calorimeter DSC profile for form A1 is shown in figure 7.

According to the present invention, the thermogravimetric analysis TGA curve of the crystalline form A1 is shown in fig. 8.

According to the invention, the crystal form A1 ¹ The H NMR spectrum is shown in FIG. 9.

The invention also provides a preparation method of the compound of formula (I) in crystal form A1, which comprises the following steps:

dissolving a compound shown in a formula (I) in cyclic ethers, ketones, halogenated hydrocarbons, alcohols, alkyl nitriles, aromatic hydrocarbons, hetero nitrogen, pure water or a mixed solvent thereof, volatilizing at a certain temperature in an open way, and separating out solids to obtain a crystal form A1;

in some embodiments of the invention, the heteronitrogen-based solvent may be selected from N, N-dimethylformamide or N, N-dimethylacetamide;

the ketone solvent may be selected from 2-butanone or methyl isobutyl ketone;

the cyclic ether solvent can be selected from tetrahydrofuran, 2-methyltetrahydrofuran or 1, 4-dioxane;

the alcoholic solvent may be selected from isopropanol;

The alkyl nitrile solvent may be selected from acetonitrile;

the aromatic solvent may be selected from meta-xylene;

in some embodiments of the invention, the mixed solvent may be tetrahydrofuran and methyl isobutyl ketone;

in some embodiments of the present invention, the mixed solvent may be tetrahydrofuran and dichloromethane;

in some embodiments of the invention, the mixed solvent may be 1, 4-dioxane and isopropanol;

in some embodiments of the invention, the mixed solvent may be 1, 4-dioxane and acetonitrile;

in some embodiments of the invention, the mixed solvent may be 1, 4-dioxane and meta-xylene;

in some embodiments of the invention, the volatilization temperature can be 20 ℃ to 90 ℃.

Alternatively, the present invention also provides a second process for the preparation of crystalline form A1 of the compound of formula (I), which according to the present invention comprises:

dissolving a compound of the formula (I) in ketone, alcohol, hetero-nitrogen, halogenated hydrocarbon and mixed solvents thereof at a certain temperature, and cooling until solid is separated out to obtain a crystal form A1;

in some embodiments of the invention, the ketone solvent may be selected from acetone or 2-butanone;

the alcoholic solvent may be selected from methanol;

the hetero-nitrogen solvent may be selected from N-methyl pyrrolidone;

The halogenated hydrocarbon solvent may be selected from dichloromethane;

in some embodiments of the invention, the mixed solvent may be methanol and 2-butanone;

in some embodiments of the present invention, the volume ratio of the methanol to the 2-butanone in the mixed solvent may be 1:1;

in some embodiments of the invention, the mixed solvent may be N-methylpyrrolidone and methylene chloride;

in some embodiments of the present invention, the volume ratio of the N-methylpyrrolidone and dichloromethane in the mixed solvent may be 1:49;

in some embodiments of the invention, the dissolution temperature may be 40 ℃ to 60 ℃, preferably 50 ℃ to 55 ℃.

In some embodiments of the invention, the precipitation temperature may be-30℃to 10 DEG C

Alternatively, the present invention also provides a process for preparing form A1 of the compound of formula (I), which process comprises, according to the invention:

dissolving the compound shown in the formula (I) in cyclic ether or hetero-nitrogen solvents, dripping pure water into the solution at a certain temperature, stirring, and separating out solids to obtain a crystal form A1;

in some embodiments of the invention, the heteronitrogen-based solvent may be selected from N-methylpyrrolidone, N-dimethylacetamide or N, N-dimethylformamide;

the ether solvent may be selected from tetrahydrofuran or 1, 4-dioxane.

In some embodiments of the invention, the precipitation temperature is from 0 ℃ to 50 ℃.

dissolving a compound of the formula (I) in good solvents such as alcohols, halogenated hydrocarbons, hetero nitrogen, cyclic ethers or mixed solvents thereof, placing the solution in an open manner, and performing gas-liquid diffusion in the atmosphere of poor solvents such as ethers, esters, ketones, alkyl nitriles or pure water for 1-2 weeks, and separating out solids to obtain a crystal form A1;

in some embodiments of the invention, the good solvent:

the alcoholic solvent may be selected from methanol;

the halogenated hydrocarbon solvent may be selected from dichloromethane;

the heteronitrogen-based solvent may be selected from pyridine;

the cyclic ether solvent may be selected from tetrahydrofuran;

in some embodiments of the present invention, the mixed solvent in the good solvent may be methanol and dichloromethane;

in some embodiments of the present invention, the volume ratio of the methanol to the dichloromethane in the mixed solvent may be 1:1;

in some embodiments of the present invention, the mixed solvent in the good solvent may be pyridine and tetrahydrofuran;

in some embodiments of the present invention, the volume ratio of the pyridine to the tetrahydrofuran in the mixed solvent is 1:1;

In some embodiments of the invention, in the poor solvent:

the ether solvent may be selected from anisole;

the ester solvent may be selected from ethyl acetate;

the ketone solvent may be selected from cyclohexanone or methyl isobutyl ketone;

the alkyl nitrile solvent may be selected from acetonitrile.

In a further aspect of the invention, the invention also provides form K of the compound of formula (I), the X-ray powder diffraction pattern of form K having characteristic diffraction peaks at the following 2-theta angles: 6.9 ° ± 0.2 °, 13.9 ° ± 0.2 °, 17.4 ° ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of form K has characteristic diffraction peaks at the following 2θ angles: 6.9 ° ± 0.2 °, 13.9 ° ± 0.2 °, 17.4 ° ± 0.2 °, 18.5 ° ± 0.2 °, 22.8 ° ± 0.2 °, 24.4 ° ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of form K has characteristic diffraction peaks at the following 2θ angles: 6.9 ° ± 0.2 °, 11.9 ° ± 0.2 °, 13.9 ° ± 0.2 °, 16.7 ° ± 0.2 °, 17.4 ° ± 0.2 °, 18.5 ° ± 0.2 °, 19.6 ° ± 0.2 °, 22.8 ° ± 0.2 °, 24.4 ° ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of form K has an X-ray powder diffraction pattern substantially as shown in figure 2.

According to the invention, the crystal form K is an anhydrous crystal form.

According to the invention, the differential scanning calorimetric DSC curve of form K contains 2 endothermic peaks at the positions of 172.6deg.C.+ -. 3 ℃ and 183.9deg.C.+ -. 3 ℃ (initial temperature).

Preferably, the differential scanning calorimeter DSC curve for form K is shown in figure 10.

According to the present invention, the thermogravimetric analysis TGA curve of form K is shown in fig. 11.

According to the invention, form K ¹ The H NMR spectrum is shown in FIG. 12.

The invention also provides a preparation method of the compound of the formula (I) in crystal form K, which comprises the following steps:

dissolving a compound of the formula (I) in ethers, esters, halogenated hydrocarbons, aromatic hydrocarbons or hetero nitrogen or a mixed solvent thereof, volatilizing the compound to solid at a certain temperature, and obtaining a crystal form K;

in some embodiments of the invention, the heteronitrogen-based solvent may be selected from N-methylpyrrolidone or N, N-dimethylacetamide;

the ester solvent may be selected from methyl acetate;

the ether solvent may be selected from 2-methyltetrahydrofuran, 1, 4-dioxane or methyl tertiary butyl ether;

the aromatic solvent may be selected from toluene;

the halogenated hydrocarbon solvent may be selected from dichloromethane;

in some aspects of the invention, the clearing temperature may be from 0 ℃ to 50 ℃, preferably from 20 ℃ to 30 ℃;

In some embodiments of the invention, the volatilization temperature can be 20 ℃ to 30 ℃.

Alternatively, the present invention also provides a second preparation method of the compound of formula (I) form K, which according to the present invention comprises:

dissolving a compound of the formula (I) in a cyclic ether solvent, placing the solution in an open manner in a ketone solvent atmosphere for gas-liquid diffusion, and separating out solids after 1-2 weeks to obtain a crystal form K;

in some embodiments of the invention, the cyclic ether solvent may be selected from tetrahydrofuran;

the ketone solvent may be selected from methyl isobutyl ketone.

In a further aspect of the invention, the invention also provides form H of the compound of formula (I), the X-ray powder diffraction pattern of form H having characteristic diffraction peaks at the following 2θ angles: 5.1 ° ± 0.2 °, 11.1 ° ± 0.2 °, 16.7 ° ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of form H has characteristic diffraction peaks at the following 2θ angles: 5.1 ° ± 0.2 °, 11.1 ° ± 0.2 °, 12.6 ° ± 0.2 °, 16.7 ° ± 0.2 °, 19.0 ° ± 0.2 °, 23.8 ° ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of form H has characteristic diffraction peaks at the following 2θ angles: 5.1 ° ± 0.2 °, 11.1 ° ± 0.2 °, 12.6 ° ± 0.2 °, 14.7 ° ± 0.2 °, 16.7 ° ± 0.2 °, 18.3 ° ± 0.2 °, 19.0 ° ± 0.2 °, 23.8 ° ± 0.2 °, 27.1 ° ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of form H has an X-ray powder diffraction pattern substantially as shown in figure 3.

According to the invention, the differential scanning calorimetric DSC curve of form H contains 2 endothermic peaks at the positions of 172.5.+ -. 3 ℃ and 183.5.+ -. 3 ℃ (initial temperature).

Preferably, the differential scanning calorimeter DSC curve for form H is shown in figure 13.

According to the present invention, the thermogravimetric analysis TGA curve of form H is shown in fig. 14.

According to the invention, the crystal form H ¹ The H NMR spectrum is shown in FIG. 15.

The invention also provides a preparation method of the compound of formula (I) in crystal form H, which comprises the following steps:

dissolving a compound of the formula (I) in an ether solvent, volatilizing the compound in an open way at a certain temperature until solid is separated out to obtain a crystal form H;

in some embodiments of the invention, the ethereal solvent may be selected from 1, 4-dioxane.

In some embodiments of the invention, the volatilization temperature can be from 0℃to 50℃and preferably from 20℃to 30 DEG C

In yet another aspect of the invention, the invention also provides crystalline form J of the compound of formula (I), the X-ray powder diffraction pattern of form J having characteristic diffraction peaks at the following 2-theta angles: 8.2 ° ± 0.2 °, 9.6 ° ± 0.2 °, 17.5 ° ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of form J has characteristic diffraction peaks at the following 2θ angles: 8.2 ° ± 0.2 °, 9.6 ° ± 0.2 °, 11.3 ° ± 0.2 °, 17.5 ° ± 0.2 °, 19.5 ° ± 0.2 °, 24.0 ° ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of form J has characteristic diffraction peaks at the following 2θ angles: 8.2 ° ± 0.2 °, 9.6 ° ± 0.2 °, 11.3 ° ± 0.2 °, 13.4 ° ± 0.2 °, 14.2 ° ± 0.2 °, 17.5 ° ± 0.2 °, 19.5 ° ± 0.2 °, 24.0 ° ± 0.2 °, 26.1 ° ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of form J has an X-ray powder diffraction pattern substantially as shown in figure 4.

According to the invention, the differential scanning calorimetric analysis DSC curve of the crystal form J contains 3 endothermic peaks at the positions of 93.3+/-3 ℃, 163.9 +/-3 ℃ and 178.5+/-3 ℃ (initial temperature), and 2 exothermic peaks at the positions of 121.4+/-3 ℃ and 173.1+/-3 ℃ (peak temperature).

Preferably, the differential scanning calorimeter DSC profile for form J is shown in figure 16.

According to the present invention, the thermogravimetric analysis TGA curve of form J is shown in fig. 17.

According to the invention, form J ¹ The H NMR spectrum is shown in FIG. 18.

The invention also provides a preparation method of the compound of the formula (I) in the crystal form J, which comprises the following steps:

Dissolving a compound of the formula (I) in an alcohol solvent, volatilizing at a certain temperature in an open way, and separating out solids to obtain a crystal form J;

in some embodiments of the invention, the alcoholic solvent may be selected from ethanol;

in some embodiments of the invention, the volatilization temperature can be 50 ℃ to 90 ℃, preferably 80 ℃ to 90 ℃.

Alternatively, the present invention also provides a second process for the preparation of crystalline form J of the compound of formula (I), which process comprises, according to the invention:

dissolving a compound of the formula (I) in an alcohol solvent at a certain temperature, and cooling until solid is separated out to obtain a crystal form J;

in some embodiments of the invention, the alcoholic solvent may be selected from methanol;

in some aspects of the invention, the dissolution temperature may be 40 ℃ to 60 ℃, preferably 50 ℃ to 55 ℃;

in some embodiments of the invention, the precipitation temperature may be-30℃to 10℃and preferably-30℃to-20 DEG C

In a further aspect of the invention, the invention also provides crystalline form I of the compound of formula (I). According to the invention, the X-ray powder diffraction pattern of form I has characteristic diffraction peaks at the following 2θ angles: 5.0 ° ± 0.2 °, 7.2 ° ± 0.2 °, 26.9 ° ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of form I has characteristic diffraction peaks at the following 2θ angles: 5.0 ° ± 0.2 °, 7.2 ° ± 0.2 °, 9.6 ° ± 0.2 °, 17.5 ° ± 0.2 °, 19.2 ° ± 0.2 °, 26.9 ° ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of form I has an X-ray powder diffraction pattern substantially as shown in figure 5.

According to the invention, the differential scanning calorimetric DSC curve of form I contains 3 endothermic peaks at 75.7deg.C.+ -. 3 ℃, 171.1deg.C.+ -. 3 ℃ and 183.1deg.C.+ -. 3 ℃ (initial temperature) and 2 exothermic peaks at 121.1deg.C.+ -. 3 ℃ and 175.9deg.C.+ -. 3 ℃ (peak temperature).

Preferably, the differential scanning calorimeter DSC curve for form I is shown in figure 19.

According to the present invention, the thermogravimetric analysis TGA profile of form I is shown in figure 20.

According to the invention, the crystal form I ¹ The H NMR spectrum is shown in FIG. 21.

The invention also provides a preparation method of the compound of formula (I) in crystal form I, which comprises the following steps:

putting a compound of the formula (I) into halohydrocarbons, alcohols or mixed solvents thereof, dissolving at a certain temperature, filtering, volatilizing at an open mouth, and separating out solids to obtain a crystal form I;

in some embodiments of the present invention, the halogenated hydrocarbon solvent may be selected from methylene chloride;

the alcoholic solvent may be selected from methanol;

in some embodiments of the invention, the mixed solvent may be dichloromethane and methanol;

In some embodiments of the present invention, the ratio of dichloromethane to methanol in the mixed solvent may be 1:1;

in some embodiments of the invention, the dissolution temperature may be from 0 ℃ to 60 ℃, preferably from 40 ℃ to 50 ℃;

in some aspects of the invention, the volatilization temperature can be from 0 ℃ to 50 ℃, preferably from 20 ℃ to 30 ℃;

in a further aspect of the invention, the invention also provides crystalline form AA of the compound of formula (I), the X-ray powder diffraction pattern of which has characteristic diffraction peaks at the following 2θ angles: 5.6 ° ± 0.2 °, 6.7 ° ± 0.2 °, 17.5 ° ± 0.2 °, 18.1 ° ± 0.2 °, 26.4 ° ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of form AA has an X-ray powder diffraction pattern substantially as shown in figure 6.

According to the invention, the differential scanning calorimetric analysis DSC curve of the crystal form AA contains 2 endothermic peaks at the positions of 152.4+/-3 ℃ and 173.9 +/-3 ℃ (initial temperature), and 2 exothermic peaks at the positions of 107.4+/-3 ℃ and 168.2+/-3 ℃ (peak temperature).

Preferably, the differential scanning calorimeter DSC profile of form AA is shown in figure 22.

The thermogravimetric analysis TGA curve of form AA according to the present invention is shown in figure 23.

The invention also provides a preparation method of the compound of formula (I) in crystal form AA, which comprises the following steps:

dissolving the compound of the formula (I) in an ether solvent, dripping the ester solvent into the solution at a certain temperature, and volatilizing until solid is separated out to obtain a crystal form AA;

in some embodiments of the invention, the ethereal solvent may be selected from 1, 4-dioxane;

the ester solvent may be selected from ethyl lactate;

in some embodiments of the invention, the dissolution and volatilization temperatures can range from 0 ℃ to 50 ℃.

In a further aspect of the invention, the invention also proposes a pharmaceutical composition comprising one or more of form A1, form K, form H, form J, form I or form AA of the aforementioned compound of formula (I), or one or more polymorphs of one or more of form A1, form K, form H, form J, form I or form AA of the compound of formula (I) prepared according to the aforementioned method, and optionally one or more pharmaceutically acceptable excipients or diluents.

In a further aspect of the invention, the invention also provides the use of one or more of form A1, form K, form H, form J, form I or form AA of the aforementioned compound of formula (I), or one or more polymorphs of one or more of form A1, form K, form H, form J, form I or form AA of the aforementioned compound of formula (I), or the aforementioned pharmaceutical composition, prepared according to the aforementioned method, in the preparation of HIF-PH inhibitors.

In a further aspect of the invention, the invention also provides the use of one or more of form A1, form K, form H, form J, form I or form AA of the aforementioned compound of formula (I), or one or more polymorphs of form A1, form K, form H, form J, form I or form AA of the compound of formula (I) prepared according to the aforementioned method, or of the aforementioned pharmaceutical composition for the preparation of a medicament for the treatment of renal anaemia in non-dialysis patients, renal anaemia in peritoneal dialysis patients and renal anaemia in hemodialysis patients.

Compared with the prior art, the crystal forms A1, K, H, J, I and AA of the formula (I) have advantages in at least one of solubility, melting point, stability, dissolution, hygroscopicity, adhesiveness, fluidity, bioavailability, processability, purification effect, preparation production, safety and the like, provide new and better choices for preparing the HIF-PH inhibitor pharmaceutical preparation, and have very important significance for drug development.

Definition and description

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.

"crystalline form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single or multicomponent crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of the compounds. The crystalline form of a substance may be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, e.g., in a nanopore or capillary, crystallization on a surface or template, e.g., on a polymer, crystallization in the presence of additives such as co-crystallizing anti-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, solvent drop milling, and the like.

"amorphous" or "amorphous form" refers to a substance that forms when particles (molecules, atoms, ions) of the substance are non-periodically arranged in three dimensions, characterized by a diffuse, non-spiking X-ray powder diffraction pattern. Amorphous is a special physical form of solid material whose locally ordered structural features suggest a myriad of interactions with crystalline material. Amorphous forms of a substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, among others.

"solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

"antisolvent" refers to a fluid that facilitates precipitation of a product (or product precursor) from a solvent. The antisolvent may comprise a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.

"solvate" means crystals having a solvent on or in the surface, or both, wherein the solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloro alkane, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like. A specific example of a solvate is a hydrate, wherein the solvent on the surface, or in the lattice, or both is water. The hydrate may or may not have other solvents than water on the surface of the substance, or in the crystal lattice, or both.

Crystalline forms or amorphous forms may be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point, differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning Electron Microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.

The X-ray powder diffraction (XRPD) can detect the information of crystal form change, crystallinity, crystal structure state and the like, and is a common means for identifying the crystal form. The peak positions of the XRPD patterns are largely dependent on the structure of the crystalline form, relatively insensitive to experimental details, and their relative peak heights depend on many factors related to sample preparation and instrument geometry. Thus, in some embodiments, the crystalline forms of the invention are characterized by XRPD patterns having certain peak locations, substantially as shown in the XRPD patterns provided in the figures of the invention. Meanwhile, the measure of 2θ of the XRPD pattern may have experimental errors, and the measure of 2θ of the XRPD pattern may slightly differ from instrument to instrument and sample to sample, so the value of 2θ cannot be regarded as absolute. Depending on the instrument conditions used in the test according to the invention, diffraction peaks have a margin of error of + -0.2 deg..

Differential Scanning Calorimeter (DSC) is a method for measuring the temperature of a sample and an inert reference substance (commonly used alpha-Al) by continuously heating or cooling under the control of a program ₂ O ₃ ) A technique in which the energy difference between them varies with temperature. The melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline forms of the invention are characterized by DSC curves having characteristic peak positions substantially as shown in the DSC curves provided in the figures of the invention. Meanwhile, the DSC curve may have experimental errors, and the peak position and peak value of the DSC curve may slightly differ from instrument to instrument and from sample to sample, so that the peak position or the value of the DSC endothermic peak cannot be regarded as absolute. Depending on the instrument conditions used in the test according to the invention, melting peaks have an error margin of + -3 ℃.

Solids of the same chemical composition often form, under different thermodynamic conditions, isoforms of different crystal structures, or variants, a phenomenon known as polymorphism or homopoly-phase. When temperature and pressure conditions change, a mutual transition occurs between variants, a phenomenon known as crystalline transformation. The mechanical, electrical, magnetic and other properties of the crystal can be changed greatly due to the crystal form transformation. When the temperature of the transition of the crystal form is within a measurable range, the transition is observed on a Differential Scanning Calorimeter (DSC) curve, which is characterized in that the DSC curve has an exothermic peak reflecting the transition and simultaneously has two or more endothermic peaks, which are characteristic endothermic peaks of different crystal forms before and after the transition, respectively. The crystalline or amorphous form of the compounds of the invention may undergo a crystalline transformation under appropriate conditions.

Thermogravimetric analysis (TGA) is a technique for measuring the mass of a substance as a function of temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition processes of a sample, and can be used to infer the presence of water of crystallization or a crystallization solvent in the crystal. The quality change exhibited by the TGA profile depends on many factors such as sample preparation and instrumentation; the quality of TGA detection varies slightly from instrument to instrument and from sample to sample. In some embodiments, calcium salt form a of the present invention loses about 5.1% weight at about 150 ℃. Depending on the instrument conditions used for the test according to the invention, there is a margin of error of + -0.3% for the mass change.

In the context of the present invention, the 2 theta values in the X-ray powder diffraction pattern are all in degrees (°).

The term "room temperature" in the present invention generally means 22℃to 28℃unless otherwise specified.

The term "substantially as shown in the figures" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern are shown in the figure.

When referring to a spectrogram or/and data appearing in the graph, a "peak" refers to a feature that one skilled in the art can recognize that is not attributable to background noise.

In the context of the present invention, when used or whether or not the word "about" or "about" is used, means within 10%, suitably within 5%, particularly within 1% of a given value or range. Alternatively, the term "about" or "approximately" means within an acceptable standard error of the average value to one of ordinary skill in the art. Whenever a number is disclosed having a value of N, any number within the values of N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+/-10% will be explicitly disclosed, where "+/-" means plus or minus.

The term "comprising" is an open-ended expression, i.e. including what is indicated by the invention, but not excluding other aspects.

Drawings

FIG. 1 is an XRPD pattern for form A1 according to example 1 of the invention;

FIG. 2 is an XRPD pattern for form K according to example 23 of the invention;

FIG. 3 is an XRPD pattern for form H according to embodiment 29 of the invention;

FIG. 4 is an XRPD pattern for form J according to embodiment 30 of the invention;

FIG. 5 is an XRPD pattern for form I according to embodiment 32 of the invention;

FIG. 6 is an XRPD pattern for form AA in accordance with example 33 of the invention;

FIG. 7 is a DSC curve of form A1 of example 1 according to the present invention;

FIG. 8 is a TGA curve of form A1 according to example 1 of the present invention;

FIG. 9 is a crystalline form A1 according to example 1 of the present invention ¹ H NMR spectrum;

FIG. 10 is a DSC curve of form K according to example 23 of the present invention;

FIG. 11 is a TGA curve of form K according to example 23 of the present invention;

FIG. 12 is form K of example 23 according to the invention ¹ H NMR spectrum;

FIG. 13 is a DSC curve of form H according to example 29 of the present invention;

FIG. 14 is a TGA curve of form H according to example 29 of the present invention;

FIG. 15 is form H of example 29 according to the invention ¹ H NMR spectrum;

FIG. 16 is a DSC curve of form J according to example 30 of the present invention;

FIG. 17 is a TGA curve of form J according to example 30 of the present invention;

FIG. 18 is form J of example 30 according to the invention ¹ H NMR spectrum;

FIG. 19 is a DSC curve of form I according to example 32 of the present invention;

FIG. 20 is a TGA curve of form I according to example 32 of the present invention;

FIG. 21 is form I of example 32 according to the invention ¹ H NMR spectrum;

FIG. 22 is a DSC curve of form AA in accordance with example 33 of the present invention;

FIG. 23 is a TGA curve of form AA according to example 33 of the present invention;

FIG. 24 is an XRPD pattern for form A1 of example 2 according to the invention;

FIG. 25 is an XRPD pattern for form A1 of example 14 according to the invention;

FIG. 26 is an XRPD pattern for form A1 of example 15 according to the invention;

FIG. 27 is an XRPD pattern for form A1 of example 21 according to the invention;

FIG. 28 is an XRPD pattern for form K of example 28 according to the invention;

FIG. 29 is a DVS curve for form A1 according to example 2 of the present invention;

FIG. 30 is a DVS curve of a crystalline form disclosed in the prior art;

FIG. 31 is a graphical representation of XRPD patterns for form A1 of example 2 according to the invention, placed at 25 ℃/60% RH for 56 days;

FIG. 32 is a graphical representation of XRPD patterns for form A1 of example 2 according to the invention, placed at 40 ℃/75% RH for 56 days;

FIG. 33 is a graph showing the XRPD patterns of form A1 after it has been placed under light (1.2 x 10 x 6lux. H) in accordance with example 2 of the present invention;

FIG. 34 is a graphical representation of the XRPD patterns of the crystalline forms disclosed in the prior art when placed at 25 ℃/60% RH for 56 days;

FIG. 35 is a graphical representation of the XRPD patterns of the crystalline forms disclosed in the prior art when placed at 40 ℃/75% RH for 56 days;

FIG. 36 is a graph comparing XRPD patterns of crystalline forms disclosed in the prior art after being placed under light (1.2X10-lux. H).

Detailed Description

The present application is described in detail below by way of examples, but is not meant to be limiting in any way. The present application has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the application.

The raw materials used in the present invention are commercially available unless otherwise specified.

The abbreviations used in the present invention are explained as follows:

XRPD: powder diffraction by X-rays

DSC: differential scanning calorimetric analysis

TGA: thermogravimetric analysis

¹ H NMR: liquid hydrogen spectrum nuclear magnetism

HPLC: high performance liquid chromatography

The X-ray powder diffraction range of the invention is collected on a Bruker D2 type ray powder diffractometer. The X-ray powder diffraction method parameters of the invention are as follows:

x-ray light source:1.54184

voltage: 30 kilovolts (kV)

Current flow: 10 milliamperes (mA)

Scanning range: from 3.0 to 50.0 DEG

The differential scanning calorimeter curve described in the present invention was collected on a DSC type 3 differential scanning calorimeter from Metrele company. The method parameters of the differential scanning calorimetric analysis are as follows:

scanning rate: 10 ℃/min

Protective gas: nitrogen gas

The thermogravimetric analysis curve described in the present invention was collected on a TGA 2-type synchronous thermal analyzer from meltler company. The method parameters of thermogravimetric analysis are as follows:

scanning rate: 10 ℃/min

Protective gas: nitrogen gas

The liquid nuclear magnetic hydrogen spectrum is collected on an Assetnd 400 liquid nuclear magnetic analyzer of Bruker (Broker) company, and the solvent is DMSO-d6.

The starting compounds of the compound (I) used in the examples below can be prepared according to the prior art, for example in patent CN102471337B, but the starting crystalline form is not a limitation of the preparation of the crystalline form of the invention.

Examples 1 to 11: preparation of Crystal form A1 (volatilization method)

Under the condition of room temperature, weighing a certain mass of a compound of formula (I) in a small bottle, adding a proper amount of solvent for dissolution, passing through a nylon filter head with the diameter of 0.45 microns to obtain a clear solution, and volatilizing the clear solution under the condition of room temperature or high temperature to obtain a crystal form A1.

The detailed test conditions in this example are shown in Table 1. The X-ray powder diffraction data for the samples of example 1 are shown in table 2, the diffraction pattern is shown in figure 1, the DSC curve is shown in figure 7, the TGA curve is shown in figure 8, ¹ the H NMR spectrum is shown in FIG. 9. The X-ray powder diffraction data of the sample of example 2 are shown in table 3 and the diffraction pattern is shown in fig. 24.

TABLE 1

TABLE 2

TABLE 3 Table 3

Examples 12 to 14: preparation of Crystal form A1 (Rapid Cooling method)

Under the condition of room temperature, weighing a certain mass of a compound of formula (I) in a small bottle, adding a proper amount of solvent at 50 ℃, stirring for 1-2 hours, filtering by using a nylon filter head with the diameter of 0.45 micrometers, directly placing the filtrate in a refrigerator with the temperature of minus 30 ℃, and separating out solids to obtain a crystal form A1.

The detailed test conditions in this example are shown in Table 4. The X-ray powder diffraction data of the sample of example 14 are shown in table 5 and the diffraction pattern is shown in fig. 25.

TABLE 4 Table 4

Examples	Solid mass (mg)	Solvent (volume ratio)	Volume (milliliter)
				12	31.5	Methanol/2-butanone (1:1)	1.0
13	31.8	N-methylpyrrolidone/dichloromethane (1:49)	1.0
				14	31.5	Acetone (acetone)	1.0

TABLE 5

Examples 15 to 19: preparation of Crystal form A1 (antisolvent addition method)

Under the condition of room temperature, weighing a certain mass of a compound of formula (I) in a small bottle, adding a certain volume of good solvent for dissolution, filtering by a nylon filter head with the diameter of 0.45 microns, dripping pure water into the filtrate, and separating out solids to obtain a crystal form A1.

The detailed test conditions in this example are shown in Table 6. The X-ray powder diffraction data of the sample of example 15 are shown in table 7 and the diffraction pattern is shown in fig. 26.

TABLE 6

TABLE 7

Examples 20 to 22: preparation of Crystal form A1 (gas-liquid diffusion method)

And (3) taking a certain mass of the compound of the formula (I) in a small bottle at room temperature, adding a proper amount of good solvent for dissolution, filtering by a nylon filter head of 0.45 microns, placing the small bottle containing the clarified solution in a 20 ml glass bottle containing 4 ml of anti-solvent, and standing until a solid is separated out, thus obtaining the crystal form A1.

The detailed test conditions in this example are shown in Table 8. The X-ray powder diffraction data of the sample of example 21 are shown in table 9 and the diffraction pattern is shown in fig. 27.

TABLE 8

Examples	Solid mass (mg)	Good solvent	Antisolvents
				20	30.0	Tetrahydrofuran (THF)	Acetic acid isopropyl ester
21	30.0	Tetrahydrofuran (THF)	Anisole (anisole)
				22	30.0	1, 4-Dioxahexacyclic ring	Anisole (anisole)

TABLE 9

Example 23: preparation of Crystal form K (gas-liquid diffusion method)

About 30 mg of the compound of formula (I) was taken in a vial, dissolved in tetrahydrofuran and filtered through a 0.45 μm nylon filter headFiltering, placing the vial containing the clarified solution into a 20 ml glass bottle containing 4 ml of methyl isobutyl ketone, standing for 1-2 weeks, and separating out solids to obtain the crystal form K. The X-ray powder diffraction data are shown in table 10, and the diffraction pattern is shown in fig. 2. The DSC curve is shown in fig. 10, the TGA curve is shown in fig. 11, ¹ HNMR patterns are shown in fig. 12.

Table 10

Examples 24 to 28: preparation of Crystal form K (volatilization method)

Under the condition of room temperature, weighing a certain mass of a compound of formula (I) in a small bottle, adding a proper amount of solvent for dissolution, filtering with a nylon filter head with 0.45 micrometer to obtain a clear solution, and volatilizing the clear solution under the condition of room temperature to obtain the crystal form K.

The detailed test conditions in this example are shown in Table 11. The X-ray powder diffraction data of the sample of example 28 are shown in table 12 and the diffraction pattern is shown in fig. 28.

TABLE 11

Examples	Solid mass (mg)	Solvent (volume ratio)	Volume (milliliter)
				24	30.0	1, 4-Dioxahexacyclic ring/dichloromethane	--
25	30.0	N-methylpyrrolidone/methyl acetate (1:30)	6.2
				26	30.0	N-methylpyrrolidone/toluene (1:30)	6.2
27	30.0	N-methylpyrrolidone/methyl tert-butyl ether (1:30)	6.2
				28	30.0	N, N-dimethylacetamide/2-methyltetrahydrofuran (1:30)	6.2

Table 12

Example 29: preparation of form H

About 30 mg of the compound of formula (I) is taken in a small bottle, and is filtered by a 2.0 ml of 1, 4-dioxane solution, a 0.45-micrometer nylon filter head, and is volatilized open at 20-30 ℃ and solid is separated out, thus obtaining the crystal form H. The X-ray powder diffraction data are shown in table 7, and the diffraction pattern is shown in fig. 3. The DSC curve is shown in fig. 13, the TGA curve is shown in fig. 14, ¹ the H NMR spectrum is shown in FIG. 15.

TABLE 13

Example 30: preparation of Crystal form J (volatilization method)

About 30 mg of the compound of formula (I) is taken in a small bottle, dissolved with 3.4 ml of ethanol, filtered by a 0.45 micron nylon filter head, volatilized open at 80-90 ℃ and precipitated as solid to obtain the crystal form J. The X-ray powder diffraction data are shown in table 14, and the diffraction pattern is shown in fig. 4. The DSC curve is shown in fig. 16, the TGA curve is shown in fig. 17, ¹ the H NMR spectrum is shown in FIG. 18.

TABLE 14

Example 31: preparation of Crystal form J (Rapid Cooling method)

31.9 mg of the compound of formula (I) are weighed into a small bottle, 1.0 ml of methanol is used for stirring for two hours at 50 ℃, the solution is filtered to obtain a clear filtrate, and the clear filtrate is transferred to a temperature of minus 30 ℃ and is kept stand until solid is separated out, so that the crystal form J is obtained.

Example 32: preparation of form I

About 30 mg of the compound of formula (I) is taken in a small bottle, dissolved with 1.0 ml of a mixed solvent of dichloromethane/methanol (volume ratio is 1:1), filtered by a 0.45-micrometer nylon filter head, volatilized open at 20-30 ℃ and separated out of solid to obtain the crystal form I. The X-ray powder diffraction data are shown in table 15, and the diffraction pattern is shown in fig. 5. The DSC curve is shown in fig. 19, the TGA curve is shown in fig. 20, ¹ the H NMR spectrum is shown in FIG. 21.

TABLE 15

Diffraction angle 2 theta	d value	Strength%
			4.97	17.76	42.8
7.20	12.26	33.6
			9.60	9.21	24.5
11.79	7.50	8.6
			12.03	7.35	7.3
17.48	5.07	50.0
			19.22	4.61	24.7
21.19	4.19	8.8
			23.08	3.85	7.3
24.89	3.57	6.2
			26.86	3.32	100.0
29.60	3.02	5.6

Example 33: preparation of crystalline form AA

About 30 mg of the compound of formula (I) is taken in a small bottle, 0.75 ml of 1, 4-dioxane solution is used for filtering by a nylon filter head with the thickness of 0.45 microns, 20.0 ml of ethyl lactate is taken as an antisolvent to be dripped into the small bottle at the temperature of 20-30 ℃, the mixture is stirred overnight, placed at the temperature of minus 30 ℃ for standing solution, and then volatilized in an open mouth to obtain the crystal form AA. The X-ray powder diffraction data are shown in table 16, and the diffraction pattern is shown in fig. 6. The DSC curve is shown in FIG. 22 and the TGA curve is shown in FIG. 23.

Table 16

Diffraction angle 2 theta	d value	Strength%
			5.56	15.88	39.7
6.72	13.14	16.4
			8.83	10.01	77.6
9.52	9.29	30.6
			9.78	9.03	29.7
17.54	5.05	51.1
			18.13	4.89	54.3
20.21	4.39	38.4
			26.41	3.37	100.0

Example 34: study of relative stability

The crystal form of the invention and the crystal form of the prior art (US 2020/0017492A 1) are weighed and subjected to suspension competition test in a saturated solvent, and as a result, the novel crystal form A1 has better stability compared with the crystal form of the prior art.

A small amount of the compound of formula (I) was added to methyl tert-butyl ether, stirred at 50℃for more than 2 hours, kept insoluble and filtered through a 45 μm filter to give a saturated solution. The crystal forms disclosed in the prior art (US 2020/0017492A 1), the novel crystal form A1, the novel crystal form K, the novel crystal form H, the novel crystal form J, the novel crystal form I and the novel crystal form AA are respectively mixed in a small amount, added into 1 ml of saturated solution of methyl tertiary butyl ether, respectively placed at the temperature of 50 ℃ and magnetically stirred for 7 days, and sampled and detected to obtain wet products XRPD. The results indicated that the new form A1 was obtained in this solvent. The suspension competition results are shown in Table 17. Therefore, the novel crystal form A1 can maintain better stability.

TABLE 17

Example 35: comparative study of hygroscopicity

The novel form A1 of the present invention and the prior art (US 2020/0017492A 1) forms were weighed approximately 15 milligrams each for dynamic moisture sorption (DVS) testing, and then sampled for XRPD testing.

Placing the new crystal form A1 in a sample tank of DVS, keeping the temperature unchanged after the mass reaches constant weight under the condition of 25 ℃ and 50% RH, gradually increasing to 95% RH by taking 5% RH as a unit, and entering the next target humidity after the mass of the sample is constant and entering the next target humidity after the mass of the sample is constant; similarly, when the relative humidity reaches 95% RH and the mass is constant, the relative humidity is reduced from 95% RH to 0% RH by taking 5% RH as a unit; and then, the temperature is raised from 0% RH to 95% RH by taking 5% RH as a unit. The mass data at each relative humidity were recorded separately to obtain a DVS curve, as shown in fig. 29

As shown in fig. 29, the mass increased 0.0554% when the relative humidity increased from 0% to 80%.

Placing the crystal form in the prior art (US 2020/0017492A 1) in a sample tank of DVS, keeping the temperature unchanged after the mass reaches constant weight under the condition of 25 ℃ and 50% RH, gradually increasing to 95% RH by taking 5% RH as a unit, and entering the next target humidity after the mass of the sample is constant and the mass of the sample is constant under each relative humidity; similarly, when the relative humidity reaches 95% RH and the mass is constant, the relative humidity is reduced from 95% RH to 0% RH by taking 5% RH as a unit; and then, the temperature is raised from 0% RH to 95% RH by taking 5% RH as a unit. The mass data at each relative humidity was recorded separately to obtain DVS curves, as shown in fig. 30.

As shown in fig. 30, the mass increased 0.1144% when the relative humidity increased from 0% to 80%.

From the above results, it is clear that the novel form A1 of the present invention has lower hygroscopicity than the prior art forms.

Example 36: stability comparison study

An amount of the novel forms A1 and I of the present invention and the forms disclosed in the prior art (US 2020/0017492A 1) were weighed, placed open in a stabilization box under conditions of 25 ℃/60% RH, 40 ℃/75% RH and light (1.2X10-6 lux. H), sampled and tested for XRPD on days 7, 14, 35 and 56, while the chromatographic purity was determined by High Performance Liquid Chromatography (HPLC). From the results, it is clear that the novel form A1 of the present invention and the forms disclosed in the prior art have similar form stability and chemical stability under the above conditions. Stability vs. study data are shown in table 18. XRPD contrast patterns of the novel form A1 stable samples of the present invention are shown in fig. 31-33, and XRPD contrast patterns of the crystalline form stable samples disclosed in the prior art are shown in fig. 34-36.

TABLE 18

In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.

While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims

1. A crystalline form A1 of a compound of formula (I), characterized in that, using Cu-ka radiation, the X-ray powder diffraction of said crystalline form A1 has characteristic peaks at 2Θ values of 7.0 ° ± 0.2 °, 18.5 ° ± 0.2 °, 21.3 ° ± 0.2 °;

2. Form A1 according to claim 1, wherein the X-ray powder diffraction of form A1 has characteristic peaks at 2Θ values of 7.0 ° ± 0.2 °, 18.5 ° ± 0.2 °, 19.4 ° ± 0.2 °, 21.3 ° ± 0.2 °, 26.6 ° ± 0.2 °, 27.5 ° ± 0.2 °.

3. Form A1 according to claim 1, wherein the X-ray powder diffraction of form A1 has characteristic peaks at 2Θ values of 7.0 ° ± 0.2 °, 9.8 ° ± 0.2 °, 16.4 ° ± 0.2 °, 18.5 ° ± 0.2 °, 19.4 ° ± 0.2 °, 21.3 ° ± 0.2 °, 25.1 ° ± 0.2 °, 26.6 ° ± 0.2 °, 27.5 ° ± 0.2 °.

4. Form A1 according to claim 1, wherein the X-ray powder diffraction pattern of form A1 has an X-ray powder diffraction pattern substantially as shown in figure 1.

5. Form A1 according to claim 1, wherein the form A1 is an anhydrous form.

6. A process for the preparation of crystalline form A1 of a compound of formula (I) according to any one of claims 1 to 5, characterized in that it is selected from any one of the following four processes:

1) Dissolving a compound shown in a formula (I) in cyclic ethers, ketones, halogenated hydrocarbons, alcohols, alkyl nitriles, aromatic hydrocarbons, hetero nitrogen, pure water or mixed solvents thereof, volatilizing at 20-90 ℃ in an open way, and separating out solids to obtain a crystal form A1; or (b)

2) Dissolving a compound of the formula (I) in ketone, alcohol, hetero-nitrogen, halogenated hydrocarbon or a mixed solvent thereof at 40-60 ℃, cooling to-30-10 ℃, and separating out solids to obtain a crystal form A1; or (b)

3) Dissolving the compound of the formula (I) in cyclic ether or hetero-nitrogen solvent, dripping pure water into the solution at 0-50 ℃ to obtain a crystal form A1 by solid precipitation; or (b)

4) Dissolving a compound of the formula (I) in alcohols, halogenated hydrocarbons, hetero nitrogen, ethers or mixed solvents thereof, placing the solution in an open mouth, and performing gas-liquid permeation in an ether, ester, ketone solvent or pure water atmosphere for 1-2 weeks, and separating out solids to obtain a crystal form A1.

7. Form K of the compound of formula (I), characterized in that it exhibits, using Cu-ka radiation, an X-ray powder diffraction having characteristic peaks at 2Θ values of 6.9 ° ± 0.2 °, 13.9 ° ± 0.2 °, 17.4 ° ± 0.2 °.

8. Form K of claim 7, wherein the X-ray powder diffraction of form K has characteristic peaks at 2Θ angles of 6.9 ° ± 0.2 °, 13.9 ° ± 0.2 °, 17.4 ° ± 0.2 °, 18.5 ° ± 0.2 °, 22.8 ° ± 0.2 °, 24.4 ° ± 0.2 °.

9. Form K of claim 7, wherein the X-ray powder diffraction of form K has characteristic peaks at 2Θ angles of 6.9 ° ± 0.2 °, 11.9 ° ± 0.2 °, 13.9 ° ± 0.2 °, 16.7 ° ± 0.2 °, 17.4 ° ± 0.2 °, 18.5 ° ± 0.2 °, 19.6 ° ± 0.2 °, 22.8 ° ± 0.2 °, 24.4 ° ± 0.2 °.

10. Form K of claim 7, wherein the X-ray powder diffraction pattern of form K has an X-ray powder diffraction pattern substantially as shown in figure 2.

11. Form K according to claim 7, characterized in that it is an anhydrous form.

12. A process for the preparation of form K of a compound of formula (I) according to any one of claims 7 to 11, characterized in that it is selected from any one of the following two processes:

1) Dissolving a compound of the formula (I) in ethers, esters, halogenated hydrocarbons, aromatic hydrocarbons, hetero nitrogen or a mixed solvent thereof, volatilizing at 20-30 ℃ in an open way, and separating out solids to obtain a crystal form K; or (b)

2) And (3) dissolving the compound shown in the formula (I) in a cyclic ether solvent, placing the solution in an open state under a ketone solvent atmosphere for gas-liquid diffusion, and separating out solids after 1-2 weeks to obtain the crystal form K.

13. Form H of the compound of formula (I) characterized by having characteristic peaks at 2Θ values of 5.1 ° ± 0.2 °, 11.1 ° ± 0.2 °, 16.7 ° ± 0.2 ° using Cu-ka radiation.

14. Form H according to claim 13, characterized in that the X-ray powder diffraction of form H has characteristic peaks at 2Θ angles of 5.1 ° ± 0.2 °, 11.1 ° ± 0.2 °, 12.6 ° ± 0.2 °, 16.7 ° ± 0.2 °, 19.0 ° ± 0.2 °, 23.8 ° ± 0.2 °.

15. Form H according to claim 13, characterized in that the X-ray powder diffraction of form H has characteristic peaks at 2Θ angles of 5.1 ° ± 0.2 °, 11.1 ° ± 0.2 °, 12.6 ° ± 0.2 °, 14.7 ° ± 0.2 °, 16.7 ° ± 0.2 °, 18.3 ° ± 0.2 °, 19.0 ° ± 0.2 °, 23.8 ° ± 0.2 °, 27.1 ° ± 0.2 °.

16. Form H of claim 13, wherein the X-ray powder diffraction pattern of form H has an X-ray powder diffraction pattern substantially as shown in figure 3.

17. Form H according to claim 13, characterized in that it is an anhydrous form.

18. A process for the preparation of form H of a compound of formula (I) as claimed in any one of claims 13 to 17,

dissolving a compound of the formula (I) in an ether solvent, volatilizing at 0-50 ℃ in an open way, and separating out solids to obtain a crystal form H.

19. Form J of the compound of formula (I), characterized in that it has characteristic peaks at 2Θ values of 8.2 ° ± 0.2 °, 9.6 ° ± 0.2 °, 17.5 ° ± 0.2 ° using Cu-ka radiation.

20. Form J of claim 19, wherein the X-ray powder diffraction of form J has characteristic peaks at 2Θ angles of 8.2 ° ± 0.2 °, 9.6 ° ± 0.2 °, 11.3 ° ± 0.2 °, 17.5 ° ± 0.2 °, 19.5 ° ± 0.2 °, 24.0 ° ± 0.2 °.

21. Form J of claim 19, wherein the X-ray powder diffraction of form J has characteristic peaks at 2Θ angles of 8.2 ° ± 0.2 °, 9.6 ° ± 0.2 °, 11.3 ° ± 0.2 °, 13.4 ° ± 0.2 °, 14.2 ° ± 0.2 °, 17.5 ° ± 0.2 °, 19.5 ° ± 0.2 °, 24.0 ° ± 0.2 °, 26.1 ° ± 0.2 °.

22. Form J of claim 19, wherein the X-ray powder diffraction pattern of form J has an X-ray powder diffraction pattern substantially as shown in figure 4.

23. Form J of claim 19, wherein form J is a hemihydrate form.

24. A process for the preparation of crystalline form J of a compound of formula (I) according to any one of claims 19 to 23, characterized in that it is selected from any one of the following two processes:

1) Dissolving a compound of the formula (I) in an alcohol solvent, volatilizing at 50-90 ℃ in an open way, and separating out solids to obtain a crystal form J; or (b)

2) Dissolving the compound of the formula (I) in an alcohol solvent at 40-60 ℃, cooling to-30-10 ℃, and separating out solids to obtain a crystal form J.

25. Form I of a compound of formula (I), characterized in that it exhibits, using Cu-ka radiation, an X-ray powder diffraction having characteristic peaks at 2Θ values of 5.0 ° ± 0.2 °, 7.2 ° ± 0.2 °, 26.9 ° ± 0.2 °.

26. Form I of claim 25, wherein the form I has an X-ray powder diffraction with characteristic peaks at 2Θ angles of 5.0 ° ± 0.2 °, 7.2 ° ± 0.2 °, 9.6 ° ± 0.2 °, 17.5 ° ± 0.2 °, 19.2 ° ± 0.2 °, 26.9 ° ± 0.2 °.

27. Form I of claim 25, wherein the X-ray powder diffraction pattern of form I has an X-ray powder diffraction pattern substantially as shown in figure 5.

28. Form I of claim 25, wherein the form I is a hydrate form.

29. A process for the preparation of a crystalline form I of a compound of formula (I) as claimed in any one of claims 25 to 28,

placing the compound of the formula (I) into halohydrocarbons, alcohols or mixed solvents thereof, dissolving the compound of the formula (I) at 40-50 ℃, volatilizing the compound of the formula at the temperature of 0-50 ℃ in an open way, and separating out solids to obtain the crystal form I.

30. A crystalline form AA of a compound of formula (I), characterized in that the crystalline form AA has characteristic peaks at 2Θ values of 5.6 ° ± 0.2 °, 6.7 ° ± 0.2 °, 17.5 ° ± 0.2 °, 18.1 ° ± 0.2 °, 26.4 ° ± 0.2 ° using Cu-ka radiation.

31. Form AA according to claim 30, wherein the X-ray powder diffraction pattern of form AA has an X-ray powder diffraction pattern substantially as shown in figure 6.

32. A process for the preparation of crystalline form AA of a compound of formula (I) as claimed in any one of claims 30 to 31,

dissolving the compound of the formula (I) in an ether solvent, dripping the ester solvent into the solution at the temperature of 0-50 ℃, and volatilizing the solution until solid is separated out to obtain the crystal form AA.

33. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of form A1 according to any one of claims 1 to 5, or form K according to any one of claims 7 to 11, or form H according to any one of claims 13 to 17, or form J according to any one of claims 19 to 23, or form I according to any one of claims 25 to 28, or form AA according to any one of claims 30 to 31, or form A1 according to the process of claim 6, or form K according to the process of claim 12, or form H according to the process of claim 18, or form J according to the process of claim 24, or form I according to the process of claim 29, or form AA according to the process of claim 32, or a combination thereof.

34. Use of form A1 of any one of claims 1 to 5, or form K of any one of claims 7 to 11, or form H of any one of claims 13 to 17, or form J of any one of claims 19 to 23, or form I of any one of claims 25 to 28, or form AA of any one of claims 30 to 31, or form A1 of prepared according to the method of claim 6, or form K of prepared according to the method of claim 12, or form H of prepared according to the method of claim 18, or form J of prepared according to the method of claim 24, or form AA of prepared according to the method of claim 32, or the pharmaceutical composition of claim 33 in the preparation of a HIF-PH inhibitor.

35. Use of form A1 according to any one of claims 1 to 5, or form K according to any one of claims 7 to 11, or form H according to any one of claims 13 to 17, or form J according to any one of claims 19 to 23, or form I according to any one of claims 25 to 28, or form AA according to any one of claims 30 to 31, or form A1 obtained by the method of claim 6, or form K obtained by the method of claim 12, or form H obtained by the method of claim 18, or form J obtained by the method of claim 24, or form AA obtained by the method of claim 32, or the pharmaceutical composition of claim 33, for the preparation of a medicament for the treatment of renal anaemia in non-dialysis patients, peritoneal dialysis patients and hemodialysis patients.