Crystal form of substituted tetrahydrofuran compound and preparation method thereof

Abstract

The present disclosure relates to a crystalline form of a substituted tetrahydrofuran compound and a method of preparing the same. Specifically, the invention provides a crystal form A and a crystal form B of (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N '-methoxyformamidino) pyridin-4-yl)-4, 5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carboxamide, and the crystal form A and the crystal form B have good stability and can be better used for clinical treatment.

Description

Technical Field

[0001] The present disclosure belongs to the field of pharmaceutical technologies and relates to a crystalline form of a substituted tetrahydrofuran compound and a preparation method thereof. Background Art

[0002] Nav is a class of transmembrane ion channel proteins. According to whether it can be effectively inhibited by nanomolar tetrodotoxin (TTX), sodium ion channels are divided into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R). Nav1.8 is of the TTX-R type, and its encoding gene is SCN10A. It is mainly present in trigeminal ganglion neurons and DRG neurons and has electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Nav 1.8, the rise of action potential is mainly composed of Nav1.8 current. In some models of neuropathic pain research, nerve injury will increase the expression level of Nav1.8 in axons and neuronal cell bodies. Using Nav1.8 antisense oligonucleotides can significantly relieve pain while reducing the expression of Nav1.8. After injecting carrageenan into the rat paw, the expression of Nav1.8 in DRG neurons increases. Nav1.8 knockout mice cannot exhibit normal visceral inflammatory pain. After the human Nav1.8 gene produces a gain-of-function mutation, it will cause peripheral neuropathic pain. Based on a series of animal experiments and human gene evidence, selective inhibition of Nav1.8 has the potential to become a new type of analgesic therapy and can be used for the treatment of various pain types such as inflammatory pain, neuropathic pain, postoperative pain, and cancer pain.

[0003] PCT / CN2023 / 114740 provides a Nav1.8 inhibitor, whose chemical name is (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-methoxymethanimidoyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, and has the structure shown in Formula 1,

[0004]

[0005] The crystal form of a medicinal active ingredient often affects the chemical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, and sometimes other crystal forms will also be generated. Generally speaking, amorphous drug products do not have regular crystal structures and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy caking, poor fluidity, etc. The polymorphs of drugs have different requirements for product storage, production, and scale-up. Therefore, it is necessary to deeply study the crystal form of the aforementioned compound and improve various properties of the aforementioned compound. Summary of the Invention

[0006] The present disclosure provides a new crystal form of the compound shown in Formula 1, which has good stability and can be better applied clinically.

[0007]

[0008] The crystal form A of the compound shown in Formula 1 provided by the present disclosure has characteristic peaks at 8.441, 18.774, 19.269, 20.678, and 22.842 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0009] In some embodiments, the crystal form of the compound shown in Formula 1 has characteristic peaks at 8.441, 9.480, 12.659, 14.696, 15.448, 16.801, 17.337, 18.774, 19.269, 20.678, 22.842, 24.125, and 28.012 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0010] In some embodiments, the crystal form of the compound shown in Formula 1 has characteristic peaks at 8.441, 9.480, 11.903, 12.071, 12.659, 14.696, 15.448, 16.801, 17.337, 17.584, 18.774, 19.269, 20.678, 22.842, 24.125, 25.311, 25.574, 28.012, 29.664, and 30.722 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0011] In some embodiments, the X-ray powder diffraction pattern of the crystal form of the compound shown in Formula 1 expressed in terms of diffraction angle 2θ is as Figure 3 shown.

[0012] The present disclosure also provides a method for preparing the crystal form of the compound shown in Formula 1, and the method is selected from any of the following methods:

[0013] Method 1: Dissolve the compound of Formula 1 in Solvent I, add Solvent II, and stir. Solvent I is selected from one of ethanol, acetonitrile, acetone, ethyl acetate, dichloromethane, and methyl tert-butyl ether, and Solvent II is selected from one of water, n-heptane, cyclohexane, and n-hexane;

[0014] Method 2: Add the compound of Formula 1 to Solvent III and stir. Solvent III is selected from one of water, n-heptane, cyclohexane, n-hexane, 50% water / methanol, and 80% water / methanol;

[0015] Method 3: Dissolve the compound of formula 1 in solvent IV, and evaporate the solvent. Solvent IV is selected from one or more of alcohol solvents, ketone solvents, ester solvents, ether solvents, nitrile solvents, hydrocarbon solvents, N,N-dimethylformamide, and dimethyl sulfoxide;

[0016] The alcohol solvents are selected from methanol, ethanol, and n-propanol;

[0017] The ketone solvents are selected from acetone, 2-butanone, and methyl isobutyl ketone;

[0018] The ester solvents are selected from ethyl acetate and isopropyl acetate;

[0019] The nitrile solvent is selected from acetonitrile;

[0020] The ether solvents are selected from tetrahydrofuran, propylene glycol monomethyl ether, isopropyl ether, 2-methyl-tetrahydrofuran, and methyl tert-butyl ether;

[0021] The hydrocarbon solvents are selected from n-heptane, dichloromethane, n-hexane, and cyclohexane;

[0022] The crystalline form B of the compound of formula 1 provided by the present disclosure has characteristic peaks at 11.008, 15.345, 19.836, 21.362, 22.163, and 24.849 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0023] In some embodiments, the crystalline form B of the compound of formula 1 has characteristic peaks at 7.331, 11.008, 13.011, 15.345, 16.708, 18.938, 19.836, 21.362, 22.163, 24.849, 27.186, 28.080, and 29.001 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0024] In some embodiments, the crystalline form B of the compound of formula 1 has characteristic peaks at 7.331, 11.008, 11.963, 13.011, 14.054, 15.345, 16.708, 18.938, 19.836, 21.362, 22.163, 22.623, 24.008, 24.849, 27.186, 28.080, 29.001, 30.010, and 34.808 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0025] In some embodiments, the X-ray powder diffraction pattern of the crystalline form B of the compound of formula 1 expressed in terms of diffraction angle 2θ is as Figure 4 shown.

[0026] The present disclosure also provides a method for preparing crystalline form B of the compound shown in Formula 1, the method comprising adding the compound of Formula 1 to isopropanol and stirring.

[0027] For crystalline form C of the compound shown in Formula 1 provided by the present disclosure, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 8.276, 9.133, 9.449, 16.059, 17.065, 19.787.

[0028] In some embodiments, for crystalline form C of the compound shown in Formula 1, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 8.276, 9.133, 9.449, 11.561, 13.160, 14.304, 15.356, 16.059, 17.065, 19.787.

[0029] In some embodiments, for crystalline form C of the compound shown in Formula 1, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 8.276, 9.133, 9.449, 11.561, 13.160, 14.304, 15.356, 16.477, 16.721, 16.059, 17.065, 18.311, 19.787, 21.943, 23.023, 24.282, 24.750, 26.383.

[0030] In some embodiments, for crystalline form C of the compound shown in Formula 1, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is as Figure 5 shown.

[0031] The present disclosure also provides a method for preparing crystalline form C of the compound shown in Formula 1, the method being selected from any of the following methods:

[0032] Method 1: Dissolving the compound of Formula 1 in solvent V and evaporating the solvent, where solvent V is selected from one of acetonitrile, 10% water / acetone, acetone / cyclohexane (v / v = 1:5), 2-butanone / n-heptane (v / v = 1:5), 2-butanone / cyclohexane (v / v = 1:5).

[0033] Method 2: Adding the compound of Formula 1 to isopropanol for dissolution and stirring.

[0034] For crystalline form D of the compound shown in Formula 1 provided by the present disclosure, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 10.583, 12.303, 15.057, 19.257, 21.458, 24.017.

[0035] In some embodiments, for polymorph D of the compound represented by Formula 1, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 10.583, 12.303, 15.057, 15.891, 16.371, 17.549, 19.257, 20.917, 21.458, 22.776, 24.017, 25.727, 26.927, 28.488, 29.828.

[0036] In some embodiments, for polymorph D of the compound represented by Formula 1, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 10.583, 11.257, 12.303, 12.803, 13.790, 15.057, 15.891, 16.371, 17.549, 18.580, 19.257, 20.917, 21.458, 22.776, 24.017, 24.493, 24.923, 25.727, 26.927, 28.488, 29.828, 34.801, 37.920.

[0037] In some embodiments, for polymorph D of the compound represented by Formula 1, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is as Figure 6 shown.

[0038] The present disclosure also provides a method for preparing polymorph D of the compound represented by Formula 1, the method including the step of dissolving the compound of Formula 1 in methyl tert-butyl ether and stirring.

[0039] For polymorph E of the compound represented by Formula 1 provided by the present disclosure, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 8.019, 8.880, 10.562, 16.811, 19.576.

[0040] In some embodiments, for polymorph E of the compound represented by Formula 1, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 7.018, 8.019, 8.880, 10.562, 11.326, 14.115, 15.020, 16.811, 19.576, 20.860, 21.361, 22.784, 24.056, 24.539.

[0041] In some embodiments, the X-ray powder diffraction pattern of crystalline form E of the compound of formula 1, expressed in terms of diffraction angle 2θ, has characteristic peaks at 7.018, 8.019, 8.880, 9.162, 10.562, 11.326, 12.897, 14.115, 15.020, 16.228, 16.811, 17.754, 19.576, 20.860, 21.361, 21.712, 22.784, 24.056, 24.539, 26.053, 27.021.

[0042] In some embodiments, the X-ray powder diffraction pattern of crystalline form E of the compound of formula 1, expressed in terms of diffraction angle 2θ, is as Figure 7 shown.

[0043] The present disclosure also provides a method for preparing crystalline form E of the compound of formula 1, which includes the step of dissolving the compound of formula 1 in methyl tert-butyl ether and evaporating the solvent.

[0044] The X-ray powder diffraction pattern of crystalline form F of the compound of formula 1 provided by the present disclosure, expressed in terms of diffraction angle 2θ, has characteristic peaks at 8.689, 10.964, 13.068, 16.715, 18.553, 20.413.

[0045] In some embodiments, the X-ray powder diffraction pattern of crystalline form F of the compound of formula 1, expressed in terms of diffraction angle 2θ, has characteristic peaks at 8.689, 10.964, 13.068, 15.062, 16.715, 18.553, 20.413, 21.948, 22.295, 24.331.

[0046] In some embodiments, the X-ray powder diffraction pattern of crystalline form F of the compound of formula 1, expressed in terms of diffraction angle 2θ, has characteristic peaks at 8.689, 10.964, 13.068, 15.062, 16.715, 17.436, 18.553, 19.566, 20.413, 21.948, 22.295, 24.331, 32.770.

[0047] In some embodiments, the X-ray powder diffraction pattern of crystalline form F of the compound of formula 1, expressed in terms of diffraction angle 2θ, is as Figure 8 shown.

[0048] The present disclosure also provides a method for preparing crystalline form F of the compound of formula 1, the method including the step of dissolving the compound of formula 1 in 10% water / isopropanol and evaporating the solvent.

[0049] Polymorph G of the compound of formula 1 provided by the present disclosure has characteristic peaks at 13.088, 15.118, 16.762, 18.529, 19.547, 20.408, 22.329 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0050] In some embodiments, polymorph G of the compound of formula 1 has characteristic peaks at 8.293, 8.709, 12.525, 13.088, 13.968, 15.118, 16.762, 18.529, 19.547, 20.408, 21.947, 22.329, 23.313, 23.912, 24.330 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0051] In some embodiments, polymorph G of the compound of formula 1 has characteristic peaks at 8.293, 8.709, 12.525, 13.088, 13.968, 15.118, 16.762, 18.529, 19.547, 20.408, 21.947, 22.329, 23.313, 23.912, 24.330, 27.769, 30.152, 31.118 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0052] In some embodiments, the X-ray powder diffraction pattern of polymorph G of the compound of formula 1 expressed in terms of diffraction angle 2θ is as Figure 9 shown.

[0053] The present disclosure also provides a method for preparing polymorph G of the compound of formula 1, the method comprising the step of adding polymorph B of the compound of formula 1 to water and stirring.

[0054] Polymorph H of the compound of formula 1 provided by the present disclosure has characteristic peaks at 8.641, 10.265, 13.716, 14.357, 17.455, 20.662 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0055] In some embodiments, polymorph H of the compound of formula 1 has characteristic peaks at 8.641, 10.265, 13.716, 14.357, 17.455, 18.962, 20.662, 21.556, 24.409, 25.500, 25.989, 29.105 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0056] In some embodiments, the X-ray powder diffraction pattern of polymorph H of the compound of formula 1 expressed in terms of diffraction angle 2θ is as Figure 10 shown.

[0057] The present disclosure also provides a method for preparing polymorph H of the compound shown in Formula 1, the method comprising the step of adding the compound of Formula 1 to methanol or 10% water / methanol and stirring.

[0058] In certain embodiments, the preparation method described in the present disclosure further comprises any one of the steps of crystallization, centrifugation (filtration), washing or drying.

[0059] The crystallization methods of the present disclosure include but are not limited to stirring crystallization, static crystallization or evaporation crystallization. In some embodiments, the crystallization is stirring crystallization. In some embodiments, the crystallization is static crystallization.

[0060] The present disclosure also provides a pharmaceutical composition comprising any one of the foregoing polymorph A, polymorph B, polymorph C, polymorph D, polymorph E, polymorph F, polymorph G or polymorph H, and a pharmaceutical excipient optionally selected from pharmaceutically acceptable excipients.

[0061] The present disclosure also provides a pharmaceutical composition prepared from any one of the foregoing polymorph A, polymorph B, polymorph C, polymorph D, polymorph E, polymorph F, polymorph G or polymorph H, and an optionally pharmaceutically acceptable excipient.

[0062] The present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing any one of the foregoing polymorph A, polymorph B, polymorph C, polymorph D, polymorph E, polymorph F, polymorph G or polymorph H with a pharmaceutically acceptable excipient.

[0063] The present disclosure also provides the use of any one of the foregoing polymorph A, polymorph B, polymorph C, polymorph D, polymorph E, polymorph F, polymorph G or polymorph H or the composition prepared therefrom in the preparation for preventing and / or treating and alleviating pain and pain-related diseases.

[0064] The use described in the present disclosure, wherein the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; the postoperative pain is preferably selected from pain after bunionectomy, pain after hernia repair and pain after abdominoplasty.

[0065] The "2θ or 2θ angle" described in the present disclosure refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree; the error range of 2θ for each characteristic peak is ±0.20 (including the case after rounding for numbers with more than one decimal place), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0066] In the present disclosure, if the numerical values such as the content of related substances are data measured and calculated, there will inevitably be a certain degree of error. Generally speaking, ±10% is within the reasonable error range. There will be a certain degree of error variation depending on the context where it is used, and this error variation does not exceed ±10%, and can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2% or ±1%, preferably ±5%.

[0067] The starting materials used in the crystal form preparation method of the present disclosure can be compounds in any form, and the specific forms include but are not limited to: amorphous, any crystal form, hydrate, solvate, etc.

[0068] The drying temperature described in the present disclosure is generally 25°C - 100°C, preferably 40°C - 70°C, and it can be dried at normal pressure or under reduced pressure.

[0069] The crystallization methods described in the present disclosure include crystallization at room temperature, cooling crystallization, solvent evaporation crystallization, adding crystal seeds to induce crystallization, etc. The cooling temperature is selected from below 65°C, preferably -10°C to 60°C, and stirring can also be carried out during the crystallization process.

[0070] The "differential scanning calorimetry or DSC" described in the present disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference during the heating or constant temperature process of the sample, so as to characterize all physical and chemical changes related to thermal effects and obtain the phase change information of the sample.

[0071] According to the description of the hygroscopicity characteristics and the definition of the hygroscopic weight gain in the "Guideline for Drug Hygroscopicity" in Part IV of the Chinese Pharmacopoeia 2015 Edition,

[0072] Deliquescence: Absorbing sufficient moisture to form a liquid;

[0073] Highly hygroscopic: The hygroscopic weight gain is not less than 15%;

[0074] Hygroscopic: The hygroscopic weight gain is less than 15% but not less than 2%;

[0075] Slightly hygroscopic: The hygroscopic weight gain is less than 2% but not less than 0.2%;

[0076] Non - hygroscopic or almost non - hygroscopic: The hygroscopic weight gain is less than 0.2%.

[0077] The "excipients" described in the present disclosure include, but are not limited to, any adjuvants, carriers, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents or emulsifiers that have been approved by the US Food and Drug Administration for use in humans or domestic animals and are acceptable. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 It is the analgesic efficacy of Compound 1 in a rat incision pain model.

[0079] Figure 2 It is the effect of Compound 1 on body weight in a rat incision pain model.

[0080] Figure 3 It is the XRPD pattern of polymorph A of Compound 1.

[0081] Figure 4 It is the XRPD pattern of polymorph B of Compound 1.

[0082] Figure 5 It is the XRPD pattern of polymorph C of Compound 1.

[0083] Figure 6 It is the XRPD pattern of polymorph D of Compound 1.

[0084] Figure 7 It is the XRPD pattern of polymorph E of Compound 1.

[0085] Figure 8 It is the XRPD pattern of polymorph F of Compound 1.

[0086] Figure 9 It is the XRPD pattern of polymorph G of Compound 1.

[0087] Figure 10 It is the XRPD pattern of polymorph H of Compound 1. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0088] The present disclosure will be explained in more detail below in combination with examples or experimental examples. The examples or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure and do not limit the essence and scope of the present disclosure.

[0089] Test conditions of the instruments used in the experiment:

[0090] The structure of the compound was determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) was given in units of 10-6 (ppm). The NMR measurement was performed using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer or a Bruker AVANCE NEO 500M, and the solvents used for the measurement were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0091] The MS measurement was performed using an Agilent 1200 / 1290DAD-6110 / 6120Quadrupole MS liquid chromatography-mass spectrometry instrument (manufacturer: Agilent, MS model: 6110 / 6120Quadrupole MS).

[0092] waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity QdaDetec-tor / waters SQ Detector)

[0093] THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO QExactive)

[0094] High performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 high performance liquid chromatography instrument.

[0095] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatography instrument.

[0096] High performance liquid chromatography preparative work was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatography instruments.

[0097] Chiral preparative work was performed using a Shimadzu LC-20AP preparative chromatography instrument.

[0098] The CombiFlash rapid preparative instrument used a Combiflash Rf200 (TELEDYNE ISCO).

[0099] For thin-layer chromatography silica gel plates, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used. The specifications of the silica gel plates used in thin-layer chromatography (TLC) are 0.15 mm to 0.2 mm, and the specifications of the silica gel plates used for separating and purifying products by thin-layer chromatography are 0.4 mm to 0.5 mm.

[0100] For silica column chromatography, silica gel with 200 - 300 mesh from Yantai Huanghai is generally used as the carrier.

[0101] The determination of the average kinase inhibition rate and IC50 value is carried out using a NovoStar microplate reader (from BMG Labtech, Germany).

[0102] The known starting materials of the present invention can be synthesized by adopting or according to methods known in the art, or can be purchased from companies such as ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, etc.

[0103] Unless otherwise specified in the examples, the reactions can all be carried out under an argon or nitrogen atmosphere.

[0104] An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

[0105] A hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

[0106] For the catalytic hydrogenation reaction, a Parr 3916EKX hydrogenator and Qinglan QL - 500 hydrogen generator or HC2 - SS hydrogenator are used.

[0107] For the hydrogenation reaction, it is usually evacuated, filled with hydrogen, and this operation is repeated 3 times.

[0108] For microwave reactions, a CEM Discover - S 908860 microwave reactor is used.

[0109] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0110] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20 °C to 30 °C.

[0111] The monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC). The eluent systems for column chromatography used to purify compounds and the developing agent systems for thin-layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0112] XRPD is X-ray powder diffraction detection: The measurement was carried out using a BRUKER D8 type X-ray diffractometer. The specific acquisition information: Cu anode (40 kV, 40 mA), Cu-Kα1 ray Kα2 ray Kβ ray Scanning mode: θ / 2θ, scanning range (2θ range): 5° to 45°.

[0113] DSC is differential scanning calorimetry: The measurement was performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter. The heating rate was 10 °C / min, and the specific temperature range was referred to the corresponding spectrum (mostly 25 - 270 °C). The nitrogen purge rate was 50 mL / min.

[0114] TGA is thermogravimetric analysis: The detection was carried out using a METTLER TOLEDO TGA 2 type thermogravimetric analyzer. The heating rate was 10 °C / min, and the specific temperature range was referred to the corresponding spectrum (mostly 30 - 350 °C). The nitrogen purge rate was 50 mL / min.

[0115] DVS is dynamic vapor sorption: The detection was carried out using SMSDVS Advantage. At 25 °C, the humidity changed as 50% - 95% - 0% - 95% - 50%, with a step of 10% (the last step was 5%) (the specific humidity range was subject to the corresponding spectrum, and the method listed here was mostly used). The judgment criteria were Tmax 360 min and dm / dt not greater than 0.002%.

[0116] Preparation of the compound of Formula 1 in Example 1

[0117] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-methoxyformamidinyl)pyridin-4-yl)-4,5-dimethyl

[0118] -5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1

[0119]

[0120] The first step

[0121] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1b-1

[0122] (2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1b-2

[0123] rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (12 g, 33.87 mmol, prepared by the method disclosed in Example 3 on page 231 of the specification of patent application "WO2021113627") was resolved by a chiral column (Waters SFC 150, column: DAICEL 40*250 mm, 10 μm; mobile phase A: supercritical CO 2 , mobile phase B: IPA), gradient ratio: A:B: 90:10, flow rate: 120 mL / min) to obtain the title product 1b-1 (5.5 g, yield: 45.8%) and 1b-2 (5.08 g, yield: 42.3%).

[0124] MS m / z (ESI): 353.2 [M-1].

[0125] Single configuration compound (shorter retention time) 1b-1 (5.5 g, yield: 45.8%)

[0126] MS m / z (ESI): 353.2 [M-1].

[0127] Chiral HPLC analysis: retention time 2.414 minutes, purity: 99% (column: DAICEL 100*3 mm, 3 μm; mobile phase A: supercritical CO 2 , mobile phase B: IPA (0.1% DEA)), gradient ratio: mobile phase A: 60%-95%, flow rate: 1.5 mL / min).

[0128] Single configuration compound (longer retention time) 1b-2 (5.08 g, yield: 42.3%).

[0129] MS m / z (ESI): 353.2 [M-1].

[0130] Chiral HPLC analysis: retention time 2.724 minutes, purity: 99% (column: DAICEL 100*3 mm, 3 μm; mobile phase A: supercritical CO 2 , mobile phase B: IPA (0.1% DEA)), gradient ratio: mobile phase A: 60%-95%, flow rate: 1.5 mL / min).

[0131] Second step: (2R,3S,4S,5R)-N-(2-cyanopyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1d

[0132] Dissolve compound 1b-1 (50 mg, 141 μmol) in dichloromethane (10 mL). Add oxalyl chloride (40 mg, 315 μmol) and 1 drop of N,N-dimethylformamide under ice bath. React at room temperature for 1 hour. Concentrate the reaction solution under reduced pressure. Dissolve the residue in dichloromethane (3 mL). Add N,N-diisopropylethylamine (60 mg, 464 μmol). Dropwise add a dichloromethane solution (1 mL) of 4-aminopyridine-2-carbonitrile 1c (30 mg, 251 μmol, Shanghai Hanhong) under ice bath. Stir and react for 2 hours. Concentrate the reaction solution under reduced pressure. Purify the residue by silica gel column chromatography with elution system B to obtain the title compound 1d (45 mg, yield: 70%).

[0133] MS m / z (ESI): 456.2 [M+1].

[0134] Third step

[0135] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-methoxyformamidinyl)pyridin-4-yl)-4,5-dimethyl

[0136] -5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1

[0137] Dissolve compound 1d (100 mg, 219.6 μmol) in 10 mL of isopropanol. Add N,N-diisopropylethylamine (85.1 mg, 658.8 μmol), mercaptoacetic acid (40.5 mg, 439 μmol, Shanghai Bide), methoxylamine hydrochloride (55 mg, 658.8 μmol). React at 80 °C for 14 hours. Concentrate the reaction solution under reduced pressure. Purify the residue by preparative high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to obtain the title compound 1 (10 mg, yield: 18%).

[0138] MS m / z (ESI): 503.2 [M+1].

[0139] 1 H NMR (500 MHz, DMSO-d 6): δ 10.69 (s, 1H), 8.44 (d, 1H), 8.11 (d, 1H), 7.72 (dd, 1H), 7.18 (dt, 2H), 6.07 (s, 1H), 5.09 (d, 1H), 4.25 (dd, 1H), 3.96 (d, 3H), 3.79 (d, 3H), 2.78 (t, 1H), 2.01 (q, 1H), 1.61 (s, 3H), 0.73 (d, 3H).

[0140] Test Example 1: Determination of the inhibitory activity of the compounds of the present disclosure against Nav1.8

[0141] The purpose of the experiment was to investigate the effect of the compounds on the Nav1.8 ion channel in in vitro experiments. The Nav1.8 ion channel was stably expressed on HEK293 cells. After the Nav1.8 current was stabilized, the magnitude of the Nav1.8 current before and after the application of the compounds was compared to obtain the effect of the compounds on the Nav1.8 ion channel.

[0142] 1 Experimental materials and instruments

[0143] 1) Patch clamp amplifier: patch clamp PC-505B (WARNER instruments) / MultiClamp700A (Axon instrument)

[0144] 2) Digital-to-analog converter: Digidata 1440A (Axon CNS) / Digidata 1550A (Axoninstruments)

[0145] 3) Micromanipulator: MP-225 (SUTTER instrument)

[0146] 4) Inverted microscope: TL4 (Olympus)

[0147] 5) Glass microelectrode puller: PC-10 (NARISHIGE)

[0148] 6) Microelectrode glass capillary: B12024F (Wuhan Microprobe Scientific Instruments Co., Ltd.)

[0149] 7) Dimethyl sulfoxide (DMSO) D2650 (Sigma-Aldrich)

[0150] 8) TTX AF3014 (Affix Scientific)

[0151] 2 Experimental procedures

[0152] 2.1 Compound preparation

[0153] Compounds for preparing intracellular and extracellular solutions were purchased from Sigma (St. Louis, MO), except for NaOH and KOH used in acid-base titration. The extracellular solution (mM) was: NaCl, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2 , 1; HEPES, 10; glucose, 10; pH 7.4 (titrated with NaOH). The intracellular solution (mM) was aspartic acid, 140; MgCl 2 , 2; EGTA 11; HEPES, 10; pH 7.2 (titrated with CsOH). All test compound and control compound solutions contained 1 μM TTX.

[0154] The stock concentration of the test compound was 9 mM, dissolved in dimethyl sulfoxide (DMSO). It was redissolved in the extracellular solution on the day of the test to prepare the required concentration.

[0155] 2.2 Manual patch clamp test procedure

[0156] 1) After the compound was prepared into a solution of the specified concentration, the drug solutions were added to each pipette in ascending order of concentration, and each pipette was labeled.

[0157] 2) The cell was transferred to the perfusion chamber, positive pressure was applied inside the electrode, the tip of the electrode was brought into contact with the cell, the three-way valve of the aspiration device was adjusted to the three-way state, and then negative pressure was applied to the electrode to form a high-resistance seal with the cell. Negative pressure was continuously applied to rupture the cell membrane and form a current path.

[0158] 3) After the cell rupture current was stable, perfusions at different concentrations were carried out in sequence. If the current was stable for at least one minute, the next concentration could be used for perfusion. The perfusion time for each concentration was no more than five minutes.

[0159] 4) The perfusion chamber was cleaned. It was rinsed in descending order of drug solution concentration, and each concentration of the drug solution was rinsed for 20 s. Finally, it was rinsed with the extracellular solution for 1 min.

[0160] 2.3 Test voltage equation (resting) and results

[0161] The cell was clamped at -80 mV, and then depolarized to 10 mV with a 10-ms square wave to obtain Nav1.8 current. This procedure was repeated every 5 s. The maximum current induced by the square wave was detected. After it was stable, the test compound was perfused. When the response was stable, the blocking intensity was calculated.

[0162] 3. Data analysis

[0163] The data will be stored in a computer system for analysis. Data collection and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA), and the analysis results will be reviewed by the management staff. Current stability refers to the current varying within a limited range over time. The magnitude of the current after stabilization is used to calculate the effect of the compound at this concentration.

[0164] The inhibitory activity of the compounds disclosed herein against Nav1.8 was determined by the above tests, and the measured IC 50 values are shown in Table 1.

[0165] Table 1 IC of the compounds disclosed herein against Nav1.8 channel activity 50

[0166] Example number <![CDATA[IC 50 (nM)]]> 1 0.33

[0167] Conclusion: The compounds in the present disclosure have a significant inhibitory effect on Nav1.8 channel activity.

[0168] Test Example 2: Pharmacokinetic Evaluation

[0169] I. SD Rat Experiment

[0170] Using SD rats as the test animals, the LC / MS / MS method was used to determine the drug concentrations in the plasma of SD rats at different time points after intragastric (i.g.) administration of the compounds of the examples. The pharmacokinetic behavior of the compounds disclosed herein in SD rats was studied to evaluate their pharmacokinetic characteristics.

[0171] 1.1 Experimental Protocol

[0172] Experimental animals: 4 male SD rats, provided by Vital River Laboratory Animal Technology Co., Ltd. After fasting overnight, they were administered drugs by intragastric gavage respectively.

[0173] Drug preparation: Weigh a certain amount of the test compound respectively, add 5% DMSO + 5% Tween 80 + 90% normal saline to prepare a 0.2 mg / mL colorless and clear solution.

[0174] Drug administration: The administration dose was 2 mg / kg, and the administration volume was 10.0 mL / kg.

[0175] Operation method

[0176] Before drug administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after drug administration, 0.2 mL of blood was collected from the orbital cavity, placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10000 rpm for 1 minute (4 °C), the plasma was separated within 1 hour, and stored in dry ice for testing. The process from blood collection to centrifugation was carried out under ice bath conditions. Food was provided 2 hours after drug administration.

[0177] Determine the content of the compound to be measured in the plasma of SD rats after administration of drugs at different concentrations: Take 25 μL of the plasma samples of SD rats at each time point after administration, add 200 μL of acetonitrile containing the internal standard (verapamil 100 ng / ml), vortex mix, and centrifuge at 3700 rpm for 10 minutes. Take 0.1 μL of the supernatant for LC / MS / MS analysis.

[0178] 1.2 Results of pharmacokinetic parameters

[0179] Table 2. Pharmacokinetic parameters of the compounds of the present disclosure

[0180]

[0181] Conclusion: The compounds of the present disclosure have high blood drug concentration and high exposure in SD rats, and have obvious pharmacokinetic advantages.

[0182] II. C57 mouse experiment

[0183] 2.1 Experimental animals

[0184] 18 C57 mice, half male and half female, were evenly divided into 2 groups, with 9 mice in each group, and 3 mice at each time point in each group. They were provided by Vital River Laboratory Animal Technology Co., Ltd., with production licenses SCXK(Zhe)2019-0001 and SCXK(Jing)2019-0006, and were administered by gavage and intravenous injection respectively.

[0185] 2.2 Drug preparation

[0186] Weigh a certain amount of the test compound respectively, add 5% DMSO + 5% Tween 80 + 90% normal saline to prepare a 0.1 mg / mL colorless and clear solution (gavage administration group) and a 0.1 mg / mL colorless and clear solution (intravenous injection administration group).

[0187] 2.3 Administration

[0188] Gavage administration group: The administration dose is 2.0 mg / kg, and the administration volume is 20 mL / kg.

[0189] Intravenous injection administration group: The administration dose is 1.0 mg / kg, and the administration volume is 10 mL / kg.

[0190] 2.4 Operations

[0191] Gavage administration group: Before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, 0.1 mL of blood was collected from the orbital cavity, placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10,000 rpm for 1 minute (4 °C), plasma was separated within 1 hour, and stored at -80 °C for further measurement. The process from blood collection to centrifugation was carried out under ice bath conditions.

[0192] Intravenous injection administration group: Before administration and at 5 minutes, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24 hours after administration, blood was collected, and the treatment was the same as that of the gavage administration group.

[0193] Determination of the content of the compound to be measured in the plasma of C57 mice after administration of different concentrations of the drug: Compound 1: Take 20 μL of the plasma samples of C57 mice at each time point after administration. Add 200 μL of acetonitrile containing 100 ng / ml of camptothecin (internal standard) to each sample to precipitate proteins, vortex for 5 minutes, and centrifuge at 3700 rpm for 10 minutes. Take 50 μL of the supernatant, add 100 μL of water, vortex for 5 minutes, and inject 1 μL for LC / MS / MS analysis.

[0194] 2.5 Results of pharmacokinetic parameters

[0195] Table 3. Pharmacokinetic parameters of the compounds of the present disclosure

[0196]

[0197] Conclusion: The compounds of the present disclosure have high blood drug concentrations, large exposures, low clearance rates, and relatively high bioavailability in C57 mice, showing pharmacokinetic advantages.

[0198] Test Example 3 Pharmacodynamic experiment

[0199] 1. Experimental purpose

[0200] To evaluate the analgesic efficacy of the compounds of the present disclosure in inhibiting pain in a rat incision pain model.

[0201] 2. Experimental drugs

[0202] Compound of Example 1.

[0203] Use a solution of 25% PEG400 + 75% (10% TPGS + 1% HPMC K100LV).

[0204] 3. Experimental methods and experimental materials

[0205] 3.1 Experimental animals and feeding conditions

[0206] Experimental animals: Sprague-Dawley (SD) rats were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (License number: SCXK(Zhe)2019-0001), and their body weight was approximately 180 g at the time of purchase.

[0207] Feeding conditions: Five rats were housed in each cage, with a 12 / 12-hour light / dark cycle, a constant temperature of 23 ± 1°C, and a humidity of 50 to 60%. They had free access to food and water.

[0208] 3.2 Animal grouping

[0209] After the SD rats were adaptively fed, the grouping was as follows:

[0210] Table 4

[0211]

[0212] Note: One dose means administering the drug only once; i.g. means intragastric administration.

[0213] 3.3 Experimental method:

[0214] Nine SD rats with a body weight of 170 - 190 g were selected, and their mechanical pain thresholds were measured using an electronic tactile measuring instrument. Then, an incision pain surgery was performed. During the surgery, after anesthesia with Zoletil (Zoletil-50, 250 mg, diluted to 50 ml with normal saline after dissolution, and 2 ml was injected for a 200 g body weight), a 1 cm long incision was made in the middle of the plantar surface of the left hind paw using a No. 10 surgical blade. After cutting through the skin and fascia, the skin was sutured with 3-0 sterile silk surgical sutures. The injured area was disinfected with penicillin, and the animals were returned to their original places to recover overnight. After overnight recovery from the surgery, intragastric administration was performed. Five hours after the rats were administered the drug (about 24 hours after the surgery), the mechanical pain threshold was measured using an electronic tactile measuring instrument.

[0215] 3.4 Data statistics

[0216] The Excel statistical software was used to record the data: the average value was calculated as avg; the SD value was calculated as STDEV; the SEM value was calculated as STDEV / SQRT (the number of animals in each group); the GraphPad Prism software was used to plot the graph, and one-way ANOVA and t-test were used for statistical analysis of the data.

[0217] Percentage increase in threshold (%) = [(G t - G 0 ) / G 0 × 100 (%), where G t is the plantar pain threshold of the drug-administered group, and G 0 is the plantar pain threshold of the vehicle group.

[0218] 4. Results

[0219] The analgesic efficacy of the compound in Example 1 in the rat incision pain model is as follows Figure 1 As shown in Table 5, the effect of body weight is shown in Figure 2 ;

[0220] Table 5 Analgesic efficacy of the disclosed compounds in the rat incision pain model

[0221]

[0222] Note: one dose means administration only once; ig means administration by intragastric administration.

[0223] 5. Conclusion

[0224] The pain threshold of normal rats (weight 170-190g) is 26.2±1.6gf, and that of the vehicle control group is 10.0±0.7gf. The pain thresholds of Example 1 compound at 200, 100, and 50mg / kg are 22.3, 14.9, and 10.8gf, respectively, which are significantly higher than those of the vehicle control group by 122% (p<0.001), 49% (p<0.05), and 7%, respectively. The pain threshold of 200mg / kg is significantly higher than that of 100mg / kg (p<0.01), and the pain threshold of 100mg / kg is significantly higher than that of 50mg / kg (p<0.05). The analgesic effect is obviously dose-dependent, and the administration has no effect on the weight of rats.

[0225] Example 2 Preparation of Form A

[0226] 120 mg of the compound shown in Formula 1 was added to 1.2 mL of ethanol to dissolve, 2.4 mL of water was added, stirred for crystallization, filtered under reduced pressure, and dried in vacuum to obtain a solid. The product was defined as Form A by X-ray powder diffraction detection, and the XRPD spectrum was as follows: Figure 3 , and the positions of its characteristic peaks are shown in Table 6. The DSC spectrum shows that the peak value of the endothermic peak is 130.10℃. The TGA spectrum shows that there is no obvious weight loss. The DVS test shows that under normal storage conditions (i.e. 25℃, 60% RH), the sample has a moisture absorption weight gain of about 0.11%; under accelerated experimental conditions (i.e. 70% RH), the moisture absorption weight gain is about 0.20%; under extreme conditions (90% RH), the moisture absorption weight gain is about 0.60%. After the DVS test, the crystal form was retested and the crystal form did not change.

[0227] Table 6

[0228]

[0229]

[0230] Example 3 Preparation of Form A

[0231] The crystalline form A was prepared by the precipitation method, and the solvent pairs selected for precipitation are shown in Table 7 below. Dissolve 6 mg of the compound shown in Formula 1 in 0.06 mL of Solvent A, add 0.3 mL of Solvent B, stir for crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product. After X-ray powder diffraction detection, this product is crystalline form A.

[0232] Table 7

[0233]

[0234] Preparation of crystalline form A in Example 4

[0235] Add 5 mg of the compound shown in Formula 1 to 0.5 mL of the solvent, which is shown in Table 8 below, stir for crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product. After X-ray powder diffraction detection, this product is crystalline form A.

[0236] Table 8

[0237] Solvent Crystal form Water Crystal form A n-Heptane Crystal form A 50% water / methanol Crystal form A Cyclohexane Crystal form A n-Hexane Crystal form A 80% water / methanol Crystal form A

[0238] Preparation of crystalline form A in Example 5

[0239] Dissolve 5 mg of the compound shown in Formula 1 in 0.05 mL of the solvent shown in Table 9 below, evaporate the solvent to obtain a solid. After X-ray powder diffraction detection, this product is crystalline form A.

[0240] Table 9

[0241]

[0242]

[0243] Preparation of crystalline form B in Example 6

[0244] Add the compound shown in Formula 1 (400 mg) to isopropanol (6 mL), continuously stir at room temperature for 24 hours to precipitate a solid, filter and collect the filter cake, and dry it under vacuum at room temperature for 72 hours to obtain a solid product. After X-ray powder diffraction detection, this product is defined as crystalline form B. The X-ray powder diffraction data are shown in Table 10, and the X-ray powder diffraction pattern is as Figure 4 shown. The DSC pattern shows endothermic peaks at 88.20 °C, 104.28 °C, and 145.81 °C. The TGA pattern shows that from 30 °C to 90 °C, the compound loses 6.78% in weight, and from 90 °C to 170 °C, the compound loses 3.16% in weight.

[0245] Table 10

[0246]

[0247] Preparation of crystalline form C in Example 7

[0248] The compound shown in Formula 1 (2.0 g) was added to isopropanol (40 mL), and the mixture was heated and stirred at 60 °C for 10 minutes until it became clear. It was then allowed to cool naturally to room temperature and stirred for 24 hours. A solid precipitated, which was filtered and the filter cake was collected. The solid was dried in vacuo at 60 °C for 16 hours to obtain a solid product. After detection by X-ray powder diffraction, this product was defined as Crystal Form C. The X-ray powder diffraction data are shown in Table 11, and the X-ray powder diffraction pattern is as Figure 5 shown. The DSC pattern showed that the endothermic peak was at 145.27 °C. The TGA pattern showed that from 30 °C to 150 °C, the compound had almost no weight loss.

[0249] DVS detection showed that under normal storage conditions (i.e., 25 °C, 60% RH), the moisture absorption weight gain of this sample was approximately 0.23%; under accelerated test conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 0.28%; under extreme conditions (90% RH), the moisture absorption weight gain was approximately 0.57%. And after DVS detection, the crystal form was retested and no crystal form transformation occurred.

[0250] Table 11

[0251]

[0252]

[0253] Preparation of Crystal Form C of Example 8

[0254] 5 mg of the compound shown in Formula 1 was dissolved in 0.05 mL of the solvent shown in Table 12 below, and the solvent was evaporated to obtain a solid. After detection by X-ray powder diffraction, this product was Crystal Form C.

[0255] Table 12

[0256]

[0257] Preparation of Crystal Form D of Example 9

[0258] The amorphous form (30 mg) of the compound shown in Formula 1 was added to methyl tert-butyl ether (0.4 mL), and the mixture was stirred and sonicated for dissolution. A solid precipitated, and it was stirred at room temperature for 24 hours. The solid was filtered and the filter cake was collected. The solid was dried in vacuo at room temperature for 1 hour to obtain a solid product (20 mg, yield: 66.6%). After detection by X-ray powder diffraction, this product was defined as Crystal Form D. The X-ray powder diffraction data are shown in Table 13, and the X-ray powder diffraction pattern is as Figure 6 shown. The DSC pattern showed that the endothermic peaks were at 71.78 °C and 144.60 °C. The TGA pattern showed that from 30 °C to 110 °C, the compound had a weight loss of 1.48%.

[0259] Table 13

[0260]

[0261] Preparation of Crystal Form E in Example 10

[0262] Dissolve 5 mg of the compound shown in Formula 1 in 0.05 mL of methyl tert-butyl ether, and crystallize by evaporation to obtain the product.

[0263] Detected by X-ray powder diffraction, this product is defined as Crystal Form E, and the XRPD pattern is as Figure 7 , and the characteristic peak positions are shown in Table 14. The DSC pattern shows endothermic peak maxima at 73.30 °C and 144.52 °C. The TGA pattern shows a weight loss of 2.84% from 30 °C to 120 °C.

[0264] Table 14

[0265]

[0266] Preparation of Crystal Form F in Example 11

[0267] Dissolve 5 mg of the compound shown in Formula 1 in 0.05 mL of 10% water / isopropanol, and crystallize by evaporation to obtain the product. Detected by X-ray powder diffraction, this product is defined as Crystal Form F, and the XRPD pattern is as Figure 8 , and the characteristic peak positions are shown in Table 15. The DSC pattern shows endothermic peak maxima at 80.00 °C and 144.77 °C, and an exothermic peak maximum at 102.20 °C. The TGA pattern shows a weight loss of 3.85% from 30 °C to 120 °C.

[0268] Table 15

[0269]

[0270]

[0271] Preparation of Crystal Form G in Example 12

[0272] Disperse 400 mg of Crystal Form B of the compound shown in Formula 1 in 4 mL of water, stir for 24 hours, filter and collect the filter cake, and dry it in vacuo at 40 °C for 3 hours to obtain a solid. Detected by X-ray powder diffraction, this product is defined as Crystal Form G, and the X-ray powder diffraction data are shown in Table 16, and the X-ray powder diffraction pattern is as Figure 9 shown. The DSC pattern shows endothermic peak maxima at 106.33 °C, 110.02 °C, and 143.36 °C. The TGA pattern shows that the compound loses 3.37% of its weight from 40 °C to 110 °C.

[0273] The DVS experimental data shows that under normal storage conditions (i.e., 25°C, 60% RH), the moisture absorption weight gain of this sample is approximately 0.12%; under accelerated test conditions (i.e., 70% RH), the moisture absorption weight gain is approximately 0.15%; under extreme conditions (90% RH), the moisture absorption weight gain is approximately 0.23%. During the humidity change process from 0% to 95%, the desorption process of this sample coincides with the adsorption process. The XRPD pattern shows that the crystal form has not changed before and after DVS detection.

[0274] Table 16

[0275]

[0276]

[0277] Preparation of Crystal Form H of Example 13

[0278] Add 5 mg of the compound shown in Formula 1 to 0.05 mL of methanol, stir for crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product. After detection by X-ray powder diffraction, this product is defined as crystal form H, and the XRPD pattern is as Figure 10 , and the characteristic peak positions are shown in Table 17. The DSC pattern shows that the peak values of the endothermic peaks are 96.47°C and 145.12°C, and the peak value of the exothermic peak is 105.49°C. The TGA pattern shows that the weight loss is 0.74% from 30°C to 130°C.

[0279] Table 17

[0280]

[0281] Study on the Stability of Influencing Factors in Example 14

[0282] Place crystal forms A and C open and flat, and investigate the stability of the samples under the conditions of light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH75%, RH 92.5%) respectively. The sampling investigation period is 1 month.

[0283] Table 18 Stability of Influencing Factors of Crystal Form A

[0284]

[0285]

[0286] Conclusion: Crystal form A has good physical and chemical stability under the influencing factor conditions.

[0287] Table 19 Stability of Influencing Factors of Crystal Form C

[0288]

[0289] Conclusion: Polymorph C has good physicochemical stability under stress conditions.

[0290] Experimental Example 15 Long-term / Accelerated Stability

[0291] The stabilities of polymorphs A and C were investigated under the conditions of 25°C / 60% RH and 40°C / 75% RH respectively:

[0292] Table 20 Long-term / Accelerated Stability of Polymorph A

[0293]

[0294] Conclusion: Polymorph A has good physical and chemical stabilities under long-term / accelerated conditions.

[0295] Table 21 Long-term / Accelerated Stability of Polymorph C

[0296]

[0297] Conclusion: Polymorph C has good physical and chemical stabilities under long-term / accelerated conditions.

Claims

1. A crystalline form A of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed as a diffraction angle 2θ has characteristic peaks at 8.441, 18.774, 19.269, 20.678, and 22.842, preferably at 8.441, 9.480, 12.659, 14.696, 15.448, 16.801, 17.337, 18.774, 19.269, 20.678, 22.842, 24.125, 28.012 There are characteristic peaks at 8.441, 9.480, 11.903, 12.071, 12.659, 14.696, 15.448, 16.801, 17.337, 17.584, 18.774, 19.269, 20.678, 22.842, 24.125, 25.311, 25.574, 28.012, 29.664, and 30.722, more preferably, there are characteristic peaks at 8.441, 9.480, 11.903, 12.071, 12.659, 14.696, 15.448, 16.801, 17.337, 17.584, 18.774, 19.269, 20.678, 22.842, 24.125, 2. The crystalline form A according to claim 1, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG3 .

3. A method for preparing the crystalline form A according to claim 1 or 2, wherein the method is selected from any of the following methods: Method 1: dissolving the compound of formula 1 in solvent I, adding solvent II, and stirring, wherein the solvent I is selected from one of ethanol, acetonitrile, acetone, ethyl acetate, dichloromethane, and methyl tert-butyl ether, and the solvent II is selected from one of water, n-heptane, cyclohexane, and n-hexane; Method 2: Add the compound of formula 1 into solvent III and stir, wherein the solvent III is selected from water, n-heptane, cyclohexane, n-hexane, 50% water / methanol, and 80% water / methanol; Method 3: dissolving the compound of formula 1 in solvent IV, and volatilizing the solvent, wherein the solvent IV is selected from one or more of alcohol solvents, ketone solvents, ester solvents, ether solvents, nitrile solvents, hydrocarbon solvents, N,N-dimethylformamide, and dimethyl sulfoxide; The alcohol solvent is selected from methanol, ethanol, and n-propanol; The ketone solvent is selected from acetone, 2-butanone, methyl isobutyl ketone, The ester solvent is selected from ethyl acetate and isopropyl acetate; The nitrile solvent is selected from acetonitrile; The ether solvent is selected from tetrahydrofuran, propylene glycol monomethyl ether, isopropyl ether, 2-methyl-tetrahydrofuran, and methyl tert-butyl ether; The hydrocarbon solvent is selected from n-heptane, dichloromethane, n-hexane and cyclohexane.

4. A crystalline form B of the compound represented by formula 1, having an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 11.008, 15.340, 19.836, 21.362, 22.163, and 24.849, preferably at 7.331, 11.008, 13.011, 15.340, 16.708, 18.938, 19.836, 21.362, 22.163, 24.849, 27.186, 28.080, and 29.

001. More preferably, there are characteristic peaks at 7.331, 11.008, 11.963, 13.011, 14.054, 15.345, 16.708, 18.938, 19.836, 21.362, 22.163, 22.623, 24.008, 24.849, 27.186, 28.080, 29.001, 30.010, and 34.

808.

5. The crystal form B according to claim 4, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG4 .

6. A method for preparing the crystalline form B as claimed in claim 4 or 5, comprising the step of adding the compound of formula 1 to isopropanol and stirring.

7. According to the crystal form according to any one of claims 1-2, 4-5, the 2θ angle error range is ±0.

20.

8. A pharmaceutical composition comprising the crystal form according to any one of claims 1-2, 4-5 and optionally a pharmaceutically acceptable excipient.

9. A method for preparing a pharmaceutical composition, comprising the step of mixing the crystal form according to any one of claims 1-2, 4-5 and a pharmaceutically acceptable excipient.

10. Use of the crystalline form according to any one of claims 1-2, 4-5, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing pain and pain-related diseases.

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