A process for the preparation of clazosentan sodium

Abstract

The application provides a preparation method of clasten sodium, which comprises the following steps: A) mixing a compound of formula I, a catalyst and azidotrimethylsilane in a solvent under a protective atmosphere, and performing a reaction to obtain a compound of formula II; and B) mixing the compound of formula II, methanol and sodium methoxide, and performing a reaction to obtain a compound of formula III, clasten sodium. In the application, azidotrimethylsilane is used instead of sodium azide as a source of azide group, the reaction risk is greatly reduced, the compound II is filtered to remove azidotrimethylsilane, the use of sodium nitrite under acidic conditions to remove sodium azide is avoided, and the risk of nitrosamine impurities in the finished product is avoided.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to a method for preparing clasentan sodium. Background Technology

[0002] Clarsentan sodium is a selective endothelin receptor antagonist that can be used to inhibit subarachnoid hemorrhage, intracranial vasospasm, and associated cerebral infarction and postoperative cerebral ischemia.

[0003] 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.

[0004]

[0005] Patent WO2023111299 introduces tetrazolium using 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, the system is in a clear, dissolved state, requiring pH adjustment to acidity to precipitate a solid. However, the reaction of sodium azide with acid produces toxic and explosive azidoic acid. Therefore, sodium azide must first be quenched with sodium nitrite before adjusting the pH to acidity, and the solid clasentan is obtained by filtration. 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 high risk and easily produces toxic impurities.

[0006] Summary of the Invention

[0007] The purpose of this invention is to provide a method for preparing clasentan sodium. The preparation method of this invention has greatly reduced the reaction risk and can avoid the impurity of nitrosamines in the finished product.

[0008] This invention provides a method for preparing clasenum sodium, comprising the following steps:

[0009] 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.

[0010] B) The compound of formula II, methanol and sodium methoxide are mixed and reacted to obtain the compound of formula III, sodium clasentan.

[0011]

[0012] Preferably, the catalyst is one or more of dibutyltin oxide, tributyltin hydroxide, aluminum trichloride, zinc fluoride, and tetrabutylammonium fluoride trihydrate.

[0013] Preferably, the molar ratio of the compound of formula I to the catalyst is 1:(0.1 to 5).

[0014] Preferably, the molar ratio of the compound of formula I to azidotrimethylsilane is 1:(1.2-5).

[0015] Preferably, the solvent is one or more of toluene, xylene, and N,N-dimethylformamide.

[0016] Preferably, the reaction temperature in step A) is 25–140°C, and the reaction time in step A) is 5–30 hours.

[0017] Preferably, the mass-to-volume ratio of the compound of formula II to methanol is 1 g:(3-7) mL.

[0018] Preferably, the molar ratio of the compound of formula II to sodium methoxide is 1:(2.2-4).

[0019] Preferably, the reaction temperature in step B) is 40-45°C, and the reaction time in step B) is 1-3 hours.

[0020] 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.

[0021] 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. Detailed Implementation

[0022] This invention provides a method for preparing clasentan sodium, comprising the following steps:

[0023] 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.

[0024] B) The compound of formula II, methanol and sodium methoxide are mixed and reacted to obtain the compound of formula III, sodium clasentan.

[0025]

[0026] 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.

[0027] 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.

[0028] In this invention, the solvent is preferably one or more of toluene, xylene, and N,N-dimethylformamide.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] To further illustrate the present invention, the following detailed description of a method for preparing clasenum sodium provided by the present invention is provided in conjunction with embodiments, but it should not be construed as limiting the scope of protection of the present invention.

[0038] Example 1

[0039] 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.

[0040] 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.

[0041] N-nitrosodimethylamine (NDMA) in the finished product of clasentan sodium was detected by GC-MS, and the result was not detected.

[0042] Example 2

[0043] 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.

[0044] 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.

[0045] N-nitrosodimethylamine (NDMA) in the finished product of clasentan sodium was detected by GC-MS, and the result was not detected.

[0046] Comparative Example 1 was prepared according to the method of patent WO2023111299.

[0047] 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.

[0048] 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.

[0049] The N-nitrosodimethylamine (NDMA) in the finished product of clasentan sodium was detected by GC-MS, and the result was 12.5 ppm.

[0050] 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) The compound of formula II, methanol and sodium methoxide are mixed and reacted to obtain the compound of formula III, sodium clasentan.

2. The preparation method according to claim 1, characterized in that, The catalyst is one or more of dibutyltin oxide, tributyltin hydroxide, aluminum trichloride, zinc fluoride, and tetrabutylammonium fluoride trihydrate.

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

4. The preparation method according to claim 1, characterized in that, 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 preparation method according to claim 1, characterized in that, The molar ratio of the compound of formula II to sodium methoxide is 1:(2.2-4).

9. The preparation method according to claim 1, characterized in that, The reaction temperature in step B) is 40-45°C, and the reaction time in step B) is 1-3 hours.

10. The preparation method 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.

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