TW201623294A - Crystal forms of 1-{2-fluoro-4-[5-(4-isobutyl phenyl)-1,2,4-oxadiazole-3-yl]-benzyl}-3-azetidinecarboxylic acid - Google Patents

Abstract

The invention discloses crystal forms of a drug, i.e., 1-{2-fluoro-4-[5-(4-isobutyl phenyl)-1,2,4-oxadiazole-3-yl]-benzyl}-3-azetidinecarboxylic acid, for diseases or conditions mediated by an S1P1 receptor. The invention also discloses preparation methods for the crystal forms, a pharmaceutical composition of the crystal forms and application of the crystal forms in preparation of drugs used for treatment and/or prevention of diseases or conditions mediated by the S1P1 receptor.

Description

Crystal of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid type

This application belongs to the technical field of medicinal chemical crystallization. In particular, the drug 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3 is involved in a disease or condition mediated by the S1P1 receptor. A crystalline form of -yl]-benzyl}-3-azetidinecarboxylic acid, and a process for the preparation of the crystalline form, pharmaceutical compositions and uses thereof.

Polymorphs are properties of some molecular and molecular compositions. The same molecules may form different crystals due to different arrangements. The polymorphs have different crystal structures and physical properties such as solubility, stability, thermal properties, mechanical properties, purification capabilities, X-ray diffraction patterns, infrared absorption spectra, Raman spectra, and solid state nuclear magnetics. One or more analytical assays can be used to distinguish between different crystal forms of the same compound.

New crystalline forms of pharmaceutically active ingredients (including anhydrates, hydrates, solvates) have been found to provide materials with superior processing properties, and new crystalline and solvate-free materials have been found to provide better physicochemical properties, such as better Bioavailability, storage stability, easy processing, easy purification or as an intermediate crystal form that promotes conversion to other crystal forms. New crystalline forms of pharmaceutically useful compounds may also be indicative of improved drug performance. It expands the choices that formulation scientists can use to optimize formulation performance. The type of raw materials, such as improved dissolution, improved shelf life, easier processing, and the like.

1-{2-Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid with S1P1 The receptor agonist activity and selection specificity, and has a significantly shortened in vivo half-life, is therefore a good second-generation S1P1 receptor agonist. Numerous studies have shown that there are a variety of S1P1 receptor agonists that are capable of binding to homologous receptors expressed on lymphocytes and leading to internalization of the S1P1 receptor, which in turn prevents lymphocyte export. Therefore, the S1P1 receptor agonist can reduce the ability of the human body to initiate an immune response by preventing the transport of lymphocytes, and thus can be used as an immunosuppressive agent for treating various autoimmune diseases. Chemical formula of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid It is C ₂₃ H ₂₄ FN ₃ O ₃ ; molecular weight 409.45; the chemical structural formula is as follows:

1-{2-Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxo is disclosed in the patent document CN103450171A, which is incorporated herein by reference. Confirmation, preparation, composition and use of oxazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. Specifically, a method of preparing such a compound is disclosed in Example 2.

In view of the deficiencies of the prior art, 1-{2-fluoro-4-[5-(4-isobutyl) was studied. The crystal form of phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is of great practical significance.

The object of the present invention is to provide 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole The crystalline form and amorphous form of butyrocarboxylic acid, and methods for their preparation, pharmaceutical compositions and uses thereof.

According to an object of the present invention, the present invention provides 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- Form I of 3-azetidinecarboxylic acid (hereinafter referred to as "Form I") and a process for the preparation thereof, wherein Form I is a hemihydrate.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of Form I is 4.8 ± 0.2°, 5.5 ± 0.2°, 8.2 ± 0.2°, 15.0 ± 0.2°, 17.0 ± 0.2° at a diffraction angle 2θ and There are characteristic peaks at 18.6±0.2°.

Preferably, the X-ray powder diffraction pattern of the Form I is 4.8±0.2°, 5.5±0.2°, 8.2±0.2°, 10.1±0.2°, 11.1±0.2°, 12.1± at a diffraction angle 2θ. Characteristic peaks were found at 0.2°, 15.0±0.2°, 17.0±0.2°, 18.6±0.2°, 24.0±0.2°, 24.9±0.2°, and 27.0±0.2°.

Further, the X-ray powder diffraction pattern of the Form I has a characteristic peak and its relative intensity at a position where the diffraction angle 2θ is:

Without limitation, in one embodiment of the invention, the X-ray powder diffraction pattern of Form I is as shown in FIG.

The Form I also has at least one of the following characteristics: Without limitation, in one embodiment of the invention, the FT-IR pattern of Form I is as shown in Figure 5.

The Form I is prepared by any one of the following methods: (1) 1-{2-Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole -3-yl]-benzyl}-3-azetidinecarboxylic acid is formed into a suspension in the following solvent system, stirred and crystallized, and the precipitated crystals are separated and dried to obtain 1-{2-fluoro-4-[ Form I of 5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid, wherein the solvent system is selected from Water or a mixture of water and an organic solvent selected from the group consisting of C ₁ -C ₄ alcohols, C ₅ -C ₆ ethers, C ₃ -C ₄ ketones, ethyl acetate, nitromethane, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, chloroform, toluene, dimethyl hydrazine, C ₇ alkane and mixtures thereof; preferably, the organic solvent is selected from the group consisting of methanol, ethanol, propanol, butanol, methyl three Butyl ether, diisopropyl ether, acetone, methyl ethyl ketone, ethyl acetate, nitromethane, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, chloroform, toluene, dimethyl hydrazine, methyl Cyclohexane or n-heptane; preferably, the volume of water in the mixture of water and organic solvent is at least 0.01% by volume, more preferably Less than 0.1%; preferably, 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- The amount of 3-azetidinecarboxylic acid used is 1.1 to 50 times, more preferably 1.5 to 10 times, the solubility in the solvent system at the operating temperature; preferably, the temperature of the crystallization is room temperature to 60 ° C, more preferably room temperature; preferably, the operating temperature is room temperature; preferably, the crystallization time is 3-14 days, more preferably 3-7 days; (2) a certain temperature 1-{2-Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylate The acid is formed into a solution in a mixed system of water and tetrahydrofuran, cooled and stirred to crystallize, and the precipitated crystal is separated and dried to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1. Form I of 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid; preferably, the volume of water in the mixed system of water and tetrahydrofuran is 0.01% by volume ~50%, more preferably 0.1% to 50%; preferably, 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4- in the solution The amount of oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 0.1~ of its solubility in the mixed system at a certain temperature. 1 time, more preferably 0.5 to 1 time; preferably, the certain temperature is 40 ° C ~ 50 ° C; preferably, the temperature after cooling is room temperature; preferably, the crystallization time is 0.5 to 72 hours, more preferably 0.5 to 10 hours; (3) to 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3 -Based with -benzyl}-3-azetidinecarboxylic acid, water is added to a solution formed in an organic solvent, stirred and crystallized, and the precipitated crystals are separated and dried to obtain 1-{2-fluoro-4-[5 Form I of (4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid, wherein the organic solvent is selected from the group consisting of ethanol And a mixture of trifluoroethanol, tetrahydrofuran, 1,4-dioxane, dimethyl hydrazine or a mixture thereof; preferably, the organic solvent is selected from a trifluoroethanol solution of ethanol (the volume content of ethanol is 66%) , tetrahydrofuran, 1,4-dioxane or dimethyl hydrazine; preferably, the volume ratio of the water to the organic solvent is 1:1 to 50:1, more preferably 1:1 to 10:1; Preferably, in the solution, 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- The amount of 3-azetidine carboxylic acid is the operating temperature The solubility in the solvent is 0.1 to 1 times; more preferably 0.5 to 1 times; preferably, the operating temperature is room temperature; preferably, the temperature of the crystallization is from room temperature to 60 ° C, more preferably Room temperature; preferably, the crystallization time is 0.5 to 72 hours, more preferably 0.5 to 10 hours; (4) 1-{2-fluoro-4-[5-(4-isobutylbenzene) 1,1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is volatilized in a solution of a mixed system of water and an organic solvent, and the precipitated crystal is separated, Drying to give 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylate The crystalline form I of the acid; wherein the organic solvent is selected from the group consisting of propanol, acetone, tetrahydrofuran or a mixture thereof; preferably, the organic solvent is selected from the group consisting of isopropanol, acetone or tetrahydrofuran; preferably, the water and the organic The volume of water in the mixture of solvents is from 0.01% to 50%, more preferably from 0.1% to 50%; preferably, 1-{2-fluoro-4-[5-(4-isobutylphenyl) The amount of -1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 0.1 to 1 times the solubility in the solvent system at the operating temperature, more preferably 0.5 to 1 times; preferably, The operating temperature is room temperature; preferably, the temperature of the crystallization is from room temperature to 60 ° C, more preferably room temperature; preferably, the crystallization time is from 1 to 7 days, more preferably 3~ 7 days; in the preparation method of the above (1) to (4) crystal form I, the drying temperature is room temperature to 60 ° C, preferably 40 ° C; the drying time is 1 to 48 hours, preferably 1 ~24 hours.

The crystal form I has the following beneficial effects:

(1) The Form I is placed in a room temperature drier, room temperature open, room temperature -97% RH, room temperature - 75% RH or room temperature - 44% RH for 1 month, the crystal form is unchanged;

(2) The crystal form I has a quality change of only about 0.8% in the range of humidity change of 20 to 80% RH, and is not easy to absorb moisture;

(3) The crystalline form I is the most stable crystalline form in an aqueous system, and thus has a better application value in wet granulation or suspension dosage forms.

(4) The formulation prepared by using Form I as raw material did not change its crystal form and dissolution after standing for 6 months, indicating that it is suitable for the application of the preparation product.

The above properties of the crystalline form I indicate that the crystalline form I of the present invention has good crystal form stability and low hygroscopicity, and can better resist the content caused by time, humidity and the like during the manufacture, storage and transportation of the drug. Problems such as unevenness and reduced purity reduce the risk of decrease in efficacy and safety risk caused by crystal form change, unstable content and increased impurity content of the active substance; and the crystalline form I of the present invention is the most stable crystal form in the aqueous system, It is more suitable for the wet granulation process of the solid preparation or the preparation of the suspension, has good formulation processing suitability, good production reproducibility, and is favorable for later storage and transportation.

According to an object of the present invention, the present invention provides 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- Form IV of 3-azetidinecarboxylic acid (hereinafter referred to as "Form IV") and a method for producing the same, wherein Form IV is an anhydride.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of Form IV is 4.8 ± 0.2°, 9.0 ± 0.2°, 15.1 ± 0.2°, 15.9 ± 0.2°, 17.5 ± 0.2° at a diffraction angle 2θ and There are characteristic peaks at 17.7±0.2°.

Preferably, the X-ray powder diffraction pattern of Form IV is 4.8±0.2°, 9.0±0.2°, 9.8±0.2°, 12.4±0.2°, 13.7±0.2°, 14.8± at a diffraction angle 2θ. Characteristic peaks were found at 0.2°, 15.1±0.2°, 15.9±0.2°, 17.5±0.2°, 17.7±0.2°, 18.2±0.2°, and 19.8±0.2°.

Further, the X-ray powder diffraction pattern of Form IV has a characteristic peak and its relative intensity at a position where the diffraction angle 2θ is:

Without limitation, in one embodiment of the invention, the X-ray powder diffraction pattern of Form IV is as shown in FIG.

The Form IV also has at least one of the following characteristics: Non-limiting, in one embodiment of the invention, the FT-IR pattern of Form IV is as shown in FIG.

The Form IV is prepared by any of the following methods: (1) 1-{2-Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole -3-yl]-benzyl}-3-azetidinecarboxylic acid is formed into a suspension in the following organic solvent system, stirred and crystallized, and the precipitated crystals are separated and dried to obtain 1-{2-fluoro-4- Form IV of [5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid, wherein the organic solvent is selected From C ₂ ~ C ₃ alcohol, acetone, C ₄ ~ C ₅ ester, tetrahydrofuran, 1,4-dioxane, acetonitrile and mixtures thereof; preferably, the organic solvent is selected from the group consisting of acetone, ethyl acetate, acetic acid Isopropyl ester, 1,4-dioxane, acetonitrile, acetone in ethanol (50% by volume of acetone), tetrahydrofuran in ethanol (tetrahydrofuran in a volume of 50%) and acetonitrile in ethanol (acetonitrile) The volume content is 50%), more preferably acetone, ethyl acetate, isopropyl acetate, 1,4-dioxane and acetonitrile; preferably, the organic solvent is dried, and the volume of water in the organic solvent The content is less than 0.001%; preferably, 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl The amount of the base -3-azetidinecarboxylic acid is 1.1 to 50 times, more preferably 1.5 to 10 times, the solubility in the solvent system at the operating temperature; preferably, the operating temperature is room temperature. Preferably, the temperature of the crystallization is from room temperature to 60 ° C, more preferably room temperature; preferably, the crystallization time is from 3 to 14 days, more preferably from 3 to 7 days; At a certain temperature, 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole Butylpyridinecarboxylic acid is formed into a solution in an organic solvent, cooled and stirred to crystallize, and the precipitated crystal is separated and dried to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1. Form IV of 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid, wherein the organic solvent is selected from the group consisting of C ₁ -C ₄ alcohols, C ₃ -C ₄ ketones, C ₄ ~ C ₅ ester, 1,4-dioxane, acetonitrile, toluene and mixtures thereof; preferably, the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, 2-butanol, An acetonitrile solution of n-butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, 1,4-dioxane, toluene and ethanol (volume content of ethanol is 25%), more preferably methanol, ethanol, Isopropyl alcohol, Butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, 1,4-dioxane, toluene; preferably, the organic solvent is dried, and the volume of water in the organic solvent is less than 0.001%. Preferably, in the solution, 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl} The -3-azetidinecarboxylic acid is used in an amount of 0.1 to 1 times, more preferably 0.5 to 1 times the solubility in the organic solvent at a certain temperature; preferably, the certain temperature is 40 to 80 ° C. More preferably, the temperature is from 50 ° C to 80 ° C; preferably, the temperature after cooling is room temperature; preferably, the crystallization time is from 0.5 to 72 hours, more preferably from 0.5 to 10 hours; (3) To 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid A slightly soluble or insoluble solvent is added to the solution formed in the soluble solvent, and the crystallized is stirred, and the precipitated crystal is separated and dried to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)- Form IV of 1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid, wherein the soluble solvent is selected from the group consisting of trifluoroethanol, tetrahydrofuran, and 1,4-di Oxytetracycline, dimethyl hydrazine or a mixture thereof; The sparingly soluble or insoluble solvent is selected from the group consisting of C ₃ -C ₄ alcohols, C ₄ -C ₅ esters, isopropyl ether, n-heptane or a mixture thereof; preferably, the soluble solvent is selected from the group consisting of trifluoroethanol and tetrahydrofuran. , 1,4-dioxane or dimethyl hydrazine; preferably, the sparingly soluble or insoluble solvent is selected from the group consisting of n-propanol, n-butanol, 2-butanol, ethyl acetate, isopropyl acetate, Isopropyl ether or n-heptane; preferably, the solvent is dried, and the volume content of water in the organic solvent is less than 0.001%; preferably, the volume ratio of the sparingly soluble or insoluble solvent to the soluble solvent is 1:1~50:1, more preferably 1:1~10:1; preferably, 1-{2-fluoro-4-[5-(4-isobutylphenyl)- in the solution 1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 0.1 to 1 times the solubility in the soluble solvent at the operating temperature; more preferably Preferably, the operating temperature is room temperature; preferably, the temperature of the crystallization is from room temperature to 60 ° C, more preferably room temperature; preferably, the crystallization The time is 0.5 to 72 hours, more preferably 0.5 to 10 hours; (4) 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole -3-yl] The solution of -benzyl}-3-azetidinecarboxylic acid in an organic solvent is volatilized, and the precipitated crystals are separated and dried to obtain 1-{2-fluoro-4-[5-(4-isobutylbenzene). Form IV of -1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid; wherein the organic solvent is selected from the group consisting of C ₁ -C ₄ alcohols, C ₄ ~C ₅ ester, methyl ethyl ketone, tetrahydrofuran, dimethyl hydrazine or a mixture thereof; preferably, the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, 2-butanol, n-butanol, and butyl a ketone, ethyl acetate, isopropyl acetate, tetrahydrofuran or dimethyl hydrazine; preferably, the organic solvent is dried, and the volume content of water in the organic solvent is less than 0.001%; preferably, 1-{2- The amount of fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is the operating temperature The solubility in the solvent system is 0.1 to 1 time, more preferably 0.5 to 1 time; preferably, the operating temperature is room temperature; preferably, the crystallization temperature is room temperature to 60 ° C, More preferably, it is room temperature; preferably, the crystallization time is 1 to 7 days, more preferably 3 to 7 days; in the preparation method of the above (1) to (4) crystal form IV, the dry Temperature is room temperature ~ 60 ℃, preferably 40 ℃; the drying time is 1 to 48 hours, preferably 1 to 24 hours.

The Form IV has the following beneficial effects: (1) The Form IV is dried at room temperature, room temperature, room temperature -97% RH, room temperature - 75% RH or room temperature - 44% RH After being left for 1 month, the crystal form is unchanged; (2) the quality change of the crystal form IV in the humidity range of 20-80% RH is about 1.6%; (3) the crystal form IV is the most pure organic solvent condition. a stable crystalline form; (4) the crystalline form IV is a rod-shaped particle, the particle is larger, and the fluidity is good; (5) the formulation prepared by using the crystalline form IV as a raw material, after being placed for 6 months, its crystal form and dissolution The degree of change did not change, indicating that it is suitable for the application of the preparation product.

The above properties of the crystalline form IV indicate that the crystalline form IV of the present invention has good crystal form stability and low hygroscopicity, and can better resist the content caused by factors such as time and humidity during the manufacture, storage and transportation of the drug. Unevenness and reduced purity The problem is to reduce the risk and safety risk of the therapeutic effect caused by the change of the crystalline form of the active substance, the unstable content and the increase of the impurity content; and the crystalline form IV of the present invention is the most stable crystalline form in the pure organic solvent, and has good formulation processing. Suitability, good reproducibility, and favorable for later storage and transportation; the crystal form VI of the invention has good particle shape and good fluidity, is favorable for accurate quantification and dumping in preparation of the preparation, and has good reproducibility. Has good formulation processing suitability.

According to an object of the present invention, the present invention provides 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- Form XII of 3-azetidinecarboxylic acid (hereinafter referred to as "Form XII") and a process for producing the same, wherein Form XII is an anhydride.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of Form XII is at 6.3 ± 0.2°, 9.5 ± 0.2°, 12.7 ± 0.2°, 18.0 ± 0.2°, and 19.3 ± 0.2° at a diffraction angle 2θ There are characteristic peaks.

Preferably, the X-ray powder diffraction pattern of the Form XII is 6.3±0.2°, 9.5±0.2°, 12.7±0.2°, 18.0±0.2°, 19.3±0.2°, 21.8± at a diffraction angle 2θ. Characteristic peaks were found at 0.2°, 22.1±0.2°, 22.4±0.2°, 24.2±0.2°, 24.6±0.2°, and 25.7±0.2°.

Further, the X-ray powder diffraction pattern of the Form XII has a characteristic peak and its relative intensity at a position where the diffraction angle 2θ is:

Without limitation, in one embodiment of the invention, the X-ray powder diffraction pattern of Form XII is as shown in FIG.

The Form XII also has at least one of the following characteristics: Non-limiting, in one embodiment of the invention, the FT-IR pattern of the Form XII is as shown in Figure 15.

The Form XII was prepared by the following method: 1-{2-Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl The base -3-azetidine carboxylic acid is formed into a suspension in anhydrous methanol, stirred and crystallized, and the precipitated crystals are separated and dried to obtain the 1-{2-fluoro-4-[5-(4-isobutyl) Form XII of phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid; preferably, 1-{2-fluoro-4-[ 5-(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in anhydrous methanol at the operating temperature The solubility is 1.1 to 50 times, more preferably 1.5 to 10 times; preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably room temperature; preferably, the operating temperature is room temperature; Preferably, the crystallization time is 3-14 days, more preferably 3-7 days; in the preparation method of the above Form XII, the drying temperature is room temperature to 60 ° C, preferably 40 ° C; The drying time is from 1 to 48 hours, preferably from 1 to 24 hours.

The Form XII has the following beneficial effects: (1) The Form XII is dried at room temperature, room temperature, room temperature -97% RH, room temperature - 75% RH or room temperature - 44% RH After being left for 1 month, the crystal form is unchanged; (2) the crystal form XII has a quality change of only about 1.3% in the range of humidity change of 20-80% RH; (3) the crystal form XII has better quality in water. Stability; (4) The preparation prepared by using Form XII as raw material did not change its crystal form and dissolution after 6 months of storage, indicating that it is suitable for the application of the preparation product.

The above properties of the crystalline form XII indicate that the crystalline form XII of the present invention has good crystal form stability and low hygroscopicity, and can better resist the content caused by factors such as time and humidity during the manufacture, storage and transportation of the drug. Problems such as unevenness and reduced purity reduce the risk of decrease in efficacy and safety risk caused by crystal form change, unstable content and increase of impurity content of the active substance; and the crystal form XII of the present invention has certain stability in water, and is more suitable The wet granulation process of the solid preparation or the preparation of the suspension has good formulation processing suitability, good production reproducibility, and is favorable for later storage and transportation.

According to an object of the present invention, the present invention provides 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- Form II of 3-azetidinecarboxylic acid (hereinafter referred to as "Form II") and a process for its preparation.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of Form II is 5.3 ± 0.2°, 12.8 ± 0.2°, 14.7 ± 0.2°, 16.9 ± 0.2°, 19.1 ± 0.2° at a diffraction angle 2θ and There are characteristic peaks at 19.5±0.2°.

Preferably, the X-ray powder diffraction pattern of the Form II is 5.3±0.2°, 6.3±0.2°, 8.1±0.2°, 9.8±0.2°, 12.8±0.2°, 14.7± at a diffraction angle 2θ. Characteristic peaks were present at 0.2°, 15.6±0.2°, 16.9±0.2°, 18.5±0.2°, 19.1±0.2°, 19.5±0.2°, and 21.7±0.2°.

Further, the X-ray powder diffraction pattern of the Form II has a characteristic peak and its relative intensity at a position where the diffraction angle 2θ is:

Without limitation, in one embodiment of the invention, the X-ray powder diffraction pattern of Form II is as shown in FIG.

The Form II also has at least one of the following characteristics: Non-limiting, in a specific embodiment of the present invention, the FT-IR pattern of the Form II is as shown in FIG.

The Form II was prepared by the following method: 1-{2-Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl The crystal form I of the -3-azetidinecarboxylic acid is heated to completely remove the water of crystallization, and then naturally cooled to room temperature to obtain 1-{2-fluoro-4-[5-(4-isobutylbenzene). Form II of -1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid; preferably, the temperature raising method is TGA, DSC, hot stage or An oven; preferably, the elevated temperature is from 100 ° C to 150 ° C; preferably, the crystallization time is from 0.5 to 24 hours.

According to an object of the present invention, the present invention provides 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- Form III of 3-azetidinecarboxylic acid (hereinafter referred to as "Form III") and a process for its preparation.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of Form III is 4.1 ± 0.2°, 4.9 ± 0.2°, 8.2 ± 0.2°, 8.8 ± 0.2°, 11.3 ± 0.2° at a diffraction angle 2θ and There are characteristic peaks at 12.3±0.2°.

Preferably, the X-ray powder diffraction pattern of the crystal form III is 4.1±0.2°, 4.9±0.2°, 8.2±0.2°, 8.8±0.2°, 9.8±0.2°, 11.3± at a diffraction angle 2θ. Characteristic peaks were found at 0.2°, 12.3±0.2°, 19.8±0.2°, 22.0±0.2°, and 24.8±0.2°.

Further, the X-ray powder diffraction pattern of the Form III has a characteristic peak and its relative intensity at a position where the diffraction angle 2θ is:

Without limitation, in a particular embodiment of the invention, The X-ray powder diffraction pattern of Form III is shown in Fig. 18.

The Form III also has at least one of the following characteristics: Non-limiting, in one embodiment of the invention, the FT-IR pattern of Form III is as shown in Figure 19.

Form III is prepared by any of the following methods: (1) to 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole An anti-solvent is added to a solution of -3-yl]-benzyl}-3-azetidinecarboxylic acid in trifluoroethanol, and the crystals are stirred and separated, and the precipitated crystals are separated without drying to obtain 1-{2- Form III of fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid, wherein The anti-solvent is selected from the group consisting of water, C ₃ -C ₄ ketone, C ₄ ester, C ₅ -C ₆ ether, acetonitrile or a mixture thereof; preferably, the anti-solvent is selected from the group consisting of water, acetone, ethyl acetate, and isopropyl Ether, methyl tertiary butyl ether, acetonitrile; preferably, the volume ratio of the antisolvent to trifluoroethanol is 1:1 to 50:1, more preferably 1:1 to 10:1; preferably , in the solution, 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole The amount of the butane carboxylic acid is 0.1 to 1 times; more preferably 0.5 to 1 times the solubility in trifluoroethanol at the operating temperature; preferably, the operating temperature is room temperature; preferably, the The crystallization temperature is from room temperature to 60 ° C, more preferably room temperature; preferably, the crystallization The time is 0.5 to 72 hours, more preferably 0.5 to 10 hours; (2) 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole The solution of -3-yl]-benzyl}-3-azetidinecarboxylic acid in trifluoroethanol is volatilized, and the precipitated crystal is separated without drying to obtain 1-{2-fluoro-4-[5 Form III of (4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid; preferably, 1-{2 - Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid in an amount at operating temperature The solubility in trifluoroethanol is 0.1 to 1 time, more preferably 0.5 to 1 time; preferably, the operating temperature is room temperature; preferably, the crystallization temperature is room temperature; preferably The crystallization time is 1 to 7 days, more preferably 3 to 7 days.

According to an object of the present invention, the present invention provides 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- Form V of 3-azetidinecarboxylic acid (hereinafter referred to as "Form V") and a process for its preparation.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of the Form V is 6.2 ± 0.2°, 11.4 ± 0.2°, 13.5 ± 0.2°, 17.2 ± 0.2°, 17.8 ± 0.2° at a diffraction angle 2θ and There are characteristic peaks at 18.9 ± 0.2°.

Preferably, the X-ray powder diffraction pattern of the Form V is 6.2±0.2°, 8.0±0.2°, 11.4±0.2°, 12.6±0.2°, 13.5±0.2°, 16.2± at a diffraction angle 2θ. Characteristic peaks were found at 0.2°, 17.2±0.2°, 17.8±0.2°, 18.9±0.2°, 20.4±0.2°, and 22.6±0.2°.

Further, the X-ray powder diffraction pattern of the Form V has a characteristic peak and its relative intensity at a position where the diffraction angle 2θ is:

Without limitation, in one embodiment of the invention, the X-ray powder diffraction pattern of Form V is as shown in FIG.

The Form V also has at least one of the following characteristics: Without limitation, in one embodiment of the invention, the FT-IR pattern of the Form V is as shown in FIG.

The Form V is prepared by the following method: 1-{2-Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl The base -3-azetidine carboxylic acid is formed into a suspension in n-butanol, stirred and crystallized, and the precipitated crystal is separated and dried to obtain 1-{2-fluoro-4-[5-(4-isobutyl) Form V of phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid; preferably, 1-{2-fluoro-4-[5 -(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid is used in n-butanol at the operating temperature The solubility is 1.1 to 50 times, more preferably 1.5 to 10 times; preferably, the operating temperature is room temperature; Preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably room temperature; preferably, the crystallization time is from 3 to 14 days, more preferably from 3 to 7 days; In the preparation method, the drying temperature is from room temperature to 60 ° C, preferably 40 ° C; and the drying time is from 1 to 48 hours, preferably from 1 to 24 hours.

According to an object of the present invention, the present invention provides 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- Form VI of 3-azetidinecarboxylic acid (hereinafter referred to as "Form VI") and a process for its preparation.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of the Form VI is at 6.4 ± 0.2°, 7.2 ± 0.2°, 8.9 ± 0.2°, 17.2 ± 0.2°, and 17.7 ± 0.2° at a diffraction angle 2θ There are characteristic peaks.

Preferably, the X-ray powder diffraction pattern of the Form VI is 5.7±0.2°, 6.2±0.2°, 6.8±0.2°, 7.2±0.2°, 8.9±0.2°, 13.6± at a diffraction angle 2θ. Characteristic peaks were found at 0.2°, 14.5±0.2°, 17.2±0.2°, 17.7±0.2°, 18.4±0.2°, and 19.4±0.2°.

Further, the X-ray powder diffraction pattern of the Form VI has a characteristic peak and its relative intensity at a position where the diffraction angle 2θ is:

Without limitation, in one embodiment of the invention, the X-ray powder diffraction pattern of Form VI is as shown in FIG.

The Form VI was prepared by the following method: 1-{2-Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl A suspension of carboxylic acid is formed in ethanol, stirred and crystallized, and the precipitated crystals are separated and dried to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl) a crystalline form VI of -1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid; preferably, 1-{2-fluoro-4-[5-( The amount of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 1.1~ of its solubility in ethanol at the operating temperature. 50 times, more preferably 1.5 to 10 times; Preferably, the operating temperature is room temperature; preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably room temperature; preferably, the crystallization time is 3-14 days, more Preferably, in the preparation method of the above Form VI, the drying temperature is from room temperature to 60 ° C, preferably 40 ° C; the drying time is from 1 to 48 hours, preferably from 1 to 24 hours. .

According to an object of the present invention, the present invention provides 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- Form VII of 3-azetidinecarboxylic acid (hereinafter referred to as "Form VII") and a process for its preparation.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of Form VII is 5.6 ± 0.2°, 8.4 ± 0.2°, 11.3 ± 0.2°, 19.9 ± 0.2°, 22.8 ± 0.2° at a diffraction angle 2θ and There are characteristic peaks at 25.8 ± 0.2°.

Further, the X-ray powder diffraction pattern of Form VII has a characteristic peak and its relative intensity at a position where the diffraction angle 2θ is:

Without limitation, in one embodiment of the invention, the X-ray powder diffraction pattern of Form VII is as shown in Figure 23.

The Form VII also has at least one of the following characteristics: Without limitation, in one embodiment of the invention, the FT-IR pattern of Form VII is as shown in Figure 24.

Form VII is prepared by the formation of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl a solution of -3-butyridinecarboxylic acid in dimethyl hydrazine, the reaction bottle opening of the solution is placed in a sealed atmosphere filled with water, and the water vapor is diffused into the dimethyl arsenide solution for crystallization. The precipitated crystals were separated without drying to give 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl} Form VII of -3-azetidinecarboxylic acid; preferably, the volume ratio of the water to dimethyl hydrazine is from 1:1 to 50:1, more preferably from 1:1 to 10:1; preferably. 1-{2-Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid The amount used is 0.1 to 1 times; more preferably 0.5 to 1 times the solubility in dimethyl hydrazine at the operating temperature; preferably, the operating temperature is room temperature; preferably, the crystallization temperature It is room temperature to 60 ° C, more preferably room temperature; preferably, the crystallization time is 3 to 14 days, more preferably 7-14 days.

According to an object of the present invention, the present invention provides 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- Form VIII of 3-azetidinecarboxylic acid (hereinafter referred to as "Form VIII") and a process for its preparation.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of Form VIII is 3.5±0.2°, 7.2±0.2°, 14.5±0.2°, 17.7±0.2°, 18.5±0.2° at the diffraction angle 2θ. And characteristic peaks at 19.5 ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of Form VIII is 3.5±0.2°, 7.2±0.2°, 9.8±0.2°, 12.7±0.2°, 14.5±0.2°, 16.8± at a diffraction angle 2θ. Characteristic peaks were found at 0.2°, 17.2±0.2°, 17.7±0.2°, 18.2±0.2°, 18.5±0.2°, and 19.5±0.2°.

Further, the X-ray powder diffraction pattern of Form VIII has a characteristic peak and its relative intensity at a position where the diffraction angle 2θ is:

Without limitation, in a particular embodiment of the invention, The X-ray powder diffraction pattern of Form VIII is shown in Figure 25.

The Form VIII also has at least one of the following characteristics: Without limitation, in one embodiment of the invention, the FT-IR pattern of Form VIII is as shown in Figure 26.

Form VIII is prepared by the method of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl The crystal form VI of the -3-azetidinecarboxylic acid is formed into a suspension in ethanol, stirred and crystallized, and the precipitated crystal is separated and dried to obtain 1-{2-fluoro-4-[5-(4-iso) Form VIII of butylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid; preferably, the amount of Form VI is at operating temperature The solubility in ethanol is 1.1 to 50 times, more preferably 1.5 to 10 times; preferably, the operating temperature is room temperature; preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably Preferably, the crystallization time is 3-14 days, more preferably 3-7 days; in the preparation method of the above Form VIII, the drying temperature is room temperature to 60 ° C, preferably 40 ° C; the drying time is 1 to 48 hours, preferably 1 to 24 hours.

According to an object of the present invention, the present invention provides 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- Form IX of 3-azetidinecarboxylic acid (hereinafter referred to as "Form IX") and a process for its preparation.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of Form IX is 6.2 ± 0.2°, 7.0 ± 0.2°, 12.5 ± 0.2°, 17.1 ± 0.2°, 17.5 ± 0.2° at a diffraction angle 2θ and Characteristic peak at 17.9±0.2°°

Preferably, the X-ray powder diffraction pattern of Form IX is 4.8±0.2°, 6.2±0.2°, 7.0±0.2°, 8.2±0.2°, 9.7±0.2°, 11.5± at a diffraction angle 2θ. Characteristic peaks were found at 0.2°, 12.5±0.2°, 13.4±0.2°, 14.3±0.2°, 17.1±0.2°, 17.5±0.2°, and 17.9±0.2°.

Further, the X-ray powder diffraction pattern of the Form IX has a characteristic peak and its relative intensity at a position where the diffraction angle 2θ is: 24.2 ± 0.2 ° 11.3.

Without limitation, in one embodiment of the invention, the X-ray powder diffraction pattern of Form IX is as shown in Figure 27.

The Form IX also has at least one of the following characteristics: Without limitation, in one embodiment of the invention, the FT-IR pattern of the Form IX is as shown in Figure 28.

The Form IX was prepared by the following method: 1-{2-Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl A suspension of -3-azetidine carboxylic acid in isopropanol is stirred and crystallized, and the precipitated crystals are separated and dried to obtain 1-{2-fluoro-4-[5-(4-isobutyl) Form IX of phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid; preferably, 1-{2-fluoro-4-[5 -(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in isopropyl alcohol at the operating temperature The solubility is 1.1 to 50 times, more preferably 1.5 to 10 times; preferably, the operating temperature is room temperature; preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably room temperature; Preferably, the crystallization time is 3-14 days, more preferably 3-7 days; in the preparation method of the above Form IX, the drying temperature is room temperature to 60 ° C, preferably 40 ° C; The drying time is from 1 to 48 hours, preferably from 1 to 24 hours.

According to an object of the present invention, the present invention provides 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- Form X of 3-azetidinecarboxylic acid (hereinafter referred to as "Form X") and a process for its preparation.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of Form X is at a diffraction angle 2θ of 3.1±0.2°, 5.9±0.2°, 6.4±0.2°, 17.7±0.2°, and 18.1±0.2°. There are characteristic peaks.

Preferably, the X-ray powder diffraction pattern of the Form X is 3.1±0.2°, 5.9±0.2°, 6.4±0.2°, 14.5±0.2°, 16.5±0.2°, 17.7± at a diffraction angle 2θ. Characteristic peaks were found at 0.2°, 18.1±0.2°, 18.4±0.2°, 19.2±0.2°, and 22.2±0.2°.

Further, the X-ray powder diffraction pattern of the Form X has a characteristic peak and its relative intensity at a position where the diffraction angle 2θ is:

Without limitation, in one embodiment of the invention, the X-ray powder diffraction pattern of Form X is as shown in FIG.

The Form X also has at least one of the following characteristics: without limitation, in one embodiment of the invention, the Form X The FT-IR diagram is shown in Figure 30.

The Form X was prepared by the following method: 1-{2-Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl The solution of -3-azetidinecarboxylic acid in 1,4-dioxane is volatilized, and the precipitated crystal is separated and dried to obtain 1-{2-fluoro-4-[5-(4- Form X of isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid; preferably, 1-{2-fluoro-4 -[5-(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid is present at an operating temperature of 1, The solubility in the 4-dioxane is 0.1 to 1 times, more preferably 9.5 to 1 times; preferably, the operating temperature is room temperature; preferably, the crystallization temperature is room temperature to 60 ° C More preferably, the crystallization time is 1 to 7 days, more preferably 3 to 7 days; in the preparation method of the above crystal form X, the drying temperature is room temperature to 60 ° C, It is preferably 40 ° C; the drying time is 1 to 48 hours, preferably 1 to 24 hours.

According to an object of the present invention, the present invention provides 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- Form XI of 3-azetidinecarboxylic acid (hereinafter referred to as "Form XI") and a process for its preparation.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of Form XI is at a diffraction angle 2θ of 8.9 ± 0.2°, 15.0 ± 0.2°, 15.7 ± 0.2°, 18.2 ± 0.2°, and 18.7 ± 0.2°. There are characteristic peaks.

Preferably, the X-ray powder diffraction pattern of the Form XI is 8.9±0.2°, 9.6±0.2°, 15.0±0.2°, 15.7±0.2°, 16.4±0.2°, 17.0± at a diffraction angle 2θ. 0.2°, There are characteristic peaks at 17.3 ± 0.2 °, 17.7 ± 0.2 °, 18.2 ± 0.2 °, and 18.7 ± 0.2 °.

Further, the X-ray powder diffraction pattern of the Form XI has a characteristic peak and its relative intensity at a position where the diffraction angle 2θ is:

Without limitation, in one embodiment of the invention, the X-ray powder diffraction pattern of Form XI is as shown in FIG.

The Form XI also has at least one of the following characteristics: without limitation, in a particular embodiment of the invention, the Form XI The FT-IR diagram is shown in Figure 32.

The Form XI was prepared by the following method: 1-{2-Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl A suspension of -3-azetidine carboxylic acid in toluene is stirred and crystallized, and the precipitated crystals are separated and dried to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl) a crystalline form XI of -1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid; preferably, 1-{2-fluoro-4-[5-( The amount of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 1.1~ of the solubility in toluene at the operating temperature. 50 times, more preferably 1.5 to 10 times; preferably, the operating temperature is 60 ° C; preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably 60 ° C; preferably, The crystallization time is 3-14 days, more preferably 3-7 days; in the preparation method of the above Form XI, the drying temperature is room temperature to 60 ° C, preferably 40 ° C; the drying time is 1 ~48 hours, preferably 1 to 24 hours.

Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form X and Form XI of the present invention In the above preparation method, the stirring may be carried out by a conventional method in the art, such as magnetic stirring, mechanical stirring or the like. The stirring rate is 50 to 1800 rpm, preferably 300 to 900 rpm.

Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form X and Form XI of the present invention In the above preparation method, the precipitated crystal is divided by a conventional method in the art. Leave, wash and dry. The separation is carried out by a conventional method in the art such as filtration, centrifugation, etc.; the specific operation of the filtration is: placing the sample to be separated on the filter paper and vacuum-filtering; the specific operation of the centrifugation is: placing the sample to be separated In a centrifuge tube, after high speed rotation until the solids all sink to the bottom of the centrifuge tube, the centrifugation rate is, for example, 6000 rpm. The solvent to be washed is preferably the same as the solvent used in the method for preparing the crystal form, and the amount of the washing solvent is 2 to 10 times that of the crystallization solvent. The drying is carried out by a conventional method in the art such as natural drying, blast drying or reduced pressure drying; the drying device is a fume hood, a blast oven or a vacuum oven; the drying is carried out under reduced pressure or no reduced pressure, preferably the pressure is less than 0.09Mpa; drying temperature is about room temperature to 60 ° C; drying time is 1 to 48 hours, preferably 1 to 24 hours.

In the present invention, the "room temperature" means about 10 to 30 °C.

In the present invention, "crystal", "crystal form" or "amorphous" means that it is confirmed by the X-ray diffraction pattern representation shown. Those skilled in the art will appreciate that the experimental error therein depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that X-ray diffraction patterns typically vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In addition, the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ±0.2° is usually allowed. In addition, due to experimental factors such as sample height, the overall offset of the peak angle is caused, and a certain offset is usually allowed. Thus, it will be understood by those skilled in the art that any crystal form having the same or similar peak as the characteristic peak of the present invention is within the scope of the present invention. Place By "single crystal form" is meant that the X-ray powder diffraction detection is a single crystal form.

Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI of the present invention are Pure, single, basically without any other crystal form or amorphous. In the present invention, "substantially free" when used to refer to a new crystalline form means that the other crystalline form or amorphous substance contained in the new crystalline form is less than 20% by weight, more preferably less than 10% by weight. In particular, it means less than 5% by weight, especially less than 1% by weight.

The starting material of the present invention 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole Butyl carboxylic acid can be obtained by referring to the preparation method of the patent document CN103450171A.

Further, the present invention provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more of the crystalline forms and amorphous forms of the present invention or crystalline forms and amorphous forms prepared by the method of the present invention, And at least one pharmaceutically acceptable carrier. Wherein, 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid The crystalline form and amorphous form include Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form X , Form XI and amorphous. Furthermore, the pharmaceutical composition may further comprise 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl} Other pharmaceutically acceptable crystalline forms or amorphous forms of -3-azetidinecarboxylic acid, or 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4- Oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid and 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxa A pharmaceutically acceptable crystalline form or amorphous form of the other salt of oxazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. Pharmaceutical compositions described herein It may be a pharmaceutical preparation itself, or it may be formulated into a pharmaceutical preparation or a combination preparation with other adjuvants or drugs.

The above pharmaceutical composition can be formulated into a certain dosage form, preferably by oral administration, parenteral administration (including subcutaneous, intramuscular and intravenous), rectal administration, transdermal administration, buccal administration, nasal administration. Dosage forms such as, but not limited to, solid dosage forms, liquid dosage forms, semi-liquid dosage forms, aerosols or suppositories. For example, dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, syrups or suspensions; suitable forms for parenteral administration include aqueous or nonaqueous solutions or Emulsions; dosage forms suitable for rectal administration include suppositories using hydrophilic or hydrophobic carriers; dosage forms suitable for transdermal administration include ointments, creams; and formulations suitable for nasal administration include aerosols, sprays. The above dosage forms may be adapted to the rapid release, delayed release or modified release of the active ingredient, as desired.

The pharmaceutically acceptable carrier of the present invention includes a solid carrier, and specifically includes, but not limited to, a diluent such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium hydrogen phosphate, tricalcium phosphate. , mannitol, sorbitol, sugar, etc.; binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, etc.; disintegrant For example, starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal cerium oxide, etc.; lubricants such as stearic acid, magnesium stearate, stearic acid Zinc acid, sodium benzoate, sodium acetate, etc.; glidants such as colloidal cerium oxide; complex forming agents such as various grades of cyclodextrin and resins; release rate controlling agents such as hydroxypropylcellulose, hydroxymethyl Cellulose, hydroxypropyl methylcellulose, ethylcellulose Vitamins, methylcellulose, methyl methacrylate, wax, etc. The pharmaceutically acceptable carrier of the present invention further comprises a liquid carrier, and specifically includes, but not limited to, a solvent of an aqueous, oily or alcoholic solution such as sterile water, physiological saline solution, dextrose solution, mannitol solution, vegetable oil, cod liver oil, Ethanol, propanol, glycerin, etc. Further, a carrier such as polyethylene glycol or polypropylene glycol can also be used. Other pharmaceutically acceptable carriers may also be selected depending on the dosage form, including, but not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, penetrants, buffers. Wait. Each carrier must be acceptable, compatible with the other ingredients in the formulation, and not deleterious to the patient.

The pharmaceutical compositions can be prepared using methods well known to those skilled in the art. When preparing a pharmaceutical composition, the crystalline form I, the crystalline form IV, the crystalline form XII, the crystalline form II, the crystalline form III, the crystalline form V, the crystalline form VI, the crystalline form VII, the crystalline form VIII, the crystalline form IX, the crystal of the present invention Form X, Form XI, amorphous or a combination thereof is admixed with one or more pharmaceutically acceptable carriers, optionally with one or more other pharmaceutically active ingredients. The solid preparation may be prepared by a process such as mixing, granulation, or the like, and the liquid or semi-liquid dosage form may be prepared by a process of mixing, dissolving, dispersing, emulsifying, or the like.

Further, the present invention provides the use of the crystalline form and the amorphous form of the present invention or the crystalline form and amorphous form obtained by the production method of the present invention for the preparation of a medicament for treating and/or preventing a disease or condition mediated by the SlP1 receptor. . Wherein the crystalline form and amorphous form include 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form of 3-azetidinecarboxylic acid X, Form XI, Amorphous or a combination thereof. The disease or condition mediated by the S1P1 receptor is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, autoimmune disease, chronic inflammatory disease, asthma, inflammatory neuropathy, arthritis, transplantation, Crohn's disease, ulcerative colitis, lupus erythematosus, psoriasis, ischemia-reperfusion injury, solid tumors, angiogenesis-related diseases, vascular diseases, pain conditions, acute viral diseases, inflammatory bowel diseases, insulin and Non-insulin dependent diabetes and other related immune diseases; preferably, the disease or condition is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis.

Further, the invention provides a method of treating and/or preventing a disease or condition mediated by an S1P1 receptor, the method comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a crystalline form of the invention and A styling or combination thereof or a pharmaceutical composition thereof, wherein the crystalline form and amorphous form include 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, of -3-yl]-benzyl}-3-azetidinecarboxylic acid Form VIII, Form IX, Form X, Form XI, amorphous or a combination thereof. The disease or condition mediated by the S1P1 receptor is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, autoimmune disease, chronic inflammatory disease, asthma, inflammatory neuropathy, arthritis, transplantation, Crohn's disease, ulcerative colitis, lupus erythematosus, psoriasis, ischemia-reperfusion injury, solid tumors, angiogenesis-related diseases, vascular diseases, pain conditions, acute viral diseases, inflammatory bowel diseases, insulin and Non-insulin dependent diabetes and other related immune diseases; preferably, the disease or condition is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis. The subject This includes, but is not limited to, mammals. The crystalline forms and amorphous forms provided by the present invention, or combinations thereof, or pharmaceutical compositions thereof, can be co-administered with other therapies or therapeutic agents. Furthermore, the dose of the compound or pharmaceutical composition required to effect a therapeutic, prophylactic or ameliorating effect will generally depend on the particular compound administered, the patient, the particular disease or condition and its severity, the route and frequency of administration, and the like, and The physician is judged on a case-by-case basis.

Figure 1 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention XRPD pattern of Form I of butyrocarboxylic acid.

Figure 2 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention PLM profile of Form I of butyroincarboxylic acid.

Figure 3 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention TGA/DSC pattern of Form I of butyrocarboxylic acid.

Figure 4 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention DVS isotherm adsorption diagram of Form I of butyrocarboxylic acid.

Figure 5 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention FT-IR spectrum of Form I of butyrocarboxylic acid.

Figure 6 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention XRPD pattern of Form IV of butyrocarboxylic acid.

Figure 7 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention PLM profile of Form IV of butyrocarboxylic acid.

Figure 8 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention TGA/DSC pattern of Form IV of butyrocarboxylic acid.

Figure 9 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention DVS isotherm adsorption diagram of Form IV of butyrocarboxylic acid.

Figure 10 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention FT-IR spectrum of Form IV of butyrocarboxylic acid.

Figure 11 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention XRPD pattern of Form XII of butanecarboxylic acid.

Figure 12 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention PLM profile of Form XII of butadiene carboxylic acid.

Figure 13 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention TGA/DSC pattern of Form XII of butanecarboxylic acid.

Figure 14 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention DVS isotherm adsorption diagram of Form XII of butyroincarboxylic acid.

Figure 15 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention FT-IR spectrum of Form XII of butanecarboxylic acid.

Figure 16 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention XRPD pattern of Form II of butyrocarboxylic acid.

Figure 17 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention FT-IR spectrum of Form II of butyrocarboxylic acid.

Figure 18 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention XRPD pattern of Form III of butyrocarboxylic acid.

Figure 19 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention FT-IR spectrum of Form III of butyrocarboxylic acid.

Figure 20 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention XRPD pattern of Form V of butyric acid.

Figure 21 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention FT-LR spectrum of Form V of butyrocarboxylic acid.

Figure 22 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention XRPD pattern of Form VI of butyrocarboxylic acid.

Figure 23 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention XRPD pattern of Form VII of butyrocarboxylic acid.

Figure 24 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention FT-IR spectrum of Form VII of butyrocarboxylic acid.

Figure 25 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention XRPD pattern of Form VIII of butanecarboxylic acid.

Figure 26 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention FT-IR spectrum of Form VIII of butyrocarboxylic acid.

Figure 27 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention XRPD pattern of Form IX of butanecarboxylic acid.

Figure 28 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention FT-IR spectrum of Form IX of butanecarboxylic acid.

Figure 29 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention XRPD pattern of Form X of butyrocarboxylic acid.

Figure 30 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention FT-IR spectrum of Form X of butyric acid.

Figure 31 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention XRPD pattern of Form XI of butyrocarboxylic acid.

Figure 32 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention FT-IR spectrum of Form XI of butyrocarboxylic acid.

Figure 33 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention Amorphous XRPD pattern of butanecarboxylic acid.

Figure 34 is a 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention Amorphous FT-IR spectrum of butanecarboxylic acid.

The invention is further understood by the following examples, but is not intended to limit the invention.

Testing equipment and methods: X-ray powder diffraction (XPRD): The instrument used was a Bruker D8 Advance diffractometer with a Ka X-ray with a copper target wavelength of 1.54 nm, a θ-2θ goniometer at 40 kV and 40 mA operating conditions, Mo Monochromator, Lynxeye detector. The instrument is calibrated with silicon carbide before use. The acquisition software is Diffrac Plus XRD Commander. The sample is tested at room temperature and the sample to be tested is placed on a non-reflecting plate. The detailed detection conditions are as follows, the angle range is 3-40 ° 2θ, the step size is 0.02 ° 2θ, and the speed is 0.2 sec / step.

Differential Thermal Analysis (DSC): The data is taken from TAInstrumentsQ200MDSC, the instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. A sample of 1-10 mg was usually placed in an aluminum pan, and the sample was raised from room temperature to 250 ° C under the protection of 40 mL/min dry N ₂ at a heating rate of 10 ° C/min.

Thermogravimetric Analysis (TGA): The data was taken from the TAInstrumentsQ500TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually, 1-15 mg of the sample is placed in a platinum crucible, and the sample is raised from room temperature to 300 ° C under the protection of 40 mL/min dry N ₂ at a heating rate of 10 ° C/min using a segmented high-resolution detection method. .

Isothermal adsorption curve (DVS): The data was taken from the TA Instruments Q5000 TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. A sample of 1-10 mg is usually placed in a platinum crucible, and the TA software records the change in weight of the sample during a change in relative humidity from 0% to 90% to 0%. Depending on the specifics of the sample, different adsorption and desorption steps are also applied to the sample.

Nuclear magnetic resonance spectroscopy data ( ¹ H NMR) were taken from a Bruker Avance II DMX 400 MHZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated chloroform (CDCl ₃ ) to prepare a solution of 2 mg/mL to 10 mg/mL.

Fourier infrared spectroscopy (FT-IR) data was obtained from Bruker Tensor 27, and the instrument control software and data analysis software were OPUS. ATR device usually within the range 600-4000cm ^-1, collecting an infrared absorption spectrum, and the scanning time of the sample on a white background is 32 sec, the resolution of 4cm ^-1.

The various reagents used in the examples are commercially available unless otherwise specified.

The ultrasonic operation in the examples facilitated dissolution of the sample and the apparatus was an ultrasonic cleaner operated at 40 kHz for 15 minutes.

Preparation Example 1

Compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid It is prepared by referring to the production method of Example 2 of Patent Document CN103450171A. Specifically: 2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzaldehyde (0.90 g, 2.78 mmol) at room temperature , a solution of 3-azetidinecarboxylic acid (0.28 g, 2.78 mmol) and acetic acid (1 mL) in methanol-tetrahydrofuran (20 mL / 20 mL) for 2 hrs, and sodium cyanoborohydride (1.03 g, 16.35 mmol) The solution (60 mL) was stirred at room temperature for 16 hr then filtered and washed with methanol (10 mL) and dried to give a white solid product 1-{2-fluoro-4-[5-(4-isobutylphenyl)- 1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid (Compound 2) (0.20 g). 1H-NMR (400MHz, CD3OD) δ: 8.13 (d, J = 8.4 Hz, 2H), 8.05 (m, 1H), 7.97 (m, 1H), 7.68 (t, J = 8.0 Hz, 7.6 Hz, 1H) , 7.42 (d, J = 8.4 Hz, 2H), 4.40 (s, 2H), 4.15 (m, 4H), 3.41 (m, 1H), 2.61 (d, J = 7.2 Hz, 2H), 1.95 (m, 1H), 0.94 (d, J = 7.2 Hz, 6H).

The X-ray powder diffraction pattern is an amorphous material as shown in Fig. 33.

The FT-IR spectrum is shown in Figure 34.

Example 1

Add 130.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 20 mL glass vial at room temperature } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 13.0 mL of acetone aqueous solution (water volume content of 67%), ultrasonic suspension for 15 minutes to obtain white suspension Liquid (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole in the suspension The amount of butyric acid carboxylic acid used is 50 times that in an aqueous acetone solution at room temperature, and the mixture is stirred at room temperature for 7 days to be crystallized, filtered, and the obtained solid is dried under vacuum at 40 ° C for 48 hours to obtain 1-0 of the present invention. Form I of 2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 120.1 mg; the yield was 95%.

The X-ray powder diffraction pattern is as shown in Fig. 1, and is a crystal form I.

The PLM map is shown in Figure 2. Display: fine crystals.

The DSC and TGA spectra are shown in Figure 3. It shows that Form I has a broad endothermic peak (solvent peak) at 3~115°C, and the melting point of the sample after removal of water is 179°C; the crystal form I has a step weight loss of about 2.2% before 50~125°C, and the hemihydrate theory The value (2.2%) corresponds and the decomposition temperature is 182 °C.

The DVS map is shown in Figure 4. Show: 20% RH ~ 80% RH weight change is 0.8%.

The FT-IR spectrum is shown in Figure 5.

The above test results show that the crystal form I is a hemihydrate and is not easily hygroscopic.

Example 2

0.9 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 20 mL glass vial at room temperature. A white suspension was obtained by sonication for 15 minutes with ultrasonication in the presence of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1 , 2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid is used in an amount of 50 times its solubility in water at room temperature, and is stirred at 60 ° C for 7 days for crystallization. After filtration, the obtained solid was dried under vacuum at room temperature for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3- of the present invention. Form I of benzyl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.7 mg; the yield was 78%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 3

15.4 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. A liquid suspension of 5-methylbutyridincarboxylic acid and 2.5 mL of ethanol (50% by volume of water) was obtained by ultrasonication for 15 minutes (1-{2-fluoro-4-[5-(4-) in the suspension Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl]-3-azetididinecarboxylic acid is used in an amount of 10 times its solubility in aqueous ethanol at room temperature) The mixture was stirred for 3 days at room temperature, and the resulting solid was vacuum dried at 40 ° C for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1 of the present invention. Form I of 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 13.1 mg; the yield was 85%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 4

Add 1.3 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 5 mL glass vial at room temperature A liquid suspension was obtained by ultrasonication for 15 minutes to obtain a white suspension (1-{2-fluoro-4-[5-(4-) in the suspension). Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 1.1 times its solubility in aqueous methanol at room temperature) The mixture was stirred for 3 days at room temperature, and the resulting solid was vacuum dried at room temperature for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1 of the present invention. 2,4-oxadiazole-3- Form I of benzyl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.1 mg; the yield was 0.8%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 5

0.6 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. A solution of } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 1.3 mL of n-propanol (water volume 1.0%), sonicated for 15 minutes to give a white suspension (1-{2-fluoro-4-[5-( The amount of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is its solubility in aqueous solution of n-propanol at room temperature. 1.5 times), crystallized at room temperature for 7 days, centrifuged, and the obtained solid was dried under vacuum at 40 ° C for 48 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl) of the present invention. Form I of-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.3 mg; the yield was 50%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 6

Add 3.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 5 mL glass vial at room temperature A liquid suspension of 5-methylbutyridincarboxylic acid and 1.0 mL of isopropanol (5.0% by volume of water) was obtained by ultrasonication for 15 minutes (1-{2-fluoro-4-[5-( The amount of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is its solubility in aqueous solution of isopropanol at room temperature. 10 times), crystallized at room temperature for 7 days, filtered, and the obtained solid was dried under vacuum at 40 ° C for 48 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl) of the present invention. Form I of-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 2.7 mg; the yield was 87%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 7

Add 3.2 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 5 mL glass vial at room temperature A solution of } 吖 吖 啶 羧酸 carboxylic acid and 1.6 mL of n-butanol (water volume 0.01%), sonicated for 15 minutes to give a white suspension (1-{2-fluoro-4-[5-( The amount of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is its solubility in n-butanol aqueous solution at room temperature. 10 times), crystallized at 60 ° C for 7 days, filtered, and the obtained solid was dried under vacuum at 60 ° C for 48 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl) of the present invention. Form I of-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 2.5 mg; the yield was 78%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 8

3.0 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. A solution of } 吖 吖 啶 羧酸 carboxylic acid and 1.5 mL of 2-butanol (water volume 0.1%), sonicated for 15 minutes to give a white suspension (1-{2-fluoro-4-[5-( 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an aqueous solution of 2-butanol at room temperature 10 times of solubility), stirred at room temperature for 14 days, crystallized, and centrifuged, and the obtained solid was vacuum dried at 60 ° C for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylbenzene) of the present invention. Form I of -1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 2.7 mg; the yield was 90%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 9

Add 3.0 mg 1-{2-fluorine in a 100 mL single-mouth bottle at room temperature 4-[5-(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid and 60 mL of methyltributyl Aqueous ether solution (water volume 0.1%), sonicated for 15 minutes to give a white suspension (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4- in the suspension) Oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 50 times its solubility in aqueous methyl tertiary butyl ether solution at room temperature, and stirred at room temperature for 14 days. Crystallization, centrifugation, and drying the obtained solid under vacuum at 60 ° C for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole of the present invention. Form I of -3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 2.7 mg; the yield was 90%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 10

2.9 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 100 mL single-mouth bottle at room temperature. A solution of } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 60 mL of isopropyl ether (water volume 0.01%), sonicated for 15 minutes to give a white suspension (1-{2-fluoro-4-[5-(4) -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of its solubility in aqueous isopropyl ether at room temperature 50 times), stirred at room temperature for 7 days, crystallized, filtered, and the obtained solid was dried under vacuum at room temperature for 1 hour to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl) of the present invention. Form I of -1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 2.0 mg; the yield was 69%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 11

4.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 2.0 mL D Aqueous ketone solution (water volume content 0.1%), sonicated for 15 minutes to give a white suspension (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4- in the suspension) The amount of oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 10 times that of the aqueous solution in butanone at room temperature, and the mixture is stirred for 3 days at room temperature, and centrifuged. The obtained solid was dried under vacuum at 40 ° C for 1 hour to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl] of the present invention. Form I of -benzyl}-3-azetidinecarboxylic acid. The yield was 3.3 mg; the yield was 80%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 12

2.5 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. a white suspension was obtained by ultrasonication for 15 minutes (1 -{2-fluoro-4-[5-() in the suspension. The amount of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is its solubility in aqueous ethyl acetate at room temperature 50 times), crystallized at room temperature for 7 days, centrifuged, and the obtained solid was dried under vacuum at 40 ° C for 1 hour to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl) of the present invention. Form I of-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 2.1 mg; the yield was 84%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 13

Add 1.8 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 5 mL glass vial at room temperature A solution of } 吖 吖 啶 羧酸 carboxylic acid and 3.6 mL of aqueous nitromethane (water volume content 1.0%), obtained by ultrasonication for 15 minutes to obtain a white suspension (1-{2-fluoro-4-[5-( 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl The base -3-azetidine carboxylic acid is used in an amount of 50 times the solubility in an aqueous solution of nitromethane at room temperature, and the mixture is stirred at 40 ° C for 7 days to be crystallized, filtered, and the obtained solid is vacuum dried at 40 ° C. In the hour, the 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention is obtained. Form I of the pyridinecarboxylic acid. The yield was 1.3 mg; the yield was 72%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 14

2.0 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. a white suspension was obtained by ultrasonication for 15 minutes (1 -{2-fluoro-4-[5-(() in this suspension). The amount of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is its solubility in aqueous dichloromethane at room temperature 40 times), stirred at 40 ° C for 7 days, crystallized, filtered, and the obtained solid was dried under vacuum at room temperature for 1 hour to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl) of the present invention. Form I of-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.8 mg; the yield was 40%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 15

5.8 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 1.0 mL of 1,4-dioxane aqueous solution (water volume content of 20%), ultrasonic 15 minutes to obtain a white suspension (1-{2-Fluoro-4- in this suspension) [5-(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid is used in an amount of 1, 4-fold solubility in 4-dioxane aqueous solution), stirred at 60 ° C for 7 days, crystallized, and centrifuged to obtain a solid of 60 ° C. Drying for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3 of the present invention - Form I of azetocarboxylic acid. The yield was 4.9 mg; the yield was 84%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 16

4.7 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. A liquid suspension of 吖 吖 吖 羧酸 羧酸 carboxylic acid and 4.7 mL of acetonitrile (40% by volume of water), obtained by ultrasonication for 15 minutes to obtain a white suspension (1-{2-fluoro-4-[5-(4- in the suspension) Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid is used in an amount of 10 times its solubility in an aqueous solution of acetonitrile at room temperature) The mixture was stirred at room temperature for 14 days, and the resulting solid was vacuum dried at 40 ° C for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1 of the present invention. Form I of 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 3.0 mg; the yield was 64%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 17

3.0 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. A solution of } 吖 吖 啶 羧酸 carboxylic acid and 1.0 mL of chloroform in water (0.01% by volume of water), obtained by ultrasonication for 15 minutes to obtain a white suspension (1-{2-fluoro-4-[5-(4-) in the suspension Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 5 times its solubility in aqueous chloroform at room temperature) The mixture was stirred at room temperature for 7 days, and the resulting solid was vacuum dried at room temperature for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1 of the present invention. Form I of 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 2.3 mg; the yield was 77%. XRPD The X-ray powder diffraction pattern substantially the same as in Fig. 1 was detected.

Example 18

Add 1.8 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 5 mL glass vial at room temperature A solution of } 吖 吖 啶 羧酸 carboxylic acid and 3.6 mL of toluene (water volume 0.1%), sonicated for 15 minutes to give a white suspension (1-{2-fluoro-4-[5-(4-) in this suspension Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid is used in an amount of 50 times its solubility in aqueous toluene at room temperature) The mixture was stirred at 40 ° C for 7 days, and the resulting solid was vacuum dried at 60 ° C for 48 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1 of the present invention. Form I of 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.5 mg; the yield was 28%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 19

Add 2.3 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 5 mL glass vial at room temperature A solution of } 吖 吖 啶 羧酸 carboxylic acid and 1.5 mL of dimethyl hydrazine in water (10% by volume of water), obtained by ultrasonication for 15 minutes to obtain a white suspension (1-{2-fluoro-4-[5- in the suspension) (4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an aqueous solution of dimethyl hydrazine at room temperature 1.5 times the solubility in the medium, and the mixture was stirred at 40 ° C for 7 days, and the resulting solid was vacuum dried at 60 ° C for 48 hours to obtain 1-{2-fluoro-4-[5-(4-isobutyl) of the present invention. Form I of phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.6 mg; the yield was 26%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 20

16.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. A solution of } 吖 吖 啶 羧酸 carboxylic acid and 1.0 mL of tetrahydrofuran (10% by volume of water), obtained by ultrasonication for 15 minutes to obtain a white suspension (1-{2-fluoro-4-[5-(4-) in the suspension Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid is used in an amount of 10 times its solubility in aqueous tetrahydrofuran at room temperature) The mixture was stirred at room temperature for 7 days, and the resulting solid was vacuum dried at room temperature for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1 of the present invention. Form I of 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 13.0 mg; the yield was 81%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 21

1.7 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 50 mL single-mouth bottle at room temperature. A solution of } 吖 吖 啶 羧酸 carboxylic acid and 34.0 mL of methylcyclohexane (water volume 0.01%), sonicated for 15 minutes to give a white suspension (1-{2-fluoro-4-[5 in this suspension) -(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in the form of methylcyclohexane at room temperature 50 times of the solubility in the aqueous solution of the alkoxide, and the mixture was stirred at 40 ° C for 7 days, and the resulting solid was vacuum dried at 40 ° C for 24 hours to obtain 1-{2-fluoro-4-[5-(4-iso) of the present invention. Form I of butylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 1.0 mg; the yield was 59%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 22

1.9 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 50 mL single-mouth bottle at room temperature. A solution of } 吖 吖 啶 羧酸 carboxylic acid and 38.0 mL of n-heptane (water volume 0.1%), sonicated for 15 minutes to give a white suspension (1-{2-fluoro-4-[5-( The amount of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is its solubility in n-heptane aqueous solution at room temperature. 50 times), crystallized at room temperature for 7 days, filtered, and the obtained solid was dried under vacuum at 60 ° C for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl) of the present invention. Form I of-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.7 mg; the yield was 37%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 23

2.5 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. Base -3-azetidinecarboxylic acid and 1.0 mL of tetrahydrofuran aqueous solution (50% by volume of water) and heated to 50 ° C in a water bath, stirred until the sample is completely dissolved (1-{2-fluoro-4-[5-(4) -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid in an amount of 50 ° C in the aqueous solution of tetrahydrofuran 0.5 times), the water bath was closed to cool to room temperature, and stirring was continued for 10 hours to obtain a white solid, which was filtered and dried under vacuum at 40 ° C for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutyl) of the present invention. Form I of phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 1.2 mg; the yield was 48%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 24

Add 5.1 mg 1-{2-Fluorine in a 20 mL glass vial at room temperature 4-[5-(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid and 10.0 mL of tetrahydrofuran aqueous solution (water Volume content 0.1%) and heated to 40 ° C in a water bath, stirred until the sample is completely dissolved (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole- The amount of 3-yl]-benzyl}-3-azetidinecarboxylic acid was 0.1 times in the aqueous solution of the tetrahydrofuran at 40 ° C, and the mixture was cooled to room temperature with a closed water bath and stirring was continued for 72 hours. White solid, filtered, vacuum dried at 60 ° C for 72 hours to give 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl. Form I of -benzyl}-3-azetidinecarboxylic acid. The yield was 3.0 mg; the yield was 59%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 25

7.9 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. Base -3-azetidine carboxylic acid and 1.0 mL of tetrahydrofuran aqueous solution (volume content of water 0.01%) and heated to 50 ° C in a water bath, stirred until the sample is completely dissolved (1-{2-fluoro-4-[5-(4) -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid in an amount of 50 ° C in the aqueous solution of tetrahydrofuran 1 time), the water bath was closed to cool to room temperature, and stirring was continued for 1 hour to obtain a white solid, which was centrifuged and dried under vacuum at 40 ° C for 1 hour to obtain 1-{2-fluoro-4-[5-(4-isobutyl) of the present invention. Form I of phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 3.7 mg; the yield was 47%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 26

1.6 mg 1-{2-Fluorine in a 20 mL glass vial at room temperature 4-[5-(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid and 1.0 mL of tetrahydrofuran, sonicated for 5 minutes After the sample is completely dissolved (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole The amount of the pyridine carboxylic acid is 1 time of its solubility in tetrahydrofuran at room temperature, and 10 mL of water is added dropwise thereto to immediately obtain a white solid, which is stirred at room temperature for 10 hours, centrifuged, and vacuum dried at 40 ° C for 1 hour to obtain the present invention. Crystal of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid Type I. The yield was 1.0 mg; the yield was 62%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 27

1.5 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 150 mL single-mouth bottle at room temperature. a solution of -3-butyridinecarboxylic acid and 1.0 mL of ethanol in trifluoroethanol (66% by volume of ethanol), and the sample was completely dissolved after 5 minutes of sonication (1-{2-fluoro-4-[5-( The amount of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is at room temperature in a solution of ethanol in trifluoroethanol 0.5 times of the solubility), 100 mL of water was added dropwise thereto, and a white solid was immediately obtained, stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C for 24 hours to obtain 1-{2-fluoro-4-[5-( Form I of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 1.3 mg; the yield was 87%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 28

1.7 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 50 mL single-mouth bottle at room temperature.吖 吖 吖 啶 羧酸 carboxylic acid and 28.0 mL of 1,4-dioxane, the sample was completely dissolved after 5 minutes of sonication (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole- The amount of 3-yl]-benzyl}-3-azetidinecarboxylic acid is 0.1 times its solubility in 1,4-dioxane at room temperature), 1-{2-fluoro-4- 1,4-Dioxane solution of [5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid After adding to 10.0 mL of water, a white solid was immediately obtained, stirred at 60 ° C for 0.5 hour, filtered, and dried under vacuum at 60 ° C for 1 hour to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl) of the present invention. Form I of-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.7 mg; the yield was 41%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 29

1.9 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 20 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 1.9 mL of dimethyl hydrazine, the sample was completely dissolved after 5 minutes of ultrasound (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1, The amount of 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 1 time of its solubility in dimethyl hydrazine at room temperature, and 10 mL of water is added thereto. A white solid was obtained immediately, stirred at room temperature for 0.5 hour, filtered, and dried under vacuum at 40 ° C for 24 hours to give 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2 of the present invention. Form I of 4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 1.4 mg; the yield was 74%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 30

1.9 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 20 mL glass vial at room temperature.吖 吖 吖 啶 羧酸 carboxylic acid and 6.3 mL of isopropyl alcohol aqueous solution (50% by volume of water), and ultrasonication for 15 minutes to obtain a colorless clear solution (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1) in this solution , the amount of 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 1 times its solubility in an aqueous solution of isopropanol at this temperature, and is 0.45 μm (μm) The organic filter membrane was filtered, and the filtrate was placed in a 5 mL glass vial at 60 ° C for open volatilization, and the obtained solid was vacuum dried at 40 ° C for 48 hours to obtain 1-{2-fluoro-4-[5-( Form I of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 1.4 mg; the yield was 74%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 31

1.7 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 20 mL glass vial at room temperature. } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 10.0 mL of tetrahydrofuran aqueous solution (water volume of 0.1%), ultrasonic 15 minutes to obtain a colorless clear solution (1-{2-fluoro-4-[5-(4) -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid in an amount of 0.1 times its solubility in aqueous tetrahydrofuran at room temperature The solution was filtered through a 0.45 μm organic filtration membrane, and the filtrate was placed in a 20 mL glass vial and evaporated at room temperature for 3 days to crystallize. The obtained solid was vacuum dried at room temperature for 24 hours to obtain 1-{2-fluoro-4 of the present invention. Form I of [5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.4 mg; the yield was 24%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 32

0.8 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 20 mL glass vial at room temperature.吖 吖 吖 啶 羧酸 carboxylic acid and 8.0 mL of acetone aqueous solution (water volume content of 0.01%), ultrasonication for 15 minutes to obtain a colorless clear solution (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2) , the amount of 4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 0.5 times its solubility in aqueous acetone solution at room temperature, and is filtered through a 0.45 μm organic filtration membrane. The filtrate was placed in a 20 mL glass vial and evaporated at room temperature for 1 day to crystallize. The obtained solid was vacuum dried at 60 ° C for 1 hour to obtain 1-{2-fluoro-4-[5-(4-isobutylbenzene) of the present invention. Form I of -1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.4 mg; the yield was 40%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 1.

Example 33

Add 30.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 5 mL glass vial at room temperature } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 3.0 mL of acetone (volume content of 0.0000% water), ultrasonic for 15 minutes to obtain a white suspension (1-{2-fluoro-4-[5-(4) in this suspension -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 50 times its solubility in acetone at room temperature) The mixture was stirred at room temperature for 7 days, and the resulting solid was vacuum dried at room temperature for 72 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1 of the present invention. Form IV of 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 27.5 mg; the yield was 91%.

The X-ray powder diffraction pattern is shown in Figure 6, which is Form IV.

The PLM map is shown in Figure 7. Display: rod crystals.

The DSC and TGA spectra are shown in Figure 8. It is shown that the melting point of Form IV is 174 ° C; Form IV has substantially no weight loss before 125 ° C, and the decomposition temperature is 183 ° C.

The DVS spectrum is shown in Figure 9. Display: 20% RH~80% RH weight The change was 1.6%.

The FT-IR spectrum is shown in Figure 10.

The above test results show that the crystal form IV is an anhydrate, has a good morphology and is stable at high temperatures.

Example 34

3.7 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 20 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 7.4 mL of ethyl acetate (volume content of water 0.0000%), ultrasonication for 15 minutes to obtain a white suspension (1-{2-fluoro-4-[5- in this suspension) (4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid is used in its solubility in ethyl acetate at room temperature 50 times), crystallized at 40 ° C for 7 days, filtered, and the obtained solid was dried under vacuum at room temperature for 48 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl) of the present invention. Form IV of-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 3.0 mg; the yield was 81%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 35

1.5 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 150 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 100 mL of isopropyl acetate (volume content of 0.0000% water), sonicated for 15 minutes to obtain a white suspension (1-{2-fluoro-4-[5- in this suspension) (4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in isopropyl acetate at room temperature 1.5 times of solubility), crystallized at room temperature for 7 days, filtered, and the obtained solid was vacuum dried at room temperature for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylbenzene) of the present invention. Form IV of -1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.7 mg; the yield was 47%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 36

6.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 1.0 mL of 1,4-dioxane (volume content of 0.0001%), sonicated for 15 minutes to obtain a white suspension (1-{2-fluoro-4 in the suspension) -[5-(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is used at room temperature at 1 , 10 times the solubility in 4-dioxane), crystallized at 60 ° C for 7 days, filtered, and the obtained solid was dried under vacuum at 40 ° C for 48 hours to obtain 1-{2-fluoro-4-[5 of the present invention. Form IV of -(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 4.5 mg; the yield was 74%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 37

1.2 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 2.4 mL of acetonitrile (volume content of 0.00005%), sonicated for 15 minutes to obtain a white suspension (1-{2-fluoro-4-[5-(4) in the suspension) -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 50 times its solubility in acetonitrile at room temperature) The mixture was stirred at room temperature for 7 days, and the resulting solid was vacuum dried at 60 ° C for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1 of the present invention. Form IV of 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.7 mg; the yield was 58%. XRPD inspection The X-ray powder diffraction pattern substantially the same as in Fig. 6 was measured.

Example 38

5.9 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. A solution of ethyl -3-azetidine carboxylic acid and 1.0 mL of acetone in ethanol (50% by volume of acetone and 0.00005% by volume of water), and ultrasonication for 15 minutes to obtain a white suspension (1-{ in the suspension) The amount of 2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is The solution was dissolved in acetone in ethanol at room temperature for 10 times), and the mixture was stirred at room temperature for 14 days to crystallize, filtered, and the obtained solid was vacuum dried at room temperature for 24 hours to obtain 1-{2-fluoro-4-[ Form IV of 5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 3.3 mg; the yield was 56%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 39

10.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. a solution of benzylidene-3-oxetidinecarboxylic acid and 0.5 mL of tetrahydrofuran in ethanol (tetrahydrofuran in a volume of 50%, water in a volume of 0.0002%), and ultrasonication for 15 minutes to obtain a white suspension (1-{ in the suspension) The amount of 2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is The solution was dissolved in tetrahydrofuran in ethanol at room temperature for 10 times), and the mixture was stirred at room temperature for 3 days to crystallize, filtered, and the obtained solid was vacuum dried at room temperature for 24 hours to obtain 1-{2-fluoro-4-[ Form IV of 5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 8.1 mg; the yield was 80%. XRPD inspection The X-ray powder diffraction pattern substantially the same as in Fig. 6 was measured.

Example 40

1.9 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. a solution of ketone-3-oxetidinecarboxylic acid and 0.3 mL of acetonitrile in ethanol (50% by volume of acetonitrile, 0.0002% by volume of water), and a white suspension obtained by ultrasonication for 15 minutes (1-{ in the suspension) The amount of 2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 10 times of solubility in an acetonitrile solution of ethanol at room temperature, crystallizing at room temperature for 7 days, filtering, and drying the obtained solid at room temperature for 24 hours to obtain 1-{2-fluoro-4-[ Form IV of 5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 1.0 mg; the yield was 53%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 41

10.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 1.0 mL of methanol (volume content of 0.0001% water) and heated to 60 ° C in a water bath, stirred until the sample is completely dissolved (1-{2-fluoro-4-[5-(4) -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid in an amount of 1.0 in the methanol at 60 ° C The mixture was cooled to room temperature and then stirred for 10 hours to obtain a white solid, which was filtered and dried under vacuum at 40 ° C for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutyl) of the present invention. Form IV of phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 8.7 mg; the yield was 86%. The XRPD detection obtains the same X-ray as the sixth image. Line powder diffraction pattern.

Example 42

9.7 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 2.0 mL of ethanol (volume content of 0.0002% water) and heated to 70 ° C in a water bath, stirred until the sample is completely dissolved (1-{2-fluoro-4-[5-(4 -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid in an amount of 0.5 ° C in the ethanol at 70 ° C The mixture was cooled to room temperature and then stirred for 0.5 hour to obtain a white solid, which was filtered and dried under vacuum at 40 ° C for 48 hours to obtain 1-{2-fluoro-4-[5-(4-isobutyl) of the present invention. Form IV of phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 8.1 mg; the yield was 84%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 43

9.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. Base -3-azetidine carboxylic acid and 2.0 mL of isopropanol (volume content of 0.0005% water) and heated to 75 ° C in a water bath, stirred until the sample is completely dissolved (1-{2-fluoro-4-[5- The amount of (4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 75 ° C in the isopropanol 1 time), the water bath was cooled off to room temperature, and stirring was continued for 72 hours to obtain a white solid, which was filtered and dried under vacuum at 60 ° C for 24 hours to obtain 1-{2-fluoro-4-[5-(4) of the present invention. Form IV of -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 6.4 mg; the yield was 70%. The XRPD detection obtains the same X-ray as the sixth image. Line powder diffraction pattern.

Example 44

9.0 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 4.0 mL of n-propanol (volume content of 0.001% water) and heated to 75 ° C in a water bath, stirred until the sample is completely dissolved (1-{2-fluoro-4-[5- The amount of (4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 75 ° C in the n-propanol 0.5 times the solubility), the water bath was cooled off to room temperature, and stirring was continued for 72 hours to obtain a white solid, which was filtered and dried under vacuum at 60 ° C for 48 hours to obtain 1-{2-fluoro-4-[5-(4) of the present invention. Form IV of -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 5.6 mg; the yield was 62%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 45

8.5 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. Base -3-azetidine carboxylic acid and 4.0 mL of n-butanol (volume content of 0.0001% water) and heated to 80 ° C in a water bath, stirred until the sample is completely dissolved (1-{2-fluoro-4-[5- The amount of (4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 80 ° C in the n-butanol 1 time), closed in a water bath, naturally cooled to room temperature, and stirring was continued for 10 hours to obtain a white solid, which was filtered and dried under vacuum at 60 ° C for 48 hours to obtain 1-{2-fluoro-4-[5-(4) of the present invention. Form IV of -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 6.1 mg; the yield was 72%. The XRPD detection obtains the same X-ray as the sixth image. Line powder diffraction pattern.

Example 46

9.2 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 4.0 mL of 2-butanol (volume content of 0.0001% water) and heated to 70 ° C in a water bath, stirred until the sample is completely dissolved (1-{2-fluoro-4-[5- The amount of (4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 70 ° C at the 2-butanol 1 time), closed in a water bath, naturally cooled to room temperature, and then stirred for 72 hours to obtain a white solid, which was filtered and dried under vacuum at 60 ° C for 24 hours to obtain 1-{2-fluoro-4-[5-( Form IV of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 5.9 mg; the yield was 64%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 47

3.7 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. Base -3-azetidine carboxylic acid and 1.0 mL of acetone (volume content of 0.001% water) and heated to 50 ° C in a water bath, stirred until the sample is completely dissolved (1-{2-fluoro-4-[5-(4) -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid in an amount of 50 ° C in the solubility of the acetone in the acetone The mixture was cooled to room temperature and then stirred for 10 hours to obtain a white solid, which was filtered and dried under vacuum at room temperature for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutyl) of the present invention. Form IV of phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 1.8 mg; the yield was 49%. XRPD detection obtained the same X-ray powder as in Figure 6. The end of the diffraction spectrum.

Example 48

4.0 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 3.0 mL of methyl ethyl ketone (volume content of 0.0001%) and heated to 40 ° C in a water bath, stirred until the sample is completely dissolved (1-{2-fluoro-4-[5-( The amount of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is its solubility in the butanone at 40 ° C 0.5 times), the water bath was closed to cool to room temperature, and stirring was continued for 10 hours to obtain a white solid, which was filtered and dried under vacuum at room temperature for 24 hours to obtain 1-{2-fluoro-4-[5-(4-iso) of the present invention. Form IV of butylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 1.7 mg; the yield was 42%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 49

10.9 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 1.5 mL of ethyl acetate (volume content of 0.0002% water) and heated to 60 ° C in a water bath, stirred until the sample is completely dissolved (1-{2-fluoro-4-[5- The amount of (4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 60 ° C in the ethyl acetate 1 time), closed in a water bath, naturally cooled to room temperature, and stirring was continued for 10 hours to obtain a white solid, which was filtered and dried under vacuum at 40 ° C for 24 hours to obtain 1-{2-fluoro-4-[5-(4) of the present invention. Form IV of -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 9.7 mg; the yield was 89%. XRPD detection is basically the same as Figure 6 The same X-ray powder diffraction pattern.

Example 50

8.7 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 1.5 mL of isopropyl acetate (volume content of 0.0001% water) and heated to 80 ° C in a water bath, stirred until the sample is completely dissolved (1-{2-fluoro-4-[5 - (4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid in an amount of 80 ° C in the isopropyl acetate The solubility in the ester was 0.8 times), the water bath was naturally cooled to room temperature, and stirring was continued for 10 hours to obtain a white solid, which was filtered and dried under vacuum at 40 ° C for 48 hours to obtain 1-{2-fluoro-4-[5- Form IV of (4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 6.5 mg; the yield was 75%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 51

10.3 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 1.0 mL of 1,4-dioxane (volume content of 0.0005% water) and heated to 60 ° C in a water bath, stirred until the sample is completely dissolved (1-{2-fluoro-4 -[5-(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid in an amount of 60 ° C 1 time) of the solubility in 1,4-dioxane, the mixture was cooled to room temperature after being cooled to room temperature, and stirring was continued for 10 hours to obtain a white solid, which was filtered and dried under vacuum at room temperature for 48 hours to obtain 1-{2- of the present invention. Form IV of fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 9.5 mg; the yield was 92%. XRPD detection is obtained with Figure 6 This same X-ray powder diffraction pattern.

Example 52

6.7 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. Base -3-azetidine carboxylic acid and 2.0 mL of toluene (volume content of 0.0005% water) and heated to 85 ° C in a water bath, stirred until the sample is completely dissolved (1-{2-fluoro-4-[5-(4) -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid in an amount of 0.8 in the toluene at 85 ° C The mixture was cooled to room temperature and then stirred for 10 hours to obtain a white solid, which was filtered and dried under vacuum at 60 ° C for 48 hours to obtain 1-{2-fluoro-4-[5-(4-isobutyl) of the present invention. Form IV of phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 5.9 mg; the yield was 88%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 53

6.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. a solution of -3-azetidine carboxylic acid and 1.0 mL of ethanol in acetonitrile (25% by volume of ethanol, 0.0005% by volume of water) and heated to 70 ° C in a water bath, stirred until the sample is completely dissolved (1-{ The amount of 2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 70 ° C It is 1 time in the acetonitrile solution of the ethanol, and the mixture is cooled to room temperature after being cooled to room temperature, and stirring is continued for 10 hours to obtain a white solid, which is filtered and dried under vacuum at 40 ° C for 48 hours to obtain 1-{2 of the present invention. Form IV of -fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. Yield is 5.1 mg; yield 76%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 54

1.9 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 1.9 mL of dimethyl hydrazine (volume content of 0.001%), the sample is completely dissolved after 5 minutes of ultrasound (1-{2-fluoro-4-[5-(4- The amount of isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 1 in the solubility of dimethyl hydrazine at room temperature.倍), the dimethyl sulfoxide solution was added dropwise to a 5 mL glass bottle containing 1.9 mL of 2-butanol, stirred at room temperature for 72 hours, centrifuged, and vacuum dried at 40 ° C for 24 hours to obtain 1-{2-fluorine of the present invention. Form IV of -4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.5 mg; the yield was 26%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 55

1.5 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 1.0 mL of trifluoroethanol (volume content of 0.0005%), the sample is completely dissolved after 5 minutes of ultrasound (1-{2-fluoro-4-[5-(4-iso) The amount of butylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 0.5 times that of its solubility in trifluoroethanol at room temperature) The trifluoroethanol solution was added dropwise to a 20 mL glass bottle containing 10.0 mL of n-butanol, stirred at room temperature for 10 hours, centrifuged, and vacuum dried at 60 ° C for 24 hours to obtain 1-{2-fluoro-4- of the present invention. Form IV of [5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. Production The amount was 0.3 mg; the yield was 20%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 56

Add 3.2 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 20 mL glass vial at room temperature } 吖 吖 啶 羧酸 carboxylic acid and 20.0 mL of tetrahydrofuran (volume content of 0.001%), the sample is completely dissolved after 5 minutes of ultrasound (1-{2-fluoro-4-[5-(4-isobutyl) The amount of phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 0.1 times its solubility in tetrahydrofuran at room temperature, and the tetrahydrofuran solution is used. The mixture was added dropwise to a 150 mL single-mouth flask containing 100.0 mL of ethyl acetate, stirred at room temperature for 48 hours, centrifuged, and vacuum-dried at room temperature for 48 hours to obtain 1-{2-fluoro-4-[5-(4-) of the present invention. Form IV of isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.6 mg; the yield was 19%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 57

1.5 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 1.5 mL of dimethyl hydrazine (volume content of 0.0005%), the sample is completely dissolved after 5 minutes of ultrasound (1-{2-fluoro-4-[5-(4- The amount of isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 1 in the solubility of dimethyl hydrazine at room temperature.倍), the dimethyl sulfoxide solution was added dropwise to a 100 mL single-mouth bottle containing 50.0 mL of isopropyl acetate, stirred at room temperature for 10 hours, centrifuged, and vacuum dried at 60 ° C for 48 hours to obtain 1-{2- of the present invention. Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid Form IV. The yield was 0.5 mg; the yield was 33%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 58

1.2 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 2.0 mL of 1,4-dioxane (volume content of 0.0005%), the sample is completely dissolved after 5 minutes of ultrasound (1-{2-fluoro-4-[5- The amount of (4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 1,4-dioxo at room temperature One time the solubility in the six rings), the 1,4-dioxane solution was added dropwise to a 20 mL glass vial containing 10.0 mL of n-heptane, stirred at room temperature for 0.5 hours, filtered, and vacuum dried at 40 ° C. In the hour, the 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention is obtained. Form IV of the pyridinecarboxylic acid. The yield was 0.7 mg; the yield was 58%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 59

Add 1.8 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 20 mL glass vial at room temperature } 吖 吖 啶 羧酸 carboxylic acid and 6.0 mL of 1,4-dioxane (volume content of 0.0008%), the sample is completely dissolved after 5 minutes of ultrasound (1-{2-fluoro-4-[5- The amount of (4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 1,4-dioxo at room temperature 0.5 times of solubility in the six rings), 6.0 mL of isopropyl ether was added dropwise thereto, stirred at room temperature for 10 hours, filtered, and dried under vacuum at 40 ° C for 24 hours to obtain 1-{2-fluoro-4-[5 of the present invention. Form IV of -(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. Yield is 1.0 mg; yield was 56%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 60

Add 1.8 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 20 mL glass vial at room temperature } 吖 吖 啶 羧酸 carboxylic acid and 6.0 mL of 1,4-dioxane (volume content of 0.0005%), the sample is completely dissolved after 5 minutes of ultrasound (1-{2-fluoro-4-[5- The amount of (4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 1,4-dioxo at room temperature 0.5 times the solubility in the six rings), 12.0 mL of n-propanol was added dropwise thereto, stirred at room temperature for 10 hours, centrifuged, and vacuum dried at 40 ° C for 24 hours to obtain 1-{2-fluoro-4-[5 of the present invention. Form IV of -(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.3 mg; the yield was 17%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 61

Add 1.8 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 5 mL glass vial at room temperature } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 3.0 mL of methanol (volume content of 0.0001% water), ultrasonic 15 minutes to obtain a colorless clear solution (1-{2-fluoro-4-[5-(4-) in this solution The amount of isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 1 times its solubility in methanol at this temperature), The mixture was filtered through a 0.45 μm organic filtration membrane, and the filtrate was placed in a 5 mL glass vial to open and crystallize at room temperature, and the obtained solid was vacuum dried at room temperature for 1 hour to obtain 1-{2-fluoro-4-[5 of the present invention. -(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidine Form IV of the carboxylic acid. The yield was 1.4 mg; the yield was 78%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 62

1.6 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 4.0 mL of ethanol (volume content of 0.0005% water), ultrasonic 15 minutes to obtain a colorless clear solution (1-{2-fluoro-4-[5-(4- in this solution) The amount of isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 0.5 times its solubility in ethanol at this temperature), The mixture was filtered through a 0.45 μm organic filtration membrane, and the filtrate was placed in a 5 mL glass vial at 60 ° C for open volatilization, and the obtained solid was vacuum dried at 40 ° C for 24 hours to obtain 1-{2-fluoro-4-[5 of the present invention. Form IV of -(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 1.0 mg; the yield was 62%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 63

1.2 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 5.0 mL of isopropanol (volume content of 0.0005% water), ultrasonic 15 minutes to obtain a colorless clear solution (1-{2-fluoro-4-[5-( The amount of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is its solubility in isopropanol at this temperature. 0.8 times), filtered through a 0.45 μm organic filtration membrane, and the filtrate was placed in a 5 mL glass vial at 60 ° C to open and volatilize, and the obtained solid was vacuum dried at 60 ° C for 24 hours to obtain 1-{2-fluoro-- 4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3- Form IV of azetocarboxylic acid. The yield was 0.5 mg; the yield was 42%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 64

Add 1.3 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 5 mL glass vial at room temperature } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 4.0 mL of n-propanol (volume content of 0.0005% water), ultrasonic 15 minutes to obtain a colorless clear solution (1-{2-fluoro-4-[5-( The amount of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is its solubility in n-propanol at this temperature. 1 time), filtered with a 0.45 μm organic filtration membrane, and the filtrate was placed in a 5 mL glass vial to open and crystallize at room temperature, and the obtained solid was vacuum dried at 40 ° C for 48 hours to obtain 1-{2-fluoro- Form IV of 4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.6 mg; the yield was 46%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 65

1.0 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 5.0 mL of n-butanol (volume content of 0.0001% water), ultrasonic 15 minutes to obtain a colorless clear solution (1-{2-fluoro-4-[5-( The amount of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is its solubility in n-butanol at this temperature. 1 time), filtered with a 0.45 μm organic filtration membrane, and the filtrate was placed in a 5 mL glass vial at 60 ° C to open and volatilize, and the obtained solid was vacuum dried at 60 ° C for 48 hours to obtain 1-{2-fluoro-- 4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3- Form IV of azetocarboxylic acid. The yield was 0.5 mg; the yield was 50%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 66

0.8 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 5.0 mL of 2-butanol (volume content of 0.0001% water), ultrasonic 15 minutes to obtain a colorless clear solution (1-{2-fluoro-4-[5-( The amount of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is its solubility in 2-butanol at this temperature 0.8 times), filtered through a 0.45 μm organic filtration membrane, and the filtrate was placed in a 5 mL glass vial at 60 ° C for open volatilization, and the obtained solid was vacuum dried at 60 ° C for 24 hours to obtain 1-{2-fluorine of the present invention. Form IV of -4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.6 mg; the yield was 75%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 67

1.0 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 5.0 mL of methyl ethyl ketone (volume content of 0.0001%), ultrasonic 15 minutes to obtain a colorless clear solution (1-{2-fluoro-4-[5-(4) -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid in an amount of 1 times its solubility in methyl ethyl ketone at this temperature The solution was filtered through a 0.45 μm organic filtration membrane, and the filtrate was placed in a 5 mL glass vial to open and crystallize at room temperature, and the obtained solid was vacuum dried at room temperature for 1 hour to obtain 1-{2-fluoro-4- of the present invention. [5-(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidine Form IV of the carboxylic acid. The yield was 0.6 mg; the yield was 60%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 68

2.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 4.0 mL of dimethyl hydrazine (volume content of 0.0005% water), ultrasonic 15 minutes to obtain a colorless clear solution (1-{2-fluoro-4-[5- in this solution) The amount of (4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is at this temperature in dimethyl sulfoxide The solution was filtered with a 0.45 μm organic filter membrane, and the filtrate was placed in a 5 mL glass vial at 60 ° C to open and volatilize, and the obtained solid was vacuum dried at 60 ° C for 48 hours to obtain 1-{2- of the present invention. Form IV of fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 1.0 mg; the yield was 48%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 69

0.5 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 5.0 mL of ethyl acetate (volume content of 0.0001% water), ultrasonic 15 minutes to obtain a colorless clear solution (1-{2-fluoro-4-[5-( The amount of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is its solubility in ethyl acetate at this temperature. 1 time), filtered with a 0.45 μm organic filtration membrane, and the filtrate was placed in a 5 mL glass vial at 60 ° C for open volatilization, and the obtained solid was vacuum dried at 60 ° C for 1 hour to obtain 1-{2-fluoro- 4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3- Form IV of azetocarboxylic acid. The yield was 0.1 mg; the yield was 20%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 70

0.4 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 4.0 mL of isopropyl acetate (volume content of 0.0002%), ultrasonic 15 minutes to obtain a colorless clear solution (1-{2-fluoro-4-[5- in this solution) The amount of (4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is such that it is in isopropyl acetate at this temperature. The solution was filtered by a 0.45 μm organic filter membrane, and the filtrate was placed in a 5 mL glass vial at 40 ° C to open and volatilize, and the obtained solid was vacuum dried at 40 ° C for 24 hours to obtain 1-{2- of the present invention. Form IV of fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.2 mg; the yield was 50%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 71

Add 3.2 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 5 mL glass vial at room temperature } 吖 吖 啶 羧酸 羧酸 carboxylic acid and 2.0 mL of tetrahydrofuran (volume content of 0.0005% water), ultrasonic 15 minutes to obtain a colorless clear solution (1-{2-fluoro-4-[5-(4-) The amount of isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 1 times its solubility in tetrahydrofuran at this temperature), The mixture was filtered through a 0.45 μm organic filtration membrane, and the filtrate was placed in a 5 mL glass vial to open and crystallize at room temperature, and the obtained solid was vacuum dried at room temperature for 24 hours to obtain 1-{2-fluoro-4-[5 of the present invention. -(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl Form IV of -3-butyridinecarboxylic acid. The yield was 2.0 mg; the yield was 62%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 6.

Example 72

Taking 5.9 mg of Form I, it was directly placed on a hot stage which had been heated to 125 ° C for 1 hour to crystallize, and directly cooled to room temperature for detection to obtain 1-{2-fluoro-4-[5-(4-iso) of the present invention. Form II of butylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 5.9 mg; the yield was 100%.

The X-ray powder diffraction pattern is shown in Fig. 16, which is Form II.

The FT-IR spectrum is shown in Figure 17.

Example 73

Take 2.7mg of Form I, use DSC to raise the temperature to 150 ° C at 10 ° C / min and keep it for 0.5 hours to crystallize, and directly cool to room temperature to detect, to obtain 1-{2-fluoro-4-[5-(4- Form II of isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 2.7 mg; the yield was 100%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 16.

Example 74

3.2 mg of Form I was taken, and the temperature was raised to 110 ° C at 10 ° C / min with TGA and incubated for 0.5 hours, and directly cooled to room temperature to obtain 1-{2-fluoro-4-[5-(4-) Form II of isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 3.2 mg; the yield was 100%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 16.

Example 75

Taking 5.3 mg of Form I, it was directly placed in an oven at 100 ° C for 24 hours, and directly cooled to room temperature to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl) of the present invention. Form II of-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 5.3 mg; the yield was 100%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 16.

Example 76

4.5 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 20 mL glass vial at room temperature. The sample was completely dissolved after 5 minutes of sonication (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2) , the amount of 4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 0.5 times that of its solubility in trifluoroethanol at room temperature), and 3.0 mL of water is added thereto, immediately Obtained as a white solid, stirred at room temperature for 0.5 hr, filtered, and dried to give 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxan. Form III of oxazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 3.1 mg; the yield was 69%.

The X-ray powder diffraction pattern is shown in Fig. 18 as Form III.

The FT-IR spectrum is shown in Figure 19.

Example 77

4.2 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. The sample was completely dissolved after 5 minutes of sonication (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2) , the amount of 4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 1 time of its solubility in trifluoroethanol at room temperature), and the trifluoroethanol solution is added dropwise to Loaded with 14 mL of acetone In a 20 mL glass vial, a white solid was obtained immediately, stirred at room temperature for 10 hours, filtered, and dried to give 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1 of the present invention. Form III of 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 2.4 mg; the yield was 57%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 18.

Example 78

6.0 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. The sample was completely dissolved after 5 minutes of sonication (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2) , the amount of 4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 1 time of its solubility in trifluoroethanol at room temperature), and the trifluoroethanol solution is added dropwise to A 100 mL single-mouth bottle containing 100 mL of ethyl acetate was immediately obtained as a white solid, stirred at room temperature for 72 hours, filtered, and dried to give 1-{2-fluoro-4-[5-(4-isobutyl) of the present invention. Form III of phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 1.3 mg; the yield was 22%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 18.

Example 79

3.9 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 200 mL single-mouth bottle at room temperature. The sample was completely dissolved after 5 minutes of sonication (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2, The amount of 4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 0.1 times that of the solution in trifluoroethanol at room temperature), and 130 mL of isopropyl ether is added dropwise thereto. A white solid was obtained immediately, stirred at room temperature for 10 hours, filtered, and dried to give 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-ox. Diazol-3-yl]-benzyl}-3-indole Form III of the pyridinecarboxylic acid. The yield was 0.8 mg; the yield was 21%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 18.

Example 80

4.8 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 20 mL glass vial at room temperature. The sample was completely dissolved after 5 minutes of sonication (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2) , the amount of 4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 1 time of its solubility in trifluoroethanol at room temperature, and 16 mL of acetonitrile is added dropwise thereto, immediately Obtained as a white solid, stirred at room temperature for 0.5 hr, filtered, and dried to give 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxan. Form III of oxazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 1.3 mg; the yield was 27%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 18.

Example 81

5.9 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. The sample was completely dissolved after 5 minutes of sonication (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2) , the amount of 4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is 1 time of its solubility in trifluoroethanol at room temperature), and the trifluoroethanol solution is added dropwise to A 50 mL single-mouth bottle containing 20 mL of methyl tertiary butyl ether was immediately obtained as a white solid, stirred at room temperature for 10 hours, filtered, and dried to give 1-{2-fluoro-4-[5-( Form III of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 2.0 mg; the yield was 34%. XRPD detection obtained the same X-ray powder as that of Figure 18 The end of the diffraction spectrum.

Example 82

4.5 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 20 mL glass vial at room temperature. The sample was completely dissolved after 5 minutes of sonication (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2, 4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid in an amount of 0.1 times its solubility in trifluoroethanol at room temperature), filtered through a 0.45 μm organic filtration membrane, The filtrate was placed in a 20 mL glass vial and exposed to crystallization at room temperature for 7 days without drying to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2 of the present invention. Form III of 4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.3 mg; the yield was 7%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 18.

Example 83

5.2 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. The sample was completely dissolved after 5 minutes of sonication (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2) , the amount of 4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid is 0.5 times that of its solubility in trifluoroethanol at room temperature, and is filtered through a 0.45 μm organic filtration membrane. The filtrate was placed in a 5 mL glass vial and exposed to crystallization at room temperature for 3 days without drying to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1 of the present invention. Form III of 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 2.1 mg; the yield was 40%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 18.

Example 84

6.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. The sample was completely dissolved after 5 minutes of sonication (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2) , the amount of 4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid is 1 time of its solubility in trifluoroethanol at room temperature), and filtered through a 0.45 μm organic filtration membrane. The filtrate was placed in a 5 mL glass vial and exposed to crystallization at room temperature for 1 day without drying to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1 of the present invention. Form III of 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 3.8 mg; the yield was 62%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 18.

Example 85

8.0 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. a white suspension was obtained by sonication for 15 minutes by ultrasonication (in the suspension) 1-{2-fluoro-4-[5-(4-isobutylphenyl) -1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 10 times its solubility in n-butanol at room temperature), and stirred at 60 ° C Crystallization was carried out for 7 days, filtered, and the obtained solid was vacuum dried at room temperature for 48 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxo of the present invention. Form V of oxazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 6.1 mg; the yield was 76%.

The X-ray powder diffraction pattern is shown in Fig. 20 as a crystal form V.

The FT-IR spectrum is shown in Figure 21.

Example 86

Add 9.3 mg of 1-{2-fluorine in a 50 mL single-mouth bottle at room temperature -4-[5-(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid and 31.0 mL of n-butanol, ultrasound A white suspension was obtained in 15 minutes (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl group in the suspension } 吖 吖 啶 羧酸 羧酸 羧酸 羧酸 的 的 的 羧酸 羧酸 羧酸 羧酸 羧酸 羧酸 羧酸 羧酸 羧酸 羧酸 羧酸 , , , , , , , , , , , , , , , , , , , , , , , , , The present invention provides 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidine carboxylate Acid crystal form V. The yield was 4.0 mg; the yield was 43%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Fig. 20.

Example 87

10.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. a white suspension was obtained by sonication for 15 minutes (1 -{2-fluoro-4-[5-(4-isobutylphenyl) in the suspension). -1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 50 times its solubility in n-butanol at room temperature), and stirred at 60 ° C After 14 days of crystallization, filtration, the obtained solid was dried under vacuum at 60 ° C for 1 hour to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxo of the present invention. Form V of oxazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 8.3 mg; the yield was 82%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Fig. 20.

Example 88

4.4 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 20 mL glass vial at room temperature. a white suspension obtained by sonication for 15 minutes (1 -{2-fluorine in the suspension) -4-[5-(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used at room temperature 1.1 times the solubility in n-butanol, crystallized at room temperature for 7 days, filtered, and the obtained solid was vacuum dried at 40 ° C for 24 hours to obtain 1-{2-fluoro-4-[5-(4) of the present invention. Form V of -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 1.9 mg; the yield was 43%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Fig. 20.

Example 89

7.9 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. A white suspension was obtained by sonication for 15 minutes on a solution of 1-butyridinecarboxylic acid and 1.0 mL of ethanol (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1) in the suspension , 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 10 times its solubility in ethanol at room temperature, and is stirred at room temperature for 7 days. , filtration, and drying the obtained solid at room temperature for 48 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3 of the present invention. Form VI of -yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 6.3 mg; the yield was 80%.

The X-ray powder diffraction pattern is shown in Fig. 22 as the crystal form VI.

Example 90

Add 2.4 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 5 mL glass vial at room temperature A white suspension was obtained by sonication for 15 minutes with ultrasound in the presence of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1 , 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 1.5 times its solubility in ethanol at room temperature, and is stirred at room temperature for 3 days. , filtering, will get The resulting solid was dried under vacuum at 40 ° C for 1 hour to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]- Form VI of benzyl}-3-azetidinecarboxylic acid. The yield was 1.5 mg; the yield was 63%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Fig. 22.

Example 91

80.2 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. A white suspension was obtained by sonication for 15 minutes with ultrasound in the presence of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1 , 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 50 times its solubility in ethanol at room temperature, and is stirred at 60 ° C for 14 days. , filtration, and drying the obtained solid under vacuum at 60 ° C for 48 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3 of the present invention. Form VI of -yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 75.8 mg; the yield was 95%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Fig. 22.

Example 92

Add 1.8 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 5 mL glass vial at room temperature A white suspension was obtained by sonication for 15 minutes with ultrasound in the presence of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1 , 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 1.1 times its solubility in ethanol at room temperature, and is stirred at room temperature for 3 days. , filtration, and solidification of the obtained solid at room temperature for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3 of the present invention. Form VI of -yl]-benzyl}-3-azetidinecarboxylic acid. Yield is 0.5 mg; yield 28%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Fig. 22.

Example 93

4.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 20 mL glass vial at room temperature. Base -3-azetidinecarboxylic acid and 4.0 mL of dimethyl hydrazine, the sample was completely dissolved after 5 minutes of sonication (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1, The amount of 2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 1 time of its solubility in dimethyl hydrazine at room temperature, using a 0.45 μm organic filter Filtration, the glass vial containing the filtrate was placed in a closed atmosphere of 50 mL of water-100 mL space for 14 days, and 40.0 mL of water was diffused into the dimethyl sulfoxide solution, a large amount of solid appeared, and the solid was vacuum dried at 60 ° C. After 24 hours, 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole of the present invention was obtained. Form VII of butyric acid. The yield was 2.4 mg; the yield was 59%.

The X-ray powder diffraction pattern is shown in Fig. 23 as Form VII.

The FT-IR spectrum is shown in Figure 24.

Example 94

2.0 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 20 mL glass vial at room temperature. Base -3-azetidinecarboxylic acid and 4.0 mL of dimethyl hydrazine, the sample was completely dissolved after 5 minutes of sonication (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1, The amount of 2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 0.5 times that of dimethyl sulfonium at room temperature), using a 0.45 μm organic filter Filtration, the glass vial containing the filtrate was placed in a closed atmosphere of 20 mL water-100 mL space for 7 days, 4.0 mL of water was diffused into the dimethyl hydrazine solution, a large amount of solid appeared, and then filtered, and the obtained solid was vacuum dried at 40 ° C for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutyl) of the present invention. Form VII of phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.4 mg; the yield was 20%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Fig. 23.

Example 95

Add 6.4 mg of Form VI and 0.8 mL of ethanol to a 5 mL glass vial at room temperature and sonicate for 15 minutes to obtain a white suspension (1-{2-Fluoro-4-[5-(4-isobutyl) in this suspension) Phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 10 times its solubility in ethanol at room temperature), at room temperature After stirring for 7 days, the crystals were crystallized, filtered, and the obtained solid was dried under vacuum at room temperature for 48 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4- Form VIII of oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 5.8 mg; the yield was 91%.

The X-ray powder diffraction pattern is shown in Fig. 25 as Form VIII.

The FT-IR spectrum is shown in Figure 26.

Example 96

Add 2.8 mg of Form VI and 2.3 mL of ethanol to a 5 mL glass vial at room temperature and sonicate for 15 minutes to obtain a white suspension (1-{2-Fluoro-4-[5-(4-isobutyl) in this suspension) Phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 1.5 times its solubility in ethanol at room temperature), at room temperature After stirring for 3 days, crystallizing, filtering, and drying the obtained solid at 40 ° C for 1 hour under vacuum to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4- Form VIII of oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. Production The amount was 1.5 mg; the yield was 54%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 25.

Example 97

Add 39.8 mg of Form VI and 1.0 mL of ethanol to a 5 mL glass vial at room temperature and sonicate for 15 minutes to obtain a white suspension (1-{2-Fluoro-4-[5-(4-isobutyl) in this suspension) Phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 50 times its solubility in ethanol at room temperature, at 60 ° C The mixture was stirred for 14 days, crystallized, filtered, and the obtained solid was dried under vacuum at 60 ° C for 48 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4- of the present invention. Form VIII of oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 37.6 mg; the yield was 94%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 25.

Example 98

Add 1.8 mg Form VI and 2.1 mL of ethanol to a 5 mL glass vial at room temperature and sonicate for 15 minutes to obtain a white suspension (1-{2-Fluoro-4-[5-(4-isobutyl) in this suspension) Phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 1.1 times its solubility in ethanol at room temperature, at room temperature The mixture was stirred for 3 days, crystallized, filtered, and the obtained solid was dried under vacuum at room temperature for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4- Form VIII of oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.3 mg; the yield was 17%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 25.

Example 99

Add 2.9 mg of 1-{2-fluoro-4-[5-(4-) to a 5 mL glass vial at room temperature. Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid and 1.0 mL of isopropanol, sonicated for 15 minutes to give a white suspension (the suspension) 1-{2-Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid in solution The amount is 10 times of the solubility in isopropanol at room temperature), and the mixture is stirred at room temperature for 7 days to crystallize, filtered, and the obtained solid is vacuum dried at room temperature for 48 hours to obtain 1-{2-fluorine of the present invention. Form IX of -4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 2.4 mg; the yield was 83%.

The X-ray powder diffraction pattern is shown in Fig. 27 as Form IX.

The FT-IR spectrum is shown in Figure 28.

Example 100

4.5 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 20 mL glass vial at room temperature. A white suspension was obtained by sonication for 15 minutes by ultrasonication in the presence of 1-{2-fluoro-4-[5-(4-isobutylphenyl) in the suspension. -1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 1.5 times its solubility in isopropanol at room temperature, and stirred at room temperature Crystallization was carried out for 3 days, filtered, and the obtained solid was dried under vacuum at 40 ° C for 1 hour to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxo of the present invention. Form IX of oxazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 1.5 mg; the yield was 33%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 27.

Example 101

15.2 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature.吖 吖 吖 啶 羧酸 carboxylic acid and 1.0 mL of isopropanol, sonicated for 15 minutes to give a white suspension (1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole in the suspension - The amount of 3-yl]-benzyl}-3-azetidinecarboxylic acid is 50 times that of isopropanol at room temperature), and the mixture is stirred at 60 ° C for 14 days, and the resulting solid is filtered. Drying at 60 ° C for 48 hours under vacuum afforded 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl} Form IX of -3-azetidinecarboxylic acid. The yield was 11.9 mg; the yield was 78%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 27.

Example 102

Add 3.3 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl in a 20 mL glass vial at room temperature A white suspension was obtained by sonication for 15 minutes by ultrasonication in the presence of 1-{2-fluoro-4-[5-(4-isobutylphenyl) in the suspension. -1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 1.1 times its solubility in isopropanol at room temperature, and stirred at room temperature Crystallization was carried out for 3 days, filtered, and the obtained solid was dried under vacuum at room temperature for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxo of the present invention. Form IX of oxazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 1.2 mg; the yield was 36%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 27.

Example 103

6.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 20 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 10.0 mL of 1,4-dioxane, the sample was completely dissolved after 5 minutes of ultrasound (1-{2-fluoro-4-[5-(4-isobutylphenyl)) -1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid in an amount of room temperature It is 1 times the solubility in 1,4-dioxane), filtered through a 0.45 μm organic filtration membrane, and the filtrate is placed in a 20 mL glass vial and exposed to room temperature for 7 days at room temperature to obtain a solid. Drying at room temperature for 48 hours under vacuum afforded 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl} Form X of -3-azetidinecarboxylic acid. The yield was 5.7 mg; the yield was 93%.

The X-ray powder diffraction pattern is shown in Fig. 29 as the crystal form X.

The FT-IR spectrum is shown in Figure 30.

Example 104

1.5 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 20 mL glass vial at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 5.0 mL of 1,4-dioxane, the sample is completely dissolved after 5 minutes of ultrasound (1-{2-fluoro-4-[5-(4-isobutylphenyl)) -1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid is present in an amount of 0.5 times its solubility in 1,4-dioxane at room temperature) The mixture was filtered through a 0.45 μm organic filtration membrane, and the filtrate was placed in a 20 mL glass vial to open and crystallize for 1 day at room temperature, and the obtained solid was vacuum dried at 40 ° C for 24 hours to obtain 1-{2-fluoro-4 of the present invention. Form X of [5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.5 mg; the yield was 33%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 29.

Example 105

5.9 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 100 mL single-mouth bottle at room temperature. } 吖 吖 啶 羧酸 carboxylic acid and 100.0 mL of 1,4-dioxane, the sample is completely dissolved after 5 minutes of ultrasound (1-{2-fluorine) The amount of -4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is at room temperature The solubility in 1,4-dioxane was 0.1 times), filtered through a 0.45 μm organic filtration membrane, and the filtrate was placed in a 100 mL single-mouth flask and exposed to volatilization at 60 ° C for 3 days, and the obtained solid was vacuumed at 60 ° C. After drying for 1 hour, 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3- Form X of azetocarboxylic acid. The yield was 2.1 mg; the yield was 36%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 29.

Example 106

10.2 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 150 mL single-mouth bottle at room temperature. a white suspension was obtained by ultrasonication for 15 minutes (1 -{2-fluoro-4-[5-(4-isobutylphenyl)-1) in the suspension. , 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 10 times its solubility in toluene at room temperature, and is stirred at room temperature for 7 days. , filtration, and drying the obtained solid at room temperature for 48 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3 of the present invention. Form XI of -yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 7.4 mg; the yield was 73%.

The X-ray powder diffraction pattern is shown in Fig. 31 as Form XI.

The FT-IR spectrum is shown in Figure 32.

Example 107

1.5 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 150 mL single-mouth bottle at room temperature. a white suspension was obtained by ultrasonication for 15 minutes with ultrasonication of 10-3-butyridinecarboxylic acid and 100.0 mL of toluene (1-{2-fluorine in the suspension) -4-[5-(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used at room temperature 1.5 times the solubility in toluene, crystallized at room temperature for 3 days, filtered, and the obtained solid was vacuum dried at 40 ° C for 1 hour to obtain 1-{2-fluoro-4-[5-(4-iso) of the present invention. Form XI of butylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.5 mg; the yield was 33%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Fig. 31.

Example 108

2.5 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. A white suspension was obtained by sonication for 15 minutes by ultrasonication (in the suspension) 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1 , 2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 50 times its solubility in toluene at room temperature, and is stirred at 60 ° C for 14 days. , filtration, and drying the obtained solid under vacuum at 60 ° C for 48 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3 of the present invention. Form XI of -yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 1.9 mg; the yield was 76%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Fig. 31.

Example 109

1.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 150 mL single-mouth bottle at room temperature. a white suspension was obtained by ultrasonication for 15 minutes (1 -{2-fluoro-4-[5-(4-isobutylphenyl)-1) in the suspension. , 2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid is used in an amount of 1.1 times its solubility in toluene at room temperature, and stirred at room temperature for 3 days. Crystallization, filtration, and drying the obtained solid at room temperature for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole of the present invention- Form XI of 3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.2 mg; the yield was 22%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Fig. 31.

Example 110

12.1 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. A white suspension was obtained by sonication for 15 minutes with ultrasound in the presence of 1-{2-fluoro-4-[5-(4-isobutylphenyl)- 1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 10 times its solubility in anhydrous methanol at room temperature, and stirred at room temperature for 7 days. Crystallization, filtration, and drying the obtained solid at room temperature for 48 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole of the present invention. Form XII of -3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 9.4 mg; the yield was 78%.

The X-ray powder diffraction pattern is shown in Fig. 11 and is Form XII.

The PLM map is shown in Figure 12. Display: fine crystals.

The DSC and TGA spectra are shown in Figure 13. It is shown that Form XII has a broad endothermic peak (solvent peak) at 25-90 ° C, and the sample after de-water removal melts and decomposes at 148 ° C; Form XII loses 1.7% of surface solvent before 100 ° C, and the decomposition temperature is 142 ° C. The decomposition temperature was 142 °C.

The DVS map is shown in Figure 14. Display: 20% RH ~ 80% RH weight change is 1.3%.

The FT-IR spectrum is shown in Figure 15.

The above test results show that the crystal form XII is anhydrate and is not easy to absorb moisture.

Example 111

1.4 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. A white suspension was obtained by sonication for 15 minutes with ultrasound in the presence of 1-{2-fluoro-4-[5-(4-isobutylphenyl)- 1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid is used in an amount of 1.5 times its solubility in anhydrous methanol at room temperature, and stirred at room temperature for 3 days. Crystallization, filtration, and drying the obtained solid under vacuum at 40 ° C for 1 hour to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole of the present invention. Form XII of -3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 0.6 mg; the yield was 43%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 11.

Example 112

29.8 mg of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl was added to a 5 mL glass vial at room temperature. A white suspension was obtained by sonication for 15 minutes with ultrasonication of 1.0-azetidine carboxylic acid and 1.0 mL of anhydrous methanol (1-{2-fluoro-4-[5-(4-isobutylphenyl)-) 1,2,4-oxadiazol-3-yl]-benzyl}-3-azetididinecarboxylic acid is used in an amount of 50 times its solubility in anhydrous methanol at room temperature, and stirred at 60 ° C for 14 days. Crystallization, filtration, and drying the obtained solid under vacuum at 60 ° C for 24 hours to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole of the present invention. Form XII of -3-yl]-benzyl}-3-azetidinecarboxylic acid. The yield was 25.1 mg; the yield was 84%. The XRPD detection gave substantially the same X-ray powder diffraction pattern as in Figure 11.

Comparative example 1

Taking 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidine of the present invention Form I of the carboxylic acid, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI The amorphous crystal test was carried out in accordance with the amorphous form prepared in Preparation Example 1.

The specific operations are as follows:

(1) 2 mg each of Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI and amorphous, respectively in isopropanol, water, ethanol (the volume ratio of ethanol to water are 1:1, 1:5, 1:10 and 1:100, respectively), ethanol, acetone solution (acetone and The volume ratio of water was 1:1, 1:5, 1:10, and 1:100, respectively, and a suspension was formed in acetone, and the mixture was stirred at room temperature for 3 days, and then subjected to XRPD characterization.

(2) Each of 5 mg of Form IV and Form XII was taken, and a suspension was formed in water and acetone, respectively, and stirred at room temperature for 3 days, and then subjected to XRPD characterization.

(3) Each of 5 mg of Form I and Form XII was taken, and a suspension was formed in ethanol, and stirred at room temperature for 3 days, and then subjected to XRPD characterization.

The results are shown in Table 1, and found:

(1) At room temperature, Form I in the aqueous system is the most stable crystal form, while Form IV in the pure organic solvent is the most stable crystal form.

(2) At room temperature, the crystal form XII and the crystal form IV compete for the crystal slurry in water to be more stable for the crystal form XII, and the crystal form XII and the crystal form IV compete for the crystal form in acetone to be more stable.

Table 1: Statistics of Competitive Crystallization Experiments

Comparative example 2

The crystalline form I, the crystalline form IV and the crystalline form XII of the present invention were subjected to a stability placement test.

The specific operations are as follows: Take 5mg of Form I, Form IV and Form XII, respectively, and place them in a room temperature desiccator, room temperature, room temperature -97% RH, room temperature -75% RH or room temperature -44% RH. XRPD characterization was compared 1 month later.

The results are shown in Table 2. It is found that after one month of standing at room temperature dryer, room temperature open, room temperature -97% RH, room temperature -75% RH or room temperature -44% RH, crystal form I, crystal Both Form IV and Form XII remain unchanged.

Comparative example 3

Taking Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form of the present invention XI and the amorphous material prepared according to Preparation Example 1, using a pharmaceutically acceptable excipient conventionally used in the art, according to a conventional method for preparing a capsule, a capsule of each crystal form or amorphous form is prepared, and then The crystal form change and the dissolution degree comparison test were carried out for the capsules for 0 days and 6 months.

The specific operation is as follows: using the paddle method, using water as the dissolution medium, the temperature is 37 ° C, the stirring paddle rotation speed is 50 rpm, and the capsule (decapsule shell) is stirred with 900 mL of pure water to form a suspension, respectively, in 2 minutes, 20 mL was sampled at 10 minutes, 20 minutes, 40 minutes, 60 minutes, 120 minutes, and 24 hours, and each sample was taken up with water, and the concentration of the sample at each time point was determined by HPLC.

The experimental results show that: (1) After the capsule is left for 6 months, the amorphous form and the crystalline form II, crystalline form III, crystalline form V, crystalline form VI, crystalline form VII, crystalline form VIII, and crystalline form of the present invention are present. In the capsules of IX, Form X and Form XI, part or all of the crystal form thereof is changed, and in the capsules of Form I, Form IV and Form XII of the present invention, the crystal form remains unchanged. , It is indicated that the crystalline form I, the crystalline form IV and the crystalline form XII of the present invention have good crystal form stability; (2) the amorphous form and the crystalline form II, crystalline form III, crystalline form V, crystalline form VI, of the present invention, The dissolution of capsules of Form VII, Form VIII, Form IX, Form X and Form XI at 0 and 6 months changes due to the transformation of their crystal forms, thus resulting in a lack of product quality. Stable, which in turn affects the efficacy of the drug. However, the capsules of Form I, Form IV and Form XII of the present invention have substantially no dissolution at 0 and 6 months, and thus Form I, Form IV and Form XII of the present invention are more suitable for preparation. Product application.

All patent documents and non-patent publications cited in the present specification are hereby incorporated by reference in their entirety.

The above is only the specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can change without thinking of creative work within the technical scope of the present invention. Alternatives are intended to be covered by the scope of the present invention.

Claims (15)

A 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3- Form I of azetidine carboxylic acid, Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the Form I is 4.8±0.2°, 5.5±0.2°, 8.2±0.2°, 15.0±0.2°, 17.0±0.2 at a diffraction angle 2θ. There are characteristic peaks at ° and 18.6 ± 0.2 °. The crystal form I according to claim 1, wherein the X-ray powder diffraction pattern of the crystal form I is 4.8±0.2°, 5.5±0.2°, 8.2±0.2°, 10.1±0.2 at a diffraction angle 2θ. Characteristic peaks at °, 11.1 ± 0.2 °, 12.1 ± 0.2 °, 15.0 ± 0.2 °, 17.0 ± 0.2 °, 18.6 ± 0.2 °, 24.0 ± 0.2 °, 24.9 ± 0.2 °, and 27.0 ± 0.2 °. The crystal form I according to claim 2, wherein the X-ray powder diffraction pattern of the crystal form I has a characteristic peak and a relative intensity thereof at a position where the diffraction angle 2θ is: The method for producing the crystalline form I according to any one of claims 1 to 3, wherein the preparation method employs any one of the following methods: (1) 1-{2-fluoro-4-[5 -(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indolyl carboxylic acid is formed into a suspension in the following solvent system, stirred and crystallized The precipitated crystals are separated and dried to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl} a crystalline form I of -3-azetidinecarboxylic acid; wherein the solvent system is selected from the group consisting of water or a mixture of water and an organic solvent; the organic solvent is selected from the group consisting of C ₁ -C ₄ alcohols, C ₅ -C ₆ ethers, C ₃ -C ₄ ketone, ethyl acetate, nitromethane, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, chloroform, toluene, dimethyl hydrazine, C ₇ alkane, and mixtures thereof; a volume of water in a mixture of water and an organic solvent of at least 0.01%; 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3- The amount of benzyl]-benzyl}-3-azetidinecarboxylic acid is 1.1 to 50 times the solubility in the solvent system at the operating temperature; the temperature of the crystallization is from room temperature to 60 ° C; Operating temperature Is room temperature; the crystallization time is 3-14 days; (2) 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2, at a certain temperature 4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is formed into a solution in a mixed system of water and tetrahydrofuran, cooled and stirred to crystallize, and the precipitated crystal is separated and dried to obtain 1- Form I of {2-Fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid Wherein, the volume of water in the mixed system of water and tetrahydrofuran is 0.01% to 50%; in the solution, 1-{2-fluoro-4-[5-(4-isobutylphenyl)- 1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 0.1 to 1 times the solubility in the mixed system at a certain temperature; The temperature is 40 ° C ~ 50 ° C; the temperature after cooling is room temperature; the crystallization time is 0.5 ~ 72 hours; (3) to 1-{2-fluoro-4-[5-(4-iso Adding water to a solution of butylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid in an organic solvent, stirring and crystallization, and precipitating The crystals were separated and dried to give 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- Form I of 3-azetidinecarboxylic acid; wherein the organic solvent is selected from the group consisting of ethanol and a mixture of trifluoroethanol, tetrahydrofuran, 1,4-dioxane, dimethyl hydrazine or a mixture thereof; The volume ratio of the organic solvent is 1:1 to 50:1; in the solution, 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole The -3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of 0.1 to 1 times the solubility in the organic solvent at the operating temperature; the operating temperature is room temperature; the crystallization The temperature is from room temperature to 60 ° C; the crystallization time is 0.5 to 72 hours; (4) 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2 , 4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is volatilized in a solution of a mixed system of water and an organic solvent, and the precipitated crystal is separated and dried to obtain 1-{ Form I of 2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid; Wherein, the organic solvent is selected from the group consisting of propanol, acetone, tetrahydrofuran or a mixture thereof; the volume of water in the mixture of water and organic solvent is 0.01% to 50%; 1-{2-fluoro-4-[5- (4-isobutylphenyl)-1,2,4-oxadiazole-3- The amount of -benzyl}-3-azetidinecarboxylic acid is 0.1 to 1 times its solubility in the solvent system at the operating temperature; the operating temperature is room temperature; the temperature of the crystallization is room Warming to 60 ° C; the crystallization time is 1 to 7 days; in the preparation method of the above (1) to (4) crystal form I, the drying temperature is room temperature to 60 ° C; the drying time It is 1~48 hours. A 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3- Form IV of azetoincarboxylic acid, Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the Form IV is 4.8±0.2°, 9.0±0.2°, 15.1±0.2°, 15.9±0.2°, 17.5±0.2 at a diffraction angle 2θ. There are characteristic peaks at ° and 17.7 ± 0.2 °. The crystalline form IV according to claim 5, wherein the X-ray powder diffraction pattern of the crystalline form IV is 4.8±0.2°, 9.0±0.2°, 9.8±0.2°, 12.4±0.2 at a diffraction angle 2θ. Characteristic peaks at °, 13.7 ± 0.2 °, 14.8 ± 0.2 °, 15.1 ± 0.2 °, 15.9 ± 0.2 °, 17.5 ± 0.2 °, 17.7 ± 0.2 °, 18.2 ± 0.2 °, and 19.8 ± 0.2 °. The crystal form IV according to claim 6, wherein the X-ray powder diffraction pattern of the crystal form IV has a characteristic peak and a relative intensity thereof at a position where the diffraction angle 2θ is: A method for producing a crystalline form IV according to any one of claims 5 to 7, wherein the preparation method employs any one of the following methods: (1) 1-{2-fluoro-4- [5-(4-Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is formed into a suspension in an organic solvent system as follows. The crystals were stirred and the precipitated crystals were separated and dried to give 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]- Form IV of benzyl}-3-azetidinecarboxylic acid; wherein the organic solvent is selected from the group consisting of C ₂ -C ₃ alcohol, acetone, C ₄ -C ₅ ester, tetrahydrofuran, 1,4-dioxane And acetonitrile and a mixture thereof; the organic solvent is dried, and the volume content of water in the organic solvent is less than 0.001%; 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2 , 4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid is used in an amount of from 1.1 to 50 times its solubility in the solvent system at the operating temperature; The temperature of the crystallization is from room temperature to 60 ° C; the crystallization time is 3-14 days; (2) at a certain temperature, 1-{2-fluoro-4-[5-(4- Isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl a solution of a hydrazide carboxylic acid is formed in an organic solvent, cooled and stirred to crystallize, and the precipitated crystal is separated and dried to obtain 1-{2-fluoro-4-[5-(4-isobutyl) Form IV of phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid; wherein the organic solvent is selected from the group consisting of C ₁ -C ₄ alcohols, C ₃ ~ C ₄ ketone, C ₄ ~ C ₅ ester, 1,4-dioxane, acetonitrile, toluene and mixtures thereof; the organic solvent is dried, the volume content of water in the organic solvent is less than 0.001%; In the solution, 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidine The carboxylic acid is used in an amount of 0.1 to 1 times the solubility in the organic solvent at a certain temperature; the certain temperature is 40 ° C to 80 ° C; the temperature after the cooling is room temperature; the crystallization time is 0.5~72 hours; (3) to 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}- A slightly soluble or insoluble solvent is added to a solution of 3-azetidinecarboxylic acid in a soluble solvent, and the crystals are stirred and separated, and the precipitated crystals are separated and dried to obtain 1-{2-fluoro-4-[5-(4) -isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-indole a crystalline form IV of a pyridinecarboxylic acid; wherein the soluble solvent is selected from the group consisting of trifluoroethanol, tetrahydrofuran, 1,4-dioxane, dimethyl hydrazine or a mixture thereof; the sparingly soluble or insoluble solvent is selected from the group consisting of C ₃ ~ C ₄ alcohol, C ₄ ~ C ₅ ester, isopropyl ether, n-heptane or a mixture thereof; the sparingly soluble or insoluble solvent is selected from the group consisting of n-propanol, n-butanol, 2-butanol, ethyl acetate, Isopropyl acetate, isopropyl ether or n-heptane; the solvent is dried, the volume content of water in the organic solvent is less than 0.001%; the volume ratio of the slightly soluble or insoluble solvent to the soluble solvent is 1:1 ~50:1; 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl} in the solution The -3-azetidinecarboxylic acid is used in an amount of 0.1 to 1 times the solubility in the soluble solvent at the operating temperature; the operating temperature is room temperature; and the crystallization temperature is room temperature to 60 ° C The crystallization time is 0.5 to 72 hours; (4) 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3 a solution of -benzyl]-benzyl}-3-azetidinecarboxylic acid in an organic solvent is volatilized, and the precipitated crystals are separated and dried to obtain 1-{2-fluoro-4-[5-(4-iso) Ding Phenyl) -1,2,4-oxadiazol-3-yl] - benzyl} -3 Form IV azetidine carboxylic acid; wherein said organic solvent is selected from C ₁ ~ C ₄ alcohols, C ₄ ~ C ₅ ester, methyl ethyl ketone, tetrahydrofuran, dimethyl hydrazine or a mixture thereof; the organic solvent is dried, the volume content of water in the organic solvent is less than 0.001%; 1-{2-fluoro-4-[5 The amount of -(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is the operating temperature in the solvent system The solubility is 0.1 to 1 times; the operating temperature is room temperature; the temperature of the crystallization is room temperature to 60 ° C; the crystallization time is 1 to 7 days; the above (1) to (4) crystal In the preparation method of the type IV, the drying temperature is from room temperature to 60 ° C; and the drying time is from 1 to 48 hours. A 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3- Form XII of azetocarboxylic acid, Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the Form XII is 6.3±0.2°, 9.5±0.2°, 12.7±0.2°, 18.0±0.2°, and 19.3±0.2 at a diffraction angle 2θ. There are characteristic peaks at °. The crystal form XII according to claim 9, wherein the X-ray powder diffraction pattern of the form XII is 6.3 ± 0.2°, 9.5 ± 0.2°, 12.7 ± 0.2°, and 18.0 ± 0.2 at a diffraction angle 2θ. Characteristic peaks at °, 19.3 ± 0.2 °, 21.8 ± 0.2 °, 22.1 ± 0.2 °, 22.4 ± 0.2 °, 24.2 ± 0.2 °, 24.6 ± 0.2 °, and 25.7 ± 0.2 °. The crystal form XII according to claim 10, wherein the X-ray powder diffraction pattern of the form XII has a characteristic peak and a relative intensity thereof at a position where the diffraction angle 2θ is: A method of producing Form XII according to any one of Claims 9-11, wherein The preparation method is prepared by the following method: 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl }-3-吖butylpyridinecarboxylic acid is formed into a suspension in anhydrous methanol, stirred and crystallized, and the precipitated crystal is separated and dried to obtain 1-{2-fluoro-4-[5-(4-isobutylphenyl) a crystalline form XII of-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid; wherein the 1-{2-fluoro-4-[5-( The amount of 4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidincarboxylic acid is 1.1 of its solubility in anhydrous methanol at the operating temperature. ~50 times; the temperature of the crystallization is from room temperature to 60 ° C; the operating temperature is room temperature; the crystallization time is 3-14 days; in the preparation method of the above form XII, the drying The temperature is from room temperature to 60 ° C; the drying time is from 1 to 48 hours. A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more of the crystals according to any one of claims 1 to 3, wherein the crystal according to any one of claims 5 to 7 The crystalline form XII according to any one of the claims 9-11, the crystalline form I obtained according to the preparation method of claim 4, the crystalline form IV obtained according to the preparation method of claim 8, or according to the request Form XII obtained by the preparation of Item 12, and at least one pharmaceutically acceptable carrier. The crystal form I according to any one of claims 1 to 3, wherein the crystal form IV according to any one of claims 5 to 7, and the form XII according to any one of claims 9 to 11, according to Form I obtained by the preparation method of claim 4, the preparation method according to claim 8 Use of the obtained Form IV or the Form XII obtained according to the preparation method of Claim 12 for the preparation of a medicament for the treatment and/or prevention of a disease or condition mediated by the SlP1 receptor. A pharmaceutical composition for treating and/or preventing a disease or condition mediated by an S1P1 receptor, the pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more selected from any one of claims 1-3 The crystalline form I according to any one of the preceding claims, wherein the crystalline form X of any one of claims 5-7, the crystalline form XII according to any one of claims 9 to 11, and the preparation method according to claim 4 Form I, Form IV obtained according to the preparation method described in Claim 8 or Form XII obtained according to the preparation method described in Claim 12, and at least one pharmaceutically acceptable carrier.