WO2022127863A1 - Crystal forms of hemifumarate salt of carboxylic acid compound and preparation method therefor - Google Patents

Abstract

Provided are a crystal form 2, a crystal form 8, a crystal form 10, and a crystal form 16 of a hemifumarate salt of formula (I), preparation methods therefor, and uses thereof. The crystal form 2, crystal form 8, crystal form 10, and crystal form 16 of the hemifumarate salt of a compound of formula (I) have advantages in at least one of solubility, melting point, stability, dissolution, hygroscopicity, adhesiveness, fluidity, biological effectiveness, processability, purification effect, formulation production, safety and the like, thus providing a new better choice for the preparation of pharmaceutical preparations containing the hemifumarate salt of the compound of formula (I), and having very important significance for drug development.

Description

A kind of crystal form of carboxylic acid compound hemi-fumarate and preparation method thereof technical field

The invention relates to the field of chemical medicine, in particular to a crystal form of a carboxylic acid compound hemi-fumarate and a preparation method thereof.

Background technique

Sphingosine-1-phosphate (S1P) is a pleiotropic signaling molecule derived from the sphingolipid metabolic pathway, and its metabolism is regulated by many factors. S1P is synthesized by the phosphorylation of sphingosine catalyzed by intracellular sphingosine kinases (SphKs), and can be released to the outside of the cell through transporters. S1P can modulate a variety of important biological effects through extracellular binding to its specific G protein-coupled receptors and intracellular effects. As an extracellular mediator and intracellular messenger, S1P also plays an important regulatory role in the immune system. S1P is involved in the migration, proliferation, differentiation and clearance of dead cells of immune cells.

1-(4-[1-[(E)-4-Cyclohexyl-3-trifluoromethyl-hydroxybenzylamine]-ethyl]-2-ethyl-benzyl)-azetidinyl- 3-Carboxylic acid is a potent and highly selective inhibitor of S1P, which is effective for autoimmune diseases. At present, certain progress has been made in the treatment of multiple sclerosis. Its structural formula is as follows:

Patent WO2004103306A2 discloses the compound of formula (I) and its synthesis. The disclosed synthesis method needs to be purified by LC/MS. The preparation method is complicated in process and low in yield, and a simpler, safer and higher-yield preparation method needs to be developed.

Five crystal forms (Form A/B/C/D/E) of the compound of formula (I) hemi-fumarate are disclosed in WO2010080409A1, and two types of hemi-fumarate of the compound of formula (I) are disclosed in WO2019144094A1 Crystal form (Form 3/7), two crystal forms (Form SHF1/SHF2) of the compound of formula (I) hemi-fumarate are disclosed in WO2019064184A1. Among these crystal forms, Form A and C are relatively close in terms of preparation conditions, making the distinction more complicated, and the difficulty of process realization is relatively large. Form B has only one diffraction peak and has poor crystallinity. Form E can only be air-dried from Form B with only one diffraction peak, and the preparation conditions are harsh; at the same time, due to the lack of corresponding data, the application prospect of Form E is not yet clear. In addition, after comparison, the XRPD patterns of Form 3 and Form SHF1 can be overlapped; at the same time, Form 3/7 and Form SHF1/SHF2 only disclose diffraction peak data, and no effect evaluation is made. Therefore, it is necessary to develop a crystal form with a simple preparation method and a reliable process for subsequent development and use.

The hemi-fumarate Form A in the claims requires X-ray powder diffraction at 2θ values of 6.9°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 20.4°±0.2° and 20.7°±0.2 There are characteristic peaks at °.

The hemi-fumarate Form B only claims its XRPD diffractogram in the claims. It is disclosed in the specification that it has a characteristic peak only at 2.7°±0.2° in 2θ value.

The hemi-fumarate Form C only claims its XPRD diffractogram in the claims. It is disclosed in the specification that its X-ray powder diffraction has 2θ values of 7.0°±0.2°, 9.5°±0.2°, 11.3°±0.2°, 12.5°±0.2°, 15.2°±0.2°, 18.0°±0.2°, There are characteristic peaks at 19.4°±0.2°, 21.4°±0.2°, 21.8°±0.2° and 24.7°±0.2°.

The hemi-fumarate Form D only claims its XRPD diffractogram in the claims. It is disclosed in the specification that its X-ray powder diffraction has 2θ values of 3.5°±0.2°, 7.1°±0.2°, 10.7°±0.2°, 12.0°±0.2°, 14.3°±0.2°, 20.0°±0.2°, There are characteristic peaks at 21.5°±0.2° and 25.2°±0.2°.

The hemi-fumarate Form E only discloses data for FT-Raman.

The hemi-fumarate Form 3 discloses in the specification its X-ray powder diffraction at 2θ values of 12.6°±0.2°, 15.7°±0.2°, 17.5°±0.2°, 23.4°±0.2°, 11.5°± There are characteristic peaks at 0.2°, 13.5°±0.2°, 14.5°±0.2°, 19.5°±0.2° and 21.9°±0.2°.

The hemi-fumarate Form 7 discloses in the specification that its X-ray powder diffraction has 2θ values of 16.4°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 22.7°±0.2°, 25.4°± There are characteristic peaks at 0.2°, 13.6°±0.2°, 14.2°±0.2°, 16.8°±0.2°, 21.8°±0.2° and 24.4°±0.2°.

The hemi-fumarate Form SHF1 in the claim requires X-ray powder diffraction at 2θ values of 7.5°±0.2°, 11.4°±0.2°, 12.5°±0.2°, 13.3°±0.2°, 14.3°±0.2 There are characteristic peaks at 15.6°±0.2° and 17.4°±0.2°.

Described hemi-fumarate Form SHF2 in the claim requires X-ray powder diffraction at 2θ values of 5.4°±0.2°, 8.1°±0.2°, 10.9°±0.2°, 13.7°±0.2°, 15.0°±0.2 There are characteristic peaks at °, 16.5°±0.2°, 19.2°±0.2°, 20.7°±0.2°, 22.1°±0.2° and 23.2°±0.2°.

In addition, different crystal forms of the same drug have significant differences in solubility, melting point, density, stability, etc., thus affecting the stability, homogeneity, bioavailability, efficacy and safety of the drug to varying degrees. Therefore, it is one of the important research contents that can not be ignored to carry out comprehensive and systematic polymorph screening in drug research and development, and select the most suitable crystal form for development. Based on this, it is necessary to screen the polymorphic form of compound (I) hemi-fumarate to provide more and better choices for the subsequent development of the drug.

SUMMARY OF THE INVENTION

The present invention provides four crystal forms of the compound hemi-fumarate of formula (I): crystal form 2, crystal form 8, crystal form 10, crystal form 16 and uses thereof. The present invention also provides preparation methods of the four crystal forms.

1. Compound 1-(4-[1-[(E)-4-cyclohexyl-3-trifluoromethyl-hydroxybenzylamine]-ethyl]-2-ethyl-benzyl represented by formula (I) Hemifumarate crystal form 2, namely crystal form 2, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form 2 is at 2θ The value is 4.9±0.2°, there are characteristic peaks at 23.4°±0.2° and 14.8°±0.2°,

2. the preparation method of the crystal form 2 described in above-mentioned 1, is characterized in that, described method comprises:

The compound of formula (I) and fumaric acid are added to a cyclic ether solvent, and after stirring, the solid is separated to obtain crystal form 2.

3. The compound represented by formula (I) 1-(4-[1-[(E)-4-cyclohexyl-3-trifluoromethyl-hydroxybenzylamine]-ethyl]-2-ethyl-benzyl Hemifumarate crystal form 8, namely crystal form 8, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form 8 is at 2θ The value is 10.7°±0.2°, there are characteristic peaks at 21.5°±0.2° and 18.9°±0.2°,

4. the preparation method of the crystal form 8 described in above-mentioned 3, is characterized in that,

(1) adding the compound of formula (I) and fumaric acid to pure water, after stirring, separating the solid to obtain crystal form 8; or

(2) Add the amorphous sample of the compound of formula (I) to cyclic ethers, pure water or a mixed solvent thereof, and after stirring, separate the solid to obtain crystal form 8.

5. The compound represented by formula (I) 1-(4-[1-[(E)-4-cyclohexyl-3-trifluoromethyl-hydroxybenzylamine]-ethyl]-2-ethyl-benzyl Hemifumarate crystal form 10, namely crystal form 10, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form 10 is at 2θ The value is 11.2°±0.2°, there are characteristic peaks at 22.5°±0.2° and 16.0°±0.2°,

6. the preparation method of the crystal form 10 described in above-mentioned 5, it is characterized in that,

(1) Dissolving the compound of formula (I) and fumaric acid in a halogenated hydrocarbon or alkyl nitrile solvent, volatilizing the solvent until the solid is precipitated to obtain crystal form 10; or

(2) adding the hemifumarate amorphous sample of the compound of formula (I) to halogenated hydrocarbons, alkyl nitriles, pure water or a mixed solvent thereof, after stirring, separating the solid to obtain crystal form 10; or

(3) placing the hemifumarate amorphous sample of the compound of formula (I) in a halogenated hydrocarbon solvent atmosphere for gas-solid infiltration to obtain crystal form 10; or

(4) dissolving the hemifumarate of the compound of formula (I) in a halogenated hydrocarbon solvent, adding an alkyl nitrile solvent dropwise to the solution, adding dropwise while stirring, and a solid is precipitated to obtain crystal form 10; or

(5) Dissolving the hemifumarate of the compound of formula (I) in a halogenated hydrocarbon solvent, quickly adding it to an ester solvent, and adding dropwise while stirring, a solid is precipitated to obtain crystal form 10.

7. The compound represented by formula (I) 1-(4-[1-[(E)-4-cyclohexyl-3-trifluoromethyl-hydroxybenzylamine]-ethyl]-2-ethyl-benzyl Hemifumarate crystal form 16, namely crystal form 16, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form 16 is at 2θ The value is 8.1°±0.2°, there are characteristic peaks at 24.9°±0.2° and 19.0°±0.2°,

8. the preparation method of the crystal form 16 described in above-mentioned 7, is characterized in that,

The compound of formula (I) and fumaric acid are added to ketones, halogenated hydrocarbons and mixed solvents thereof, and after stirring, the solids are separated and dried to obtain crystal form 16.

9. A pharmaceutical composition comprising the crystal of any one of the above 1, 3, 5 and 7 and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition having an S1P inhibitor, which contains the crystal of any one of the above 1, 3, 5 and 7 as an active ingredient.

11. A prophylactic or therapeutic drug for multiple sclerosis, secondary progressive multiple sclerosis and/or relapsing-remitting multiple sclerosis, comprising the crystal described in any one of 1, 3, 5 and 7 above as an active ingredient.

Compared with the prior art, the hemi- fumarate crystal forms 2, 8, 10 and 16 of the compound of formula (I) provided by the present invention have better solubility, melting point, stability, dissolution, wettability, adhesion and fluidity. , biological effectiveness and processing performance, purification, preparation production, safety, etc., there are advantages in at least one aspect, which provides new and better preparations for the preparation of pharmaceutical preparations containing the compound of formula (I) hemi-fumarate. The choice is of great significance for drug development.

Description of drawings

Figure 1 XRPD pattern of Form 2

Figure 2 XRPD pattern of Form 8

Figure 3 XRPD pattern of Form 10

Figure 4 XRPD pattern of Form 16

Figure 5 XRPD pattern of Form 17

Figure 6 Amorphous XRPD pattern

Figure 7 Amorphous ¹ H NMR spectrum

Figure 8 ¹ H NMR spectrum of Form 2

Figure 9 TGA curve of Form 8

Figure 10 DSC curve of Form 8

Figure 11 ¹ H NMR spectrum of Form 8

Figure 12 TGA curve of Form 10

Figure 13 DSC curve of Form 10

Figure 14 ¹ H NMR spectrum of Form 10

Figure 15 TGA curve of Form 16

Figure 16 DSC curve of Form 16

Figure 17 ¹ H NMR spectrum of Form 16

Figure 18 Solubility curves of different crystal forms in SGF

Figure 19 Solubility curves of different crystal forms in FaSSIF

Figure 20 XRPD comparison chart of the stability test of crystal form 8 under the conditions of 25C/60%RH and 40C/75%RH

Figure 21 Dynamic moisture adsorption diagram of Form 8

Figure 22 Dynamic moisture adsorption diagram of Form 10

Fig. 23 Particle size distribution of Form 8

Fig. 24 Particle size distribution of Form A

Detailed ways

Compound represented by formula (I) 1-(4-[1-[(E)-4-cyclohexyl-3-trifluoromethyl-hydroxybenzylamine]-ethyl]-2-ethyl-benzyl) - Hemi-fumarate crystal form 2 of azetidine-3-carboxylic acid, namely crystal form 2, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form 2 has a 2θ value There are characteristic peaks at 4.9°±0.2°, 23.4°±0.2° and 14.8°±0.2°,

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 2 has one or two or three 2θ values of 19.6°±0.2°, 20.6°±0.2°, and 11.3°±0.2°. There are characteristic peaks.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 2 has characteristic peaks at 2θ values of 19.6°±0.2°, 20.6°±0.2° and 11.3°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 2 has one or two or three 2θ values of 12.1°±0.2°, 28.7°±0.2°, and 10.6°±0.2°. There are characteristic peaks.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 2 has characteristic peaks at 2θ values of 12.1°±0.2°, 28.7°±0.2° and 10.6°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 2 has 2θ values of 4.9°±0.2°, 23.4°±0.2°, 14.8°±0.2°, 19.6°±0.2°, 20.6°± 0.2°, 11.3°±0.2°, 12.1°±0.2°, 28.7°±0.2°, 10.6°±0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 2 has 2θ values of 4.9°±0.2°, 23.4°±0.2°, 14.8°±0.2°, 19.6°±0.2°, 20.6°± There are characteristic peaks at 0.2°, 11.3°±0.2°, 12.1°±0.2°, 28.7°±0.2° and 10.6°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form 2 is shown in FIG. 1 .

The preparation method of described crystal form 2 is characterized in that,

The compound of formula (I) and fumaric acid are added to a cyclic ether solvent, and after stirring, the solid is separated to obtain crystal form 2.

In one embodiment of the present invention, the cyclic ether solvent is tetrahydrofuran.

In one embodiment of the present invention, the stirring temperature is 5°C to 50°C, preferably 20°C to 30°C.

In one embodiment of the present invention, stirring is performed until a solid precipitates out.

In one embodiment of the present invention, the stirring time is 1-7 days, preferably 1-3 days.

Compound represented by formula (I) 1-(4-[1-[(E)-4-cyclohexyl-3-trifluoromethyl-hydroxybenzylamine]-ethyl]-2-ethyl-benzyl) - Hemifumarate crystal form 8 of azetidine-3-carboxylic acid, namely crystal form 8, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form 8 has a 2θ value There are characteristic peaks at 10.7°±0.2°, 21.5°±0.2° and 18.9°±0.2°,

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 8 has characteristic peaks at one or two locations in the 2θ value of 15.6°±0.2° and 14.3°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 8 has characteristic peaks at 2θ values of 15.6°±0.2° and 14.3°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction of the crystalline form 8 has characteristic peaks at one or two locations of 2θ values of 7.1°±0.2° and 23.8°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 8 has characteristic peaks at 2θ values of 7.1°±0.2° and 23.8°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 8 has 2θ values of 10.7°±0.2°, 21.5°±0.2°, 18.9°±0.2°, 15.6°±0.2°, 14.3°± 0.2°, 7.1°±0.2°, and 23.8°±0.2° have characteristic peaks at any 4 positions, or 5 positions, or 6 positions, or 7 positions.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 8 has 2θ values of 10.7°±0.2°, 21.5°±0.2°, 18.9°±0.2°, 15.6°±0.2°, 14.3°± There are characteristic peaks at 0.2°, 7.1°±0.2° and 23.8°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form 8 is shown in FIG. 2 .

The preparation method of described crystal form 8, is characterized in that,

(1) The compound of formula (I) and fumaric acid are added to pure water, and after stirring, the solid is separated to obtain crystal form 8.

In one embodiment of the present invention, the stirring temperature is 5°C to 50°C, preferably 20°C to 30°C.

In one embodiment of the present invention, stirring is performed until a solid precipitates out.

In one embodiment of the present invention, the stirring time is 1-7 days, preferably 1-3 days.

(2) Add the amorphous hemifumaric acid sample of the compound of formula (I) to cyclic ethers, water or a mixed solvent thereof, and after stirring, separate the solid to obtain crystal form 8.

In one embodiment of the present invention, the cyclic ether solvent is tetrahydrofuran.

In one embodiment of the present invention, the mixed solvent is a mixture of tetrahydrofuran and water.

In one embodiment of the present invention, the volume ratio of tetrahydrofuran to water in the mixture is 9-0.1:1.

In one embodiment of the present invention, the stirring temperature is 0°C to 50°C, preferably 0°C to 5°C.

In one embodiment of the present invention, the stirring time is 1 day to 10 days, preferably 7 to 10 days.

Compound represented by formula (I) 1-(4-[1-[(E)-4-cyclohexyl-3-trifluoromethyl-hydroxybenzylamine]-ethyl]-2-ethyl-benzyl) - Hemi-fumarate crystal form 10 of azetidine-3-carboxylic acid, namely crystal form 10, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form 10 has a 2θ value There are characteristic peaks at 11.2°±0.2°, 22.5°±0.2° and 16.0°±0.2°,

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 10 is at one or two or three locations in the 2θ value of 16.9°±0.2°, 13.8°±0.2°, and 15.2°±0.2° There are characteristic peaks.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 10 has characteristic peaks at 2θ values of 16.9°±0.2°, 13.8°±0.2° and 15.2°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 10 has one or two or three 2θ values of 5.6°±0.2°, 21.2°±0.2°, and 19.3°±0.2°. There are characteristic peaks.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 10 has characteristic peaks at 2θ values of 5.6°±0.2°, 21.2°±0.2° and 19.3°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 10 has 2θ values of 11.2°±0.2°, 22.5°±0.2°, 16.0°±0.2°, 16.9°±0.2°, 13.8°± 0.2°, 15.2°±0.2°, 5.6°±0.2°, 21.2°±0.2°, 19.3°±0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 10 has 2θ values of 11.2°±0.2°, 22.5°±0.2°, 16.0°±0.2°, 16.9°±0.2°, 13.8°± There are characteristic peaks at 0.2°, 15.2°±0.2°, 5.6°±0.2°, 21.2°±0.2° and 19.3°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form 10 is shown in FIG. 3 .

The preparation method of described crystal form 10 is characterized in that,

(1) The compound of formula (I) and fumaric acid are dissolved in a halogenated hydrocarbon solvent, and the solvent is volatilized until a solid is precipitated to obtain crystal form 10.

In one embodiment of the present invention, the halogenated hydrocarbon solvent is dichloromethane.

In one embodiment of the present invention, the dissolution and volatilization temperature is 5°C to 50°C, preferably 20°C to 30°C.

In one embodiment of the present invention, the mass ratio of the high polymer to the compound of formula (I) is 1:4-10.

(2) Add the amorphous sample of compound hemi-fumarate of formula (I) to halogenated hydrocarbons, alkyl nitriles, water or a mixed solvent thereof, and after stirring, separate the solid to obtain crystal form 10.

In one embodiment of the present invention, the halogenated hydrocarbon solvent is dichloromethane.

In one embodiment of the present invention, the alkyl nitrile solvent is acetonitrile.

In one embodiment of the present invention, the mixed solvent is a mixture of acetonitrile and water.

In one embodiment of the present invention, the volume ratio of acetonitrile to water in the mixture is 49-0.5:1.

In one embodiment of the present invention, a high polymer is added during the suspension and stirring of the acetonitrile.

In one embodiment of the present invention, the high polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, methylcellulose, and polycaproic acid. ester, polyethylene glycol, polymethyl methacrylate, sodium alginate or hydroxyethyl cellulose.

In one embodiment of the present invention, the stirring temperature is 5°C to 50°C, preferably 20°C to 30°C.

In one embodiment of the present invention, the stirring time is 1-7 days, preferably 1-3 days.

(3) placing the amorphous sample of the compound hemi-fumarate of the formula (I) in a halogenated hydrocarbon solvent atmosphere for gas-solid infiltration for a period of time to obtain crystal form 10.

In one embodiment of the present invention, the halogenated hydrocarbon solvent is dichloromethane.

In one embodiment of the present invention, the gas-solid permeation time is 1 to 4 weeks, for example, 2 weeks.

In one embodiment of the present invention, the gas-solid permeation temperature is 5°C to 50°C, preferably 20°C to 30°C.

(4) dissolving the compound hemi-fumarate of formula (I) in a halogenated hydrocarbon solvent, adding an alkyl nitrile solvent dropwise to the solution, adding dropwise while stirring, and after stirring for a period of time, the solid is precipitated to obtain Form 10.

In one embodiment of the present invention, the halogenated hydrocarbon solvent is dichloromethane.

In one embodiment of the present invention, the alkyl nitrile solvent is acetonitrile.

In one embodiment of the present invention, the temperature of the dissolution, dropwise addition, stirring and precipitation is -20°C to 50°C, preferably 20°C to 30°C.

In one embodiment of the present invention, the stirring time is 1 to 7 days, for example, 3 days.

(5) dissolving the compound hemi-fumarate of formula (I) in the halogenated hydrocarbon solvent, adding it to the ester solvent rapidly, adding dropwise while stirring, after stirring for a period of time, the solid is precipitated to obtain crystal form 10 .

In one embodiment of the present invention, the halogenated hydrocarbon solvent is chloroform.

In one embodiment of the present invention, the ester solvent is ethyl acetate.

In one embodiment of the present invention, the temperature of the dissolution, dropwise addition, stirring and precipitation is -20°C to 50°C, preferably 20°C to 30°C.

In one embodiment of the present invention, the stirring time is 1 to 7 days, for example, 3 days.

Compound represented by formula (I) 1-(4-[1-[(E)-4-cyclohexyl-3-trifluoromethyl-hydroxybenzylamine]-ethyl]-2-ethyl-benzyl) - Hemi-fumarate crystal form 16 of azetidine-3-carboxylic acid, namely crystal form 16, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form 16 has a 2θ value There are characteristic peaks at 8.1°±0.2°, 24.9°±0.2° and 19.0°±0.2°,

In one embodiment of the present invention, the X-ray powder diffraction of the crystalline form 16 has characteristic peaks at one or two positions in the 2θ value of 25.5°±0.2° and 16.3°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 16 has characteristic peaks at 2θ values of 25.5°±0.2° and 16.3°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction of the crystalline form 16 has characteristic peaks at one or two positions in the 2θ value of 27.7°±0.2° and 11.4°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 16 has characteristic peaks at 27.7°±0.2° and 11.4°±0.2° at 2θ values.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 16 has 2θ values of 8.1°±0.2°, 24.9°±0.2°, 19.0°±0.2°, 25.5°±0.2°, 16.3°± 0.2°, 27.7°±0.2°, and 11.4°±0.2° at any 4 places, or 5 places, or 6 places, or 7 places have characteristic peaks.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 16 has 2θ values of 8.1°±0.2°, 24.9°±0.2°, 19.0°±0.2°, 25.5°±0.2°, 16.3°± There are characteristic peaks at 0.2°, 27.7°±0.2° and 11.4°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form 16 is shown in FIG. 4 .

The preparation method of described crystal form 16 is characterized in that,

The compound of formula (I) and fumaric acid are added to ketones, halogenated hydrocarbons and mixed solvents thereof, and after stirring, the solids are separated and dried to obtain crystal form 16.

In one embodiment of the present invention, the ketone solvent is acetone.

In one embodiment of the present invention, the halogenated hydrocarbon solvent is dichloromethane.

In one embodiment of the present invention, the mixed solvent is a mixture of acetone and dichloromethane.

In one embodiment of the present invention, the volume ratio of acetone to dichloromethane in the mixture is 9-0.1:1.

In one embodiment of the present invention, the stirring and drying temperature is 5°C to 50°C, preferably 20°C to 30°C.

In one embodiment of the present invention, the stirring time is 1-7 days, preferably 1-3 days.

Compound represented by formula (I) 1-(4-[1-[(E)-4-cyclohexyl-3-trifluoromethyl-hydroxybenzylamine]-ethyl]-2-ethyl-benzyl) - Hemi-fumarate crystal form 17 of azetidine-3-carboxylic acid, namely crystal form 17, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form 17 has a 2θ value There are characteristic peaks at 11.0°±0.2°, 22.1°±0.2° and 7.0°±0.2°,

In one embodiment of the present invention, the X-ray powder diffraction of the crystalline form 17 has characteristic peaks at one or two positions in the 2θ value of 15.9°±0.2° and 16.6°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 17 has characteristic peaks at 2θ values of 15.9°±0.2° and 16.6°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction of the crystalline form 17 has characteristic peaks at one or two positions in the 2θ value of 5.4°±0.2° and 10.2°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 17 has characteristic peaks at 2θ values of 5.4°±0.2° and 10.2°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 17 has 2θ values of 11.0°±0.2°, 22.1°±0.2°, 7.0°±0.2°, 15.9°±0.2°, 16.6°± 0.2°, 5.4°±0.2°, and 10.2°±0.2° have characteristic peaks at any 4 places, or 5 places, or 6 places, or 7 places.

In one embodiment of the present invention, the X-ray powder diffraction of the crystal form 17 has 2θ values of 11.0°±0.2°, 22.1°±0.2°, 7.0°±0.2°, 15.9°±0.2°, 16.6°± There are characteristic peaks at 0.2°, 5.4°±0.2°, and 10.2°±0.2°.

In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form 17 is shown in FIG. 5 .

The preparation method of described crystal form 17 is characterized in that,

The compound of formula (I) and fumaric acid are added to ketones, halogenated hydrocarbons and their mixed solvents, and after stirring, the solids are separated to obtain crystal form 17.

In one embodiment of the present invention, the ketone solvent is acetone.

In one embodiment of the present invention, the halogenated hydrocarbon solvent is dichloromethane.

In one embodiment of the present invention, the mixed solvent is a mixture of acetone and dichloromethane.

In one embodiment of the present invention, the volume ratio of acetone to dichloromethane in the mixture is 9-0.1:1.

In one embodiment of the present invention, the stirring temperature is 5°C to 50°C, preferably 20°C to 30°C.

In one embodiment of the present invention, the stirring time is 1-7 days, preferably 1-3 days.

Detailed ways

The following will further illustrate the present invention through specific examples, which are not intended to limit the protection scope of the present invention. Those skilled in the art can make improvements to the preparation method and using instruments within the scope of the claims, and these improvements should also be regarded as the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims.

In the present invention, "room temperature" generally refers to 22°C to 28°C unless otherwise specified. .

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

XRPD: X-ray Powder Diffraction

DSC: Differential Scanning Calorimetry

TGA: Thermogravimetric Analysis

¹ H NMR: Hydrogen Nuclear Magnetic Resonance Spectroscopy

DVS: Dynamic Moisture Sorption

The X-ray powder diffraction patterns of the present invention were collected on Empyrean and X'Pert ³ X-ray powder diffractometers of Panalytical Corporation. The method parameters of X-ray powder diffraction of the present invention are as follows:

X-ray light source: Cu, Kα

Kα1

1.54060; Kα2

1.54443

Kα2/Kα1 intensity ratio: 0.50

Voltage: 45 kilovolts (kV)

Current: 40 milliamps (mA)

Scanning range: from 3.0 to 40.0 degrees (2θ angle)

The differential scanning calorimetry analysis diagram of the present invention is collected on the Q200 type and Discovery DSC 2500 type differential scanning calorimeter of TA company. The method parameters of the differential scanning calorimetry analysis of the present invention are as follows:

Scan rate: 10°C/min

Shielding gas: nitrogen

The thermogravimetric analysis diagram of the present invention is collected on the Discovery TGA 5500 type and Q5000 type thermogravimetric analyzer of TA company. The method parameters of thermogravimetric analysis of the present invention are as follows:

Scan rate: 10°C/min

Shielding gas: nitrogen

The dynamic moisture adsorption diagram of the present invention is collected on the Intrinsic type and Intrinsic Plus type dynamic moisture adsorption instrument of SMS company. The method parameters of the dynamic moisture adsorption test of the present invention are as follows:

Temperature: 25℃

Protective gas and flow: N ₂ , 200 ml/min

dm/dt: 0.002%/min

Minimum dm/dt equilibration time: 10 minutes

Maximum Equilibration Time: 180 minutes

Relative humidity range: 0%RH-95%RH-0%RH

Relative humidity gradient: 10% (0%RH-90%RH-0%RH), 5% (90%RH-95%RH and 95%RH-90%RH)

The starting material of compound (I) used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2004103306A2, but the starting crystal form is not a limitation for preparing the crystal form of the present invention.

Example 1: Preparation of Hemifumarate Amorphous

At room temperature, weigh 1000.2 mg of the solid compound of formula (I) and 112.0 mg of fumaric acid and place it in a 20-mL glass vial, add 10 mL of methyl tert-butyl ether to the vial, and magnetically stir (rotating speed) at room temperature. After about 1000 rpm) for about two days, a solid precipitated. The crystal form A of the hemifumarate disclosed in WO2010080409A1 is obtained.

The precipitated solid was filtered with a Buchner funnel, dried in a vacuum drying box, taken out after about 24 hours, and the solid was dissolved with 15 ml of methanol/dichloromethane (volume ratio 2:1), and a 0.45-micron pore size was used. The sample solution was filtered into a new 50 ml round-bottomed flask using a teflon filter membrane, and the sample was spin-dried using a rotary evaporator at 40 degrees Celsius, and the sample showed foaming. Subsequently, the foamed sample was placed in a vacuum drying oven to dry for about 24 hours to obtain an amorphous form. The X-ray powder diffraction data is shown in Figure 6, and the ¹ H NMR result is shown in Figure 7, and the molar ratio of the compound of formula (I) to fumaric acid is 1:0.5.

Example 2: Preparation of hemi-fumarate crystal form 2

Weigh 2.2 mg of formula (I) compound solid and 0.2 mg of fumaric acid in a 2 ml glass vial under room temperature conditions, add 0.2 ml of tetrahydrofuran in the vial, magnetic stirring at room temperature (rotating speed is about 1000 rev/ minutes) after about 1 day, a solid was precipitated to obtain the hexafumarate crystal form 2. The X-ray powder diffraction data are shown in Table 1, the diffractogram is shown in Figure 1, the ¹ H NMR result is shown in Figure 8, and the molar ratio of the compound of formula (I) to fumaric acid is 1:0.4.

Table 1

Diffraction angle 2θ	d value	strength%
4.94	17.90	100.00
5.59	15.80	3.21
10.61	8.34	8.14
11.30	7.83	14.90
12.06	7.34	12.91
13.51	6.55	3.58
13.85	6.39	5.56
14.84	5.97	17.54
15.57	5.69	5.48
17.03	5.21	2.08
17.52	5.06	4.45

Diffraction angle 2θ	d value	strength%
18.39	4.83	3.00
19.60	4.53	69.50
19.85	4.47	24.53
20.18	4.40	11.21
20.59	4.31	15.90
21.44	4.14	7.11
23.42	3.80	23.82
23.94	3.72	4.83
24.89	3.58	7.25
25.69	3.47	7.98
28.01	3.19	10.52
28.74	3.11	20.83
29.32	3.05	2.25
29.83	3.00	7.51
30.41	2.94	1.79
30.91	2.89	1.68
32.52	2.75	1.12
33.49	2.68	0.59
34.71	2.58	2.80
35.68	2.52	0.66

Example 3: Preparation of hemi-fumarate crystal form 8

Weigh 19.5 milligrams of formula (I) compound solids and 2.2 milligrams of fumaric acid and place them in a 2 milliliter glass vial under room temperature conditions, add 0.5 milliliters of pure water to the vial, and magnetically stir at room temperature (rotating speed is about 1000. rev/min) for about 1 day, a solid was precipitated to obtain the hemi-fumarate crystal form 8. Its X-ray powder diffraction data is shown in Table 2, and the diffraction pattern is shown in Figure 2. The sample is at about 10.7°±0.2°, about 21.5°±0.2°, about 18.9°±0.2°, about 15.6°±0.2°, about 14.3°±0.2°, about 7.1°±0.2°, about 23.8°±0.2 There are characteristic peaks at °, about 11.5° ± 0.2°, about 17.2° ± 0.2°, about 22.3° ± 0.2° and about 25.3° ± 0.2°. The TGA and DSC data are shown in Figure 9 and Figure 10, respectively, and the ¹ H NMR results are shown in Figure 11, and the molar ratio of the compound of formula (I) to fumaric acid is 1:0.5.

Table 2

Diffraction angle 2θ	d value	strength%
7.10	12.46	35.42
10.68	8.28	56.40
11.51	7.69	15.87
12.76	6.94	9.17

Diffraction angle 2θ	d value	strength%
14.27	6.21	29.90
15.58	5.69	25.57
17.20	5.15	32.87
17.86	4.97	17.37
18.93	4.69	24.40
21.48	4.14	100.00
22.29	3.99	14.94
23.81	3.74	31.82
25.28	3.52	3.94
28.79	3.10	4.31

Example 4: Preparation of hemi-fumarate crystal form 8

9.8 mg of the compound of formula (I) hemi-fumarate described in Example 1 was weighed at room temperature, placed in a 2 ml glass vial, and 0.5 ml of tetrahydrofuran/water (volume ratio 4/1) was added to the vial. , after about 3 days of magnetic stirring at room temperature (rotation speed is about 1000 rpm), transfer to 5 °C and continue to stir for 10 days, a solid is precipitated, and crystal form 8 of hemi-fumarate is obtained. Its X-ray powder diffraction data is shown in Table 3, the sample is at about 10.7°±0.2°, about 21.5°±0.2°, about 19.1°±0.2°, about 15.7°±0.2°, about 14.3°±0.2°, There are characteristic peaks at about 7.1°±0.2°, about 23.8°±0.2°, about 11.5°±0.2°, about 17.5°±0.2°, about 25.1°±0.2° and about 12.6°±0.2°.

table 3

Diffraction angle 2θ	d value	strength%
7.10	12.44	20.94
10.68	8.28	38.77
11.51	7.69	78.10
12.64	7.01	30.15
14.26	6.21	24.10
15.70	5.65	32.48
17.49	5.07	43.91
19.10	4.65	23.93
21.48	4.14	100.00
23.82	3.74	37.55
25.14	3.54	14.82

Example 5: Preparation of hemi-fumarate crystal form 10

Weigh 14.6 mg of the solid compound of formula (I) and 1.8 mg of fumaric acid into a 2 ml glass vial under room temperature conditions, add 0.5 ml of dichloromethane, and magnetically stir at room temperature (rotating speed is about 1000 rev/min) After about 1 day, the sample was clarified, and it was transferred to open volatilization at room temperature until a solid was precipitated, and the hemi-fumarate crystal form 10 was obtained. The X-ray powder diffraction data are shown in Table 4, the diffractogram is shown in Figure 3, the TGA and DSC data are shown in Figure 12 and Figure 13, respectively, and the ¹ H NMR results are shown in Figure 14, the compound of formula (I) and The molar ratio of fumaric acid was 1:0.5.

Table 4

Diffraction angle 2θ	d value	strength%
5.56	15.90	10.12
7.26	12.18	12.78
7.56	11.69	7.85
10.54	8.40	5.56
11.20	7.90	100.00
13.34	6.64	4.02
13.79	6.42	7.53
15.22	5.82	6.55
16.01	5.54	22.88
16.85	5.26	17.47
17.74	5.00	3.46
19.29	4.60	2.90
21.22	4.19	4.55
22.54	3.94	23.14
23.97	3.71	2.72
26.62	3.35	2.79

Example 6: Preparation of hemi-fumarate crystal form 10

Weigh 14.7 mg of the amorphous sample of the hemi-fumarate salt of the compound of formula (I) obtained in Example 1 into a 3-mL glass vial, and place the open mouth in a 20-mL prefilled with 4 mL of dichloromethane. ml in a glass bottle. After being sealed and placed at room temperature for gas-solid permeation for about 12 days, the crystal form 10 of the hemi-fumarate was obtained, and the X-ray powder diffraction data are shown in Table 5.

table 5

Diffraction angle 2θ	d value	strength%
5.58	15.85	9.13
7.26	12.18	9.42
7.55	11.71	7.20
10.56	8.38	5.52
11.20	7.90	100.00
13.78	6.43	4.65
15.23	5.82	7.44

Diffraction angle 2θ	d value	strength%
15.97	5.55	41.69
16.83	5.27	22.33
17.75	5.00	5.89
19.31	4.60	6.43
21.20	4.19	11.47
22.52	3.95	42.98
23.98	3.71	5.84
26.61	3.35	7.31
29.48	3.03	2.64

Example 7: Preparation of hemi-fumarate crystal form 10

Weigh 9.6 mg of the amorphous solid of the compound of formula (I) hemi-fumarate obtained in Example 1 into a 2 mL glass vial, add 0.5 mL of acetonitrile/water (volume ratio 19/1) A suspension was obtained. The suspension was magnetically stirred at room temperature (the rotation speed was about 1000 rpm) for about two days, and the solid was separated to obtain the hemi-fumarate crystal form 10. The X-ray powder diffraction data are shown in Table 6.

Table 6

Diffraction angle 2θ	d value	strength%
5.58	15.84	3.81
7.28	12.14	25.65
7.58	11.66	23.49
10.60	8.35	9.26
11.20	7.90	100.00
13.82	6.41	17.15
14.62	6.06	5.90
15.36	5.77	17.92
15.98	5.55	48.77
16.74	5.30	28.44
17.85	4.97	12.17
19.26	4.61	6.04
20.84	4.26	5.73
21.27	4.18	10.56
21.65	4.10	8.22
22.49	3.95	31.60
26.70	3.34	5.59

Example 8: Preparation of hemi-fumarate crystal form 10

At room temperature, 15 mg of the amorphous solid of the compound of formula (I) hemi-fumarate obtained in Example 1 was weighed and placed in a 2 mL glass vial, and 0.5 mL of dichloromethane was added to obtain a suspension. After about 30 minutes of magnetic stirring (rotation speed is about 1000 rev/min) of this suspension liquid at room temperature, the solid is dried to obtain hemi-fumarate crystal form 10, and its X-ray powder diffraction data are as shown in Table 7. Show.

Table 7

Diffraction angle 2θ	d value	strength%
5.58	15.83	7.59
7.26	12.17	1.79
10.57	8.37	1.43
11.20	7.90	100.00
13.41	6.60	0.87
13.78	6.43	1.07
15.29	5.80	1.73
15.95	5.56	7.89
16.84	5.26	15.74
17.77	4.99	1.11
19.29	4.60	0.95
21.21	4.19	2.84
22.53	3.95	34.41
24.05	3.70	1.08
26.67	3.34	1.96
29.41	3.04	0.40
31.63	2.83	0.41
34.20	2.62	0.23

Example 9: Preparation of hemi-fumarate crystal form 10

Weigh 9.7 mg of the amorphous solid of the compound of formula (I) hemi-fumarate obtained in Example 1, and 2.3 mg of the polymer (polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate) at room temperature. Ester, hydroxypropyl methylcellulose, etc. quality mixture) was placed in a 2 ml glass vial, and 0.5 ml of acetonitrile was added to obtain a suspension. The suspension was magnetically stirred at room temperature (the rotation speed was about 1000 rpm) for about 3 days, and the solid was separated to obtain crystal form 10 of the hemi-fumarate salt.

Example 10: Preparation of hemi-fumarate crystal form 10

9.8 mg of the amorphous solid of the compound of formula (I) hemi-fumarate obtained in Example 1 was weighed into a 5 mL glass vial at room temperature, and 0.1 mL of dichloromethane was added to obtain a clear solution. Subsequent magnetic stirring (about 1000 rpm) gave a clear solution, to which acetonitrile was added dropwise as an anti-solvent for anti-solvent addition. When acetonitrile was added to 0.3 ml, the sample appeared oily, and after the sample was magnetically stirred at room temperature for 3 days, a solid was precipitated, and the hemi-fumarate crystal form 10 was obtained.

Example 11: Preparation of hemi-fumarate crystal form 10

10.0 mg of the amorphous solid of the compound of formula (I) hemi-fumarate obtained in Example 1 was weighed into a 5 mL glass vial at room temperature, and 0.1 mL of chloroform was added to obtain a clear solution. Subsequently, the solution was rapidly added to 5.0 ml of ethyl acetate, and the mixed solution was magnetically stirred (the rotation speed was about 1000 rpm) while adding, and the anti-solvent was added in the reverse direction. After stirring at room temperature for 3 days, a solid was precipitated to obtain a half Form 10 of fumarate salt, the X-ray powder diffraction data are shown in Table 8.

Table 8

Diffraction angle 2θ	d value	strength%
5.60	15.79	5.80
7.27	12.17	7.14
7.64	11.57	5.47
10.21	8.66	4.92
11.20	7.90	100.00
12.27	7.21	1.32
13.85	6.40	6.95
14.80	5.98	2.54
15.35	5.77	3.40
16.05	5.52	8.93
16.43	5.40	12.88
16.82	5.27	12.00
17.23	5.15	4.34
17.83	4.98	1.75
18.37	4.83	1.86
19.38	4.58	0.98
20.84	4.26	1.65
21.30	4.17	2.06
21.65	4.11	2.56
22.46	3.96	24.65
23.26	3.82	2.52
24.55	3.63	1.85
27.04	3.30	0.89
28.26	3.16	0.86

Example 12: Preparation of hemi-fumarate crystal form 16

Weigh 100.4 mg of the solid compound of formula (I) and 11.2 mg of fumaric acid in a 5 ml glass vial at room temperature, add 2 ml of acetone and 1.5 ml of dichloromethane, and magnetically stir at room temperature (rotating speed is about 1000 rpm. /min) about 1 day later, the solid was precipitated, and after suction filtration, the solid was air-dried at room temperature to obtain the hemi-fumarate crystal form 16. The X-ray powder diffraction data are shown in Table 9, the diffractogram is shown in Figure 4, the TGA and DSC data are shown in Figure 15 and Figure 16, respectively, and the ¹ H NMR results are shown in Figure 17, the compound of formula (I) and The molar ratio of fumaric acid was 1:0.5.

Table 9

Diffraction angle 2θ	d value	strength%
8.15	10.85	100.00
11.39	7.77	9.07
16.27	5.45	13.83
16.88	5.25	22.37
17.22	5.15	13.89
17.95	4.94	8.43
19.03	4.66	16.85
22.81	3.90	2.54
24.92	3.57	51.40
25.52	3.49	23.38
26.57	3.35	6.03
27.72	3.22	10.42
30.84	2.90	6.42

Example 13: Preparation of hemi-fumarate crystal form 17

Weigh 100.4 mg of the solid compound of formula (I) and 11.2 mg of fumaric acid in a 5 ml glass vial at room temperature, add 2 ml of acetone and 1.5 ml of dichloromethane, and magnetically stir at room temperature (rotating speed is about 1000 rpm. /min) after about 1 day, the solid was precipitated, and after suction filtration, crystal form 17 of hemi-fumarate was obtained. The X-ray powder diffraction data are shown in Table 10, and the diffraction pattern is shown in Figure 5.

Table 10

Diffraction angle 2θ	d value	strength%
5.39	16.38	6.24
6.96	12.71	62.20
10.23	8.65	3.76
11.02	8.03	100.00
14.82	5.98	1.35
15.90	5.57	5.28

Diffraction angle 2θ	d value	strength%
16.57	5.35	4.21
20.90	4.25	3.06
22.12	4.02	93.67

Example 14: Solubility of Crystal Forms

The crystalline form 10 of the present invention and Form A disclosed in the prior art were prepared into suspensions with SGF (simulated artificial gastric fluid) and FaSSIF (simulated artificial intestinal fluid in fasting state), respectively, at 1 hour, 2 hours, 4 hours and 24 hours. After equilibration, filtered to obtain a saturated solution. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The test results are shown in Table 11, and the solubility curves are shown in Figures 18 to 19, respectively. The test results show that the solubility of the crystal form 10 of the present invention in SGF and FaSSIF is higher than that of Form A disclosed in the prior art.

Table 11

Example 15: Compressibility of crystal forms

Use a manual tablet press to perform tablet compression. When tableting, select a circular flat punch that can be compressed into a cylindrical tablet, and add a certain amount of crystal form 2/8/10/16 of the present invention and disclosed in the prior art. Form A, compressed into round tablets with 10kN pressure, placed in a desiccator for 24 hours, and tested its radial crushing force (hardness, H) with a tablet hardness tester after complete elastic recovery. The diameter (D) and thickness (L) of the tablet were measured with a vernier caliper, and the tensile strength of the powder with different hardnesses was calculated using the formula T=2H/πDL. Under a certain pressure, the higher the tensile strength, the better the compressibility. The results show that the crystalline form 2/8/10/16 of the present invention has higher tensile strength and better compressibility than Form A disclosed in the prior art.

Example 16: Intrinsic Dissolution Rate of Crystalline Form

Weigh about 100 mg each of the crystal form 2/8/10/16 of the present invention and Form A disclosed in the prior art, pour into the inherent dissolution mold, and continue for 1 minute under the pressure of 5kN to make a sheet with a surface area of 0.5cm ² , Take the complete tablet and transfer it to the dissolution apparatus to test the inherent dissolution rate. The dissolution conditions are shown in Table 12. Calculate the slope according to the measurement point between 10 and 30 minutes, expressed in mg/ml, and further calculate the inherent dissolution rate (Intrinsic dissolution rate) according to the slope. rate, IDR), expressed in mg/min/cm ² . The results show that the dissolution rate of the crystal form 2/8/10/16 of the present invention is faster than that of Form A disclosed in the prior art.

Table 12

Dissolution Apparatus	CSE-051Agilent 708DS
method	pulp method
medium	pH 6.8 Phosphate Buffer
medium volume	900ml
Rotating speed	100 rpm
medium temperature	37 ℃
Sampling point	1,2,3,4,5,10,15,20,25,30min
supplementary medium	No

Example 17: Comparative stability study

Weigh about 15 mg of the crystal form 8 of the present invention (initial purity 98.06%), open it and place it in a stable box under the conditions of 25°C/60%RH and 40°C/75%RH, and take samples after 7 days to measure XRPD and HPLC . The experimental results are shown in Table 13, and the stability is shown in Figure 20. It can be seen from the results that the crystal form 8 of the present invention has better physical/chemical stability under the conditions of 25°C/60%RH and 40°C/75%RH.

Table 13

Example 18: Comparative study on wettability

Weigh about 10 mg each of crystal form 8/10 of the present invention for dynamic moisture adsorption (DVS) test, the experimental results are shown in Table 14, the DVS of crystal form 8 is shown in Figure 21, and the DVS of crystal form 10 is shown in Figure 22. Show. It can be seen from the results that the crystalline form 8/10 of the present invention has lower hygroscopicity.

Table 14

Crystal form	Weight gain at 80% relative humidity	hygroscopicity
Form 8	0.6631	slightly hygroscopic
Form 10	2.3405	hygroscopic

About hygroscopic characteristics description and definition of hygroscopic weight gain (Chinese Pharmacopoeia 2015 edition general rule drug hygroscopic test guidelines):

Deliquescence: Absorbs sufficient water to form a liquid

Extremely hygroscopic: wet weight gain is not less than 15%

Moisture: Moisture gain is less than 15% but not less than 2%

Slightly hygroscopic: wet weight gain is less than 2% but not less than 0.2%

No or almost no hygroscopicity: wet weight gain is less than 0.2%

Example 19: Crystal Habit Comparative Study

Weigh about 10 mg each of the crystal form 2/8/10/16 of the present invention and Form A disclosed in the prior art, place them on a glass slide respectively, add a little vacuum silicone oil dropwise to disperse the samples, then cover with a cover glass, and place them on a glass slide. Observed under a polarizing microscope. Compared with the prior art Form A, the crystal form 2/8/10/16 of the present invention has better crystal habit.

Example 20: Comparative study of particle size distribution

Weigh about 10-30 mg of the crystal form 8 of the present invention and Form A disclosed in the prior art, then add about 5 ml of Isopar G (containing 0.2% lecithin), fully mix the sample to be tested and add it to the SDC sampling system , make the shading degree reach an appropriate range, start the experiment, and test the particle size distribution after 30 seconds of ultrasound. The test results are shown in Table 15, the particle size distribution of Form 8 is shown in Figure 23, and the particle size distribution of Form A is shown in Figure 24. It can be seen from the results that the crystal form 8 of the present invention has a more uniform particle size distribution compared with Form A disclosed in the prior art.

Table 15

Crystal form	Average particle size (microns)	D10 (micron)	D50 (micron)	D90 (micron)
Form 8	299.3	75.74	263.8	555.9
Form A	36.72	1.428	4.45	100.9

Example 21: Adhesion Comparative Study

About 30 mg of each of the crystal form 2/8/10/16 of the present invention and Form A disclosed in the prior art were weighed, then added to an 8 mm round flat punch, and subjected to tablet compression at a pressure of 10 kN. Hold for about half a minute and weigh the amount of powder absorbed by the punch. After two consecutive pressings using this method, the final sticking amount accumulated by the punch, the highest sticking amount and the average sticking amount during the pressing process were recorded. The adhesion of the crystal form 2/8/10/16 of the present invention is better than that of Form A disclosed in the prior art.

The above-mentioned embodiments are only intended to illustrate the technical concept and characteristics of the present invention, and the purpose is to enable those who are familiar with the art to understand the content of the present invention and implement accordingly, and cannot limit the protection scope of the present invention by this. All equivalent changes or modifications made according to the spirit of the present invention should be included within the protection scope of the present invention.

Claims (11)

1. Compound represented by formula (I) 1-(4-[1-[(E)-4-cyclohexyl-3-trifluoromethyl-hydroxybenzylamine]-ethyl]-2-ethyl-benzyl) - Hemi-fumarate crystal form 10 of azetidine-3-carboxylic acid, namely crystal form 10, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form 10 has a 2θ value There are characteristic peaks at 11.2°±0.2°, 22.5°±0.2° and 16.0°±0.2°,

   
2. The preparation method of crystal form 10 according to claim 1, is characterized in that,

   (1) Dissolving the compound of formula (I) and fumaric acid in a halogenated hydrocarbon or alkyl nitrile solvent, volatilizing the solvent until the solid is precipitated to obtain crystal form 10; or

   (2) adding the hemifumaric acid amorphous sample of the compound of formula (I) to halogenated hydrocarbons, alkyl nitriles, water or a mixed solvent thereof, after stirring, separating the solid to obtain crystal form 10; or

   (3) placing the hemifumarate amorphous sample of the compound of formula (I) in a halogenated hydrocarbon solvent for gas-solid infiltration to obtain crystal form 10; or

   (4) dissolving the hemifumarate of the compound of formula (I) in a halogenated hydrocarbon solvent, adding an alkyl nitrile solvent dropwise to the solution, and after stirring, the solid is precipitated to obtain crystal form 10; or

   (5) Dissolving the hemifumarate of the compound of formula (I) in a halogenated hydrocarbon solvent, quickly adding it to an ester solvent, after stirring, the solid is precipitated to obtain crystal form 10.
3. Compound represented by formula (I) 1-(4-[1-[(E)-4-cyclohexyl-3-trifluoromethyl-hydroxybenzylamine]-ethyl]-2-ethyl-benzyl) - Hemifumarate crystal form 8 of azetidine-3-carboxylic acid, namely crystal form 8, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form 8 has a 2θ value There are characteristic peaks at 10.7°±0.2°, 21.5°±0.2° and 18.9°±0.2°,

   
4. The preparation method of crystal form 8 according to claim 3, is characterized in that,

   (1) adding the compound of formula (I) and fumaric acid to pure water, after stirring, separating the solid to obtain crystal form 8; or

   (2) Add the amorphous hemifumaric acid sample of the compound of formula (I) to cyclic ethers, water or a mixed solvent thereof, and after stirring, separate the solid to obtain crystal form 8.
5. Compound represented by formula (I) 1-(4-[1-[(E)-4-cyclohexyl-3-trifluoromethyl-hydroxybenzylamine]-ethyl]-2-ethyl-benzyl) - Hemi-fumarate crystal form 2 of azetidine-3-carboxylic acid, namely crystal form 2, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form 2 has a 2θ value There are characteristic peaks at 4.9±0.2°, 23.4°±0.2° and 14.8°±0.2°,

   
6. The preparation method of crystal form 2 according to claim 5, wherein the method comprises:

   The compound of formula (I) and fumaric acid are added to an ether solvent, and after stirring, the solid is separated to obtain crystal form 2.
7. Compound represented by formula (I) 1-(4-[1-[(E)-4-cyclohexyl-3-trifluoromethyl-hydroxybenzylamine]-ethyl]-2-ethyl-benzyl) - Hemi-fumarate crystal form 16 of azetidine-3-carboxylic acid, namely crystal form 16, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form 16 has a 2θ value There are characteristic peaks at 8.1°±0.2°, 24.9°±0.2° and 19.0°±0.2°,

   
8. The preparation method of crystal form 16 according to claim 7, is characterized in that,

   The compound of formula (I) and fumaric acid are added to ketones, halogenated hydrocarbons and mixed solvents thereof, and after stirring, the solids are separated and dried to obtain crystal form 16.
9. A pharmaceutical composition comprising the crystal of any one of claims 1, 3, 5 and 7 and a pharmaceutically acceptable carrier.
10. A pharmaceutical composition with an S1P inhibitor, which contains the crystal of any one of claims 1, 3, 5 and 7 as an active ingredient.
11. A prophylactic or therapeutic drug for multiple sclerosis, secondary progressive multiple sclerosis and/or relapsing-remitting multiple sclerosis, comprising the crystal according to any one of claims 1, 3, 5 and 7 as Active ingredients.

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