Solid form of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one and preparation method therefor

Abstract

The present application relates to a crystal form of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one, a preparation method therefor, a composition containing the crystal form and the use thereof in the treatment of phosphodiesterase-related diseases.

Description

Solid form of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one and method for its preparation

[0001] This application claims priority to Chinese application CN202410353935.1 filed on March 26, 2024 and Chinese application CN202510315617.0 filed on March 17, 2025. Field of the Invention

[0002] The present invention relates to a solid form of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (hereinafter referred to as "Compound A") and / or its tautomers, a method for preparing the solid form, a pharmaceutical composition containing the solid form, and use of the solid form for preventing and / or treating phosphodiesterase-related diseases.

[0003] Background of the Invention

[0004] Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease of the respiratory system characterized by persistent respiratory inflammatory symptoms and airflow limitation due to airway and / or alveolar abnormalities, often related to exposure to toxic particles and gases. Common symptoms of COPD include dyspnea, cough, and sputum production. In 2015, an estimated 3.17 million people died from COPD worldwide, accounting for 5% of all deaths worldwide that year. In 2016, there were 251 million cases of COPD worldwide. By 2030, COPD is projected to become the third leading cause of death worldwide. First-line treatments for COPD primarily include various bronchodilators, including short-acting and long-acting β2-agonists, short-acting and long-acting anticholinergics, combinations of β2-agonists and anticholinergics, oral methylxanthines and roflumilast, and combinations of glucocorticoids and long-acting β2-agonists. However, there is no clinical evidence that existing drug therapies can mitigate the long-term decline in lung function in COPD patients. Therefore, as a chronic inflammatory disease, effective anti-inflammatory treatment for COPD patients should slow down the progression and exacerbation of the disease and reduce mortality and the occurrence of COPD-related complications.

[0005] Cyclic adenosine monophosphate (cAMP) is an important second messenger in cells. It mainly participates in physiological activities such as visual conduction, cell proliferation and differentiation, gene expression, inflammatory response, cell apoptosis and metabolism by activating the PKA pathway. The increase of intracellular cAMP levels can regulate a variety of inflammatory mediators, thereby achieving a broad-spectrum anti-inflammatory effect. The balance of cAMP in the body is mainly regulated by adenylate cyclase (CA) and phosphodiesterase (PDE). CA catalyzes the synthesis of cAMP from ATP, and PDE promotes the degradation of cAMP into inactive 5 ’Therefore, targeted inhibition of PDE activity can increase the level of intracellular cAMP, thereby achieving a broad-spectrum anti-inflammatory effect, among which PDE4 is the most important cAMP degrading enzyme.

[0006] Roflumilast is the first selective PDE4 inhibitor for the treatment of COPD. Initially, it was developed by Nycomed and approved in Europe and Canada in 2010 for the adjuvant treatment of patients with severe chronic obstructive pulmonary disease who are frequently exacerbated. However, due to dose-dependent side effects, such as nausea, vomiting and other gastrointestinal adverse reactions, their severity is sufficient to reduce their compliance. More and more evidence shows that PDE4 inhibitors have greatly limited the widespread clinical use of this type of drug due to adverse reactions such as nausea and vomiting caused by acting on PDE4 in the central nervous system (see CN202210096345.6, which is incorporated herein by reference in its entirety).

[0007] SUMMARY OF THE INVENTION

[0008] In one aspect, the present invention provides Compound A (4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one) as shown below, which undergoes tautomerism at a certain temperature. The present invention relates to a solid form of Compound A and / or its tautomers:

[0009] In another aspect, the present invention provides crystalline forms of Compound A (4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one) (and / or its tautomers), including Form I and Form II, wherein Compound A is an anhydrate.

[0010] In another aspect, the present invention provides a method for preparing crystalline forms of Compound A (and / or its tautomers) of the present invention, including Form I and Form II.

[0011] In another aspect, the present invention provides a pharmaceutical composition comprising any one or more crystalline forms of Compound A (and / or its tautomers) of the present invention (e.g., Form I and Form II), and one or more pharmaceutically acceptable carriers or excipients.

[0012] In another aspect, the present invention provides use of a crystalline form (eg, Form I and Form II) of Compound A (and / or its tautomers) of the present invention in the preparation of a medicament for preventing and / or treating phosphodiesterase-related diseases.

[0013] The crystalline form of Compound A (and / or its tautomers) of the present invention not only has excellent effects in preventing and / or treating phosphodiesterase-related diseases, but also has other advantages. For example, the crystalline form of Compound A (and / or its tautomers) of the present invention has excellent physical properties (including solubility, dissolution rate, light resistance, low hygroscopicity, high temperature resistance, high humidity resistance, fluidity, etc.), and in properties such as bioavailability, physical and / or chemical stability and ease of preparation, the crystalline form of Compound A (and / or its tautomers) of the present invention has more excellent properties. The crystalline form of Compound A (and / or its tautomers) of the present invention has good powder properties, is more suitable and convenient for large-scale production and for forming preparations, can reduce irritation and improve absorption, solves the problem of metabolic rate, significantly reduces the toxicity caused by drug accumulation, improves safety, and effectively guarantees the quality and efficacy of the drug product. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG1 is an X-ray powder diffraction pattern of Form I of anhydrate of Compound A.

[0015] FIG2 is a differential scanning calorimetry (DSC) spectrum and a thermogravimetric analysis (TGA) spectrum of Form I of anhydrate of Compound A.

[0016] FIG3 is a scanning electron micrograph of Form I of anhydrate of Compound A.

[0017] FIG4 is an X-ray powder diffraction pattern of Form II of anhydrate of Compound A.

[0018] FIG5 is a differential scanning calorimetry (DSC) spectrum and a thermogravimetric analysis (TGA) spectrum of Form II of anhydrate of Compound A.

[0019] FIG6 is a scanning electron micrograph of Form II of anhydrate of Compound A.

[0020] FIG7 is a comparison of XRPD patterns of Form I of anhydrate of Compound A before and after the room temperature stability test.

[0021] FIG8 is a comparison of XRPD patterns of the anhydrate crystalline form I of compound A in the water activity experiment.

[0022] FIG9 is a comparison of HPLC spectra of Form I of anhydrate of Compound A before and after the solid stability experiment.

[0023] FIG10 is a comparison of HPLC spectra of Form II of anhydrate of Compound A before and after the solid stability experiment.

[0024] FIG11 is a comparison of X-ray powder diffraction patterns of Form I and Form II of anhydrate of Compound A before and after the solid stability experiment.

[0025] FIG12 is a comparison of X-ray powder diffraction patterns of Form I of anhydrate of Compound A before and after the high humidity stability test.

[0026] FIG13 is a comparison of X-ray powder diffraction patterns of Form I of Compound A anhydrate before and after the physical grinding experiment.

[0027] FIG14 is a scanning electron micrograph of Form I of anhydrate of Compound A before and after the physical grinding experiment.

[0028] FIG15 is an XRPD pattern of samples obtained by competitive beating of Form I and Form II of Compound A anhydrate.

[0029] Figure 16 is the XRPD patterns of the samples obtained by competitive beating of Form I and Form II of Compound A anhydrate at 50°C.

[0030] FIG17 is an XRPD pattern of the samples obtained by competitive beating of Form I and Form II of Compound A anhydrate at room temperature.

[0031] Figure 18 is the XRPD patterns of the samples obtained by competitive beating of Form I and Form II of Compound A anhydrate at 30-40°C.

[0032] FIG19 is a scanning electron micrograph of a micronized sample of Form I of Compound A anhydrate.

[0033] FIG20 is a scanning electron micrograph of a micronized sample of Form II of Compound A anhydrate.

[0034] FIG21 is a scanning electron micrograph of a suspension prepared using a micronized sample of Form I of Compound A anhydrate after standing at room temperature for 15 days.

[0035] FIG22 is a scanning electron micrograph of a suspension prepared using a micronized sample of Form II of anhydrate of Compound A after standing at room temperature for 15 days.

[0036] FIG23 is an X-ray powder diffraction pattern of compound A obtained by medium-pressure column chromatography.

[0037] FIG24 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of compound A obtained by medium-pressure column chromatography.

[0038] Detailed Description of the Invention

[0039] definition

[0040] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0041] As used herein, the terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0042] As used herein, the term "about" means within an acceptable standard error of the stated value considered by one of ordinary skill in the art, e.g., ±0.05, ±0.1, ±0.2, ±0.3, ±1, ±2, or ±3, etc.

[0043] The term "solid form" used in the present invention includes all solid forms of Compound A or any hydrate thereof, such as crystalline forms or amorphous forms.

[0044] As used herein, the term "amorphous" refers to any solid material that is not ordered in three dimensions. In some cases, amorphous solids can be characterized by known techniques including XRPD crystallography, solid-state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques. As described below, amorphous solids produce diffuse X-ray powder diffraction patterns (XRPD patterns) that typically include one or two broad peaks (i.e., peaks with a base width of about 5° 2θ or greater).

[0045] As used herein, the term "crystalline form," "crystal form," or "crystal" refers to any solid material that exhibits a three-dimensional ordering, as opposed to amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.

[0046] As used herein, the term "X-ray powder diffraction pattern (XRPD pattern)" refers to an experimentally observed diffraction pattern or parameters derived therefrom. An XRPD pattern is typically characterized by peak positions (abscissa) and / or peak intensities (ordinate).

[0047] As used herein, the term "2θ" refers to the peak position expressed in degrees based on the experimental setup of an X-ray diffraction experiment, and is typically the unit of the abscissa in a diffraction pattern. If the reflection is diffracted when the incident beam forms an angle θ with a certain lattice plane, the experimental setup requires recording the reflected beam at an angle of 2θ. It should be understood that the specific 2θ values ​​for a particular crystalline form mentioned herein are intended to represent the 2θ values ​​(expressed in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, using Cu-Kα ( 1.540598 and 1.544426) as the radiation source.

[0048] As used herein, "1%" means peak intensity percentage.

[0049] As used herein, the term "differential scanning calorimetry (DSC) spectrum" refers to a curve recorded by a differential scanning calorimeter. Unless otherwise specified, the temperature mentioned when describing a characteristic peak in a DSC spectrum refers to the onset temperature of the peak.

[0050] The term "thermogravimetric analysis (TGA) spectrum" as used herein refers to a curve recorded by a thermogravimetric analyzer.

[0051] As used herein, the term "substantially the same" for X-ray diffraction peak positions means that representative peak position and intensity variations are taken into account. For example, one skilled in the art will understand that peak positions (2θ) will show some variation, typically up to ±0.1, ±0.2, or ±0.3 degrees, and that the instrument used to measure diffraction will also show some variation. In addition, one skilled in the art will understand that relative peak intensities will show variation between instruments as well as variation due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to one skilled in the art. Similarly, as used herein, "substantially the same" for DSC spectra is also intended to encompass variations associated with these analytical techniques known to one skilled in the art. For example, for well-defined peaks, there will typically be variations of up to ±0.3°C in differential scanning calorimetry spectra, and even greater (e.g., up to ±1°C) for broad peaks.

[0052] The liquid-state NMR spectra in this application were preferably collected on a Bruker 400M NMR spectrometer, using DMSO-d6 as the solvent unless otherwise stated.

[0053] The polarizing microscopy data in this application are preferably collected by Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN).

[0054] As used herein, numerical ranges (e.g., "1-10," "1-6," "2-10," "2-6," "3-10," "5-10," "3-6") and the like encompass any number (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) in the stated numerical range.

[0055] The prepared salt or its crystalline form can be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration or any other technique for solid recovery under pressure or under reduced pressure. The recovered solid can be optionally dried. "Drying" in the present invention is carried out under reduced pressure (preferably vacuum) until the content of residual solvent is reduced to within the limits given by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. The residual solvent content depends on the type of solvent, but does not exceed about 5000 ppm, or preferably about 4000 ppm, or more preferably about 3000 ppm. The drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, etc. The drying can be carried out at a temperature of less than about 100° C., less than about 80° C., less than about 60° C., less than about 50° C., less than about 30° C., or any other suitable temperature, at atmospheric pressure or reduced pressure (preferably vacuum) for any desired time (such as about 1, 2, 3, 5, 10, 15, 20, 24 hours or overnight) that can achieve the desired result, as long as the quality of the salt does not deteriorate. The drying can be carried out any desired number of times until the desired product quality is achieved. The dried product can optionally undergo a pulverizing operation to produce the desired particle size. Grinding or micronization can be performed before or after drying of the product. Techniques that can be used to reduce particle size include, but are not limited to, ball milling, roller milling, and hammer milling, as well as jet milling.

[0056] The term "anhydrate" as used herein preferably means a crystalline form which does not contain water molecules as structural elements.

[0057] A "good solvent" is a solvent that has a good solubility for the solute.

[0058] "Anti-solvent" refers to a solvent that is miscible with the solvent but slightly soluble, slightly soluble, extremely slightly soluble, or almost insoluble or insoluble in the solute in a given solution system.

[0059] "Alkanes having 5-10 carbon atoms" refers to straight-chain or branched saturated hydrocarbon groups having 5 to 10 carbon atoms. Preferably, the alkane is an alkane containing 5-8 carbon atoms. Preferably, the alkane is selected from n-pentane, n-hexane, n-heptane and n-octane.

[0060] "Olefins having 5-10 carbon atoms" refers to straight-chain or branched hydrocarbon groups having 5 to 10 carbon atoms and at least one carbon-carbon double bond.

[0061] "Alkynes having 5-10 carbon atoms" refers to straight or branched chain hydrocarbon groups having 5 to 10 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds.

[0062] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0063] Thus, a "halogenated alkane having 5-10 carbon atoms" refers to the aforementioned "alkanes having 5-10 carbon atoms" substituted with one or more halogen groups. An "aromatic hydrocarbon having 6-10 carbon atoms" refers to a group having a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 "aryl"; for example, naphthyl, e.g., 1-naphthyl and 2-naphthyl).

[0064] "Ether having 2 to 10 carbon atoms" refers to a chain or cyclic compound of the formula RO-R' having 2 to 10 carbon atoms, wherein R and R' each represent C 1-6 Alkyl and C 1-6 One or more (e.g., 1, 2, 3, or 4) carbon atoms in the alkyl group are optionally replaced by oxygen atoms, or R and R' together with the oxygen atom to which they are attached form a 3-8 membered cyclic ether, which optionally contains 1-2 oxygen atoms. In one embodiment, the ether is an ether having 3-10 carbon atoms. In one embodiment, the ether is a 3-6 membered cyclic ether containing 1-2 oxygen atoms, preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane. In one embodiment, the ether is a chain ether having 2-6 carbon atoms containing 1-2 oxygen atoms, preferably ethyl ether, propyl ether, butyl ether, diisopropyl ether, and methyl tert-butyl ether, more preferably ethyl ether, diisopropyl ether, and methyl tert-butyl ether.

[0065] "Ketone having 3 to 10 carbon atoms" refers to a chain or cyclic compound of the formula RC(=O)-R' having 3 to 10 carbon atoms, wherein R and R' each represent C1-6 Alkyl and C 1-6 One or more (e.g., 1, 2, 3, or 4) carbon atoms in the alkyl group are optionally replaced by oxygen atoms, or R and R' together with the carbon atoms to which they are attached form a 3-8 membered cyclic ketone. In one embodiment, the ketone is a chain hydrocarbon ketone of 3-6 carbon atoms selected from acetone, butanone, pentanone, and hexanone, preferably selected from acetone and butanone.

[0066] "Esters having 4 to 10 carbon atoms" refers to esters of the formula RC(=O)O-R' having 4 to 10 carbon atoms, wherein R and R' each represent C 1-6 alkyl.

[0067] "Alcohols having 3 to 8 carbon atoms" refers to alcohols of the formula R-OH having 3 to 8 carbon atoms, wherein R represents C 1-6 alkyl.

[0068] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms.

[0069] Crystalline forms and methods of preparing the same

[0070] In one embodiment, the present invention provides a crystalline form I of an anhydrate of Compound A (and / or its tautomers):

[0071] The XRPD pattern of the Form I includes characteristic peaks at diffraction angles (2θ) (°) of approximately 12.6±0.3, 20.3±0.3, 20.9±0.3, 22.0±0.3, and 23.1±0.3.

[0072] In a preferred embodiment, the XRPD pattern of the Form I further includes characteristic peaks at approximately 4.0±0.3, 12.6±0.3, 20.3±0.3, 20.9±0.3, 22.0±0.3, 22.5±0.3, 23.1±0.3, 24.1±0.3, 25.2±0.3 and 26.2±0.3 2θ (°).

[0073] In a more preferred embodiment, the XRPD pattern of Form I further includes characteristic peaks at approximately 4.0±0.3, 8.4±0.3, 11.3±0.3, 12.6±0.3, 15.3±0.3, 16.9±0.3, 20.3±0.3, 20.9±0.3, 22.0±0.3, 22.5±0.3, 23.1±0.3, 24.1±0.3, 25.2±0.3, 26.2±0.3 and 26.7±0.3 2θ (°).

[0074] In a more preferred embodiment, the XRPD pattern of Form I comprises peaks at about the following 2θ (°) positions: 4.0±0.3, 8.4±0.3, 11.3±0.3, 11.9±0.3, 12.6±0.3, 14.0±0.3, 15.3±0.3, 16.9±0.3, 18.3±0.3, 18.9±0.3, 19.9±0.3, 20.3±0.3, 20.9±0.3, 21.2±0.3 , 22.0±0.3, 22.5±0.3, 23.1±0.3, 24.1±0.3, 24.7±0.3, 25.2±0.3, 25.8±0.3, 26.2±0.3, 26.7±0.3, 27.9±0.3, 29.1±0.3, 29.5±0.3, 29.8±0.3, 30.4±0.3, 31.3±0.3, 31.6±0.3, 38.2±0.3 and 40.3±0.3.

[0075] In the most preferred embodiment, the XRPD pattern of the crystalline Form I comprises peaks at the following diffraction angles (2θ):

[0076] In a more preferred embodiment, the XRPD pattern of the Form I comprises peaks at diffraction angles (2θ) substantially the same as those shown in Figure 1. In a most preferred embodiment, the Form I has an XRPD pattern substantially the same as that shown in Figure 1.

[0077] In a more preferred embodiment, the differential scanning calorimetry (DSC) spectrum of the crystalline form I includes larger endothermic peaks at approximately 96±3°C and 129±3°C, preferably smaller endothermic peaks at 113±3°C, 118±3°C and 124±3°C, and there are multiple thermal events in the DSC.

[0078] In a more preferred embodiment, in thermogravimetric analysis (TGA), the crystalline Form I does not lose significant weight before being heated to the melting point.

[0079] In a more preferred embodiment, the DSC-TGA spectrum of the crystalline form I includes characteristic peaks substantially the same as those shown in Figure 2. In the most preferred embodiment, the crystalline form I has a DSC-TGA spectrum substantially the same as that shown in Figure 2. The DSC-TGA spectrum of the crystalline form I shows that the crystalline form I is an anhydrous crystalline form and that the compound has complex crystal transformation behavior under heating conditions. In addition, H NMR spectroscopy analysis was performed on the crystalline form I at room temperature and 50°C. The chemical shifts of the H NMR spectrum of the sample are different under high temperature and room temperature conditions, which may be due to tautomerism; indicating that the compound may have tautomeric polymorphs.

[0080] In a more preferred embodiment, the scanning electron microscope photograph of Form I is substantially the same as that shown in FIG3 .

[0081] In some embodiments, the present invention provides a method for preparing Form I, comprising the following steps:

[0082] 1) adding 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers) to a good solvent to obtain a solution;

[0083] 2) adding an anti-solvent to the solution obtained in step 1), and stirring to obtain the crystalline form.

[0084] More specifically, the present invention provides a method for preparing Form I, comprising the following steps:

[0085] 1) adding compound A (4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one) (and / or its tautomers) to a good solvent, stirring to dissolve compound A to obtain a solution, and optionally filtering the solution to obtain a filtrate;

[0086] 2) adding an antisolvent to the solution or filtrate obtained in step 1), collecting the precipitated solid by filtration, and optionally drying it to obtain Form I.

[0087] In some embodiments, the present invention provides a method for preparing Form I, comprising the following steps: adding 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers) to an anti-solvent to obtain a suspension, and stirring to obtain the Form I.

[0088] In some embodiments, the present invention provides a method for preparing Form I, comprising dissolving Compound A (and / or its tautomers) in a good solvent (which can be carried out at room temperature or under heating conditions (e.g., heating to 30-70° C., preferably 50° C.)) to form a solution (the mixture can be filtered to obtain a solution as needed). An antisolvent is then added to the solution, and a solid is precipitated under stirring (the addition of the antisolvent and stirring can be carried out at room temperature or under cooling conditions (e.g., cooling to 0-10° C., preferably 5° C.)), which is then filtered to obtain crystals.

[0089] In some embodiments, the good solvent is an ether having 3-10 carbon atoms, preferably a cyclic ether, such as furans (including tetrahydrofurans) and dioxanes, preferably tetrahydrofuran, 2-methyltetrahydrofuran or dioxane. Alternatively, the good solvent is a simple ketone with 3-10 carbon atoms, preferably an acyclic ketone, such as acetone or butanone; the anti-solvent is a hydrocarbon with 5-10 carbon atoms (including alkanes with 5-10 carbon atoms, halogenated alkanes with 5-10 carbon atoms, alkenes with 5-10 carbon atoms, alkynes with 5-10 carbon atoms, and aromatic hydrocarbons, specifically including but not limited to n-hexane, n-heptane, and toluene), an ether with 2-6 carbon atoms (preferably a chain ether, such as diethyl ether, diisopropyl ether, or methyl tert-butyl ether), an ester with 4-10 carbon atoms (preferably ethyl acetate or isopropyl acetate), an alcohol with 3-8 carbon atoms (preferably isopropanol), and water. Preferably, the anti-solvent is a chain ether with 2-6 carbon atoms containing 1-2 oxygen atoms. More preferably, the anti-solvent is an alkane containing 5-8 carbon atoms, preferably n-heptane.

[0090] In some embodiments, in the method for preparing Form I, the weight-to-volume ratio (g / mL) of Compound A (and / or its tautomers) and good solvent is about 1:(1-50), preferably about 1:(5-30), preferably 1:10 or 1:30; more preferably 1:(5-10); preferably 1:5, 1:6, 1:7, 1:8 or 1:9.

[0091] In some embodiments, in the method for preparing Form I, the volume ratio of the good solvent to the anti-solvent is about 1:1 to 1:10, preferably 1:3.

[0092] In another embodiment, the present invention provides Form II of an anhydrate of Compound A (and / or its tautomers):

[0093] The XRPD pattern of Form II includes characteristic peaks at approximately 12.5±0.3, 17.3±0.3, 20.6±0.3, and 23.2±0.3 2θ (°).

[0094] In a preferred embodiment, the XRPD pattern of Form II further comprises characteristic peaks at approximately 4.1±0.3, 8.3±0.3, 12.5±0.3, 17.3±0.3, 20.6±0.3, 21.0±0.3, 23.2±0.3, 23.5±0.3 and 26.5±0.3 2θ (°).

[0095] In a more preferred embodiment, the XRPD pattern of Form II further includes characteristic peaks at approximately 4.1±0.3, 8.3±0.3, 10.9±0.3, 12.5±0.3, 17.3±0.3, 19.0±0.3, 19.5±0.3, 20.6±0.3, 21.0±0.3, 23.2±0.3, 23.5±0.3, and 26.5±0.3 2θ (°).

[0096] In a more preferred embodiment, the XRPD pattern of Form II comprises peaks at approximately the following 2θ (°) positions: 4.1±0.3, 8.3±0.3, 10.9±0.3, 11.5±0.3, 12.0±0.3, 12.5±0.3, 13.4±0.3, 16.1±0.3, 16.7±0.3, 17.3±0.3, 19.0±0.3, 19. 5±0.3, 20.6±0.3, 21.0±0.3, 21.3±0.3, 21.5±0.3, 22.1±0.3, 23.2±0.3, 23.5±0.3, 24.4±0.3, 24.6±0.3, 25.4±0.3, 25.7±0.3, 26.5±0.3, 27.7±0.3, 28.2±0.3 and 29.7±0.3.

[0097] In the most preferred embodiment, the XRPD pattern of Form II comprises peaks at the following diffraction angles (2θ):

[0098] In a more preferred embodiment, the XRPD pattern of the Form II includes peaks at diffraction angles (2θ) substantially the same as those shown in Figure 4. In a most preferred embodiment, the Form II has an XRPD pattern substantially the same as that shown in Figure 4.

[0099] In a more preferred embodiment, the differential scanning calorimetry (DSC) spectrum of the Form II includes endothermic peaks at about 108±3°C and 128±3°C, and an exothermic peak at about 270±3°C. In a more preferred embodiment, in thermogravimetric analysis (TGA), the Form II does not show significant weight loss before being heated to the melting point.

[0100] In a more preferred embodiment, the DSC-TGA spectrum of the crystalline Form II includes characteristic peaks substantially the same as those shown in Figure 5. In a most preferred embodiment, the crystalline Form II has a DSC-TGA spectrum substantially the same as that shown in Figure 5.

[0101] In a more preferred embodiment, the scanning electron microscope image of the Form II is substantially the same as that shown in FIG6 .

[0102] In some embodiments, the present invention provides a method for preparing Form II, comprising the following steps:

[0103] Under heating conditions, 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers) or Form I is suspended in a solvent system to obtain the Form II.

[0104] In some embodiments, the present invention provides a method for preparing Form II, comprising the following steps:

[0105] 1) adding 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers) or Form I to a good solvent to obtain a solution;

[0106] 2) adding an antisolvent to the solution obtained in step 1), and stirring at room temperature or under heating conditions to obtain the crystal form II.

[0107] More specifically, in some embodiments, a solvent system is used to convert the anhydrate form I of compound A (and / or its tautomers) into form II under heating conditions (e.g., heating to 30-70°C, preferably 50°C), and the form I is suspended in an anti-solvent system (e.g., for 1-5 days, such as 3 days), and filtered to obtain crystals.

[0108] In some embodiments, the solvent system is a two-solvent system formed by mixing a good solvent and an anti-solvent system.

[0109] The solvent system is a mixture of a good solvent and an anti-solvent system.

[0110] The good solvent is an ether having 3-10 carbon atoms, preferably a cyclic ether, such as furans (including tetrahydrofurans) and dioxanes, preferably tetrahydrofuran, 2-methyltetrahydrofuran or dioxane, or a simple ketone having 3-10 carbon atoms, preferably a non-cyclic ketone, such as acetone or butanone. The anti-solvent is a hydrocarbon with 5-10 carbon atoms (including alkanes with 5-10 carbon atoms, halogenated alkanes with 5-10 carbon atoms, alkenes with 5-10 carbon atoms, alkynes with 5-10 carbon atoms, and aromatic hydrocarbons with 6-10 carbon atoms, specifically including but not limited to n-hexane, n-heptane, and toluene), an ether with 2-6 carbon atoms (preferably a chain ether, such as diethyl ether, diisopropyl ether, or methyl tert-butyl ether), an ester with 4-10 carbon atoms (preferably ethyl acetate or isopropyl acetate), an alcohol with 3-8 carbon atoms (preferably isopropanol), and water. Preferably, the anti-solvent is a chain ether with 2-6 carbon atoms containing 1-2 oxygen atoms. More preferably, the anti-solvent is an alkane containing 5-8 carbon atoms, preferably n-heptane.

[0111] In some embodiments, in the preparation method of Form II, the weight volume ratio (g / mL) of compound A (and / or its tautomers) and good solvent is about 1:(1-50), preferably about 1:(5-30), preferably 1:10 or 1:30; more preferably 1:(5-10); preferably 1:5, 1:6, 1:7, 1:8 or 1:9.

[0112] In some embodiments, in the method for preparing Form II, the volume ratio of the good solvent to the anti-solvent is about 1:1 to 1:10.

[0113] Detailed Description of the Invention

[0114] Specifically, the present invention relates to the following technical solutions.

[0115] In one embodiment, the present invention relates to a crystalline form of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers).

[0116] In a more specific embodiment, the present invention provides Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), which comprises peaks at approximately 12.6±0.3, 20.3±0.3, 20.9±0.3, 22.0±0.3 and 23.1±0.3 2θ (°) in an X-ray powder diffraction (XRPD) pattern obtained using Cu Kα radiation.

[0117] In a more specific embodiment, the present invention provides Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the XRPD pattern further comprises peaks at approximately 4.0±0.3, 22.5±0.3, 24.1±0.3, 25.2±0.3, and 26.2±0.3 2θ (°).

[0118] In a more specific embodiment, the present invention provides Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the XRPD pattern further comprises peaks at approximately 8.4±0.3, 11.3±0.3, 15.3±0.3, 16.9±0.3 and 26.7±0.3 2θ (°).

[0119] In a more specific embodiment, the present invention provides a crystalline Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the XRPD pattern comprises peaks at approximately the following 2θ (°) positions: 4.0±0.3, 8.4±0.3, 11.3±0.3, 11.9±0.3, 12.6±0.3, 14.0±0.3, 15.3±0.3, 16.9±0.3, 18.3±0.3, 18.9±0.3, 19.9±0.3, .3, 20.3±0.3, 20.9±0.3, 21.2±0.3, 22.0±0.3, 22.5±0.3, 23.1±0.3, 24.1±0.3, 24.7±0.3, 25.2±0.3, 25.8±0.3, 26.2±0.3, 26.7±0.3, 27.9±0.3, 29.1±0.3, 29.5±0.3, 29.8±0.3, 30.4±0.3, 31.3±0.3, 31.6±0.3, 38.2±0.3 and 40.3±0.3.

[0120] In a more specific embodiment, the present invention provides Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the XRPD pattern comprises peaks at approximately:

[0121] In a more specific embodiment, the present invention provides Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers) having an XRPD pattern substantially the same as shown in FIG1 .

[0122] In a more specific embodiment, the present invention provides Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), which has endothermic peaks at 96±3°C and 129±3°C in the differential scanning calorimetry (DSC) spectrum.

[0123] In a more specific embodiment, the present invention provides Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), which has a thermogravimetric analysis (TGA) spectrum, wherein the TGA spectrum shows that the crystalline form does not lose significant weight before being heated to the melting point.

[0124] In a more specific embodiment, the present invention provides Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), which has a DSC-TGA spectrum substantially the same as shown in Figure 2.

[0125] In one embodiment, the present invention provides a method for preparing Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), comprising:

[0126] Method 1: includes the following steps:

[0127] 1) adding 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomer) to a good solvent to obtain a solution; and

[0128] 2) adding an anti-solvent to the solution obtained in step 1) and stirring to obtain the crystalline form; or

[0129] Method 2: includes the following steps:

[0130] 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomer) is added to an anti-solvent to obtain a suspension, which is stirred to obtain the crystalline form.

[0131] In a more specific embodiment, step 1) of method 1 or method 2 is carried out at room temperature or under heating conditions, and the heating is heating to 30-70°C, preferably heating to 50°C.

[0132] In a more specific embodiment, the stirring in step 2) of method 1 is carried out at room temperature or under cooling conditions, and the cooling is cooling to 0-10°C, preferably cooling to 5°C.

[0133] In a more specific embodiment, the present invention provides a method for preparing Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the good solvent is selected from an ether solvent having 3 to 10 carbon atoms and a ketone solvent having 3 to 10 carbon atoms.

[0134] In a more specific embodiment, the present invention provides a method for preparing Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the ether solvent is a 3-6 membered cyclic ether containing 1-2 oxygen atoms, preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran and dioxane; wherein the ketone solvent is a chain hydrocarbon ketone of 3-6 carbon atoms, preferably selected from acetone and butanone.

[0135] In a more specific embodiment, the present invention provides a method for preparing Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the anti-solvents in Method 1 and Method 2 are each an alkane having 5-10 carbon atoms, a halogenated alkane having 5-10 carbon atoms, an olefin having 5-10 carbon atoms, an alkyne having 5-10 carbon atoms, an aromatic hydrocarbon having 6-10 carbon atoms, an ether having 2-6 carbon atoms, an ester having 4-10 carbon atoms, an alcohol having 3-8 carbon atoms, and water; preferably, the anti-solvents are each an alkane containing 5-8 carbon atoms.

[0136] In a more specific embodiment, the present invention provides a method for preparing Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the antisolvent is selected from n-hexane, n-heptane, ethyl acetate, isopropanol, toluene, diethyl ether, diisopropyl ether, methyl tert-butyl ether and water.

[0137] In a more specific embodiment, the present invention provides a method for preparing Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the weight volume ratio (g / mL) of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers) to the good solvent is about 1:(1-50), preferably 1:(5-30), preferably 1:10 or 1:30; more preferably 1:(5-10); preferably 1:5, 1:6, 1:7, 1:8 or 1:9.

[0138] In a more specific embodiment, the present invention provides a method for preparing Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the volume ratio of the good solvent to the antisolvent is about 1:1 to 1:10, preferably 1:3.

[0139] In one embodiment, the present invention provides Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), which comprises peaks at approximately 12.5±0.3, 17.3±0.3, 20.6±0.3, and 23.2±0.3 2θ (°) in an X-ray powder diffraction (XRPD) pattern obtained using Cu Kα radiation.

[0140] In a more specific embodiment, the present invention provides Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the XRPD pattern further comprises peaks at approximately 4.1±0.3, 8.3±0.3, 21.0±0.3, 23.5±0.3 and 26.5±0.3 2θ (°).

[0141] In a more specific embodiment, the present invention provides Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the XRPD pattern further comprises peaks at approximately 10.9±0.3, 19.0±0.3, and 19.5±0.3 2θ (°).

[0142] In a more specific embodiment, the present invention provides Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the XRPD pattern comprises peaks at approximately the following 2θ (°) positions: 4.1±0.3, 8.3±0.3, 10.9±0.3, 11.5±0.3, 12.0±0.3, 12.5±0.3, 13.4±0.3, 16.1±0.3, 1 6.7±0.3, 17.3±0.3, 19.0±0.3, 19.5±0.3, 20.6±0.3, 21.0±0.3, 21.3±0.3, 21.5±0.3, 22.1±0.3, 23.2±0.3, 23.5±0.3, 24.4±0.3, 24.6±0.3, 25.4±0.3, 25.7±0.3, 26.5±0.3, 27.7±0.3, 28.2±0.3 and 29.7±0.3.

[0143] In a more specific embodiment, the present invention provides Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the XRPD pattern comprises peaks at approximately:

[0144] In a more specific embodiment, the present invention provides Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers) having an XRPD pattern substantially the same as shown in FIG. 4 .

[0145] In a more specific embodiment, the present invention provides Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), which includes endothermic peaks at approximately 108±3°C and 128±3°C and an exothermic peak at approximately 270±3°C in a differential scanning calorimetry (DSC) spectrum.

[0146] In a more specific embodiment, the present invention provides Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), which has a thermogravimetric analysis (TGA) spectrum, wherein the TGA spectrum shows that the crystalline form has no obvious weight loss before being heated to the melting point.

[0147] In a more specific embodiment, the present invention provides Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), which has a DSC-TGA spectrum substantially the same as shown in Figure 5.

[0148] In one embodiment, the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), comprising:

[0149] Method I: It includes the following steps:

[0150] Suspending 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers) or Form I in a solvent system at room temperature or under heating conditions to obtain the Form II; or

[0151] Method II, which comprises the following steps:

[0152] 1) adding 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers) or Form I to a good solvent to obtain a solution;

[0153] 2) adding an antisolvent to the solution obtained in step 1), and stirring at room temperature or under heating conditions to obtain the crystal form II.

[0154] In a more specific embodiment, the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the heating in step 2) of method I or method II is heating to 30-70°C, preferably 50°C.

[0155] In a more specific embodiment, the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the solvent system is a two-solvent system composed of a mixture of a good solvent and an anti-solvent system.

[0156] In a more specific embodiment, the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the good solvent is selected from an ether solvent having 3 to 10 carbon atoms and a ketone solvent having 3 to 10 carbon atoms.

[0157] In a more specific embodiment, the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the ether solvent is a 3-6 membered cyclic ether containing 1-2 oxygen atoms, preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran and dioxane; wherein the ketone solvent is a chain hydrocarbon ketone of 3-6 carbon atoms, preferably selected from acetone and butanone.

[0158] In a more specific embodiment, the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the anti-solvent is an alkane having 5-10 carbon atoms, a halogenated alkane having 5-10 carbon atoms, an olefin having 5-10 carbon atoms, an alkyne having 5-10 carbon atoms, an aromatic hydrocarbon having 6-10 carbon atoms, an ether having 2-6 carbon atoms, an ester having 4-10 carbon atoms, an alcohol having 3-8 carbon atoms, and water; preferably, the anti-solvent is an alkane containing 5-8 carbon atoms.

[0159] In a more specific embodiment, the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the antisolvent is selected from n-hexane, n-heptane, ethyl acetate, isopropanol, toluene, diethyl ether, diisopropyl ether, methyl tert-butyl ether and water.

[0160] In a more specific embodiment, the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the weight volume ratio (g / mL) of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers) to the good solvent is about 1:(1-50), preferably about 1:(5-30), preferably 1:10 or 1:30; more preferably 1:(5-10); preferably 1:5, 1:6, 1:7, 1:8 or 1:9.

[0161] In a more specific embodiment, the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and / or its tautomers), wherein the volume ratio of the good solvent to the antisolvent is about 1:1 to 1:10.

[0162] In one embodiment, the present invention provides a composition comprising Form I and / or Form II and a pharmaceutically acceptable carrier or excipient.

[0163] In one embodiment, the present invention provides a composition comprising a crystalline form of a compound of the formula 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2-(1H)-one or a tautomer thereof:

[0164] In a more specific embodiment, the present invention provides a composition comprising the above-described crystalline form, wherein the crystalline form comprises peaks at approximately 12.6±0.3, 20.3±0.3, 20.9±0.3, 22.0±0.3, and 23.1±0.3 2θ (°) in an X-ray powder diffraction (XRPD) pattern obtained using Cu Ka radiation. In a more specific embodiment, the XRPD pattern of the crystalline form further comprises peaks at approximately 4.0±0.3, 22.5±0.3, 24.1±0.3, 25.2±0.3, and 26.2±0.3 2θ (°). In a more specific embodiment, the XRPD pattern of the crystalline form further comprises peaks at approximately 8.4±0.3, 11.3±0.3, 15.3±0.3, 16.9±0.3, and 26.7±0.3 2θ (°).

[0165] In a more specific embodiment, the present invention provides a composition comprising the above-mentioned crystalline form, wherein the XRPD pattern of the crystalline form comprises peaks at about the following 2θ (°) positions: 4.0±0.3, 8.4±0.3, 11.3±0.3, 11.9±0.3, 12.6±0.3, 14.0±0.3, 15.3±0.3, 16.9±0.3, 18.3±0.3, 18.9±0.3, 19.9±0.3, 20.3±0.3, 20.9±0.3, 0.3, 21.2±0.3, 22.0±0.3, 22.5±0.3, 23.1±0.3, 24.1±0.3, 24.7±0.3, 25.2±0.3, 25.8±0.3, 26.2±0.3, 26.7±0.3, 27.9±0.3, 29.1±0.3, 29.5±0.3, 29.8±0.3, 30.4±0.3, 31.3±0.3, 31.6±0.3, 38.2±0.3 and 40.3±0.3.

[0166] In a more specific embodiment, the present invention provides a composition comprising the above-described crystalline form, wherein the XRPD pattern of the crystalline form comprises a peak at about:

[0167] In a more specific embodiment, the present invention provides a composition comprising the above-described crystalline form, wherein the crystalline form has an XRPD pattern substantially the same as that shown in FIG. 1 .

[0168] In a more specific embodiment, the crystalline form comprises endothermic peaks at 96±3°C and 129±3°C in a differential scanning calorimetry (DSC) spectrum. In a more specific embodiment, the crystalline form has a thermogravimetric analysis (TGA) spectrum, and the TGA spectrum shows that the crystalline form does not lose significant weight before being heated to the melting point. In a more specific embodiment, the crystalline form has a DSC-TGA spectrum substantially the same as that shown in Figure 2.

[0169] In a more specific embodiment, the present invention provides a composition comprising a crystalline form, wherein the crystalline form comprises peaks at approximately 12.5 ± 0.3, 17.3 ± 0.3, 20.6 ± 0.3, and 23.2 ± 0.3 2θ (°) in an X-ray powder diffraction (XRPD) pattern obtained using Cu Ka radiation. In a more specific embodiment, the XRPD pattern of the crystalline form further comprises peaks at approximately 4.1 ± 0.3, 8.3 ± 0.3, 21.0 ± 0.3, 23.5 ± 0.3, and 26.5 ± 0.3 2θ (°). In a more specific embodiment, the XRPD pattern of the crystalline form further comprises peaks at approximately 10.9 ± 0.3, 19.0 ± 0.3, and 19.5 ± 0.3 2θ (°).

[0170] In a more specific embodiment, the present invention provides a composition comprising a crystalline form, wherein the XRPD pattern of the crystalline form comprises peaks at about the following 2θ (°) positions: 4.1±0.3, 8.3±0.3, 10.9±0.3, 11.5±0.3, 12.0±0.3, 12.5±0.3, 13.4±0.3, 16.1±0.3, 16.7±0.3, 17.3±0.3, 1 9.0±0.3, 19.5±0.3, 20.6±0.3, 21.0±0.3, 21.3±0.3, 21.5±0.3, 22.1±0.3, 23.2±0.3, 23.5±0.3, 24.4±0.3, 24.6±0.3, 25.4±0.3, 25.7±0.3, 26.5±0.3, 27.7±0.3, 28.2±0.3 and 29.7±0.3.

[0171] In a more specific embodiment, the present invention provides a composition comprising a crystalline form, wherein said XRPD pattern of said crystalline form comprises a peak at about:

[0172] In a more specific embodiment, the present invention provides a composition comprising a crystalline form, wherein the crystalline form has an XRPD pattern substantially the same as shown in FIG. 4 .

[0173] In a more specific embodiment, the present invention provides a composition comprising a crystalline form, wherein the crystalline form comprises endothermic peaks at about 108±3°C and 128±3°C and an exothermic peak at about 270±3°C in a differential scanning calorimetry (DSC) spectrum. In a more specific embodiment, wherein the crystalline form has a thermogravimetric analysis (TGA) spectrum, wherein the TGA spectrum shows that the crystalline form does not lose significant weight before being heated to the melting point. In a more specific embodiment, the present invention provides a composition comprising a crystalline form, wherein the crystalline form has a DSC-TGA spectrum substantially the same as that shown in Figure 5.

[0174] In one embodiment, the present invention provides the use of Form I or Form II or a composition comprising the same in the preparation of a medicament for preventing and / or treating a phosphodiesterase-related disease. In a more specific embodiment, the phosphodiesterase-related disease is chronic obstructive pulmonary disease (COPD) and / or asthma. Example

[0175] The present invention will be explained in more detail below with reference to embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention and are not used to limit the scope of the present invention. Those skilled in the art may make some non-essential improvements and adjustments, which still fall within the scope of protection of the present invention.

[0176] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0177] The detection instruments and conditions used in the following examples are as follows:

[0178] (1) X-ray powder diffraction (XRPD)

[0179] Instrument model: Bruker D8 advance, equipped with LynxEye detector

[0180] Test conditions: the anode target material is copper, the light tube is set to (40KV 40mA), the 2θ scanning angle of the sample is from 3° to 40°, and the scanning step is 0.02°.

[0181] (2) Differential Scanning Calorimetry (DSC)

[0182] Instrument model: TA Discovery DSC 250 (TA Instruments, US)

[0183] Test conditions: heating rate of 10°C / min, dry nitrogen was used as purge gas.

[0184] (3) Thermogravimetric analysis (TGA)

[0185] Instrument model: Discovery TGA 55 (TA Instruments, US)

[0186] Test conditions: automatic weighing in a heating furnace, heating rate of 10°C / min, dry nitrogen as purge gas.

[0187] (4) Polarized light microscopy (PLM)

[0188] Instrument model: Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN)

[0189] abbreviation:

[0190] THF: Tetrahydrofuran

[0191] DABCO: 1,4-diazabicyclo[2.2.2]-octane

[0192] Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0)

[0193] HP(t-Bu)3BF4: tri-tert-butylphosphine tetrafluoroborate

[0194] Pd / C: Palladium / Carbon

[0195] Example 1: Preparation of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (Compound A)

[0196] first step:

[0197] Methyltriphenylphosphonium iodide (33.4 g, 64 mmol), potassium tert-butoxide (9.3 g, 64 mmol), and anhydrous THF (100 mL) were added sequentially to a three-necked flask and reacted at room temperature under argon atmosphere for 1 hour. A-1 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (7.7 g, 32 mmol) was dissolved in anhydrous THF (20 mL) and slowly added dropwise to the reaction solution via a constant pressure dropping funnel. After the addition was complete, the reaction was continued for 3 hours. The THF was evaporated under reduced pressure, and the reaction solution was quenched with saturated ammonium chloride solution (30 mL). The solution was extracted three times with ethyl acetate (3 × 50 mL), and the organic phases were combined. The organic phase was washed once with saturated sodium chloride solution, separated, and dried over anhydrous sodium sulfate. After separation by medium-pressure column chromatography and concentration, A-2 was obtained as a colorless, transparent oil in a 92% yield.

[0198] 1H NMR (400MHz, CDCl3) δ7.11(d,J=8.2Hz,1H),6.99(d,J=2.0Hz,1H),6.96(dd,J=8.2,2.0Hz,1H),6.65(dd,J=17.6,12.2Hz,1H),6.62(t,J=76.0Hz ,1H),5.68(dd,J=17.5,0.8Hz,1H),5.25(dd,J=10.8,0.8Hz,1H),3.89(d ,J=6.9Hz,2H),1.34-1.26(m,1H),0.68-0.63(m,2H),0.38-0.34(m,2H).

[0199] Step 2:

[0200] To a sealed tube, A-2 (1.1 g, 4.56 mmol), 1-benzyl-4-bromopyridin-2(1H)-one (1.2 g, 4.56 mmol), Pd(dba) (42 mg, 0.0456 mmol), HP(t-Bu)BF (53 mg, 0.1824 mmol), and DABCO (1.53 g, 13.68 mmol) were added sequentially. Anhydrous dioxane (15 mL) was added, the atmosphere was replaced with argon, and the stopper was tightened. The reaction was stirred at 100°C for 36 hours. After the reaction solution was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted three times with ethyl acetate (3 × 20 mL). The organic phases were combined, washed twice with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. A-3 was obtained as a white solid by medium-pressure column chromatography in a 52.4% yield.

[0201] 1 H NMR (400MHz, CDCl3) δ7.36-7.26(m,5H),7.21(d,J=7.1Hz,1H),7.13(d,J=8.0Hz,1H),7.08-6.98(m,3H),6.8 3-6.31(m,4H),5.12(s,2H),3.91(d,J=6.9Hz,2H),1.32-1.27(m,1H),0.68-0.63(m,2H),0.38-0.34(m,2H).

[0202] Step 3:

[0203] A-3 (70 mg, 0.17 mmol) was dissolved in methanol (20 mL), and Pd / C (20 mg) was added. The reaction was stirred at 90°C under a hydrogen atmosphere for 5 hours. The palladium-carbon was removed by filtration through celite, and the celite layer was washed with ethyl acetate (3 × 10 mL). The organic phases were combined and separated by medium-pressure column chromatography to obtain 47 mg of a white solid, Compound A, in a yield of 83.8%. Its XRPD pattern is shown in Figure 23, and its DSC and TGA patterns are shown in Figure 24.

[0204] 1 H NMR (400MHz, MeOD) δ7.33 (d, J=6.6Hz, 1H), 7.01 (d, J=8.1Hz, 1H), 6.88 (d, J= 4.4Hz,1H),6.76(d,J=8.1Hz,1H),6.70-6.47(m,1H),6.32(d,J=6.8Hz,1H),6 .29(s,1H),3.86(dd,J=6.8,1.6Hz,2H),2.90(t,J=7.6Hz,2H),2.81(t,J=7. 4Hz,2H),1.25(m,1H),0.66-0.56(m,2H),0.35(d,J=5.0Hz,2H).MS(ESI):m / z C 18 H 20 Calculated for F2NO3 (M+H) + :336.13, measured value (M+H) + :336.14.

[0205] Example 2: Preparation of Form I of Compound A Anhydrate (Method 1)

[0206] Compound A (3.18 g) was added to acetone (22.3 mL) and stirred at room temperature until completely dissolved. The resulting solution was filtered and the filtrate was collected. n-Heptane (66.8 ml) was slowly added dropwise to the filtrate and stirred overnight at room temperature to precipitate a solid. The suspension was filtered and dried under vacuum at 40°C to obtain a crystalline form. X-ray powder diffraction analysis revealed an XRPD pattern as shown in Figure 1; DSC and TGA analysis revealed DSC and TGA patterns as shown in Figure 2; and scanning electron microscopy revealed the crystal morphology as shown in Figure 3.

[0207] Thermogravimetric analysis (TGA) showed that the crystalline sample had no obvious weight loss before being heated to the melting point, indicating that the crystalline form did not contain water of crystallization.

[0208] Example 3: Preparation of Form I of Compound A Anhydrate (Method 2)

[0209] Compound A (200 mg) was added to ethyl acetate (4 mL), and the resulting suspension was stirred at room temperature overnight. The suspension was filtered and dried under vacuum at 40°C to obtain a crystalline form. X-ray powder diffraction analysis revealed an XRPD pattern identical to that shown in Figure 1.

[0210] Example 4: Preparation of Form I of Compound A Anhydrate (Method 3)

[0211] Compound A (200 mg) was added to isopropanol (6 mL), and the resulting suspension was stirred at room temperature overnight. The suspension was filtered and dried under vacuum at 40°C to obtain a crystalline form. X-ray powder diffraction analysis revealed an XRPD pattern identical to that shown in Figure 1.

[0212] Example 5: Preparation of Form I of Compound A Anhydrate (Method 4)

[0213] Compound A (200 mg) was added to methyl tert-butyl ether (6 mL), and the resulting suspension was stirred at room temperature overnight. The suspension was filtered and dried under vacuum at 40°C to obtain a crystalline form. X-ray powder diffraction analysis revealed an XRPD pattern identical to that shown in Figure 1.

[0214] Example 6: Preparation of Form I of Compound A Anhydrate (Method 5)

[0215] Compound A (200 mg) was added to n-heptane (6 mL), and the resulting suspension was stirred at 50°C overnight. The suspension was filtered and dried under vacuum at 40°C to obtain a crystalline form. X-ray powder diffraction analysis revealed an XRPD pattern identical to that shown in Figure 1.

[0216] Example 7: Preparation of Form I of Compound A Anhydrate (Method 6)

[0217] Compound A (200 mg) was added to THF (1.6 mL) and stirred at room temperature until completely dissolved. 4 mL of water was slowly added dropwise to the filtrate and stirred overnight at room temperature to precipitate a solid. The suspension was filtered and dried under vacuum at 40°C to obtain a crystalline form. X-ray powder diffraction analysis revealed an XRPD pattern as shown in Figure 1.

[0218] Example 8: Preparation of Form II of Compound A Anhydrate (Method 1)

[0219] Compound A (30.0 g) was added to acetone (210 mL) and stirred at 50°C until completely dissolved. The resulting solution was filtered and the filtrate was collected. N-heptane (630 ml) was slowly added dropwise to the filtrate. After the addition was complete, the mixture was kept at 50°C for 4 hours, stirred at room temperature overnight, and a solid was precipitated. The suspension was filtered and dried in vacuo at 40°C to obtain a crystalline form. X-ray powder diffraction analysis showed that its XRPD pattern was shown in Figure 4; DSC and TGA analysis showed that its DSC and TGA patterns were shown in Figure 5; the sample was observed under a scanning electron microscope, and the crystal morphology was shown in Figure 6. Thermogravimetric analysis (TGA) showed that the crystalline sample had no obvious weight loss before being heated to the melting point, indicating that the crystalline form did not contain water of crystallization.

[0220] Example 9: Preparation of Form II of Compound A Anhydrate (Method 2)

[0221] Compound A Form I (15.0 g) was added to a mixed solvent of acetone (105 mL) and n-heptane (315 mL). The mixture was stirred at 50°C for 4 hours and then at room temperature overnight to precipitate a solid. The suspension was filtered and dried under vacuum at 40°C to obtain the crystalline form. X-ray powder diffraction analysis revealed an XRPD pattern as shown in Figure 4.

[0222] Example 10: Preparation of Form II of Compound A Anhydrate (Method 3)

[0223] Compound A (200 mg) was added to water (6 mL), and the suspension was stirred at room temperature overnight. The suspension was filtered and dried under vacuum at 40° C. to obtain a crystalline form. X-ray powder diffraction analysis showed an XRPD pattern as shown in FIG4 .

[0224] Example 11: Preparation of Form II of Compound A Anhydrate (Method 4)

[0225] Compound A (200 mg) was added to methyl tert-butyl ether (6 mL), and the suspension was stirred at 50° C. overnight. The suspension was filtered and dried under vacuum at 40° C. to obtain a crystalline form. X-ray powder diffraction analysis revealed an XRPD pattern as shown in FIG4 .

[0226] Example 12: Preparation of Form II of Compound A Anhydrate (Method 5)

[0227] Compound A (200 mg) was added to n-heptane (6 mL), and the suspension was stirred at 70° C. overnight. The suspension was filtered and dried under vacuum at 40° C. to obtain a crystalline form. X-ray powder diffraction analysis showed an XRPD pattern as shown in FIG4 .

[0228] Example 13: Preparation of Form II of Compound A Anhydrate (Method 6)

[0229] Compound A (200 mg) was added to acetone (4 mL) and stirred at room temperature until completely dissolved. Water (5.6 mL) was slowly added dropwise to the filtrate and stirred overnight at room temperature to precipitate a solid. The suspension was filtered and dried under vacuum at 40°C to obtain a crystalline form. X-ray powder diffraction analysis revealed the XRPD pattern shown in Figure 4.

[0230] Experimental example

[0231] Experimental Example 1: Room Temperature Stability Test

[0232] Form I prepared in Example 2 and Form II prepared in Example 8 were placed in pharmaceutical-grade low-density polyethylene bags, sealed, and stored at room temperature for 180 days. XRPD measurements were then performed using a Bruker D8 advance X-ray powder diffractometer. The results showed no change in the crystalline form of Form I and Form II samples after 180 days, demonstrating good stability. A comparison of the XRPD patterns of Form I before and after 180 days at room temperature is shown in Figure 7.

[0233] Experimental Example 2: Water Activity Experiment

[0234] A water activity test was conducted on Form I prepared in Example 2. Form I was added to acetone containing varying water ratios at room temperature to prepare suspensions. After three days, the remaining solid was analyzed by XRPD using a Bruker D8 advance X-ray powder diffractometer. The results, shown in Figure 8, demonstrate that Form I remains stable in acetone / water (1 / 1, aw = 0.89), with no hydrated form observed.

[0235] Experimental Example 3: Solid Stability Experiment

[0236] Form I prepared in Example 2 and Form II prepared in Example 8 were evaluated for solid stability over a period of 7 days at 60°C and 40°C / 75% RH. A portion of the solid sample was dissolved and analyzed for purity by HPLC (see Figures 9 and 10 ), and the remaining solid was analyzed by XRPD using a Bruker D8 advance X-ray powder diffractometer to determine its crystal form (see Figure 11 ). No significant degradation or crystal form transitions were observed during the testing, indicating that Form I and Form II are physically and chemically stable under the tested conditions.

[0237] Experimental Example 4: High Humidity Stability Test

[0238] The Form I prepared in Example 2 was left unopened at 92.5% RH / 25°C for 7 days for stability testing. The XRPD pattern was measured using a Bruker D8 advance X-ray powder diffractometer (see Figure 12). The results showed that the Form I sample showed no change in crystalline form at 92.5% RH / 25°C for 7 days, indicating excellent stability.

[0239] Experimental Example 5: Physical grinding stability experiment

[0240] Form I prepared in Example 2 was physically ground for 2 minutes, and then its XRPD pattern was measured using a Bruker D8 advance X-ray powder diffractometer (see Figure 13). The results showed that the Form I sample had no change in crystalline form and excellent stability. Scanning electron micrographs before and after grinding are shown in Figure 14.

[0241] Experimental Example 6: Crystal Transformation Experiment

[0242] The crystal transformation experiments of Form I prepared in Example 2 and Form II prepared in Example 8 were carried out by competitive beating in different solvents. Equal amounts of different crystal forms were added to a saturated solution of the compound, and the resulting suspension was stirred at room temperature or 50°C. The resulting solid was subjected to XRPD analysis using a Bruker D8 advance X-ray powder diffractometer as appropriate. Detailed results are shown in Table 1 and Figures 15, 16, 17, and 18. All mixtures were transformed into Form I at room temperature to 35°C and into Form II at 40 to 50°C. Therefore, Form I and Form II are in an interconversion relationship in the solvent system; Form I is stable at room temperature to 35°C in the solvent system, while Form II is stable at ≥40°C.

[0243] Table 1

[0244] Experimental Example 7: Stability Test

[0245] 15 mg of disodium edetate and 75 mg of sodium citrate were placed in a measuring cup, and 150 mL of water was added and stirred to dissolve to prepare a blank solution. Form I prepared in Example 2 or Form II prepared in Example 8 was micronized to a D90 of ≤ 10 μm. Scanning electron micrographs of these samples are shown in Figures 19 and 20, respectively. 1.0 g of the micronized Form I or Form II sample was added to 1.6 g of Tween 80, followed by the blank solution. The mixture was homogenized at 850 bar for 6 minutes to obtain a suspension of the Form I or Form II sample. After the suspension of the Form I or Form II sample was left at room temperature for 15 days, a portion of the suspension was filtered and washed, and the filter cake was smeared on a glass slide. After drying, scanning electron microscopy was used to observe that the particle size of the Form I sample in the suspension remained basically unchanged compared to the initial state, while the particle size of the Form II sample in the suspension was significantly aggregated and larger than the initial state, indicating that the Form I sample was more stable than the Form II sample in the suspension. Scanning electron micrographs of their suspensions after being left at room temperature for 15 days are shown in Figures 21 and 22, respectively.

[0246] The crystalline form of the present invention exhibits excellent stability, with its color and properties remaining unchanged after prolonged storage at room temperature (e.g., 180 days). Furthermore, the crystalline form of the present invention exhibits excellent stability under high temperature or high humidity conditions. For example, Form I exhibits no change in crystalline form after storage at high temperature (e.g., 60°C) for 30 days.

[0247] In addition, the crystalline form of the present invention has good fluidity and is easy to crush, thereby facilitating the preparation of pharmaceutical compositions.

[0248] Furthermore, the preparation method of the crystalline form of the present invention is simple, easy to implement, and has mild reaction conditions. Furthermore, it does not require multiple purifications, is safe and environmentally friendly to operate, and is conducive to the industrial production of the crystalline form.

[0249] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A crystalline form of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2-(1H)-one.

2. The crystalline form of claim 1, comprising peaks at approximately 12.6±0.3, 20.3±0.3, 20.9±0.3, 22.0±0.3, and 23.1±0.3 2θ (°) in an X-ray powder diffraction (XRPD) pattern obtained using Cu Ka radiation.

3. The crystalline form of claim 2, wherein the XRPD pattern further comprises peaks at approximately 4.0±0.3, 22.5±0.3, 24.1±0.3, 25.2±0.3, and 26.2±0.3 2θ (°).

4. The crystalline form of claim 2 or 3, wherein the XRPD pattern further comprises peaks at approximately 8.4±0.3, 11.3±0.3, 15.3±0.3, 16.9±0.3, and 26.7±0.3 2θ (°).

5. The crystalline form of claim 2, wherein the XRPD pattern comprises peaks at approximately the following 2θ (°) positions: 4.0 ± 0.3, 8.4 ± 0.3, 11.3 ± 0.3, 11.9 ± 0.3, 12.6 ± 0.3, 14.0 ± 0.3, 15.3 ± 0.3, 16.9 ± 0.3, 18.3 ± 0.3, 18.9 ± 0.3, 19.9 ± 0.3, 20.3 ± 0.3, 20.9 ± 0.3, 21.2 ± 0.3 3, 22.0±0.3, 22.5±0.3, 23.1±0.3, 24.1±0.3, 24.7±0.3, 25.2±0.3, 25.8±0.3, 26.2±0.3, 26.7±0.3, 27.9±0.3, 29.1±0.3, 29.5±0.3, 29.8±0.3, 30.4±0.3, 31.3±0.3, 31.6±0.3, 38.2±0.3 and 40.3±0.

3.

6. The crystalline form of claim 2, wherein the XRPD pattern comprises a peak at approximately:

7. The crystalline form of claim 2, which has an XRPD pattern substantially the same as that shown in Figure 1.

8. The crystalline form of any one of claims 2 to 7, which comprises endothermic peaks at 96±3°C and 129±3°C in a differential scanning calorimetry (DSC) spectrum.

9. The crystalline form of any one of claims 2-8, having a thermogravimetric analysis (TGA) pattern, wherein the TGA pattern shows that the crystalline form has no significant weight loss before being heated to the melting point.

10. The crystalline form of any one of claims 2 to 9, which has a DSC-TGA pattern substantially the same as that shown in Figure 2.

11. A method for preparing the crystalline form of any one of claims 2 to 10, comprising: Method 1: includes the following steps: 1) adding 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one to a good solvent to obtain a solution; and 2) adding an anti-solvent to the solution obtained in step 1) and stirring to obtain the crystalline form; or Method 2: includes the following steps: 4-[3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one was added to an anti-solvent to obtain a suspension, which was stirred to obtain the crystalline form.

12. The method according to claim 11, wherein step 1) of method 1 or method 2 is carried out at room temperature or under heating conditions, and the heating is heating to 30-70°C, preferably heating to 50°C.

13. The method according to claim 11 or 12, wherein the stirring in step 2) of method 1 is carried out at room temperature or under cooling conditions, and the cooling is cooling to 0-10°C, preferably cooling to 5°C.

14. The method according to any one of claims 11 to 13, wherein the good solvent is selected from an ether solvent having 3 to 10 carbon atoms and a ketone solvent having 3 to 10 carbon atoms.

15. The method according to claim 14, wherein the ether solvent is a 3-6 membered cyclic ether containing 1-2 oxygen atoms, preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran and dioxane; wherein the ketone solvent is a chain hydrocarbon ketone with 3-6 carbon atoms, preferably selected from acetone and butanone.

16. The method according to any one of claims 11 to 15, wherein the anti-solvent in method one and method two is each an alkane having 5-10 carbon atoms, a halogenated alkane having 5-10 carbon atoms, an olefin having 5-10 carbon atoms, an alkyne having 5-10 carbon atoms, an aromatic hydrocarbon having 6-10 carbon atoms, an ether having 2-6 carbon atoms, an ester having 4-10 carbon atoms, an alcohol having 3-8 carbon atoms, and water; preferably, the anti-solvent is an alkane containing 5-8 carbon atoms.

17. The method of claim 16, wherein the anti-solvent is selected from the group consisting of n-hexane, n-heptane, ethyl acetate, isopropanol, toluene, diethyl ether, diisopropyl ether, methyl tert-butyl ether and water.

18. The method of any one of claims 11 to 17, wherein the weight-to-volume ratio (g / mL) of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one to the good solvent is about 1:(1-50), preferably about 1:(5-30), preferably 1:10 or 1:30; more preferably 1:(5-10); preferably 1:5, 1:6, 1:7, 1:8 or 1:

9.

19. The method of any one of claims 11-18, wherein the volume ratio of the good solvent to the antisolvent is about 1:1 to 1:

10.

20. The crystalline form of claim 1, comprising peaks at approximately 12.5 ± 0.3, 17.3 ± 0.3, 20.6 ± 0.3, and 23.2 ± 0.3 2θ (°) in an X-ray powder diffraction (XRPD) pattern obtained using Cu Ka radiation.

21. The crystalline form of claim 20, wherein the XRPD pattern further comprises peaks at approximately 4.1 ± 0.3, 8.3 ± 0.3, 21.0 ± 0.3, 23.5 ± 0.3, and 26.5 ± 0.3 2Θ (°).

22. The crystalline form of claim 20 or 21, wherein the XRPD pattern further comprises peaks at approximately 10.9 ± 0.3, 19.0 ± 0.3, and 19.5 ± 0.3 2θ (°).

23. The crystalline form of claim 20, wherein the XRPD pattern comprises peaks at approximately the following 2θ (°) positions: 4.1 ± 0.3, 8.3 ± 0.3, 10.9 ± 0.3, 11.5 ± 0.3, 12.0 ± 0.3, 12.5 ± 0.3, 13.4 ± 0.3, 16.1 ± 0.3, 16.7 ± 0.3, 17.3 ± 0.3, 19.0 ± 0.3, 1 9.5±0.3, 20.6±0.3, 21.0±0.3, 21.3±0.3, 21.5±0.3, 22.1±0.3, 23.2±0.3, 23.5±0.3, 24.4±0.3, 24.6±0.3, 25.4±0.3, 25.7±0.3, 26.5±0.3, 27.7±0.3, 28.2±0.3 and 29.7±0.

3.

24. The crystalline form of claim 20, wherein the XRPD pattern comprises a peak at approximately:

25. The crystalline form of claim 20, which has an XRPD pattern substantially the same as that shown in Figure 4.

26. The crystalline form of any one of claims 20-25, comprising endothermic peaks at about 108±3°C and 128±3°C and an exothermic peak at about 270±3°C in a differential scanning calorimetry (DSC) spectrum.

27. The crystalline form of any one of claims 20-26, having a thermogravimetric analysis (TGA) pattern showing no significant weight loss of the crystalline form upon heating to its melting point.

28. The crystalline form of any one of claims 20-27, which has a DSC-TGA pattern substantially the same as that shown in Figure 5.

29. A method for preparing the crystalline form of any one of claims 20 to 28, comprising Method I: It includes the following steps: At room temperature or under heating conditions, suspending 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one or the crystalline form of claims 2-10 in a solvent system to obtain the crystalline form; or method II, which comprises the following steps: 1) adding 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one or the crystalline form of claim 2-10 to a good solvent to obtain a solution; 2) adding an anti-solvent to the solution obtained in step 1), and stirring at room temperature or under heating conditions to obtain the crystalline form.

30. The method of claim 29, wherein the heating in step 2) of method I or method II is heating to 30-70°C, preferably 50°C.

31. The method of claim 29 or 30, wherein the solvent system is a two-solvent system formed by mixing a good solvent and an anti-solvent system.

32. The method of any one of claims 29-31, wherein the good solvent is selected from ether solvents having 3 to 10 carbon atoms and ketone solvents having 3 to 10 carbon atoms.

33. The method of claim 32, wherein the ether solvent is a 3-6 membered cyclic ether containing 1-2 oxygen atoms, preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran and dioxane; wherein the ketone solvent is a chain hydrocarbon ketone with 3-6 carbon atoms, preferably selected from acetone and butanone.

34. The method of any one of claims 31-33, wherein the anti-solvent is an alkane having 5-10 carbon atoms, a halogenated alkane having 5-10 carbon atoms, an olefin having 5-10 carbon atoms, an alkyne having 5-10 carbon atoms, an aromatic hydrocarbon having 6-10 carbon atoms, an ether having 2-6 carbon atoms, an ester having 4-10 carbon atoms, an alcohol having 3-8 carbon atoms, and water; preferably, the anti-solvent is an alkane containing 5-8 carbon atoms.

35. The method of claim 34, wherein the anti-solvent is selected from the group consisting of n-hexane, n-heptane, ethyl acetate, isopropanol, toluene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, and water.

36. The method of any one of claims 31-35, wherein the weight-to-volume ratio (g / mL) of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one to the good solvent is about 1:(1-50), preferably about 1:(5-30), preferably 1:10 or 1:30; more preferably 1:(5-10); preferably 1:5, 1:6, 1:7, 1:8 or 1:

9.

37. The method of any one of claims 31-36, wherein the volume ratio of the good solvent to the antisolvent is about 1:1 to 1:

10.

38. A composition comprising the crystalline form of any one of claims 1-10 and 20-28 and a pharmaceutically acceptable carrier or excipient.

39. Use of the crystalline form of any one of claims 1-10 and 20-28 or the composition of claim 38 in the preparation of a medicament for preventing and / or treating phosphodiesterase-related diseases.

40. The use according to claim 39, wherein The phosphodiesterase-related disease is chronic obstructive pulmonary disease (COPD) and / or asthma.

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