Crystal form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and preparation method and application thereof

Abstract

The invention relates to the technical field of compound crystal forms, in particular to a crystal form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid as well as a preparation method and application thereof. The crystal form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid comprises at least one of a crystal form I, a crystal form II, a crystal form III and a crystal form IV in the specification, and the crystal forms have characteristic peaks in some 2 theta values of an X-ray powder diffraction pattern. The crystal forms are confirmed through an X-ray powder diffraction diagram, a thermogravimetric analysis diagram, a differential scanning calorimetry analysis diagram and a liquid nuclear magnetic hydrogen spectrogram, the dynamic solubility and stability of the crystal forms in different solvents are researched at the same time, and the crystal forms have good effects, so that the clinical efficacy can be better exerted.

Description

Technical Field

[0001] The present application belongs to the technical field of pharmaceutical crystal forms, and in particular relates to a crystal form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, a preparation method thereof, and an application thereof. Background Art

[0002] Currently, there are several drugs on the market for treating neurodegenerative diseases, such as Parkinson's disease. These drugs primarily work by increasing or mimicking the effects of dopamine, improving motor function and quality of life in Parkinson's patients. However, these drugs still have certain limitations. Therefore, there is a continued need to develop new drugs that are more effective, safer, and more neuroprotective.

[0003] The compound 4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid has been disclosed as a drug with neuroprotective effects, but it has problems with low solubility and poor stability, which easily affect its absorption and bioavailability in the body, thereby reducing its clinical efficacy. Summary of the Invention

[0004] The purpose of this application is to provide a crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, a preparation method and application thereof, aiming to improve the solubility and stability of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid to better exert its pharmacological efficacy.

[0005] To achieve the above application objectives, the technical solutions adopted in this application are as follows:

[0006] In a first aspect, the present application provides a crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, including at least one of crystalline form I, crystalline form II, crystalline form III and crystalline form IV; wherein,

[0007] The X-ray powder diffraction pattern of the crystalline form I has at least three characteristic peaks at 2θ values ​​of 6.7°±0.2°, 7.2°±0.2°, 11.9°±0.2°, 13.4°±0.2°, 14.4°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 20.2°±0.2°, 21.7°±0.2°, and 25.6°±0.2;

[0008] The X-ray powder diffraction pattern of the crystalline form II has at least three characteristic peaks at 2θ values ​​of 6.0°±0.2°, 6.4°±0.2°, 7.0°±0.2°, 8.7°±0.2°, 13.5°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 19.1°±0.2°, 21.0°±0.2°, and 22.3°±0.2;

[0009] The X-ray powder diffraction pattern of the crystalline form III has at least three characteristic peaks at 2θ values ​​of 5.0°±0.2°, 8.0°±0.2°, 13.4°±0.2°, 15.0°±0.2°, 16.3°±0.2°, 17.7°±0.2°, 19.7°±0.2°, and 24.1°±0.2°;

[0010] The X-ray powder diffraction pattern of the crystalline form IV has at least five characteristic peaks at 2θ values ​​of 5.6°±0.2°, 6.6°±0.2°, 13.8°±0.2°, 15.9°±0.2°, 18.3°±0.2°, 18.5°±0.2°, 18.9°±0.2°, 19.6°±0.2°, 20.2°±0.2°, and 21.8°±0.2°.

[0011] In a second aspect, the present application provides a method for preparing a crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, comprising: subjecting (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and calcium hydroxide to solid-liquid separation to form a solution formed by dissolving the solution in a mixed solvent of ethanol and n-heptane to obtain the crystalline form I of the crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid provided in the first aspect of the present application.

[0012] In a third aspect, the present application provides a method for preparing a crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, comprising: subjecting (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and calcium hydroxide to solid-liquid separation of a solution formed by dissolving the solution in methyl tert-butyl ether to obtain the crystalline form II of the crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid provided in the first aspect of the present application.

[0013] In a fourth aspect, the present application provides a method for preparing a crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, comprising: performing solid-liquid separation on a solution formed by dissolving (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and magnesium hydroxide in a mixed solvent of toluene and n-heptane to obtain the crystalline form III of the crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid provided in the first aspect of the present application.

[0014] In a fifth aspect, the present application provides a method for preparing a crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, comprising: subjecting (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and sodium hydroxide to solid-liquid separation to form a solution formed in a mixed solvent of chloroform and n-heptane to obtain the crystalline form IV of the crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid provided in the first aspect of the present application.

[0015] In a sixth aspect, the present application provides an application, namely, the use of the above-mentioned crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and / or the crystalline form prepared by the above-mentioned preparation method in the preparation of a drug for treating neurodegenerative diseases;

[0016] The first aspect of the present application provides a crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, including at least one crystalline salt of Form I, Form II, Form III and Form IV. The present application confirms the above-mentioned crystalline forms through X-ray powder diffraction patterns, thermogravimetric analysis patterns, differential scanning calorimetry analysis patterns and liquid nuclear magnetic hydrogen spectra, and verifies that their dynamic solubility and stability in different solvents are very good, thereby better exerting clinical efficacy.

[0017] The second, third, fourth and fifth aspects of the present application provide methods for preparing a crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid. The above preparation methods have simple processes, low costs, can be produced on a large scale, and can prepare crystalline forms with high purity, good solubility and stability.

[0018] The application provided in the sixth aspect of this application is based on the fact that the crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid provided in this application has good solubility and stability, and can therefore be used to prepare drugs for treating neurodegenerative diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the following briefly introduces the drawings required for use in the embodiments or descriptions of the prior art. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.

[0020] Figure 1 is the XRPD pattern of Form I of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid;

[0021] Figure 2are TGA and DSC diagrams of Form 1 of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid;

[0022] Figure 3 is the XRPD pattern of Form II of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid;

[0023] Figure 4 are TGA and DSC diagrams of Form II of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid;

[0024] Figure 5 is the XRPD pattern of Form III of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid;

[0025] Figure 6 are TGA and DSC diagrams of Form III of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid;

[0026] Figure 7 is an XRPD pattern of Form IV of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid;

[0027] Figure 8 are TGA and DSC diagrams of Form IV of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid;

[0028] Figure 9 It is the crystalline form I of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid 1 H-NMR spectrum;

[0029] Figure 10 It is the crystalline form II of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid 1 H-NMR spectrum;

[0030] Figure 11 It is the crystalline form III of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid 1 H-NMR spectrum;

[0031] Figure 12 It is the crystalline form IV of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid 1 H-NMR spectrum;

[0032] Figure 13 is a comparison of XRPD patterns of Form I of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid before and after stability evaluation;

[0033] Figure 14 is a comparison of XRPD patterns of Form II of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid before and after stability evaluation;

[0034] Figure 15 is a comparison of XRPD patterns of Form III of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid before and after stability evaluation;

[0035] Figure 16 is a comparison of XRPD patterns of Form IV of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid before and after stability evaluation;

[0036] Figure 17 This is a graph showing the protective effect of the crystalline form III of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid on the reduction of dopamine and its metabolite content induced by MPTP; relative to the normal group ###p<0.001, relative to the MPTP group *p<0.05, **p<0.01, ***p<0.001. DETAILED DESCRIPTION

[0037] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application more clearly understood, this application is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit this application.

[0038] In this application, the term "and / or" describes the relationship between associated objects, indicating that three possible relationships exist. For example, A and / or B can represent: A exists alone, A and B exist simultaneously, and B exists alone. A and B can be singular or plural. The character " / " generally indicates that the associated objects are in an "or" relationship.

[0039] In this application, "at least one" means one or more, "more than one" means two or more. "At least one of the following" or similar expressions refers to any combination of these items, including any combination of single or plural items.

[0040] It should be understood that in the various embodiments of the present application, the size of the serial numbers of the above-mentioned processes does not mean the order of execution. Some or all of the steps can be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0041] The terms used in the embodiments of the present application are for the purpose of describing specific embodiments only and are not intended to limit the present application. The singular forms "a", "an", "the" and "the" used in the embodiments of the present application and the appended claims are also intended to include plural forms unless the context clearly indicates otherwise.

[0042] The weights of the relevant components mentioned in the examples of this application may not only refer to the specific content of each component, but also represent the weight ratio between the components. Therefore, as long as the content of the relevant components is proportionally enlarged or reduced according to the examples of this application, it is within the scope disclosed in the examples of this application. Specifically, the mass described in the examples of this application may be a mass unit known in the chemical industry, such as μg, mg, g, kg, etc.

[0043] The terms "first" and "second" are used solely for descriptive purposes to distinguish objects, such as substances, from one another and should not be understood to indicate or imply relative importance or to implicitly specify the quantity of the technical features being referred to. For example, without departing from the scope of the embodiments of this application, a first XX may also be referred to as a second XX, and similarly, a second XX may also be referred to as a first XX. Thus, features defined as "first" or "second" may explicitly or implicitly include one or more of such features.

[0044] Based on the problems of low solubility and poor stability of the currently disclosed 4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, the present invention develops a new crystal form of 4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid with high purity, good solubility and stability.

[0045] This application discovered four new crystalline salt forms of compound 1 (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, designated Form I, Form II, Form III, and Form IV, by screening for polymorphic salts. These salt forms exhibit high purity, good solubility, and stability, and are simple and inexpensive to prepare. They can be used to treat neurodegenerative diseases such as Parkinson's disease.

[0046]

[0047] The present application embodiment provides the above-mentioned compound 1, i.e., one or more crystal forms of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, specifically including at least one of crystal form I, crystal form II, crystal form III and crystal form IV, which are all new crystal salts of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid. The present application embodiment provides X-ray powder diffraction patterns, thermogravimetric analysis patterns, differential scanning calorimetry analysis patterns and liquid nuclear magnetic hydrogen spectra of each crystal form, as well as dynamic solubility comparison data and stability assessment results in different solvents, to prove their structure and performance, and provide a basis for their quality control. These patterns and data show the structural differences and similarities between different crystal salts, as well as the features in thermal stability and molecular structure.

[0048] For Form I, its X-ray powder diffraction pattern has at least three characteristic peaks at 2theta (θ) values ​​of 6.7°±0.2°, 7.2°±0.2°, 11.9°±0.2°, 13.4°±0.2°, 14.4°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 20.2°±0.2°, 21.7°±0.2°, and 25.6°±0.2°. Illustratively, the 2theta value of one of the at least three characteristic peaks of Form I is 6.7°±0.2°. Furthermore, the 2theta values ​​of the other two characteristic peaks are 7.2°±0.2° and 18.0°±0.2°, respectively.

[0049] In some embodiments, the X-ray powder diffraction pattern of Form I has at least six characteristic peaks at 2theta values ​​of 6.7°±0.2°, 7.2°±0.2°, 11.9°±0.2°, 13.4°±0.2°, 14.4°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 20.2°±0.2°, 21.7°±0.2°, and 25.6°±0.2°. The 2theta values ​​of the at least six characteristic peaks are 6.7°±0.2°, 7.2°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 13.4°±0.2°, and 21.7°±0.2°, respectively.

[0050] In some embodiments, the X-ray powder diffraction pattern of Form I has characteristic peaks at 2theta values ​​of 6.7°±0.2°, 7.2°±0.2°, 11.9°±0.2°, 13.4°±0.2°, 14.4°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 20.2°±0.2°, 21.7°±0.2°, and 25.6°±0.2. The corresponding XRPD pattern of Form I is as follows: Figure 1 As shown, the corresponding thermogravimetric analysis diagram and differential scanning calorimetry analysis diagram of Form I are basically as follows Figure 2 shown.

[0051] The present application also provides a method for preparing the above-mentioned crystalline form I of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, comprising: performing solid-liquid separation on a solution formed by dissolving (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and calcium hydroxide in a mixed solvent of ethanol and n-heptane to obtain crystalline form I of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid.

[0052] Specifically, in the mixed solvent of ethanol and n-heptane, the volume ratio of ethanol to n-heptane can be (1-2):(9-8), for example, 1:9. The mass ratio of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid to calcium hydroxide can be 190-210:24-40.

[0053] Specifically, the solid-liquid separation step may include: dissolving (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and calcium hydroxide in a mixed solvent of ethanol and n-heptane, stirring the solution for 48 to 72 hours, separating the solid by vacuum filtration, washing with n-heptane, and drying to obtain Form I.

[0054] For Form II, its X-ray powder diffraction pattern has at least three characteristic peaks at 2theta values ​​of 6.0°±0.2°, 6.4°±0.2°, 7.0°±0.2°, 8.7°±0.2°, 13.5°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 19.1°±0.2°, 21.0°±0.2°, and 22.3°±0.2°. Illustratively, the 2theta value of one of the at least three characteristic peaks of Form II is 6.0°±0.2°, and further, the 2theta values ​​of the other two characteristic peaks are 6.4°±0.2° and 8.7°±0.2°, respectively.

[0055] In some embodiments, the X-ray powder diffraction pattern of Form II has at least six characteristic peaks at 2theta values ​​of 6.0°±0.2°, 6.4°±0.2°, 7.0°±0.2°, 8.7°±0.2°, 13.5°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 19.1°±0.2°, 21.0°±0.2°, and 22.3°±0.2°. The 2theta values ​​of the at least six characteristic peaks are 6.0°±0.2°, 6.4°±0.2°, 8.7°±0.2°, 13.5°±0.2°, 17.5°±0.2°, and 19.1°±0.2°, respectively.

[0056] In some embodiments, the X-ray powder diffraction pattern of Form II has characteristic peaks at 2theta values ​​of 6.0°±0.2°, 6.4°±0.2°, 7.0°±0.2°, 8.7°±0.2°, 13.5°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 19.1°±0.2°, 21.0°±0.2°, and 22.3°±0.2. The corresponding XRPD pattern of Form II is as follows: Figure 3 As shown, the corresponding thermogravimetric analysis diagram and differential scanning calorimetry analysis diagram of Form II are basically as follows Figure 4 shown.

[0057] The present application also provides a method for preparing the above-mentioned Form II of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, comprising: performing solid-liquid separation on a solution formed by dissolving (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and calcium hydroxide in methyl tert-butyl ether to obtain Form II of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid.

[0058] Specifically, the solid-liquid separation step may include: dissolving (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and calcium hydroxide in methyl tert-butyl ether solvent, stirring the solution for 48 to 72 hours, separating the solid by vacuum filtration, washing with n-heptane, and drying to obtain Form II. The mass ratio of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid to calcium hydroxide may be 190 to 210:24 to 40.

[0059] For Form III, its X-ray powder diffraction pattern has at least three characteristic peaks at 2theta values ​​of 5.0°±0.2°, 8.0°±0.2°, 13.4°±0.2°, 15.0°±0.2°, 16.3°±0.2°, 17.7°±0.2°, 19.7°±0.2°, and 24.1°±0.2°. Illustratively, the 2theta value of one of the at least three characteristic peaks of Form III is 5.0°±0.2°, and the 2theta values ​​of the other two characteristic peaks are 8.0°±0.2° and 24.1°±0.2°, respectively.

[0060] In some embodiments, the X-ray powder diffraction pattern of Form III has at least five characteristic peaks at 2theta values ​​of 5.0°±0.2°, 8.0°±0.2°, 13.4°±0.2°, 15.0°±0.2°, 16.3°±0.2°, 17.7°±0.2°, 19.7°±0.2°, and 24.1°±0.2°. The 2theta values ​​of the at least five characteristic peaks are 5.0°±0.2°, 8.0°±0.2°, 16.3°±0.2°, 13.4°±0.2°, and 24.1°±0.2°, respectively.

[0061] In some embodiments, the X-ray powder diffraction pattern of Form III has characteristic peaks at 2theta values ​​of 5.0°±0.2°, 8.0°±0.2°, 13.4°±0.2°, 15.0°±0.2°, 16.3°±0.2°, 17.7°±0.2°, 19.7°±0.2°, and 24.1°±0.2°. The corresponding XRPD pattern of Form III is as follows: Figure 5 As shown, the corresponding thermogravimetric analysis diagram and differential scanning calorimetry analysis diagram of Form III are basically as follows Figure 6 shown.

[0062] The present application also provides a method for preparing the above-mentioned crystalline form III of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, comprising: performing solid-liquid separation on a solution formed by dissolving (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and magnesium hydroxide in a mixed solvent of toluene and n-heptane to obtain crystalline form III of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid.

[0063] Specifically, in the mixed solvent of toluene and n-heptane, the volume ratio of toluene to n-heptane can be (1-2):(9-8), for example, 1:9. The mass ratio of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid to magnesium hydroxide can be 190-210:24-40.

[0064] Specifically, the solid-liquid separation step may include: dissolving (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and magnesium hydroxide in a mixed solvent of toluene and n-heptane, stirring the solution for 48 to 72 hours, separating the solid by vacuum filtration, washing with n-heptane, and drying to obtain Form III.

[0065] For Form IV, its X-ray powder diffraction pattern has at least five characteristic peaks at 2theta values ​​of 5.6°±0.2°, 6.6°±0.2°, 13.8°±0.2°, 15.9°±0.2°, 18.3°±0.2°, 18.5°±0.2°, 18.9°±0.2°, 19.6°±0.2°, 20.2°±0.2°, and 21.8°±0.2°. Illustratively, the 2theta values ​​of the at least five characteristic peaks are 5.6°±0.2°, 6.6°±0.2°, 15.9°±0.2°, 18.9°±0.2°, and 19.6°±0.2°, respectively.

[0066] In some embodiments, the X-ray powder diffraction pattern of Form IV has characteristic peaks at 2theta values ​​of 5.6°±0.2°, 6.6°±0.2°, 13.8°±0.2°, 15.9°±0.2°, 18.3°±0.2°, 18.5°±0.2°, 18.9°±0.2°, 19.6°±0.2°, 20.2°±0.2°, and 21.8°±0.2°. The corresponding XRPD pattern of Form IV is as follows: Figure 7 As shown, the corresponding thermogravimetric analysis diagram and differential scanning calorimetry analysis diagram of Form IV are basically as follows Figure 8 shown.

[0067] The present application also provides a method for preparing the above-mentioned Form IV of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, comprising: performing solid-liquid separation on a solution formed by dissolving (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and sodium hydroxide in a mixed solvent of chloroform and n-heptane to obtain Form IV of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid.

[0068] Specifically, in the mixed solvent of chloroform and n-heptane, the volume ratio of chloroform to n-heptane can be (1-2):(9-8), for example, 1:9. The mass ratio of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid to sodium hydroxide can be 190-210:24-40.

[0069] Specifically, the solid-liquid separation step may include: dissolving (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and sodium hydroxide in a mixed solvent of chloroform and n-heptane, stirring the solution for 48 to 72 hours, separating the solid by vacuum filtration, washing with n-heptane, and drying to obtain Form IV.

[0070] The present invention provides a method for preparing different crystalline salts, achieving high-purity, high-efficiency, and low-cost preparation of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid crystalline forms, thereby providing feasibility for large-scale production. The above-mentioned preparation method starts from anhydrous crystalline forms and obtains crystalline products of different crystalline salts by selecting different solvents or additives. It does not require complicated operations and equipment, and is low in cost.

[0071] For different preparation methods, there may be other synthetic routes or reaction conditions, and identical or similar compounds can be obtained. For example, by steps such as different esterifications, reduction reactions, oxidation reactions, from different raw materials, synthetic (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid can be produced. It is also possible to influence the transformation efficiency and the selectivity in the reaction process by changing factors such as reaction temperature, time, catalyst, solvent, thereby obtaining identical or similar compounds. Further, it is possible to influence the nucleation and growth mechanism in the crystallization process by changing factors such as crystallization temperature, time, stirring velocity, solvent ratio, thereby obtaining different crystal formations or forms. It is also possible to change the solution chemistry in the crystallization process by adding materials such as different eutectics, solvating agents, pH adjusting agents, thereby obtaining different crystal formations or forms.

[0072] The above-mentioned crystalline forms of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid provided in the examples of this application have good solubility and stability and can therefore be used to prepare drugs for treating neurodegenerative diseases. Specifically, at least one of the new crystalline salts of Form I, Form II, Form III, and Form IV can be used as a component of a pharmaceutical composition for treating neurodegenerative diseases such as Parkinson's disease. This can improve the effectiveness and safety of drugs in treating neurodegenerative diseases.

[0073] Specifically, the above-mentioned crystal forms I, II, III and IV have good purity, solubility and stability; in particular, the crystal form III is not prone to crystal transformation during drug storage and development, thus having stable bioavailability and efficacy.

[0074] Specifically, by comparing the dynamic solubility data and stability evaluation results of different crystalline salts in different solvents, the solubility and stability of the compound were evaluated and compared, providing a reference for its efficacy and safety. These data and results show the change in solubility of different crystalline salts in common solvents such as water, ethanol, and methanol over time, as well as the stability under different conditions of temperature, humidity, and light. Among them, Form III exhibits the best solubility and stability, is not prone to crystal transformation, and thus has good in vivo absorption and bioavailability.

[0075] For different uses, other drug combinations or administration routes may exist that can achieve the same or similar therapeutic effects. For example, the above-mentioned crystalline salt can be combined with other drugs with neuroprotective or synergistic effects to form a compound drug for the treatment of neurodegenerative diseases. Alternatively, by varying the route of administration, such as oral, injection, or patch, the distribution and metabolism of the drug in the body can be influenced to achieve the same or similar therapeutic effects.

[0076] In addition, the new crystalline salt provided in the examples of the present application can be used as a component of a pharmaceutical composition for the development of new indications and formulation research to explore its pharmacological activity and clinical application in the field of new drug research and development.

[0077] The following describes the details in conjunction with specific embodiments.

[0078] It should be noted that the abbreviations used in the examples of this application are explained as follows:

[0079] The term "pure" as used herein means that Compound 1 is at least 95% pure, further at least 99% pure, further at least 99.5% pure in the crystalline salts of the present application: Form I, Form II, Form III and Form IV.

[0080] XRPD: X-ray powder diffraction; DSC: differential scanning calorimetry; TGA: thermogravimetric analysis; 1 H-NMR: liquid phase nuclear magnetic resonance; HPLC: high-performance liquid chromatography; MTBE: methyl tert-butyl ether; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

[0081] The X-ray powder diffraction patterns in the examples of this application were collected on an Analytical X-ray powder diffractometer. The X-ray powder diffraction method parameters include: X-ray reflection parameters: Cu, Kα; 1.540598; 1.544426; Kα2 / Kα1 intensity ratio: 0.50; voltage: 45 kilovolts (kV); current: 40 milliamperes (mA); scanning range: from 3.0 to 40.0 degrees; scanning step: 0.0167; scanning mode: continuous.

[0082] The differential scanning calorimetry (DSC) analysis patterns in the examples of this application were collected on a TA Q200 / 2000. The DSC analysis parameters included: method: linear heating; sample pan: aluminum pan, press-fit; scan rate: 10°C / min; protective gas: nitrogen.

[0083] The thermogravimetric analysis graphs in the examples of this application were collected on a TA Q500 / 5000. The thermogravimetric analysis method parameters include: method: linear heating; sample pan: aluminum pan, press cover; scan rate: 10°C / min; protective gas: nitrogen.

[0084] The liquid-state H-NMR spectra in the examples of the present application were collected on a Bruker 400M NMR spectrometer, and dimethyl sulfoxide (DMSO-d6) was used as the solvent.

[0085] In the examples herein, HPLC data were acquired on an Agilent 1100 / 1260 HPLC. Method parameters included: chromatographic column: Waters Xbridge C18, 150 x 4.6 mm, 5 μm; mobile phases: A: 0.1% phosphoric acid in water, B: acetonitrile; flow rate: 1.0 ml / min; detection wavelength: 210 nm (reference wavelength: 500 nm); column temperature: 40°C; gradient as shown in Table 1.

[0086] Table 1

[0087]

[0088] Example 1 Preparation of Form I

[0089] 201.0 mg of Compound 1 (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid) and 31.8 mg of calcium hydroxide were weighed and added to a 20 mL glass vial. 5 mL of a mixed solvent of ethanol and n-heptane (ethanol / n-heptane volume ratio = 1:9) was added to the vial to form a turbid solution. The mixture was magnetically stirred (approximately 1000 rpm) at room temperature for approximately 3 days. The solid was isolated by vacuum filtration, washed with n-heptane, and dried under vacuum overnight at room temperature. The solid product was collected as Form I.

[0090] The XRPD pattern of the above-obtained Form I is as follows: Figure 1 As shown, TGA and DSC diagrams are as follows Figure 2 As stated, 1 H-NMR Figure 9 The X-ray powder diffraction data are shown in Table 2.

[0091] Table 2

[0092] 2theta(°) d interval strength% 6.6879 13.22 100.00 7.1990 12.28 57.31 11.9161 7.43 6.34 13.3799 6.62 8.09 14.4031 6.15 5.16 17.9851 4.93 16.09 18.5431 4.79 8.64 20.2010 4.40 2.76 21.6834 4.10 7.92 25.5764 3.48 3.78

[0093] 1 The H-NMR data are as follows: 1H NMR (400MHz, DMSO-d6) δ6.78(d,J=2.2Hz,1H),6.73(d,J=2.1Hz,1H),6.60(d,J=8.0Hz,1H),2.72(s,1H),2.17(s,3H),1.98(d,J=8.1Hz,1H), 1.80(d,J=7.5Hz,1H), 1.74(dt,J=12.8,6.2Hz,1H), 1.58(dd,J=13.6,8.3Hz,1H), 1.47(s,1H), 0.94(d,J=6.6Hz,3H), 0.63(d,J=6.6Hz,3H).

[0094] Example 2 Preparation of Form II

[0095] 199.6 mg of Compound 1, i.e., (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, and 31.6 mg of calcium hydroxide were weighed and added to a 20 mL glass bottle. 5 mL of MTBE was added to the glass bottle to form a turbid solution. The mixture was magnetically stirred (at approximately 1000 rpm) at room temperature for approximately 3 days. The solid was isolated by vacuum filtration, washed with n-heptane, and dried under vacuum overnight at room temperature. The solid product was collected to obtain Form II.

[0096] The XRPD pattern of the above-obtained Form II is as follows: Figure 3 As shown, TGA and DSC diagrams are as follows Figure 4 As shown, 1 H-NMR Figure 10 The X-ray powder diffraction data are shown in Table 3.

[0097] Table 3

[0098] 2theta(°) d interval strength% 5.9637 14.82 100.00 6.3839 13.85 43.16 7.0211 12.59 4.82 8.7406 10.12 26.88 13.5325 6.54 13.67 15.9699 5.55 3.34 17.4873 5.07 10.87 19.1276 4.64 6.15 21.0286 4.22 3.64 22.3497 3.98 3.24 24.9305 3.57 2.57 27.1852 3.28 1.38 37.5641 2.39 0.99

[0099] 1 The H-NMR data are as follows: 1 H NMR (400MHz, DMSO-d6) δ6.78(d,J=2.2Hz,1H),6.73(d,J=2.2Hz,1H),6.61(d,J=8.0Hz,1H),2.72(s,1H),2.17(s,3H),1.98(dd,J=10. 0,5.9Hz,1H),1.84–1.68(m,1H),1.60(dt,J=13.9,8.0Hz,1H),1.48(s,1H),1.11(s,1H),0.94(d,J=6.5Hz,3H),0.63(d,J=6.6Hz,3H).

[0100] Example 3 Preparation of Form III

[0101] 200.1 mg of Compound 1, (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, and 24.8 mg of magnesium hydroxide were weighed and added to a 20 mL glass bottle. 5 mL of a mixed solvent of toluene and n-heptane (toluene / n-heptane volume ratio = 1:9) was added to the glass bottle to form a turbid solution. The mixture was magnetically stirred (approximately 1000 rpm) at room temperature for approximately 3 days. The solid was isolated by vacuum filtration, washed with n-heptane, and dried under vacuum overnight at room temperature. The solid product was collected to obtain Form III.

[0102] The XRPD pattern of the above-obtained Form III is as follows: Figure 5 As shown, TGA and DSC diagrams are as follows Figure 6 As shown, 1 H-NMR Figure 11 The X-ray powder diffraction data are shown in Table 4.

[0103] Table 4

[0104] 2theta(°) d interval strength% 4.9580 17.82 100.00 8.0043 11.05 58.69 13.3999 6.61 10.91 14.9601 5.92 6.36 16.3052 5.44 13.27 17.6572 5.02 7.68 19.7477 4.50 6.87 20.8023 4.27 4.42 24.1291 3.69 19.99 24.9802 3.56 2.15 27.0474 3.30 2.56 29.9749 2.98 1.00 33.1660 2.70 0.65 34.2654 2.62 1.37 35.2384 2.55 1.08

[0105] 1 The H-NMR data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.86(s,1H),6.77(s,1H),6.74(dd,J=8.0,2.1Hz,1H),6.62(d,J=8.0Hz,1 H), 2.16 (s, 3H), 1.92 (s, 1H), 1.76 (d, J = 31.3Hz, 4H), 0.92 (d, J = 6.5Hz, 3H), 0.66 (d, J = 6.6Hz, 3H).

[0106] Example 4 Preparation of Form IV

[0107] 199.6 mg of Compound 1 (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid) and 33.4 mg of sodium hydroxide were weighed and added to a 20 mL glass vial. 5 mL of a mixed solvent of chloroform and n-heptane (chloroform / n-heptane volume ratio = 1:9) was added to the vial to form a turbid solution. The mixture was magnetically stirred (approximately 1000 rpm) at room temperature for approximately 3 days. The solid was isolated by vacuum filtration, washed with n-heptane, and dried under vacuum overnight at room temperature. The solid product was collected as Form IV.

[0108] The XRPD pattern of the above-obtained Form IV is as follows: Figure 7 As shown, TGA and DSC diagrams are as follows Figure 8 As shown, 1 H-NMR Figure 12 The X-ray powder diffraction data are shown in Table 5.

[0109] Table 5

[0110]

[0111]

[0112] 1 The H-NMR data are as follows: 1 H NMR(400MHz,DMSO-d6)δ6.78(d,J=2.2Hz,1H),6.73(dd,J=8.1,2.2Hz,1H),6 .57(d,J=8.0Hz,1H),2.79(ddd,J=12.8,10.1,3.3Hz,1H),2.16(s,3H),2.01( tt,J=12.4,3.9Hz,1H),1.78(ddt,J=12.2,9.6,5.7Hz,2H),1.48(td,J=11.9 ,4.5Hz,1H),1.37–1.27(m,1H),0.97(d,J=6.5Hz,3H),0.59(d,J=6.5Hz,3H).

[0113] Performance Test 1 Dynamic Solubility

[0114] The dynamic solubility (1 hour and 4 hours) of Form I, Form II, Form III and Form IV prepared in the above examples was compared with that of anhydrous crystalline sample of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid in SGF (simulated gastric fluid) at pH = 1.8, FeSSIF (simulated artificial intestinal fluid in the fed state) at pH = 5.0, FaSSIF (simulated artificial intestinal fluid in the fasted state) at pH = 6.5, and pure water.

[0115] The procedure involved mixing approximately 20 mg of sample with 2 mL of ultrapure water or SGF, FaSSIF, or FeSSIF in a 3 mL glass vial. The mixture was incubated at 37°C with magnetic stirring (1000 rpm) for 1 or 4 hours. Afterward, 0.6 mL of the suspension was removed and centrifuged at 10,000 rpm. The sample content in the supernatant was determined by high-performance liquid chromatography. The experimental results are shown in Table 6.

[0116] Table 6

[0117]

[0118] The above data show that the solubility of Form I, Form II, Form III and Form IV prepared in the examples of the present application is higher than that of the anhydrous crystalline sample of Compound 1, especially Form III and Form IV have obvious advantages in solubility.

[0119] Performance Test 2 Stability

[0120] Weigh 8-12 mg of the crystalline form sample prepared in the above example into a 1.5-mL HPLC vial; After sealing the film, poke about 20 small pinholes and place it under 25℃ / 60%RH and 40℃ / 75%RH conditions for 7 days. XRPD test was performed on the samples before and after placement. After one week, samples were taken for HPLC and XRPD testing, and the spectra before and after placement were compared.

[0121] The comparison results of Form I are shown in Figure 13 , the comparison results of Form II are shown in Figure 14 , the comparison results of Form III are shown in Figure 15 , the comparison results of Form IV are shown in Figure 16 The results showed that Forms I and III maintained their purity and crystal form, and their characteristic peaks remained highly consistent. Form II maintained its purity, but its crystal form transformed into Form I. Form IV maintained its purity, but its crystal form changed at 25°C / 60% RH and formed a gel at 40°C / 75% RH, so XRPD characterization was not performed. All of these crystal forms exhibited a certain degree of stability, with Forms I and III showing the highest stability.

[0122] Performance Test 3 Animal Testing

[0123] Eight-week-old adult male C57BL / 6J mice (weighing 18-22 g) were used as experimental animals. Mice in the MPTP group were intraperitoneally injected with normal saline (0.1 mL / 10 g) once daily for two consecutive days, starting on day one, and 20 mg / kg MPTP hydrochloride (Sigma Aldrich, St. Louis, MO) once daily for seven consecutive days, starting on day three, to establish a Parkinson's disease model. Mice in the normal control (CON) group were intraperitoneally injected with normal saline (0.1 mL / 10 g) once daily for ten consecutive days, starting on day one. Mice in the drug-treated group were intraperitoneally injected with (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid Form III (10 mg / kg) in 30% PEG-70% saline once daily for ten consecutive days, starting on day one, and 20 mg / kg MPTP hydrochloride once daily for seven consecutive days, starting on day three. Ten days later, the mice were killed, and the striatum was quickly isolated and collected and stored in liquid nitrogen. The striatum was weighed and transferred to a 1.5 mL centrifuge tube. 75 μL of ice-cold Milli-Q water was added, homogenized, and centrifuged at 14,000 rpm for 20 minutes. The supernatant was taken, water was added to a total volume of 75 μL, and 75 μL of ethyl acetate was added. The mixture was vigorously vortexed and centrifuged at 14,000 rpm for 10 minutes. The supernatant was taken and analyzed by LC-MS. The content of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum was determined by LC-MS analysis and expressed in ng / mg striatum.

[0124] The results are as follows Figure 17 As shown: The DA content in the striatum of mice administered with Form III was 8.59±1.14 ng / mg, significantly higher than the 6.26±0.55 ng / mg in the MPTP group, with a statistically significant difference (P<0.05). The DOPAC content in the striatum of mice administered with Form III was 6.13±0.20 ng / mg, significantly higher than the 5.10±0.12 ng / mg in the MPTP group, with a statistically significant difference (P<0.01). The HVA content in the striatum of mice administered with Form III was 3.79±0.31 ng / mg, significantly higher than the 2.69±0.26 ng / mg in the MPTP group, with a statistically significant difference (P<0.001).

[0125] The above data show that MPTP induces a decrease in the levels of dopamine and its metabolites, and that administration of Form III of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid can significantly inhibit the MPTP-induced effect. This indicates that Form III of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid has neuroprotective activity in mice in vivo, increasing the balance between dopamine synthesis and metabolism, thereby inhibiting damage to dopamine neurons. Therefore, Form III of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid has a good effect in treating Parkinson's disease.

[0126] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present application should be included in the scope of protection of the present application.

Claims

1. A crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, characterized in that: Including at least one of Form I, Form II, Form III and Form IV; wherein, The X-ray powder diffraction pattern of the crystalline form I has at least three characteristic peaks at 2θ values ​​of 6.7°±0.2°, 7.2°±0.2°, 11.9°±0.2°, 13.4°±0.2°, 14.4°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 20.2°±0.2°, 21.7°±0.2°, and 25.6°±0.2; The X-ray powder diffraction pattern of the crystalline form II has at least three characteristic peaks at 2θ values ​​of 6.0°±0.2°, 6.4°±0.2°, 7.0°±0.2°, 8.7°±0.2°, 13.5°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 19.1°±0.2°, 21.0°±0.2°, and 22.3°±0.2; The X-ray powder diffraction pattern of the crystalline form III has at least three characteristic peaks at 2θ values ​​of 5.0°±0.2°, 8.0°±0.2°, 13.4°±0.2°, 15.0°±0.2°, 16.3°±0.2°, 17.7°±0.2°, 19.7°±0.2°, and 24.1°±0.2°; The X-ray powder diffraction pattern of the crystalline form IV has at least five characteristic peaks at 2θ values ​​of 5.6°±0.2°, 6.6°±0.2°, 13.8°±0.2°, 15.9°±0.2°, 18.3°±0.2°, 18.5°±0.2°, 18.9°±0.2°, 19.6°±0.2°, 20.2°±0.2°, and 21.8°±0.2°.

2. The crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid according to claim 1, wherein The X-ray powder diffraction pattern of the crystalline form I has characteristic peaks at least at 2θ values ​​of 6.7°±0.2°, 7.2°±0.2°, and 18.0°±0.2°; or The X-ray powder diffraction pattern of the crystalline form II has characteristic peaks at least at 2θ values ​​of 6.0°±0.2°, 6.4°±0.2°, and 8.7°±0.2°; or The X-ray powder diffraction pattern of the crystalline form III has characteristic peaks at least at 2θ values ​​of 5.0°±0.2°, 8.0°±0.2°, and 24.1°±0.2°; or The X-ray powder diffraction pattern of the crystalline form IV has characteristic peaks at least at 2θ values ​​of 5.6°±0.2°, 6.6°±0.2°, 15.9°±0.2°, 18.9°±0.2°, and 19.6°±0.2°.

3. The crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid according to claim 2, characterized in that The X-ray powder diffraction pattern of the crystalline form I has characteristic peaks at least at 2θ values ​​of 6.7°±0.2°, 7.2°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 13.4°±0.2°, and 21.7°±0.2°; or The X-ray powder diffraction pattern of the crystalline form II has characteristic peaks at least at 2θ values ​​of 6.0°±0.2°, 6.4°±0.2°, 8.7°±0.2°, 13.5°±0.2°, 17.5°±0.2°, and 19.1°±0.2°; or The X-ray powder diffraction pattern of the crystalline form III has characteristic peaks at least at 2θ values ​​of 5.0°±0.2°, 8.0°±0.2°, 16.3°±0.2°, 13.4°±0.2°, and 24.1°±0.

2.

4. The crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid according to any one of claims 1 to 3, characterized in that The X-ray powder diffraction pattern of the crystalline form I has characteristic peaks at 2θ values ​​of 6.7°±0.2°, 7.2°±0.2°, 11.9°±0.2°, 13.4°±0.2°, 14.4°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 20.2°±0.2°, 21.7°±0.2°, and 25.6°±0.2; or The X-ray powder diffraction pattern of the crystalline form II has characteristic peaks at 2θ values ​​of 6.0°±0.2°, 6.4°±0.2°, 7.0°±0.2°, 8.7°±0.2°, 13.5°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 19.1°±0.2°, 21.0°±0.2°, and 22.3°±0.2; or The X-ray powder diffraction pattern of the crystalline form III has characteristic peaks at 2θ values ​​of 5.0°±0.2°, 8.0°±0.2°, 13.4°±0.2°, 15.0°±0.2°, 16.3°±0.2°, 17.7°±0.2°, 19.7°±0.2°, and 24.1°±0.2°; or, The X-ray powder diffraction pattern of the crystalline form IV has characteristic peaks at 2θ values ​​of 5.6°±0.2°, 6.6°±0.2°, 13.8°±0.2°, 15.9°±0.2°, 18.3°±0.2°, 18.5°±0.2°, 18.9°±0.2°, 19.6°±0.2°, 20.2°±0.2°, and 21.8°±0.2°.

5. A method for preparing a crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, characterized in that: include: A solution of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and calcium hydroxide dissolved in a mixed solvent of ethanol and n-heptane is subjected to solid-liquid separation to obtain the crystalline form I of the (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid according to any one of claims 1 to 4.

6. A method for preparing a crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, characterized in that: include: A solution formed by dissolving (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and calcium hydroxide in methyl tert-butyl ether is subjected to solid-liquid separation to obtain the crystalline form II of the (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid according to any one of claims 1 to 4.

7. A method for preparing a crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, characterized in that: include: A solution of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and magnesium hydroxide dissolved in a mixed solvent of toluene and n-heptane is subjected to solid-liquid separation to obtain the crystalline form III of the (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid according to any one of claims 1 to 4.

8. A method for preparing a crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid, characterized in that: include: A solution of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid and sodium hydroxide dissolved in a mixed solvent of chloroform and n-heptane is subjected to solid-liquid separation to obtain the crystalline form IV of the (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid according to any one of claims 1 to 4.

9. Use of the crystalline form of (S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid according to any one of claims 1 to 4 and / or the crystalline form prepared by any one of the preparation methods (1) to (4) below in the preparation of a medicament for treating neurodegenerative diseases; (1) The preparation method according to claim 5; (2) The preparation method according to claim 6; (3) The preparation method according to claim 7; (4) The preparation method according to claim 8.

10. The use according to claim 9, characterized in that The drug for treating neurodegenerative diseases includes a drug for treating Parkinson's disease; and / or, The crystal form includes crystal form III.

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