Beta-lactamase inhibitor crystalline particles and preparation method thereof

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to crystalline particles of a compound shown in a formula I and a preparation method of the crystalline particles. The particles prepared by the method have round particle shapes and larger particle sizes, are good in fluidity, and are very suitable for large-scale industrial production.

Description

Technical Field

[0001] This application belongs to the field of medicinal chemistry, specifically relating to a method for preparing crystalline particles of a compound represented by Formula I. This method is simple to operate, operates under mild reaction conditions, and yields crystalline particles with ideal particle size, better flowability and crystallinity, making it highly suitable for large-scale industrial production. Background Technology

[0002] Document WO2017206947 discloses a compound of formula I, chemically named (2S,5R)-2-((2-(guanidinooxy)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3,2,1]octane-6-yl-monosulfate (referred to as compound 1). This compound is a β-lactamase inhibitor used to treat bacterial infections.

[0003]

[0004] Patent WO2019105479A discloses a method for preparing compound 1 and its crystal form A. However, this route uses 1,2-dibromoethane as the starting material and involves nine process steps to obtain compound 1. This process route is quite complex. Furthermore, in the final step of preparing compound 1 using trifluoroacetic acid to remove the protecting group, numerous byproducts are generated, making effective product purification by crystallization impossible. High-performance liquid chromatography (HPLC) is required for product separation and purification, and the yield of this single-step reaction is less than 20%. The overall yield of the entire route is low, approximately 2%, resulting in high production costs. In addition, the crystal form A obtained by this method has excessively small particle size, irregular shape, low homogeneity, and a low median volume diameter, leading to poor product flowability. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the inventors, through extensive experimental research, discovered a method for preparing crystalline particles of the compound shown in Formula I. This method is simple to operate, has mild reaction conditions, few side reactions, high yield, and high purity, reducing costs and operational risks, making it highly suitable for large-scale industrial production.

[0006] The first aspect of this invention provides a method for preparing crystalline particles of compound 1 shown in Formula I, the method comprising the following steps:

[0007] (1) Place compound 1 in a mixed solution of water and organic solvent, heat to 45-55°C to dissolve, then filter, cool the filtrate to 30-40°C while stirring, add crystal seed A of compound 1, and keep warm and stir for 0.5-1.5 hours;

[0008] (2) Slowly add organic solvent, control the temperature at 30-40℃, and stir for 0.5-1.5 hours; then slowly cool down to -5 to -15℃, and keep warm while stirring for 0.5-1.5 hours;

[0009] (3) Filtration, the filter cake was vacuum dried at 45±5℃ for 4 to 8 hours to obtain crystal particles of compound 1 crystal form A;

[0010] The organic solvents used in steps (1)-(2) are independently selected from C3-C6 ketones, preferably acetone or methyl ethyl ketone.

[0011] In any of the technical solutions of the present invention, the dissolution temperature in step (1) is 48-52°C, preferably 50°C.

[0012] In any of the technical solutions of the present invention, in step (1), the temperature of the filtrate is reduced to 35°C; after adding crystal seed of compound 1 in crystal form A, the mixture is kept warm and stirred for 1 hour.

[0013] In any technical solution of the present invention, the temperature is controlled at 35°C and stirred for 1 hour in step (2).

[0014] In any of the technical solutions of the present invention, in step (2), the temperature is slowly lowered to -10°C and kept warm while stirring for 1 hour.

[0015] In any of the technical solutions of the present invention, the vacuum drying temperature of the filter cake in step (3) is 45°C and the time is 6 hours.

[0016] In any of the technical solutions of the present invention, the mass-volume ratio of compound 1 to water in step (1) is 1:1.8 to 2.5, preferably 1:2.1 to 2.2, unit: mg / mL.

[0017] In any of the technical solutions of the present invention, the mass-volume ratio of compound 1 to organic solvent in step (1) is 1:2.0 to 3.0, preferably 1:2.5, unit: mg / mL.

[0018] In any of the technical solutions of the present invention, the mass-volume ratio of compound 1 in step (1) to the organic solvent slowly added in step (2) is 1:10-15, preferably 1:12.5, unit: mg / mL.

[0019] In any technical solution of the present invention, the preparation method includes the following steps: (1) Compound 1 is placed in a mixed solution of water and acetone, heated to 50°C to dissolve, then filtered, the filtrate is cooled to 35°C while stirring, crystal form A of Compound 1 is added, and the mixture is kept warm and stirred for 1 hour; (2) Acetone is slowly added, the temperature is controlled at 35°C, and the mixture is stirred for 1 hour; then the temperature is slowly lowered to -10°C, and the mixture is kept warm and stirred for 1 hour; (3) the mixture is filtered, and the filter cake is vacuum dried at 45±5°C for 6 hours to obtain crystal particles of crystal form A of Compound 1.

[0020] In any technical solution of the present invention, the preparation method includes the following steps: adding 26 mL of purified water and 30 mL of acetone to 12 g of compound 1, and heating to 50 °C to dissolve; cooling the solution to 35 °C while stirring, adding 0.12 g of crystal seed of compound 1 crystal form A, and stirring for 1 hour; slowly adding 150 mL of acetone to the solution; after the addition is complete, controlling the temperature at 35 °C and stirring for 1 hour; then slowly cooling to -10 °C, stirring for 1 hour, filtering to obtain a filter cake, and vacuum drying at 45 ± 5 °C for 6 hours to obtain crystalline particles of compound 1 crystal form A.

[0021] The present invention also provides crystalline particles of crystal form A of compound 1 of formula I, having a median volume diameter of ≥60μm or ≥70μm; the X-ray powder diffraction pattern of crystal form A has characteristic diffraction peaks at the following 2θ angles: 16.053±0.2°, 16.53±0.2°, 22.782±0.2°, 25.742±0.2°. Preferably, the crystalline particles of crystal form A have a median volume diameter of ≥100 μm; the X-ray powder diffraction pattern of crystal form A has characteristic diffraction peaks at the following 2θ angles: 16.053±0.2°, 16.53±0.2°, 18.501±0.2°, 21.302±0.2°, 21.778±0.2°, 22.782±0.2°, 25.742±0.2°, 27.833±0.2°.

[0022] Advantages of this invention: The crystalline particles of the obtained compound 1 have ideal particle size, greater bulk density, better flowability and crystallinity, making them very suitable for large-scale industrial production.

[0023] It should be noted that, unless otherwise specified, the amounts of the reaction solvent and related reagents used are conventional amounts for the reaction, which can be determined by those skilled in the art based on existing technology; the reagents used in this invention are all conventional reagents that can be purchased from the market, and the starting materials used can all be prepared from existing literature or purchased from the market. Attached Figure Description

[0024] Figure 1 XRPD image of the crystalline particles obtained in Example 1.

[0025] Figure 2 Electron micrograph of the crystalline particles obtained in Example 1 (×100x);

[0026] Figure 3 Electron micrograph of the particles obtained in Comparative Example 1 (×200x). Detailed Implementation

[0027] The following detailed description of specific embodiments further illustrates the above-mentioned content of the present invention, but should not be construed as limiting the scope of protection of the present invention in any way. All technical solutions implemented based on the above-mentioned content of the present invention fall within the scope of the present invention. The present invention provides a general and / or specific description of the materials and experimental methods used in the experiments. Those skilled in the art will understand that, unless otherwise specified, the operations performed in the present invention are conducted under conventional room temperature conditions, which have a well-known technical meaning in the art, generally referring to 10–30°C, preferably 15–25°C, and more preferably 20–25°C. In the present invention, compound 1 and its crystal form A seed crystals can be prepared using WO2019105479.

[0028] Example 1: Preparation of crystal particles of compound 1, crystal form A

[0029] Add 26 mL of purified water and 30 mL of acetone to 12 g of compound 1, and heat to 50 °C to dissolve. Filter the solution into a crystallizer, stir, and cool to 35 °C. Add 0.12 g of crystal form A of compound 1, and maintain the temperature with stirring for 1 hour. Slowly add 150 mL of acetone to the crystallizer. After addition, maintain the temperature at 35 °C and stir for 1 hour. Slowly cool the solution to -10 °C and maintain the temperature with stirring for 1 hour. Filter to obtain a filter cake, and vacuum dry at 45 ± 5 °C for 6 hours to obtain 10.87 g of crystalline particles of crystal form A of compound 1, with a yield of 90.6% and a purity of 99.59%. The XRPD results are as follows: Figure 1 As shown, the scanning electron microscope results are as follows: Figure 2 As shown. The median volume diameter was determined to be D. V (50) = 72.4 μm, and its bulk density is 0.42 g / mL.

[0030] Comparative Example 1: Preparation of Crystal Form A of Compound 1 in the Prior Art

[0031] 10 g of compound 1 was added to 50 mL of purified water and heated to 55–60 °C to dissolve. The solution was then slowly cooled to 0 °C with stirring, and crystallized over 12 hours. The crystals were filtered and dried to obtain crystal form A of compound 1. The scanning electron microscopy results are shown below. Figure 3 As shown. The median volume diameter was determined to be D. V (50) = 37.8 μm, and its bulk density is 0.18 g / mL.

[0032] The crystalline particles prepared in Example 1 have a spherical shape and a larger median volume diameter compared to the particles obtained in Comparative Example 1. The crystalline particles prepared in Example 1 also exhibit better flowability, which is beneficial for mixing, packaging, and other processes in commercial production.

[0033] Experimental Example 1: X-ray Powder Diffraction (XRPD)

[0034] Solid samples were analyzed using an X-ray powder diffractometer (X'Pert PRO). An appropriate amount of fine powder was placed in the groove of the sample holder and pressed into a flat and dense plane using a glass slide. The XRPD measurement parameters are shown in Table 6-2.

[0035] Table 1 XRPD Test Parameters

[0036] instrument PANalytical, X'Pert PRO light source Cu target Scanning angle <![CDATA[3-60 ° (2θ)]]> Scan speed <![CDATA[8 ° / min]]> Phototube voltage / current 40KV / 40mA Diverging slit <![CDATA[1 / 8 ° ]]>

[0037] Experimental Example 2: Particle Size and Particle Size Distribution

[0038] Take an appropriate amount of this product and determine its particle size and particle size distribution using the dry method according to the method for determination of particle size and particle size distribution (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0982, Method III). Report the values ​​of d(0.1), d(0.5), and d(0.9).

[0039] Table 2. Particle size and particle size distribution detection conditions

[0040]

[0041] Experimental Example 3: Bulk Density

[0042] Take an appropriate amount of this product and place it into a graduated cylinder with a mass of m1. Measure its volume as V. Accurately weigh the graduated cylinder containing the sample as m2. The formula for calculating the bulk density ρ is: ρ = (m2 - m1) / V.

Claims

1. A method for preparing crystalline particles of compound 1 as shown in Formula I, the method comprising the following steps: (1) Place compound 1 in a mixed solution of water and organic solvent, heat to 45-55°C to dissolve, then filter, cool the filtrate to 30-40°C while stirring, add crystal seed A of compound 1, and keep warm while stirring; (2) Slowly add organic solvent, control the temperature at 30-40℃, and stir for 0.5-1.5 hours; then slowly cool down to -5 to -15℃ and keep stirring at the same temperature; (3) Filtration yielded crystal particles of compound 1, crystal form A; The organic solvents mentioned in steps (1) and (2) are independently selected from C3-C6 ketones, preferably acetone or methyl ethyl ketone.

2. The preparation method according to claim 1, characterized in that, The heat preservation and stirring time for steps (1) and (2) is 0.5 to 1.5 hours.

3. The preparation method according to claim 1, characterized in that, The dissolution temperature in step (1) is 48-52℃, preferably 50℃; the temperature of the filtrate in step (1) is reduced to 35℃; after adding crystal seed A of compound 1, the mixture is kept warm and stirred for 1 hour.

4. The preparation method according to any one of claims 1-3, characterized in that, In step (2), the temperature is controlled at 35°C and stirred for 1 hour; in step (2), the temperature is slowly lowered to -10°C and stirred for 1 hour.

5. The preparation method according to any one of claims 1-4, characterized in that, Step (3) may optionally include the following steps: the filter cake obtained by filtration is vacuum dried at 45±5℃ for 4 to 8 hours, preferably, the vacuum drying temperature of the filter cake is 45℃ and the time is 6 hours.

6. The preparation method according to any one of claims 1-5, characterized in that, In step (1), the mass-to-volume ratio of compound 1 to water is 1:1.8 to 2.5, preferably 1:2.1 to 2.2, in mg / mL; in step (1), the mass-to-volume ratio of compound 1 to organic solvent is 1:2.0 to 3.0, preferably 1:2.5, in mg / mL.

7. The preparation method according to any one of claims 1-6, characterized in that, The mass-to-volume ratio of compound 1 in step (1) to the organic solvent slowly added in step (2) is 1:10-15, preferably 1:12.5, unit: mg / mL.

8. The preparation method according to claim 1, characterized in that, The preparation method includes the following steps: (1) Compound 1 is placed in a mixed solution of water and acetone, heated to 50°C to dissolve, then filtered, the filtrate is cooled to 35°C while stirring, crystal form A of Compound 1 is added, and the mixture is kept warm and stirred for 1 hour; (2) Acetone is slowly added, the temperature is controlled at 35°C, and the mixture is stirred for 1 hour; then the temperature is slowly lowered to -10°C, and the mixture is kept warm and stirred for 1 hour; (3) The mixture is filtered, and the filter cake is vacuum dried at 45±5°C for 6 hours to obtain crystal particles of crystal form A of Compound 1.

9. The preparation method according to claim 1, characterized in that, The preparation method includes the following steps: 26 mL of purified water and 30 mL of acetone are added to 12 g of compound 1, and the mixture is heated to 50 °C to dissolve; the solution is cooled to 35 °C while stirring, and 0.12 g of crystal seed of compound 1 (crystal form A) is added, and the mixture is kept warm and stirred for 1 hour; 150 mL of acetone is slowly added to the solution; after the addition is complete, the temperature is controlled at 35 °C and stirred for 1 hour; then the temperature is slowly lowered to -10 °C, and the mixture is kept warm and stirred for 1 hour; the filter cake is obtained by filtration, and the filter cake is dried under vacuum at 45 ± 5 °C for 6 hours to obtain crystalline particles of compound 1 (crystal form A).

10. Crystalline particles of crystal form A of compound 1 of formula I, having a median volume diameter of ≥60 μm or ≥70 μm; the X-ray powder diffraction pattern of crystal form A has characteristic diffraction peaks at the following 2θ angles: 16.053±0.2°, 16.53±0.2°, 22.782±0.2°, 25.742±0.2°; 11. The crystalline particles according to claim 10, characterized in that, The crystalline particles have a median volume diameter of ≥100 μm; the X-ray powder diffraction pattern of crystal form A has characteristic diffraction peaks at the following 2θ angles: 16.053±0.2°, 16.53±0.2°, 18.501±0.2°, 21.302±0.2°, 21.778±0.2°, 22.782±0.2°, 25.742±0.2°, 27.833±0.2°.

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