Amorphous compound SX-682 and preparation process thereof

Abstract

The invention discloses an amorphous compound SX-682 and a preparation process thereof. The preparation process comprises the following steps: stirring, dissolving and clarifying # imgabs0 # compound 2-(2-boric acid-5-trifluoromethoxy-benzyl sulfydryl)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide in a good solvent, and filtering; and dropwise adding the filtrate into a rapidly stirred poor solvent to precipitate a solid, filtering out the solid, and drying to obtain an amorphous compound SX-682. The preparation process is simple and convenient to operate and can realize industrial production; and the amorphous compound SX-682 obtained by the process is good in stability and high in solubility, and can meet the requirements of drug development, preparation formula preparation and industrial production.

Description

Technical Field

[0001] The present invention relates to the field of chemical medicine, and in particular to an amorphous compound SX-682 and a preparation process thereof. Background Art

[0002] SX-682 was developed by Syntrix Pharmaceuticals, a biopharmaceutical company, and is currently being studied for the treatment of myelodysplastic syndrome (MDS) with disease progression or intolerance to previous treatment. As a dual allosteric inhibitor targeting CXCR1 and CXCR2, SX-682 can block the recruitment of tumor myeloid-derived suppressor cells, enhance T cell activation and anti-tumor immunity.

[0003] The chemical name of SX-682 is 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide, and its molecular structure is shown below:

[0004]

[0005] In the process of drug development, nearly 75% of candidate drugs have low solubility and slow dissolution rate, which leads to incomplete oral absorption and low bioavailability. For most drugs with poor water solubility, since amorphous has higher solubility than crystal, it will increase drug absorption and bioavailability. Therefore, preparing drugs into amorphous is one of the effective means to overcome solubility defects. With the emergence of more and more poorly soluble drugs, amorphous drugs are also receiving more and more attention.

[0006] Common methods for preparing amorphous drugs include rotary evaporation, freeze drying, spray drying, grinding, melt cooling, desolvation, and supercritical fluid technology. When using vacuum rotary evaporation to prepare amorphous drugs, the temperature, speed, vacuum degree, and solvent type of the rotary evaporation are greatly affected, especially the evaporation rate is difficult to control, and it is easy to form a colloid or oily substance. When using freeze drying, the selected solvent is generally water. Most poorly soluble drugs are insoluble in water, and the choice of solvent for freezing is relatively limited. When using spray drying, for drugs with a low glass transition temperature (Tg), once the outlet temperature of the spray drying is higher than the Tg value, a supercooled state may be obtained. Generally speaking, when using grinding to prepare amorphous drugs, the heat generated by friction and other effects will give the drug more energy, making it easier for the drug to arrange in a more stable lattice structure, thereby causing crystal transformation. For drugs that are not resistant to high temperatures, melt cooling and desolvation are also not applicable. Supercritical fluid technology has high equipment requirements, high process operating pressure, and large one-time investment. These problems limit its industrial-scale application and need to be further resolved.

[0007] Therefore, there is an urgent need in the art to develop a preparation process for the amorphous compound SX-682 that is simple to operate and can be industrially produced; the amorphous compound obtained by this process needs to have good stability and high solubility to meet the needs of drug development, formulation preparation and industrial production. Summary of the invention

[0008] In view of the problems existing in the above-mentioned prior art, the object of the present invention is to provide an amorphous compound SX-682 and a preparation process thereof which are simple to operate and can be industrially produced; the amorphous compound SX-682 obtained by this process has good stability and high solubility, and can meet the needs of drug development, formulation preparation and industrial production.

[0009] In order to achieve one of the above purposes, a preparation process of an amorphous compound SX-682 is provided. The present invention adopts the following technical scheme:

[0010] A preparation process of an amorphous compound SX-682 comprises the following steps:

[0011]

[0012] The compound of formula I, 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide, is stirred and dissolved in a good solvent and filtered; the filtrate is then added dropwise to a rapidly stirred poor solvent to precipitate a solid, and the solid is filtered and dried to obtain an amorphous compound SX-682.

[0013] Preferably, the benign solvent is selected from ethanol, 2-methyltetrahydrofuran or methyl isobutyl ketone.

[0014] Furthermore, the benign solvent is ethanol.

[0015] Furthermore, the mass volume ratio of the 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide to the benign solvent is 1:(5-15).

[0016] Furthermore, the mass volume ratio of the 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide to the benign solvent is 1:10.

[0017] Preferably, the poor solvent is selected from n-heptane, triethylamine or methyl tert-butyl ether.

[0018] Furthermore, the poor solvent is n-heptane.

[0019] Furthermore, the mass volume ratio of the 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide to the poor solvent is 1:(25-100).

[0020] Furthermore, the mass volume ratio of the 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide to the poor solvent is 1:50.

[0021] Preferably, the drying temperature is 20-40°C.

[0022] The second object of the present invention is to provide an amorphous compound SX-682, which is prepared according to the above-mentioned preparation process.

[0023] Beneficial effects:

[0024] (1) The amorphous preparation process provided by the present invention is simple and easy to operate, has low cost, and does not require high production equipment, and is suitable for drug research and development and industrial production.

[0025] (2) The amorphous compound SX-682 obtained by the preparation process of the present invention has good physical stability.

[0026] (3) The amorphous compound SX-682 obtained by the preparation process of the present invention has good solubility, which is conducive to improving bioavailability and further improving clinical treatment effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The present invention is further described below in conjunction with the accompanying drawings and embodiments.

[0028] Figure 1 It is the XRPD pattern of the solid obtained in Example 1 of the present invention.

[0029] Figure 2 This is the XRPD spectrum of the solid obtained in Comparative Example 3 (prepared by referring to the method disclosed in US Pat. No. 8,969,365 B2).

[0030] Figure 3 This is the XRPD comparison pattern of the solid obtained in Example 1 of the present invention before and after being placed at 25°C / 92.5% RH for 30 days (the lower is the XRPD pattern of the solid before being placed at 25°C / 92.5% RH, and the upper is the XRPD pattern of the solid after being placed at 25°C / 92.5% RH for 30 days).

[0031] Figure 4This is the XRPD comparison pattern of the solid obtained in Example 1 of the present invention before and after being placed at 40°C / 75% RH for 30 days (the lower one is the XRPD pattern of the solid before being placed at 40°C / 75% RH, and the upper one is the XRPD pattern of the solid after being placed at 40°C / 75% RH for 30 days).

[0032] Figure 5 The XRPD comparison patterns of the solid obtained in Comparative Example 4 before and after being placed at 25° C. / 92.5% RH for 7 days are shown. DETAILED DESCRIPTION

[0033] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used in the text have the same meanings as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials described in the text are for demonstration purposes only.

[0034] The solvents used in the present invention are all analytically pure and have a water content of about 0.1%. The compounds of formula I used as raw materials in the examples are all purchased.

[0035] The abbreviations used in the present invention are explained as follows:

[0036] XRPD: X-ray powder diffraction

[0037] DVS: Dynamic Water Sorption

[0038] GC: Gas Chromatography

[0039] The test parameters of the instrument used in the present invention are as follows:

[0040] XRPD determination method:

[0041] Instrument model: Bruker D2 Phaser

[0042] X-ray tube voltage: 30kV

[0043] X-ray tube current: 10mA

[0044] X-ray source and wavelength: Cu, Kα; 1.540598, 1.544426

[0045] Kα2 / Kα1 intensity ratio: 0.50

[0046] Scanning range: 3-40°(2θ), scanning step 0.02°, scanning speed 0.1s / step

[0047] DVS determination method:

[0048] Instrument model: TA Discovery SA

[0049] Test temperature: 25℃

[0050] Protective gas and flow rate: N2, 200mL / min

[0051] Relative humidity range: 0% RH-90% RH-0% RH

[0052] Relative humidity gradient: 10% RH

[0053] dm / dt: 0.01% / min

[0054] Minimum dm / dt balance time: 60min

[0055] Maximum balancing time: 120min

[0056] GC determination method:

[0057] Chromatographic column: Use a commercially available capillary column (30m X 0.32mm X 1.8μm) with 6% cyanopropylphenyl-94% dimethylchlorosilane as the stationary phase or a capillary column with similar polarity.

[0058] Program temperature rise: starting temperature 40℃, hold for 5 min, increase to 85℃ at a rate of 5℃ / min, hold for 2 min, then increase to 235℃ at a rate of 30℃ / min, hold for 2 min;

[0059] Inlet temperature: 150°C

[0060] Detector temperature: 250°C

[0061] Line speed: 19.6cm / s

[0062] Split ratio: 10:1

[0063] Headspace conditions: 90℃ equilibration for 30min

[0064] Unless otherwise specified, “%” in the text represents mass fraction.

[0065] The "mass-to-volume ratio" in the present invention refers to the ratio of the mass of the compound of Formula I to the volume of the good solvent or the poor solvent. When the mass is expressed in "g", the corresponding volume unit is "ml". That is, the unit level of the mass-to-volume ratio is g / mL, kg / L or other units of equivalent magnitude.

[0066] According to a preferred embodiment of the present invention, a process for preparing an amorphous compound SX-682 comprises the following steps:

[0067]

[0068] The compound of formula I, 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide, is stirred and dissolved in a good solvent (dissolved and clarified), and filtered; the filtrate is then added dropwise to a rapidly stirred poor solvent to precipitate a solid, and the solid is filtered and dried to obtain an amorphous compound SX-682.

[0069] The good solvent refers to a solvent with good solubility for the compound SX-682, and the poor solvent refers to a solvent with poor solubility for the compound SX-682. Based on the preparation method of the present invention, the sample is first dissolved and clarified in a good solvent to form a homogeneous solution, and then the homogeneous solution is slowly added dropwise to the poor solvent to form a solid amorphous substance.

[0070] Preferably, the benign solvent is selected from ethanol, 2-methyltetrahydrofuran or methyl isobutyl ketone. More preferably, the benign solvent is ethanol.

[0071] The mass volume ratio of the 2-(2-boric acid-5-trifluoromethoxy-benzylthio)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide to the benign solvent is 1:(5-15). More preferably, the mass volume ratio of the 2-(2-boric acid-5-trifluoromethoxy-benzylthio)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide to the benign solvent is 1:10.

[0072] The poor solvent is selected from n-heptane, triethylamine or methyl tert-butyl ether. More preferably, the poor solvent is n-heptane.

[0073] The mass volume ratio of the 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide to the poor solvent is 1:(25-100). More preferably, the mass volume ratio of the 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide to the poor solvent is 1:50.

[0074] Preferably, the drying temperature is 20-40° C., preferably 30° C. The drying method is air drying or vacuum drying.

[0075] According to the preparation process of the above embodiment, an amorphous compound SX-682 can be prepared.

[0076] Based on the above implementation, the following specific examples are applied:

[0077] Example 1

[0078] 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide (1.09 g) was added to a single-necked flask (50 mL) filled with ethanol (11 mL), stirred at 30°C to dissolve, filtered, and the filtrate was added dropwise to rapidly stirred n-heptane (55 mL). Solid precipitated during the addition, which was filtered after the addition was completed. The solid was dried at 30°C for 16 h to obtain 0.98 g of a white solid. The obtained solid was subjected to XRPD test, and its XRPD pattern is as shown below: Figure 1 shown.

[0079] Example 2

[0080] 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide (0.84 g) was added to a single-necked flask (50 mL) filled with 2-methyltetrahydrofuran (8.5 mL), stirred at 28°C until dissolved, filtered, and the filtrate was added dropwise to rapidly stirred triethylamine (42 mL). Solid precipitated during the addition, which was filtered after the addition was completed. The solid was dried at 30°C for 18 h to obtain 0.75 g of an off-white solid. The obtained solid was subjected to XRPD test, and its XRPD pattern was consistent with Figure 1 Consistent.

[0081] Example 3

[0082] 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide (0.93 g) was added to a single-necked flask (50 mL) filled with methyl isobutyl ketone (9.3 mL), stirred at 25°C until dissolved, filtered, and the filtrate was added dropwise to rapidly stirred methyl tert-butyl ether (46.5 mL). Solid precipitated during the addition, which was filtered after the addition was completed. The solid was dried at 30°C for 18 h to obtain 0.78 g of an off-white solid. The obtained solid was subjected to XRPD test, and its XRPD pattern was consistent with Figure 1 Consistent.

[0083] Comparative Example 1

[0084] 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide (0.44 g) was added to a single-necked flask (25 mL) filled with ethanol (4.5 mL), stirred at 25°C to dissolve, filtered, and the filtrate was concentrated on a rotary evaporator at 25°C to remove the solvent under reduced pressure, and then vacuum dried at 40°C for 18 h to obtain 0.37 g of an off-white solid. The obtained solid was subjected to XRPD test, and its XRPD pattern was consistent with Figure 1 Consistent.

[0085] Comparative Example 2

[0086] 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide (0.44 g) was added to a single-necked flask (25 mL) filled with tert-butyl alcohol / water (1:1, v / v, 5.0 mL), and the solution was dissolved by ultrasonic at 50°C. The solution was filtered, and the filtrate was quickly pre-frozen in dry ice and sublimated in a freeze dryer to remove the solvent to obtain 0.41 g of an off-white solid. The obtained solid was subjected to XRPD test, and its XRPD pattern was consistent with Figure 1 Consistent.

[0087] Comparative Example 3

[0088] Referring to the method disclosed in US8969365 (B2), 2-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethoxy-benzylmercapto]-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide (5.66 g, 10.3 mmol, 1 eq) was dissolved in methanol (100 mL), and 4.5 M aqueous potassium bifluoride (11.5 mL, eq) was filled in the reaction vessel, and the solution was stirred for 1 hour. Methanol was then removed by rotary evaporation at room temperature, and the obtained mixture of yellow and yellow-white solids was suspended in acetone, and the suspension was gravity filtered to remove insoluble salts to obtain a clear yellow solution. The solution was added to water and placed in a refrigerator. After cooling for about 1.5 hours, a yellow-white precipitate was collected by vacuum filtration, rinsed with water, and vacuum dried overnight. The obtained yellow-white solid was subjected to XRPD testing, and its X-ray powder diffraction data is shown in Table 1, and its spectrum is as shown in Table 1. Figure 2 shown.

[0089] Table 1. XRPD test spectrum of comparative example 3

[0090]

[0091]

[0092] Comparative Example 4

[0093] The crystalline form (0.52 g) obtained by the method disclosed in US8969365 (B2) was added to an agate mortar and ground with a pestle for 30 min to obtain 0.41 g of an off-white solid. The obtained solid was subjected to XRPD testing and found that its XRPD pattern was similar to Figure 1 Consistent, amorphous.

[0094] The performance test results of each embodiment are as follows:

[0095] Test Example 1: Solvent Residue

[0096] The solvent residue of the amorphous compound prepared by the present invention was measured. The results are shown in the following table:

[0097] Table 2. Comparison results of solvent residue test

[0098] Starting sample Residual solvent (%) Amorphous (Example 1) No solvent excess Amorphous (Comparative Example 1) Ethanol: 0.67

[0099] It can be seen from the data in Table 2 that the amorphous compound of Example 1 has a higher solvent residue than the amorphous compound of Comparative Example 1.

[0100] Test Example 2: Moisture absorption

[0101] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Guidelines for hygroscopicity testing of drugs in Appendix XIX J of the 2020 edition of the Chinese Pharmacopoeia):

[0102] Deliquesce: Absorbs enough water to form a liquid;

[0103] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%;

[0104] Hygroscopic: weight gain due to moisture absorption is less than 15% but not less than 2%;

[0105] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0106] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0107] 10 mg of the amorphous materials prepared by different processes in Example 1 of the present invention and Comparative Example 2 were taken respectively, and their hygroscopicity was tested by a dynamic moisture sorption instrument (DVS). The test results are shown in Table 3.

[0108] Table 3. Humidity comparison results

[0109] Starting sample 0~80%RH mass change Amorphous (Example 1) 1.6％ Amorphous (Comparative Example 2) 5.4％

[0110] It can be seen from the data in Table 3 that the amorphous material of Example 1 is slightly hygroscopic, but compared with the amorphous material of Comparative Example 2, the latter is significantly more hygroscopic.

[0111] Test Example 3: Solubility

[0112] 15 mg of the amorphous form prepared in Example 1 of the present invention and 15 mg of the crystalline form prepared in Comparative Example 3 according to the method disclosed in US8969365 (B2) were respectively dispersed in 3 mL of SGF buffer (simulated fasting gastric juice) with a pH value of 1.6, stirred for 24 h at 37 ° C, and then allowed to stand for 1 h to observe the solid dissolution phenomenon and calculate the corresponding rough solubility. The specific data are shown in Table 4.

[0113] Table 4. Crystal solubility comparison results

[0114]

[0115] It can be seen from the data in Table 4 that the amorphous form of Example 1 of the present invention is better soluble in SGF buffer than the crystalline form obtained in Comparative Example 3 (prepared with the method disclosed in US Pat. No. 8,969,365B2).

[0116] Test Example 4: Physical Stability

[0117] The amorphous materials prepared by different processes in Example 1 and Comparative Example 4 of the present invention were placed open for a certain period of time under different conditions, and XRPD detection was performed on the samples before and after the placement, and the XRPD patterns of the solids before and after the placement were compared. The specific results are shown in Table 5.

[0118] Table 5. Physical stability comparison results

[0119]

[0120]

[0121] By comparing the XRPD patterns before and after placement, it can be seen that the amorphous phase obtained by the preparation process provided by the present invention is stable for at least 30 days when placed in an open environment under the conditions of 25°C / 92.5% RH and 40°C / 75% RH, indicating that the amorphous phase obtained by the preparation process of the present invention has good physical stability under certain temperature and humidity.

[0122] The above-mentioned ideal embodiments of the present invention are inspirations. Through the above-mentioned description content, relevant personnel can make various changes and modifications without departing from the technical idea of ​​the present invention. These equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A process for preparing an amorphous compound SX-682, characterized in that: The steps include: The compound of formula I, 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide, is stirred and dissolved in a good solvent and filtered; the filtrate is then added dropwise to a rapidly stirred poor solvent to precipitate a solid, and the solid is filtered and dried to obtain an amorphous compound SX-682.

2. The preparation process of the amorphous compound SX-682 according to claim 1, characterized in that: The benign solvent is selected from ethanol, 2-methyltetrahydrofuran or methyl isobutyl ketone.

3. The preparation process of the amorphous compound SX-682 according to claim 2, characterized in that: The benign solvent is ethanol.

4. The preparation process of the amorphous compound SX-682 according to claim 2 or 3, characterized in that: The mass volume ratio of the 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide to the benign solvent is 1:(5-15).

5. The preparation process of the amorphous compound SX-682 according to claim 4, characterized in that: The mass volume ratio of the 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide to the benign solvent is 1:

10.

6. The preparation process of the amorphous compound SX-682 according to claim 1, characterized in that: The poor solvent is selected from n-heptane, triethylamine or methyl tert-butyl ether.

7. The preparation process of the amorphous compound SX-682 according to claim 6, characterized in that: The poor solvent is n-heptane.

8. The preparation process of the amorphous compound SX-682 according to claim 6 or 7, characterized in that: The mass volume ratio of the 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide to the poor solvent is 1:(25-100).

9. The process for preparing the amorphous compound SX-682 according to claim 8, characterized in that: The mass volume ratio of the 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide to the poor solvent is 1:

50.

10. An amorphous compound SX-682, prepared according to the preparation process according to any one of claims 1 to 9.

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