Salt of boronic acid β-lactamase inhibitor, crystal form, and preparation method therefor

Abstract

The present disclosure relates to a salt of a boronic acid β-lactamase inhibitor, a crystal form, and a preparation method therefor. Specifically, provided in the present disclosure are a crystal form and a salt form of a compound represented by formula I and a preparation method therefor. The corresponding salt has good stability and can be better used in clinical treatment.

Description

Salts, crystal forms, and preparation methods of borate β-lactamase inhibitors Technical Field

[0001] This invention relates to salts, crystal forms, and preparation methods of borate β-lactamase inhibitors, and also to the application of said salts and crystal forms in the preparation of medicaments for treating related diseases. Background Technology

[0002] β-lactam antibiotics are the most commonly used antibacterial drugs. The main resistance mechanism of Gram-negative bacteria and some Gram-positive bacteria to β-lactam antibiotics is the production of various β-lactamases that hydrolyze the β-lactam ring, causing inactivation of these antibiotics. β-lactamase inhibitors, on the other hand, can bind to and inactivate the enzymes produced by bacteria, thereby reducing drug resistance and improving the efficacy of antibiotics. β-lactamase inhibitors are mainly divided into inhibitors containing a β-lactam ring structure and inhibitors without a β-lactam ring structure.

[0003] Inhibitors containing a β-lactam ring structure, also known as suicide enzyme inhibitors or irreversible competitive enzyme inhibitors, work by forming a strong and irreversible non-covalent complex with β-lactamases. Serine nucleophilically attacks the amide bond, opening the β-lactam ring, followed by rearrangement, thus inactivating the enzyme and destroying its own structure. These inhibitors can inhibit most class A β-lactamases except carbapenemases, but have no inhibitory effect on the vast majority of class B, C, and D enzymes. Inhibitors without a β-lactam ring structure reversibly bind to the active site of bacterial β-lactamases without destroying their own structure, thus exhibiting long-lasting enzyme inhibition.

[0004] Compound 1 not only has a broader antibacterial spectrum and stronger antibacterial effect, but its safety is also better than that of existing inhibitors, and it has broad clinical application prospects and huge market potential.

[0005] There are currently no reports on the salt forms and crystal forms of Formula 1 compounds. Therefore, in-depth research into the crystal forms and salt forms of Formula 1 compounds that have superior physicochemical or pharmaceutical properties is of great significance for drug storage and clinical treatment. Summary of the Invention

[0006] The present invention provides a crystal form A of the compound of Formula 1, which, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 9.16±0.20°, 24.32±0.20°, and 25.45±0.20°.

[0007] In some embodiments of the present invention, the aforementioned crystal form A, which is subjected to Cu-Kα radiation, has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 7.70±0.20°, 8.44±0.20°, 9.16±0.20°, 14.45±0.20°, 23.76±0.20°, 24.32±0.20°, 25.45±0.20°, and 26.50±0.20°.

[0008] In some embodiments of the present invention, the aforementioned crystal form A, irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 7.26±0.10°, 7.70±0.10°, 8.44±0.10°, 9.16±0.10°, 10.44±0.10°, 11.59±0.10°, 12.82±0.10°, 14.10±0.10°, 14.45±0.10°, 14.86±0.10°, 15.26±0.10°, 16.06±0.10°, 16.86±0.10°, 17.15±0.10°, 17.67±0.10°. 0.10°, 18.35±0.10°, 19.29±0.10°, 20.80±0.10°, 21.25±0.10°, 22.03±0.10°, 22.71±0.10°, 23.10±0.10°, 23.76±0.10°, 24.32±0.10°, 25.45±0.10°, 26.50±0.10°, 27.43±0.10°, 28.50±0.10°, 29.61±0.10°, 31.03±0.10°, 35.69±0.10°, 37.13±0.10°, 38.14±0.10° and 39.54±0.10°.

[0009] In some embodiments of the present invention, the XRPD pattern of the crystal form A is shown in Figure 1.

[0010] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form A has a peak value of an endothermic peak at 213.6±3℃.

[0011] In some embodiments of the present invention, the DSC spectrum of the crystal form A is shown in Figure 2.

[0012] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form A shows a weight loss of 0.6% between 25°C and 150°C, and a weight loss of 10.4% between 150°C and 230°C.

[0013] In some embodiments of the present invention, the TGA spectrum of the crystal form A is shown in Figure 3.

[0014] The present invention provides a crystal form B of the compound of Formula 1, which, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 6.01±0.20°, 21.95±0.20°, and 27.37±0.20°.

[0015] In some embodiments of the present invention, the aforementioned crystal form B, which is subjected to Cu-Kα radiation, has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 6.01±0.20°, 16.22±0.20°, 17.11±0.20°, 18.24±0.20°, 21.95±0.20°, 22.24±0.20°, 25.64±0.20°, and 27.37±0.20°.

[0016] In some embodiments of the present invention, the aforementioned crystal form B, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 6.01±0.10°, 6.56±0.10°, 10.81±0.10°, 12.12±0.10°, 14.47±0.10°, 16.22±0.10°, 17.11±0.10°, and 18.24±0.10°. 20.92±0.10°, 21.95±0.10°, 22.24±0.10°, 23.64±0.10°, 24.59±0.10°, 25.64±0.10°, 26.46±0.10°, 27.37±0.10°, 28.09±0.10°, 28.44±0.10°, 31.12±0.10°, 33.14±0.10° and 34.45±0.10°.

[0017] In some embodiments of the present invention, the XRPD pattern of the crystal form B is shown in Figure 4.

[0018] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form B has a peak value of an endothermic peak at 171.9±3℃.

[0019] In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form B is shown in Figure 5.

[0020] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form B shows a weight loss of 1.2% between 30°C and 100°C, and a weight loss of 26.4% between 100°C and 210°C.

[0021] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form B is shown in Figure 6.

[0022] This invention provides a pharmaceutically acceptable salt of compound of formula 1.

[0023] The medicinal salts are selected from sodium salts, potassium salts, N'N-dibenzylethylenediamine salts, and choline salts.

[0024] In some technical solutions of the present invention, the pharmaceutically acceptable salt of the compound of formula 1 is selected from sodium salt, potassium salt, N'N-dibenzylethylenediamine salt and choline salt.

[0025] In some technical solutions of the present invention, the pharmaceutically acceptable salt of the above-mentioned compound of formula 1 is selected from sodium salts, preferably the molar ratio of compound of formula 1 to sodium hydroxide is 1:0 to 2.1, more preferably 1:1.0 to 2.0, more preferably 1.5:2.05, and most preferably 1:2 or 1:2.05.

[0026] In some technical solutions of the present invention, the pharmaceutically acceptable salt of the above-mentioned compound of formula I is selected from potassium salts, preferably the molar ratio of compound of formula I to potassium hydroxide is 1:0 to 2.1, more preferably 1:1.0 to 2.0, more preferably 1:1.5 to 2.0, and most preferably 1:2 or 1:1.6.

[0027] In some technical solutions of the present invention, the pharmaceutically acceptable salt of the above-mentioned compound of formula 1 is selected from choline salts, preferably the molar ratio of compound of formula 1 to choline is 1:0 to 2.1, more preferably 1:1.0 to 2.0, more preferably 1:1.50 to 2.0, and most preferably 1:1.8 or 1:1.85.

[0028] This invention provides a method for preparing a pharmaceutically acceptable salt of a compound of formula 1, the method comprising:

[0029] 1) Weigh an appropriate amount of compound 1 and basic ligand into a sample vial, add an appropriate solvent and carry out a salt formation reaction at 50°C. After stirring for an appropriate time, suspend the sample under appropriate conditions for a certain period of time.

[0030] 2) After centrifuging the suspension, place the resulting solid sample in a vacuum drying oven at room temperature or 40°C and dry overnight to obtain the product.

[0031] In some technical solutions of the present invention, the method for preparing the pharmaceutically acceptable salt of the compound of formula 1 uses a solvent selected from one or more of hydrocarbon solvents, ether solvents, alcohol solvents, ester solvents, ketone solvents, nitrile solvents, halogenated hydrocarbon solvents, nitrogen-containing solvents, water, and dimethyl sulfoxide.

[0032] In some technical solutions of the present invention, the method for preparing the pharmaceutically acceptable salt of the compound of formula 1 includes, but is not limited to, cyclohexane, n-heptane, and toluene as the hydrocarbon solvent; the ether solvent includes, but is not limited to, ethylene glycol methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, propylene glycol methyl ether, methyl tert-butyl ether, or 1,4-dioxane as the ether solvent; the alcohol solvent includes, but is not limited to, methanol, ethanol, isopropanol, n-propanol, or trifluoroethanol as the alcohol solvent; the ester solvent includes, but is not limited to, ethyl acetate, isopropyl acetate, ethyl formate, or butyl formate as the ester solvent; the ketone solvent includes, but is not limited to, acetone or 4-methyl-2-pentanone as the ketone solvent; the nitrile solvent includes, but is not limited to, acetonitrile as the nitrile solvent; the halogenated hydrocarbon solvent includes, but is not limited to, dichloromethane, chloroform, or carbon tetrachloride as the halogenated hydrocarbon solvent; and the nitrogen-containing solvent includes, but is not limited to, N-methylpyrrolidine and dimethylacetamide as the nitrogen-containing solvent.

[0033] The present invention provides a sodium salt crystal form A of Formula 1, which, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 7.16±0.20°, 9.22±0.20°, and 36.31±0.20°.

[0034] In some embodiments of the present invention, the sodium salt crystal form A of the above-mentioned Formula 1 compound is characterized by having characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction (XRPD) pattern of the crystal form when subjected to Cu-Kα radiation: 7.16±0.20°, 9.22±0.20°, 14.33±0.20°, 15.15±0.20°, 15.48±0.20°, 21.58±0.20°, 26.28±0.20°, 36.31±0.20°.

[0035] In some embodiments of the present invention, the sodium salt crystal form A of the above-mentioned Formula 1 compound, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 7.16±0.10°, 9.22±0.10°, 14.33±0.10°, 15.15±0.10°, 15.48±0.10°, 16.84±0.10°, 17.46±0.10°, 18.20±0.10°, 18.88±0.10°, 21.58±0.10°, 22.34±0.10°, 22.65±0.10°, 26.28±0.10°, and 26.91±0.10°. 0°, 27.47±0.10°, 27.86±0.10°, 28.23±0.10°, 28.89±0.10°, 29.49±0.10°, 30.60±0.10°, 31.22±0.10°, 31.82±0.10°, 32.56±0.10°, 33.94±0.10°, 36.06±0.10°, 36.31±0.10°, 37.79±0.10°, 38.24±0.10°, 39.85±0.10°, 40.55±0.10°, 41.29±0.10°, 42.69±0.10° and 43.91±0.10°.

[0036] In some embodiments of the present invention, the sodium salt crystal form A of the above-mentioned Formula 1 compound has an XRPD spectrum as shown in Figure 7.

[0037] In some embodiments of the present invention, the sodium salt crystal form A of the above-mentioned Formula 1 compound has a peak value of an endothermic peak at 194.4±3℃ in its differential scanning calorimetry curve.

[0038] In some embodiments of the present invention, the DSC spectrum of the sodium salt crystal form A of the above-mentioned Formula 1 compound is shown in Figure 8.

[0039] In some embodiments of the present invention, the thermogravimetric analysis curve of sodium salt crystal form A of the above-mentioned Formula 1 compound shows a weight loss of 0.6% between 25°C and 120°C, and a weight loss of 9.9% between 120°C and 230°C.

[0040] In some embodiments of the present invention, the TGA spectrum of sodium salt crystal form A of the above-mentioned Formula 1 compound is shown in Figure 9.

[0041] In some embodiments of the present invention, when the sodium salt crystal form A of a compound of Formula 1 is analyzed by single-crystal X-ray diffraction, the crystal form belongs to the monoclinic crystal system and the space group is P21 / c.

[0042] In some embodiments of the present invention, the cell parameters of sodium salt crystal form A of the above-mentioned Formula 1 compound are: α = 90°, β = 97.806(8)°, γ = 90°, crystal volume

[0043] In some embodiments of the present invention, when the sodium salt crystal form A of the above-mentioned Formula 1 compound is analyzed using single-crystal X-ray diffraction, the crystal form belongs to the monoclinic crystal system with space group P21 / c; the cell parameters of the crystal form are: α = 90°, β = 97.806(8)°, γ = 90°, crystal volume The crystal size is 0.25 × 0.04 × 0.02 mm. 3 The molecular formula is C 11 H 12 BNNa2O7 has a molecular weight of 327.01.

[0044] The present invention provides sodium salt crystal form B of Formula 1, which, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 8.15±0.20°, 13.11±0.20°, and 16.31±0.20°.

[0045] In some embodiments of the present invention, the sodium salt crystal form B of the above-mentioned Formula 1 compound, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 6.25±0.20°, 8.15±0.20°, 13.11±0.20°, 16.31±0.20°, 17.99±0.20°, 24.55±0.20°, 26.01±0.20°, and 26.36±0.20°.

[0046] In some embodiments of the present invention, the sodium salt crystal form B of the above-mentioned Formula 1 compound, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 6.25±0.10°, 8.15±0.10°, 9.45±0.10°, 12.47±0.10°, 13.11±0.10°, 13.83±0.10°, 16.31±0.10°, 17.52±0.10°, 17.99±0.10°, 19.27±0.10°, 20.67±0.10°, 21.02±0.10°, 22.61±0.10°, 24.19±0.10°, 24.55±0.10°, 24. 79±0.10°, 26.01±0.10°, 26.36±0.10°, 26.77±0.10°, 28.07±0.10°, 29.08±0.10°, 29.65±0.10°, 31.59±0.10°, 32.17±0.10°, 33.03±0.10°, 33.79±0 0.10°, 34.41±0.10°, 35.36±0.10°, 35.71±0.10°, 36.02±0.10°, 37.58±0.10°, 38.37±0.10°, 39.79±0.10°, 41.44±0.10°, 42.63±0.10° and 44.57±0.10°.

[0047] In some embodiments of the present invention, the sodium salt crystal form B of the above-mentioned Formula 1 compound has an XRPD pattern as shown in Figure 10.

[0048] In some embodiments of the present invention, the sodium salt crystal form B of the above-mentioned Formula 1 compound has a peak value of an endothermic peak at 76.0±3℃ and 116.3±3℃ respectively in its differential scanning calorimetry curve.

[0049] In some embodiments of the present invention, the DSC spectrum of the sodium salt crystal form B of the above-mentioned Formula 1 compound is shown in Figure 11.

[0050] In some embodiments of the present invention, the thermogravimetric analysis curve of sodium salt crystal form B of the above-mentioned Formula 1 compound shows a weight loss of 5.0% between 25°C and 80°C, and a weight loss of 10.6% between 80°C and 150°C.

[0051] In some embodiments of the present invention, the TGA spectrum of sodium salt crystal form B of the above-mentioned Formula 1 compound is shown in Figure 12.

[0052] The present invention provides sodium salt crystal form C of Formula 1, which, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 6.32±0.20°, 7.35±0.20°, and 13.59±0.20°.

[0053] In some embodiments of the present invention, the sodium salt crystal form C of the above-mentioned Formula 1 compound, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 6.32±0.20°, 7.35±0.20°, 11.55±0.20°, 12.76±0.20°, 13.59±0.20°, 16.45±0.20°, 22.22±0.20°, and 26.58±0.20°.

[0054] In some embodiments of the present invention, the sodium salt crystal form C of the above-mentioned Formula 1 compound, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 6.32±0.10°, 7.35±0.10°, 10.33±0.10°, 11.55±0.10°, 12.76±0.10°, 13.59±0.10°, 15.13±0.10°. 0.10°, 16.45±0.10°, 18.16±0.10°, 18.98±0.10°, 19.6±0.10°, 21.02±0.10°, 22.22±0.10°, 24.2±0.10°, 24.9±0.10°, 26.58±0.10°, 30.09±0.10°, 35.24±0.10° and 37.87±0.10°.

[0055] In some embodiments of the present invention, the sodium salt crystal form C of the above-mentioned Formula 1 compound has an XRPD pattern as shown in Figure 13.

[0056] In some embodiments of the present invention, the sodium salt crystal form C of the above-mentioned Formula 1 compound has a differential scanning calorimetry curve with an endothermic peak at 63.6±3℃ and 99.4±3℃.

[0057] In some embodiments of the present invention, the sodium salt crystal form C of the above-mentioned Formula 1 compound has a DSC spectrum as shown in Figure 14.

[0058] In some embodiments of the present invention, the TGA spectrum of sodium salt crystal form C of the above-mentioned Formula 1 compound is shown in Figure 15.

[0059] The present invention provides a sodium salt crystal form D of Formula 1, which, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 5.47±0.20°, 6.05±0.20°, and 25.70±0.20°.

[0060] In some embodiments of the present invention, the sodium salt crystal form D of the above-mentioned Formula 1 compound, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 5.47±0.20°, 6.05±0.20°, 10.97±0.20°, 13.79±0.20°, 20.74±0.20°, 25.70±0.20°, 27.99±0.20°, and 29.06±0.20°.

[0061] In some embodiments of the present invention, the sodium salt crystal form D of the above-mentioned Formula 1 compound, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 5.47±0.10°, 6.05±0.10°, 9.41±0.10°, 10.97±0.10°, 11.40±0.10°, 12.93±0.10°, 13.42±0.10°, 13.79±0.10°, 14.62±0.10°, and 15.52±0.10°. 0°, 15.91±0.10°, 16.51±0.10°, 16.95±0.10°, 17.97±0.10°, 18.49±0.10°, 19.42±0.10°, 19.99±0.10°, 20.74±0.10°, 25.70±0.10°, 27.99±0.10°, 29.06±0.10°, 30.29±0.10°, 36.12±0.10°, 36.97±0.10° and 39.17±0.10°.

[0062] In some embodiments of the present invention, the sodium salt crystal form D of the above-mentioned Formula 1 compound has an XRPD spectrum as shown in Figure 16.

[0063] In some embodiments of the present invention, the sodium salt crystal form D of the above-mentioned Formula 1 compound has a peak value of an endothermic peak at 85.3±3℃ in its differential scanning calorimetry curve.

[0064] In some embodiments of the present invention, the sodium salt crystal form D of the above-mentioned Formula 1 compound has a DSC spectrum as shown in Figure 17.

[0065] In some embodiments of the present invention, the thermogravimetric analysis curve of sodium salt crystal form D of the above-mentioned Formula 1 compound shows a weight loss of 18.7% between 31°C and 200°C.

[0066] In some embodiments of the present invention, the TGA spectrum of sodium salt crystal form D of the above-mentioned Formula 1 compound is shown in Figure 18.

[0067] The present invention provides a sodium salt crystal form E of Formula 1, which, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 5.02±0.20°, 9.96±0.20°, and 10.29±0.20°.

[0068] In some embodiments of the present invention, the sodium salt crystal form E of the above-mentioned Formula 1 compound, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 5.02±0.20°, 8.21±0.20°, 9.96±0.20°, 10.29±0.20°, 19.91±0.20°, 26.05±0.20°, 34.35±0.20°, and 39.75±0.20°.

[0069] In some embodiments of the present invention, the sodium salt crystal form E of the above-mentioned Formula 1 compound, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 5.02±0.10°, 8.21±0.10°, 9.96±0.10°, 10.29±0.10°, 13.09±0.10°, 13.92±0.10°, 16.35±0.10°, 18.00±0.10°, 19.91±0.10°, 26.05±0.10°, 34.35±0.10°, 35.40±0.10°, and 39.75±0.10°.

[0070] In some embodiments of the present invention, the sodium salt crystal form E of the above-mentioned Formula 1 compound has an XRPD spectrum as shown in Figure 19.

[0071] In some embodiments of the present invention, the differential scanning calorimetry curve of the sodium salt of the above-mentioned Formula 1 compound, crystal form E, has a peak value of an endothermic peak at 55.6±3℃, 100.5±3℃ and 157.3±3℃.

[0072] In some embodiments of the present invention, the sodium salt crystal form E of the above-mentioned Formula 1 compound has a DSC spectrum as shown in Figure 20.

[0073] In some embodiments of the present invention, the thermogravimetric analysis curve of sodium salt crystal form E of the above-mentioned Formula 1 compound shows a weight loss of 15.4% between 30°C and 180°C.

[0074] In some embodiments of the present invention, the TGA spectrum of the sodium salt crystal form E of the above-mentioned Formula 1 compound is shown in Figure 21.

[0075] The present invention provides a sodium salt crystal form F of Formula 1, which, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 5.72±0.20°, 11.45±0.20°.

[0076] In some embodiments of the present invention, the sodium salt crystal form F of the above-mentioned Formula 1 compound has an XRPD spectrum as shown in Figure 22.

[0077] In some embodiments of the present invention, the sodium salt crystal form F of the above-mentioned Formula 1 compound has a peak value of an endothermic peak at 106.8±3℃ in its differential scanning calorimetry curve.

[0078] In some embodiments of the present invention, the sodium salt crystal form F of the above-mentioned Formula 1 compound has a DSC spectrum as shown in Figure 23.

[0079] In some embodiments of the present invention, the TGA spectrum of the sodium salt crystal form F of the above-mentioned Formula 1 compound is shown in Figure 24.

[0080] The present invention provides a sodium salt crystal form G of Formula 1, which, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 6.54±0.20°, 13.18±0.20°, and 17.38±0.20°.

[0081] In some embodiments of the present invention, the sodium salt crystal form G of the above-mentioned Formula 1 compound, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 6.54±0.20°, 13.18±0.20°, 13.71±0.20°, 17.38±0.20°, 25.02±0.20°, 26.65±0.20°, 27.39±0.20°, and 35.26±0.20°.

[0082] In some embodiments of the present invention, the sodium salt crystal form G of the above-mentioned Formula 1 compound, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 6.54±0.10°, 9.98±0.10°, 13.18±0.10°, 13.71±0.10°, 15.21±0.10°, 16.47±0.10°, 17.38±0.10°, 21.09±0.10°, 22.16±0.10°, 23.76±0.10°, 25.02±0.10°, 26.65±0.10°, 27.39±0.10°, 35.26±0.10°, and 36.80±0.10°.

[0083] In some embodiments of the present invention, the sodium salt crystal form G of the above-mentioned Formula 1 compound has an XRPD spectrum as shown in Figure 25.

[0084] In some embodiments of the present invention, the sodium salt crystal form G of the above-mentioned Formula 1 compound has a peak value of an endothermic peak at 58.1±3℃ and 317.3±3℃ in its differential scanning calorimetry curve.

[0085] In some embodiments of the present invention, the sodium salt crystal form G of the above-mentioned Formula 1 compound has a DSC spectrum as shown in Figure 26.

[0086] In some embodiments of the present invention, the thermogravimetric analysis curve of the sodium salt crystal form G of the above-mentioned Formula 1 compound shows a weight loss of 6.2% between 23°C and 210°C.

[0087] In some embodiments of the present invention, the TGA spectrum of the sodium salt crystal form G of the above-mentioned Formula 1 compound is shown in Figure 27.

[0088] The present invention provides a potassium salt crystal form A of Formula 1, which, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 7.47±0.20°, 22.49±0.20°, and 34.00±0.20°.

[0089] In some embodiments of the present invention, the potassium salt crystal form A of the above-mentioned Formula 1 compound, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 7.47±0.20°, 15.81±0.20°, 22.49±0.20°, 30.13±0.20°, 33.07±0.20°, 34.00±0.20°, 37.91±0.20°, and 39.36±0.20°.

[0090] In some embodiments of the present invention, the potassium salt crystal form A of the above-mentioned Formula 1 compound, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 7.47±0.10°, 9.06±0.10°, 14.95±0.10°, 15.28±0.10°, 15.81±0.10°, 20.08±0.10°, 21.52±0.10°, 22.49±0.10°, 23.10±0.10°, 25.02±0.10°, 25.86±0.10°, 26. 21±0.10°, 27.37±0.10°, 27.74±0.10°, 29.47±0.10°, 30.13±0.10°, 31.90±0.10°, 33.07±0.10°, 34.00±0.10°, 34.62±0.10°, 35.26±0.10°, 36.74±0.10°, 37.91±0.10°, 39.36±0.10°, 39.68±0.10°, 40.36±0.10°, 41.13±0.10° and 43.52±0.10°.

[0091] In some embodiments of the present invention, the potassium salt crystal form A of the above-mentioned Formula 1 compound has an XRPD spectrum as shown in Figure 28.

[0092] In some embodiments of the present invention, the potassium salt crystal form A of the above-mentioned Formula 1 compound has a peak value of an endothermic peak at 152.6±3℃ in its differential scanning calorimetry curve.

[0093] In some embodiments of the present invention, the DSC spectrum of the potassium salt crystal form A of the above-mentioned Formula 1 compound is shown in Figure 29.

[0094] In some embodiments of the present invention, the thermogravimetric analysis curve of potassium salt crystal form A of the above-mentioned Formula 1 compound shows a weight loss of 11.0% between 28°C and 160°C.

[0095] In some embodiments of the present invention, the TGA spectrum of potassium salt crystal form A of the above-mentioned Formula 1 compound is shown in Figure 30.

[0096] The present invention provides a crystal form A of the N'N-dibenzylethylenediamine salt of Formula 1, which, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 4.75±0.20°, 8.07±0.20°, and 9.32±0.20°.

[0097] In some embodiments of the present invention, the N'N-dibenzylethylenediamine salt crystal form A of the above-mentioned Formula 1 compound, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 4.75±0.10°, 8.07±0.10°, 9.32±0.10°, 12.23±0.10°, and 16.80±0.10°.

[0098] In some embodiments of the present invention, the crystal form A of the above-mentioned compound N'N-dibenzylethylenediamine salt of Formula 1 is shown in Figure 31.

[0099] In some embodiments of the present invention, the differential scanning calorimetry curve of the N'N-dibenzylethylenediamine salt of the above-mentioned compound of formula 1, crystal form A, has an endothermic peak at 69.1±3℃ and 145.6±3℃.

[0100] In some embodiments of the present invention, the DSC spectrum of the N'N-dibenzylethylenediamine salt of the above-mentioned Formula 1 compound, crystal form A, is shown in Figure 32.

[0101] In some embodiments of the present invention, the TGA spectrum of the crystal form A of the above-mentioned compound N'N-dibenzylethylenediamine salt of Formula 1 is shown in Figure 33.

[0102] The present invention provides a choline salt crystal form A of Formula 1, which, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 10.95±0.20°, 20.41±0.20°, and 22.67±0.20°.

[0103] In some embodiments of the present invention, the choline salt crystal form A of the above-mentioned Formula 1 compound, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 10.95±0.20°, 20.10±0.20°, 20.41±0.20°, 21.19±0.20°, 22.05±0.20°, 22.67±0.20°, 24.20±0.20°, and 25.66±0.20°.

[0104] In some embodiments of the present invention, the choline salt crystal form A of the above-mentioned Formula 1 compound, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 7.68±0.10°, 9.67±0.10°, 10.07±0.10°, 10.95±0.10°, 13.24±0.10°, 14.70±0.10°, 15.13±0.10°, 15.67±0.10°, 16.31±0.10°, 16.51±0.10°, 17.25±0.10°, 17.48±0.10°, 17.89±0.10°, 18.26±0.10°, and 18.68±0.10°. 10°, 19.56±0.10°, 20.10±0.10°, 20.41±0.10°, 21.19±0.10°, 22.05±0.10°, 22.67±0.10°, 23.50±0.10°, 24.20±0.10°, 25.66±0.10°, 25.93±0.10°, 26.42±0.10°, 27.29±0.10°, 28.21±0.10°, 29.06±0.10°, 29.49±0.10°, 32.74±0.10°, 33.22±0.10°, 33.71±0.10°, 34.76±0.10° and 35.48±0.10°.

[0105] In some embodiments of the present invention, the choline salt crystal form A of the above-mentioned Formula 1 compound has an XRPD spectrum as shown in Figure 34.

[0106] In some embodiments of the present invention, the differential scanning calorimetry curve of the choline salt A of the above-mentioned Formula 1 compound has a peak value of an endothermic peak at 65.2±3℃, 147.0±3℃ and 223.5±3℃.

[0107] In some embodiments of the present invention, the choline salt crystal form A of the above-mentioned Formula 1 compound has a DSC spectrum as shown in Figure 35.

[0108] In some embodiments of the present invention, the thermogravimetric analysis curve of choline salt crystal form A of the above-mentioned Formula 1 compound shows a weight loss of 5.9% between 26°C and 100°C, and a weight loss of 6.3% between 100°C and 180°C.

[0109] In some embodiments of the present invention, the TGA spectrum of choline salt crystal form A of the above-mentioned Formula 1 compound is shown in Figure 36.

[0110] This disclosure also provides the application of the crystal forms A, B, and G of Compound 1, the sodium salt of Compound 1, and the sodium salt crystal forms A, B, C, D, E, F, G, and G of Compound 1, as well as the application of these crystal forms in the preparation of drugs for treating bacterial infections. Among these, the sodium salt crystal form A of Compound 1 is not only readily available but also possesses good physical and chemical stability, along with excellent PK properties and good drug-likeness, demonstrating significant practical value and economic potential in industrial applications. The infections described include those caused by Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae, Acinetobacter baumannii, or Pseudomonas aeruginosa.

[0111] Definitions and Explanations

[0112] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0113] The intermediate compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0114] The chemical reactions in the specific embodiments of this invention are carried out in a suitable solvent, which must be suitable for the chemical changes of this invention and the reagents and materials required therefor. To obtain the compounds of this invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0115] The present invention will be described in detail below through embodiments, which are not intended to limit the present invention in any way.

[0116] All solvents used in this invention are commercially available and can be used without further purification.

[0117] The solvents used in this invention are commercially available. The following abbreviations are used in this invention: DMSO-d6 represents deuterated dimethyl sulfoxide; MeB(OH)2 represents methylboronic acid; THF represents tetrahydrofuran; MeCN represents acetonitrile; TFA represents trifluoroacetic acid; MeOD represents deuterated methanol;

[0118] The present invention relates to an X-ray powder diffractometer (XRPD) method.

[0119] Instrument Model: Bruker D8 Advance X-ray Diffractometer

[0120] Rays: Cu target Kα1 rays

[0121] Scan range (2θ range): 3–45°

[0122] Scan step size: 0.02°

[0123] Exposure time: 0.08 seconds

[0124] Voltage: 40kV, Current: 40mA

[0125] This invention relates to a differential scanning calorimeter (DSC) method.

[0126] Instrument Model: TA Discovery 250 Differential Scanning Calorimeter

[0127] Purge gas: Nitrogen;

[0128] Nitrogen purging rate: 50 mL / min

[0129] Heating rate: 10.0℃ / min

[0130] Temperature range: 25℃-300℃ or 25℃-400℃

[0131] The present invention relates to a thermogravimetric analysis (TGA) method.

[0132] Instrument Model: TA Discovery 550 Thermogravimetric Analyzer

[0133] Purge gas: Nitrogen;

[0134] Nitrogen purging rate: 60 mL / min at the sample site, 40 mL / min at the balance site.

[0135] Heating rate: 10.0℃ / min

[0136] Temperature range: 25℃-350℃ or 25℃-450℃

[0137] This invention presents a method for dynamic vapor adsorption analysis (DVS).

[0138] Instrument model: DVS Intrinsic / DVS Intrinsic Plus (SMS, UK)

[0139] Temperature: 25℃

[0140] Humidity variation: 50%-95%-0%-50%

[0141] Humidity test step: 10%

[0142] Judgment criterion: dm / dt < 0.002%

[0143] Hygroscopicity classification and evaluation are as follows:

[0144] The high-performance liquid chromatography (HPLC) purity method of this invention uses an instrument model of SHIMADZU LC-20A (Shimadzu, JP).

[0145] Test conditions: Attached Figure Description

[0146] Figure 1: XRPD pattern of crystal form A of compound 1;

[0147] Figure 2: DSC spectrum of crystal form A of compound of formula 1;

[0148] Figure 3: TGA spectrum of crystal form A of compound 1;

[0149] Figure 4: XRPD pattern of crystal form B of compound 1;

[0150] Figure 5: DSC spectrum of crystal form B of compound 1;

[0151] Figure 6: TGA spectrum of crystal form B of compound 1;

[0152] Figure 7: XRPD pattern of sodium salt crystal form A of compound 1;

[0153] Figure 8: DSC spectrum of sodium salt crystal form A of compound 1;

[0154] Figure 9: TGA spectrum of sodium salt crystal form A of compound 1;

[0155] Figure 10: XRPD pattern of sodium salt B of Formula 1;

[0156] Figure 11: DSC spectrum of sodium salt B of Formula 1;

[0157] Figure 12: TGA spectrum of sodium salt B of Formula 1;

[0158] Figure 13: XRPD pattern of sodium salt crystal form C of Formula 1;

[0159] Figure 14: DSC spectrum of sodium salt crystal form C of compound 1;

[0160] Figure 15: TGA spectrum of sodium salt crystal form C of compound 1;

[0161] Figure 16: XRPD pattern of sodium salt crystal form D of compound 1;

[0162] Figure 17: DSC spectrum of sodium salt crystal form D of compound 1;

[0163] Figure 18: TGA spectrum of sodium salt crystal form D of compound 1;

[0164] Figure 19: XRPD pattern of sodium salt crystal form E of compound 1;

[0165] Figure 20: DSC spectrum of sodium salt E of Formula 1 compound;

[0166] Figure 21: TGA spectrum of sodium salt E of Formula 1 compound;

[0167] Figure 22: XRPD pattern of sodium salt crystal form F of Formula 1;

[0168] Figure 23: DSC spectrum of sodium salt crystal form F of compound 1;

[0169] Figure 24: TGA spectrum of sodium salt crystal form F of compound 1;

[0170] Figure 25: XRPD pattern of sodium salt G of Formula 1;

[0171] Figure 26: DSC spectrum of sodium salt G of Formula 1;

[0172] Figure 27: TGA spectrum of sodium salt G of Formula 1;

[0173] Figure 28: XRPD pattern of potassium salt crystal form A of Formula 1;

[0174] Figure 29: DSC spectrum of potassium salt crystal form A of Formula 1;

[0175] Figure 30: TGA spectrum of potassium salt crystal form A of Formula 1;

[0176] Figure 31: XRPD pattern of N'N-dibenzylethylenediamine salt crystal form A of Formula 1;

[0177] Figure 32: DSC spectrum of N'N-dibenzylethylenediamine salt crystal form A of Formula 1;

[0178] Figure 33: TGA spectrum of N'N-dibenzylethylenediamine salt crystal form A of Formula 1;

[0179] Figure 34: XRPD pattern of choline salt A of Formula 1;

[0180] Figure 35: DSC spectrum of choline salt A of Formula 1;

[0181] Figure 36: TGA spectrum of choline salt A of Formula 1;

[0182] Figure 37: Schematic diagram of the asymmetric structural unit of sodium salt crystal form A of Formula 1;

[0183] Figure 38: Antibacterial effect of sodium salt A of Formula 1 combined with meropenem in a mouse urinary tract infection model. Detailed Implementation

[0184] Example 1: Preparation of crystal form A of compound of formula 1

[0185] Step 1: Synthesis of 3-bromo-6-methoxyphthalic acid (compounds 1-2)

[0186] At room temperature, potassium permanganate (440.82 g, 2.789 mol) was added dropwise to a mixed solution of 1-bromo-4-methoxy-2,3-dimethylbenzene (compound 1-1, 100 g, 0.465 mol) in tert-butanol (150 mL) and water (1200 mL). The reaction solution was stirred at 100 °C for 16 hours. After the reaction was complete, the solution was filtered through diatomaceous earth, the pH of the filtrate was adjusted to 1-2, and the solution was concentrated to obtain crude compound 1-2 (150 g). The product was directly used in the next step. LCMS(ESI)calcd for C9H7BrO5[MH] + m / z 273,275,found 272.95,274.95.

[0187] Step 2: Synthesis of dimethyl 3-bromo-6-methoxyphthalate (compounds 1-3)

[0188] Concentrated sulfuric acid (50 mL) was added to a methanol (500 mL) solution of 75 g of crude compounds 1-2 from the previous step (0.273 mol). The reaction mixture was stirred at 65 °C for 16 hours. After the reaction was complete, the methanol was concentrated. The remaining solution was diluted with water, the pH was adjusted to 7-8, extracted with ethyl acetate, washed, dried, and concentrated. The crude product was pulped (petroleum ether / ethyl acetate = 10 / 1) to give a yellow solid product (compounds 1-3, 16.7 g, 20.21% yield). 1 H NMR (400MHz, DMSO-d6) δ7.81 (d, J = 9.2 Hz, 1H), 7.26 (d, J = 9.2 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.77 (s, 3H).

[0189] Step 3: Synthesis of 2-tert-butyl-4-methyl-5-methoxy-3-oxoisoindoline-2,4-dicarboxylic acid esters (compounds 1-4)

[0190] Palladium acetate (1.48 g, 0.007 mol) was added to a solution of dimethyl 3-bromo-6-methoxyphthalate (compounds 1-3, 19.9 g, 0.066 mol), potassium N-aminomethyltrifluoroborate (23.36 g, 0.099 mol), cesium carbonate (64.22 g, 0.197 mol), n-butyldi(1-adamantyl)phosphine (4.71 g, 0.013 mol) in 1,4-dioxane (250 mL) and water (50 mL). The reaction mixture was stirred at 100 °C under nitrogen protection for 16 hours. The reaction mixture was filtered through diatomaceous earth, extracted with ethyl acetate, washed, dried, filtered, and concentrated. The residue was pulped (petroleum ether / ethyl acetate = 10 / 1) to give a yellow solid product (compounds 1-4, 17.2 g, 53.16% yield). 1 H NMR (400MHz, DMSO-d6) 7.68 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 4.72 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 1.51 (s, 9H).

[0191] Step 4: Synthesis of methyl 5-methoxy-3-oxoisoindoline-4-carboxylic acid (compounds 1-5)

[0192] A solution of hydrochloric acid / ethyl acetate (4 M, 100 mL) was added to 2-tert-butyl-4-methyl-5-methoxy-3-oxoisoindoline-2,4-dicarboxylic acid ester (compounds 1-4, 17.2 g, 0.053 mol), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered to give a yellow solid product (compounds 1-5, 11.7 g, 99.06% yield).1 H NMR (400MHz, DMSO-d6) δ8.63(s,1H),7.60(d,J=8.8Hz,1H),7.34(d,J=8.8Hz,1H),4.31(s,2H),3.83(s,3H),3.79(s,3H).

[0193] Step 5: Synthesis of 5-methoxy-3-oxoisoindoline-4-carboxylic acid (compounds 1-6)

[0194] Lithium hydroxide hydrate (6.64 g, 0.162 mol) was added to a mixture of methyl 5-methoxy-3-oxoisoindoline-4-carboxylic acid (compounds 1-5, 11.7 g, 0.053 mol) in tetrahydrofuran (100 mL) / methanol (100 mL) / water (100 mL). The mixture was stirred at 65 °C for 16 hours. After the reaction was completed, the mixture was concentrated, the pH was adjusted to 2-3, and the mixture was filtered to give a yellow solid product (compounds 1-6, 9.50 g, 86.77% yield). 1 H NMR (400MHz, DMSO-d6) δ12.97(s,1H),8.58(s,1H),7.54(d,J=8.4Hz,1H),7.31(d,J=8.4Hz,1H),4.30(s,2H),3.83(s,3H).

[0195] Step 6: Synthesis of 6-bromo-5-hydroxy-3-oxoisoindole-4-carboxylic acid (compounds 1-7)

[0196] Liquid bromine (22.01 g, 137.70 mmol) was added dropwise to a concentrated sulfuric acid solution (100 mL) of 5-methoxy-3-oxoisoindoline-4-carboxylic acid (compounds 1-6, 9.5 g, 45.89 mmol) and silver sulfate (17.17 g, 55.01 mmol). The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and then added to ice water. The solid precipitated and was filtered to give the crude product (compounds 1-7, 36.0 g), which was used directly in the next step.

[0197] Step 7: Synthesis of 6-bromo-5-((tert-butoxycarbonyl)oxy)-3-oxoisoindoline-2,4-dicarboxylic acid ditert-butyl ester (compounds 1-8)

[0198] To a solution of crude 6-bromo-5-hydroxy-3-oxoisoindoline-4-carboxylic acid (compounds 1-7, 36.0 g, 0.048 mol, 30% purity) and di-tert-butyl dicarbonate (93.89 g, 0.430 mol) in tert-butanol (150 mL) and tetrahydrofuran (150 mL), 4-dimethylaminopyridine (5.84 g, 0.048 mol) was added, and the reaction mixture was stirred at 60 °C for 3 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1) to give a white solid product (compounds 1-8, 8.60 g, 33.89% yield). 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),4.79(s,2H),1.53(s,9H),1.52(s,9H),1.49(s,9H).

[0199] Steps 8-9: Synthesis of 5-((tert-butoxycarbonyl)oxy)-3-oxo-6-((E)-2-((3aR,4R,6R,7aS)-3A,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborhexacyclopenten-2-yl)vinyl)isoindoline-2,4-dicarboxylic acid ditert-butyl ester (compounds 1-10)

[0200] Under nitrogen atmosphere, bis(tri-tert-butylphosphine)palladium (0.83 g, 0.002 mol) was added to a toluene (130 mL) solution of compounds 1-8 (8.60 g, 0.016 mol), vinylboronic acid pinacol ester (2.99 g, 0.019 mol), and triethylamine (3.28 g, 0.032 mol). The reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated to give crude product (compound 1-9, 9.5 g). (1R,2R,3S,5R)-(-)-2,3-pinenediol (13.45 g, 0.079 mol) was added to a tetrahydrofuran (100 mL) solution of the above crude product (compound 1-9, 9.5 g, 0.016 mol). The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to give a yellow solid product (compounds 1-10, 4.20 g, 40.51% yield). 1H NMR (400MHz, DMSO-d6) δ8.11(s,1H),7.24(d,J=18.4Hz,1H),6.40(d,J=18.4Hz,1 H),4.81(s,2H),4.44(dd,J=8.4,1.2Hz,1H),2.30-2.40(m,1H),2.15-2.25(m,1H) ,2.02(t,J=5.2Hz,1H),1.85-1.92(m,1H),1.71-1.80(m,1H),1.53(s,9H),1.52(s ,9H),1.46(s,9H),1.38(s,3H),1.27(s,3H),1.00(d,J=10.8Hz,1H),0.84(s,3H).

[0201] Step 10: Synthesis of 5-((tert-butoxycarbonyl)oxy)-3-oxo-6-(2-((3aR,4R,6R,7aS)-3A,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxabor-2-yl)ethyl)isoindoline-2,4-dicarboxylic acid ditert-butyl ester (compounds 1-11)

[0202] A 10% palladium / carbon solution (65 mg) was added to a methanol (10 mL) solution of compound 1-10 (400 mg, 0.611 mmol). The mixture was stirred for 2 hours under a hydrogen atmosphere, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to give a yellow solid product (compound 1-11, 350 mg, 87.26% yield). 1 H NMR (400MHz, DMSO-d6) δ7.65 (s, 1H), 4.75 (s, 2H), 4.31 (dd, J = 8.4Hz, 1.2Hz, 2H), 2. 58-2.68(m,2H),2.25-2.34(m,1H),2.11-2.20(m,1H),1.92-2.00(t,J=5.6Hz,1H),1 .82-1.89(d,J=2.6Hz,1H),1.65-1.72(m,1H),1.52(s,9H),1.51(s,9H),1.47(s,9H ), 1.31 (s, 3H), 1.24 (s, 3H), 1.03-1.10 (m, 2H), 0.93 (d, J = 10.4Hz, 1H), 0.81 (s, 3H).

[0203] Step 11: Synthesis of 2-hydroxy-8-oxo-2,3,4,6,7,8-hexahydro-[1,2]oxoboroimino[5,6-f]isoindole-9-carboxylic acid (compound 1)

[0204] Concentrated hydrochloric acid (1.5 mL) was added to a THF (1.5 mL) solution of compounds 1-11 (150 mg, 0.229 mmol) and MeB(OH)2 (27.44 mg, 0.457 mmol), and the reaction mixture was stirred at room temperature for 5 h. The reaction solution was filtered and purified by C18 column chromatography (eluting with 5%-95% MeCN / H2O, water containing 0.1% TFA) to give compound 1 as a yellow solid (10 mg, 17.37% yield).

[0205] LCMS(ESI)calcd for C 11 H 10 BNO5[M+H] + m / z 248.07, found 248.00. 1 H NMR (400MHz, MeOD) δ7.66(s,1H),4.50(s,2H),2.74(s,2H),0.95(s,2H).

[0206] X-ray powder diffraction (XRPD) analysis was performed, and the XRPD spectrum is shown in Figure 1. The positions of the characteristic peaks are shown in Table 1. This product is defined as crystal form A of compound of formula 1. The DSC spectrum is shown in Figure 2, with an endothermic peak value of 213.6℃±3℃. The TGA spectrum is shown in Figure 3, showing a weight loss of 0.6% between 25℃ and 150.0℃, and a weight loss of 10.4% between 150.0℃ and 230℃.

[0207] Table 1: Characteristic peaks of crystal form A of compound 1

[0208] Example 2: Preparation of crystal form B of compound of formula 1

[0209] Approximately 24.7 mg of compound A (formula 1) was weighed into a sample vial, and isopropanol was added as solvent. The mixture was suspended at room temperature for 17 h, then transferred to 50 °C for 4 h, and finally suspended at room temperature for 3 h. After centrifugation, the resulting solid sample was placed in a vacuum drying oven at room temperature and dried overnight to obtain the product. X-ray powder diffraction (XRPD) was performed, and the XRPD spectrum is shown in Figure 4. The characteristic peak positions are shown in Table 2. This product was defined as compound B (formula 1). The DSC spectrum is shown in Figure 5, with an endothermic peak value of 171.9 °C ± 3 °C. The TGA spectrum is shown in Figure 6, showing a weight loss of 1.2% between 30 °C and 100.0 °C, and a weight loss of 26.4% between 100 °C and 210 °C.

[0210] Table 2: Characteristic peaks of crystal form B of compound 1

[0211] Example 3: Preparation of sodium salt crystal form A of compound 1

[0212] Approximately 2.0 g of crystal form A of compound 1 and sodium hydroxide were weighed into a sample vial. Acetone / water solvent (v / v = 10:1) was added, and a salt-forming reaction was carried out at 50 °C. After stirring for approximately 3-4 hours, the sample was suspended at 40 °C for 6 hours. After centrifugation, the resulting solid sample was placed in a vacuum drying oven at 40 °C and dried overnight to obtain the product. X-ray powder diffraction (XRPD) was performed, and the XRPD spectrum is shown in Figure 7. The characteristic peak positions are shown in Table 3. This product was defined as crystal form A of the sodium salt of compound 1. The DSC spectrum is shown in Figure 8, with an endothermic peak value of 194.4 °C ± 3 °C. The TGA spectrum is shown in Figure 9, showing a weight loss of 0.6% between 25 °C and 120.0 °C, and a weight loss of 9.9% between 120.0 °C and 230 °C. Ion chromatography results showed that the ratio of the compound to sodium ions was 1:2.

[0213] Table 3: Characteristic peaks of sodium salt crystal form A of compound 1

[0214] Example 4: Preparation of sodium salt crystal form B of Formula 1

[0215] 800.5 mg of sodium salt crystal form A of compound 1 was weighed into a sample bottle, and a certain volume of water was added. The mixture was magnetically stirred until dissolved, filtered, and then a certain volume of the antisolvent isopropanol was gradually added dropwise. The mixture was stirred at room temperature for 24 hours. After centrifugation of the suspension, the resulting solid sample was placed in a vacuum drying oven at room temperature and dried overnight to obtain the product. X-ray powder diffraction (XRPD) was performed, and the XRPD spectrum is shown in Figure 10. The positions of the characteristic peaks are shown in Table 4. This product was defined as sodium salt crystal form B of compound 1. The DSC spectrum is shown in Figure 11, with endothermic peak values ​​of 76.0℃±3℃ and 116.3℃±3℃. The TGA spectrum is shown in Figure 12, showing a weight loss of 5.0% between 25℃ and 80.0℃, and a weight loss of 10.6% between 80.0℃ and 150℃.

[0216] Table 4: Characteristic peaks of sodium salt B of Formula 1

[0217] Example 5: Preparation of sodium salt crystal form C of compound 1

[0218] 19.9 mg of sodium salt crystal form A of compound 1 was weighed into a sample vial, methanol was added as solvent, and the mixture was stirred at 50 °C for 24 hours. After centrifugation of the suspension, the resulting solid sample was placed in a vacuum drying oven at room temperature and dried overnight to obtain the product. X-ray powder diffraction (XRPD) was performed, and the XRPD spectrum is shown in Figure 13. The positions of the characteristic peaks are shown in Table 5. This product was defined as sodium salt crystal form C of compound 1. The DSC spectrum is shown in Figure 14, with endothermic peak values ​​of 63.6 °C ± 3 °C and 99.4 °C ± 3 °C. The TGA spectrum is shown in Figure 15, indicating continuous weight loss after heating.

[0219] Table 5: Characteristic peaks of sodium salt crystal form C of compound 1

[0220] Example 6: Preparation of sodium salt crystal form D of compound 1

[0221] 19.9 mg of sodium salt crystal form A of compound 1 was weighed into a sample bottle, and a certain volume of water was added. The mixture was magnetically stirred until dissolved, filtered, and then added dropwise to 10 times its volume of ethanol, a poor solvent. The mixture was stirred at room temperature for 24 hours. After centrifugation of the suspension, the resulting solid sample was placed in a vacuum drying oven at room temperature and dried overnight to obtain the product. X-ray powder diffraction (XRPD) was performed, and the XRPD spectrum is shown in Figure 16. The positions of the characteristic peaks are shown in Table 6. This product was defined as sodium salt crystal form D of compound 1. The DSC spectrum is shown in Figure 17, with an endothermic peak value of 85.3℃±3℃. The TGA spectrum is shown in Figure 18, with a weight loss of 18.7% between 31℃ and 200.0℃.

[0222] Table 6: Characteristic peaks of sodium salt crystal form D of compound 1

[0223] Example 7: Preparation of sodium salt crystal form E of Formula 1

[0224] 19.8 mg of sodium salt crystal form A of Formula 1 was weighed into a sample vial. A certain amount of the unsuitable solvent isopropanol was added at 50 °C to form a suspension. Preheated water was added dropwise until the solid was just completely dissolved. The solution was filtered and allowed to stand at room temperature for 24 h, then transferred to 4 °C and -15 °C for further standing. After centrifugation of the suspension, the resulting solid sample was placed in a vacuum drying oven at room temperature and dried overnight to obtain the product. X-ray powder diffraction (XRPD) was performed, and the XRPD spectrum is shown in Figure 19. The positions of the characteristic peaks are shown in Table 7. This product was defined as sodium salt crystal form E of Formula 1. The DSC spectrum is shown in Figure 20, with endothermic peak values ​​of 55.6 °C ± 3 °C, 100.5 °C ± 3 °C, and 157.3 °C ± 3 °C. The TGA spectrum is shown in Figure 21, showing a weight loss of 15.4% between 30 °C and 180.0 °C.

[0225] Table 7: Characteristic peaks of sodium salt crystal form E of compound 1

[0226] Example 8: Preparation of sodium salt crystal form F of Formula 1

[0227] Weigh 20.0 mg of sodium salt crystal form A of compound 1 into a sample vial, add a certain volume of water to dissolve it, and then place the solution in a methanol atmosphere as an antisolvent and let it stand at room temperature until a solid precipitates. Remove the solution from the system with the precipitated solid using a syringe. The wet sample is then analyzed by X-ray powder diffraction. The XRPD spectrum is shown in Figure 22, and the positions of its characteristic peaks are shown in Table 8. This product is defined as sodium salt crystal form F of compound 1. The DSC spectrum is shown in Figure 23, with an endothermic peak value of 106.8℃±3℃; the TGA spectrum is shown in Figure 24, showing continuous weight loss after heating.

[0228] Table 8: Characteristic peaks of sodium salt crystal form F of compound 1

[0229] Example 9: Preparation of sodium salt crystal form G of Formula 1

[0230] 19.7 mg of sodium salt crystal form A of compound 1 was weighed into a sample vial, and an appropriate amount of solvent isopropanol / trifluoroethanol (v / v, 1:1) was added. The mixture was stirred at 50 °C for 24 h. After centrifugation of the suspension, the resulting solid sample was placed in a vacuum drying oven at room temperature and dried overnight to obtain the product. X-ray powder diffraction (XRPD) was performed, and the XRPD spectrum is shown in Figure 25. The positions of the characteristic peaks are shown in Table 9. This product was defined as sodium salt crystal form G of compound 1. The DSC spectrum is shown in Figure 26, with endothermic peak values ​​of 58.1 °C ± 3 °C and 317.3 °C ± 3 °C. The TGA spectrum is shown in Figure 27, showing a weight loss of 6.2% between 23 °C and 210.0 °C.

[0231] Table 9: Characteristic peaks of sodium salt G of Formula 1

[0232] Example 10: Preparation of potassium salt crystal form A of Formula 1

[0233] Approximately 24.7 mg of compound 1 and potassium hydroxide were weighed into a sample vial, and isopropanol was added as solvent. A salt-forming reaction was carried out at 50°C, and after stirring for approximately 3-4 hours, the sample was suspended overnight at 25°C. The suspension was centrifuged, and the resulting solid sample was placed in a vacuum drying oven at room temperature and dried overnight to obtain the product. X-ray powder diffraction (XRPD) was performed, and the XRPD spectrum is shown in Figure 28. The characteristic peak positions are shown in Table 10. This product was defined as potassium salt crystal form A of compound 1. The DSC spectrum is shown in Figure 29, with an endothermic peak value of 152.6°C ± 3°C. The TGA spectrum is shown in Figure 30, with a weight loss of 11.0% between 28°C and 160.0°C. Ion chromatography results showed that the ratio of the compound to potassium ions was 1:1.6.

[0234] Table 10: Characteristic peaks of potassium salt crystal form A of compound 1

[0235] Example 11: Preparation of crystal form A of N'N-dibenzylethylenediamine salt of Formula 1

[0236] Approximately 24.7 mg of compound 1 and N'N-dibenzylethylenediamine were weighed into a sample vial, and isopropanol was added as solvent. A salt-forming reaction was carried out at 50 °C, and after stirring for approximately 3-4 hours, the sample was suspended overnight at 25 °C. The suspension was centrifuged, and the resulting solid sample was placed in a vacuum drying oven at room temperature and dried overnight to obtain the product. X-ray powder diffraction (XRPD) was performed, and the XRPD spectrum is shown in Figure 31. The positions of the characteristic peaks are shown in Table 11. This product was defined as crystal form A of N'N-dibenzylethylenediamine salt of compound 1. The DSC spectrum is shown in Figure 32, with endothermic peak values ​​of 69.1 °C ± 3 °C and 145.6 °C ± 3 °C. The TGA spectrum is shown in Figure 33, showing continuous weight loss after heating.

[0237] Table 11: Characteristic peaks of crystal form A of N'N-dibenzylethylenediamine salt of Formula 1

[0238] Example 12: Preparation of choline salt crystal form A of Formula 1 compound

[0239] Approximately 24.7 mg of compound 1 and choline were weighed into a sample vial, and isopropanol / ethyl acetate (v / v, 1:1) was added as solvent. A salt-forming reaction was carried out at 50 °C, and after stirring for approximately 3-4 hours, the mixture was suspended overnight at 25 °C. The suspension was centrifuged, and the resulting solid sample was placed in a vacuum drying oven at room temperature and dried overnight to obtain the product. X-ray powder diffraction (XRPD) was performed, and the XRPD spectrum is shown in Figure 34. The characteristic peak positions are shown in Table 12. This product was defined as choline salt crystal form A of compound 1. The DSC spectrum is shown in Figure 35, with endothermic peak values ​​of 65.2 °C ± 3 °C, 147.0 °C ± 3 °C, and 223.5 °C ± 3 °C. The TGA spectrum is shown in Figure 36, showing a weight loss of 5.9% between 26 °C and 100 °C, and a weight loss of 6.3% between 100 °C and 180 °C.

[0240] Table 12: Characteristic peaks of choline salt crystal form A of compound 1

[0241] Experimental Example 1. Hygroscopicity Study

[0242] DVS tests were performed on sodium salt crystal form A, sodium salt crystal form B, sodium salt crystal form F of compound 1 and potassium salt crystal form A of compound 1. The results are shown in Table 13.

[0243] Table 13: Results of Hygroscopicity Study

[0244] The results showed that sodium salt crystal form A of Formula 1 increased in weight by 5.15% under 20% RH-80% RH conditions, and the crystal form remained unchanged after DVS testing. Its hygroscopicity was significantly better than that of sodium salt crystal forms B and F of Formula 1, indicating better solid-state stability and druggability. Potassium salt crystal form A of Formula 1 increased in weight by 0.64% under 20% RH-80% RH conditions.

[0245] Experimental Example 2: Stability Study of Influencing Factors

[0246] Approximately 20 mg of sample (sodium salt crystal form A of Formula 1) was weighed and placed in a weighing bottle. The bottle was then subjected to high temperature (60℃), high humidity (25℃ / 92.5%RH), light irradiation (25℃ / 4500 Lux), and accelerated irradiation (40℃ / 75%RH) conditions, respectively. Samples were taken at 5, 10, and 15 days for XRPD characterization and HPLC analysis. The results are shown in Table 14.

[0247] Table 14: Results of the stability study

[0248] Conclusion: XRPD results showed that the sodium salt crystal form A of Formula 1 remained essentially stable for 15 days under high temperature, high humidity, light irradiation, and accelerated conditions, with no significant XRPD changes. HPLC results showed that the chemical purity of the sodium salt crystal form A of Formula 1 did not change significantly after 15 days under the above conditions.

[0249] Experiment Example 3: Water Activity Competition Experiment

[0250] Weigh appropriate amounts of sodium salt of Formula 1, crystal form A, and add them to a suitable amount of solvent system at room temperature to form saturated solutions. If the solution is clear, continue adding the compound until a saturated solution is reached. Filter the solution through a 0.45 μm nylon needle filter into a liquid chromatography vial. Then, add almost equal amounts of sodium salt of Formula 1, crystal forms A, B, and F to the vial to form suspensions. Suspend and stir the suspensions at a selected specific temperature. Take samples at 1, 3, and 6 days for XRPD characterization of the wet samples. The experimental results are shown in Table 15 below.

[0251] Table 15: Results of the Water Activity Competition Experiment

[0252] The results showed that sodium salt crystal forms A and B of Formula 1, after 6 days of suspension and pulping at room temperature and a water activity of 0.2, yielded sodium salt crystal form A of Formula 1. However, with increasing water activity or temperature, suspension and pulping for 1 day yielded sodium salt crystal form A of Formula 1. Sodium salt crystal forms A and F of Formula 1, after 1 day of suspension and pulping, also yielded sodium salt crystal form A of Formula 1.

[0253] Experiment Example 4: Solubility Study

[0254] Preliminary solubility assessment:

[0255] Approximately 20 mg of sodium salt crystal form A and potassium salt crystal form A of Formula 1 were weighed separately to roughly determine their solubility in water and PBS 7.4. The medium was added to 2.0 mL and the mixture was shaken at 25 °C for 2 h. The pH value was then tested, and the evaluation results are shown in Table 16 below.

[0256] Table 16: Preliminary Solubility Assessment Results

[0257] The solution concentration for 2 hours was 10 mg / mL.

[0258] #Solubility is calculated according to Equation 1

[0259] The results showed that the solubility of sodium salt A and potassium salt A of Formula 1 in PBS 7.4 and water was greater than 200 mg / mL.

[0260] Dynamic solubility assessment:

[0261] A certain amount of sodium salt crystal form A of Formula 1 and crystal form A of Formula 1 were added to water, 5% glucose, 0.9% physiological saline and PBS 7.4 medium and shaken at 25℃ for 24h. After filtration through a 0.22μm aqueous filter membrane, some samples with higher concentrations were appropriately diluted with diluent and analyzed by HPLC. The evaluation test results are shown in Table 17 below.

[0262] Table 17: Dynamic solubility test in media and water

[0263] #Solubility is calculated according to Equation 1

[0264] in conclusion:

[0265] The results showed that the sodium salt crystal form A of compound 1 was readily soluble in all four media. After shaking for 24 hours, the solubility order was 5% glucose > water > PBS 7.4 > 0.9% physiological saline. The solubility order of compound 1 crystal form A after shaking for 24 hours in the four media was PBS 7.4 > water ≈ 5% glucose ≈ 0.9% physiological saline.

[0266] Experimental Example 5: Single-crystal X-ray diffraction analysis of sodium salt crystal form A of compound 1 (Example 5)

[0267] Experimental methods:

[0268] (1) Crystal culture: Take 20 mg of sodium salt of Formula 1, add 1 mL of DMF to form a suspension at 80 °C, and then gradually add preheated water (0.8 mL) until the solid is completely dissolved. After the solid is dissolved, filter the liquid and transfer it to room temperature to stand. The needle-like crystals (sodium salt of Formula 1 crystal form A) are obtained by volatilization crystallization.

[0269] (2) X-ray single-crystal diffraction: A single crystal with suitable morphology and size was selected from the cultured single-crystal samples, attached to a loop ring, and then the single-crystal sample was placed on a crystal stage. Single-crystal diffraction data were collected using an XtaLAB Pro II (Rigaku, JPN) single-crystal diffractometer (Cu target light source). The diffraction was performed at 150.0 K. The diffraction data were analyzed using CrysAlisPro 1.171.43.98a software. The diffraction data were collected within the angular range of 3.58° < θ < 67.78°, yielding 2821 diffraction points. These points were analyzed using CrysAlisPro and refined using the least squares method to obtain the crystal's unit cell parameters and orientation matrix. The data completeness corresponding to the highest θ angle (θ = 66.49°) was 99.70%.

[0270] (3) Data Restoration: The CrysAlisPro 1.171.43.98a (Rigaku Oxford Diffraction, 2023) program was used to restore and integrate each frame of diffraction images acquired by the detector. The SCALE3 ABSPACK scaling algorithm was used to perform absorption correction on the diffraction data. This crystal sample is sensitive to wavelength... The linear absorption coefficient of the X-rays is 1.761 mm. -1 The minimum transmittance (Tmin) is 0.804, and the maximum transmittance (Tmax) is 1.000. The intensities of all equivalent diffraction points are essentially equal within the experimental error range, with a Rint of 6.75%.

[0271] (4) Structure Analysis and Refinement: The single-crystal structure was analyzed using OLEX2 software. The olex2.solve 1.5 (Bourhis et al., 2015) program was used to initially solve the diffraction data and determine the crystal's space group as P21 / c. Subsequently, the SHELXL2014 / 1 (Sheldrick, 2015) program was used for structure refinement. The coordinates of all non-hydrogen atoms were determined using several rounds of Fourier interpolation, followed by anisotropic refinement of all non-hydrogen atoms using full-matrix least squares. All hydrogen atoms were calculated using theoretical hydrogen addition.

[0272] (5) Experimental Conclusion: The single-crystal structure analysis results show that the sodium salt crystal form A of Formula 1 belongs to the monoclinic crystal system, space group P21 / c, and its cell parameters are as follows: α=90°, β=97.806(8)°, γ=90°, The crystallographic data and refinement parameters of the crystal are detailed in Table 18. Figure 37 is a schematic diagram of the asymmetric structural unit of the crystal, which contains one free ion of compound of formula 1, two sodium ions and one water molecule.

[0273] Table 18: Crystallographic parameters of sodium salt of Formula 1, crystal form A

[0274] Experimental Example 6: Antibacterial effect of sodium salt crystal form A of compound 1 in combination with meropenem in a mouse model of urinary tract infection.

[0275] Experimental methods

[0276] Experimental day definition: The day the animal was infected is defined as day 0 or hour 0.

[0277] Immunosuppressive pretreatment in animals: On Day 4 and Day 1 before infection, mice were intraperitoneally injected with cyclophosphamide at doses of 150 mg / kg and 100 mg / kg, respectively, to induce immunosuppression. The administration volume was 10 mL / kg.

[0278] Modeling: On day 0, animals in groups 1-7 were anesthetized with a combination of salbutamol and celazine and then inoculated with Klebsiella pneumoniae ATCC BAA-2343 via urethral injection at a dose of ~3.00E+09 CFU / mouse and a volume of 50 μL.

[0279] Animals were given the corresponding treatments according to the compound treatment regimens in Table 19 of the experimental test protocol. The administration volume was 10 mL / kg / dose, and the administration method was subcutaneous injection.

[0280] Daily monitoring: During the experiment, weight monitoring, clinical health and survival tests were conducted once a day.

[0281] Experimental endpoints: In Group 1, mice were euthanized 14 hours post-infection. Kidney and bladder tissues were aseptically harvested and homogenized in 1 mL of sterile saline. The homogenate was then serially diluted and subjected to TLC counting. In Groups 2–7, mice were euthanized 2 hours after the last administration (48 hours post-infection). Kidney and bladder tissues were aseptically harvested and homogenized in 1 mL of sterile saline. The homogenate was then serially diluted and subjected to TLC counting.

[0282] Statistical analysis: Experimental data are expressed as mean ± standard error (mean ± SEM). Data were analyzed using Graphpad Prism with appropriate statistical methods.

[0283] Table 19: Experimental Test Scheme

[0284] Results: The effects of sodium form A of Formula 1 on Klebsiella pneumoniae strain ATCC BAA-2343 were evaluated in a 24-hour mouse urinary tract infection model. This strain expresses KPC enzyme and is resistant to carbapenems. Meropenem and sodium form A of Formula 1 were administered every 2 hours for 48 hours (5 doses of the specified amount per day). In this study, meropenem at a dose of 25 mg / kg every 2 hours failed to control the infection, while co-administration of sodium form A of Formula 1 (calculated as Formula 1) at doses of 3.125–25 mg / kg had a static effect in the kidneys and bladder, as shown in Figure 38. All three dose groups achieved a reduction of >1 log CFU / mouse compared to meropenem alone, and a reduction of >1 log CFU / mouse compared to the initial infection group (Group 1).

Claims

1. A crystal form A of a compound of formula 1, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 9.16±0.20°, 24.32±0.20°, and 25.45±0.20°.

2. The crystal form A of the compound of formula 1 according to claim 1, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 7.70±0.20°, 8.44±0.20°, 9.16±0.20°, 14.45±0.20°, 23.76±0.20°, 24.32±0.20°, 25.45±0.20°, and 26.50±0.20°.

3. The crystal form A of the compound of formula 1 according to claim 2, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form exhibits characteristic diffraction peaks at the following 2θ angles: 7.26±0.10°, 7.70±0.10°, 8.44±0.10°, 9.16±0.10°, 10.44±0.10°, 11.59±0.10°, 12.82±0.10°, 14.10±0.10°, 14.45±0.10°, 14.86±0.10°, 15.26±0.10°, 16.06±0.10°, 16.86±0.10°, 17.15±0.10°, 17.67±0.10°, 18.3°. 5±0.10°, 19.29±0.10°, 20.80±0.10°, 21.25±0.10°, 22.03±0.10°, 22.71±0.10°, 23.10±0.10°, 23.76±0.10°, 24.32±0.10°, 25.45±0.10°, 26.50±0.10°, 27.43±0.10°, 28.50±0.10°, 29.61±0.10°, 31.03±0.10°, 35.69±0.10°, 37.13±0.10°, 38.14±0.10° and 39.54±0.10°.

4. The crystal form A of the compound of formula 1 according to claim 3, its XRPD pattern is shown in Figure 1.

5. A crystal form B of a compound of formula 1, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 6.01±0.20°, 21.95±0.20° and 27.37±0.20°.

6. The crystal form of compound B of formula 1 according to claim 5, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 6.01±0.20°, 16.22±0.20°, 17.11±0.20°, 18.24±0.20°, 21.95±0.20°, 22.24±0.20°, 25.64±0.20°, and 27.37±0.20°.

7. The compound B crystal form according to claim 6, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction (XRPD) pattern: 6.01±0.10°, 6.56±0.10°, 10.81±0.10°, 12.12±0.10°, 14.47±0.10°, 16.22±0.10°, 17.11±0.10°, 18.24±0.10°. °, 20.92±0.10°, 21.95±0.10°, 22.24±0.10°, 23.64±0.10°, 24.59±0.10°, 25.64±0.10°, 26.46±0.10°, 27.37±0.10°, 28.09±0.10°, 28.44±0.10°, 31.12±0.10°, 33.14±0.10° and 34.45±0.10°.

8. The XRPD spectrum of compound B of formula 1 according to claim 7 is shown in Figure 4.

9. A pharmaceutically acceptable salt of a compound of formula 1, wherein the pharmaceutically acceptable salt is selected from sodium salts, potassium salts, N'N-dibenzylethylenediamine salts, or choline salts.

10. The pharmaceutically acceptable salt of the compound of formula 1 according to claim 9, characterized in that, The pharmaceutically usable salt is a sodium salt, and the molar ratio of the compound of Formula 1 to sodium hydroxide is 1:0 to 2.1, more preferably 1:1.0 to 2.0, more preferably 1.5:2.05, and most preferably 1:2 or 1:2.

05.

11. The pharmaceutically acceptable salt of the compound of formula 1 according to claim 9, characterized in that, The pharmaceutically usable salt is a potassium salt, and the molar ratio of the compound of Formula 1 to potassium hydroxide is 1:0 to 2.1, more preferably 1:1.0 to 2.0, more preferably 1:1.5 to 2.0, and most preferably 1:2 or 1:1.

6.

12. The pharmaceutically acceptable salt of the compound of formula 1 according to claim 9, characterized in that, The pharmaceutically usable salt is a choline salt, and the molar ratio of the compound of Formula 1 to choline is 1:0 to 2.1, more preferably 1:1.0 to 2.0, more preferably 1:1.50 to 2.0, and most preferably 1:1.8 or 1:1.

85.

13. A method for preparing a pharmaceutically acceptable salt of a compound of formula 1, the method comprising: 1) Weigh an appropriate amount of compound 1 and basic ligand into a sample vial, add an appropriate solvent and carry out a salt formation reaction at 50°C. After stirring for an appropriate time, suspend the sample under appropriate conditions for a certain period of time. 2) After centrifuging the suspension, place the resulting solid sample in a vacuum drying oven at room temperature or 40°C and dry overnight to obtain the product.

14. The method for preparing the pharmaceutically acceptable salt of the compound of formula 1 according to claim 13, characterized in that, The solvent is selected from one or more of hydrocarbon solvents, ether solvents, alcohol solvents, ester solvents, ketone solvents, nitrile solvents, halogenated hydrocarbon solvents, nitrogen-containing solvents, water, and dimethyl sulfoxide.

15. The method for preparing a pharmaceutically acceptable salt of the compound of formula 1 according to claim 14, characterized in that, The hydrocarbon solvents include, but are not limited to, cyclohexane, n-heptane, and toluene; the ether solvents include, but are not limited to, ethylene glycol methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, propylene glycol methyl ether, methyl tert-butyl ether, or 1,4-dioxane; the alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, or trifluoroethanol; the ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, ethyl formate, or butyl formate; the ketone solvents include, but are not limited to, acetone or 4-methyl-2-pentanone; the nitrile solvents include, but are not limited to, acetonitrile; the halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, chloroform, or carbon tetrachloride; and the nitrogen-containing solvents include, but are not limited to, N-methylpyrrolidine and dimethylacetamide.

16. A sodium salt crystal form A of a compound of formula 1, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 7.16±0.20°, 9.22±0.20° and 36.31±0.20°.

17. The sodium salt crystal form A of the compound of formula 1 according to claim 16, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 7.16±0.20°, 9.22±0.20°, 14.33±0.20°, 15.15±0.20°, 15.48±0.20°, 21.58±0.20°, 26.28±0.20°, and 36.31±0.20°.

18. The sodium salt crystal form A of the compound of formula 1 according to claim 17, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form exhibits characteristic diffraction peaks at the following 2θ angles: 7.16±0.10°, 9.22±0.10°, 14.33±0.10°, 15.15±0.10°, 15.48±0.10°, 16.84±0.10°, 17.46±0.10°, 18.20±0.10°, 18.88±0.10°, 21.58±0.10°, 22.34±0.10°, 22.65±0.10°, 26.28±0.10°, 26.91±0.10°, 27.47±0.10°. 0°, 27.86±0.10°, 28.23±0.10°, 28.89±0.10°, 29.49±0.10°, 30.60±0.10°, 31.22±0.10°, 31.82±0.10°, 32.56±0.10°, 33.94±0.10°, 36.06±0.10°, 36.31±0.10°, 37.79±0.10°, 38.24±0.10°, 39.85±0.10°, 40.55±0.10°, 41.29±0.10°, 42.69±0.10° and 43.91±0.10°.

19. The sodium salt crystal form A of the compound of formula 1 according to claim 18, the XRPD pattern of which is shown in Figure 7.

20. A sodium salt crystal form A of a compound of formula 1, characterized in that, When analyzed using single-crystal X-ray diffraction, this crystal form belongs to the monoclinic system with space group P21 / c.

21. The sodium salt crystal form A of the compound of formula 1 according to claim 20, characterized in that, The unit cell parameters of this crystal form are: α = 90°, β = 97.806(8)°, γ = 90°, crystal volume 22. The sodium salt crystal form A of the compound of formula 1 according to claim 20, characterized in that... When analyzed using single-crystal X-ray diffraction, this crystal form belongs to the monoclinic crystal system with space group P21 / c; the unit cell parameters of this crystal form are: α = 90°, β = 97.806(8)°, γ = 90°, crystal volume The crystal size is 0.25 × 0.04 × 0.02 mm. 3 The molecular formula is C 11 H 12 BNNa2O7 has a molecular weight of 327.

01.

23. A sodium salt crystal form B of a compound of formula 1, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 8.15±0.20°, 13.11±0.20°, and 16.31±0.20°.

24. The sodium salt crystal form B of the compound of formula 1 according to claim 23, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 6.25±0.20°, 8.15±0.20°, 13.11±0.20°, 16.31±0.20°, 17.99±0.20°, 24.55±0.20°, 26.01±0.20°, 26.36±0.20°.

25. The sodium salt crystal form B of the compound of formula 1 according to claim 24, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form exhibits characteristic diffraction peaks at the following 2θ angles: 6.25±0.10°, 8.15±0.10°, 9.45±0.10°, 12.47±0.10°, 13.11±0.10°, 13.83±0.10°, 16.31±0.10°, 17.52±0.10°, 17.99±0.10°, 19.27±0.10°, 20.67±0.10°, 21.02±0.10°, 22.61±0.10°, 24.19±0.10°, 24.55±0.10°, 24.79±0.10°, 26. 01±0.10°, 26.36±0.10°, 26.77±0.10°, 28.07±0.10°, 29.08±0.10°, 29.65±0.10°, 31.59±0.10°, 32.17±0.10°, 33.03±0.10°, 33.79±0.10°, 34.41±0.10°, 35.36±0.10°, 35.71±0.10°, 36.02±0.10°, 37.58±0.10°, 38.37±0.10°, 39.79±0.10°, 41.44±0.10°, 42.63±0.10° and 44.57±0.10°.

26. The sodium salt crystal form B of the compound of formula 1 according to claim 25, the XRPD pattern of which is shown in Figure 10.

27. A sodium salt crystal form C of compound of formula 1, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 6.32±0.20°, 7.35±0.20°, and 13.59±0.20°.

28. The sodium salt crystal form C of compound of formula 1 according to claim 27, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 6.32±0.20°, 7.35±0.20°, 11.55±0.20°, 12.76±0.20°, 13.59±0.20°, 16.45±0.20°, 22.22±0.20°, and 26.58±0.20°.

29. The sodium salt crystal form C of compound of formula 1 according to claim 28, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form exhibits characteristic diffraction peaks at the following 2θ angles: 6.32±0.10°, 7.35±0.10°, 10.33±0.10°, 11.55±0.10°, 12.76±0.10°, 13.59±0.10°, 15.13±0.10°, 16.45±0.10°. 0.10°, 18.16±0.10°, 18.98±0.10°, 19.6±0.10°, 21.02±0.10°, 22.22±0.10°, 24.2±0.10°, 24.9±0.10°, 26.58±0.10°, 30.09±0.10°, 35.24±0.10° and 37.87±0.10°.

30. The sodium salt crystal form C of the compound of formula 1 according to claim 29, the XRPD pattern of which is shown in Figure 13.

31. A sodium salt of compound of formula 1, crystal form D, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 5.47±0.20°, 6.05±0.20°, and 25.70±0.20°.

32. The sodium salt crystal form D of compound of formula 1 according to claim 31, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 5.47±0.20°, 6.05±0.20°, 10.97±0.20°, 13.79±0.20°, 20.74±0.20°, 25.70±0.20°, 27.99±0.20°, 29.06±0.20°.

33. The sodium salt crystal form D of compound of formula 1 according to claim 32, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form exhibits characteristic diffraction peaks at the following 2θ angles: 5.47±0.10°, 6.05±0.10°, 9.41±0.10°, 10.97±0.10°, 11.40±0.10°, 12.93±0.10°, 13.42±0.10°, 13.79±0.10°, 14.62±0.10°, 15.52±0.10°, and 15.91±0.10°. 0°, 16.51±0.10°, 16.95±0.10°, 17.97±0.10°, 18.49±0.10°, 19.42±0.10°, 19.99±0.10°, 20.74±0.10°, 25.70±0.10°, 27.99±0.10°, 29.06±0.10°, 30.29±0.10°, 36.12±0.10°, 36.97±0.10° and 39.17±0.10°.

34. The sodium salt crystal form D of the compound of formula 1 according to claim 33, its XRPD spectrum is shown in Figure 16.

35. A sodium salt of compound of formula 1, crystal form E, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 5.02±0.20°, 9.96±0.20°, and 10.29±0.20°.

36. The sodium salt crystal form E of compound of formula 1 according to claim 35, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 5.02±0.20°, 8.21±0.20°, 9.96±0.20°, 10.29±0.20°, 19.91±0.20°, 26.05±0.20°, 34.35±0.20°, and 39.75±0.20°.

37. The sodium salt crystal form E of compound of formula 1 according to claim 36, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form exhibits characteristic diffraction peaks at the following 2θ angles: 5.02±0.10°, 8.21±0.10°, 9.96±0.10°, 10.29±0.10°, 13.09±0.10°, 13.92±0.10°, 16.35±0.10°, 18.00±0.10°, 19.91±0.10°, 26.05±0.10°, 34.35±0.10°, 35.40±0.10°, and 39.75±0.10°.

38. The sodium salt crystal form E of the compound of formula 1 according to claim 37, the XRPD spectrum of which is shown in Figure 19.

39. A sodium salt of compound of formula 1, crystal form F, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 5.72±0.20°, 11.45±0.20°.

40. The sodium salt crystal form F of the compound of formula 1 according to claim 39, the XRPD pattern of which is shown in Figure 22.

41. A sodium salt of compound of formula 1, crystal form G, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 6.54±0.20°, 13.18±0.20°, and 17.38±0.20°.

42. The sodium salt crystal form G of compound of formula 1 according to claim 41, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 6.54±0.20°, 13.18±0.20°, 13.71±0.20°, 17.38±0.20°, 25.02±0.20°, 26.65±0.20°, 27.39±0.20°, and 35.26±0.20°.

43. The sodium salt crystal form G of compound of formula 1 according to claim 42, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form exhibits characteristic diffraction peaks at the following 2θ angles: 6.54±0.10°, 9.98±0.10°, 13.18±0.10°, 13.71±0.10°, 15.21±0.10°, 16.47±0.10°, 17.38±0.10°, 21.09±0.10°, 22.16±0.10°, 23.76±0.10°, 25.02±0.10°, 26.65±0.10°, 27.39±0.10°, 35.26±0.10°, and 36.80±0.10°.

44. The sodium salt crystal form G of the compound of formula 1 according to claim 43, the XRPD pattern of which is shown in Figure 25.

45. A potassium salt of compound of formula 1, crystal form A, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 7.47±0.20°, 22.49±0.20°, and 34.00±0.20°.

46. ​​The potassium salt crystal form A of compound of formula 1 according to claim 45, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 7.47±0.20°, 15.81±0.20°, 22.49±0.20°, 30.13±0.20°, 33.07±0.20°, 34.00±0.20°, 37.91±0.20°, and 39.36±0.20°.

47. The potassium salt crystal form A of compound of formula 1 according to claim 46, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form exhibits characteristic diffraction peaks at the following 2θ angles: 7.47±0.10°, 9.06±0.10°, 14.95±0.10°, 15.28±0.10°, 15.81±0.10°, 20.08±0.10°, 21.52±0.10°, 22.49±0.10°, 23.10±0.10°, 25.02±0.10°, 25.86±0.10°, 26.21±0.10°, 27. 37±0.10°, 27.74±0.10°, 29.47±0.10°, 30.13±0.10°, 31.90±0.10°, 33.07±0.10°, 34.00±0.10°, 34.62±0.10°, 35.26±0.10°, 36.74±0.10°, 37.91±0.10°, 39.36±0.10°, 39.68±0.10°, 40.36±0.10°, 41.13±0.10° and 43.52±0.10°.

48. The potassium salt crystal form A of the compound of formula 1 according to claim 47, the XRPD pattern of which is shown in Figure 28.

49. A crystal form A of N'N-dibenzylethylenediamine salt of Formula 1, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 4.75±0.20°, 8.07±0.20°, and 9.32±0.20°.

50. The N'N-dibenzylethylenediamine salt crystal form A of compound of formula 1 according to claim 49, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 4.75±0.10°, 8.07±0.10°, 9.32±0.10°, 12.23±0.10° and 16.80±0.10°.

51. The crystal form A of the N'N-dibenzylethylenediamine salt of compound 1 according to claim 50, its XRPD spectrum is shown in Figure 31.

52. A choline salt of Formula 1, crystal form A, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 10.95±0.20°, 20.41±0.20° and 22.67±0.20°.

53. The choline salt crystal form A of compound of formula 1 according to claim 52, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 10.95±0.20°, 20.10±0.20°, 20.41±0.20°, 21.19±0.20°, 22.05±0.20°, 22.67±0.20°, 24.20±0.20°, and 25.66±0.20°.

54. The choline salt crystal form A of compound of formula 1 according to claim 53, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form exhibits characteristic diffraction peaks at the following 2θ angles: 7.68±0.10°, 9.67±0.10°, 10.07±0.10°, 10.95±0.10°, 13.24±0.10°, 14.70±0.10°, 15.13±0.10°, 15.67±0.10°, 16.31±0.10°, 16.51±0.10°, 17.25±0.10°, 17.48±0.10°, 17.89±0.10°, 18.26±0.10°, 18.68±0.10°, 19.56±0.10°. 0°, 20.10±0.10°, 20.41±0.10°, 21.19±0.10°, 22.05±0.10°, 22.67±0.10°, 23.50±0.10°, 24.20±0.10°, 25.66±0.10°, 25.93±0.10°, 26.42±0.10°, 27.29±0.10°, 28.21±0.10°, 29.06±0.10°, 29.49±0.10°, 32.74±0.10°, 33.22±0.10°, 33.71±0.10°, 34.76±0.10° and 35.48±0.10°.

55. The choline salt crystal form A of compound of formula 1 according to claim 54, its XRPD spectrum is shown in Figure 34.

56. The crystal form A of the compound of formula 1 according to any one of claims 1 to 4, the crystal form B of the compound of formula 1 according to any one of claims 5 to 8, the pharmaceutically acceptable salt of the compound of formula 1 according to any one of claims 9 to 12, the method for preparing the pharmaceutically acceptable salt of the compound of formula 1 according to any one of claims 13 to 15, the crystal form A of the sodium salt of the compound of formula 1 according to any one of claims 16 to 22, the crystal form B of the sodium salt of the compound of formula 1 according to any one of claims 23 to 26, the crystal form C of the sodium salt of the compound of formula 1 according to any one of claims 27 to 30, and any one of claims 31 to 34. The use of the sodium salt crystal form D of the compound of formula 1, the sodium salt crystal form E of the compound of formula 1 according to any one of claims 35 to 38, the sodium salt crystal form F of the compound of formula 1 according to any one of claims 39 to 40, the sodium salt crystal form G of the compound of formula 1 according to any one of claims 41 to 44, the potassium salt crystal form A of the compound of formula 1 according to any one of claims 45 to 48, the N'N-dibenzylethylenediamine salt crystal form A of the compound of formula 1 according to any one of claims 49 to 51, and the choline salt crystal form A of the compound of formula 1 according to any one of claims 52 to 55 in the preparation of drugs for treating bacterial infections.

57. The application according to claim 56, wherein the infection comprises an infection selected from: Klebsiella pneumoniae, Enterobacter, Enterobacter cloacae, Acinetobacter baumannii, or Pseudomonas aeruginosa.

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