Crystal form of 2-(3-methoxyphenylethyl)phenol and uses thereof

Abstract

The present application discloses a crystal form of 2-(3-methoxyphenylethyl)phenol and its use. The X-ray powder diffraction pattern of the crystal form includes diffraction peaks at 2θ angles of 9.21±0.2°, 17.53±0.2°, 18.53±0.2° and 21.62±0.2°. The crystal form of the present application has good physical and chemical stability; in particular, the physical and chemical stability of the crystal form of the present application is significantly better than that of other crystal forms.

Description

Technical Field

[0001] This application belongs to the field of biopharmaceutical technology, specifically relating to a crystal form of 2-(3-methoxyphenylethyl)phenol and its uses. Background Technology

[0002] 2-(3-Methoxyphenylethyl)phenol is a key raw material for the synthesis of saxagrel ester. Currently, commercially available 2-(3-Methoxyphenylethyl)phenol is prone to melting and clumping during transportation in hot summer weather, requiring low-temperature transportation and cold storage, which greatly increases production and transportation costs.

[0003] Therefore, it is necessary to develop a 2-(3-methoxyphenylethyl)phenol with better crystal stability. Summary of the Invention

[0004] This application aims to at least partially address one of the technical problems existing in the prior art. To this end, this application provides a crystal form of 2-(3-methoxyphenylethyl)phenol.

[0005] In a first aspect of this application, a crystal form of 2-(3-methoxyphenylethyl)phenol is provided. According to embodiments of this application, the X-ray powder diffraction pattern of the crystal form has diffraction peaks at a 2θ angle including: 9.21±0.2°, 17.53±0.2°, 18.53±0.2°, and 21.62±0.2°.

[0006] According to embodiments of this application, the above-mentioned crystal form may further include at least one of the following technical features: In an optional embodiment of this application, the X-ray powder diffraction pattern of the crystal form has diffraction peaks at a 2θ angle including: 9.21±0.2°, 14.09±0.2°, 14.32±0.2°, 15.30±0.2°, 17.53±0.2°, 18.53±0.2°, 19.99±0.2°, and 21.62±0.2°.

[0007] In an optional embodiment of this application, the X-ray powder diffraction pattern of the crystal form has diffraction peaks at a 2θ angle including: 9.21±0.2°, 14.09±0.2°, 14.32±0.2°, 15.30±0.2°, 15.97±0.2°, 17.53±0.2°, 18.53±0.2°, 19.99±0.2°, 21.44±0.2°, 21.62±0.2°, 23.92±0.2°, and 24.18±0.2°.

[0008] In an optional embodiment of this application, the X-ray powder diffraction pattern of the crystal form shows diffraction peaks at a 2θ angle including: 9.21±0.2°, 10.63±0.2°, 11.58±0.2°, 14.09±0.2°, 14.32±0.2°, 15.30±0.2°, 15.97±0.2°, 17.53±0.2°, 17 0.90±0.2°, 18.53±0.2°, 19.99±0.2°, 20.73±0.2°, 21.44±0.2°, 21.62±0.2°, 22.28±0.2°, 22.66±0.2°, 23.13±0.2°, 23.92±0.2°, 24.18±0.2° and 28.99±0.2°.

[0009] In one optional embodiment of this application, the crystal form loses 0.062% of its weight when heated to between 45.75°C and 3°C.

[0010] In an optional embodiment of this application, the crystal form contains an endothermic peak at 45.75±3℃.

[0011] In an optional embodiment of this application, the crystal form has the following characteristics: Figure 3 The X-ray powder diffraction pattern shown.

[0012] In an optional embodiment of this application, the crystal form has the following characteristics: Figure 4 The TGA diagram shown.

[0013] In an optional embodiment of this application, the crystal form has the following characteristics: Figure 4 The DSC diagram shown.

[0014] In a second aspect of this application, a method for preparing the crystal form described in the first aspect is proposed. Specifically, as follows: In one aspect, this application provides a method for preparing the crystal form described in the first aspect. According to an embodiment of this application, the method includes: mixing 2-(3-methoxyphenylethyl)phenol with 1,4-dioxane; and crystallizing the mixture at 20°C to 30°C to obtain the crystal form.

[0015] On the other hand, this application proposes a method for preparing the crystal form described in the first aspect. According to an embodiment of this application, the method includes: mixing 2-(3-methoxyphenylethyl)phenol with a good solvent; and crystallizing the mixture using an antisolvent to obtain the crystal form; wherein the good solvent is selected from at least one of acetonitrile, dichloromethane, and isopropyl acetate; and the antisolvent is selected from at least one of water and n-hexane.

[0016] In one optional embodiment of this application, the good solvent is selected from acetonitrile, and the antisolvent is selected from water.

[0017] In one optional embodiment of this application, the good solvent is selected from dichloromethane or isopropyl acetate, and the antisolvent is selected from n-hexane.

[0018] In one optional embodiment of this application, the volume ratio of the good solvent to the anti-solvent is 1:(4~6).

[0019] In a third aspect of this application, a method for preparing the compound shown in formula (I) is provided. According to an embodiment of this application, the preparation method includes: reacting the crystal form described in the first aspect or the crystal form obtained according to the preparation method described in the second aspect with epichlorohydrin to obtain the compound shown in formula (I); (I).

[0020] In a fourth aspect of this application, the use of the crystal form described in the first aspect or the crystal form obtained according to the preparation method described in the second aspect in the preparation of sargrelate is proposed.

[0021] Beneficial effects: 1. The crystal form B of this application has good physicochemical stability; in particular, compared with other crystal forms, the physical and chemical stability of crystal form B is significantly better; the crystal form B of this application does not need to be stored at low temperature in hot summer weather, and can maintain high yield and output in the industrial production of sargrelate intermediate.

[0022] 2. The crystal form B of this application has high fluidity, which facilitates the industrial production of saxagrel ester intermediate.

[0023] Additional aspects and advantages of this application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of this application. Attached Figure Description

[0024] The above and / or additional aspects and advantages of this application will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which: Figure 1 This is the X-ray powder diffraction pattern of crystal form A in Example 4 of this application; Figure 2 The TGA and DSC diagrams of crystal form A in Example 4 of this application are shown. Figure 3 This is the X-ray powder diffraction pattern of crystal form B in Example 4 of this application; Figure 4 The TGA and DSC diagrams of crystal form B in Example 4 of this application are shown. Figure 5This is the DVS diagram of crystal form B in Example 4 of this application; Figure 6 This is the X-ray powder diffraction pattern of crystal form C in Example 4 of this application; Figure 7 This is the HPLC spectrum of crystal form A in Example 6 of this application after being stored at 35°C for 6 months; Figure 8 This is the HPLC spectrum of crystal form B in Example 6 of this application after being stored at 35°C for 6 months; Figure 9 The structural formulas of impurities SG-IMP3, SG-IMP4, and SG-IMP7 in Example 6 of this application are shown below; Figure 10 The structural formulas of impurities SG-IMP11, SG-IMP12, and SG-IMP21 in Embodiment 7 of this application are shown below. Figure 11 This is an image of crystal form A in Example 5 of this application; Figure 12 This is an image of crystal form B in Example 5 of this application. Detailed Implementation

[0025] The embodiments of this application are described in detail below. The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application.

[0026] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this application, unless otherwise stated, "multiple" means two or more.

[0027] In this document, the terms “comprising” or “including” are open-ended expressions, meaning that they include the contents specified in this application but do not exclude other contents.

[0028] In this document, the terms “optionally,” “optionally,” or “optionally” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0029] In this document, the term "crystal form" or "crystalline form" refers to a solid having a highly regular chemical structure, and the crystalline form of a substance can be obtained by many methods known in the art. These methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, such as in nanopores or capillaries, crystallization on a surface or template; crystallization, for example on a polymer, in the presence of additives such as co-crystallized antimolecules, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent droplet grinding, etc.

[0030] In this document, the term "solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in the implementation of this application include, but are not limited to, water, acetic acid, ethyl acetate, acetone, acetonitrile, methanol, toluene, isopropanol, tetrahydrofuran, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, xylene, mixtures thereof, etc.

[0031] In this document, the term "antisolvent" refers to a fluid that promotes the precipitation of a product (or product precursor) from a solvent. Antisolvents may include cold gases, fluids that promote precipitation through chemical reactions, or fluids that reduce the solubility of a product in a solvent; they may be the same liquid as the solvent but at a different temperature, or they may be a different liquid from the solvent.

[0032] Crystalline or amorphous forms can be identified using a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0033] X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions of XRPD spectra mainly depend on the structure of the crystal form, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of this application has XRPD spectra with certain peak positions, which are basically as shown in the XRPD spectra provided in the accompanying drawings. Meanwhile, the measurement of 2θ in XRPD spectra can have experimental errors; the measurement of 2θ in XRPD spectra may differ slightly between different instruments and different samples, therefore the value of 2θ cannot be considered absolute.

[0034] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly α-Al₂O₃) as a function of temperature under programmed control by continuously heating or cooling. The height of the endothermic peak in the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the DSC chart of the crystal form described in this application has characteristic peak positions, which are essentially as shown in the DSC chart provided in the accompanying drawings. However, DSC spectra can have experimental errors; the peak positions and peak values ​​of DSC spectra may differ slightly between different instruments and different samples. Therefore, the peak positions or peak values ​​of the endothermic peaks in DSC cannot be considered absolute. Thermogravimetric analysis (TGA) is a technique that measures the mass change of a substance as a function of temperature under programmed control. It is suitable for examining the loss of solvent in crystals or the process of sample sublimation and decomposition, and can infer the presence of water of crystallization or crystallization solvent in the crystal. The mass change shown in the TGA curve depends on many factors such as sample preparation and instrument; the mass change detected by TGA varies slightly between different instruments and different samples. In the context of this application, 2θ values ​​in X-ray powder diffraction patterns are in degrees (°).

[0035] In this document, the term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in an X-ray powder diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum are shown in its figure.

[0036] In the context of this application, when the words “approximately” or “about” are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, to those skilled in the art, the terms “approximately” or “about” mean within an acceptable standard error of the average. Whenever a number with a value of N is disclosed, any number having a value within N+ / –1%, N+ / –2%, N+ / –3%, N+ / –5%, N+ / –7%, N+ / –8%, or N+ / –10% is explicitly disclosed, where “+ / –” means addition or subtraction.

[0037] This application discloses a crystal form of 2-(3-methoxyphenylethyl)phenol and its uses, which will be described in detail below.

[0038] Crystal forms of 2-(3-methoxyphenylethyl)phenol In a first aspect of this application, a crystal form of 2-(3-methoxyphenylethyl)phenol is provided. According to embodiments of this application, the X-ray powder diffraction pattern of the crystal form has diffraction peaks at a 2θ angle including: 9.21±0.2°, 17.53±0.2°, 18.53±0.2°, and 21.62±0.2°.

[0039] The crystal form of this application exhibits good physicochemical stability; in particular, compared with other crystal forms, the crystal form of this application has significantly better physical and chemical stability.

[0040] According to embodiments of this application, the above-mentioned crystal form may further include at least one of the following technical features: In an optional embodiment of this application, the X-ray powder diffraction pattern of the crystal form shows diffraction peaks at a 2θ angle including: 9.21±0.2°, 14.09±0.2°, 14.32±0.2°, 15.30±0.2°, 17.53±0.2°, 18.53±0.2°, 19.99±0.2°, and 21.62±0.2°. Exemplary reference is made to crystal form B of 2-(3-methoxyphenylethyl)phenol.

[0041] In an optional embodiment of this application, the X-ray powder diffraction pattern of the crystal form shows diffraction peaks at a 2θ angle including: 9.21±0.2°, 14.09±0.2°, 14.32±0.2°, 15.30±0.2°, 15.97±0.2°, 17.53±0.2°, 18.53±0.2°, 19.99±0.2°, 21.44±0.2°, 21.62±0.2°, 23.92±0.2°, and 24.18±0.2°. Exemplary reference is made to crystal form B of 2-(3-methoxyphenylethyl)phenol.

[0042] In an optional embodiment of this application, the X-ray powder diffraction pattern of the crystal form shows diffraction peaks at a 2θ angle including: 9.21±0.2°, 10.63±0.2°, 11.58±0.2°, 14.09±0.2°, 14.32±0.2°, 15.30±0.2°, 15.97±0.2°, 17.53±0.2°, 17 0.90±0.2°, 18.53±0.2°, 19.99±0.2°, 20.73±0.2°, 21.44±0.2°, 21.62±0.2°, 22.28±0.2°, 22.66±0.2°, 23.13±0.2°, 23.92±0.2°, 24.18±0.2°, and 28.99±0.2°. Exemplary reference is made to crystal form B of 2-(3-methoxyphenylethyl)phenol.

[0043] In one alternative embodiment of this application, the crystal form experiences a weight loss of 0.062% when heated to approximately 45.75°C ± 3°C. Exemplary reference is made to crystal form B of 2-(3-methoxyphenylethyl)phenol.

[0044] In an optional embodiment of this application, the crystal form contains an endothermic peak at 45.75 ± 3 °C. Exemplary reference is made to crystal form B of 2-(3-methoxyphenylethyl)phenol.

[0045] In an optional embodiment of this application, the crystal form has substantially the following characteristics: Figure 3 The X-ray powder diffraction pattern shown.

[0046] In an optional embodiment of this application, the crystal form has substantially the following characteristics: Figure 4 The TGA diagram shown.

[0047] In an optional embodiment of this application, the crystal form has substantially the following characteristics: Figure 4 The DSC diagram shown.

[0048] Preparation method of crystalline form of 2-(3-methoxyphenylethyl)phenol In a second aspect of this application, a method for preparing the crystal form described in the first aspect is proposed. Specifically, as follows: In one aspect, this application provides a method for preparing the crystal form described in the first aspect. According to an embodiment of this application, the method includes: mixing 2-(3-methoxyphenylethyl)phenol with 1,4-dioxane; and crystallizing the mixture at 20°C to 30°C to obtain the crystal form.

[0049] The preparation method of this application can prepare the crystal form described in the first aspect. This preparation method is relatively simple and uses relatively green and environmentally friendly solvents. Furthermore, the prepared crystal form has advantages such as good stability and high fluidity, which facilitates the industrial production of sargrelate intermediates.

[0050] On the other hand, this application proposes a method for preparing the crystal form described in the first aspect. According to an embodiment of this application, the method includes: mixing 2-(3-methoxyphenylethyl)phenol with a good solvent; and crystallizing the mixture using an antisolvent to obtain the crystal form; wherein the good solvent is selected from at least one of acetonitrile, dichloromethane, and isopropyl acetate; and the antisolvent is selected from at least one of water and n-hexane.

[0051] The preparation method of this application can prepare the crystal form described in the first aspect. This preparation method is relatively simple and uses relatively green and environmentally friendly solvents. Furthermore, the prepared crystal form has advantages such as good stability and high fluidity, which facilitates the industrial production of sargrelate intermediates.

[0052] In one optional embodiment of this application, the good solvent is selected from acetonitrile, and the antisolvent is selected from water.

[0053] In one optional embodiment of this application, the good solvent is selected from dichloromethane or isopropyl acetate, and the antisolvent is selected from n-hexane.

[0054] In one optional embodiment of this application, the volume ratio of the good solvent to the anti-solvent is 1:(4~6).

[0055] In one optional embodiment of this application, the mass-to-volume ratio of 2-(3-methoxyphenylethyl)phenol to a good solvent is 1:(0.5~2.0) g / mL.

[0056] Preparation method of the compound shown in formula (I) In a third aspect of this application, a method for preparing the compound shown in formula (I) is provided. According to an embodiment of this application, the preparation method includes: reacting the crystal form described in the first aspect or the crystal form obtained according to the preparation method described in the second aspect with epichlorohydrin to obtain the compound shown in formula (I); (I).

[0057] As is known from the foregoing, the crystal form described in the first aspect of this application has the advantages of good stability and high fluidity, which facilitates the industrial production of the compound shown in formula (I) (i.e., saxagrel ester intermediate), and the compound shown in formula (I) prepared has few impurities and a high yield.

[0058] use In a fourth aspect of this application, the use of the crystal form described in the first aspect or the crystal form obtained according to the preparation method described in the second aspect in the preparation of sargrelate is proposed.

[0059] As previously known, the crystal form described in the first aspect of this application has advantages such as good stability and high fluidity, which facilitates the industrial production of the compound shown in formula (I) (i.e., the sarpogrelate intermediate), and the compound shown in formula (I) obtained has few impurities and a high yield. Therefore, sarpogrelate can be prepared using the above crystal form, and the sarpogrelate obtained has few impurities and a high yield.

[0060] The following will explain the solution of this application with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of this application. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0061] Example 1: Preparation of 2-(3-methoxyphenylethyl)phenol solid 10 g of 2-(2-hydroxy-2-(3-methoxyphenyl)vinyl)phenol, 0.4 g of 10% palladium on carbon, and 80 mL of anhydrous ethanol were mixed and hydrogenated at 50 °C under normal pressure for 16 hours. The mixture was filtered, and the filter cake was washed with ethanol. After drying the filtrate, an oily liquid of 2-(3-methoxyphenylethyl)phenol was obtained. A certain amount of the oily liquid of 2-(3-methoxyphenylethyl)phenol was added to isopropyl ether and recrystallized to obtain solid 2-(3-methoxyphenylethyl)phenol. The solid crystal was analyzed by XRD, and the diffraction angle (2θ) of the obtained solid crystal had diffraction peaks at 9.2±0.2°, 9.4±0.2°, 10.6±0.2°, 15.5±0.2°, 17.7±0.2°, 18.7±0.2°, 20.2±0.2°, and 21.8±0.2°. The crystal form was identified as crystal form A.

[0062] In addition, 2-(3-methoxyphenylethyl)phenol was purchased from Hunan Huateng Pharmaceutical Co., Ltd. XRD analysis showed that the obtained solid crystal exhibited diffraction peaks at angles (2θ) of 9.2±0.2°, 9.4±0.2°, 10.6±0.2°, 15.5±0.2°, 17.7±0.2°, 18.7±0.2°, 20.2±0.2°, and 21.8±0.2°, indicating that its crystal form was crystal form A.

[0063] Example 2: Crystal sieve test 1. 25℃ suspension curing method 1. The polymorphism of materials was investigated at 25 °C using the suspension ripening method. The specific experimental steps are as follows: 1) Weigh approximately 200 mg of 2-(3-methoxyphenylethyl)phenol solid (preparation process as described in Example 1) into a small glass vial; 2) Add appropriate volumes of different solvents according to the solubility of the compound in different solvents to form a suspension in the system; 3) Place the obtained suspension system at 25 ℃ and stir overnight; 4) Centrifuge the solid sample and perform XRPD testing. Compare the XRPD results with the starting material XRPD to determine if a new crystal form is formed. Name the new crystal form according to the standard operating procedure (SOP) and characterize it using TGA, DSC, PLM, HPLC, etc.

[0064] The test results for different solvents and their samples are shown in the table below:

[0065] 2. Slow evaporation at 25℃ The polymorphism of the material was investigated using the slow volatilization method at 25 °C. The specific experimental steps are as follows: 1) Weigh approximately 200 mg of 2-(3-methoxyphenylethyl)phenol solid (preparation process as described in Example 1) into a glass bottle; 2) Add appropriate volumes of different solvents according to the solubility of the compound in different solvents, and stir the system at 25 °C to form a clear solution; 3) Filter the solution from the clear solution into another small glass vial and place it in an environment of 25°C (N2) for slow evaporation; 4) After the solid precipitates, centrifuge the sample and perform XRPD testing on the solid sample. Compare the XRPD results with the XRPD of the starting material to determine whether a new crystal form has been generated.

[0066] The test results for different solvents and their samples are shown in the table below:

[0067] 3. Antisolvent addition method The polymorphism of the material was investigated by adding an antisolvent. The specific experimental steps are as follows: 1) Weigh 200 mg of 2-(3-methoxyphenylethyl)phenol solid (preparation process as described in Example 1) into a small vial; 2) Based on the solubility data, add appropriate volumes of different solvents and stir at 25 °C to obtain a clear solution; 3) Slowly drip the clear solution into another small glass vial containing the antisolvent; 4) After the dripping is complete, keep it at 5℃ and stir for 3-5 hours; 5) Centrifuge the system containing the precipitated solid, and perform XRPD testing on the resulting solid sample. Compare the XRPD results with those of the starting material to determine if a new crystal form has been formed.

[0068] The test results for different solvents and their samples are shown in the table below:

[0069] 4. Polymer-induced method The polymorphism of materials was investigated using a polymer-induced method. The specific experimental steps are as follows: 1) Weigh 30 mg of 2-(3-methoxyphenylethyl)phenol solid (preparation process as described in Example 1) into a small bottle of appropriate volume; 2) Add an appropriate volume of solvent based on the solubility data obtained from the test, and stir the system at 25°C to form a clear solution; 3) Filter the clear solution through a syringe and filter into another appropriately sized vial; 4) Add 3mg of polymer and allow it to slowly evaporate at 25℃; 5) After the solvent has evaporated, perform XRD tests on the system of precipitated solids to determine whether a new crystal form has been formed.

[0070] The test results for different solvents and their samples are shown in the table below:

[0071] Example 3: Preparation of 2-(3-methoxyphenylethyl)phenol crystal form B Mix 10 g of 2-(2-hydroxy-2-(3-methoxyphenyl)vinyl)phenol, 0.4 g of 10% palladium on carbon, and 80 mL of anhydrous ethanol, and hydrogenate at 50 °C and atmospheric pressure for 16 hours. Filter, and wash the filter cake with ethanol. After drying the filtrate, an oily liquid of 2-(3-methoxyphenylethyl)phenol was obtained. 200g of the oily liquid was added to 25 mL of 1,4-dioxane for recrystallization to obtain solid 2-(3-methoxyphenylethyl)phenol. The resulting solid crystal was analyzed by XRD, and the diffraction angles (2θ) of the solid crystal showed diffraction peaks at 9.21±0.2°, 14.09±0.2°, 14.32±0.2°, 15.30±0.2°, 17.53±0.2°, 18.53±0.2°, 19.99±0.2°, and 21.62±0.2°. The crystal form was identified as crystal form B.

[0072] Example 4: Crystal form detection 1. X-ray powder diffraction (XRPD) The relevant parameters of the X-ray powder diffraction (XRPD) instrument are shown in the table below:

[0073] 2. Thermogravimetric analysis (TGA) The relevant parameters of the TGA instrument are shown in the table below:

[0074] 3. Differential Scanning Calorimeter (DSC) The relevant parameters of the DSC instrument are shown in the table below:

[0075] 4. Dynamic Vapor Adsorption (DVS) The DVS test was conducted at 25 ℃, relative humidity 50-0-90-0-50 %RH, and dm / dt=0.002 % / min, recording the dynamic water adsorption curve. The relevant parameters of the testing instrument are shown in the table below:

[0076] 5. High Performance Liquid Chromatography (HPLC) Analysis Method The HPLC testing methods and related parameters are shown in the table below:

[0077] 6. Test Results 1) The solid obtained in Example 1 is crystal form A, and its X-ray powder diffraction pattern is as follows. Figure 1 As shown, the TGA & DSC diagrams of crystal form A are as follows: Figure 2 As shown.

[0078] DSC analysis showed that the onset points of this crystal form were 33.56 ℃ and 100.68 ℃, while TGA analysis showed a weight loss of 51.39% before reaching 100 ℃.

[0079] The X-ray powder diffraction peak data of crystal form A are shown in the table below:

[0080] 2) The crystal form obtained by the 25 °C suspension curing method of 1,4-dioxane in Example 2 is crystal form B. The X-ray powder diffraction pattern of crystal form B is shown below. Figure 3 As shown, the TGA & DSC diagrams of crystal form B are as follows: Figure 4 As shown, the DVS diagram of crystal form B is as follows: Figure 5 As shown.

[0081] DSC showed that the onset point of this crystal form was 45.75 ℃, and TGA results showed that the weight loss was 0.062% before 45.75 ℃.

[0082] Crystal form B has low hygroscopicity, with a maximum hygroscopicity of 0.015% as shown by DVS. The crystal form did not change before and after the DVS test. XRD showed that the material has good crystallinity. HPLC test showed that the sample purity was 100%.

[0083] The X-ray powder diffraction peak data of crystal form B are shown in the table below:

[0084] 3) The X-ray powder diffraction pattern of crystalline C obtained by slow volatilization at 25 °C in Example 2 is shown below. Figure 6 As shown.

[0085] XRPD showed that crystal form C had poor crystallinity, and DSC showed that the onset point of this crystal form was 51.95 ℃. Although the onset point of this crystal form was higher, crystal form C easily transformed into crystal form A under high humidity conditions of 25 ℃ and 75% RH, which is not conducive to industrial storage and production. Therefore, this crystal form was not further investigated.

[0086] The X-ray powder diffraction peak data of crystal form C are shown in the table below:

[0087] Example 5: Flowability of Crystal Form A and Crystal Form B The flowability of crystal form A prepared in Example 1 and crystal form B prepared in Example 3 were tested. The specific steps are as follows: (1) Bulk density test: Select a standard graduated cylinder (100 mL), clean and dry it, weigh the empty graduated cylinder, slowly pour the powder into the graduated cylinder, avoid piling it too full or creating gaps, weigh the initial mass of graduated cylinder + powder, read the volume of powder, and calculate the bulk density of powder.

[0088] (2) Tap density test: Fix the measuring cylinder on the tap density meter, set the vibration parameters (frequency 250±1 times / minute, amplitude about 3±0.2 mm, vibration times 500 times, volume no longer significantly reduced after 1250), record the volume data, and calculate the tap density of the powder.

[0089] Hausnerby HR = tapped density / loose density.

[0090] Flowability = (tap density - loose density) / tap density × 100%, experimental data are shown in the table below.

[0091]

[0092] Crystal form B has excellent fluidity, making it suitable for industrial production.

[0093] Example 6: Stability of different crystal forms at 25°C and 35°C The crystal forms prepared in the above examples were placed at high temperatures of 25°C and 35°C for 6 months, and the physicochemical stability of the samples was investigated by HPLC and XRPD. The results of the stability study are shown in the table below, and the structural formulas of impurities SG-IMP3, SG-IMP4, and SG-IMP7 are shown in the table below. Figure 9 The HPLC spectrum of crystal form A after storage at 35℃ for 6 months is shown below. Figure 7 As shown, the HPLC spectrum of crystal form B after storage at 35℃ for 6 months is as follows. Figure 8 As shown.

[0094] Stability study results (stored at 25°C for 6 months):

[0095] Stability study results (stored at 35°C for 6 months):

[0096] Example 7: Preparation of saxagrel ester intermediates by various crystal forms

[0097] Synthesis process: Weigh and sequentially add 117.90 kg of ACN and 25.00 kg of SG-SM1 (crystal form A and crystal form B, respectively, after being stored at 35℃ for 6 months) to a 300 L reactor. Stir for 10 min, maintaining the system temperature at 20℃. Weigh 5.83 kg of NaOH and add it to the system, stirring for 30 min. Weigh 60.79 kg of SG-SM2 and add it to the reaction system. Heat to 60℃ until SM1 reacts completely. Cool to 20℃, filter, wash the filter cake with 20 kg of ethyl acetate, combine the filtrates, and concentrate at 50℃ until no obvious droplets fall. After concentration, add 175.00 kg of drinking water and 112.5 kg of EA to the system, stir, let stand, separate the liquids, add 90.00 kg of EA to the aqueous phase, stir, let stand, separate the liquids, combine the organic phases, and concentrate under reduced pressure at 60℃ to obtain SG-1. The purity of the reaction was analyzed using the following method: 1) Chromatographic conditions: Column: Agilent Eclipse XDB-C18 4.6mm×150mm, 5μm or equivalent column; Capture column: Welch Ghost-Buster Column 4.6mm×50mm; Column temperature: 30℃; Sample inlet temperature: 4℃; Detection wavelength: 220nm; Flow rate: 1.0 mL / min; Injection volume: 5 μl; Mobile phase: Mobile phase A: Weigh 2.28 g of dipotassium hydrogen phosphate and dissolve it in 1 L of water. Add 0.5 mL of triethylamine and adjust the pH to 6.50 with phosphoric acid. Mobile phase B: Acetonitrile; Diluent: Acetonitrile-water (50:50); Perform gradient elution according to the table below:

[0098] 2) Solution preparation Blank (diluent): Acetonitrile-water (50:50).

[0099] SG-1 test solution: Accurately weigh approximately 10 mg of the test sample, place it in a 25 mL volumetric flask, add diluent to dissolve and dilute to the mark. (Prepare three portions using the same method) 3) Sample introduction sequence At least one blank injection and three injections of the test solution.

[0100] The structural formulas of impurities SG-IMP11, SG-IMP12, and SG-IMP21 are shown in [reference needed]. Figure 10 The purity, yield, and impurities of the sargrelate intermediates prepared from each crystal form are shown in the table below:

[0101] The results showed that crystal form A easily generates specific impurities (RT≈1.03) and specific impurities (RT≈1.17) during high-temperature storage at 35℃. The sarpogrelate intermediate prepared from crystal form A will produce specific impurities (RT=12.00). The preparation of sarpogrelate from this intermediate requires an additional impurity removal step, and the removal of these impurities is quite difficult. However, compared to crystal form A, crystal form B, due to the absence of specific impurities (RT≈1.03) and specific impurities (RT≈1.17), results in fewer impurities, higher purity, and higher yield during the preparation of SG-2 from crystal form B.

[0102] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0103] Although embodiments of this application have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting this application. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of this application.

Claims

1. A crystal form of 2-(3-methoxyphenylethyl)phenol, characterized in that, The X-ray powder diffraction pattern of the crystal form includes the following diffraction peaks at the 2θ angle: 9.21±0.2°, 10.63±0.2°, 11.58±0.2°, 14.09±0.2°, 14.32±0.2°, 15.30±0.2°, 15.97±0.2°, 17.53±0.2°, 17.90±0.2°, 18.53±0.2°, 19.99±0.2°, 20.73±0.2°, 21.44±0.2°, 21.62±0.2°, 22.28±0.2°, 22.66±0.2°, 23.13±0.2°, 23.92±0.2°, 24.18±0.2° and 28.99±0.2°.

2. The crystal form according to claim 1, characterized in that, The crystal form satisfies one or more of the following conditions: a) The crystal form exhibits a weight loss of 0.062% when heated to 45.75℃±3℃; b) The crystal form contains an endothermic peak at 45.75±3℃.

3. The crystal form according to claim 1, characterized in that, The crystal form satisfies one or more of the following conditions: a) The crystal form has the X-ray powder diffraction pattern shown in Figure 3; b) The crystal form has a TGA diagram as shown in Figure 4; c) The crystal form has a DSC diagram as shown in Figure 4.

4. A method for preparing the crystal form according to any one of claims 1 to 3, characterized in that, include: 2-(3-methoxyphenylethyl)phenol was mixed with 1,4-dioxane; The mixed product is crystallized at 20°C to 30°C to obtain the crystal form.

5. A method for preparing the crystal form according to any one of claims 1 to 3, characterized in that, include: 2-(3-methoxyphenylethyl)phenol was mixed with a good solvent; The mixed product is subjected to crystallization treatment using an anti-solvent in order to obtain the crystal form described above; The good solvent is selected from at least one of acetonitrile, dichloromethane, and isopropyl acetate; The antisolvent is selected from at least one of water and n-hexane.

6. The preparation method according to claim 5, characterized in that, The good solvent is selected from acetonitrile, and the antisolvent is selected from water; or The good solvent is selected from dichloromethane or isopropyl acetate, and the antisolvent is selected from n-hexane.

7. The preparation method according to claim 6, characterized in that, The volume ratio of the good solvent to the anti-solvent is 1:(4~6).

8. A method for preparing a compound of formula (I), characterized in that, include: The crystal form according to any one of claims 1 to 3 or the crystal form obtained by the preparation method according to any one of claims 4 to 7 is reacted with epichlorohydrin to obtain the compound shown in formula (I); (I)。 9. Use of the crystal form according to any one of claims 1 to 3 or the crystal form obtained by the preparation method according to any one of claims 4 to 7 in the preparation of saxagrel ester.

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