Preparation method of bosentan

Abstract

The present invention provides a bosentan preparation method, which comprises: mixing phosphorus oxychloride and 5-(2-methoxyphenoxy)-[2, 2 '-dipyrimidine]-4, 6 (1H, 5H)-diketone, and carrying out a reaction to obtain 4, 6-dichloro-5-(2-methoxyphenoxy)-2, 2'-dipyrimidine, and carrying out a reaction to obtain 4, 6-dichloro-5-(2-methoxyphenoxy)-2, 2 '-dipyrimidine, mixing the N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidyl] benzenesulfonamide with 4-tert-butyl benzenesulfonamide, an acid-binding agent and a polar aprotic solvent, and carrying out a reaction to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidyl] benzenesulfonamide potassium salt; then mixing the bosentan precursor with ethylene glycol, alkali metal hydroxide and tetrahydrofuran to obtain a bosentan precursor; and finally, mixing with ethanol and water, reacting, cooling and crystallizing to obtain bosentan. According to the preparation method of bosentan, the reaction time can be greatly saved, the reaction yield can be improved, the impurity content can be reduced, the post-treatment operation can be simplified, the preparation cost can be reduced, and industrial large-scale production and application can be facilitated.

Description

Technical Field

[0001] The present invention relates to pharmaceutical chemistry technology, in particular to a preparation method of bosentan. Background Art

[0002] Bosentan is a dual ET (ETA / ETB) receptor antagonist, suitable for the treatment of pulmonary hypertension in patients with WHO stage III and IV primary pulmonary hypertension, or pulmonary hypertension caused by scleroderma. The main ingredient of Bosentan is: 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methyl-phenoxy)-[2,2']dipyrimidin-4-yl]benzenesulfonamide-hydrate, and its chemical structure is:

[0003] At present, there are many process synthesis routes for bosentan, but most of the reactions involved have problems such as long reaction time, complex post-processing, low yield of reaction products and high impurity content, which greatly limits the industrial production and market supply of bosentan.

[0004] In view of this, it is urgent to propose a preparation method of bosentan with short reaction time, simple post-treatment, high reaction product yield and less impurities. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing bosentan, so as to solve the problems of long synthesis reaction time, complex post-treatment, low yield of reaction product and high impurity content of bosentan in the prior art.

[0006] In order to solve the above technical problems, the technical solution of the present invention is as follows: A method for preparing bosentan comprises the following steps: (1) Phosphorus oxychloride and 5-(2-methoxyphenoxy)-[2,2'-dipyrimidine]-4,6(1H,5H)-dione are mixed at -10°C to 0°C, and then reacted at 106-116°C for 4-8 hours to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine; (2) Mixing the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine obtained in step (1) with 4-tert-butylbenzenesulfonamide, an acid-binding agent and a polar aprotic solvent, and reacting at 115-125° C. for 4-8 hours to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt; (3) mixing the potassium salt of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide obtained in step (2) with ethylene glycol, an alkali metal hydroxide and tetrahydrofuran, and reacting at 55-75° C. for 1-3 hours to obtain a bosentan precursor; (4) Mixing the bosentan precursor obtained in step (3) with ethanol and water, reacting at 60-70° C. for 20-40 min, cooling and crystallizing to obtain bosentan.

[0007] Preferably, step (1) further comprises the step of post-treating the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine product after the reaction: The reaction solution after the reaction was cooled to -10°C-0°C, and an ice-water mixture was added thereto at a rate of 50 ml / min to quench the remaining phosphorus oxychloride, and then stirred at -10°C-0°C for 10-30 minutes, and filtered to obtain a first filter cake; Water is added to the obtained first filter cake for slurrying, and the pH value of the mixed solution is adjusted to 6.0-8.0 with a sodium carbonate solution, and then filtered and dried to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine.

[0008] Preferably, the method for preparing bosentan further comprises the step of washing 1-3 times with water of 0.2-0.6 times the volume of the filter cake after the filtration; Optionally, in the ice-water mixture, the volume ratio of ice to water is 1:(1-5); Optionally, the amount of water used for beating is 0.2-0.6 times the volume of the filter cake; Optionally, the sodium carbonate solution is a saturated sodium carbonate solution.

[0009] Preferably, in step (1), the molar ratio of the 5-(2-methoxyphenoxy)-[2,2'-dipyrimidine]-4,6(1H,5H)-dione to the phosphorus oxychloride is 1:(3-5); Optionally, in step (1), the 5-(2-methoxyphenoxy)-[2,2'-dipyrimidine]-4,6(1H,5H)-dione is added to the phosphorus oxychloride and mixed.

[0010] Preferably, in step (2), the acid binding agent is one or more of sodium carbonate, potassium carbonate and sodium hydroxide; Optionally, the polar aprotic solvent is one or more of acetonitrile, acetone, dimethylformamide, and dimethyl sulfoxide; Optionally, the molar ratio of the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine to 4-tert-butylbenzenesulfonamide, the acid-binding agent and the polar aprotic solvent is 1:(1-1.2):(3-5):(8-12).

[0011] Preferably, step (2) specifically includes the following steps: First, 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine is mixed with 4-tert-butylbenzenesulfonamide and a polar aprotic solvent, and then an acid-binding agent is added at 115-125°C in 2-6 times, each time with an interval of 1 hour, and then the mixture is reacted at 115-125°C for 4-8 hours to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt; Optionally, step (2) further comprises the step of post-treating the product of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt after the reaction: The reaction liquid after the reaction is cooled to 10-30° C. and filtered to obtain a second filter cake; the polar aprotic solvent is added to the obtained second filter cake for slurrying, and then filtered, washed, and dried to obtain a third filter cake; water is added to the obtained third filter cake for slurrying, and then filtered, washed, and dried to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt.

[0012] Preferably, in step (2), the washing is performed by washing with a polar aprotic solvent of 2-8 times the volume of the filter cake for 1-3 times; and / or washing with water of 2-8 times the volume of the filter cake for 1-3 times; Optionally, the amount of the polar aprotic solvent added to the slurry is 2-8 times the volume of the filter cake; Optionally, the amount of water added for slurrying is 2-8 times the volume of the filter cake.

[0013] 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; Optionally, the volume ratio of the potassium salt of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide to ethylene glycol, alkali metal hydroxide and tetrahydrofuran is 1:(90-110):(15-25):(6-8).

[0014] Preferably, step (3) specifically includes the following steps: First, the ethylene glycol and the tetrahydrofuran are mixed, and then an alkali metal hydroxide is added thereto, and the mixture is stirred at 60-70° C. for 1-3 hours, and then the temperature is lowered to 10-30° C., and 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 reaction for 2-4 hours to obtain a bosentan precursor; Optionally, step (3) further comprises the step of post-treatment of the bosentan precursor product after the reaction: (a) cooling the reaction liquid to 10-30° C., removing tetrahydrofuran from the reaction liquid by evaporation, and adjusting the pH value to 2-3 with hydrochloric acid; adding water thereto, stirring at -10° C. to 0° C. for 0.5-1 h, and obtaining a fourth filter cake by crystallization, filtering, and washing; (b) dissolving the fourth filter cake in a mixture of acetonitrile and methanol at 70-90° C., cooling the mixture to 15-35° C. at a rate of 10° C. / h, and then placing the mixture at -5-5° C. for crystallization for 0.5-1 h, filtering and washing the mixture to obtain a fifth filter cake; (c) repeating step (b) 1-4 times to obtain a recrystallized filter cake, which is then dried to obtain a bosentan precursor; Optionally, in step (b), in the mixture of acetonitrile and methanol, the volume ratio of acetonitrile to methanol is 1:1; Optionally, in step (b), the volume ratio of the mixture of acetonitrile and methanol to the fourth filter cake is 1:(1-3); Optionally, in step (b), the washing is performed using methanol, and the volume ratio of the methanol used for washing to the mixed solution of acetonitrile and methanol is 1:(1-3).

[0015] Preferably, step (4) specifically includes the following steps: The bosentan precursor obtained in step (3) is mixed with ethanol, stirred at 60-70° C. for 20-40 min, and then water is added thereto at a rate of 200 ml / min to obtain a mixed solution; the mixed solution is stirred at 60-70° C. for 20-40 min, and then stirred at 10-20° C. for 6-12 h, filtered, and dried to obtain bosentan; Optionally, the volume ratio of the bosentan precursor, ethanol and water is 1:(8-15):(8-15).

[0016] The above solution of the present invention includes at least the following beneficial effects: (1) The method for preparing bosentan of the present invention can greatly save reaction time, improve reaction yield, reduce impurity content, simplify post-processing operations, reduce preparation costs, and facilitate industrial large-scale production and application.

[0017] In step (1), the side reactions are reduced by feeding at low temperature, and the reaction temperature is set to 106-116°C so that phosphorus oxychloride is above the boiling point. No solvent is added, and phosphorus oxychloride can directly react with 5-(2-methoxyphenoxy)-[2,2'-dipyrimidine]-4,6(1H,5H)-dione. The reaction can almost achieve quantitative reaction with a yield of more than 98%. (2) The method for preparing bosentan of the present invention further comprises, in step (1), a step of post-treating the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine product after the reaction. This step can effectively remove the excess phosphorus oxychloride that does not participate in the synthesis reaction, reduce impurities and the influence of impurities on subsequent reactions, and make the purity of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine reach more than 99%.

[0018] (3) In the method for preparing bosentan of the present invention, by quantitatively adding the acid-binding agent in batches in step (2), the reaction efficiency can be improved, the reaction time can be shortened, and the yield of the reaction product can be increased. The product post-treatment step in step (2) is simple to operate and can greatly improve the purity of the product.

[0019] (4) In the method for preparing bosentan of the present invention, the reaction time of step (3) is short and the yield is high. The product post-treatment step in step (3) is simple to operate and can greatly improve the purity of the product.

[0020] (5) In the method for preparing bosentan of the present invention, in step (4), ethanol and water are used to react with the bosentan precursor, and the speed of adding water is controlled, thereby improving the yield of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is a synthetic route diagram of the preparation method of bosentan prepared in Experimental Example 1 of the present invention. DETAILED DESCRIPTION

[0022] In the embodiments of the present invention, if the specific conditions are not specified, the conventional conditions or the conditions recommended by the manufacturer are followed. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially. Raw materials of different manufacturers and models do not affect the implementation of the technical solution of the present invention and the realization of the technical effects.

[0023] Example 1 The preparation method of Bosentan in this embodiment comprises the following steps: (1) taking 5-(2-methoxyphenoxy)-[2,2'-dipyrimidine]-4,6(1H,5H)-dione and phosphorus oxychloride at a molar ratio of 1:4, adding the 5-(2-methoxyphenoxy)-[2,2'-dipyrimidine]-4,6(1H,5H)-dione to the phosphorus oxychloride at -10°C and mixing them; then reacting at 106°C for 6 hours to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine; The obtained 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine is post-treated as follows: The reaction solution was cooled to -10°C, and an ice-water mixture with a volume ratio of ice to water of 1:4 was added thereto at a rate of 50 ml / min to quench the remaining phosphorus oxychloride, and then stirred at -5°C for 10 minutes, filtered, and washed with water to obtain a first filter cake; Water was added to the obtained first filter cake for slurrying, and a saturated sodium carbonate solution was used to adjust the pH value of the mixed solution to 7.0, and then the mixture was filtered, washed with water, and dried to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine.

[0024] It should be noted that the amount of water used for pulping, the amount of water used for washing and the number of washing times are not unique, and those skilled in the art can make adjustments within a certain range according to actual conditions. The amount of water used for pulping includes but is not limited to 0.2-0.6 times the volume of the filter cake; the washing with water 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, which will not be repeated below).

[0025] In this embodiment, under the low temperature condition of -10°C to 0°C, the 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6(1H,5H)-dione is added to the phosphorus oxychloride for mixing, which can be achieved by ice water bath, ice salt bath, or other low temperature means. Similarly, the low temperature conditions in other embodiments or other steps can also be achieved by low temperature means such as ice water bath, ice salt bath, etc. (the same below, which will not be repeated in the following text).

[0026] In this embodiment, the amount of the ice-water mixture is to quench the remaining phosphorus oxychloride, and the reaction can be judged to be over by the fact that the reaction liquid no longer undergoes an exothermic reaction with the addition of the ice-water mixture under stirring conditions (the same below, which will not be repeated below).

[0027] (2) Mixing the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine obtained in step (1) with 4-tert-butylbenzenesulfonamide, an acid-binding agent and a polar aprotic solvent, and reacting at 115° C. for 6 h to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt; As a specific implementation of this embodiment, step (2) is as follows: The 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine, 4-tert-butylbenzenesulfonamide, an acid-binding agent and a polar aprotic solvent are taken in a molar ratio of 1:1.1:5:8; wherein the acid-binding agent is sodium hydroxide; and the polar aprotic solvent is acetonitrile.

[0028] First, 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine is mixed with 4-tert-butylbenzenesulfonamide and a polar aprotic solvent, and then an acid-binding agent is added at 115°C in 4 times, each time with an interval of 1 hour, and then the reaction is carried out at 115°C for 6 hours to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt; The obtained 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt is subjected to product post-treatment: The reaction liquid after the reaction is cooled to 20° C. and filtered to obtain a second filter cake; the polar aprotic solvent is added to the obtained second filter cake for slurrying, and then filtered, washed, and dried to obtain a third filter cake; water is added to the obtained third filter cake for slurrying, and then filtered, washed, and dried to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt.

[0029] It should be noted that the solution used for the washing, the amount of solution, the number of washes, and the amount of solution used for the pulping are not unique, and those skilled in the art can make adjustments within a certain range according to actual conditions. The washing includes but is not limited to washing 1-3 times with a polar aprotic solvent of 2-8 times the volume of the filter cake; and / or washing 1-3 times with water of 2-8 times the volume of the filter cake. The amount of the polar aprotic solvent added to the pulping includes but is not limited to 2-8 times the volume of the filter cake; the amount of water added to the pulping includes but is not limited to 2-8 times (the same below, no further description will be given below).

[0030] (3) mixing the potassium salt of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide obtained in step (2) with ethylene glycol, alkali metal hydroxide and tetrahydrofuran, and reacting at 65° C. for 3 h to obtain a bosentan precursor; As a specific implementation of this embodiment, step (3) is as follows: The potassium salt of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide, 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; First, the ethylene glycol and the tetrahydrofuran are mixed, and then an alkali metal hydroxide is added thereto, and the mixture is stirred at 60° C. for 3 hours, and then the temperature is lowered to 20° C., and 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt is added thereto, and the mixture is stirred and reacted at 65° C. for 3 hours to obtain a bosentan precursor; Product post-processing of bosentan precursor: (a) cooling the reaction liquid to 10° C., removing tetrahydrofuran from the reaction liquid by evaporation, and adjusting the pH value to 3 with hydrochloric acid; adding water thereto, stirring at 0° C. for 1 h, and obtaining a fourth filter cake by crystallization, filtration, and washing; (b) dissolving the fourth filter cake in a mixture of acetonitrile and methanol at 70° C., cooling the mixture to 15° C. at a rate of 10° C. / h, and then placing the mixture at 0° C. for crystallization for 1 h, filtering and washing the mixture to obtain a fifth filter cake; (c) repeating step (b) once to obtain a recrystallized filter cake, and drying to obtain a bosentan precursor; It should be noted that in step (a), the amount of water used is not unique. In this embodiment, the amount of water used is 2 times the volume of the tetrahydrofuran. The washing is performed with water 1 times the volume of the tetrahydrofuran. Those skilled in the art can adjust the amount of water according to the situation.

[0031] 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.

[0032] (4) The bosentan precursor obtained in step (3) is mixed with ethanol and water, reacted at 65° C. for 40 min, cooled and crystallized to obtain bosentan.

[0033] As a specific implementation of this embodiment, step (4) is as follows: The bosentan precursor, ethanol and water are taken in a molar ratio of 1:12:15, the bosentan precursor and ethanol are mixed, stirred at 65°C for 30 minutes, and then water is added thereto at a rate of 200 ml / min to obtain a mixed solution; the mixed solution is stirred and reacted at 65°C for 40 minutes, and then stirred at 10°C for 6 hours, filtered and dried to obtain bosentan.

[0034] Example 2 The preparation method of Bosentan in this embodiment comprises the following steps: (1) taking 5-(2-methoxyphenoxy)-[2,2'-dipyrimidine]-4,6(1H,5H)-dione and phosphorus oxychloride at a molar ratio of 1:3, adding the 5-(2-methoxyphenoxy)-[2,2'-dipyrimidine]-4,6(1H,5H)-dione to the phosphorus oxychloride at 0°C and mixing them; then reacting at 116°C for 5 hours to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine; The obtained 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine is post-treated as follows: The reaction solution was cooled to 0°C, and an ice-water mixture with a volume ratio of ice to water of 1:1 was added thereto at a rate of 50 ml / min to quench the remaining phosphorus oxychloride, and then stirred at -10°C for 20 minutes, filtered, and washed with water to obtain a first filter cake; Water was added to the first filter cake to make a pulp, and a saturated sodium carbonate solution was used to adjust the pH value of the mixed solution to 6.0, and then the mixture was filtered, washed with water, and dried to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine.

[0035] (2) mixing the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine obtained in step (1) with 4-tert-butylbenzenesulfonamide, an acid-binding agent and a polar aprotic solvent, and reacting at 125° C. for 8 h to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt; As a specific implementation of this embodiment, step (2) is as follows: The 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine, 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.

[0036] First, 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine is mixed with 4-tert-butylbenzenesulfonamide and a polar aprotic solvent, and then an acid-binding agent is added at 125°C for 6 times, each time with an interval of 1 hour, and then the mixture is reacted at 115-125°C for 6 hours to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt; The obtained 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt is subjected to product post-treatment: The reaction solution after the reaction is cooled to 10° C. and filtered to obtain a second filter cake; the polar aprotic solvent is added to the obtained second filter cake for slurrying, and then filtered, washed, and dried to obtain a third filter cake; water is added to the obtained third filter cake for slurrying, and then filtered, washed, and dried to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt.

[0037] (3) mixing the potassium salt of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide obtained in step (2) with ethylene glycol, alkali metal hydroxide and tetrahydrofuran, and reacting at 75° C. for 1 h to obtain a bosentan precursor; As a specific implementation of this embodiment, step (3) is as follows: The potassium salt of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide, ethylene glycol, alkali metal hydroxide and tetrahydrofuran are taken in a molar ratio of 1:100:25:7; wherein the alkali metal hydroxide is sodium hydroxide; First, the ethylene glycol and the tetrahydrofuran are mixed, and then an alkali metal hydroxide is added thereto, and the mixture is stirred at 70° C. for 1 hour, and then the temperature is lowered to 10° C., and 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt is added thereto, and the mixture is stirred and reacted at 75° C. for 1 hour to obtain a bosentan precursor; Product post-processing of bosentan precursor: (a) cooling the reaction liquid to 20° C., removing tetrahydrofuran from the reaction liquid by evaporation, and adjusting the pH value to 3 with hydrochloric acid; adding water thereto, stirring at −5° C. for 0.5 h, and obtaining a fourth filter cake by crystallization, filtration, and washing; (b) dissolving the fourth filter cake in a mixture of acetonitrile and methanol at 90° C., cooling the mixture to 20° C. at a rate of 10° C. / h, and then placing the mixture at 5° C. for crystallization for 0.5 h, filtering and washing the mixture to obtain a fifth filter cake; (c) repeating step (b) 4 times to obtain a recrystallized filter cake, which is then dried to obtain a bosentan precursor; It should be noted that in step (a), the amount of water used is not unique. In this embodiment, the amount of water used is 2 times the volume of the tetrahydrofuran. The washing is performed with water 1 times the volume of the tetrahydrofuran. Those skilled in the art can adjust the amount of water according to the situation.

[0038] 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 1:3; the washing is performed with methanol, and the volume ratio of the methanol used for washing to the mixture of acetonitrile and methanol is 1:1.

[0039] (4) The bosentan precursor obtained in step (3) is mixed with ethanol and water, reacted at 60° C. for 20 min, cooled and crystallized to obtain bosentan.

[0040] As a specific implementation of this embodiment, step (4) is as follows: 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 minutes, and then water is added thereto at a rate of 200 ml / min to obtain a mixed solution; the mixed solution is stirred and reacted at 60°C for 20 minutes, and then stirred at 20°C for 12 hours, filtered and dried to obtain bosentan.

[0041] Example 3 The preparation method of Bosentan in this embodiment comprises the following steps: (1) taking 5-(2-methoxyphenoxy)-[2,2'-dipyrimidine]-4,6(1H,5H)-dione and phosphorus oxychloride at a molar ratio of 1:5, adding the 5-(2-methoxyphenoxy)-[2,2'-dipyrimidine]-4,6(1H,5H)-dione to the phosphorus oxychloride at -5°C and mixing them; then reacting at 112°C for 4 hours to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine; The obtained 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine is post-treated as follows: The reaction solution was cooled to -5°C, and an ice-water mixture with a volume ratio of ice to water of 1:5 was added thereto at a rate of 50 ml / min to quench the remaining phosphorus oxychloride, and then stirred at 0°C for 30 minutes, filtered, and washed with water to obtain a first filter cake; Water was added to the obtained first filter cake for slurrying, and a saturated sodium carbonate solution was used to adjust the pH value of the mixed solution to 8.0, and then the mixture was filtered, washed with water, and dried to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine.

[0042] (2) mixing the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine obtained in step (1) with 4-tert-butylbenzenesulfonamide, an acid-binding agent and a polar aprotic solvent, and reacting at 120° C. for 4 h to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt; As a specific implementation of this embodiment, step (2) is as follows: The 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine, 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; and the polar aprotic solvent is dimethylformamide.

[0043] First, 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine is mixed with 4-tert-butylbenzenesulfonamide and a polar aprotic solvent, and then an acid-binding agent is added twice at 120°C, each time with an interval of 1 hour, and then the mixture is reacted at 115-125°C for 6 hours to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt; The obtained 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt is subjected to product post-treatment: The reaction liquid after the reaction is cooled to 30° C. and filtered to obtain a second filter cake; the polar aprotic solvent is added to the obtained second filter cake for slurrying, and then filtered, washed, and dried to obtain a third filter cake; water is added to the obtained third filter cake for slurrying, and then filtered, washed, and dried to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt.

[0044] (3) mixing the potassium salt of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide obtained in step (2) with ethylene glycol, alkali metal hydroxide and tetrahydrofuran, and reacting at 65° C. for 3 h to obtain a bosentan precursor; As a specific implementation of this embodiment, step (3) is as follows: The potassium salt of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide, 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; First, the ethylene glycol and the tetrahydrofuran are mixed, and then an alkali metal hydroxide is added thereto, and the mixture is stirred at 65° C. for 2 hours, and then the temperature is lowered to 30° C., and 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt is added thereto, and the mixture is stirred and reacted at 65° C. for 3 hours to obtain a bosentan precursor; Product post-processing of bosentan precursor: (a) cooling the reaction solution to 30° C., removing tetrahydrofuran from the reaction solution by evaporation, and adjusting the pH value to 2 with hydrochloric acid; adding water thereto, stirring at −10° C. for 1 h, and obtaining a fourth filter cake by crystallization, filtration, and washing; (b) dissolving the fourth filter cake in a mixture of acetonitrile and methanol at 80° C., cooling the mixture to 35° C. at a rate of 10° C. / h, and then placing the mixture at -5° C. for crystallization for 1 hour, filtering and washing the mixture to obtain a fifth filter cake; (c) repeating step (b) twice to obtain a recrystallized filter cake, and drying to obtain a bosentan precursor; It should be noted that in step (a), the amount of water used is not unique. In this embodiment, the amount of water used is 2 times the volume of the tetrahydrofuran. The washing is performed with water 1 times the volume of the tetrahydrofuran. Those skilled in the art can adjust the amount of water according to the situation.

[0045] 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 with methanol, and the volume ratio of the methanol used for washing to the mixture of acetonitrile and methanol is 1:3.

[0046] (4) The bosentan precursor obtained in step (3) is mixed with ethanol and water, reacted at 70° C. for 40 min, cooled and crystallized to obtain bosentan.

[0047] As a specific implementation of this embodiment, step (4) is as follows: The bosentan precursor, ethanol and water are taken in a molar ratio of 1:8:12, the bosentan precursor and ethanol are mixed, stirred at 60°C for 40 minutes, and then water is added thereto at a rate of 200 ml / min to obtain a mixed solution; the mixed solution is stirred and reacted at 65°C for 30 minutes, and then stirred at 15°C for 8 hours, filtered and dried to obtain bosentan.

[0048] Example 4 The preparation method of Bosentan in this embodiment is as follows Figure 1 As shown, the following steps are included: (1) Phosphorus oxychloride and 5-(2-methoxyphenoxy)-[2,2'-dipyrimidine]-4,6(1H,5H)-dione were mixed at -5°C, and then reacted at 110°C for 6 hours to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine; As a specific implementation of this embodiment, step (1) is as follows: 5-(2-methoxyphenoxy)-[2,2'-dipyrimidine]-4,6(1H,5H)-dione and phosphorus oxychloride are taken in a molar ratio of 1:4, and 5-(2-methoxyphenoxy)-[2,2'-dipyrimidine]-4,6(1H,5H)-dione is added to the phosphorus oxychloride at -5°C to mix; and then reacted at 110°C for 6 hours to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine; The obtained 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine is post-treated as follows: The reaction solution was cooled to -5°C, and an ice-water mixture with a volume ratio of ice to water of 1:3 was added thereto at a rate of 50 ml / min to quench the remaining phosphorus oxychloride, and then stirred at -5°C for 20 minutes, filtered, and washed with water to obtain a first filter cake; Water was added to the obtained first filter cake for slurrying, and a saturated sodium carbonate solution was used to adjust the pH value of the mixed solution to 7.0, and then the mixture was filtered, washed with water, and dried to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine.

[0049] It should be noted that the amount of water used for beating, the amount of water used for washing with water, and the number of washing times are not unique, and those skilled in the art can make adjustments within a certain range according to actual conditions. The amount of water used for beating includes but is not limited to 0.2-0.6 times the volume of the filter cake; the washing with water includes but is not limited to washing 1-3 times with water 0.2-0.6 times the volume of the filter cake. In this embodiment, the amount of water used for beating is 0.6 times the volume of the filter cake; the washing with water is washing 3 times with water 0.6 times the volume of the filter cake.

[0050] In this embodiment, under the low temperature condition of -10°C to 0°C, the 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6(1H,5H)-dione is added to the phosphorus oxychloride for mixing, which can be achieved by ice water bath, ice salt bath, or other low temperature means. Similarly, the low temperature conditions in other steps can also be achieved by low temperature means such as ice water bath, ice salt bath, etc.

[0051] In this embodiment, the amount of the ice-water mixture is to quench the remaining phosphorus oxychloride. The reaction can be concluded when the reaction liquid no longer undergoes an exothermic reaction with the addition of the ice-water mixture under stirring conditions.

[0052] (2) mixing the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine obtained in step (1) with 4-tert-butylbenzenesulfonamide, an acid-binding agent and a polar aprotic solvent, and reacting at 120° C. for 6 h to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt; As a specific implementation of this embodiment, step (2) is as follows: The 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine, 4-tert-butylbenzenesulfonamide, an acid-binding agent and a 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.

[0053] First, 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine is mixed with 4-tert-butylbenzenesulfonamide and a polar aprotic solvent, and then an acid-binding agent is added at 120°C in 4 times, each time with an interval of 1 hour, and then the mixture is reacted at 120°C for 6 hours to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt; The obtained 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt is subjected to product post-treatment: The reaction liquid after the reaction is cooled to 20° C. and filtered to obtain a second filter cake; the polar aprotic solvent is added to the obtained second filter cake for slurrying, and then filtered, washed, and dried to obtain a third filter cake; water is added to the obtained third filter cake for slurrying, and then filtered, washed, and dried to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt.

[0054] It should be noted that the solution used for the washing, the amount of solution, the number of washes, and the amount of solution used for the pulping are not unique. Those skilled in the art can make adjustments within a certain range according to actual conditions. In this embodiment, the washing is to use a polar aprotic solvent with a volume of 6 times the filter cake for washing 3 times, and to use water with a volume of 6 times the filter cake for washing 3 times. The amount of the polar aprotic solvent added for pulping is 6 times the volume of the filter cake; the amount of water added for pulping is 6 times the volume of the filter cake.

[0055] (3) mixing the potassium salt of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide obtained in step (2) with ethylene glycol, alkali metal hydroxide and tetrahydrofuran, and reacting at 65° C. for 3 h to obtain a bosentan precursor; As a specific implementation of this embodiment, step (3) is as follows: The potassium salt of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide, ethylene glycol, alkali metal hydroxide and tetrahydrofuran are mixed in a molar ratio of 1:100:20:6; wherein the alkali metal hydroxide is sodium hydroxide; First, the ethylene glycol and the tetrahydrofuran are mixed, and then an alkali metal hydroxide is added thereto, and the mixture is stirred at 65° C. for 2 hours, and then the temperature is lowered to 20° C., and 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt is added thereto, and the mixture is stirred and reacted at 65° C. for 3 hours to obtain a bosentan precursor; Product post-processing of bosentan precursor: (a) cooling the reaction solution to 20° C., removing tetrahydrofuran from the reaction solution by evaporation, and adjusting the pH value to 2-3 with hydrochloric acid; adding water thereto, stirring at -5° C. for 1 h, and obtaining a fourth filter cake by crystallization, filtration, and washing; (b) dissolving the fourth filter cake in a mixture of acetonitrile and methanol at 80° C., cooling the mixture to 20° C. at a rate of 10° C. / h, and then placing the mixture at -5° C. for crystallization for 1 hour, filtering and washing the mixture to obtain a fifth filter cake; (c) repeating step (b) three times to obtain a recrystallized filter cake, which is then dried to obtain a bosentan precursor; It should be noted that in step (a), the amount of water used is not unique. In this embodiment, the amount of water used is 2 times the volume of the tetrahydrofuran. The washing is performed with water 1 times the volume of the tetrahydrofuran. Those skilled in the art can adjust the amount of water according to the situation.

[0056] 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 with methanol, and the volume ratio of the methanol used for washing to the mixture of acetonitrile and methanol is 1:2.

[0057] (4) The bosentan precursor obtained in step (3) is mixed with ethanol and water, reacted at 65° C. for 30 min, cooled and crystallized to obtain bosentan.

[0058] As a specific implementation of this embodiment, step (4) is as follows: The bosentan precursor, ethanol and water are taken in a molar ratio of 1:10:10, the bosentan precursor and ethanol are mixed, stirred at 65°C for 30 minutes, and then water is added thereto at a rate of 200 ml / min to obtain a mixed solution; the mixed solution is stirred and reacted at 65°C for 30 minutes, and then stirred at 15°C for 8 hours, filtered and dried to obtain bosentan.

[0059] Comparative Example 1 The preparation method of bosentan in this comparative example is the same as that in Example 4, except that: in step (1), the phosphorus oxychloride and 5-(2-methoxyphenoxy)-[2,2'-dipyrimidine]-4,6(1H,5H)-dione are mixed at room temperature and then reacted at 110°C for 6 hours.

[0060] Comparative Example 2 The preparation method of bosentan in this 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'-dipyrimidine product after the reaction is not included.

[0061] Comparative Example 3 The preparation method of bosentan in this comparative example is the same as that in Example 4, except that in step (1), after the reaction, the ice-water mixture is not added to extinguish the remaining phosphorus oxychloride.

[0062] Comparative Example 4 The preparation method of bosentan in this comparative example is the same as that in Example 4, except that in step (1), after the reaction, the ice-water mixture is added at a rate of 100 ml / min to quench the remaining phosphorus oxychloride.

[0063] Comparative Example 5 The preparation method of bosentan in this comparative example is the same as that in Example 4, except that in step (2), the acid binding agent is added once.

[0064] Comparative Example 6 The preparation method of bosentan in this comparative example is the same as that in Example 4, except that: in step (2), the step of post-treating the product of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt after the reaction is not included.

[0065] Comparative Example 7 The preparation method of bosentan in this comparative example is the same as that in Example 4, except that step (3) is different.

[0066] Step (3) is: mixing the potassium salt of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide obtained in step (2) with ethylene glycol, alkali metal hydroxide and tetrahydrofuran, and reacting at 65° C. for 5 hours to obtain a bosentan precursor.

[0067] Comparative Example 8 The preparation method of bosentan in this comparative example is the same as that in Example 4, except that step (3) does not include a step of post-treatment of the bosentan precursor product after the reaction.

[0068] Comparative Example 9 The preparation method of bosentan in the comparative example is the same as that in Example 4, except that in step (3), the step of post-treatment of the bosentan precursor product after the reaction is different.

[0069] Specifically, in step (b), the mixed solution of acetonitrile and methanol is replaced with acetonitrile.

[0070] Comparative Example 10 The preparation method of bosentan in the comparative example is the same as that in Example 4, except that in step (3), the step of post-treatment of the bosentan precursor product after the reaction is different.

[0071] Specifically, in step (b), the mixed solution of acetonitrile and methanol is replaced by methanol.

[0072] Effect experiment example In order to verify the technical effect of the preparation method of bosentan described in the present invention, the following experiments were performed: Bosentan was prepared according to the methods in the examples and comparative examples. The purity of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine in step (1) was determined by high performance liquid chromatography (HPLC), which was 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) was determined, which was recorded as the purity of product 2; the purity of bosentan precursor in step (3) was determined, which was recorded as the purity of product 3; the purity of bosentan in step (4) was determined, which was recorded as the purity of product 4; and the yields of products 1-4 were calculated respectively.

[0073] After experimentation, the results are as follows:

[0074] According to the above results, the preparation method of bosentan of the present invention can greatly save reaction time, improve reaction yield, reduce impurity content, simplify post-processing operations, reduce preparation costs, and facilitate industrial large-scale production and application.

[0075] It is known from common technical knowledge that the present invention can be implemented by other embodiments that do not deviate from its spirit or essential features. Therefore, the above disclosed embodiments are only illustrative in all respects and are not exclusive. All changes within the scope of the present invention or within the scope equivalent to the present invention are included in the present invention.

Claims

1. A method for preparing bosentan, characterized in that: The steps include: (1) Phosphorus oxychloride and 5-(2-methoxyphenoxy)-[2,2'-dipyrimidine]-4,6(1H,5H)-dione are mixed at -10°C to 0°C, and then reacted at 106-116°C for 4-8 hours to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine; (2) Mixing the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine obtained in step (1) with 4-tert-butylbenzenesulfonamide, an acid-binding agent and a polar aprotic solvent, and reacting at 115-125° C. for 4-8 hours to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt; (3) mixing the potassium salt of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide obtained in step (2) with ethylene glycol, an alkali metal hydroxide and tetrahydrofuran, and reacting at 55-75° C. for 1-3 hours to obtain a bosentan precursor; (4) Mixing the bosentan precursor obtained in step (3) with ethanol and water, reacting at 60-70° C. for 20-40 min, cooling and crystallizing to obtain bosentan.

2. The method for preparing bosentan according to claim 1, characterized in that: Step (1) further includes a step of post-treating the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine product after the reaction: The reaction solution after the reaction was cooled to -10°C-0°C, and an ice-water mixture was added thereto at a rate of 50 ml / min to quench the remaining phosphorus oxychloride, and then stirred at -10°C-0°C for 10-30 minutes, and filtered to obtain a first filter cake; Water is added to the obtained first filter cake for slurrying, and the pH value of the mixed solution is adjusted to 6.0-8.0 with a sodium carbonate solution, and then filtered and dried to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine.

3. The method for preparing bosentan according to claim 2, characterized in that: The method further comprises the step of washing the filter cake 1 to 3 times with water of 0.2 to 0.6 times the volume of the filter cake after the filtration; Optionally, in the ice-water mixture, the volume ratio of ice to water is 1:(1-5); Optionally, the amount of water used for beating is 0.2-0.6 times the volume of the filter cake; Optionally, the sodium carbonate solution is a saturated sodium carbonate solution.

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

5. 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; Optionally, the polar aprotic solvent is one or more of acetonitrile, acetone, dimethylformamide, and dimethyl sulfoxide; Optionally, the molar ratio of the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine to 4-tert-butylbenzenesulfonamide, the acid-binding agent and the polar aprotic solvent is 1:(1-1.2):(3-5):(8-12).

6. The method for preparing bosentan according to claim 1, characterized in that: Step (2) specifically includes the following steps: First, 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine is mixed with 4-tert-butylbenzenesulfonamide and a polar aprotic solvent, and then an acid-binding agent is added at 115-125°C in 2-6 times, each time with an interval of 1 hour, and then the mixture is reacted at 115-125°C for 4-8 hours to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt; Optionally, step (2) further comprises the step of post-treating the product of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt after the reaction: The reaction liquid after the reaction is cooled to 10-30° C. and filtered to obtain a second filter cake; the polar aprotic solvent is added to the obtained second filter cake for slurrying, and then filtered, washed, and dried to obtain a third filter cake; water is added to the obtained third filter cake for slurrying, and then filtered, washed, and dried to obtain 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide potassium salt.

7. The method for preparing bosentan according to claim 6, characterized in that: In step (2), the washing is performed by washing with a polar aprotic solvent 2-8 times the volume of the filter cake for 1-3 times; and / or washing with water 2-8 times the volume of the filter cake for 1-3 times; Optionally, the amount of the polar aprotic solvent added to the slurry is 2-8 times the volume of the filter cake; Optionally, the amount of water added for slurrying is 2-8 times the volume of the filter cake.

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

9. 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, and then an alkali metal hydroxide is added thereto, and the mixture is stirred at 60-70° C. for 1-3 hours, and then the temperature is lowered to 10-30° C., and 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 reaction for 2-4 hours to obtain a bosentan precursor; Optionally, step (3) further comprises the step of post-treatment of the bosentan precursor product after the reaction: (a) cooling the reaction liquid to 10-30° C., removing tetrahydrofuran from the reaction liquid by evaporation, and adjusting the pH value to 2-3 with hydrochloric acid; adding water thereto, stirring at -10° C. to 0° C. for 0.5-1 h, and obtaining a fourth filter cake by crystallization, filtering, and washing; (b) dissolving the fourth filter cake in a mixture of acetonitrile and methanol at 70-90° C., cooling the mixture to 15-35° C. at a rate of 10° C. / h, and then placing the mixture at -5-5° C. for crystallization for 0.5-1 h, filtering and washing the mixture to obtain a fifth filter cake; (c) repeating step (b) 1-4 times to obtain a recrystallized filter cake, which is then dried to obtain a bosentan precursor; Optionally, in step (b), in the mixture of acetonitrile and methanol, the volume ratio of acetonitrile to methanol is 1:1; Optionally, in step (b), the volume ratio of the mixture of acetonitrile and methanol to the fourth filter cake is 1:(1-3); Optionally, in step (b), the washing is performed using methanol, and the volume ratio of the methanol used for washing to the mixed solution of acetonitrile and methanol is 1:(1-3).

10. 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, stirred at 60-70° C. for 20-40 min, and then water is added thereto at a rate of 200 ml / min to obtain a mixed solution; the mixed solution is stirred at 60-70° C. for 20-40 min, and then stirred at 10-20° C. for 6-12 h, filtered, and dried to obtain bosentan; Optionally, the volume ratio of the bosentan precursor, ethanol and water is 1:(8-15):(8-15).

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