A process for the preparation of bosentan

Abstract

The application provides a preparation method of bosentan, which comprises the following steps: mixing phosphorus oxychloride and 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6(1H,5H)-dione, reacting to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine; then mixing the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine with 4-tert-butylbenzenesulfonamide, an acid binding agent and a polar aprotic solvent, and reacting to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt; then mixing the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt with ethylene glycol, an alkali metal hydroxide and tetrahydrofuran to obtain a bosentan precursor; and finally mixing the bosentan precursor with ethanol and water, reacting, cooling and crystallizing to obtain bosentan. The preparation method of bosentan can greatly save reaction time, improve reaction yield, reduce impurity content, simplify post-treatment operation, reduce preparation cost and be convenient for industrial large-scale production and application.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of bosentan. BACKGROUND

[0002] Bosentan is a dual ET (ETA / ETB) receptor antagonist, which is suitable for treating pulmonary hypertension of patients with WHO stage III and IV primary pulmonary hypertension or pulmonary hypertension caused by scleroderma. The main component of bosentan is 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methyl-phenoxy)-[2,2']bipyrimidin-4-yl]benzenesulfonamide-hydrate, and the chemical structural formula is as follows:

[0003]

[0004] At present, there are various synthetic routes of bosentan, but most of the reactions involved have problems of long reaction time, complex post-treatment, low yield of reaction products and high impurity content, which greatly limit the industrialized production and market supply of bosentan.

[0005] Therefore, it is urgent to provide a preparation method of bosentan with short reaction time, simple post-treatment, high yield of reaction products and less impurities. SUMMARY

[0006] The present application aims to provide a preparation method of bosentan, so as to solve the problems of long reaction time, complex post-treatment, low yield of reaction products and high impurity content of bosentan in the prior art.

[0007] To solve the above technical problems, the technical scheme of the present application is as follows:

[0008] A preparation method of bosentan comprises the following steps:

[0009] (1) mixing phosphorus oxychloride and 5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4,6(1H,5H)-dione at-10-0℃, and then reacting at 106-116℃ for 4-8h to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine;

[0010] (2) mixing 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine obtained in step (1), 4-tert-butylbenzenesulfonamide, an acid binding agent and a polar aprotic solvent, and then reacting at 115-125℃ for 4-8h to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt;

[0011] (3) mixing the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl] benzenesulfonamide potassium salt obtained in step (2) with ethylene glycol, alkali metal hydroxide, and tetrahydrofuran, and reacting at 55-75°C for 1-3 hours to obtain a bosentan precursor;

[0012] (4) mixing the bosentan precursor obtained in step (3) with ethanol and water, and reacting at 60-70°C for 20-40 minutes to obtain bosentan.

[0013] Preferably, step (1) further comprises, after the reaction, a step of post-treating the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-pyrimidine product:

[0014] cooling the reaction solution after the reaction to -10-0°C, and adding an ice-water mixture to quench the residual phosphorus oxychloride at a rate of 50 ml / min, and stirring at -10-0°C for 10-30 minutes to obtain a first filter cake;

[0015] slurrying the first filter cake obtained with water, and adjusting the pH of the mixture to 6.0-8.0 with a sodium carbonate solution, and filtering and drying to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-pyrimidine.

[0016] Preferably, the method for preparing bosentan further comprises, after the filtering, a step of washing the filter cake with water in an amount of 0.2-0.6 times the volume of the filter cake for 1-3 times;

[0017] Optionally, the ice-water mixture has a volume ratio of ice to water of 1:(1-5);

[0018] Optionally, the water used for the slurrying has a volume of 0.2-0.6 times the volume of the filter cake;

[0019] Optionally, the sodium carbonate solution is a saturated sodium carbonate solution.

[0020] Preferably, in step (1), the molar ratio of the 5-(2-methoxyphenoxy)-[2,2'-pyrimidine]-4,6(1H,5H)-dione to the phosphorus oxychloride is 1:(3-5);

[0021] Optionally, in step (1), the 5-(2-methoxyphenoxy)-[2,2'-pyrimidine]-4,6(1H,5H)-dione is mixed with the phosphorus oxychloride.

[0022] Preferably, in step (2), the acid-binding agent is one or more of sodium carbonate, potassium carbonate, and sodium hydroxide.

[0023] Optionally, the polar aprotic solvent is one or more of acetonitrile, acetone, dimethylformamide, dimethyl sulfoxide;

[0024] Optionally, the molar ratio of the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine to 4-tert-butylbenzenesulfonamide, the acid binding agent and the polar aprotic solvent is 1:(1-1.2):(3-5):(8-12).

[0025] Preferably, step (2) specifically comprises the following steps:

[0026] First, 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine is mixed with 4-tert-butylbenzenesulfonamide and a polar aprotic solvent, then an acid binding agent is added in 2-6 portions at 115-125°C with an interval of 1 hour between each portion, and then the reaction is carried out at 115-125°C for 4-8 hours to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt;

[0027] Optionally, step (2) further comprises the following step after the reaction: carrying out post-treatment of the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt product.

[0028] The reaction solution after the reaction is cooled to 10-30°C, filtered to obtain a second filter cake; the obtained second filter cake is added with the polar aprotic solvent for beating, and then filtered, washed and dried to obtain a third filter cake; the obtained third filter cake is added with water for beating, and then filtered, washed and dried to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt.

[0029] Preferably, in step (2), the washing is carried out 1-3 times with 2-8 times the volume of the filter cake of the polar aprotic solvent; and / or, the washing is carried out 1-3 times with 2-8 times the volume of the filter cake of water;

[0030] Optionally, the amount of the polar aprotic solvent used for beating is 2-8 times the volume of the filter cake;

[0031] Optionally, the amount of water used for beating is 2-8 times the volume of the filter cake.

[0032] Preferably, in step (3), the alkali metal hydroxide is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate;

[0033] Optionally, the volume ratio of the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt, ethylene glycol, alkali metal hydroxide, and tetrahydrofuran is 1:(90-110):(15-25):(6-8).

[0034] Preferably, step (3) specifically comprises the following steps:

[0035] The ethylene glycol and the tetrahydrofuran are mixed first, and then the alkali metal hydroxide is added thereto. The mixture is stirred at 60-70°C for 1-3h, and then cooled to 10-30°C. The 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt is added thereto, and the mixture is stirred at 60-70°C for 2-4h to obtain the bosentan precursor.

[0036] Optionally, step (3) further comprises the following step of post-treatment of the bosentan precursor product after the reaction:

[0037] (a) The reaction solution after the reaction is cooled to 10-30°C, and the tetrahydrofuran in the reaction solution is evaporated. Hydrochloric acid is used to adjust the pH value to 2-3. Water is added thereto, and the mixture is stirred at -10°C-0°C for 0.5-1h. The fourth filter cake is obtained through crystallization, filtration, and washing.

[0038] (b) The fourth filter cake is dissolved in a mixed solution of acetonitrile and methanol at 70-90°C, and then cooled to 15-35°C at a rate of 10°C / h. Then, the mixture is crystallized at -5-5°C for 0.5-1h. The fifth filter cake is obtained through filtration and washing.

[0039] (c) Step (b) is repeated 1-4 times to obtain the recrystallized filter cake, which is dried to obtain the bosentan precursor.

[0040] Optionally, in step (b), the volume ratio of acetonitrile to methanol in the mixed solution of acetonitrile and methanol is 1:1.

[0041] Optionally, in step (b), the volume ratio of the mixed solution of acetonitrile and methanol to the fourth filter cake is 1:(1-3).

[0042] Optionally, in step (b), the washing is performed using methanol. The volume ratio of the methanol used for washing to the mixed solution of acetonitrile and methanol is 1:(1-3).

[0043] Preferably, step (4) specifically comprises the following steps:

[0044] Mix the bosentan precursor obtained in step (3) with ethanol, stir at 60-70℃ for 20-40min, then add water at a speed of 200ml / min to obtain a mixture; stir the mixture at 60-70℃ for 20-40min, then stir at 10-20℃ for 6-12h, filter and dry to obtain bosentan;

[0045] Optionally, the volume ratio of the bosentan precursor, ethanol and water is 1:(8-15):(8-15).

[0046] The above scheme of the present application at least includes the following beneficial effects:

[0047] (1) The preparation method of bosentan can greatly save reaction time, improve reaction yield, reduce impurity content, simplify post-treatment operation, reduce preparation cost and facilitate industrial large-scale production and application.

[0048] In step (1), by low-temperature feeding, the occurrence of side reactions is reduced, and by setting the reaction temperature to 106-116℃, the phosphorus oxychloride is above the boiling point, without adding a solvent, it can directly react with 5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4,6(1H,5H)-dione, the reaction can be almost quantitative, and the yield is more than 98%;

[0049] (2) The preparation method of bosentan further includes a step of treating the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin product after the reaction in step (1). This step can effectively remove excess phosphorus oxychloride that does not participate in the synthesis reaction, reduce impurities and the influence of impurities on subsequent reactions, so that the purity of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin can be more than 99%.

[0050] (3) In step (2) of the preparation method of bosentan, by adding the acid-binding agent quantitatively in several times, the reaction efficiency can be improved, the reaction time can be shortened, and the yield of the reaction product can be improved. The product treatment step in step (2) is simple to operate, and can greatly improve the product purity.

[0051] (4) The reaction time of step (3) of the preparation method of bosentan is short, and the yield is high. The product treatment step in step (3) is simple to operate, and can greatly improve the product purity.

[0052] (5) In step (4) of the preparation method of bosentan, by using ethanol, water and bosentan precursor for reaction, and controlling the water adding speed, the yield of the product can be improved. BRIEF DESCRIPTION OF DRAWINGS

[0053] Figure 1is a synthetic route map of the preparation method of bosentan prepared in the experimental example 1 of the present application. DETAILED DESCRIPTION

[0054] The specific conditions not specified in the embodiments of the present application are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not specified by the manufacturer, and are conventional products that can be obtained by purchase. Different manufacturers and models of raw materials do not affect the implementation of the technical solutions and the realization of the technical effects of the present application.

[0055] Example 1

[0056] The preparation method of bosentan of the present embodiment comprises the following steps:

[0057] (1) 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6(1H,5H)-dione and phosphorus oxychloride are taken in a molar ratio of 1:4, and the 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6(1H,5H)-dione is mixed into the phosphorus oxychloride at -10°C; then reacted at 106°C for 6h to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine;

[0058] The obtained 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine is subjected to product post-treatment:

[0059] The reaction liquid after reaction is cooled to -10°C, and an ice-water mixture with a volume ratio of ice to water of 1:4 is added at a speed of 50ml / min to quench the remaining phosphorus oxychloride, and then stirred at -5°C for 10min, filtered, washed with water to obtain a first filter cake;

[0060] The obtained first filter cake is added with water for beating, and a saturated sodium carbonate solution is used to adjust the pH value of the mixed liquid to 7.0, and then filtered, washed with water, and dried to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine.

[0061] It should be noted that the water amount for beating, the water amount for washing, and the washing times are not unique, and a person skilled in the art can adjust them within a certain range according to the actual situation. The water amount for beating includes but is not limited to 0.2-0.6 times the volume of the filter cake; the water washing includes but is not limited to washing with 0.2-0.6 times the volume of the filter cake for 1-3 times (the same below, not described again hereinafter).

[0062] In this embodiment, the 5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4,6(1H,5H)-dione is mixed with the phosphorus oxychloride under low temperature conditions of -10°C to 0°C. An ice water bath, an ice salt bath, or other low temperature means can be used to achieve the low temperature conditions. Similarly, low temperature conditions in other embodiments or other steps can also be achieved using an ice water bath, an ice salt bath, or other low temperature means (the same applies hereinafter and will not be described again hereinafter).

[0063] In this embodiment, the amount of the ice water mixture used is to quench the remaining phosphorus oxychloride. The reaction is determined to be complete when the reaction solution no longer generates heat with the addition of the ice water mixture under stirring (the same applies hereinafter and will not be described again hereinafter).

[0064] (2) The 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine obtained in step (1) is mixed with 4-tert-butylbenzenesulfonamide, an acid binding agent, and a polar aprotic solvent, and reacted at 115°C for 6h to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt.

[0065] As a specific implementation of this embodiment, step (2) is specifically as follows:

[0066] The 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine, the 4-tert-butylbenzenesulfonamide, the acid binding agent, and the polar aprotic solvent are taken in a molar ratio of 1:1.1:5:8; the acid binding agent is sodium hydroxide; and the polar aprotic solvent is acetonitrile.

[0067] The 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine, the 4-tert-butylbenzenesulfonamide, and the polar aprotic solvent are first mixed, and then the acid binding agent is added in four portions at 115°C with an interval of 1h between each addition, followed by reaction at 115°C for 6h to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt.

[0068] The obtained 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt is subjected to product post-treatment.

[0069] The reaction solution after reaction is cooled to 20°C, filtered to obtain a second filter cake; the obtained second filter cake is beaten with the polar aprotic solvent, and then filtered, washed, and dried to obtain a third filter cake; the obtained third filter cake is beaten with water, and then filtered, washed, and dried to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt.

[0070] It is to be noted that the solution used for the washing, the solution amount, the washing times, and the solution amount used for the beating are not unique, and those skilled in the art can adjust them within a certain range according to the actual situation. The washing includes but is not limited to washing 1-3 times with 2-8 times the volume of the filter cake of a polar aprotic solvent; and / or washing 1-3 times with 2-8 times the volume of the filter cake of water. The amount of the polar aprotic solvent used for beating includes but is not limited to 2-8 times the volume of the filter cake; the amount of water used for beating includes but is not limited to 2-8 times (the same below, which will not be repeated hereinafter).

[0071] (3) mixing the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl] benzene sulfonamide potassium salt obtained in step (2) with ethylene glycol, alkali metal hydroxide, and tetrahydrofuran, and reacting at 65°C for 3h to obtain a bosentan precursor;

[0072] As a specific implementation manner of the embodiment, step (3) is specifically as follows:

[0073] The 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl] benzene sulfonamide potassium salt, ethylene glycol, alkali metal hydroxide, and tetrahydrofuran are taken in a molar ratio of 1:90:20:6; wherein the alkali metal hydroxide is sodium carbonate;

[0074] First, the ethylene glycol is mixed with the tetrahydrofuran, and then the alkali metal hydroxide is added thereto, and stirred at 60°C for 3h, and then cooled to 20°C, and then the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl] benzene sulfonamide potassium salt is added thereto, and stirred at 65°C for 3h to obtain a bosentan precursor;

[0075] The bosentan precursor is subjected to product post-treatment:

[0076] (a) cooling the reaction solution after the reaction to 10°C, evaporating the tetrahydrofuran in the reaction solution, and adjusting the pH value to 3 with hydrochloric acid; then adding water thereto, and stirring at 0°C for 1h, and then obtaining a fourth filter cake through crystallization, filtration, and washing;

[0077] (b) dissolving the fourth filter cake in a mixed solution of acetonitrile and methanol at 70°C, and then cooling to 15°C at a speed of 10°C / h, and then crystallizing at 0°C for 1h, and then obtaining a fifth filter cake through filtration and washing;

[0078] (c) repeating step (b) once to obtain a recrystallized filter cake, and then drying to obtain a bosentan precursor;

[0079] It should be noted that in step (a), the amount of water is not unique, in this embodiment, the amount of water is 2 times the volume of the tetrahydrofuran. The washing is carried out with 1 times the volume of the tetrahydrofuran. The skilled person can adjust the amount of water according to the situation.

[0080] In step (b) of this embodiment, the volume ratio of acetonitrile to methanol in the mixture of acetonitrile and methanol is 1:1; the volume ratio of the mixture of acetonitrile and methanol to the fourth filter cake is 1:1; the washing is carried out with methanol, and the volume ratio of the methanol used for washing to the mixture of acetonitrile and methanol is 1:2.

[0081] (4) The bosentan precursor obtained in step (3) is mixed with ethanol and water, and reacted at 65°C for 40 min, cooled and crystallized to obtain bosentan.

[0082] As a specific implementation of this embodiment, step (4) is as follows:

[0083] The bosentan precursor, ethanol and water are taken in a molar ratio of 1:12:15, the bosentan precursor is mixed with ethanol, stirred at 65°C for 30 min, then water is added at a speed of 200 ml / min to obtain a mixture; the mixture is stirred and reacted at 65°C for 40 min, then stirred at 10°C for 6 h, filtered and dried to obtain bosentan.

[0084] Example 2

[0085] The preparation method of bosentan in this embodiment comprises the following steps:

[0086] (1) 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6(1H,5H)-dione and phosphorus oxychloride are taken in a molar ratio of 1:3, the 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6(1H,5H)-dione is added to the phosphorus oxychloride at 0°C for mixing; then reacted at 116°C for 5 h to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine;

[0087] The obtained 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine is subjected to product post-treatment:

[0088] The reaction solution after reaction is cooled to 0°C, and an ice-water mixture with a volume ratio of ice to water of 1:1 is added at a speed of 50 ml / min to quench the remaining phosphorus oxychloride, then stirred at -10°C for 20 min, filtered and washed with water to obtain a first filter cake;

[0089] The first filter cake obtained is slurried with water, and the pH value of the mixture is adjusted to 6.0 with a saturated sodium carbonate solution, and then filtered, washed with water, and dried to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine.

[0090] (2) The 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine obtained in step (1) is mixed with 4-tert-butylbenzenesulfonamide, an acid-binding agent, and a polar aprotic solvent, and reacted at 125°C for 8h to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt;

[0091] As a specific implementation manner of the embodiment, step (2) is specifically as follows:

[0092] The 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine, 4-tert-butylbenzenesulfonamide, an acid-binding agent, and a polar aprotic solvent are taken in a molar ratio of 1:1.2:4:10; wherein the acid-binding agent is potassium carbonate; and the polar aprotic solvent is acetone.

[0093] The 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine, 4-tert-butylbenzenesulfonamide, and a polar aprotic solvent are first mixed, and then the acid-binding agent is added in 6 portions at an interval of 1h, and then reacted at 115-125°C for 6h to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt;

[0094] The product obtained is post-treated to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt.

[0095] The reaction solution after reaction is cooled to 10°C, filtered to obtain a second filter cake; the second filter cake obtained is slurried with the polar aprotic solvent, and then filtered, washed, and dried to obtain a third filter cake; the third filter cake obtained is slurried with water, and then filtered, washed, and dried to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt.

[0096] (3) The 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt obtained in step (2) is mixed with ethylene glycol, an alkali metal hydroxide, and tetrahydrofuran, and reacted at 75°C for 1h to obtain a bosentan precursor.

[0097] As a specific implementation manner of the embodiment, step (3) is specifically as follows:

[0098] The 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt, ethylene glycol, alkali hydroxide, and tetrahydrofuran are taken in a molar ratio of 1:100:25:7; the alkali hydroxide is sodium hydroxide;

[0099] The ethylene glycol and the tetrahydrofuran are mixed first, and then the alkali hydroxide is added thereto, and stirred at 70°C for 1 h, and then cooled to 10°C, and the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt is added thereto, and stirred at 75°C for 1 h to obtain the bosentan precursor;

[0100] The bosentan precursor is subjected to product post-treatment:

[0101] (a) The reaction solution after reaction is cooled to 20°C, and the tetrahydrofuran in the reaction solution is evaporated, and the pH value is adjusted to 3 by using hydrochloric acid; water is added thereto, and stirred at -5°C for 0.5 h, and then subjected to crystallization, filtration, and washing to obtain a fourth filter cake;

[0102] (b) The fourth filter cake is dissolved in a mixed solution of acetonitrile and methanol at 90°C, and then cooled to 20°C at a speed of 10°C / h, and then subjected to crystallization at 5°C for 0.5 h, and then subjected to filtration and washing to obtain a fifth filter cake;

[0103] (c) Step (b) is repeated 4 times to obtain a recrystallized filter cake, which is dried to obtain the bosentan precursor;

[0104] It should be noted that the amount of water used in step (a) is not unique, and in this embodiment, the amount of water used is 2 times the volume of the tetrahydrofuran. The washing is performed by using water in an amount of 1 times the volume of the tetrahydrofuran. The amount of water used can be adjusted by a person skilled in the art according to the situation.

[0105] In step (b) of this embodiment, the volume ratio of acetonitrile to methanol in the mixed solution of acetonitrile and methanol is 1:1; the volume ratio of the mixed solution of acetonitrile and methanol to the fourth filter cake is 1:3; the washing is performed by using methanol, and the volume ratio of the methanol used to the mixed solution of acetonitrile and methanol is 1:1.

[0106] (4) The bosentan precursor obtained in step (3) is mixed with ethanol and water, and reacted at 60°C for 20 min, and then cooled and crystallized to obtain bosentan.

[0107] As a specific implementation manner of this embodiment, step (4) is specifically as follows:

[0108] The bosentan precursor, ethanol and water are taken in a molar ratio of 1:15:8, the bosentan precursor is mixed with ethanol, stirred at 70°C for 20 min, water is added thereto at a speed of 200 ml / min to obtain a mixed solution; the mixed solution is stirred and reacted at 60°C for 20 min, then stirred at 20°C for 12 h, filtered, dried to obtain bosentan.

[0109] Example 3

[0110] The method for preparing bosentan of the present example comprises the following steps:

[0111] (1) The 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6(1H,5H)-dione and phosphorus oxychloride are taken in a molar ratio of 1:5, the 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6(1H,5H)-dione is added to the phosphorus oxychloride at -5°C for mixing; then reacted at 112°C for 4 h to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine;

[0112] The obtained 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine is subjected to product post-treatment:

[0113] The reaction solution after reaction is cooled to -5°C, an ice-water mixture with a volume ratio of ice to water of 1:5 is added thereto at a speed of 50 ml / min to quench the residual phosphorus oxychloride, then stirred at 0°C for 30 min, filtered, washed with water to obtain a first filter cake;

[0114] The obtained first filter cake is added with water for beating, and a saturated sodium carbonate solution is used to adjust the pH value of the mixed solution to 8.0, then filtered, washed with water, dried to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine.

[0115] (2) The 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine obtained in step (1) is mixed with 4-tert-butylbenzenesulfonamide, an acid binding agent and a polar aprotic solvent, reacted at 120°C for 4 h to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt;

[0116] As a specific implementation manner of the present example, step (2) is specifically as follows:

[0117] The 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine, 4-tert-butylbenzenesulfonamide, an acid binding agent and a polar aprotic solvent are taken in a molar ratio of 1:1:3:12; wherein the acid binding agent is sodium carbonate; the polar aprotic solvent is dimethylformamide.

[0118] First, 4, 6-dichloro-5- (2-methoxyphenoxy) -2, 2'-pyrimidine is mixed with 4-tert-butyl phenyl sulfonamide and a polar aprotic solvent, then 120 °C is added twice with an acid binding agent, each interval of 1 hour, then, at 115-125 °C for 6h, to obtain 4-tert-butyl-N-[6-chloro-5- (2-methoxyphenoxy) -4-pyrimidyl] potassium salt of phenyl sulfonamide;

[0119] The obtained 4-tert-butyl-N-[6-chloro-5- (2-methoxyphenoxy) -4-pyrimidyl] potassium salt of phenyl sulfonamide is subjected to product post-processing:

[0120] The reaction solution after reaction is cooled to 30 °C, filtered to obtain a second filter cake; the obtained second filter cake is added with the polar aprotic solvent for beating, then filtered, washed and dried to obtain a third filter cake; the obtained third filter cake is added with water for beating, then filtered, washed and dried to obtain 4-tert-butyl-N-[6-chloro-5- (2-methoxyphenoxy) -4-pyrimidyl] potassium salt of phenyl sulfonamide.

[0121] (3) The 4-tert-butyl-N-[6-chloro-5- (2-methoxyphenoxy) -4-pyrimidyl] potassium salt of phenyl sulfonamide obtained in step (2) is mixed with ethylene glycol, alkali metal hydroxide and tetrahydrofuran, and reacted at 65 °C for 3h to obtain a bosentan precursor.

[0122] As a specific implementation manner of the embodiment, step (3) is specifically as follows:

[0123] The 4-tert-butyl-N-[6-chloro-5- (2-methoxyphenoxy) -4-pyrimidyl] potassium salt of phenyl sulfonamide, ethylene glycol, alkali metal hydroxide and tetrahydrofuran are taken in a molar ratio of 1:110:15:8; wherein the alkali metal hydroxide is lithium hydroxide.

[0124] First, the ethylene glycol is mixed with the tetrahydrofuran, then the alkali metal hydroxide is added thereto, stirred at 65 °C for 2h, then cooled to 30 °C, and the 4-tert-butyl-N-[6-chloro-5- (2-methoxyphenoxy) -4-pyrimidyl] potassium salt of phenyl sulfonamide is added thereto, stirred at 65 °C for 3h to obtain a bosentan precursor.

[0125] The bosentan precursor is subjected to product post-processing:

[0126] (a) The reaction solution after reaction is cooled to 30 °C, and the tetrahydrofuran in the reaction solution is evaporated, and the pH value is adjusted to 2 with hydrochloric acid; water is added thereto, stirred at -10 °C for 1h, and a fourth filter cake is obtained by crystallization, filtration and washing;

[0127] (b) dissolving the fourth filter cake in a mixture of acetonitrile and methanol at 80°C, cooling to 35°C at a rate of 10°C / h, and then crystallizing at -5°C for 1 h, and then filtering and washing to obtain a fifth filter cake;

[0128] (c) repeating step (b) twice to obtain a recrystallized filter cake, and then drying to obtain the bosentan precursor;

[0129] It should be noted that the amount of water used in step (a) is not unique, and in this embodiment, the amount of water used is 2 times the volume of the tetrahydrofuran. The washing is performed using water in an amount of 1 times the volume of the tetrahydrofuran. The amount of water can be adjusted by a person skilled in the art according to the situation.

[0130] In step (b) of this embodiment, the volume ratio of acetonitrile to methanol in the mixture of acetonitrile and methanol is 1:1; the volume ratio of the mixture of acetonitrile and methanol to the fourth filter cake is 1:2; and the washing is performed using methanol, and the volume ratio of the methanol used to the mixture of acetonitrile and methanol is 1:3.

[0131] (4) mixing the bosentan precursor obtained in step (3) with ethanol and water, and reacting at 70°C for 40 min, and then cooling and crystallizing to obtain bosentan.

[0132] As a specific implementation of this embodiment, step (4) is as follows:

[0133] The bosentan precursor, ethanol, and water are taken in a molar ratio of 1:8:12, the bosentan precursor is mixed with ethanol, stirred at 60°C for 40 min, and then water is added thereto at a rate of 200 ml / min to obtain a mixture; the mixture is stirred at 65°C for 30 min, and then stirred at 15°C for 8 h, and then filtered and dried to obtain bosentan.

[0134] Example 4

[0135] The preparation method of bosentan in this embodiment, as shown in Figure 1 , comprises the following steps:

[0136] (1) mixing phosphorus oxychloride and 5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4,6(1H,5H)-dione at -5°C, and then reacting at 110°C for 6 h to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin;

[0137] As a specific implementation of this embodiment, step (1) is as follows:

[0138] Mix 5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4,6(1H,5H)-dione with phosphorus oxychloride in a molar ratio of 1:4, add the 5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4,6(1H,5H)-dione to the phosphorus oxychloride at -5°C; then react at 110°C for 6h to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin;

[0139] Perform product post-treatment on the obtained 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin:

[0140] Cool the reacted reaction solution to -5°C, and add an ice-water mixture with a volume ratio of ice to water of 1:3 to quench the residual phosphorus oxychloride at a speed of 50ml / min, then stir at -5°C for 20min, filter, wash with water, and obtain a first filter cake;

[0141] Add water to the obtained first filter cake to perform beating, and use a saturated sodium carbonate solution to adjust the pH value of the mixture to 7.0, then filter, wash with water, and dry to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin.

[0142] It should be noted that the water amount used for beating, the water amount used for washing, and the number of washing times are not unique, and a person skilled in the art can adjust them within a certain range according to the actual situation. The water amount used for beating includes but is not limited to 0.2-0.6 times the volume of the filter cake; the water washing includes but is not limited to washing 1-3 times with 0.2-0.6 times the volume of the filter cake. In this embodiment, the water amount used for beating is 0.6 times the volume of the filter cake; the water washing is washing 3 times with 0.6 times the volume of the filter cake.

[0143] In this embodiment, the 5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4,6(1H,5H)-dione is mixed with the phosphorus oxychloride under low-temperature conditions of -10°C-0°C, which can be achieved by using an ice-water bath, an ice-salt bath, or other low-temperature means. Similarly, the low-temperature conditions in other steps can also be achieved by using an ice-water bath, an ice-salt bath, or other low-temperature means.

[0144] In this embodiment, the amount of the ice-water mixture used for quenching the residual phosphorus oxychloride can be determined by whether the reaction solution no longer generates heat with the addition of the ice-water mixture under stirring.

[0145] (2) mixing 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine obtained in step (1) with 4-tert-butylbenzenesulfonamide, an acid binding agent and a polar aprotic solvent, and reacting at 120°C for 6h to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt;

[0146] As a specific implementation of the present embodiment, step (2) is specifically as follows:

[0147] The 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine, the 4-tert-butylbenzenesulfonamide, the acid binding agent and the polar aprotic solvent are taken in a molar ratio of 1:1.1:4:10; wherein the acid binding agent is sodium hydroxide; and the polar aprotic solvent is dimethyl sulfoxide.

[0148] First, the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine is mixed with the 4-tert-butylbenzenesulfonamide and the polar aprotic solvent, and then the acid binding agent is added in 4 portions at 120°C with an interval of 1h, and then reacted at 120°C for 6h to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt;

[0149] The obtained 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt is subjected to product post-treatment:

[0150] The reaction liquid after reaction is cooled to 20°C, filtered to obtain a second filter cake; the obtained second filter cake is added with the polar aprotic solvent for beating, and then filtered, washed and dried to obtain a third filter cake; the obtained third filter cake is added with water for beating, and then filtered, washed and dried to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt.

[0151] It should be noted that the solution used for washing, the amount of solution, the number of washing times, and the amount of solution for beating are not unique, and those skilled in the art can adjust them within a certain range according to the actual situation. In the present embodiment, the washing is performed by using 6 times the volume of the filter cake of the polar aprotic solvent for 3 times, and 6 times the volume of the filter cake of water for 3 times. The amount of the polar aprotic solvent used for beating is 6 times the volume of the filter cake; and the amount of water used for beating is 6 times the volume of the filter cake.

[0152] (3) mixing the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl] benzenesulfonamide potassium salt obtained in step (2) with ethylene glycol, alkali metal hydroxide, and tetrahydrofuran, and reacting at 65°C for 3h to obtain a bosentan precursor;

[0153] As a specific implementation of the present embodiment, step (3) is specifically as follows:

[0154] The 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl] benzenesulfonamide potassium salt, ethylene glycol, alkali metal hydroxide, and tetrahydrofuran are taken in a molar ratio of 1:100:20:6; wherein the alkali metal hydroxide is sodium hydroxide;

[0155] The ethylene glycol and the tetrahydrofuran are first mixed, and then the alkali metal hydroxide is added thereto, and stirred at 65°C for 2h, and then cooled to 20°C, and then the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl] benzenesulfonamide potassium salt is added thereto, and stirred at 65°C for 3h to obtain a bosentan precursor;

[0156] The bosentan precursor is subjected to product post-treatment:

[0157] (a) cooling the reaction solution after reaction to 20°C, evaporating the tetrahydrofuran in the reaction solution, and adjusting the pH value to 2-3 with hydrochloric acid; adding water thereto, and stirring at -5°C for 1h, and then subjecting to crystallization, filtration, and washing to obtain a fourth filter cake;

[0158] (b) dissolving the fourth filter cake in a mixed solution of acetonitrile and methanol at 80°C, and then cooling to 20°C at a speed of 10°C / h, and then subjecting to crystallization at -5°C for 1h, and then subjecting to filtration and washing to obtain a fifth filter cake;

[0159] (c) repeating step (b) for 3 times to obtain a recrystallized filter cake, and then drying to obtain a bosentan precursor;

[0160] It should be noted that in step (a), the amount of water is not unique, and in the present embodiment, the amount of water is 2 times the volume of the tetrahydrofuran. The washing is performed with water in an amount of 1 times the volume of the tetrahydrofuran. The amount of water can be adjusted by those skilled in the art according to the situation.

[0161] In step (b) of the present embodiment, the volume ratio of acetonitrile to methanol in the mixed solution of acetonitrile and methanol is 1:1; the volume ratio of the mixed solution of acetonitrile and methanol to the fourth filter cake is 1:2; the washing is performed with methanol, and the volume ratio of the methanol used for washing to the mixed solution of acetonitrile and methanol is 1:2.

[0162] (4) The bosentan precursor obtained in step (3) is mixed with ethanol and water, and reacted at 65°C for 30 min, and then cooled to crystallize to obtain bosentan.

[0163] As a specific implementation of the present embodiment, step (4) is specifically as follows:

[0164] The bosentan precursor, ethanol and water are taken in a molar ratio of 1:10:10, the bosentan precursor is mixed with ethanol, stirred at 65°C for 30 min, and then water is added thereto at a speed of 200 ml / min to obtain a mixed solution; the mixed solution is stirred at 65°C for 30 min, and then stirred at 15°C for 8 h, and then filtered and dried to obtain bosentan.

[0165] Comparative Example 1

[0166] The preparation method of bosentan in the present comparative example is the same as that in Example 4, except that in step (1), the phosphorus oxychloride is mixed with 5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4,6(1H,5H)-dione at room temperature, and then reacted at 110°C for 6 h.

[0167] Comparative Example 2

[0168] The preparation method of bosentan in the present comparative example is the same as that in Example 4, except that in step (1), the step of post-treatment of the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine product after reaction is not included.

[0169] Comparative Example 3

[0170] The preparation method of bosentan in the present comparative example is the same as that in Example 4, except that in step (1), the ice-water mixture is not added after reaction to quench the residual phosphorus oxychloride.

[0171] Comparative Example 4

[0172] The preparation method of bosentan in the present comparative example is the same as that in Example 4, except that in step (1), the ice-water mixture is added at a speed of 100 ml / min after reaction to quench the residual phosphorus oxychloride.

[0173] Comparative Example 5

[0174] The preparation method of bosentan in the present comparative example is the same as that in Example 4, except that in step (2), the deacidifying agent is added once.

[0175] Comparative Example 6

[0176] The preparation method of bosentan in the present comparative example is the same as that in Example 4, except that in step (3), the step of carrying out the post-treatment of the bosentan precursor product after the reaction is not included.

[0177] Comparative Example 7

[0178] The preparation method of bosentan in the present comparative example is the same as that in Example 4, except that step (3) is different.

[0179] Step (3) is: mixing the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl] benzenesulfonamide potassium salt obtained in step (2) with ethylene glycol, alkali metal hydroxide, and tetrahydrofuran, and reacting at 65°C for 5h to obtain a bosentan precursor.

[0180] Comparative Example 8

[0181] The preparation method of bosentan in the present comparative example is the same as that in Example 4, except that in step (3), the step of carrying out the post-treatment of the bosentan precursor product after the reaction is not included.

[0182] Comparative Example 9

[0183] The preparation method of bosentan in the present comparative example is the same as that in Example 4, except that in step (3), the step of carrying out the post-treatment of the bosentan precursor product after the reaction is not included.

[0184] Specifically, in step (b), the mixture of acetonitrile and methanol is replaced by acetonitrile.

[0185] Comparative Example 10

[0186] The preparation method of bosentan in the present comparative example is the same as that in Example 4, except that in step (3), the step of carrying out the post-treatment of the bosentan precursor product after the reaction is not included.

[0187] Specifically, in step (b), the mixture of acetonitrile and methanol is replaced by methanol.

[0188] Effect Experimental Example

[0189] In order to verify the technical effect of the preparation method of bosentan according to the present application, the following test was carried out:

[0190] The bosentan is prepared according to the method in the embodiments and the comparative examples, and the purity of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine in step (1) is determined by using a high performance liquid chromatograph (HPLC), which is recorded as the purity of product 1; the purity of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl] benzenesulfonamide potassium salt in step (2) is determined, which is recorded as the purity of product 2; the purity of the bosentan precursor in step (3) is determined, which is recorded as the purity of product 3; the purity of the bosentan in step (4) is determined, which is recorded as the purity of product 4; and the yield of products 1-4 is calculated respectively.

[0191] Through experiments, the results are as follows:

[0192]

[0193] According to the above results, it can be known that the preparation method of the bosentan can greatly save reaction time, improve reaction yield, reduce impurity content, simplify post-treatment operation, reduce preparation cost, and is convenient for industrial large-scale production and application.

[0194] It can be known from common technical knowledge that the present application can be realized by other embodiments without departing from the spirit or essential characteristics thereof. Therefore, the above disclosed embodiments are only illustrative in all aspects, and are not the only ones. All changes within the scope of the present application or within the scope equivalent to the present application are included in the present application.

Claims

1. A method for preparing bosentan, characterized in that, Includes the following steps: (1) At -10℃ to 0℃, phosphorus oxychloride was mixed with 5-(2-methoxyphenoxy)-[2,2'-diamyrimidine]-4,6(1H,5H)-dione and then reacted at 106-116℃ for 4-8h to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-diamyrimidine; (2) First, mix the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-diamyrimidine obtained in step (1) with 4-tert-butylbenzenesulfonamide and a polar aprotic solvent, and then add the acid-binding agent in 2-6 portions at 115-125℃, with an interval of 1 hour each time. Then, react at 115-125℃ for 4-8 hours to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt; (3) The potassium salt of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide obtained in step (2) is mixed with ethylene glycol, alkali metal hydroxide and tetrahydrofuran, and reacted at 55-75℃ for 1-3 h to obtain the bosentan precursor; (4) The bosentan precursor obtained in step (3) is mixed with ethanol and water, reacted at 60-70℃ for 20-40 min, cooled and crystallized to obtain bosentan; Step (1) also includes a post-treatment step of the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-diamyrimidine product after the reaction: The reaction solution was cooled to -10℃ to 0℃, and an ice-water mixture was added to quench the remaining phosphorus oxychloride at a rate of 50 ml / min. The mixture was then stirred at -10℃ to 0℃ for 10-30 min, filtered, and the first filter cake was obtained. Water was added to the first filter cake to make a slurry, and the pH of the mixture was adjusted to 6.0-8.0 using sodium carbonate solution. After filtration and drying, 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-diamyrimidine was obtained.

2. The method for preparing bosentan according to claim 1, characterized in that, In the ice-water mixture, the volume ratio of ice to water is 1:(1-5). The sodium carbonate solution is a saturated sodium carbonate solution.

3. The method for preparing bosentan according to claim 1, characterized in that, In step (1), the molar ratio of 5-(2-methoxyphenoxy)-[2,2'-diamyrimidine]-4,6(1H,5H)-dione to phosphorus oxychloride is 1:(3-5). In step (1), 5-(2-methoxyphenoxy)-[2,2'-diamyrimidine]-4,6(1H,5H)-dione is added to phosphorus oxychloride and mixed.

4. The method for preparing bosentan according to claim 1, characterized in that, In step (2), the acid-binding agent is one or more of sodium carbonate, potassium carbonate, and sodium hydroxide; The polar aprotic solvent is one or more of acetonitrile, acetone, dimethylformamide, and dimethyl sulfoxide; The molar ratio of the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-diamyrimidine to 4-tert-butylbenzenesulfonamide, the acid-binding agent, and the polar aprotic solvent is 1:(1-1.2):(3-5):(8-12).

5. The method for preparing bosentan according to claim 1, characterized in that, Step (2) also includes a post-treatment step of the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt product after the reaction: The reaction solution was cooled to 10-30℃ and filtered to obtain a second filter cake. The polar aprotic solvent was added to the second filter cake and slurried. After filtration, washing and drying, a third filter cake was obtained. Water was added to the third filter cake and slurried. After filtration, washing and drying, 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt was obtained.

6. The method for preparing bosentan according to claim 1, characterized in that, In step (3), the alkali metal hydroxide is one or more of lithium hydroxide, sodium hydroxide, and potassium hydroxide.

7. The method for preparing bosentan according to claim 1, characterized in that, Step (3) specifically includes the following steps: First, the ethylene glycol and the tetrahydrofuran are mixed, then an alkali metal hydroxide is added, and the mixture is stirred at 60-70°C for 1-3 hours. Then, the mixture is cooled to 10-30°C, and 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt is added. The mixture is stirred at 60-70°C for 2-4 hours to obtain the bosentan precursor.

8. The method for preparing bosentan according to claim 7, characterized in that, Step (3) also includes a post-processing step of the bosentan precursor product after the reaction: (a) Cool the reaction solution to 10-30℃, remove tetrahydrofuran from the reaction solution by evaporation, and adjust the pH value to 2-3 with hydrochloric acid; add water to it, stir at -10℃-0℃ for 0.5-1h, and obtain the fourth filter cake by crystallization, filtration and washing. (b) The fourth filter cake is dissolved in a mixture of acetonitrile and methanol at 70-90°C, then cooled to 15-35°C at a rate of 10°C / h, and then placed at -5-5°C for 0.5-1h to crystallize. After filtration and washing, the fifth filter cake is obtained. (c) Repeat step (b) 1-4 times to obtain recrystallized filter cake, which is then dried to obtain bosentan precursor; In step (b), the volume ratio of acetonitrile to methanol in the mixture of acetonitrile and methanol is 1:

1. In step (b), the washing is performed using methanol, and the volume ratio of the methanol to the mixture of acetonitrile and methanol used for washing is 1:(1-3).

9. The method for preparing bosentan according to claim 1, characterized in that, Step (4) specifically includes the following steps: The bosentan precursor obtained in step (3) is mixed with ethanol and stirred at 60-70℃ for 20-40 min. Water is then added to the mixture at a rate of 200 ml / min to obtain a mixture. The mixture is stirred at 60-70℃ for 20-40 min and then stirred at 10-20℃ for 6-12 h. After filtration and drying, bosentan is obtained. The volume ratio of the bosentan precursor, ethanol, and water is 1:(8-15):(8-15).

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