Method for preparing clazosentan sodium, method for preparing amorphous substance of clazosentan sodium, and crystal form i and crystal form ii of clazosentan sodium, and preparation method therefor

Abstract

Provided in the present invention is a method for preparing clazosentan sodium. In the present invention, azidotrimethylsilane is used as a source of an azido group in place of sodium azide, thereby significantly reducing reaction hazards. The azidotrimethylsilane can be removed from compound II by filtration, which eliminates the need to quench sodium azide with sodium nitrite under acidic conditions, thereby avoiding the risk of producing nitrosamine impurities in a finished product. Provided in the present invention are crystal form I and crystal form II of clazosentan sodium and a preparation method therefor. Crystal form I and crystal form II of clazosentan sodium prepared in the present invention have low residual solvent levels, which is beneficial to improving the product quality. Provided in the present invention is a method for preparing an amorphous substance of clazosentan sodium. In the present invention, the amorphous substance of clazosentan sodium is prepared by lyophilization. The amorphous substance obtained in the present invention exhibits a sodium content closer to a theoretical value and lower residual solvent content. The process is easy to operate and yields a superior powdery solid with higher purity and reduced water content that meets the requirements for API.

Description

A method for preparing clasentan sodium, a method for preparing clasentan sodium amorphous form, clasentan sodium crystal form I and crystal form II and their preparation methods

[0001] This application claims priority to Chinese Patent Application No. CN202510198783.7, filed on February 21, 2025, entitled "A method for preparing amorphous clasentan sodium"; Chinese Patent Application No. 202510202100.0, filed on February 21, 2025, entitled "A method for preparing clasentan sodium"; and Chinese Patent Application No. 202510202087.9, filed on February 21, 2025, entitled "Clarsentan sodium crystal form I and crystal form II and preparation method thereof", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical technology, and particularly relates to a method for preparing clasentan sodium, a method for preparing clasentan sodium amorphous form, clasentan sodium crystal form I and crystal form II and their preparation methods. Background Technology

[0003] Clazosentan sodium, chemically known as N-{6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide disodium salt of 5-methyl-pyridine-2-sulfonic acid, is a selective endothelin receptor antagonist used to inhibit subarachnoid hemorrhage, intracranial vasospasm, and associated cerebral infarction and postoperative cerebral ischemia. Its structural formula is as follows:

[0004] The method in patent WO2023111299 uses 4-[4,6-dichloro-5-(2-methoxyphenoxy)-pyrimidin-2-yl]-pyridine 1-oxide as a synthetic raw material. First, a single sulfonamide is introduced, then another chlorine is replaced with ethylene glycol, then a cyano group is introduced, and then clasentan is obtained by reacting the cyano group with sodium azide. Clarsentan sodium is obtained by reacting clasentan with sodium methoxide.

[0005] The method of introducing tetrazolium in patent WO2023111299 is to use sodium azide. DMF and ammonium chloride are added to the reaction system, followed by an aqueous solution of sodium azide. The reaction is maintained at 95°C for 12-15 hours. After the reaction is completed, the reaction system is in a dissolved state. The pH needs to be adjusted to acidic to precipitate solid. However, the reaction between sodium azide and acid in the reaction system will produce toxic and explosive azidoic acid. Sodium azide must be extracted with sodium nitrite first, and then the pH is adjusted to acidic. After filtration, solid clasentan is obtained.

[0006] On the one hand, during the high-temperature reaction, N,N-dimethylformamide decomposes to produce dimethylamine. Dimethylamine reacts with sodium nitrite under acidic conditions to produce highly toxic N-nitrosodimethylamine (NDMA). This reaction carries a high risk and easily produces toxic impurities.

[0007] On the other hand, in the existing technology, the prepared clasentan sodium usually has residual solvent, which affects the product quality.

[0008] On the other hand, compared to crystalline structures, amorphous forms are the most advantageous for enhancing the efficacy of drugs in a metastable state. Amorphous is a special crystalline state, and the physical properties of amorphous drugs differ significantly from those of crystalline drugs. Amorphous structures can greatly influence the stability, compatibility, dissolution rate, hygroscopicity, and solvent adsorption tendency of products. Therefore, developing a simple, safe, low-cost method suitable for industrial production of amorphous crystalline form of clasentan sodium is essential and has economic and practical value. Summary of the Invention

[0009] The purpose of this invention is to provide a method for preparing clasentan sodium. The preparation method of this invention greatly reduces the reaction risk and can avoid the nitrosamine impurity in the finished product. The purpose of this invention is also to provide clasentan sodium crystal form I and crystal form II and their preparation method. Currently, no method has been found to prepare the two crystal forms described in this application. Furthermore, the crystal forms I and II of this invention have low solvent residue and the preparation method is simple. The purpose of this invention is also to provide a method for preparing clasentan sodium amorphous products. The preparation method of this invention can prepare clasentan sodium amorphous products with low water content and low residual solvent. The method is simple, safe, low-cost, and suitable for industrial production.

[0010] This invention provides a method for preparing clasentan sodium, comprising the following steps:

[0011] A) Under a protective atmosphere, the compound of formula I, the catalyst, and the azide-trimethylsilane were mixed in a solvent and reacted. The mixture was then filtered to obtain the solid compound of formula II.

[0012] B) The compound of formula II, methanol and sodium methoxide are mixed and reacted to obtain the compound of formula III, sodium clasentan.

[0013] Preferably, the catalyst is one or more of dibutyltin oxide, tributyltin hydroxide, aluminum trichloride, zinc fluoride, and tetrabutylammonium fluoride trihydrate.

[0014] Preferably, the molar ratio of the compound of formula I to the catalyst is 1:(0.1 to 5).

[0015] Preferably, the molar ratio of the compound of formula I to azidotrimethylsilane is 1:(1.2-5).

[0016] Preferably, the solvent is one or more of toluene, xylene, and N,N-dimethylformamide.

[0017] Preferably, the reaction temperature in step A) is 25–140°C, and the reaction time in step A) is 5–30 hours.

[0018] Preferably, the mass-to-volume ratio of the compound of formula II to methanol is 1 g:(3-7) mL.

[0019] Preferably, the molar ratio of the compound of formula II to sodium methoxide is 1:(2.2-4).

[0020] Preferably, the reaction temperature in step B) is 40-45°C, and the reaction time in step B) is 1-3 hours.

[0021] Preferably, after the reaction in step B) is completed, the mixture is cooled to -20 to -10°C, and then filtered, recrystallized, and dried sequentially to obtain sodium clasentan, compound of formula III.

[0022] This invention provides a method for preparing clasentan sodium, comprising the following steps: A) under a protective atmosphere, mixing compound I, a catalyst, and azidotrimethylsilane in a solvent and reacting to obtain compound II; B) mixing compound II, methanol, and sodium methoxide and reacting to obtain compound III, clasentan sodium. This invention uses azidotrimethylsilane instead of sodium azide as the source of the azide group, significantly reducing the reaction risk. Compound II is purified by filtration to remove azidotrimethylsilane, avoiding the use of sodium nitrite to quench sodium azide under acidic conditions and thus avoiding the risk of nitrosamine impurities in the final product.

[0023] The present invention provides a sodium clasenum crystal form I, wherein the X-ray powder diffraction pattern of sodium clasenum crystal form I has diffraction peaks at the following 2θ angles: 7.06°, 8.22°, 8.43°, 10.07°, 21.33°, 21.89°.

[0024] Preferably, the X-ray powder diffraction pattern of the sodium clasenum crystal form I is shown in Figure 1.

[0025] This invention provides a method for preparing clasenum sodium crystal form I as described above, comprising the following steps:

[0026] Clarsentan sodium was mixed with water, heated to dissolve, then cooled to crystallize, filtered, and the solid was dried to obtain crystalline form I of clarsentan sodium.

[0027] The mass ratio of the clasenum sodium to the volume of water is 1 g: (2-20) mL.

[0028] Preferably, the temperature for heating and dissolving is 30–90°C.

[0029] Preferably, the cooling and crystallization temperature is 0–15°C.

[0030] This invention provides a sodium clasenum crystal form II, the X-ray powder diffraction pattern of which has diffraction peaks at the following 2θ angles: 8.44°, 10.13°, 11.24°, 12.43°, 13.19°, 14.86°, 16.88°, 17.15°, 19.83°, 20.62°, 21.13°, 22.25°, 22.66°, 25.62°.

[0031] Preferably, the X-ray powder diffraction pattern of the sodium clasenum crystal form II is shown in Figure 2.

[0032] This invention provides a method for preparing clasenum sodium crystal form II as described above, comprising the following steps:

[0033] Clarsentan sodium crystal form I was refluxed in a solvent and pulped, then cooled and filtered. The filtered solid was dried to obtain clarsentan sodium crystal form II.

[0034] The solvent includes one or more of methanol, ethanol and isopropanol.

[0035] Preferably, the temperature of the reflux pulping is 50–100°C, and the reflux pulping time is 1–24 hours.

[0036] Preferably, the cooling temperature is -10 to 20°C.

[0037] This invention obtains a new crystal form I, clasentan sodium, with low residual solvent by recrystallization using water as a solvent, and further obtains a new crystal form II by high-temperature pulping. No other preparation of this crystal form has been found to date. Moreover, the clasentan sodium crystal forms I and II prepared by this invention have low residual solvent content, which is beneficial to improving product quality.

[0038] This invention provides a method for preparing clasenum sodium amorphous product, comprising the following steps:

[0039] A) Mix sodium clasenum with water, heat to dissolve, and then cool until completely solidified;

[0040] B) The solid was freeze-dried to powder to obtain clasenum sodium amorphous product.

[0041] Preferably, the mass ratio of the clasenum sodium to the volume of water is 1 g: (8-100) mL.

[0042] Preferably, the temperature for heating and dissolving in step A) is 30–90°C.

[0043] Preferably, the cooling temperature in step A) is -50 to 0°C.

[0044] Preferably, the freeze-drying temperature is -5 to 45°C.

[0045] Preferably, the freeze-drying time is 1 to 48 hours.

[0046] Preferably, the purity of the prepared clasenum sodium amorphous product is >99.7%.

[0047] Preferably, the moisture content of the prepared clasenum sodium amorphous product is ≤0.9wt%.

[0048] Preferably, the solvent residue of the prepared clasenum sodium amorphous product is ≤20ppm.

[0049] Preferably, the sodium clasenum in step A) has a purity of 99.92%, methanol content of 1000-2000 ppm, and moisture content of 4-5%.

[0050] This invention provides a method for preparing amorphous clasentan sodium, comprising the following steps: A) mixing clasentan sodium with water, heating to dissolve, and then cooling until completely solidified; B) freeze-drying the solid to obtain amorphous clasentan sodium. This invention prepares amorphous clasentan sodium by freeze-drying, and the sodium content of the obtained amorphous product is closer to the theoretical value, with lower residual solvent. The process is easy to operate, yields a better powdered solid with high purity and lower moisture content, meeting API requirements. Attached Figure Description

[0051] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0052] Figure 1 is a powder X-ray diffraction pattern of sodium clasenum crystal form I in Example 1 of the present invention;

[0053] Figure 2 is a powder X-ray diffraction pattern of sodium clasenum crystal form II in Example 2 of the present invention;

[0054] Figure 3 is a powder X-ray diffraction pattern of the clasentan sodium amorphous material prepared in Example 5 of the present invention;

[0055] Figure 4 is the HPLC chromatogram of the amorphous clasenian sodium obtained in Example 5 of the present invention;

[0056] Figure 5 shows the DSC spectrum of the clasentan sodium amorphous material prepared in Example 5 of the present invention;

[0057] Figure 6 is the HPLC chromatogram of the clasentan sodium amorphous product prepared in Example 6 of the present invention;

[0058] Figure 7 is a powder X-ray diffraction pattern of the sodium clasenum amorphous material prepared in Comparative Example 2 of the present invention.

[0059] Figure 8 shows the HPLC chromatogram of the amorphous clasenum sodium prepared in Comparative Example 2 of this invention. Detailed Implementation

[0060] This invention provides a method for preparing clasentan sodium, comprising the following steps:

[0061] A) Under a protective atmosphere, the compound of formula I, the catalyst, and the azide-trimethylsilane were mixed in a solvent and reacted. The mixture was then filtered to obtain the solid compound of formula II.

[0062] B) The compound of formula II, methanol and sodium methoxide are mixed and reacted to obtain the compound of formula III, sodium clasentan.

[0063] In this invention, the compound of formula I and the catalyst are mixed in a solvent under a protective atmosphere, and then azidotrimethylsilane is added to carry out the reaction. After the reaction is completed, the mixture is cooled to room temperature and the azidotrimethylsilane is removed by filtration. The resulting filter cake is the compound of formula II.

[0064] In this invention, the protective atmosphere is preferably nitrogen and / or argon; the catalyst is preferably one or more of dibutyltin oxide, tributyltin hydroxide, aluminum trichloride, zinc fluoride, and tetrabutylammonium fluoride trihydrate; the molar ratio of the compound of formula I to the catalyst is preferably 1:(0.1-5), more preferably 1:(0.5-4.5), such as 1:0.1, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, preferably a range of values ​​with any of the above values ​​as the upper or lower limit.

[0065] In this invention, the solvent is preferably one or more of toluene, xylene, and N,N-dimethylformamide.

[0066] In this invention, the molar ratio of the compound of formula I to azidotrimethylsilane is preferably 1:(1.2-5), more preferably 1:(1.5-4), such as 1:1.2, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, and preferably a range of values ​​with any of the above values ​​as the upper or lower limit.

[0067] In this invention, the reaction temperature is preferably 25–140°C, more preferably 50–100°C, such as 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, preferably a range of values ​​with any of the above values ​​as the upper or lower limit; the reaction time is preferably 5–30 hours, more preferably 10–25 hours.

[0068] After filtration, the obtained solid was recrystallized from tetrahydrofuran. Specifically, the solid obtained by filtration was dissolved by adding tetrahydrofuran under reflux, and then most of the tetrahydrofuran was removed by atmospheric distillation. Finally, the temperature was lowered to 10-15°C and stirred for 1-2 hours to precipitate the solid, thus obtaining compound II.

[0069] After obtaining the compound of formula II, the present invention mixes the compound of formula II, methanol and sodium methoxide, and reacts them. After the reaction is completed, the mixture is cooled to 15-25°C, and then cooled to -20--10°C. The mixture is filtered and separated, and the obtained solid is recrystallized with water. Then, a mixture of methanol and ethanol is used to make a slurry filter cake, which is then filtered and dried to obtain sodium clasenum as shown in formula III.

[0070] In this invention, the mass-to-volume ratio of the compound of formula II to methanol is preferably 1 g:(3-7) mL, more preferably 1 g:(4-6) mL, such as 1 g:3 mL, 1 g:3.5 mL, 1 g:4 mL, 1 g:4.5 mL, 1 g:5 mL, 1 g:5.5 mL, 1 g:6 mL, 1 g:6.5 mL, 1 g:7 mL, preferably within the range of any of the above values ​​as the upper or lower limit. The molar ratio of the compound of formula II to sodium methoxide is preferably 1:(2.2-4), more preferably 1:(2.5-3.5), such as 1:2.2, 1:2.5, 1:3, 1:3.5, 1:4, preferably within the range of any of the above values ​​as the upper or lower limit.

[0071] In this invention, the reaction temperature is preferably 40-45°C, more preferably 41-44°C, such as 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, preferably a range of values ​​with the above values ​​as the upper or lower limit; the reaction time is preferably 1-3 hours, more preferably 2-3 hours.

[0072] In this invention, the recrystallization temperature is preferably 0-5°C, more preferably 0-4°C; in the mixed solvent of methanol and ethanol, the mass ratio of methanol to ethanol is preferably 1:(2-5), most preferably 1:(3-4); the drying temperature is preferably 60-80°C, more preferably 65-70°C; and the drying time is preferably 5-20 hours, more preferably 10-15 hours.

[0073] This invention provides a method for preparing clasentan sodium, comprising the following steps: A) under a protective atmosphere, mixing compound I, a catalyst, and azidotrimethylsilane in a solvent and reacting to obtain compound II; B) mixing compound II, methanol, and sodium methoxide and reacting to obtain compound III, clasentan sodium. This invention uses azidotrimethylsilane instead of sodium azide as the source of the azide group, significantly reducing the reaction risk. Compound II is purified by filtration to remove azidotrimethylsilane, avoiding the use of sodium nitrite to quench sodium azide under acidic conditions and thus avoiding the risk of nitrosamine impurities in the final product.

[0074] The present invention provides a sodium clasenum crystal form I, wherein the X-ray powder diffraction pattern of sodium clasenum crystal form I has diffraction peaks at the following 2θ angles: 7.06°, 8.22°, 8.43°, 10.07°, 21.33°, 21.89°.

[0075] This invention also provides a method for preparing the above-described clasenum sodium crystal form I, comprising the following steps:

[0076] Clarsentan sodium was mixed with water, heated to dissolve, then cooled to crystallize, filtered, and the solid was dried to obtain crystalline form I of clarsentan sodium.

[0077] The mass ratio of the clasenum sodium to the volume of water is 1 g: (2-20) mL.

[0078] In this invention, the source of the clasentan sodium is not particularly limited; it can be prepared by conventional methods in the art or commercially available clasentan sodium can be used directly. The water is preferably purified water.

[0079] In this invention, the mass ratio of clasentan sodium to water volume is preferably 1g:(2-20)mL, more preferably 1g:(5-15)mL, such as 1g:2mL, 1g:3mL, 1g:4mL, 1g:5mL, 1g:6mL, 1g:7mL, 1g:8mL, 1g:9mL, 1g:10mL, 1g:11mL, 1g:12mL, 1g:13mL, 1g:14mL, 1g:15mL, 1g:16mL, 1g:17mL, 1g:18mL, 1g:19mL, 1g:20mL, preferably within the range of any of the above values ​​as the upper or lower limit.

[0080] In this invention, the temperature for heating and dissolving is preferably 30-90°C, more preferably 40-80°C, such as 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, and preferably any of the above values ​​as the upper or lower limit; there is no special limitation on the time for heating and dissolving, as long as it can completely dissolve and obtain a clear solution.

[0081] In this invention, the cooling and crystallization temperature is preferably 0 to 20°C, more preferably 0 to 15°C, such as 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, preferably a range of values ​​with any of the above values ​​as the upper or lower limit; the cooling and crystallization time is not particularly limited, until no crystals precipitate.

[0082] After cooling and crystallization, the present invention filters the crystals, and the resulting filter cake is dried to obtain sodium clasenum crystal form I.

[0083] In this invention, the drying is preferably carried out in a vacuum drying oven, preferably under reduced pressure, and the drying temperature is preferably 60-80°C, more preferably 70-75°C; the drying time is preferably 1-24 hours, more preferably 12-18 hours. The vacuum degree of the drying is preferably -0.085 to -0.099 MPa.

[0084] This invention provides a sodium clasenum crystal form II, the X-ray powder diffraction pattern of which has diffraction peaks at the following 2θ angles: 8.44°, 10.13°, 11.24°, 12.43°, 13.19°, 14.86°, 16.88°, 17.15°, 19.83°, 20.62°, 21.13°, 22.25°, 22.66°, 25.62°.

[0085] This invention also provides a method for preparing clasenum sodium crystal form II, comprising the following steps:

[0086] Clarsentan sodium crystal form I was refluxed in a solvent and pulped, then cooled and filtered. The filtered solid was dried to obtain clarsentan sodium crystal form II.

[0087] The solvent includes one or more of methanol, ethanol and isopropanol.

[0088] In this invention, the clasentan sodium crystal form I is the clasentan sodium crystal form I described above or the clasentan sodium crystal form I prepared by the preparation method described above.

[0089] In this invention, the temperature of the reflux pulping is preferably 50-100℃, more preferably 60-90℃, such as 50℃, 60℃, 70℃, 80℃, 90℃, 100℃, preferably a range of values ​​with the above values ​​as the upper or lower limit; the time of the reflux pulping is preferably 1-24 hours, more preferably 2-5 hours.

[0090] In this invention, the cooling temperature is preferably -10 to 20°C, more preferably -5 to 15°C, such as -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, preferably a range of values ​​with any of the above values ​​as the upper or lower limit; the cooling time is not particularly limited, until no crystals precipitate.

[0091] In this invention, the drying is preferably carried out in a vacuum drying oven, preferably under reduced pressure, and the drying temperature is preferably 60-80°C, more preferably 70-75°C; the drying time is preferably 1-24 hours, more preferably 12-18 hours. The vacuum degree of the drying is preferably -0.085 to -0.099 MPa.

[0092] This invention provides a method for preparing clasenum sodium amorphous material, comprising the following steps:

[0093] A) Mix sodium clasenum with water, heat to dissolve, and then cool until completely solidified;

[0094] B) The solid was freeze-dried to powder to obtain clasenum sodium amorphous product.

[0095] In this invention, the clasentan sodium used as a raw material can be a commercially available product or prepared by methods known in the art. Specifically, in the embodiments of this invention, clasentan sodium prepared according to the method in patent WO2023111299A1 can be used as a raw material. In this invention, the purity of the clasentan sodium is preferably 99.9% to 99.92%, the content of the solvent methanol is preferably 1000 to 2000 ppm, more preferably 1500 ppm, and the moisture content is preferably 4% to 5%, more preferably 4.2%.

[0096] In this invention, the water mixed with clasentan sodium is preferably purified water, and the mass ratio of clasentan sodium to water volume is preferably 1g:(8-100)mL, more preferably 1g:(10-50)mL, such as 1g:8mL, 1g:10mL, 1g:15mL, 1g:20mL, 1g:25mL, 1g:30mL, 1g:35mL, 1g:40mL, 1g:45mL, 1g:50mL, 1g:100mL. Preferably, the range of values ​​above is the upper or lower limit.

[0097] In this invention, the temperature for heating and dissolving is preferably 30-90°C, more preferably 40-80°C, such as 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, and preferably any of the above values ​​as the upper or lower limit.

[0098] After heating and dissolving, a clear solution is obtained. The clear solution is then transferred to a freeze dryer for cooling until the entire solution system solidifies into a solid.

[0099] In this invention, the cooling temperature is preferably -50 to 0°C, more preferably -40 to -10°C, such as -50°C, -45°C, -40°C, -35°C, -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, 0°C, and preferably a range of values ​​with any of the above values ​​as the upper or lower limit.

[0100] After obtaining the solid, the present invention sets the temperature of the freeze dryer to the freeze drying temperature and freeze-dries it to obtain solid powdered clasentan sodium amorphous material.

[0101] In this invention, the freeze-drying temperature is preferably -5 to 45°C, more preferably 0 to 40°C, such as -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, preferably a range of values ​​with any of the above values ​​as the upper or lower limit; the freeze-drying time is preferably 1 to 48 hours, more preferably 5 to 40 hours, such as 1 hour, 5 hours, 10 hours, 15 hours, 20 hours, 25 hours, 30 hours, 35 hours, 40 hours, 45 hours, 48 ​​hours, preferably a range of values ​​with any of the above values ​​as the upper or lower limit.

[0102] The amorphous form of clasentan sodium prepared by this invention has a purity >99.7%, a moisture content ≤0.9wt%, and a solvent residue ≤20ppm.

[0103] This invention provides a method for preparing amorphous clasentan sodium, comprising the following steps: A) mixing clasentan sodium with water, heating to dissolve, and then cooling until completely solidified; B) freeze-drying the solid to obtain amorphous clasentan sodium. This invention prepares amorphous clasentan sodium by freeze-drying, and the sodium content of the obtained amorphous product is closer to the theoretical value, with lower residual solvent. The process is easy to operate, yields a better powdered solid with high purity and lower moisture content, meeting API requirements.

[0104] Example 1: Preparation of Clarsentan Sodium

[0105] 1) Add 7.00g of compound I and 0.35g of dibutyltin oxide, 70mL of toluene to the reaction flask, purge the reaction flask with nitrogen, add 4.21g of azidotrimethylsilane, after which stir is turned on and the temperature is raised to 80℃ for 20 hours; cool to room temperature, filter to remove azidotrimethylsilane, add 420mL of tetrahydrofuran to dissolve the solid under reflux, and then distill at atmospheric pressure to collect 385mL of tetrahydrofuran; cool the solution in the reaction flask to 10-15℃ and stir for 1 hour, filter to obtain 6.12g of compound II.

[0106] 2) Add 6.12g of compound II, 33ml of methanol, and 5mL of 30% sodium methoxide methanol solution to the reaction flask. Stir at 37±2℃ for 1h, then slowly cool to 20℃, and then cool to -13℃. Filter to separate the solid. Dissolve the solid in 12ml of water at 77±2℃, slowly cool to 0±2℃ and stir for 2h. Filter to separate the solid. Add the solid to a mixed solvent of 10g of methanol and 30g of ethanol, heat to 92±2℃ and reflux and stir for 2h. Distill 10g of solvent at atmospheric pressure. Cool the solution in the reaction flask to -15℃ and stir for 2h. Filter and dry to obtain 3.52g of compound III.

[0107] N-nitrosodimethylamine (NDMA) in the finished product of clasentan sodium was detected by GC-MS, and the result was not detected.

[0108] Example 2: Preparation of Clarsentan Sodium

[0109] 1) Add 7.00g of compound I and 0.36g of aluminum trichloride, 70mL of toluene to the reaction flask, purge the reaction flask with nitrogen, add 4.21g of azidotrimethylsilane, after which stir is started, heat to 80℃ and react for 20 hours; cool to room temperature, filter to remove azidotrimethylsilane, add 420mL of tetrahydrofuran to dissolve the solid under reflux, and then distill at atmospheric pressure to collect 385mL of tetrahydrofuran; cool the solution in the reaction flask to 10-15℃ and stir for 1 hour, filter to obtain 5.97g of compound II.

[0110] 2) Add 5.97g of compound II, 32ml of methanol, and 4.9mL of 30% sodium methoxide methanol solution to the reaction flask. Stir at 37±2℃ for 1h, then slowly cool to 20℃, and then cool to -13±2℃. Filter to separate the solid. Dissolve the solid in 12ml of water at 77±2℃, slowly cool to 0±2℃ and stir for 2h. Filter to separate the solid. Add the solid to a mixed solvent of 9.75g of methanol and 29.25g of ethanol, heat to 92±2℃ and reflux and stir for 2h. Distill 9.75g of solvent at atmospheric pressure. Cool the solution in the reaction flask to -15℃ and stir for 2h. Filter and dry to obtain 3.32g of compound III.

[0111] N-nitrosodimethylamine (NDMA) in the finished product of clasentan sodium was detected by GC-MS, and the result was not detected.

[0112] Comparative Example 1 was prepared according to the method of patent WO2023111299.

[0113] 1) Add 7.00g of compound I and 1.61g of ammonium chloride, 35mL of N,N-dimethylformamide to the reaction flask, and add a mixed solution of 1.95g of sodium azide and 7mL of water while stirring at room temperature. After the addition is complete, heat to 95℃ and react for 15 hours. Cool to 40℃, add a mixed solution of 4.21g of sodium nitrite and 14mL of water and stir for 30 minutes. Then add 2mol / L hydrochloric acid solution to adjust the pH to 3. Stir at room temperature for 1 hour, filter to obtain solid, add 420mL of tetrahydrofuran to dissolve under reflux, and then distill at normal pressure to collect 385mL of tetrahydrofuran. Cool the solution in the reaction flask to 12±2℃ and stir for 1 hour. Filter to obtain 6.03g of compound II.

[0114] 2) Add 6.03g of compound II, 32ml of methanol, and 5mL of 30% sodium methoxide methanol solution to the reaction flask. Stir at 37±2℃ for 1h, then slowly cool to 20℃, and then cool to -13℃. Filter to separate the solid. Dissolve the solid in 12ml of water at 77±2℃, slowly cool to 0±2℃ and stir for 2h. Filter to separate the solid. Add the solid to a mixed solvent of 9.75g of methanol and 29.25g of ethanol, heat to 92±2℃ and reflux and stir for 2h. Distill 9.75g of solvent at atmospheric pressure. Cool the solution in the reaction flask to -15℃ and stir for 2h. Filter and dry to obtain 3.42g of compound III.

[0115] The N-nitrosodimethylamine (NDMA) in the finished product of clasentan sodium was detected by GC-MS, and the result was 12.5 ppm.

[0116] Example 3: Preparation of sodium clasenum crystal form I

[0117] 10.0 g of clasentan sodium and 40 ml of purified water were added sequentially to the reaction flask. The mixture was heated to 75 ± 2 °C to dissolve completely. After dissolution, the temperature was lowered to 2 ± 2 °C and stirred for 6 h. The mixture was filtered, and the filter cake was dried under reduced pressure at 70 °C to obtain 9.1 g of clasentan sodium in new crystal form I. Residual solvents ethanol and methanol were not detected, and the moisture content was 3.7%. Its powder X-ray diffraction pattern is shown in Figure 1. Figure 1 shows peaks at the following refraction angles of 2θ (values ​​in parentheses are diffraction intensities): 7.06° (100%), 8.22° (10.86%), 8.43° (10.21%), 10.07° (19.13%), 21.33° (16.84%), and 21.89° (12.80%).

[0118] Example 4: Preparation of sodium clasenum crystal form II

[0119] 5.0 g of clasentan sodium crystal form I and 80 ml of ethanol were added sequentially to the reaction flask. The mixture was heated to 80±2℃ and stirred under reflux for 12 h. The mixture was then cooled to -7±2℃ and stirred for 2 h. After filtration, the filter cake was dried under reduced pressure at 70℃ to obtain 4.7 g of clasentan sodium crystal form II. The residual solvent was 850 ppm ethanol and the water content was 1.9%. The powder X-ray diffraction pattern is shown in Figure 2. Figure 2 shows peaks at the following refraction angles of 2θ (the values ​​in parentheses are diffraction intensities): 8.44° (100%), 10.13° (79.70%), 11.24° (13.14%), 12.43° (12.71%), 13.19° (10.31%), 14.86° (12.45%), 16.88° (24.70%), 17.15° (11.13%), 19.83° (29.54%), 20.62° (22.63%), 21.13° (13.09%), 22.25° (17.60%), 22.66° (12.84%), and 25.62° (25.79%).

[0120] Example 5: Preparation of amorphous clasenum sodium

[0121] 10.0 g of clasentan sodium crystal form A and 300 ml of purified water were added sequentially to a reaction flask. The mixture was heated to 32±2℃ to dissolve completely. After dissolution, the solution was transferred to a lyophilization tray and placed in a lyophilizer. The temperature was lowered to -17±2℃. Once the system had completely solidified, the lyophilizer temperature was set to 7±2℃, and lyophilization was initiated. The mixture was lyophilized for 25 hours until it became a powder. The powder was then desorbed and dried at 40±2℃ for 6 hours. The lyophilization was then complete, yielding 9.8 g of amorphous clasentan sodium. HPLC analysis showed that the purity of clasentan sodium was 99.92%, the moisture content was 0.9%, and the residual solvent methanol was 20 ppm. The powder X-ray diffraction pattern is shown in Figure 3. The pattern in Figure 3 shows no obvious diffraction peaks. This is because the atoms inside the amorphous substance are disordered and lack a long-range ordered structure, thus failing to produce a strong diffraction signal. Therefore, as shown in Figure 3, the product prepared in this invention is amorphous clasentan sodium. The HPLC chromatogram is shown in Figure 4, and the DSC chromatogram is shown in Figure 5.

[0122] Example 6: Preparation of amorphous clasenum sodium

[0123] 10.0 g of clasentan sodium crystal form A and 400 ml of purified water were added sequentially to the reaction flask. The mixture was heated to 32±2℃ to dissolve completely. After dissolution, the solution was transferred to a lyophilization tray and placed in a lyophilizer. The temperature was lowered to -17±2℃. When the system had completely solidified, the lyophilizer temperature was set to 7±2℃, and lyophilization was started. The mixture was lyophilized for 35 hours until it became a powder. The solution was then dried at 40±2℃ for 6 hours. The lyophilization was then complete, yielding 9.7 g of amorphous clasentan sodium. HPLC analysis showed that the purity of clasentan sodium was 99.89%, the water content was 0.6%, and the residual solvent methanol was not detected. The HPLC chromatogram is shown in Figure 6.

[0124] Comparative Example 2

[0125] 3.0 g (5.2 mmol) of clasentan (prepared according to the method in patent WO2023111299A1), 15 mL of methanol, and then 1.9 mL (10.4 mmol) of 5.4N sodium methoxide methanol solution were added sequentially to the reaction flask. The mixture was heated under reflux for 3 h, then slowly cooled to 20 °C, and then cooled to 0 °C. The solid was separated by filtration, washed with 3 mL of ice-cold methanol, and dried under reduced pressure at 70 °C to obtain 1.3 g of clasentan sodium amorphous product. This solid was a viscous solid, extremely difficult to filter, with a purity of 98.44% for related substances, 3.7% water content, and 2200 ppm residual methanol. Its powder X-ray diffraction pattern is shown in Figure 7, and its HPLC chromatogram is shown in Figure 8.

[0126] The parameters of the clasentan sodium amorphous products obtained in Example 5 and Comparative Example 2 were compared, as shown in Table 1.

[0127] Table 1. Parameter data of the krasentan amorphous materials obtained in Example 5 and Comparative Example 2.

[0128] Compared with existing methods for preparing amorphous clasenum sodium, the amorphous clasenum obtained by this invention has a sodium content closer to the theoretical value, lower residual solvent, easier process operation to obtain better powdered solid, higher purity, lower moisture content, and can meet API requirements.

[0129] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing clasentan sodium, comprising the following steps: A) Under a protective atmosphere, the compound of formula I, the catalyst, and the azide-trimethylsilane were mixed in a solvent and reacted. The mixture was then filtered to obtain the solid compound of formula II. B) mixing the compound of formula II, methanol and sodium methoxide and reacting to obtain the compound of formula III, Clenbuterol sodium; 2. The production method according to claim 1, characterized by, The catalyst is one or more of dibutyltin oxide, tributyltin hydroxide, aluminum trichloride, zinc fluoride, and tetrabutylammonium fluoride trihydrate.

3. The production method according to claim 2, characterized by, The molar ratio of the compound of formula I to the catalyst is 1:(0.1-5).

4. The production method according to claim 1, characterized by, The molar ratio of the compound of formula I to azidotrimethylsilane is 1:(1.2-5).

5. The preparation method according to claim 1, characterized in that, The solvent is one or more of toluene, xylene, and N,N-dimethylformamide.

6. The preparation method according to claim 1, characterized in that, The reaction temperature in step A) is 25–140°C, and the reaction time in step A) is 5–30 hours.

7. The preparation method according to claim 1, characterized in that, The mass-to-volume ratio of the compound of formula II to methanol is 1 g: (3-7) mL.

8. The method of claim 1, wherein, The molar ratio of the compound of formula II to sodium methoxide is 1:(2.2-4).

9. The method of claim 1, wherein, The reaction temperature in step B) is 40-45°C, and the reaction time in step B) is 1-3 hours.

10. The process according to any one of claims 1 to 9, characterized in that, After the reaction in step B) is completed, the mixture is cooled to -20 to -10°C, and then filtered, recrystallized and dried in sequence to obtain compound III, clasentan sodium.

11. A sodium clasenum crystal form I, wherein the X-ray powder diffraction pattern of sodium clasenum crystal form I has diffraction peaks at the following 2θ angles: 7.06°, 8.22°, 8.43°, 10.07°, 21.33°, 21.89°.

12. The crystalline Form I of Clastitan sodium of claim 11, characterized in that, The X-ray powder diffraction pattern of the sodium clasenum crystal form I is shown in Figure 1.

13. A method for preparing clasenum sodium crystal form I as described in claim 11 or 12, comprising the following steps: Clarsentan sodium was mixed with water, heated to dissolve, then cooled to crystallize, filtered, and the solid was dried to obtain crystalline form I of clarsentan sodium. The mass ratio of the clasenum sodium to the volume of water is 1 g: (2-20) mL.

14. The method of claim 13, wherein, The temperature for heating and dissolving is 30–90°C.

15. The preparation method according to claim 13, characterized in that, The cooling and crystallization temperature is 0–15°C.

16. A sodium clasenum crystal form II, wherein the X-ray powder diffraction pattern of the sodium clasenum crystal form II has diffraction peaks at the following 2θ angles: 8.44°, 10.13°, 11.24°, 12.43°, 13.19°, 14.86°, 16.88°, 17.15°, 19.83°, 20.62°, 21.13°, 22.25°, 22.66°, 25.62°.

17. The crystalline Form II of Clastitan sodium of claim 16, characterized in that, The X-ray powder diffraction pattern of the sodium clasenum crystal form II is shown in Figure 2.

18. A method for preparing clasenum sodium crystal form II as described in claim 16 or 17, comprising the following steps: Clarsentan sodium crystal form I was refluxed in a solvent and pulped, then cooled and filtered. The filtered solid was dried to obtain clarsentan sodium crystal form II. The solvent includes one or more of methanol, ethanol and isopropanol.

19. The method of claim 18, wherein, The temperature of the reflux pulping is 50–100°C, and the reflux pulping time is 1–24 hours.

20. The method of claim 18, wherein, The cooling temperature is -10 to 20°C.

21. A method for preparing clasenum sodium amorphous product, comprising the following steps: A) Mix sodium clasenum with water, heat to dissolve, and then cool until completely solidified; B) The solid was freeze-dried to powder form to obtain clasenum sodium amorphous product.

22. The method for preparing clasenum sodium amorphous product according to claim 21, characterized in that, The mass ratio of the clasenian sodium to the volume of water is 1 g: (8-100) mL.

23. The method of claim 21, wherein the amorphous form of clazosentan sodium is characterized by: The temperature for heating and dissolving in step A) is 30–90°C.

24. The method for preparing clasenum sodium amorphous product according to claim 21, characterized in that, The cooling temperature in step A) is -50 to 0°C.

25. The method for preparing clasenum sodium amorphous product according to claim 21, characterized in that, The freeze-drying temperature is -5 to 45°C.

26. The method for preparing clasenum sodium amorphous product according to claim 21, characterized in that, The freeze-drying time is 1 to 48 hours.

27. The method for preparing clasenum sodium amorphous product according to claim 21, characterized in that, The purity of the prepared clasenum sodium amorphous product is >99.7%.

28. The method for preparing clasenum sodium amorphous product according to claim 21, characterized in that, The moisture content of the prepared clasenum sodium amorphous product is ≤0.9wt%.

29. The method for preparing clasenum sodium amorphous product according to claim 21, characterized in that, The solvent residue of the prepared clasenum sodium amorphous product is ≤20ppm.

30. The method for preparing clasenum sodium amorphous product according to claim 21, characterized in that, The sodium clasenum in step A) has a purity of 99.9-99.92%, methanol content of 1000-2000 ppm, and moisture content of 4-5%.

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