Salt and crystalline forms of sulfonylurea ring-substituted compounds

Abstract

The present invention provides a salt form, a crystal form and a specific crystal form A of a sulfonylurea ring-substituted compound, and also provides a use thereof in the manufacture of a medicine for treating diseases associated with bacterial infection. The crystal form A of the compound is easily obtained, has good physical and chemical stability, and has high industrial applicability and economic value. The compound has good water solubility, is suitable for intravenous administration, has excellent pharmacokinetic properties, is highly safe, has good efficacy, and is used for treating diseases associated with bacterial infection.

Description

[Technical Field]

[0001] The present invention relates to salt and crystalline forms of sulfonylurea ring-substituted compounds, and specifically discloses a compound represented by formula (1), a crystalline form thereof, a method for preparing the same, pharmaceutically acceptable salts thereof, and a use thereof in the manufacture of a medicament for treating a disease associated with the treatment. [Background technology]

[0002] Beta-lactam antibiotics are important antibiotics, but with the continued emergence of drug resistance genes and antibiotic hydrolases such as extended-spectrum serine beta-lactamases (ESBLs) and serine carbapenem enzymes (e.g., KPCs), the efficacy of existing antibiotics is increasingly inadequate. In particular, in cases of severe or multidrug resistance mediated by metallo-beta-lactamases (MBLs), traditional antibiotics such as penicillins, cephalosporins, and carbapenems are no longer effective against infections caused by these resistant bacteria. To address this issue, monocyclic beta-lactam antibiotics, such as aztreonam, are a highly advantageous chemical series that are naturally stable against metallo-beta-lactamases (MBLs).

[0003] The commercially available drug aztreonam has drawbacks such as low permeability, strong efflux, a narrow antibacterial spectrum, and instability to extended-spectrum serine β-lactamases (ESBLs). To overcome these clinical issues, siderophore-mediated permeability enhancement strategies have been introduced, such as by Basilea (Patent Document 1) and Naeja Pharmaceuticals (Patent Document 2), and a series of corresponding molecules have been reported. Recently, Novartis (Patent Document 3) reported research on overcoming drug resistance by modifying the substituents of the aztreonam molecule. The general formula of the compound is shown below, where the Het group is a heteroaromatic ring or a heterocycle substituted with one or two heteroatoms.

[0004] [ka]

[0005] Given the serious drug resistance situation, it is urgent to develop a new generation of monocyclic β-lactam antibiotics to solve the current drug resistance problem, and the sulfonylurea ring-substituted monocyclic β-lactam molecule of the present invention has the potential to meet this need.

[0006] Patent Document 4 described sulfonylurea ring-substituted monocyclic β-lactam compounds, the structure of which is shown in formula (BI), which are mainly used to treat diseases associated with bacterial infections.

[0007] [ka] [Prior art documents] [Patent documents]

[0008] [Patent Document 1] WO 2007065288 [Patent Document 2] WO 2002022613 [Patent Document 3] WO 2015148379 [Patent Document 4] PCT / CN2020 / 130568 Summary of the Invention

[0009] The present invention provides crystalline form A of the compound of formula (1), whose X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 15.05±0.20°, 19.11±0.20°, and 21.15±0.20°.

[0010] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystalline Form A has characteristic diffraction peaks at 2θ angles of 15.05±0.20°, 19.11±0.20°, 20.41±0.20°, 21.15±0.20°, 22.62±0.20°, 23.48±0.20°, 27.32±0.20°, and 29.25±0.20°.

[0011] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystalline Form A has characteristic diffraction peaks at 2θ angles of 9.10±0.20°, 11.29±0.20°, 12.76±0.20°, 15.05±0.20°, 16.39±0.20°, 19.11±0.20°, 20.41±0.20°, 21.15±0.20°, 22.62±0.20°, and 23.68±0.20°.

[0012] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystalline Form A has characteristic diffraction peaks at 2θ angles of 6.90±0.20°, 9.10±0.20°, 11.29±0.20°, 11.83±0.20°, 12.76±0.20°, 13.73±0.20°, 14.57±0.20°, 15.05±0.20°, 16.10±0.20°, 16.39±0.20°, 17.81±0.20°, 18.25±0.20°, 19.11±0.20°, 20.41±0.20°, and 21.15±0.20°.

[0013] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystalline Form A has characteristic diffraction peaks at 2θ angles of 6.90±0.20°, 9.10±0.20°, 11.29±0.20°, 11.83±0.20°, 12.76±0.20°, 13.73±0.20°, 15.05±0.20°, 16.39±0.20°, 17.81±0.20°, 19.11±0.20°, 20.41±0.20°, 21.15±0.20°, 21.64±0.20°, 22.62±0.20°, and 23.48±0.20°.

[0014] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystalline Form A is 6.90±0.20°, 9.10±0.20°, 11.29±0.20°, 11.83±0.20°, 12.76±0.20°, 13.73±0.20°, 15.05±0.20°, 16.39±0.20°, 17.81±0.20°, 19.11 It has characteristic diffraction peaks at 2θ angles of 20.51±0.20°, 20.41±0.20°, 21.15±0.20°, 21.64±0.20°, 22.62±0.20°, 23.48±0.20°, 25.73±0.20°, 26.43±0.20°, 27.32±0.20°, 28.42±0.20°, and 29.25±0.20°.

[0015] In some embodiments of the present invention, the X-ray powder diffraction pattern of Form A is 15.05±0.20°, 19.11±0.20°, 21.15±0.20°, and / or 6.90±0.20°, and / or 9.10±0.20°, and / or 11.29±0.20°, and / or 11.83±0.20°, and / or 12.76±0.20°, and / or 13.73±0.20°, and / or 14.57±0.20°. 0.20°, and / or 16.10 ± 0.20°, and / or 16.39 ± 0.20°, and / or 17.81 ± 0.20°, and / or 18.25 ± 0.20°, and / or 20.41 ± 0.20°, and / or 20.79 ± 0.20°, and / or 21.64 ± 0.20°, and / or 22.62 ± 0.20°, and / or 23.48 ± 0.20°, and / or 23.68 ± 0.20°, and / or 24.00 ± 0.20°, and / or 24.81 ± 0.20°, and / or 25.73 ± 0.20°, and / or 26.43 ± 0.20°, and / or 26.66 ± 0.20°, and / or 27.32 ± 0.20°, and / or 27.64 ± 0.20°, and / or 28.42 ± 0.20°, and / or 29.25 ± 0.20°, and / or 29.92 ± 0.20°, and / or 30.36 ± 0.20°, and / or 30.73 ± 0.20°, and / or 31.51 ± 0.20°, and / or 31.83 ± 0.20°, and / or 32.05 ± and / or 32.51±0.20°, and / or 32.84±0.20°, and / or 33.13±0.20°, and / or 33.84±0.20°, and / or 34.35±0.20°, and / or 34.90±0.20°, and / or 35.50±0.20°, and / or 36.04±0.20°, and / or 36.47±0.20°, and / or 37.10±0.20°, and / or 37.57±0.20°, and / or 37.88±0.20°, and / or 38.80±0.20°.

[0016] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystalline Form A is 6.904°, 9.095°, 11.285°, 11.833°, 12.757°, 13.732°. It has characteristic diffraction peaks at 2θ angles of 14.573°, 15.050°, 26.655°, 27.323°, 27.636°, 28.420°, 29.248°, 29.922°, 30.358°, 30.733°, 31.507°, 31.830°, 32.049°, 33.049°, 33.049°, 33.049°, 33.049°, 333.049°, 34.34°, 35.500°, 36.037°, 36.467°, 37.098°, 37.573°, 37.875°, and 38.797°.

[0017] In some embodiments of the present invention, the XRPD pattern of Form A is essentially as shown in FIG.

[0018] In some embodiments of the present invention, analytical data of the X-ray powder diffraction pattern of crystalline form A is shown in Table 1.

[0019] [Table 1]

[0020] In some embodiments of the present invention, the thermogravimetric analysis curve for the crystalline form A reaches a weight loss of 6.657% at 140.000°C ± 3.000°C and a weight loss of 12.576% at 205.000°C ± 3.000°C.

[0021] In some embodiments of the present invention, the thermogravimetric analysis curve of the crystalline form A is essentially as shown in FIG.

[0022] In some embodiments of the present invention, the differential scanning calorimetry curve for crystalline Form A has an endothermic peak at 100.28°C±3.00°C, an endothermic peak at 127.61°C±3.00°C, an exothermic peak at 200.70°C±3.00°C, and an endothermic peak at 266.36°C±3.00°C.

[0023] In some embodiments of the present invention, the differential scanning calorimetry curve of crystalline Form A is essentially as shown in FIG.

[0024] The present invention further provides the use of the compound of formula (1) or crystalline form A thereof in the manufacture of a medicament for treating a disease associated with a bacterial infection. [Effects of the Invention]

[0025] Crystalline form A of compound of formula (1) of the present invention is easy to obtain, has good physical and chemical stability, and is of great industrial utility and economic value. The present invention discloses a new class of monocyclic β-lactam compounds substituted with a sulfonylurea ring that are stable against serine β-lactamases and metallo-β-lactamases. They have a broad antibacterial spectrum against Gram-negative bacteria, and in particular, excellent antibacterial activity against various carbapenem-resistant Enterobacteriaceae superbacteria that express β-lactamases. The compounds disclosed in the present invention have good water solubility, are suitable for intravenous administration, have excellent pharmacokinetic properties, are safe, and have good efficacy, and are used to treat diseases associated with bacterial infections.

[0026] Definitions and Explanations The present invention employs the following abbreviations: aq represents water, BOC represents tert-butoxycarbonyl, an amine protecting group, TEMPO represents 2,2,6,6-tetramethylpiperidine nitroxide, TCCA represents trichloroisocyanuric acid, HCl represents hydrochloric acid, TFA represents trifluoroacetic acid, DCM represents dichloromethane, MeCN represents acetonitrile, (n-Bu)NHSO represents tetrabutylammonium hydrogen sulfate, IPA represents isopropanol, eq represents equivalents, the same amount, and CBz represents benzyloxycarbonyl, an amine protecting group. [Brief explanation of the drawings]

[0027] [Figure 1]FIG. 1 is an XRPD spectrum of the crystalline form of compound A of formula (1). [Figure 2] FIG. 1 is a TGA spectrum of the crystalline form of compound A of formula (1). [Figure 3] This is a DSC spectrum diagram of the crystalline form of compound A of formula (1). (A peak information: Total exothermic (endothermic) amount -189.19 mJ, standard exothermic (endothermic) amount -82.26 J / g^-1, initial melting temperature 74.62°C, peak value 100.28°C, final melting temperature 120.89°C, left limit temperature 47.75°C, right limit temperature 113.15°C; B peak information: Total exothermic (endothermic) amount -113.80 mJ, standard exothermic (endothermic) amount -49.48 J / g^-1, initial melting temperature 105.72°C, peak value 127.61°C, final melting temperature 136.22°C, left limit temperature 113.15°C, right limit temperature Boundary temperature 136.62°C; C Peak information: Total heat (endotherm) amount 1374.45mJ, standard heat (endotherm) amount 597.59Jg^-1, initial melting temperature 170.56°C, peak value 200.70°C, final melting temperature 215.91°C, left limit temperature 136.62°C, right limit temperature 228.98°C; D Peak information: Total heat (endotherm) amount -888.43mJ, standard heat (endotherm) amount -386.27Jg^-1, initial melting temperature 229.07°C, peak value 266.36°C, final melting temperature 299.00°C, left limit temperature 228.98°C, right limit temperature 350.12°C). [Figure 4] This is a simulated XRPD spectrum of the single crystal of the compound of formula (1) (wavelengths 1.54056; 14.585, 10366; h, k, l = 4, 0, -1). DETAILED DESCRIPTION OF THE INVENTION

[0028] The present invention will be described in detail below with reference to examples, but this does not mean any adverse limitations on the present invention. The compounds of the present invention include the specific embodiments listed below, embodiments formed by combining with other chemical synthesis methods, and equivalent substitution forms known to those skilled in the art, and preferred embodiments include, but are not limited to, the embodiments of the present invention. It is obvious to those skilled in the art that various modifications and alterations can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. Example 1:

[0029] [ka]

[0030] [ka]

[0031] Step 1: Preparation of Compound A-2 Compound A-1 (1.00 kg, 6.85 mol, 1 eq) was dissolved in methanol (4 L) and Boc anhydride (1.63 kg, 7.46 mol, 1.71 L, 1.09 eq) was slowly added dropwise at 20 °C. Potassium carbonate (1.09 kg, 7.88 mol, 1.15 eq) was dissolved in water (2 L) and slowly added dropwise to the reaction mixture, which was then stirred at 20-30 °C for 1 hour. The reaction mixture was extracted twice with ethyl acetate (8 L), and the combined organic phase was concentrated under reduced pressure. The residue was added to ethyl acetate (15 L), washed once with water (10 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound A-2. 1 H NMR (400 MHz, CDCl3) δ = 5.01 (br s, 1H), 3.93 (br s, 1H), 3.65-3.50 (m, 2H), 3.44 (br d, J = 14.0 Hz, 1H), 3.33-3.19 (m, 1H), 1.46 (d, J = 1.9 Hz, 9H).

[0032] Step 2: Preparation of Compound A-3 Compound A-2 (1.15 kg, 5.48 mol, 1 eq) was dissolved in ethanol (1.5 L) and cooled to 0-5°C. Sodium hydroxide (338.50 g, 6.03 mol, 1.1 eq) was dissolved in ethanol (4 L) and slowly added dropwise to the reaction system. After the addition was complete, the temperature was slowly raised to 25°C and stirred at 25°C for 1 hour. 1N HCl was added to the reaction solution to adjust the pH to 7 and then concentrated under reduced pressure. The residue was extracted with ethyl acetate (5 L x 2), washed once with brine (1 L), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in a 3:1 mixture of petroleum ether and ethyl acetate (5 L), and 1.50 kg of 100-200 mesh silica gel was added at 15°C. The mixture was stirred for 0.5 hours and filtered. The filter cake was washed three times with a 1:3 mixture of petroleum ether and ethyl acetate (5 L). The combined filtrate was concentrated under reduced pressure to obtain compound A-3. 1 H NMR (400 MHz, CDCl3) δ = 4.76 (br s, 1H), 3.62-3.50 (m, 1H), 3.28-3.19 (m, 1H), 3.11 (br s, 1H), 2.80 (t, J = 4.3 Hz, 1H), 2.61 (dd, J = 2.6, 4.7 Hz, 1H), 1.46 (s, 9H).

[0033] Step 3: Preparation of Intermediate A Compound A-3 was dissolved in ethanol (5 L), and aqueous ammonia (4.55 kg, 32.46 mol, 5 L, 25% purity, 5.62 eq) was added at 0-5°C. The mixture was heated to 20°C and stirred for 16 hours. The reaction mixture was evaporated under reduced pressure, and solid sodium chloride was added to the residue, followed by stirring at 25°C for 0.5 hours. Ethyl acetate (2 L) was added once for extraction, and the aqueous phase was extracted with ethyl acetate (500 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried in petroleum ether / tert-butyl methyl ether = 1 / 1 at 20°C for 1 hour, filtered, and the filter cake was dried under vacuum to obtain intermediate A. 1H NMR (400 MHz, CDCl3) δ = 5.46-5.08 (m, 1H), 3.79-3.54 (m, 1H), 3.32-3.19 (m, 1H), 3.13-2.99 (m, 1H), 2.79 (dd, J = 4.0, 12.7 Hz, 1H), 1.43 (s, 9H).

[0034] Preparation of Intermediate B

[0035] [ka]

[0036] Compound B-1 (84.00 g, 593.50 mmol, 1 eq) was dissolved in dichloromethane (590 mL) at 0-10°C, and a solution of benzyl alcohol (66.11 g, 661.30 mmol, 1.03 eq) in dichloromethane (590 mL) was slowly added dropwise at 0-10°C under a nitrogen atmosphere. The reaction solution was reacted in an ice bath for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was slurried in petroleum ether (600 mL) at 25°C for 15 minutes and filtered to obtain intermediate B. 1 H NMR (400 MHz, CDCl3) δ = 7.51 - 7.36 (m, 5H), 5.33 (s, 2H).

[0037] Preparation of Intermediate C

[0038] [ka]

[0039] Step 1: Preparation of Compound C-2 1,8-Diazabicyclo[5.4.0]undecan-7-ene (536.8 g, 3.53 mol, 531.5 mL, 1.2 eq) was added to a toluene (3.5 L) solution of compound C-1 (300.0 g, 2.94 mol, 1 eq) and brominated diphenylmethane (835.2 g, 3.38 mol, 1.15 eq) at 20-30°C, and the temperature was then raised to 75-80°C and the reaction was carried out for 5 hours. Cool the reaction solution to room temperature, add water (1 L) and stir for 0.5 hours, separate the organic phase, wash with water (1 L × 2), concentrate under reduced pressure to approximately 500 mL, add n-heptane (2 L) and heat to 75-80 °C to obtain a clear solution, cool it to room temperature, stir in ice water for 1 hour, filter, wash the filter cake with toluene / n-heptane (600 mL, 1 / 5) and n-heptane (300 mL), dry the solid with an oil pump to obtain compound C-2. 1 H NMR (400 MHz, CDCl3) δ = 7.40-7.29 (m, 11H), 6.95 (s, 1H), 1.46-1.39 (m, 2H), 1.27-1.19 (m, 2H).

[0040] Step 2: Preparation of compound C-3 To a solution of compound C-2 (150.0 g, 559.1 mmol, 1 eq) and diphenylphosphonamide (156.5 g, 670.9 mmol, 1.2 eq) in tetrahydrofuran (1.5 L), sodium tert-butoxide was added in portions at 0–10°C. The temperature was controlled within the range of 0–10°C, and the reaction was carried out at 0–10°C for 2 hours under nitrogen protection. 5% sodium chloride (1 L) was added to the reaction mixture and stirred for 0.5 hours. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (500 mL × 2). The combined organic phase was washed with 5% sodium chloride solution (1 L × 2), dried over anhydrous sodium sulfate, and filtered to obtain a 2.5 L tetrahydrofuran / ethyl acetate solution of compound C-3, which was used directly in the next reaction.

[0041] Step 3: Preparation of Intermediate C Compound C-4 (106.6 g, 391.3 mmol, 0.7 eq) was added to 2.5 L of a tetrahydrofuran / ethyl acetate solution of compound C-3 (158.4 g, 559.1 mmol, 1 eq), and the mixture was allowed to react for 18 hours at 20-30° C. The reaction mixture was concentrated under reduced pressure to obtain a residue, and then ethyl acetate (400 mL) was added. The mixture was heated to 65-70° C. and stirred for 0.5 hours. After that, n-heptane (1.6 L) was added, cooled to room temperature, stirred in an ice bath for 0.5 hours, filtered, and the filter cake was washed with ethyl acetate / n-heptane (400 mL, 1 / 3) and dried under reduced pressure using an oil pump to obtain a residue. The residue was added to acetonitrile (580 mL) and acetone (1.45 L), stirred at 55-60°C for 3 hours, concentrated under reduced pressure at 40°C to remove acetone, repeatedly added acetonitrile (400 mL), concentrated under reduced pressure twice, added acetonitrile (360 mL), heated to 60°C, added dropwise with water (580 mL), cooled to room temperature, stirred for 1 hour, filtered, and the filter cake was washed successively with acetonitrile / water (300 mL, 1 / 1) and ice acetonitrile (100 mL). The solid was dried under reduced pressure with an oil pump to obtain a residue. 1 H NMR (400 MHz, DMSO-d6) δ = 11.83 (br s, 1H), 7.49 (s, 1H), 7.45 (dd, J = 1.8, 7.6 Hz, 4H), 7.30 - 7.21 (m, 6H), 6.88 (s, 1H), 1.51 (br d, J = 3.0 Hz, 2H), 1.48 (s, 9H), 1.45 - 1.40 (m, 2H).

[0042] Preparation of the compound of formula (1)

[0043] [ka]

[0044] [ka]

[0045] Step 1: Preparation of Compound 1-2 Compound 1-1 (1.5 kg, 11.35 mol, 1 eq) was dissolved in DCM (15 L). Under nitrogen protection, TEMPO (4.46 g, 28.38 mmol, 0.0025 eq) and sodium acetate (1.40 kg, 17.03 mol, 1.5 eq) were added in one portion at 10-20°C. TCCA (1.06 kg, 4.54 mol, 0.4 eq) was then added in portions over 1 hour at 0-10°C. The reaction solution was warmed to 10-20°C and stirred for 1 hour. The reaction solution was then filtered. The filtrate, a dichloromethane solution of compound 1-2, was used directly in the next step of the reaction.

[0046] Step 2: Preparation of Compounds 1-3 To the dichloromethane solution of compound 1-2, 1 eq of aqueous sodium carbonate was added, followed by the addition of 2,4-dimethoxybenzylamine (1.52 kg, 9.10 mol, 1.37 L, 1 eq), and the mixture was stirred at 10-15°C for 0.5 hours. The reaction was stopped, the layers were separated, and the organic phase was washed with saturated brine (5.0 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was a dichloromethane solution of compound 1-3, which was used directly in the next step of the reaction. Step 3: Preparation of Compounds 1-5

[0047] Compound 1-4 (2.47 kg, 11.82 mol, 1.3 eq) was dissolved in dichloromethane (12.8 L) and cooled to -40 °C. Triethylamine (3.59 kg, 35.46 mol, 4.94 L, 3.9 eq) was added and stirred at -30 to -20 °C for 30 min. The dichloromethane solution of compound 1-3 was slowly added at -20 to -30 °C. The temperature was then raised to -20 to 10 °C and stirring continued for 6 h. The reaction was quenched and washed sequentially with 3 M HCl (6 L), saturated aqueous sodium bicarbonate (6 L), and brine (6 L), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was suspended in methanol, stirred at -30 to -20 °C for 2 h, and filtered to give compound 1-5 (880.0 g, 18.5% total yield for three steps).

[0048] Step 4: Preparation of Compounds 1-6 Compound 1-5 (131.0 g, 278.42 mmol, 1 eq) was added to tetrahydrofuran (1.2 L) and water (300 mL) at 20-30 °C, and p-toluenesulfonic acid monohydrate (37.07 g, 194.89 mmol, 0.7 eq) was added and stirred at 65 °C for 4 h. The mixture was cooled to 20 °C, the pH was adjusted to 7 using saturated sodium bicarbonate solution, and the mixture was concentrated under reduced pressure at 40 °C to remove tetrahydrofuran. Water (1.2 L) was added to the remaining mixture, and the mixture was stirred at 20-30 °C for 1 h. After filtration, the filter cake was rinsed with water (600 mL) to obtain compound 1-6.

[0049] Step 5: Preparation of Compounds 1-7 Compound 1-6 (119.85 g, 278.43 mmol, 1 eq) was added to ethyl acetate (1.2 L) and water (400 mL) at 20-30 °C. Sodium periodate (65.51 g, 306.27 mmol, 1.1 eq) was added, and the mixture was stirred at 50 °C for 2 h. The temperature was lowered to 20-25 °C, and the organic and aqueous phases were separated. The aqueous phase was extracted with ethyl acetate (300 mL × 2). The combined organic phases were washed with 5% sodium chloride solution (300 mL), and concentrated under reduced pressure to obtain the crude product. The product was stirred with ethyl acetate (350 mL) at 20-30 °C for 5 h and filtered to obtain compound 1-7. 1 H NMR (400 MHz, CDCl3) δ = 9.35 (d, J = 3.3 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.42- .27 (m, 6H), 7.19 (d, J = 8.3 Hz, 1H), 6.57 (d, J = 2.1 Hz, 1H), 6.51 (dd, J = 2.3, 8.3 Hz, 1H), 5.01 (s, 2H), 4.97-4.90 (m, 1H), 4.47-4.24 (m, 2H), 4.08 (dd, J = 3.3, 5.8 Hz, 1H), 3.76 (s, 3H), 3.73 (s, 3H).

[0050] Step 6: Preparation of Compounds 1-8 Compound 1-7 (78.00 g, 195.80 mmol, 1 eq) and 4A molecular sieves (150.00 g) were added to anhydrous dichloromethane (780 mL) at 0 °C, and a solution of intermediate A (55.87 g, 293.67 mmol, 1.5 eq) in dichloromethane (200 mL) was added dropwise, stirred under nitrogen for 1 h, filtered, and the filtrate was added dropwise to a solution of sodium triacetoxyborohydride (82.99 g, 391.56 mmol, 2 eq) in acetic acid (200 mL) and stirred at 15-25 °C for 16 h under nitrogen protection. After concentrating under reduced pressure at 35°C, the mixture was diluted with water (1 L), extracted with ethyl acetate (800 mL × 2), dried over anhydrous sodium sulfate, filtered, and petroleum ether (1.5 L) was added to the filtrate. After stirring at 15 to 25°C for 1 hour, the precipitated white solid was collected by filtration to obtain compound 1-8. 1 H NMR(400 MHz, DMSO) δ = 9.57-8.96 (m, 1H), 8.88-8.41 (m, 1H), 8.17 (br d, J = 9.3 Hz, 1H), 7.44-7.28 (m, 5H), 7.19 (d, J = 8.3 Hz, 1H), 6.90 (br s, 1H), 6.58 (d, J = 2.3 Hz, 1H), 6.50 (dd, J = 2.3, 8.3 Hz, 1H), 5.61 (br s, 1H), 5.15-5.01 (m, 2H), 4.99 (dd, J = 5.1, 9.4 Hz, 1H), 4.45-4.20 (m, 2H), 3.98 (br s, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.15 (br s, 1H), 3.06 (br s, 1H), 2.99-2.90 (m, 2H), 2.84 (br d, J = 10.9 Hz, 1H), 2.64 (br t, J = 10.2 Hz, 1H), 1.38 (s, 9H).

[0051] Step 7: Preparation of Compounds 1-9 Compound 1-8 (70.00 g, 122.24 mmol, 1 eq) and triethylamine (49.48 g, 488.96 mmol, 68.06 mL, 4 eq) were added to anhydrous tetrahydrofuran (700 mL), and a solution of intermediate B (46.69 g, 187.03 mmol, 1.53 eq) in anhydrous tetrahydrofuran (300 mL) was added dropwise at 0 °C. A solution of intermediate B (6.10 g, 24.45 mmol, 0.2 eq) in anhydrous tetrahydrofuran (50 mL) was added dropwise to the mixture and stirred at 15-25 °C for 1 h to obtain a tetrahydrofuran solution of compound 1-9, which was used directly in the next step of the reaction.

[0052] Step 8: Preparation of Compounds 1-11 Compound 1-9 (97.43 g, 123.98 mmol, 1 eq) in anhydrous tetrahydrofuran (1.08 L) was added with triethylamine (25.09 g, 247.96 mmol, 34.51 mL, 2 eq), and methanesulfonyl chloride (17.31 g, 151.11 mmol, 11.70 mL, 1.22 eq) was added dropwise at 0 to 10°C. The mixture was stirred for 3 hours, and methanesulfonyl chloride (16.16 g, 14 A solution of 1.07 mmol, 10.92 mL, 1.14 eq) was added dropwise to the mixture and stirred at 0-10°C for 1 h. The temperature was lowered to 15-20°C, the mixture was poured into ice water (1.5 L), extracted with ethyl acetate (1 L x 2), the combined organic phase was washed with brine (1 L), dried over anhydrous water, and concentrated under reduced pressure. Ethyl acetate (500 mL) was added, and the mixture was stirred at 15-25°C for 16 h. The mixture was filtered to give compound 1-11. LCMS (ESI) m / z: 768.4 (M+1).

[0053] Step 9: Preparation of Compounds 1-12 Compound 1-11 (20.00 g, 26.05 mmol, 1 eq) was dissolved in acetonitrile (200 mL) and water (100 mL). The temperature was raised to 65-70 °C in a 100 °C oil bath. Potassium persulfate (31.68 g, 117.21 mmol, 4.5 eq) and potassium dihydrogen phosphate (18.15 g, 104.19 mmol, 4 eq) were added in one portion and the mixture was refluxed for 1.5 h. The mixture was then cooled to room temperature, filtered, saturated sodium bicarbonate (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 3, 10% dichloromethane) to give compound 1-12. 1 H NMR (400 MHz, CDCl3) δ = 7.44-7.20 (m, 11H), 6.02-5.50 (m, 1H), 5.31-5.16 (m, 2H), 5.11-4.90 (m, 4H), 4.02-3.97 (m, 1H), 3.97-3.86 (m, 1H), 3.70-3.44 (m, 2H), 3.43-3.09 (m, 3H), 2.97-2.81 (m, 1H), 1.89-1.57 (m, 1H), 1.36 (s, 9H).

[0054] Step 10: Preparation of Compounds 1-13 Compound 1-12 (300.0 g) and 3.0 L of methanol were placed in a 5 L glass reaction flask, stirred, and the temperature was raised to 40 °C. The mixture was stirred until the raw materials were dissolved. Under nitrogen protection, Pd / C (15.0 g, 10% purity) was added, and 564.8 g of triethylsilyl hydride was added dropwise. Stirring was continued while maintaining a nitrogen flow environment. Under nitrogen protection, Pd / C (15.0 g, 10% purity) was added, and triethylsilyl hydride was added dropwise. After the addition was completed, heating was stopped and stirring was continued for 20 minutes, while maintaining nitrogen protection. The reaction solution was suction filtered through diatomaceous earth, and the filter cake was washed twice with methanol (500 ml x 2). The filtrate was concentrated at 45 °C. 5.0 L of tert-butyl methyl ether was added to the residue, and the mixture was stirred at 15-30°C for 18 hours. The mixture was then suction filtered under nitrogen protection. The filter cake was rinsed with 1.0 L of tert-butyl methyl ether and suction filtered. The filter cake was dried by rotary evaporation using an oil pump (temperature: 50°C, time: 2 hours) to obtain compound 1-13.

[0055] Step 11: Preparation of Compounds 1-14 Compound 1-13 (20.50 g, 58.67 mmol, 1 eq) and intermediate C (28.39 g, 52.80 mmol, 0.9 eq) were dissolved in N,N-dimethylformamide (200 mL), N,N-diisopropylethylamine (22.75 g, 176.01 mmol, 30.66 mL, 3 eq) and 1-hydroxybenzotriazole (10.31 g, 76.27 mmol, 1.3 eq) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.62 g, 76.27 mmol, 1.3 eq). The reaction solution was reacted under nitrogen protection at 15-25 °C for 16 hours. The reaction mixture was poured into 1.5 L of ice water, stirred for 10 minutes, and then filtered. The filter cake was washed with water (300 mL × 2), and the filtrate was extracted with ethyl acetate (500 mL × 2). The filter cake was dissolved in the organic phase and washed sequentially with dilute hydrochloric acid (0.5 N, 100 mL × 2), saturated sodium bicarbonate (100 mL × 2), and brine (200 mL). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 1 / 2, 10% dichloromethane) to give compound 1-14.

[0056] Step 12: Preparation of Compounds 1-15 Compound 1-14 (10.00 g, 11.51 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (50 mL). Sulfur trioxide N,N-dimethylformamide complex (13.63 g, 46.03 mmol, 47% purity, 4 equiv.) was added at 0-5 °C and stirred at 0-5 °C for 3 h. The mixture was poured into a mixture of water (80 mL) and ethyl acetate (150 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic layer was washed with brine (150 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 0 / 1 + 10% dichloromethane) to give compound 1-15. LCMS (ESI) m / z: 949.1 (M+1).

[0057] Step 13: Preparation of Compound of Formula (1) Compound I-15 (6.20 g, 6.53 mmol, 1 eq) and anisole (7.06 g, 65.33 mmol, 7.10 mL, 10 eq) were dissolved in dichloromethane (60 mL). Phosphoric acid (50.40 g, 437.14 mmol, 85% purity, 66.91 eq) was added at 0-5 °C and stirred at 0-5 °C for 1.5 h. The lower phosphoric acid phase in the mixture was added dropwise to tetrahydrofuran (300 mL) at 0-5 °C and stirred at 0-5 °C for 1 h. The mixture was then filtered under nitrogen protection. The filter cake was rinsed with tetrahydrofuran (100 mL × 2) to obtain the crude product of formula (1), which was detected as an amorphous powder by XRPD. The crude product was dissolved in water (4 mL), filtered, and the filtrate was added dropwise to tetrahydrofuran (80 mL). The mixture was stirred at 25-30 °C for 4 h. It was then filtered under nitrogen protection. The filter cake was rinsed with tetrahydrofuran (50 mL × 2) and dried to obtain compound (1). Compound (1) was found to be crystalline form A by XRPD. ICPMS showed a sodium ion content of 1.59% and a phosphate ion content of 19.4%. Karl Fischer water content analysis revealed a water content of 7.5%. Compound (1) was found to be a salt form containing 0.5% sodium and 1.5% phosphate, and crystalline form A containing 3 waters of crystallization. LCMS (ESI) m / z: 583.1 (M+1). 1 H NMR(400 MHz, DMSO-d6 + D2O) δ = 6.80 (s, 1H), 5.23 (d, J = 5.7 Hz, 1H), 4.17 (q, J = 5.7 Hz, 1H), 3.84 - 3.76 (m, 2H), 3.67 (br t, J = 8.9 Hz, 1H), 3.42 (br dd, J = 5.1, 14.4 Hz, 1H), 3.16 (br dd, J = 6.2, 14.2 Hz, 1H), 3.04 (br dd, J = 5.4, 9.9 Hz, 1H), 2.98 - 2.89 (m, 1H), 2.88 - 2.79 (m, 1H), 1.29 (br d, J = 9.4 Hz, 4H).

[0058] Example 2: Crystalline form of compound A of formula (1) Method 1: The crude product of the compound of formula (1) (0.50 g, 685.33 μmol) is dissolved in water (0.5 mL), and insoluble impurities are filtered off. The solution is added dropwise to tetrahydrofuran (10 mL) at 25-30°C and stirred at 25-30°C for 4 hours. After 4 hours, the solution is dispersed uniformly, filtered under nitrogen protection, and dried to obtain crystalline form A of compound of formula (1).

[0059] Method 2: Dissolve the compound of formula (1) (100 mg, 137.07 μmol) in water (0.1 mL), add tetrahydrofuran (2 mL) dropwise to the solution until a solid precipitates, stir for about 2 hours to initiate solidification, gradually disperse, and after 4 hours, the solid is uniformly dispersed, filtered under nitrogen protection, and dried to obtain the crystalline form of compound A of formula (1).

[0060] Method 3: To the compound of formula (1) (20.00 mg, 27.4 μmol), a mixed solvent of water and tetrahydrofuran was added, followed by water / tetrahydrofuran (1 / 15=0.5 mL), (1 / 20=0.5 mL), (1 / 25=0.5 mL), and the mixture was stirred at 25-30°C to disperse the solid homogeneously for about 5 hours. The solid was then filtered and dried under nitrogen protection to obtain the crystalline form A of the compound of formula (1).

[0061] Method 4: Dissolve compound of formula (1) (500 mg, 685.33 μmol) in water (1.0 mL), add 85% phosphoric acid (67.16 mg, 685.33 mmol), add tetrahydrofuran (20.0 mL) dropwise to the solution, stir at 15-25 °C for 12 hours, filter under nitrogen protection, and dry to obtain compound of formula (1) crystalline form A.

[0062] Method 5: Dissolve compound of formula (1) (500 mg, 685.33 μmol) in water (1.0 mL), add 85% phosphoric acid (67.16 mg, 685.33 mmol), add isopropanol (6.0 mL) dropwise to the solution, stir at 15.25°C for 12 hours, filter under nitrogen protection, and dry to obtain compound of formula (1) crystalline form A. Example 3: Confirmation of the configuration of the compound of formula (1)

[0063] Take 16 mg of a sample of the crystalline form of formula (1) A and dissolve it in 900 μL of methanol / ethanol / water (1:1:1) at room temperature. The sample solution is placed in a 4 mL semi-sealed sample bottle and allowed to evaporate slowly at room temperature. The next day, colorless needle-like crystals are obtained.

[0064] The detected crystals were colorless needles (0.30 × 0.10 × 0.10 mm 3 ) and belongs to the monoclinic C2 space group. The unit cell parameters are a = 25.3958(7) Å, b = 8.0781(2) Å, c = 14.8880(2) Å, α = 90°, β = 90.224(2)°, γ = 90°, V = 3054.25(12) ų, and Z = 2. The calculated density is Dc = 1.728 g / cm³, the number of electrons in the unit cell is F(000) = 1648.0, and the linear absorption coefficient of the unit cell (Cu Kα) is 3.918 mm³. -1 , Diffraction experiment temperature T = 149.99(11)K.

[0065] The three-dimensional structural ellipsoid diagram of the needle-like crystals is shown in Figure 5, the simulated XRPD is shown in Figure 4, and the structural data and parameters are shown in Tables 2-7.

[0066] [Table 2]

[0067] [Table 3]

[0068] [Table 4]

[0069] [Table 5]

[0070] [Table 6]

[0071] 1 +X,1+Y,+Z; 2 1 / 2+X,1 / 2+Y,+Z; 3 1 / 2+X,-1 / 2+Y,+Z; 4 1-X,+Y,1-Z; 5 3 / 2-X,-1 / 2+Y,1-Z; 6 3 / 2-X,1 / 2+Y,1-Z; 7 1-X, 1+Y, 1-Z

[0072] [Table 7]

[0073] Example 4: Preparation of other salt forms of the compound of formula (1) (1) Preparation of trifluoroacetic acid (TFA):

[0074] [ka]

[0075] Intermediate 1-15 (300 mg, 308.95 μmol, 1 eq) and anisole (66.82 mg, 617.91 μmol, 67.16 μL, 2 eq) were dissolved in DCM (3 mL). TFA (704.54 mg, 6.18 mmol, 457.49 μL, 20 eq) was added to the mixture at 0 °C. The mixture was then stirred at 0-5 °C for 1 h. HO (140.04 mg, 7.77 mmol, 140.04 μL, 25.15 eq) was then added to the mixture at 0 °C and stirred at 25 °C for 24 h. The lower aqueous phase / TFA was added dropwise to a cooled MeCN solution (8 mL) at 0-5 °C. The mixture was then stirred at 0-5 °C for 0.5 h. The product was filtered under vacuum nitrogen to give the crude product (110 mg, 168.67 μmol, 54.59% yield, 89.33% purity) as an off-white solid. The solid was dissolved in 5 mL of water, adjusted to pH 7-8 with saturated sodium bicarbonate at 0 °C, and treated with (n-Bu) NHSO to pH 4-5. A preparative HPLC column (Waters Xbridge BEH C column) was used. 18 The resulting mixture was purified by preparative HPLC (Phenomenex Synergi Max-RP 250*50mm*10 μm column, mobile phase: acetonitrile / water (10 mM NH4HCO3), acetonitrile content ranging from 5% to 30%, 21 min) to give compound of formula (II), which was detected as an amorphous powder by XRPD. LCMS (ESI) m / z: 583.1 (M+1). 1H NMR (400 MHz, D2O) δ = 6.80 (s, 1H), 5.23 (d, J = 5.7 Hz, 1H), 4.17 (q, J = 5.7 Hz, 1H), 3.84 - 3.76 (m, 2H), 3.67 (br t, J = 8.9 Hz, 1H), 3.42 (br dd, J = 5.1, 14.4 Hz, 1H), 3.16 (br dd, J = 6.2, 14.2 Hz, 1H), 3.04 (br dd, J = 5.4, 9.9 Hz, 1H), 2.98 - 2.89 (m, 1H), 2.88 - 2.79 (m, 1H), 1.29 (br d, J = 9.4 Hz, 4H).

[0076] (2) Preparation of sulfate (H2SO4): The reaction was complicated and no sulfate was obtained. (3) Preparation of hydrochloride (HCl) The starting material was completely consumed, but no product was produced. (4) Preparation of acetate (AcOH) The starting material was completely consumed, but no product was produced. (5) Production of p-toluenesulfonate (TsOH): The raw material was completely consumed, but no product was produced.

[0077] Conclusion: Some other salt forms of the compound of formula (1) cannot be obtained directly.

[0078] Example 5: Stability study of crystalline forms of Compound A of formula (1) in different solvents Crystalline form A of compound A of formula (1) (30.00 mg, 44.08 μmol, 1 eq) was suspended in ethanol (0.2 mL), isopropanol (0.2 mL), acetonitrile (0.2 mL), ethyl acetate (0.2 mL), tetrahydrofuran (0.2 mL), ethanol / water = 20 / 1 (0.2 mL), isopropyl alcohol / water = 20 / 1 (0.2 mL), and acetonitrile / water = 20 / 1 (0.2 mL) at 20-30 °C for 2 days, filtered under nitrogen protection, and dried. The results are shown in Table 8.

[0079] [Table 8]

[0080] Conclusion: The crystalline form of compound A of formula (1) can be stably present in various solvents, and is easily obtained with good reproducibility.

[0081] Example 6: Search for other crystalline forms of the compound of formula (1) Objective: To explore other crystal forms by changing the crystallization conditions.

[0082] [Table 9]

[0083] Conclusion: When using the crystalline form A of compound of formula (1) in different aqueous systems, other crystalline forms cannot be obtained after first dissolving and then crystallizing.

[0084] Example 7: Study on the solid state stability of the crystalline form of Compound A of formula (1) The crystalline form of compound A of formula (1) was spread into a thin layer and placed under full exposure to high temperature, normal temperature and high humidity, light, high temperature and high humidity conditions. Samples were taken at designated time points and XRPD, appearance, content and related substances were detected and compared with the results of the 0-day sample.

[0085] [Table 10]

[0086] Conclusion: Crystalline form A of compound of formula (1) is stable under high temperature, high humidity and light irradiation conditions, and no significant changes in substance or content were observed under conditions of 60°C, 25°C / 75%RH and light irradiation.

[0087] Biological activity evaluation of the crystalline form of compound A of formula (1) Experimental Example 1: Detection of antibacterial effect (MIC) of crystalline form of compound A of formula (1) The minimum inhibitory concentration (MIC) of each compound was measured using a microfluidic dilution method according to the requirements of the Clinical and Laboratory Standards Institute (CLSI) for three strains of Klebsiella pneumoniae: ATCC BAA-205 (TEM-1 / SHV-1 / SHV-12), ATCC BAA-1705 (KPC-2), and ATCC BAA-2470 (NDM-1), Enterobacter cloacae: ATCC BAA-1143 (AmpC), and two strains of Escherichia coli: ATCC BAA-2523 (OXA-48) and ATCC 25922. Two-fold serial gradient dilutions of compounds (final concentrations ranging from 0.125 μg / mL to 128 μg / mL) were added to a round-bottom 96-orifice plate (Corning Cat. No. 3788) and plated overnight on Hinton-Miller Agar (MHA, Cat. No. 211438, BD BBL). TM ) Select fresh bacterial monoclones on plates and suspend in sterile saline sodium chloride to a concentration of 1 × 10 8 CFU / mL and 5 × 10 in Mueller-Hinton II Broth (MHB, Cat. No. 212332, BD BBL™) adjusted again with cations. 5 The solution was diluted to CFU / mL and 100 μL was added to a round-bottom 96-orifice plate containing the drug. The plate was inverted and incubated at 37°C for 20-24 hours, and the MIC value was read. The lowest drug concentration that inhibited bacterial growth was defined as the MIC. The results are shown in Table 8. Colony-forming units (CFU) refer to the total number of bacterial colonies per unit volume.

[0088] [Table 11]

[0089] Conclusion: The crystalline form of compound A of formula (1) has good inhibitory effects on various bacteria.

[0090] Experimental Example 2: Pharmacokinetic study of crystalline form of Compound A of formula (1) in rats The pharmacokinetic profile of the compound in rodents after intravenous administration was tested using standard protocols. Specifically, candidate compounds were administered intravenously to 7-10 week-old male SD rats. The compounds were dissolved in saline to form a clear solution. Plasma samples were collected and analyzed by LC-MS / MS, and pharmacokinetic parameters were calculated. The drug displacement parameters for the crystalline form of Compound A of Formula (1) are shown in Table 12.

[0091] [Table 12]

[0092] Conclusion: The exposure of the compound of the present invention increases linearly, and subsequent studies have shown that it can exert the benefits of the maximum dose of the drug within a safe range, resulting in better clinical efficacy and a good outlook for the drug.

[0093] Experimental Example 3: Spontaneous Drug Resistance Mutation Rate (FOR) of Compound A of Formula (1) in Escherichia coli ATCC 25922

[0094] Using Escherichia coli ATCC 25922, colonies with a total colony count of 2.60E+08 CFU were selected for screening by microfluidic dilution according to the requirements of the Clinical and Laboratory Standards Institute (CLSI). These colonies were cultured at 2x, 4x, 8x, 16x, and 32x the minimum inhibitory concentration (MIC) for 24 and 48 hours, respectively, to calculate the drug resistance frequency. See Table 13 for details.

[0095] [Table 13]

[0096] Conclusion: Compound (1) has a twice-high MIC and a low incidence of drug resistance, making it promising for clinical use. The crystalline form A of compound (1) provided by the present invention has stable properties, good solubility and good hygroscopicity, and has good medical prospects.

[0097] The crystalline form A of compound (1) provided by the present invention is easy to prepare, uses common reagents that are readily available on the market, is inexpensive, and can be prepared in a stable single crystalline form by various methods, with simple operations, mild conditions, high purity, and high yield.

[0098] Experimental Example 4: In vivo efficacy of crystalline form of formula (1) compound in thigh muscle infection model Seventy-eight female CD-1 mice were divided into 26 cages, with three mice in each cage, and the day of infection was counted as day 0. On the fourth day, 150 mg / kg of the immunosuppressant cyclophosphamide was intraperitoneally injected, and on the first day, 100 mg / kg of the immunosuppressant cyclophosphamide was intraperitoneally injected to induce immunodeficiency in the mice.

[0099] On day 1, the strain Klebsiella pneumoniae ATCC-BAA 2470 (NDM+) was revived on an MHA plate. The revived colonies were collected and dissolved in sterile saline to prepare a bacterial solution with a concentration of 5.95E+07 CFU / mL for infection of the thigh muscles of mice. The start of infection was recorded as 0 h, and 100 μL of the bacterial solution was injected into each thigh muscle at 0 h, resulting in an inoculum of 5.95E+06 CFU / mouse. Two hours after infection, drugs were administered according to the experimental protocol. The specific experimental design is as follows (see Table 14):

[0100] (1) 2 hours after infection: At the end of 25 cages of mice, thigh muscle tissue was collected and placed in 10 mL of sterile saline. The tissue was homogenized with a homogenizer, and the homogenate was gradient diluted and spotted, repeated twice for each mouse.

[0101] (2) 2 hours post-infection: For treatment, mice in cages 1 through 24 were treated with Formula (1) Compound A subcutaneously at 10 mL per kg of mouse body weight. The total daily dose for cages 1 through 4 was 1600 mg / kg, for cages 5 through 8 was 480 mg / kg, for cages 9 through 12 was 160 mg / kg, for cages 13 through 16 was 48 mg / kg, for cages 17 through 20 was 16 mg / kg, and for cages 21 through 24 was 4.8 mg / kg. Each dose group was administered in four different dose fractions: q3h, q6h, q12h, and q24h, respectively.

[0102] (3) 26 h post-infection: The endpoint of the study was 26 h post-infection. Thigh muscle tissues from mice in cages 1 to 26 were collected and placed in 10 mL of sterile saline. The tissues were homogenized using a homogenizer. The homogenates were gradient diluted and spotted. Each mouse was replicated twice. The bacterial load in the mouse thigh muscle tissues was counted, and the experimental results are shown in Table 15.

[0103] [Table 14]

[0104] [Table 15]

[0105] Conclusion: The crystalline form of compound A of formula (1) of the present invention has significant bactericidal effect in vivo, with a clear dose-effect relationship. Under the same daily dose, shortening the administration interval can significantly improve the efficacy in vivo.

Claims

1. Formula (1): 【Chemical 1】 As shown in A medicinal salt of a compound characterized by:

2. The X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 15.05±0.20°, 19.11±0.20°, and 21.15±0.20°, and is represented by the formula (1): 【Chemistry 2】 It is crystalline form A shown in A medicinal salt of a compound characterized by:

3. The X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 15.05±0.20°, 19.11±0.20°, 20.41±0.20°, 21.15±0.20°, 22.62±0.20°, 23.48±0.20°, 27.32±0.20°, and 29.25±0.20°. The medicinal salt according to claim 2.

4. The X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 9.10±0.20°, 11.29±0.20°, 12.76±0.20°, 15.05±0.20°, 16.39±0.20°, 19.11±0.20°, 20.41±0.20°, 21.15±0.20°, 22.62±0.20°, and 23.68±0.20°. The medicinal salt according to claim 2.

5. The X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 6.90±0.20°, 9.10±0.20°, 11.29±0.20°, 11.83±0.20°, 12.76±0.20°, 13.73±0.20°, 14.57±0.20°, 15.05±0.20°, 16.10±0.20°, 16.39±0.20°, 17.81±0.20°, 18.25±0.20°, 19.11±0.20°, 20.41±0.20°, and 21.15±0.20°. The medicinal salt according to claim 2.

6. The X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 6.90±0.20°, 9.10±0.20°, 11.29±0.20°, 11.83±0.20°, 12.76±0.20°, 13.73±0.20°, 15.05±0.20°, 16.39±0.20°, 17.81±0.20°, 19.11±0.20°, 20.41±0.20°, 21.15±0.20°, 21.64±0.20°, 22.62±0.20°, and 23.48±0.20°. The medicinal salt according to claim 2.

7. The X-ray powder diffraction pattern was 6.90±0.20°, 9.10±0.20°, 11.29±0.20°, 11.83±0.20°, 12.76±0.20°, 13.73±0.20°, 15.05±0.20°, 16.39±0.20°, 17.81±0.20°, 19.11±0.20°, 20. It has characteristic diffraction peaks at 2θ angles of 41±0.20°, 21.15±0.20°, 21.64±0.20°, 22.62±0.20°, 23.48±0.20°, 25.73±0.20°, 26.43±0.20°, 27.32±0.20°, 28.42±0.20°, and 29.25±0.20°. The medicinal salt according to claim 2.

8. The X-ray powder diffraction pattern was: 6.904°, 9.095°, 11.285°, 11.833°, 12.757°, 13.732°, 14.573°, 15.050°, 16.100°, 16.389°, 17.807°, 18.251°, 19.113°, 20.413°, 20.790°, 21.147°, 21.641°, 22.615°, 23.484°, 23.676°, 24.002°, 24.812°, 25.728°, 26.433°, 26. It has characteristic diffraction peaks at 2θ angles of 655°, 27.323°, 27.636°, 28.420°, 29.248°, 29.922°, 30.358°, 30.733°, 31.507°, 31.830°, 32.049°, 32.509°, 32.843°, 33.130°, 33.837°, 34.346°, 34.895°, 35.500°, 36.037°, 36.467°, 37.098°, 37.573°, 37.875°, and 38.797°. The medicinal salt according to claim 2.

9. The thermogravimetric analysis curve reaches a weight loss of 6.657% at 140.000°C ± 3.000°C and a weight loss of 12.576% at 205.000°C ± 3.000°C.

9. The medicinal salt according to any one of claims 2 to 8.

10. The differential scanning calorimetry curve has an endothermic peak at 100.28°C ± 3.00°C, an endothermic peak at 127.61°C ± 3.00°C, an exothermic peak at 200.70°C ± 3.00°C, and an exothermic peak at 266.36°C ± 3.00°C.

9. The medicinal salt according to any one of claims 2 to 8.

11. 10. Use of the medicinal salt of claim 1 in the manufacture of a medicament for treating a disease associated with a bacterial infection.

12. 10. Use of the medicinal salt of claim 2 in the manufacture of a medicament for treating a disease associated with a bacterial infection.

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