TW202220962A - Crystal form of selective nav inhibitor and preparation method thereof - Google Patents

Abstract

The present disclosure provides a crystal form of a selective Na _Vinhibitor and a preparation method thereof. Specifically, A-E crystal forms of a compound 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d ₃)phenoxy)-4-(trifluoromethyl)benzylamino)-6-oxopyridazine-1(6 H)-yl)methoxy)-4-oxobutyric acid (Formula I) and a preparation method thereof are provided;

Description

Crystalline forms of selective NaV inhibitors and methods for their preparation

The present disclosure belongs to the technical field of medicine, and relates to a crystalline form of a selective Na _V 1.8 inhibitor and a preparation method thereof, in particular to the compound 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy) A , B, C, D, E crystal forms and preparation methods thereof.

This application claims the priority of Chinese patent application CN202010835117.7 with an application date of August 19, 2020. This application cites the full text of the above Chinese patent application.

Pain is one of the most common clinical symptoms and originates from nociceptors in the peripheral nervous system. This is a free nerve ending widely distributed in the skin, muscles, joints and visceral tissues of the body, which can convert the felt thermal, mechanical or chemical stimuli into nerve impulses (action potentials) and pass afferents Nerve fibers transmit to the part of their cell bodies located in the dorsal root ganglia (DRG), and finally to the higher nerve centers, causing pain sensation. The generation and conduction of action potentials in neurons depend on voltage-gated sodium channels (Na _V ) on the cell membrane. When the cell membrane is depolarized, the sodium ion channel is activated and the channel opens, causing an influx of sodium ions, which further depolarizes the cell membrane, leading to the generation of action potentials. Therefore, inhibiting abnormal sodium channel activity is helpful for the treatment and relief of pain. Currently, the local anesthetic lidocaine relieves pain by inhibiting Na _V. Non-selective Na _V inhibitors such as lamotrigine, lacosamide, mexiletine have also been successfully used to treat chronic pain.

However, due to the lack of subtype selectivity and narrow therapeutic window of Na _V inhibitors currently used in the clinic, the application scope is limited. Therefore, it is necessary to develop selective Na _V 1.8 inhibitors with higher activity, better selectivity, better pharmacokinetic properties and fewer side effects. WO2020169042 provides a selective Na _V 1.8 inhibitor whose chemical name is 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- _d3 )phenoxy)-4 -(trifluoromethyl)benzylamino)-6-oxopyridine-1( 6H )-yl)methoxy)-4-oxobutyric acid (formula I), which has been found to have relatively With good pharmaceutical activity, it is expected to be developed into a new selective Na _V 1.8 inhibitor, providing patients with new treatment options.

Those skilled in the art should know that the crystalline structure of the active ingredient of a drug often affects the physicochemical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the formation of other crystal forms. Generally speaking, amorphous pharmaceutical products have no regular crystal structure, and are often accompanied by defects such as poor product stability, finer crystallization, difficult filtration, easy agglomeration, and poor fluidity. In view of the importance of solid drug crystal forms and their stability in clinical treatment, the compound 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d ₃ )phenoxy) yl)-4-(trifluoromethyl)benzylamino)-6-oxopyridine-1( 6H )-yl)methoxy)-4-oxobutyric acid free base crystalline form, suitable for development Industrial production of drugs with good biological activity is of great significance.

The present disclosure provides the compound 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d3 ₎ phenoxy)-4-(trifluoromethyl)benzylamino) )-6-oxopyridine-1(6H)-yl)methoxy)-4-oxobutanoic acid (Formula I), crystal form A, X-ray powder diffraction expressed as diffraction angle 2θ Figure, there are characteristic peaks at 17.966, 19.759, 22.119, 23.676, 24.444, 25.003 and 29.122.

In some embodiments, Form A of the compound of Formula I has characteristic peaks at 11.946, 17.966, 19.759, 22.119, 23.676, 24.444, 25.003, 29.122, 30.154, and 31.278.

In some embodiments, Form A of the compound of Formula I has characteristic peaks at 5.919, 10.000, 11.946, 17.966, 19.759, 22.119, 23.676, 24.444, 25.003, 26.266, 29.122, 30.154, and 31.278.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form A of the compound of formula I in terms of diffraction angle 2 theta is shown in FIG. 1 .

The present disclosure also provides a method for preparing a crystal form of compound A of formula I, comprising: (a) converting 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d3 )) Phenoxy)-4-(trifluoromethyl)benzylamino)-6-oxopyridine-1(6H)-yl)methoxy)-4-oxobutyric acid mixed with solvent (I) , heating or stirring to dissolve, the solvent (I) is selected from dimethyl ether; (b) crystallization.

The volume (μl) of the solvent (I) described in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30 , 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155 , 160, 165, 170, 175, 180, 185, 190, 200.

The present disclosure provides an X-ray powder diffraction pattern of Form B of the compound of formula (I), expressed in diffraction angle 2 theta , with characteristic peaks at 17.895, 18.438, 20.282, 21.661, 22.639, 22.912 and 30.946.

In some embodiments, Form B of the compound of Formula I has characteristic peaks at 11.845, 15.281, 17.895, 18.438, 20.282, 21.661, 22.639, 22.912, 27.146, and 30.946.

In some embodiments, Form B of the compound of Formula I has characteristic peaks at 10.781, 11.845, 12.865, 15.281, 17.895, 18.438, 20.282, 21.661, 22.639, 22.912, 25.964, 27.146, and 30.946.

In some embodiments, the X-ray powder diffraction pattern represented by the diffraction angle 2 theta of the crystalline form B of the compound of formula I is shown in FIG. 2 . The present disclosure also provides a method for preparing a crystal form of compound B of formula I, comprising: Method 1: (a) 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy-) d 3) phenoxy)-4-(trifluoromethyl)benzylamino)-6-oxopyridine-1(6H)-yl)methoxy)-4-oxobutanoic acid and solvent ( II) Mixing, stirring to dissolve or heating to dissolve, the solvent (II) is selected from NN dimethylformamide (DMF), NN dimethylacetamide (DMA), dimethylsulfoxide (DMSO), N - at least one of methylpyrrolidone (NMP), acetone, 1,4-dioxane, tetrahydrofuran (THF) and water; (b) crystallization; or, method two: (a) 4-((4- (5-Chloro-2-(4-fluoro-2-(methoxy- d 3)phenoxy)-4-(trifluoromethyl)benzylamino)-6-oxopyridine-1( 6H)-yl)methoxy)-4-oxobutyric acid is mixed with solvent (III) selected from at least one of tetrahydrofuran (THF), dimethylsulfoxide (DMSO) and acetone (b) adding solvent (IV), crystallizing, and the solvent (IV) is selected from C _1-6 alkyl alcohol, isopropyl acetate, methyl tertiary butyl ether, methyl isobutyl ketone, two At least one of methyl chloride and water, the C _1-6 alkyl alcohol is preferably selected from ethanol or isopropanol.

The solvent (II), (III), (IV) used in the present disclosure can be used in a volume (μl) of 1-200 times the mass (mg) of the compound of formula I, and in a non-limiting embodiment, it can be 1, 5, 10 , 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135 , 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.

The present disclosure provides an X-ray powder diffraction pattern of the compound of formula (I) in Form C, expressed in diffraction angle 2 theta , with characteristic peaks at 4.836, 9.675, 14.266, 16.039, 22.856, 24.883 and 27.494.

In some embodiments, Form C of the compound of Formula I has characteristic peaks at 4.836, 9.675, 10.965, 14.266, 16.039, 18.507, 22.856, 24.883, 26.173, and 27.494.

In some embodiments, Form C of the compound of Formula I has characteristic peaks at 4.836, 9.675, 10.965, 14.266, 16.039, 17.900, 18.507, 19.581, 22.856, 24.883, 26.173, 27.494, and 29.485.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form C of the compound of formula I in terms of diffraction angle 2 theta is shown in FIG. 5 .

The present disclosure also provides a method for preparing Form C of the compound of formula I, comprising: (a) converting 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d ₎ )phenoxy)-4-(trifluoromethyl)benzylamino)-6-oxopyridine-1(6H)-yl)methoxy)-4-oxobutanoic acid and solvent (V ) mixing, heating or stirring to dissolve, the solvent (V) is selected from the mixed solvent formed by at least one of dimethyl sulfite, water or C _1-6 alkyl alcohol and acetonitrile, the C _1-6 alkyl The alcohol is preferably methanol; (b) crystallization.

In some embodiments, the concentrated crystallization can be concentrated under reduced pressure.

The volume (μl) of the solvent (V) described in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30 , 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155 , 160, 165, 170, 175, 180, 185, 190, 200.

The present disclosure provides an X-ray powder diffraction pattern of a compound of formula I, Form D, expressed in diffraction angles 2 theta , with characteristic peaks at 11.819, 17.915, 18.337, 19.781, 21.577, 23.618, and 24.375.

In some embodiments, Form D of the compound of formula I has characteristic peaks at 11.819, 15.201, 17.915, 18.337, 19.781, 20.050, 21.577, 22.832, 23.618, and 24.375.

In some embodiments, Form D of the compound of Formula I has characteristic peaks at 10.704, 11.819, 15.201, 17.915, 18.337, 19.781, 20.050, 21.577, 22.832, 23.618, 24.375, 27.077, and 29.058.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form D of the compound of formula I in terms of diffraction angle 2 theta is shown in FIG. 6 .

The present disclosure also provides a method for preparing the crystal form D of the compound of formula I, comprising: (a) Convert 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-4-(trifluoromethyl)benzylamino)- 6-oxopyridine-1(6H)-yl)methoxy)-4-oxobutyric acid is mixed with aqueous acetone; (b) Add anti-solvent dichloromethane solution for crystallization.

The present disclosure provides an X-ray powder diffraction pattern of the compound of formula I, Form E, expressed in diffraction angles 2 theta , with characteristic peaks at 5.282, 10.624, 11.767, 20.355, 21.618, 22.599, and 25.184.

In some embodiments, Form E of the compound of Formula I has characteristic peaks at 5.282, 10.624, 11.767, 15.963, 20.355, 21.618, 22.599, 22.958, 25.184, and 27.286.

In some embodiments, Form E of the compound of Formula I has characteristic peaks at 5.282, 10.624, 11.767, 13.464, 15.963, 18.312, 20.355, 21.618, 22.599, 22.958, 25.184, 27.286, and 30.888.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form E of the compound of formula I in terms of diffraction angle 2 theta is shown in FIG. 7 .

The present disclosure also provides a method for preparing Form E of the compound of formula I, comprising: (a) converting 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d ) )phenoxy)-4-(trifluoromethyl)benzylamino)-6-oxopyridine-1(6H)-yl)methoxy)-4-oxobutanoic acid mixed with tetrahydrofuran; ( b) Crystallization.

In some embodiments, the method for preparing a crystal form described in the present disclosure further comprises steps such as filtration, washing or drying. On the other hand, "crystallization" in the present disclosure includes, but is not limited to, stirring crystallization or static crystallization or stirring and cooling crystallization.

The present disclosure also provides a pharmaceutical composition prepared from any one of the aforementioned crystal forms.

The present disclosure also provides a pharmaceutical composition comprising the aforementioned crystalline form of the compound of formula I or a crystalline form prepared by the aforementioned method, and optionally a pharmaceutically acceptable carrier, diluent or excipient.

The present disclosure also provides a preparation method of a pharmaceutical composition, comprising the step of mixing the aforementioned crystal form of the compound of formula I or the crystal form prepared by the aforementioned method with a pharmaceutically acceptable carrier, diluent or excipient.

The present disclosure also provides the crystalline form of the compound of formula I or the crystalline form of the compound of formula I prepared by the aforementioned method or the aforementioned composition or the composition prepared by the aforementioned preparation method. For use in medicine, preferably, the voltage-gated sodium channel is Na _V 1.8.

The present disclosure also provides the aforementioned crystalline form of the compound of formula I or the crystalline form of the compound of formula I prepared by the aforementioned method, or the aforementioned composition or the aforementioned composition prepared by the aforementioned preparation method in preparation for treating and/or alleviating pain and pain-related diseases , Multiple sclerosis, Charcot-Marie-Douse disease, incontinence or use in a medicament for arrhythmia, preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain Pain, musculoskeletal pain, primary pain, bowel pain and idiopathic pain.

The “2 theta or 2 theta angle” in this disclosure refers to the diffraction angle, and θ is the Bragg angle, in degrees or degrees; the error range of each characteristic peak 2 theta is ±0.20, and ±0.2 includes more than 1 decimal place. Numbers are rounded. Can be -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.

"Differential Scanning Calorimetry or DSC" as used in this disclosure refers to the measurement of the temperature difference, heat flow difference between a sample and a reference during the heating or constant temperature of the sample to characterize all physical changes related to thermal effects and Chemical changes, get the phase transition information of the sample.

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

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiologically acceptable carriers and excipients Form. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

The crystallization described in the present disclosure includes, but is not limited to, stirring, cooling, concentrating, volatilizing, and beating and crystallization.

CE crystal forms described in this disclosure include, but are not limited to, compound 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d ₃ )phenoxy)-4-(tris Solvate crystal form of fluoromethyl)benzylamino)-6-oxopyridine-1(6H)-yl)methoxy)-4-oxobutanoic acid , the solvent includes but not Limited to acetonitrile or tetrahydrofuran.

"Solvates" as used in the present disclosure include, but are not limited to, complexes formed by combining a compound of formula I with a solvent.

In order to make the above-mentioned and other objects, features and advantages of the present invention more obvious and easy to understand, the following specific embodiments are given and described in detail in conjunction with the accompanying drawings.

The present disclosure will be explained in more detail below with reference to the embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure, but do not limit the essence and scope of the present disclosure.

The reagents used in this disclosure are commercially available.

Test conditions of the instruments used in the experiments in this disclosure: 1. Differential Scanning Calorimeter (DSC); Instrument Model: Mettler Toledo DSC 3+; Purge Gas: Nitrogen; Nitrogen Purge Rate: 50 mL/min ; Heating rate: 10.0 °C/min; Temperature range: 25-350 °C; 2. X-ray Powder Diffraction (XRPD); Instrument model: Bruker D8 Focus X-ray powder diffractometer; Ray: Monochrome Cu-Kα rays (λ=1.5406); Scanning mode: θ /2 θ , scanning range (2q range): 3~50°; Voltage: 40kV, Current: 40mA; 3. Thermogravimetric Analysis, TGA); Instrument Model: Mettler Toledo TGA2; Purge Gas: Nitrogen; Nitrogen Purge Rate: 50 mL/min; Heating Rate: 10.0℃/min; Temperature Range: 25-350℃; 4. Detection of Related Substances and Content: HPLC detection; Instrument model: Agilent 1200 DAD; Chromatographic column: Phenomenex kinetex EVOC18 4.6*250mm, 5um; Mobile phase A: KH ₂ PO ₄ , Mobile phase B: Acetonitrile; Flow rate: 1.0ml/min; Column temperature: 40°C; detection wavelength: 214nm. 5. The eluent system for column chromatography and the developing solvent system for thin layer chromatography used for purifying the compound include: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system. 6. The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" ⁶ > (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methylsilane (TMS). For MS measurement, Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

。 Example 1: Compound of Formula I 4-((4-(5-Chloro-2-(4-fluoro-2-(methoxy- d3 ₎ phenoxy)-4-(trifluoromethyl)benzyl Preparation of acylamino)-6-oxopyrida-1(6H)-yl)methoxy)-4-oxobutyric acid

.

The first step: 5-chloro-2-fluoro-4-(trifluoromethyl)benzyl chloride 1b 5-Chloro-2-fluoro-4-(trifluoromethyl)benzoic acid 1a (5.00 g, 20.6 mmol) was added to 15 mL of thionite chloride, and reacted at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 1b (5.38 g). The product was directly used in the next reaction without purification.

The second step: 5-chloro-2-fluoro-N-(6-oxo-1,6-dihydropyridine-4-yl)-4-(trifluoromethyl)benzamide 1c Aminopyridin-3-one (3.06 g, 24.8 mmol, prepared by the method disclosed in Example 386 on page 100 of the specification in WO2016004417) was dissolved in 40 mL of N -methylpyrrolidone, cooled to 0°C, Sodium hydride (2.06 g, 51.5 mmol, 60% purity) was slowly added in portions and stirred at 0°C for 30 minutes. Compound 1b (5.38 g, 20.6 mmol) was dissolved in 3 mL of N -methylpyrrolidone, slowly added dropwise to the above reaction solution, and stirred at room temperature overnight. The reaction solution containing the title compound 1c was used in the next step without purification.

The third step: 1-bromo-4-fluoro-2-(methoxy- d ₃ ) benzene 1e 2-bromo-5-fluorophenol 1d (1 g, 5.2 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd. ), deuterated iodomethane (911 mg, 6.3 mmol, Saan Chemical Technology (Shanghai) Co., Ltd.), potassium carbonate (1.45 g, 10.5 mmol), added N , N -dimethylformamide (10 mL), The reaction was stirred for 6 hours. The reaction solution was cooled to room temperature, ethyl acetate (20 mL) was added, and washed with water (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with developing solvent system A to obtain the title compound 1e (840 mg), yield: 71%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.49-7.45 (m, 1H), 6.66-6.57 (m, 2H).

The fourth step: 4-fluoro-2-(methoxy- d ₃ )phenol 1f was combined with compound 1e (840 mg, 4 mmol) and triisopropyl borate (987 mg, 5.25 mmol, Shanghai Titan Technology Co., Ltd.) Add to tetrahydrofuran/toluene mixed solution (150 mL/30 mL). The air in the reaction flask was replaced with argon, the temperature was lowered to -78°C, and n-butyllithium (1.6 M, 3.8 mL, 6.1 mmol) was slowly added dropwise, and the dropwise addition was completed in 20 minutes. It was naturally warmed to room temperature and stirred overnight. The ice bath was cooled to 0 °C, methanol (50 mL) was added, hydrogen peroxide (30 wt%, 10 mL) and 10% sodium hydroxide solution (40 mL) were added dropwise, and the mixture was stirred at room temperature for 1 hour. Saturated sodium thiosulfate solution (50 mL) was slowly added dropwise to the reaction solution, and extracted with ethyl acetate (200 mL×3). The organic phase was washed with saturated sodium bicarbonate solution (150 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with developing solvent system B to obtain the title compound 1f (570 mg), Yield: 97%. MS m/z (ESI): 144.0 [M-1] ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.89 (s, 1H), 6.85-6.82 (m, 1H), 6.76-6.72 (m, 1H), 6.59-6.54 (m, 1H).

The fifth step: 5-chloro-2-(4-fluoro-2-(methoxy- d ₃ )phenoxy)-N-(6-oxo-1,6-dihydropyridine-4-yl )-4-(trifluoromethyl)benzamide 1g was combined with compound 1c (1 g, 2.98 mmol), compound 1f (433 mg, 2.98 mmol) and cesium carbonate (1.02 g, 3.13 mmol, Shaoyuan Chemical Technology ( Shanghai) Co., Ltd.) added N -methylpyrrolidone (10 mL), and reacted at 80° C. for 3 hours. The reaction solution was cooled to room temperature, ethyl acetate (20 mL) was added, and washed with water (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with developing solvent system B to obtain the title compound 1 g (280 mg), yield: 20%. MS m/z (ESI): 461.0 [M-1] ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.87 (s, 1H), 11.03 (s, 1H), 8.06 (s, 1H), 7.93 (d, 1H), 7.29-7.23 (m, 2H), 7.16-7.13 (m, 1H), 7.01 (s, 1H), 6.88-6.83 (m, 1H).

The sixth step: 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(1-(hydroxymethyl)-6-oxo-1,6-di Hydrogen-4-yl)-4-(trifluoromethyl)benzylamine 1h Compound 1 g (6.1 g, 13.2 mmol) was added to 60 mL of methanol, added with formaldehyde solution (60 mL, 37 wt%, Sinopharm Chemical Reagent Co., Ltd.), and heated to reflux under argon protection for 16 hours. The reaction solution was concentrated under reduced pressure, filtered with suction to obtain a filter cake, and dried to obtain the title compound 1h (5.6 g), yield: 86%. MS m/z (ESI): 491.2 [M+1]

Step 7: 4-((4-(5-Chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-4-(trifluoromethyl)benzylamino)- 6-oxopyridine-1(6H)-yl)methoxy)-4-oxobutyric acid I Compound 1h (3.43 g, 7 mmol) was added to 80 mL of dichloromethane, followed by succinic anhydride (1.05 g) g, 10.5 mmol, Sinopharm Chemical Reagent Co., Ltd.), 4-dimethylaminopyridine (1.09 g, 8.8 mmol), N,N -diisopropylethylamine (1.81 g, 14 mmol), and reacted at 30°C overnight. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 2767-SQ Detector2, elution system: ammonium acetate, water, acetonitrile) to obtain the title compound I (2.7 g), yield: 65%. MS m/z (ESI): 589.0 [M-1], 591.0 [M+1] ¹ H NMR (400 MHz, DMSO- d ₆ ): δ12.21 (s, 1H), 11.93 (s, 1H), 8.07 (s, 1H), 8.02 (d, 1H), 7.34 (d, 1H), 7.30-7.26 (m, 1H), 7.16-7.13 (m, 1H), 7.01 (s, 1H), 6.88-6.83 ( m, 1H), 5.91 (s, 2H), 2.67-2.46 (m, 4H).

After dissolving the above compound in the third butanol solvent, the sample was freeze-dried to obtain the sample, and the final product was determined to be amorphous by XRPD.

Test Example 1: Determination of the Inhibitory Activity of Compounds of Formula I on Na _V 1.8

1. Experimental materials and instruments Patch clamp amplifier: patch clamp PC-505B (WARNER instruments)/MultiClamp 700A (Axon instrument). Digital-to-analog converters: Digidata 1440A (Axon CNS) / Digidata 1550A (Axon instruments). 1) Micro controller: MP-225 (SUTTER instrument). 2) Inverted microscope: TL4 (Olympus). 3) Glass microelectrode drawing instrument: PC-10 (NARISHIGE). 4) Micro-electrode glass capillary: B12024F (Wuhan Micro-Exploration Scientific Instrument Co., Ltd.). 5) Dimethyl sulfoxide (DMSO) D2650 (Sigma-Aldrich). 6) TTX AF3014 (Affix Scientific).

2. Experimental steps 2.1 Compound preparation Compounds for preparing intracellular and extracellular fluids were purchased from Sigma (St. Louis, MO), except for NaOH and KOH used for acid-base titration. Extracellular fluid (mM) was: NaCl, 137; KCl, 4; CaCl ₂ , 1.8; MgCl _2, 1; HEPES, 10; Glucose 10; pH 7.4 (NaOH titration). Intracellular fluid (mM) was aspartic acid, 140; MgCl ₂ , 2; EGTA 11; HEPES, 10; pH 7.2 (CsOH titration). Both test compound and control compound solutions contained 1 μM TTX. Test compounds are stored at 9 mM in dimethylsulfoxide (DMSO). On the test day, it was redissolved in extracellular fluid to prepare the required concentration. 2.2 Manual patch-clamp test process 1) After the compound is formulated into a solution with a specified concentration, the drug solution is added to each pipeline in order from low to high concentration, and each pipeline is marked. 2) Transfer the cells to the perfusion tank, apply positive pressure to the electrode, touch the electrode tip to the cells, adjust the three-way valve of the pumping device to the three-way state, and then apply negative pressure to the electrode to form a high resistance seal between the electrode and the cell. catch. Continue to apply negative pressure to rupture the cell membrane and form a current path. 3) After the cell permeation current is stable, perform perfusion with different concentrations in sequence. If the current is stable for at least one minute, you can switch to the next concentration for perfusion. The perfusion time for each concentration did not exceed five minutes. 4) Clean the perfusion tank. Rinse according to the concentration of the liquid from high to low, and rinse each concentration of liquid for 20s. Finally, rinse with extracellular fluid for 1 min. 2.3 Testing the voltage equation (resting) and results Cells were clamped at –80 mV and then depolarized to 10 mV with a square wave lasting 10 ms to obtain Na _V 1.8 currents. This procedure is repeated every 5 seconds. The maximum current induced by the square wave was detected. After it stabilized, the test compound was perfused. When the reaction stabilized, the blocking intensity was calculated.

3. Data analysis data will be stored in the computer system for analysis. Data acquisition and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA), and management will review the analysis results. Current stabilization refers to the fact that the current varies with time within a limited range. The magnitude of the current after stabilization is used to calculate the effect of the compound's solubility here. The inhibitory activity of the compound of the present disclosure on Na _V 1.8 was determined by the above test, and the measured IC ₅₀ value was 14.5 nM, which had a significant inhibitory effect on Na _V 1.8 channel activity.

Test Example 2: Room temperature solubility of the disclosed compounds in PBS solution at pH 7.4

1. Experimental materials and reagents: dimethyl sulfoxide (analytical grade), ethanol (analytical grade), acetonitrile (chromatographic grade), NaH ₂ PO ₄ 2H ₂ O (analytical grade), Na ₂ HPO ₄ 12H ₂ O (analytical grade) pure), ammonium acetate (analytical grade), sodium hydroxide, sodium chloride (analytical grade). Apparatus: Liquid Chromatograph.

2. Experimental steps 2.1 Preparation of pH 7.4 PBS solution: weigh 0.57 g NaH ₂ PO ₄ • 2H ₂ O, 5.55 g Na ₂ HPO ₄ • 12H ₂ O and 6.48 g NaCl, add ultrapure water, use 1 M NaOH or Adjust the pH to 7.4±0.05 with 1 M HCl, and add water to make up to 1L. Store in a 4°C refrigerator (shelf life is 6 months). 2.2 Preparation of compound PBS 7.4 solution: Weigh an appropriate amount of the compound to be tested and dissolve it with DMSO or DMSO: acetonitrile: ethanol = 1:1:1 to prepare a 10 mM stock solution of the compound to be tested. Precisely measure 10 μL of the test compound stock solution and 990 μL pH7.4 PBS solution in a 2 mL sample bottle, mix well, and the final solution DMSO concentration is 1% (v/v). The solution was prepared in duplicate, shaken on a plate bed at room temperature for 24 hours, centrifuged at 5000 rpm for 20 min, and the supernatant was transferred to a liquid chromatograph for analysis. 2.3 Preparation of reference solution: Precisely measure 10 μL of the sample stock solution to be tested (concentration 10 mM, dissolved in DMSO) and 990 μL of organic mixed solvent (usually DMSO: acetonitrile: ethanol = 1:1:1) in 2. mL vial and mix to obtain a clear 100 μM sample solution. It was filtered with a 0.45 μm organic phase microporous membrane, and the subsequent filtrate was analyzed by a liquid chromatograph.

3. Data processing Solubility (μM) = peak area of sample / peak area of reference * reference concentration (μM) * sample solution dilution Take the average of the two measurements as the final solubility. The solubility of the compound of the present disclosure in a PBS solution of pH 7.4 was measured to be 34.46 μM, indicating a relatively high solubility.

Example 2: Preparation of Crystal Form of Compound A of Formula I

The compound of formula I (38.9 mg) was added to dimethyl ether (DME), heated and stirred to dissolve, filtered while hot, the mother liquor was stirred at room temperature, a solid was precipitated, filtered, the filter cake was collected, and dried in vacuo to obtain the target product 22 mg, off-white solid, yield 56.6%.

According to X-ray powder diffraction detection, the product is crystal form A, the XRPD spectrum is shown in Figure 1, and the characteristic peak positions are shown in Table 1 below. The DSC spectrum shows that the endothermic peaks are 174.74°C and 186.27°C. The TGA spectrum shows that the weight loss is 1.89% at 25°C-145°C and 23.18% at 150°C-260°C.

DVS test shows that under 60%RH, the sample has a hygroscopic weight gain of about 0.401%; under 70%RH, the hygroscopic weight gain is about 0.513%; under extreme conditions (90%RH), the hygroscopic weight gain is about is 0.962%. The desorption process of this sample does not coincide with the adsorption process during the humidity change from 0% to 95%RH. After DVS detection, the crystal form was re-measured, and the crystal form did not change, indicating that the crystal form was stable. Table 1 Peak number 2 theta value [° or degrees] Relative Strength% 1 5.919 9.6 2 10.000 6.2 3 10.777 3.2 4 11.946 13.9 5 12.453 3.3 6 14.278 3.4 7 16.945 7.1 8 17.966 20.5 9 18.636 3.8 10 19.759 50.3 11 22.119 20.5 12 23.676 92.0 13 24.444 100.0 14 25.003 20.2 15 26.266 9.6 16 27.122 5.3 17 28.779 7.0 18 29.122 35.7 19 30.154 13.0 20 31.278 13.1 twenty one 34.346 2.4 twenty two 36.045 5.8 twenty three 39.576 3.7

Example 3: Preparation of Compound B of Formula I Crystal Form

The compound (1g) shown in formula I was added to 5mL of acetone and 0.1mL of dimethylformamide (DMF) mixed solvent, heated and stirred to dissolve, cooled for crystallization, filtered, the filter cake was collected, and vacuum dried to obtain the target product 833 mg, white solid, yield 83.3%.

Through X-ray powder diffraction detection, the XRPD spectrum of the B crystal sample is shown in Figure 2, and the characteristic peak positions are shown in Table 2 below. The DSC spectrum shows that the endothermic peaks are 201.29°C and 217.66°C. The TGA spectrum shows that the weight loss is 1.36% at 35°C-180°C and 22.22% at 185°C-260°C.

DVS test shows that under 60%RH, the sample has a hygroscopic weight gain of about 0.108%; under 70%RH, the hygroscopic weight gain is about 0.131%; under extreme conditions (90%RH), the hygroscopic weight gain is about is 0.163%. The desorption process of this sample was basically consistent with the adsorption process during the humidity change from 0% to 95%RH. After DVS detection, the crystal form was re-measured, and the crystal form did not change, indicating that the crystal form was stable. Table 2 Peak number 2 theta value [° or degrees] Relative Strength% 1 10.781 13.6 2 11.845 34.7 3 12.865 12.4 4 15.281 27.4 5 17.895 47.0 6 18.438 100.0 7 20.282 36.5 8 21.661 51.4 9 22.639 77.9 10 22.912 35.2 11 23.859 8.1 12 25.964 17.2 13 27.146 28.5 14 28.211 2.4 15 28.668 3.9 16 29.170 6.9 17 29.897 7.5 18 30.946 39.6 19 34.743 7.6

Example 4: Preparation of Compound B of Formula I Crystal Form

The compound represented by formula I (32.5 mg) was added to 0.5 mL of acetone, heated to dissolve, stirred for crystallization, filtered, the filter cake was collected, and vacuum-dried to obtain 23.4 mg of the target product as an off-white solid with a yield of 72%. It was detected as B crystal form by X-ray powder diffraction.

Example 5: Preparation of the crystal form of compound B of formula I

The compound represented by formula I (35.5 mg) was added to 0.5 mL of 1,4-dioxane, heated to dissolve, filtered while hot, stirred for crystallization, filtered, the filter cake was collected, and dried in vacuo to obtain 15.5 mg of the title product, Off-white solid, yield 43.7%, X-ray powder diffraction detected as B crystal form.

Example 6: Preparation of Compound B of Formula I Crystal Form

The compound represented by formula I (34.5 mg) was added to 1 mL of water, 1 mL of DMF was added under heating, stirred and dissolved, filtered while hot, the mother liquor was stirred at room temperature, filtered, the filter cake was collected, and dried in vacuo to obtain the target product 6.7 mg , off-white solid, the yield is 19.4%, and it is the B crystal form detected by X-ray powder diffraction.

Example 7: Preparation of crystal form of compound B of formula I

The compound represented by formula I (35.7 mg) was added to 1 mL of aqueous ethanol solution, the volume ratio of ethanol to water was 1:1, heated and stirred, filtered, the filter cake was collected, and dried in vacuo to obtain 31.2 mg of the title product as an off-white solid, which was collected. The yield was 87.4%, and it was found to be crystal form B by X-ray powder diffraction.

Example 8: Preparation of the crystal form of compound B of formula I

The compound represented by formula I (35.3 mg) was added to 0.5 mL of isopropanol aqueous solution, the volume ratio of isopropanol to water was 1:1, heated and stirred, filtered, the filter cake was collected, and vacuum-dried to obtain 29.9 mg of the title product, similar to White solid, the yield was 84.7%, and it was detected as B crystal form by X-ray powder diffraction.

Example 9: Preparation of the crystal form of compound B of formula I

Add DMSO (5.10kg) and acetone (9.0kg) to the 50L reactor, start stirring, add the compound shown in formula I (refer to 2.30kg), stir and dissolve back pressure filtration, wash with 9.0kg acetone after filter pressure filtration and transfer to a Class D clean area.

Purified water (23.0kg) was slowly added dropwise to the above filtrate, stirred for crystallization at room temperature, suction filtered, washed, and air-dried to obtain 2.07kg of the title product with a yield of 90%.

Through X-ray powder diffraction detection, the XRPD characteristic peak positions of the sample are shown in Table 3 below, and the spectrum is shown in Figure 3 . The DSC spectrum shows that the peak of the endothermic peak is 203.21 °C, and the spectrum is shown in Figure 4. table 3 Peak number 2 theta value [° or degrees] Relative Strength% 1 9.44 2.6 2 10.91 13.7 3 11.85 22.6 4 12.76 6.8 5 12.93 6.0 6 15.30 20.0 7 17.38 6.1 8 17.85 51.8 9 18.42 100.0 10 19.55 5.8 11 19.84 13.8 12 20.07 18.6 13 20.36 30.3 14 21.06 8.0 15 21.36 24.7 16 21.62 75.1 17 21.82 22.3 18 22.31 8.2 19 22.59 49.4 20 23.00 56.1 twenty one 23.85 8.8 twenty two 25.13 2.9 twenty three 25.40 5.4 twenty four 25.67 8.8 25 25.98 12.7 26 27.14 38.4 27 27.96 3.7 28 28.20 9.2 29 28.61 7.5 30 29.17 8.5 31 29.82 15.1 32 30.24 3.2 33 30.91 25.1 34 31.69 3.6 35 32.67 9.0 36 33.74 2.9 37 34.59 6.9 38 34.84 8.4 39 36.13 3.9

Example 10: Preparation of Compound C of Formula I Crystal Form

The compound represented by formula I (37 mg) was added to 0.5 mL of acetonitrile, heated and stirred, added with 0.1 mL of water, dissolved, filtered while hot, the mother liquor was stirred at room temperature, filtered, the filter cake was collected, and dried in vacuo to obtain the target product 29.3 mg, off-white solid, yield 79.2%, X-ray powder diffraction detection, the XRPD spectrum of the C crystal sample is shown in Figure 5, and its characteristic peak positions are shown in Table 4 below. The DSC spectrum shows that the endothermic peaks are 106.06°C, 117.19°C, 164.56°C, 184.61°C, 192.00°C and 240.79°C; TGA spectrum shows that the weight loss is 8.7% at 30°C-160°C and 22.33% at 160°C-260°C. Table 4 Peak number 2 theta value [° or degrees] Relative Strength% 1 4.836 44.9 2 9.675 81.5 3 10.965 37.3 4 11.746 19.1 5 14.266 46.2 6 15.560 15.6 7 16.039 71.1 8 17.900 19.8 9 18.507 32.6 10 19.581 20.5 11 21.335 16.2 12 21.633 17.3 13 22.076 18.8 14 22.856 38.8 15 23.820 14.1 16 24.883 100.0 17 26.173 28.4 18 27.494 43.8 19 28.187 9.8 20 29.033 15.5 twenty one 29.485 25.9 twenty two 30.704 14.6 twenty three 32.651 7.2 twenty four 33.464 7.4

Example 11: Preparation of Compound C of Formula I Crystal Form

The compound represented by formula I (10 mg) was added to 500 μl methanol and acetonitrile solution, the volume ratio of methanol and acetonitrile was 1:1, heated and stirred to dissolve, cooled and crystallized to obtain 8.6 mg of the title product as an off-white solid, the yield was 86% , was detected as C crystal form by X-ray powder diffraction.

Example 12: Preparation of Compound D of Formula I Crystal Form

The compound shown in formula I (10 mg) was added to a 10% acetone aqueous solution and dissolved, and methylene chloride was added to stir and crystallize, filter, and dry to obtain the target product, an off-white solid 3.2 mg, a yield of 32%, obtained by X-ray powder Diffraction detected as D crystal form. The XRPD spectrum of the D crystal form sample is shown in FIG. 6 , and the characteristic peak positions thereof are shown in Table 5 below. table 5 Peak number 2 theta value [° or degrees] Relative Strength% 1 5.923 20.0 2 10.704 29.4 3 11.819 71.1 4 12.654 15.0 5 15.201 41.4 6 17.915 60.1 7 18.337 100.0 8 19.781 64.3 9 20.050 47.5 10 21.577 83.1 11 22.832 43.2 12 23.618 93.9 13 24.375 92.3 14 24.968 16.5 15 25.333 9.9 16 25.836 11.7 17 27.077 38.4 18 28.120 6.4 19 28.485 6.2 20 29.058 37.3 twenty one 29.936 11.9 twenty two 30.932 30.3 twenty three 32.642 7.5 twenty four 34.606 5.7

Example 13: Preparation of Compound E of Formula I Crystal Form

The compound shown in formula I (10mg) was added to 500m of tetrahydrofuran solution and dissolved, volatilized at room temperature, and centrifuged to dry to obtain the target product, off-white solid 8.9mg, yield 89%, detected as E crystal by X-ray powder diffraction type. The XRPD spectrum of the E crystal form sample is shown in FIG. 7 , and the characteristic peak positions thereof are shown in Table 6 below. The DSC spectrum shows that the endothermic peaks are 177.11°C, 195.88°C and 213.29°C; the TGA spectrum shows that the weight loss is 1.068% at 30°C-160°C and 22.919% at 160°C-260°C. Table 6 Peak number 2 theta value [° or degrees] Relative Strength% 1 5.282 80.1 2 10.624 65.0 3 11.767 36.7 4 13.464 10.1 5 14.781 5.4 6 15.238 10.0 7 15.963 34.2 8 17.430 9.8 9 18.312 16.9 10 20.355 48.9 11 21.618 100.0 12 22.599 54.8 13 22.958 29.3 14 23.781 9.1 15 25.184 73.4 16 26.144 8.8 17 27.286 32.5 18 29.262 2.9 19 29.992 4.8 20 30.888 11.7 twenty one 32.624 8.1 twenty two 34.561 4.4

Example 14: Stability study of compound A crystal form of formula I under accelerated conditions

The crystal form A of the compound of formula I (HPLC: 99.3%) was prepared with reference to the foregoing examples and placed under the experimental conditions in Table 7 for stability investigation under accelerated conditions. The results are shown below. Table 7 condition time (days) purity% Crystal form start 0 99.3 A Light (4500 Lux) 7 99.3 A 14 99.3 A 30 99.3 A 40℃ 7 99.3 A 14 99.3 A 30 99.2 A 60℃ 7 99.2 A 14 99.2 A 30 99.1 A 75%RH 7 99.3 A 14 99.3 A 30 99.1 A 92.5%RH 7 99.3 A 14 99.3 A 30 99.1 A

The experimental results show that the X-ray powder diffraction pattern of the crystal form A of the compound of formula I under the above conditions is consistent with the initial X-ray powder diffraction, indicating that the crystal form A of the compound of formula I has good physical stability, at 60 ℃ The change in absolute value of purity is small under the condition of 92.5% RH and 92.5%, indicating good chemical stability.

Example 15: Stability study of compound A crystal form of formula I under long-term accelerated conditions

The crystal form A of the compound of formula I (HPLC: 98.8%) was prepared with reference to the foregoing examples and placed under the experimental conditions in Table 8 for long-term and accelerated stability investigation. The results are shown below. Table 8 Test conditions time (month) purity(%) Crystal form initial 98.8 A 25℃, 60%RH 1 98.3 A 2 98.1 A 3 98.0 A 40℃, 75%RH 1 98.2 A 2 97.8 A 3 98.2 A

The experimental results show that the X-ray powder diffraction pattern of the crystal form A of the compound of formula I under the above conditions is consistent with the initial X-ray powder diffraction, indicating that the crystal form A of the compound of formula I has good physical stability. , 60% RH and 40 ℃, 75% RH under the conditions of the absolute value of purity changes are small, showing good chemical stability.

Example 16: Stability study of compound B crystal form of formula I under accelerated conditions

The crystal form B of the compound of formula I (HPLC: 99.2%) was prepared with reference to the foregoing examples and placed under the experimental conditions in Table 9 for stability investigation under accelerated conditions. The results are shown below. Table 9 condition time (days) color, character purity% Crystal form start 0 white solid 99.2 B Light (4500 Lux) 5 white solid 99.2 B 10 white solid 99.1 B 30 white solid 99.2 B 40℃ 5 white solid 99.1 B 10 white solid 99.1 B 30 white solid 99.1 B 60℃ 5 white solid 99.1 B 10 white solid 99.1 B 30 white solid 99.0 B 75%RH 5 white solid 99.1 B 10 white solid 99.1 B 30 white solid 99.1 B 92.5%RH 5 white solid 99.0 B 10 white solid 98.9 B 30 white solid 99.1 B

The experimental results show that the X-ray powder diffraction pattern of the B crystal form of the compound of formula I under the above conditions is consistent with the initial X-ray powder diffraction, indicating that the B crystal form of the compound of formula I has good physical stability, at 60 ℃ The change in absolute value of purity is small under the condition of 90% RH and 90% RH, indicating good chemical stability.

Example 17: Stability study of compound B crystal form of formula I under long-term accelerated conditions

The crystal form B of the compound of formula I (HPLC: 99.2%) was prepared with reference to the foregoing examples and placed under the experimental conditions in Table 10 for long-term and accelerated stability investigation. The results are shown below. Table 10 Test conditions time (month) purity(%) Crystal form initial 99.2 B 25℃, 60%RH 1 99.2 B 2 99.1 B 3 99.1 B 40℃, 75%RH 1 99.2 B 2 99.1 B 3 99.1 B

The experimental results show that the X-ray powder diffraction pattern of the crystal form B of the compound of formula I under the above conditions is consistent with the initial X-ray powder diffraction, indicating that the crystal form B of the compound of formula I has good physical stability. , 60% RH and 40 ℃, 75% RH under the conditions of the absolute value of purity changes are small, showing good chemical stability.

Although the present invention has been disclosed as above with examples, it is not intended to limit the present invention. Those with ordinary knowledge in the technical field to which the present invention pertains can make some changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention should be determined by the scope of the appended patent application.

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Figure 1: XRPD pattern of the crystalline form A of the compound of formula I. Figure 2: XRPD pattern of the crystalline form B of the compound of formula I. Figure 3: XRPD pattern of the crystalline form B of the compound of formula I (Example 9). Figure 4: DSC spectrum of the crystalline form B of the compound of formula I (Example 9). Figure 5: XRPD pattern of the crystalline form C of the compound of formula I. Figure 6: XRPD pattern of the crystalline form D of the compound of formula I. Figure 7: XRPD pattern of the crystalline form E of the compound of formula I.

Claims (14)

A compound 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d ₃ )phenoxy)-4-(trifluoromethyl)benzylamino)-6 -A crystal form of oxopyridine-1(6H)-yl)methoxy)-4-oxobutyric acid , wherein the X-ray powder diffraction pattern of the compound represented by the diffraction angle 2 θ angle is in Characteristic peaks at 17.966, 19.759, 22.119, 23.676, 24.444, 25.003 and 29.122, preferably at 11.946, 17.966, 19.759, 22.119, 23.676, 24.444, 25.003, 29.122, 30.154 and 31.919, 154. , 11.946, 17.966, 19.759, 22.119, 23.676, 24.444, 25.003, 26.266, 29.122, 30.154 and 31.278 have characteristic peaks, the most preferred X-ray powder diffraction pattern represented by the diffraction angle 2θ is shown in Figure 1. A method for preparing crystal form A according to claim 1, comprising: (a) 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d ₃ )benzene) Oxy)-4-(trifluoromethyl)benzylamino)-6-oxopyridine-1(6H)-yl)methoxy)-4-oxobutanoic acid mixed with solvent (I) , heating or stirring to dissolve, the solvent (I) is selected from dimethyl ether; (b) crystallization. A compound 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d ₃ )phenoxy)-4-(trifluoromethyl)benzylamino)-6 -The crystal form B of oxopyridine-1(6H)-yl)methoxy)-4-oxobutyric acid, wherein the X-ray powder diffraction pattern of the compound represented by the diffraction angle 2θ angle is at 17.895 , 18.438, 20.282, 21.661, 22.639, 22.912 and 30.946 have characteristic peaks or have characteristic peaks at 11.845, 15.281, 17.895, 18.438, 20.282, 21.661 and 22.609, preferably at 11.845, 15.2381, 2.6. Characteristic peaks at 22.639, 22.912, 27.146 and 30.946, more preferably at 10.781, 11.845, 12.865, 15.281, 17.895, 18.438, 20.282, 21.661, 22.639, 22.912, 25.964, 27.146 and 30.946 The X-ray powder diffraction pattern represented by the 2θ angle is shown in Fig. 2 . A method for preparing crystal form B according to claim 3, comprising: Method 1: (a) 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d3 ) )phenoxy)-4-(trifluoromethyl)benzylamino)-6-oxopyridine-1(6H)-yl)methoxy)-4-oxobutyric acid and solvent (II) Mixing, stirring to dissolve or heating to dissolve, the solvent (II) is selected from NN dimethylformamide, NN dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetone, 1,4- At least one of dioxane, tetrahydrofuran and water; (b) crystallization; or, method two: (a) 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy) yl- d3 )phenoxy)-4-(trifluoromethyl)benzylamino)-6-oxopyridine-1(6H)-yl)methoxy)-4-oxobutyric acid and solvent (III) mixing, the solvent (III) is selected from at least one of tetrahydrofuran, dimethylsulfoxide and acetone; (b) adding a solvent (IV) to crystallize, and the solvent (IV) is selected from C _1- At least one of ₆ alkyl alcohol, isopropyl acetate, methyl tertiary butyl ether, methyl isobutyl ketone, dichloromethane and water, the C _1-6 alkyl alcohol is preferably selected from ethanol or isopropanol . A compound 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d ₃ )phenoxy)-4-(trifluoromethyl)benzylamino)-6 -C crystalline form of oxopyridine-1(6H)-yl)methoxy)-4-oxobutyric acid , wherein the X-ray powder diffraction pattern of the compound represented by the diffraction angle 2 θ angle, in There are characteristic peaks at 4.836, 9.675, 14.266, 16.039, 22.856, 24.883 and 27.494, preferably 9.67 at 4.836, 9.675, 10.965, 14.266, 16.039, 18.507, 22.856, 24.883, 26.173 and 27.49, more preferably at 4.536. , 10.965, 14.266, 16.039, 17.900, 18.507, 19.581, 22.856, 24.883, 26.173, 27.494 and 29.485 have characteristic peaks, and the most preferred X-ray powder diffraction pattern represented by the diffraction angle 2θ is shown in Figure 3. A method for preparing crystal form C according to claim 5, comprising: (a) 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d ₃ )benzene) Oxy)-4-(trifluoromethyl)benzylamino)-6-oxopyridine-1(6H)-yl)methoxy)-4-oxobutyric acid mixed with solvent (V) , heating or stirring to dissolve, the solvent (V) is selected from the mixed solvent formed by at least one of dimethyl sulfite, water or C _1-6 alkyl alcohol and acetonitrile, the C _1-6 alkyl alcohol is preferably Methanol; (b) Crystallization. A compound 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d ₃ )phenoxy)-4-(trifluoromethyl)benzylamino)-6 -The D crystal form of oxopyridine-1(6H)-yl)methoxy)-4-oxobutyric acid, wherein the X-ray powder diffraction pattern of the compound represented by the diffraction angle 2θ angle, in Characteristic peaks at 11.819, 17.915, 18.337, 19.781, 21.577, 23.618 and 24.375, preferably at 11.819, 15.201, 17.915, 18.337, 19.781, 20.010, 21.5117, 22.832, 23.618 and 24.7375 , 15.201, 17.915, 18.337, 19.781, 20.050, 21.577, 22.832, 23.618, 24.375, 27.077 and 29.058 have characteristic peaks, and the most preferred X-ray powder diffraction pattern represented by the diffraction angle 2θ is shown in Figure 4. A compound 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d ₃ )phenoxy)-4-(trifluoromethyl)benzylamino)-6 - the tetrahydrofuran E crystal form of oxopyridine-1(6H)-yl)methoxy)-4-oxobutyric acid , wherein, the X-ray powder diffraction pattern of the compound represented by the diffraction angle 2θ angle, There are characteristic peaks at 5.282, 10.624, 11.767, 20.355, 21.618, 22.599 and 25.184, preferably at 5.282, 10.624, 11.767, 15.963, 20.355, 21.618, 22.599, 22.958, 25.184 and 27.286, more preferably at 5.282, 27.286 There are characteristic peaks at 10.624, 11.767, 13.464, 15.963, 18.312, 20.355, 21.618, 22.599, 22.958, 25.184, 27.286 and 30.888, and the most preferred X-ray powder diffraction pattern represented by the diffraction angle 2θ is shown in Figure 5. A crystalline form as claimed in any one of claims 1, 3, 5, 7 or 8, wherein the 2- theta angular error range is ±0.20. A pharmaceutical composition prepared from the crystal form described in any one of claims 1, 3, 5, 7, 8 or 9. A pharmaceutical composition comprising the crystal form according to any one of claims 1, 3, 5, 7, 8 or 9 or the crystal form prepared by the method according to any one of claims 2, 4 or 6, and Optionally from a pharmaceutically acceptable carrier, diluent or excipient. A preparation method of a pharmaceutical composition, comprising preparing the crystal form according to any one of claim 1, 3, 5, 7, 8 or 9 or the method described in any one of claim 2, 4 or 6 The step of mixing the crystalline form with a pharmaceutically acceptable carrier, diluent or excipient. A crystal form according to any one of claims 1, 3, 5, 7, 8 or 9, a crystal form prepared by the method according to any one of claims 2, 4 or 6, or a crystal form according to claim 10 or 11 Use of the composition or the composition prepared by the preparation method described in claim 12 in the preparation of a drug for inhibiting voltage-gated sodium channels in subjects, preferably, the voltage-gated sodium channels are Na _V 1.8. A crystal form according to any one of claims 1, 3, 5, 7, 8 or 9, a crystal form prepared by the method according to any one of claims 2, 4 or 6, or a crystal form according to claim 10 or 11 The composition or the composition prepared by the preparation method described in claim 12 is prepared for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, Charcot-Marie-Douse disease, Use in a drug for incontinence or arrhythmia, preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain pain.

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