CN120058685A

CN120058685A - Crystalline form of substituted tetrahydrofuran compound and preparation method thereof

Info

Publication number: CN120058685A
Application number: CN202510191673.8A
Authority: CN
Inventors: 王林; 王洁; 刘冬青; 邵启云; 杜振兴; 冯君; 王捷; 卢玉; 朱宁
Original assignee: Shandong Shengdi Pharmaceutical Co ltd
Current assignee: Shandong Shengdi Pharmaceutical Co ltd
Priority date: 2024-02-23
Filing date: 2025-02-20
Publication date: 2025-05-30
Also published as: CN120058684A

Abstract

The present disclosure relates to a crystalline form of a substituted tetrahydrofuran compound and a method of preparing the same. In particular, the present disclosure provides crystalline forms a, B of (2 r,3s,4s,5 r) -3- (3, 4-difluoro-2-methoxyphenyl) -N- (2- ((Z) - (N' -methoxyformamidino) pyridin-4-yl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carboxamide, which have good stability and can be better used in clinical therapies.

Description

Crystalline form of substituted tetrahydrofuran compound and preparation method thereof

Technical Field

The present disclosure relates to a crystalline form of a substituted tetrahydrofuran compound and a preparation method thereof, which belong to the technical field of medicines.

Background

Nav is a class of transmembrane ion channel proteins. Sodium ion channels are classified into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R) according to whether they are effectively inhibited by nanomolar tetrodotoxin (tetrodotoxin, TTX). Nav1.8 is TTX-R type, and the coding gene is SCN10A, which is mainly existed in trigeminal ganglion neuron and DRG neuron, and has electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Nav1.8, the rise in action potential is mainly composed of Nav1.8 current. In some models of neuropathic pain, nerve damage results in elevated levels of Nav1.8 expression in axons and neuronal cell bodies. The use of Nav1.8 antisense oligonucleotides significantly reduced pain while reducing Nav1.8 expression. After intra-paw carrageenan (carageenan) injection, nav1.8 expression in DRG neurons was elevated. Nav1.8 knockout mice were unable to exhibit normal visceral inflammatory pain. The human Nav1.8 gene causes peripheral neuralgia after a functional gain mutation. According to a series of animal experiments and human genetic evidence, the selective inhibition of Nav1.8 has the potential of becoming a novel analgesic therapy, and can be used for treating various pain types such as inflammatory pain, neuropathic pain, postoperative pain, cancer pain and the like.

PCT/CN2023/114740 provides a Nav1.8 inhibitor having the chemical name 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 having the structure shown in formula 1,

The crystal form of the pharmaceutical active ingredient often affects the chemical stability of the drug, and the difference in crystallization conditions and storage conditions may cause a change in the crystal form structure of the compound, and sometimes other forms of crystal form are generated. Generally, amorphous pharmaceutical products have no regular crystalline structure and often have other drawbacks such as poor product stability, finer crystallization, difficult filtration, easy caking, poor flowability, etc. The polymorphic forms of the drug have different requirements for product storage, production and scale-up. Therefore, intensive studies on the crystalline forms of the aforementioned compounds are required to improve the properties of the aforementioned compounds in various aspects.

Disclosure of Invention

The present disclosure provides a novel crystalline form of a compound of formula 1, which has good stability and can be better applied to clinic.

The present disclosure provides a crystal form a of a compound represented by formula 1, wherein the X-ray powder diffraction pattern expressed by a diffraction angle 2θ has characteristic peaks at 8.441, 18.774, 19.269, 20.678, 22.842.

In some embodiments, the crystalline form of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, with 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, 28.012.

In some embodiments, the crystalline form of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, with a characteristic peak 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、30.722.

In some embodiments, the crystalline form of the compound of formula 1, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, is shown in figure 3.

The present disclosure also provides a method for preparing a crystalline form of a compound of formula 1, selected from any one of the following methods:

Dissolving a compound shown in a formula 1 in a solvent I, adding a solvent II, and stirring, wherein the solvent I is selected from one of ethanol, acetonitrile, acetone, ethyl acetate, dichloromethane and methyl tertiary butyl ether, and the solvent II is selected from one of water, n-heptane, cyclohexane and n-hexane;

adding a compound shown in a formula 1 into a solvent III, and stirring, wherein the solvent III is selected from one of water, n-heptane, cyclohexane, n-hexane, 50% water/methanol and 80% water/methanol;

Dissolving a compound shown in a formula 1 in a solvent IV, and volatilizing the solvent IV, wherein the solvent IV is one or more selected from alcohol solvents, ketone solvents, ester solvents, ether solvents, nitrile solvents, hydrocarbon solvents, 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 and 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 tertiary butyl ether;

The hydrocarbon solvent is selected from n-heptane, dichloromethane, n-hexane and cyclohexane;

The present disclosure provides a crystalline form B of a compound of formula 1, having characteristic peaks at 11.008, 15.345, 19.836, 21.362, 22.163, 24.849 in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

In some embodiments, form B of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, with 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, 29.001.

In some embodiments, form B of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, with a characteristic peak 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、34.808.

In some embodiments, form B of the compound of formula 1 has an X-ray powder diffraction pattern as shown in fig. 4, expressed in terms of diffraction angle 2θ.

The present disclosure also provides a method of preparing the compound of formula 1, form B, comprising the steps of adding the compound of formula 1 to isopropyl alcohol and stirring.

The present disclosure provides a crystalline form C of a compound of formula 1, having characteristic peaks at 8.276, 9.133, 9.449, 16.059, 17.065, 19.787 in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

In some embodiments, form C of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, with characteristic peaks at 8.276, 9.133, 9.449, 11.561, 13.160, 14.304, 15.356, 16.059, 17.065, 19.787.

In some embodiments, form C of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, with a characteristic peak 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.

In some embodiments, form C of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, as shown in fig. 5.

The present disclosure also provides a method for preparing form C of the compound of formula 1, selected from any one of the following methods:

In a first method, a compound of formula 1 is dissolved in a solvent V, and the solvent V is volatilized, wherein the 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) and 2-butanone/cyclohexane (V/v=1:5).

In the second method, the compound of the formula 1 is added into isopropanol to be dissolved and stirred.

The present disclosure provides a crystalline form D of a compound of formula 1, having characteristic peaks at 10.583, 12.303, 15.057, 19.257, 21.458, 24.017 in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

In some embodiments, form D of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, with a characteristic peak 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.

In some embodiments, form D of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, with a characteristic peak 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.

In some embodiments, form D of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, as shown in fig. 6.

The present disclosure also provides a method for preparing the compound of formula 1, form D, comprising the steps of dissolving the compound of formula 1 in methyl tert-butyl ether and stirring.

The present disclosure provides a crystalline form E of a compound of formula 1, having characteristic peaks at 8.019, 8.880, 10.562, 16.811, 19.576 in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

In some embodiments, form E of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, with 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.

In some embodiments, form E of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, with a characteristic peak 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.

In some embodiments, form E of the compound of formula 1 has an X-ray powder diffraction pattern as shown in fig. 7, expressed in terms of diffraction angle 2θ.

The present disclosure also provides a method for preparing the compound of formula 1, form E, comprising the steps of dissolving the compound of formula 1 in methyl tert-butyl ether, and volatilizing the solvent.

The present disclosure provides a compound of formula 1, form F, having characteristic peaks at 8.689, 10.964, 13.068, 16.715, 18.553, 20.413, in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

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

In some embodiments, form F of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, with 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.

In some embodiments, form F of the compound of formula 1 has an X-ray powder diffraction pattern as shown in fig. 8, expressed in terms of diffraction angle 2θ.

The present disclosure also provides a method for preparing the compound of formula 1, form F, comprising the step of dissolving the compound of formula 1 in 10% water/isopropanol, and volatilizing the solvent.

The present disclosure provides a crystalline form G of a compound of formula 1, having characteristic peaks at 13.088, 15.118, 16.762, 18.529, 19.547, 20.408, 22.329, in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

In some embodiments, form G of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, with a characteristic peak 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 some embodiments, form G of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, with a characteristic peak 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 some embodiments, form G of the compound of formula 1 has an X-ray powder diffraction pattern as shown in fig. 9, expressed in terms of diffraction angle 2θ.

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

The present disclosure provides a compound of formula 1, form H, having characteristic peaks at 8.641, 10.265, 13.716, 14.357, 17.455, 20.662 in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

In some embodiments, form H of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, with 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 some embodiments, form H of the compound of formula 1 has an X-ray powder diffraction pattern as shown in fig. 10, expressed in terms of diffraction angle 2θ.

The present disclosure also provides a method of preparing form H of the compound of formula 1, comprising the step of adding the compound of formula 1 to methanol or 10% water/methanol, and stirring.

In certain embodiments, the methods of preparation described in the present disclosure further comprise any one of crystallization, centrifugation (filtration), washing, or drying.

The crystallization modes of the present disclosure include, but are not limited to, stirred crystallization, stationary crystallization, or volatile crystallization. In some embodiments, the crystallization is stirred crystallization. In some embodiments, the devitrification is stationary devitrification.

The present disclosure also provides a pharmaceutical composition comprising the foregoing form a, form B, form C, form D, form E, form F, form G or form H, and optionally a pharmaceutical excipient from pharmaceutically acceptable excipients.

The present disclosure also provides a pharmaceutical composition prepared from the aforementioned form a, form B, form C, form D, form E, form F, form G or form H, and optionally pharmaceutically acceptable excipients.

The present disclosure also provides a method of preparing a pharmaceutical composition comprising the step of mixing the aforementioned form a, form B, form C, form D, form E, form F, form G or form H with a pharmaceutically acceptable excipient.

The present disclosure also provides the use of the foregoing form a, form B, form C, form D, form E, form F, form G or form H or from the foregoing compositions for the preparation of a medicament for the prevention and/or treatment of pain and pain-related disorders.

The use of 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, and the postoperative pain is preferably selected from the group consisting of bunion excision pain, hernia repair pain, and abdominal plastic pain.

The term "2θ or 2θ angle" as used in this disclosure refers to diffraction angle, θ is Bragg angle, and is expressed in degrees or degrees, and the error range of each characteristic peak 2θ is + -0.20 (including the case where numbers exceeding 1 decimal are rounded), 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.

The numerical values in the present disclosure are data on the determination calculation of the content of the relevant substances, and a certain degree of error is unavoidable. Generally, ±10% all fall within a reasonable error range. There is a degree of variation in error, depending on the context in which it is used, of no more than + -10%, which may be + -9%, + -8%, + -7%, + -6%, + -5%, + -4%, + -3%, + -2% or + -1%, preferably + -5%.

The starting materials used in the methods of preparing crystalline forms of the present disclosure may be any form of the compounds, including but not limited to, amorphous, any crystalline form, hydrates, solvates, and the like.

The drying temperature in the present disclosure is generally 25 to 100 ℃, preferably 40 to 70 ℃, and may be either normal pressure drying or reduced pressure drying.

The crystallization method disclosed in the present disclosure includes room temperature crystallization, cooling crystallization, volatile solvent crystallization, seeding crystallization induction, etc., wherein the cooling temperature is selected from 65 ℃ or less, preferably-10 ℃ to 60 ℃, and the crystallization process can be further stirred.

The term "differential scanning calorimetric analysis or DSC" in the present disclosure refers to measuring the temperature difference and the heat flow difference between a sample and a reference object during the temperature rising or constant temperature process of the sample, so as to characterize all physical changes and chemical changes related to thermal effects, and obtain phase change information of the sample.

According to the description of the hygroscopicity characteristic and the definition of the hygroscopicity weight increase in the '9103 medicine hygroscopicity guiding principle' in the fourth part of the 2015 edition of Chinese pharmacopoeia,

Deliquescence, which is the absorption of sufficient water to form a liquid;

The moisture absorption performance is very good, and the weight gain is not less than 15 percent;

the moisture absorption property is that the weight gain is less than 15 percent but not less than 2 percent;

Slightly wet permeability, wherein the weight gain is less than 2 percent but not less than 0.2 percent;

no or almost no moisture permeability, and the weight gain caused by moisture is less than 0.2 percent.

The "excipient" as described in this disclosure includes, but is not limited to, any auxiliary agent, carrier, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, or emulsifying agent that has been approved by the U.S. food and drug administration for use in humans or livestock animals.

Drawings

Figure 1 is an analgesic effect of compound 1 in a rat incision pain model.

Figure 2 is the effect of compound 1 on body weight in a rat incision pain model.

Fig. 3 is an XRPD pattern of compound 1 form a.

Fig. 4 is an XRPD pattern of compound 1 form B.

Fig. 5 is an XRPD pattern of compound 1 form C.

Fig. 6 is an XRPD pattern of compound 1 form D.

Fig. 7 is an XRPD pattern of compound 1 form E.

Fig. 8 is an XRPD pattern of compound 1 form F.

Fig. 9 is an XRPD pattern of compound 1 form G.

Fig. 10 is an XRPD pattern of compound 1 form H.

Detailed Description

The present disclosure will be explained in more detail below with reference to examples or experimental examples, which are only for illustrating technical solutions in the present disclosure, and do not limit the spirit and scope in the present disclosure.

Test conditions of the instrument used for the experiment:

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) is given in units of 10-6 (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO M with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD) as the solvent and Tetramethylsilane (TMS) as the internal standard.

MS was determined using an Agilent 1200/1290DAD-6110/6120 Quadrapol MS liquid chromatography-mass spectrometry (manufacturer: agilent, MS model: 6110/6120 Quadrapol MS).

Waters ACQuity UPLC-QD/SQD (manufacturers: waters, MS model: waters ACQuity Qda Detec-tor/waters SQ Detector)

THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive)

High Performance Liquid Chromatography (HPLC) analysis used AGILENT HPLC DAD, AGILENT HPLC VWD, and WATERS HPLC E2695-2489 high performance liquid chromatographs.

Chiral HPLC analysis was determined using an Agilent 1260DAD high performance liquid chromatograph.

The high performance liquid phase was prepared by using Waters 2545-2767, waters 2767-SQ Detecor2, shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument used CombiFlash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea on a smoke table as a carrier.

The average inhibition rate of kinase and IC50 value were measured by NovoStar microplate reader (BMG, germany).

The known starting materials of the present invention may be synthesized using or following methods known in the art, or may be purchased from the companies ABCR GmbH & Co.KG, acros Organics, ALDRICH CHEMICAL Company, shao Yuan chemical technology (Accela ChemBio Inc), darui chemical, and the like.

The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.

An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses Parr 3916EKX type hydrogenometer and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 ℃ without special description in the embodiment.

The monitoring of the reaction progress in the examples adopts Thin Layer Chromatography (TLC), the developing agent used in the reaction, the system of column chromatography eluent used for purifying the compound and the developing agent system of the thin layer chromatography comprise A methylene dichloride/methanol system, B normal hexane/ethyl acetate system and C petroleum ether/ethyl acetate system, the volume ratio of the solvent is regulated according to the polarity of the compound, and small amount of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for regulation.

XRPD is X-ray powder diffraction detection, which is carried out by using BRUKER D8 type X-ray diffractometer to specifically collect information, namely Cu anode (40 kV,40 mA), cu-K alpha 1 rayKα2 rayKbeta raysThe scanning mode is theta/2 theta, and the scanning range (2 theta range) is 5-45 degrees.

DSC is differential scanning calorimeter, a METTLER TOLEDO DSC 3+ differential scanning calorimeter is adopted for measurement, the temperature rising rate is 10 ℃ per minute, the specific temperature range is referred to a corresponding map (25-270 ℃ at most), and the nitrogen purging speed is 50mL per minute.

TGA is thermogravimetric analysis, wherein a METTLER TOLEDO TGA type 2 thermogravimetric analyzer is adopted for detection, the temperature rising rate is 10 ℃ per minute, the specific temperature range is referred to a corresponding map (30-350 ℃ at most), and the nitrogen purging speed is 50mL per minute.

DVS is dynamic moisture adsorption, which is detected by SMSDVS ADVANTAGE, humidity change is 50% -95% -0% -95% -50% at 25 ℃, step is 10% (the last step is 5%) (the specific range of humidity is based on the corresponding map, most of using methods are listed here), and the judgment standard is Tmax360min, dm/dt is not more than 0.002%.

EXAMPLE 1 preparation of Compounds of formula 1

(2R, 3S,4S, 5R) -3- (3, 4-difluoro-2-methoxyphenyl) -N- (2- ((Z) - (N' -methoxycarbamimidoyl) pyridin-4-yl) -4, 5-dimethyl

-5- (Trifluoromethyl) tetrahydrofuran-2-carboxamide 1

First step

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

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

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

MS m/z(ESI):353.2[M-1]。

Single configuration Compound (shorter retention time) 1b-1 (5.5 g, yield: 45.8%)

MS m/z(ESI):353.2[M-1]。

Chiral HPLC analysis with a retention time of 2.414 minutes and a purity of 99% (column: DAICEL)100 X 3mm,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).

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

MS m/z(ESI):353.2[M-1]。

Chiral HPLC analysis with a retention time of 2.724 minutes and a purity of 99% (column: DAICEL)100 X 3mm,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).

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

Compound 1B-1 (50 mg, 141. Mu. Mol) was dissolved in methylene chloride (10 mL), oxalyl chloride (40 mg, 315. Mu. Mol) and 1 drop of N, N-dimethylformamide were added under ice bath, the reaction was resumed at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride (3 mL), N-diisopropylethylamine (60 mg, 464. Mu. Mol) was added, a solution of 4-aminopyridine-2-carbonitrile 1c (30 mg, 251. Mu. Mol) in methylene chloride (1 mL) was added dropwise under ice bath, the reaction was stirred for 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to give the title compound 1d (45 mg, yield: 70%).

MS m/z(ESI):456.2[M+1]。

Third step

-5- (Trifluoromethyl) tetrahydrofuran-2-carboxamide 1

Compound 1d (100 mg, 219.6. Mu. Mol) was dissolved in 10mL of isopropanol, N-diisopropylethylamine (85.1 mg, 658.8. Mu. Mol) and thioglycolic acid (40.5 mg, 439. Mu. Mol, shanghai Bifida) were added, and the reaction was carried out at 80℃for 14 hours, and the reaction mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC TRIART-Exrs C, 30X 150mm, 5. Mu.m; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 35% -45%, flow rate: 30 mL/min) to give the title compound 1 (10 mg, yield: 18%).

MS m/z(ESI):503.2[M+1]。

¹H NMR(500MHz,DMSO-d₆):δ10.69(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).

Test example 1 determination of Nav1.8 inhibitory Activity of the presently disclosed Compounds

The purpose of the experiment was to investigate the effect of compounds on the nav1.8 ion channel in ex vivo experiments, which nav1.8 ion channel was stably expressed on HEK293 cells. After the Nav1.8 current is stabilized, the influence of the compound on the Nav1.8 ion channel can be obtained by comparing the magnitude of the Nav1.8 current before and after the compound is applied.

1 Experimental materials and instruments

1) Patch clamp amplifier PATCH CLAMP PC-505B (WARNER instruments)/MultiClamp 700A (Axon instrument)

2) Digital to analog converter Digidata 1440A (Axon CNS)/Digidata 1550A (Axon instruments)

3) MP-225 (SUTTER instrument)

4) Reverse microscope TL4 (Olympus)

5) Glass microelectrode drawing instrument PC-10 (NARISHIGE)

6) Microelectrode glass capillary B12024F (Wuhan microprobe science instruments Co., ltd.)

7) Dimethyl sulfoxide (DMSO) D2650 (Sigma-Aldrich)

8)TTX AF3014(Affix Scientific)

2 Experimental procedure

2.1 Compound formulation

Compounds for preparing extracellular and intracellular fluids were purchased from Sigma (St. Louis, MO) company, except NaOH and KOH for acid-base titration. Extracellular fluid (mM) was NaCl,137;KCl,4;CaCl ₂,1.8;MgCl₂, 1, HEPES,10, glucose, 10, pH 7.4 (NaOH titration). The intracellular fluid (mM) is aspartic acid, 140; mgCl ₂, 2;EGTA 11;HEPES,10;pH 7.2 (CsOH titration). All test compound and control compound solutions contained 1. Mu.M TTX.

The test compound was stored at a concentration of 9mM and dissolved in dimethyl sulfoxide (DMSO). The test day is dissolved in extracellular fluid again to prepare the required concentration.

2.2 Manual patch clamp test procedure

1) After the compound is prepared into a solution with a specified concentration, the liquid medicine is sequentially added into each pipeline according to the sequence from low concentration to high concentration, and each pipeline is marked.

2) Transferring the cells into a perfusion groove, applying positive pressure in the electrode, enabling the tip of the electrode to be in contact with the cells, adjusting a three-way valve of an air extractor to be in a three-way state, and then applying negative pressure to the electrode to enable the electrode and the cells to form high-resistance sealing. Continuing to apply negative pressure, the cell membrane breaks, forming a current path.

3) And after the cell rupture current is stable, sequentially carrying out perfusion with different concentrations. And if the current is stable for at least one minute, the next concentration can be replaced for perfusion. Each concentration was perfused for no more than five minutes.

4) And cleaning the perfusion groove. The washing is carried out according to the concentration of the liquid medicine from high to low, and the washing is carried out for 20 seconds for each concentration of the liquid medicine. Finally, the cells were rinsed with extracellular fluid for 1min.

2.3 Test Voltage equation (resting) and results

Cells were clamped at-80 mV and then depolarized to 10mV with a square wave for 10 ms to give Nav1.8 current. This procedure was repeated every 5 seconds. The maximum current induced by the square wave is detected, after which the test compound is perfused and after the reaction is stable, the intensity of the blockage is calculated.

3. Data analysis

The data is stored in the computer system for analysis. Data collection and analysis will be performed using pCLAMP 10 (Molecular Devices, union City, calif.), and the manager will review the results of the analysis. Current stabilization refers to a current that varies over time within a limited range. The magnitude of the current after stabilization was used to calculate the effect of the compound on this solubility.

The inhibitory activity of the compounds of the present disclosure on nav1.8 was determined by the above assay and the IC ₅₀ values measured are shown in table 1.

TABLE 1 IC for inhibition of Nav1.8 channel Activity by the compounds of the present disclosure ₅₀

Examples numbering	IC₅₀(nM)
		1	0.33

Conclusion the compounds in the present disclosure have a significant inhibitory effect on nav1.8 channel activity.

Test example 2 pharmacokinetic evaluation

1. SD rat test

SD rats were used as test animals and the drug concentration in plasma was determined at various times after administration of the compounds of the examples by lavage (i.g.) of SD rats using LC/MS/MS method. Pharmacokinetic behavior of the compounds of the present disclosure in SD rats was studied and their pharmacokinetic profile was assessed.

1.1 Test protocol

SD rats, 4 males, were provided by Venlhua laboratory animal technologies Co. The administration was by gastric lavage after one night of fasting.

The preparation of the medicine comprises the steps of weighing a certain amount of tested compound, and adding 5% DMSO, 5% Tween 80 and 90% physiological saline to prepare 0.2mg/mL colorless clear solution.

The administration dosage is 2mg/kg, and the administration volume is 10.0mL/kg.

Method of operation

Before and after administration for 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours, 0.2mL was collected from the orbit, placed in EDTA-K2 anticoagulation test tube, centrifuged at 10000rpm for 1 minute (4 ℃) and plasma was separated in 1 hour, and dry ice was preserved for testing. The blood collection to centrifugation process was operated under ice bath conditions. Feeding was performed 2 hours after administration.

Determination of the levels of test compound in SD rat plasma after drug administration at various concentrations SD rat plasma samples were taken at various times after administration at 25. Mu.L, 200. Mu.L of acetonitrile containing internal standard (verapamil 100 ng/ml) was vortexed and centrifuged at 3700rpm for 10 minutes. 0.1. Mu.L of the supernatant was subjected to LC/MS/MS analysis.

1.2 Pharmacokinetic parameter results

TABLE 2 pharmacokinetic parameters of the compounds of the present disclosure

Conclusion that the compound disclosed by the invention has high blood concentration and high exposure in SD rats and has obvious pharmacokinetic advantage.

2. C57 mouse test

2.1 Laboratory animals

The number of C57 mice is 18, the male and female mice are divided into 2 groups and 9 groups, each group comprises 3 mice at each time point, and the mice are provided by Vetolihua laboratory animal technology Co., ltd, production license SCXK (Zhe) 2019-0001 and SCXK (Beijing) 2019-0006, and are respectively injected into stomach and intravenous injection.

2.2 Pharmaceutical formulation

A certain amount of the test compound was weighed, and 5% DMSO+5% Tween 80+90% physiological saline was added to prepare 0.1mg/mL of a colorless clear solution (a group for parenteral administration) and 0.1mg/mL of a colorless clear solution (a group for intravenous administration).

2.3 Administration of drugs

The administration dosage of the stomach-irrigating administration group is 2.0mg/kg, and the administration volume is 20mL/kg.

Intravenous administration group, administration dose is 1.0mg/kg, administration volume is 10mL/kg.

2.4 Operation

The intragastric administration group is prepared by collecting blood from eye sockets for 0.1mL before and after administration for 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0 and 24.0 hours, placing into EDTA-K2 anticoagulation test tube, centrifuging at 10000rpm for 1 min (4 ℃) to separate blood plasma within 1 hour, and storing at-80 ℃. The blood collection to centrifugation process was operated under ice bath conditions.

Intravenous administration group blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0 and 24 hours before and after administration, and the same-gastric administration group was treated.

Determination of the amount of test Compound in plasma of C57 mice after drug administration at various concentrations Compound 1. Mu.L of C57 mouse plasma samples at various moments after administration were taken, 200. Mu.L of acetonitrile precipitated protein containing 100ng/ml of camptothecin (internal standard) was added to each sample, vortexed for 5 minutes, and centrifuged at 3700rpm for 10 minutes. 50. Mu.L of the supernatant was taken, 100. Mu.L of water was added, vortexed for 5 minutes, and 1. Mu.L of sample was injected for LC/MS/MS analysis.

2.5 Pharmacokinetic parameter results

TABLE 3 pharmacokinetic parameters of the compounds of the present disclosure

The conclusion is that the compound disclosed by the invention has the advantages of high blood concentration in a C57 mouse, large exposure, low clearance rate, higher bioavailability and pharmacokinetic advantage.

Test example 3 pharmacodynamic test

1. Purpose of experiment

The compounds of the present disclosure were evaluated for their analgesic potency in inhibiting rat pain in a rat incision pain model.

2. Experimental medicine

The compound of example 1.

25% PEG400+75% (10%TPGS+1%HPMC K100LV) solution was used.

3. Experimental methods and materials

3.1 Laboratory animals and feeding conditions

SD rats purchased from Beijing Vietnam laboratory animal Co., ltd (license number: SCXK (Zhe) 2019-0001) and weighing about 180g.

The feeding condition is 5 animals/cage feeding, light/dark period adjustment for 12/12 hours, constant temperature of 23+/-1 ℃ and humidity of 50-60%, and free feeding of water.

3.2 Grouping of animals

After adaptive rearing of SD rats, the groupings were as follows:

TABLE 4 Table 4

Note that one dose is administered only 1 time and i.g. is administered intragastrically.

3.3 Experimental method:

SD rats were weighed 170-190g and 9 were measured for mechanical pain threshold using an electronic tactile gauge. Then, an incision pain operation was performed, and after the operation was performed with sultai anesthesia (sultai-50,250 mg, diluted to 50ml with physiological saline, and injected with 2ml 200g body weight), an incision of 1cm long was made in the middle of the left hind paw sole with a 10-surgical blade, and the skin was sutured with 3-0 sterile silk surgical suture lines through the skin and fascia. The injured part was disinfected with penicillin and the animals were returned to their original place overnight for recovery. After the operation was resumed overnight, the rats were orally administered by gastric lavage, and the mechanical pain threshold was measured by an electronic tactile measuring instrument 5 hours after administration (about 24 hours after the operation).

3.4 Data statistics

Data were recorded using Excel statistical software, mean calculated as avg, SD value calculated as STDEV, SEM value calculated as STDEV/SQRT (number of animals per group), plotted using GRAPHPAD PRISM software, and statistically analyzed using one-way ANOVA and t-test.

Percent increase in threshold (%) = [ (G _t-G₀)/G₀ ] ×100 (%), where G _t is the dosing group plantar pain threshold and G ₀ is the vehicle group plantar pain threshold.

4. Results

The analgesic effects of the compound of example 1 in the rat incision pain model are shown in fig. 1 and table 5, and the body weight effects are shown in fig. 2;

TABLE 5 analgesic potency of compounds of the present disclosure in rat incision pain models

5. Conclusion(s)

Normal rats (weight 170-190 g) had a tenderness threshold of 26.2+ -1.6 gf and vehicle control group of 10.0+ -0.7 gf. The compounds of example 1 had 22.3, 14.9 and 10.8gf respectively at 200, 100 and 50mg/kg tenderness thresholds which were significantly increased by 122% (p < 0.001), 49% (p < 0.05) and 7% respectively over vehicle controls. The 200mg/kg tenderness threshold is significantly higher than the 100mg/kg tenderness threshold (p < 0.01), the 100mg/kg tenderness threshold is significantly higher than the 50mg/kg tenderness threshold (p < 0.05), the analgesic effect is significantly dose-dependent, and the administration has no effect on the body weight of the rat.

EXAMPLE 2 preparation of form A

120Mg of the compound represented by formula 1 was dissolved in 1.2mL of ethanol, 2.4mL of water was added, stirred for crystallization, filtered under reduced pressure, and dried under vacuum to obtain a solid. The product was defined as form a as detected by X-ray powder diffraction, the XRPD pattern shown in figure 3 and the characteristic peak positions shown in table 6. The DSC profile shows an endothermic peak at 130.10 ℃. TGA profile showed no significant weight loss. DVS testing showed that the samples had a hygroscopic gain of about 0.11% under normal storage conditions (i.e., 25 ℃, 60% RH), about 0.20% under accelerated experimental conditions (i.e., 70% RH), and about 0.60% under extreme conditions (90% RH). And the crystal form is retested after DVS detection, and the crystal form is not transformed.

TABLE 6

EXAMPLE 3 preparation of form A

Form a was prepared using a rinse method, which selected solvent pairs as shown in table 7 below. 6mg of the compound shown in the formula 1 is dissolved in 0.06mL of solvent A, 0.3mL of solvent B is added, and the mixture is stirred, crystallized, centrifuged, and the solid is collected and dried in vacuum to obtain the product. The product is in the form of form A as detected by X-ray powder diffraction.

TABLE 7

EXAMPLE 4 preparation of form A

5Mg of the compound represented by formula 1 was added with 0.5mL of a solvent as shown in the following table 8, stirred for crystallization, centrifuged, and the solid was collected and dried in vacuo to obtain a product, which was crystalline form a as detected by X-ray powder diffraction.

TABLE 8

Solvent(s)	Crystal form
		Water and its preparation method	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

EXAMPLE 5 preparation of form A

5Mg of the compound represented by the formula 1 was dissolved in 0.05mL of the solvent shown in the following Table 9, and the solvent was evaporated to obtain a solid, which was detected by X-ray powder diffraction and was the crystalline form A.

TABLE 9

EXAMPLE 6 preparation of form B

The compound (400 mg) represented by formula 1 was added to isopropyl alcohol (6 mL), stirring was continued at room temperature for 24 hours, solids were precipitated, and the cake was filtered and collected, and dried under vacuum at room temperature for 72 hours to give a solid product. The product was defined as form B as measured by X-ray powder diffraction, the X-ray powder diffraction data are shown in table 10, and the X-ray powder diffraction pattern is shown in fig. 4. The DSC profile shows an endothermic peak of 88.20 ℃,104.28 ℃,145.81 ℃. TGA profile shows a compound weight loss of 6.78% from 30 ℃ to 90 ℃ and 3.16% from 90 ℃ to 170 ℃.

Table 10

EXAMPLE 7 preparation of form C

The compound (2.0 g) shown in formula 1 was added to isopropyl alcohol (40 mL), heated and stirred for 60 ℃ to keep a solution for 10 minutes, naturally cooled to room temperature and stirred for 24 hours, a solid was precipitated, filtered and a filter cake was collected, and vacuum dried for 16 hours at 60 ℃ to obtain a solid product. The product was defined as form C as measured by X-ray powder diffraction, the X-ray powder diffraction data are shown in table 11, and the X-ray powder diffraction pattern is shown in fig. 5. DSC spectra showed an endothermic peak at 145.27 ℃. TGA profile showed little weight loss of the compound from 30 ℃ to 150 ℃.

DVS testing showed that the samples had a hygroscopic gain of about 0.23% under normal storage conditions (i.e., 25 ℃, 60% RH), about 0.28% under accelerated experimental conditions (i.e., 70% RH), and about 0.57% under extreme conditions (90% RH). And the crystal form is retested after DVS detection, and the crystal form is not transformed.

TABLE 11

EXAMPLE 8 preparation of form C

5Mg of the compound represented by the formula 1 was dissolved in 0.05mL of the solvent represented by the following Table 12, and the solvent was evaporated to obtain a solid, which was detected by X-ray powder diffraction and was crystalline form C.

Table 12

EXAMPLE 9 preparation of form D

Amorphous compound of formula 1 (30 mg) was added to methyl t-butyl ether (0.4 mL) and stirred for ultrasonic dissolution, solid was precipitated, stirred at room temperature for 24 hours, filtered and the cake was collected, and dried at room temperature for 1 hour under vacuum to give a solid product (20 mg, yield: 66.6%). The product was defined as form D as measured by X-ray powder diffraction, the X-ray powder diffraction data are shown in table 13, and the X-ray powder diffraction pattern is shown in fig. 6. The DSC spectrum shows an endothermic peak of 71.78 ℃ and 144.60 ℃. TGA profile shows 1.48% weight loss of the compound from 30 ℃ to 110 ℃.

TABLE 13

EXAMPLE 10 preparation of form E

5Mg of the compound represented by formula 1 was dissolved in 0.05mL of methyl t-butyl ether, and the mixture was subjected to evaporation and crystallization to obtain a product.

The product was defined as form E, XRPD pattern as shown in figure 7 and the characteristic peak positions as shown in table 14, as measured by X-ray powder diffraction. DSC profile showed that the endothermic peak was 73.30 ℃ and 144.52 ℃. TGA profile shows a weight loss of 2.84% at 30-120 ℃.

TABLE 14

EXAMPLE 11 preparation of form F

5Mg of the compound represented by formula 1 was dissolved in 0.05ml of 10% water/isopropyl alcohol, and the mixture was volatilized and crystallized to obtain a product. The product was defined as form F as detected by X-ray powder diffraction, the XRPD pattern shown in figure 8 and the characteristic peak positions shown in table 15. The DSC spectrum shows an endothermic peak at 80.00 ℃ and a 144.77 ℃ and an exothermic peak at 102.20 ℃. TGA profile shows a weight loss of 3.85% at 30-120 ℃.

TABLE 15

EXAMPLE 12 preparation of form G

Crystalline form B of compound of formula 1 (400 mg) was dispersed in 4mL of water, stirred for 24 hours, filtered and the filter cake was collected and dried under vacuum at 40 ℃ for 3 hours to give a solid. The product was defined as form G as measured by X-ray powder diffraction, the X-ray powder diffraction data are shown in table 16, and the X-ray powder diffraction pattern is shown in fig. 9. The DSC spectrum shows an endothermic peak at 106.33 ℃,110.02 ℃ and 143.36 ℃. TGA profile showed 3.37% weight loss of the compound from 40 ℃ to 110 ℃.

DVS experimental data showed that the samples had a hygroscopic gain of about 0.12% under normal storage conditions (i.e., 25 ℃ 60% rh), about 0.15% under accelerated test conditions (i.e., 70% rh), and about 0.23% under extreme conditions (90% rh). In the humidity change process of 0% -95%, the desorption process and the adsorption process of the sample are coincident. XRPD patterns showed no change in the crystalline form before and after DVS detection.

Table 16

EXAMPLE 13 preparation of form H

5Mg of the compound shown in the formula 1 is added with 0.05mL of methanol, stirred for crystallization, centrifuged, and the solid is collected and dried in vacuum to obtain the product. The product was defined as form H as detected by X-ray powder diffraction, the XRPD pattern shown in figure 10 and the characteristic peak positions shown in table 17. DSC profile showed endothermic peak 96.47 ℃ and 145.12 ℃ and exothermic peak 105.49 ℃. TGA profile shows a weight loss of 0.74% from 30 ℃ to 130 ℃.

TABLE 17

Example 14 influence factor stability study

The crystal form A, C is placed in an open and flat state, the stability of the sample under the conditions of illumination (4500 Lux), high temperature (40 ℃ and 60 ℃) and high humidity (RH 75% and RH 92.5%) is respectively inspected, and the sampling inspection period is 1 month.

TABLE 18 stability of form A influencing factors

The conclusion is that the physical and chemical stability of the crystal form A is good under the condition of influencing factors.

TABLE 19 stability of form C influencing factors

The conclusion is that the physical and chemical stability of the crystal form C is good under the condition of influencing factors.

Experimental example 15 Long term/accelerated stability

The stability was investigated by placing the crystalline form A, C under conditions of 25 ℃ per 60% rh, 40 ℃ per 75% rh:

TABLE 20 Crystal form A long term/accelerated stability

Conclusion form a has good physical and chemical stability under long term/accelerated conditions.

TABLE 21 Crystal form C long term/accelerated stability

Conclusion form C has good physical and chemical stability under long term/accelerated conditions.

Claims

1. Form a of a compound of formula 1, characterized by an X-ray powder diffraction pattern having characteristic peaks at 8.441, 18.774, 19.269, 20.678, 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, more preferably 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、30.722,

2. Form a according to claim 1, characterized in that the X-ray powder diffraction pattern expressed as diffraction angle 2Θ is shown in figure 3.

3. A process for the preparation of form a according to claim 1 or 2, selected from any one of the following:

the alcohol solvent is selected from methanol, ethanol and n-propanol;

the ester solvent is selected from ethyl acetate and isopropyl acetate;

The nitrile solvent is selected from acetonitrile;

the hydrocarbon solvent is selected from n-heptane, dichloromethane, n-hexane, and cyclohexane.

4. Form B of the compound of formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, with characteristic peaks at 11.008, 15.340, 19.836, 21.362, 22.163, 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, 29.001. More preferably, there is a characteristic peak 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、34.808.

5. Form B according to claim 4, characterized in that the X-ray powder diffraction pattern expressed as diffraction angle 2Θ is shown in figure 4.

6. A process for the preparation of form B as claimed in claim 4 or 5 comprising the step of adding a compound of formula 1 to isopropanol and stirring.

7. The crystalline form of any one of claims 1-2, 4-5, having a 2Θ angle error range of ± 0.20.

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

9. A process for the preparation of a pharmaceutical composition comprising the step of mixing the crystalline form of any one of claims 1-2, 4-5 with a pharmaceutically acceptable excipient.

10. Use of the crystalline form of any one of claims 1-2, 4-5, or the pharmaceutical composition of claim 8 in the manufacture of a medicament for the treatment and/or prevention of pain relief and pain related disorders.