A method for the synthesis of alpirotenan

Abstract

The application provides a synthesis method of alogentan, and belongs to the technical field of heterocyclic compounds. Bromophenyldichloropyrimidine is used as a raw material, nucleophilic substitution is carried out between bromophenyldichloropyrimidine and excessive sulfonamide to prepare sulfanilamide, then the amino group is protected by using chloromethyl benzyl ether to form a sulfanilamide protector, the sulfanilamide protector is reacted with ethylene glycol under the condition of high temperature and strong base to form hydroxyethyl pyrimidine, the hydroxyethyl pyrimidine is reacted with 5-bromo-2-chloropyrimidine to form alogentan protector, and the chloromethyl benzyl protective group of the alogentan protector is hydrolyzed in acid to prepare alogentan. The application not only solves the problems of reactivity and selectivity of sulfonamide and pyrimidine ring, and the whole reaction process is simple, safe and high in product purity.

Description

TECHNICAL FIELD

[0001] The application relates to a synthesis method of aprocitentan and belongs to the technical field of heterocyclic compounds. BACKGROUND

[0002] Aprocitentan, formerly known as ACT-132577, is a dual endothelin receptor antagonist, a new type of small molecule drug targeting ETA / ETB endothelin receptors developed by Idorsia and Janssen. Aprocitentan is one of the metabolites of the pulmonary arterial hypertension drug Macitentan, and is also the first ETA / ETB inhibitor used for hypertension. The drug has good efficacy in the treatment of refractory hypertension. Literature Heidari Nejad, S., Azzam, O. & Schlaich, M. P. Dual Endothelin Antagonism with Aprocitentan as a Novel Therapeutic Approach for Resistant Hypertension. Curr Hypertens Rep 25, 343-352 (2023). reported the results of a phase III clinical trial (PRECISION) that showed that aprocitentan can significantly reduce the diastolic and systolic blood pressure of patients, has good tolerance, and has a lower adverse reaction rate than other drugs, and is expected to be used for the treatment of patients with refractory hypertension.

[0003] The compound structure of aprocitentan is as follows:

[0004]

[0005] At present, there are several reported synthesis routes of aprocitentan.

[0006] 1. WO 2009024906 and CN101772494A disclose the use and preparation method of aprocitentan and its salts. The strategy of first introducing sulfonamide is adopted: in the presence of a strong base, compound ZJT-3 and 5-bromo-2-chloropyrimidine are reacted to obtain intermediate ZJT-4; finally, the protecting group of intermediate ZJT-4 is removed by using boron trihalide BCl3 or BBr3 to obtain aprocitentan, and the reaction formula is as shown below:

[0007]

[0008] This route uses chloroform as the solvent in the final step, and boron tribromide for deprotection. Chloroform, a solvent with a low residual limit in the ICH standard, can affect the quality of the final product. Furthermore, boron tribromide can produce high levels of impurities, requiring column elution for post-processing, making it unsuitable for industrialization.

[0009] 2. WO 2015121397, CN105992762A, and CN107162988A report an alternative route for producing aprexitentan. Compound 2 and Compound 3, 5-(4-bromophenyl)-4,6-dichloropyrimidine, react to produce Compound 4, a chloropyrimidine. Compound 4 then reacts with a fluorinated reagent to produce Compound 5, a fluoropyrimidine. Compound 5 then reacts with sulfamoylamide in the presence of a strong base to produce aprexitentan or a salt thereof. The specific route is as follows:

[0010]

[0011] In this synthetic route, when compound 3 is first substituted with compound 2, the leaving activity of the chlorine substituent on the other pyrimidine ring is greatly reduced, making direct sulfonamide substitution difficult. Therefore, the chlorine is replaced with fluorine in this route to increase the reactivity of the nucleophilic substitution of the pyrimidine ring. This results in the addition of reaction steps such as compound 2 → compound 4 and compound 4 → compound 5 to the above reaction route. Furthermore, the expensive cesium fluoride and tetrabutylammonium fluoride used in the conversion of compound 4 → compound 5 are also generated as a byproduct, which can corrode both stainless steel and glass-lined glass. The metal fluoride dust is highly hazardous to the human body, making this route unsuitable for large-scale industrial production. Summary of the Invention

[0012] In view of this, the present application provides a method for synthesizing aprexitentan, which not only solves the reactivity and selectivity issues of sulfonamide and pyrimidine rings, but also allows the sulfonamide group to be preferentially attached to the pyrimidine ring. The entire reaction process is simple, with high conversion rate and selectivity. The materials used are green and environmentally friendly, and no corrosive substances such as hydrogen fluoride are generated, which facilitates industrial scale-up.

[0013] Specifically, this application is implemented through the following solutions:

[0014] A method for synthesizing aprexitentan comprises the following steps: using bromophenyl dichloropyrimidine (compound A) as a raw material, first subjecting bromophenyl dichloropyrimidine (compound A) to nucleophilic substitution with an excess of sulfonamide to prepare sulfadiazine (compound B), then protecting the amino group with chloromethyl benzyl ether to form a sulfadiazine protected compound (compound C), reacting the sulfadiazine protected compound with ethylene glycol under strong alkaline and high temperature (45-110° C.) conditions to form hydroxyethyl pyrimidine (compound D), reacting the hydroxyethyl pyrimidine with 5-bromo-2-chloropyrimidine to form an aprexitentan protected compound (compound E), and subjecting compound E to acidic hydrolysis (e.g., by adding p-toluenesulfonic acid monohydrate) to remove the chloromethyl benzyl protecting group to prepare aprexitentan (compound F).

[0015] The above reaction process is expressed as follows:

[0016]

[0017] Furthermore, the specific steps of the above process are as follows:

[0018] Step 1, synthesis of compound B: using bromophenyl dichloropyrimidine as a raw material, reacting with sulfonamide in the presence of an alkaline compound to generate sulfadiazine, adjusting the pH to 4-5 by adding acid, extracting the product with dichloromethane (DCM), concentrating the organic layer, and beating with a lower alcohol, water, or a mixed solution of a lower alcohol and water, and separating by crystallization to obtain solid sulfadiazine, i.e., compound B.

[0019] Step 2, synthesis of compound C: using sulfadiazine as the raw material, in a polar aprotic solvent atmosphere, N,N-diisopropylethylamine (DIPEA) as the catalyst, benzyl chloromethyl ether as the protecting agent to carry out the protection reaction to obtain the sulfadiazine protected compound, and then quenching with water, extraction, concentration, crystallization, and separation to obtain the solid sulfadiazine protected compound, namely compound C.

[0020] Step 3, synthesis of compound D: using sulfadiazine protected substance as raw material, reacting with ethylene glycol in the presence of an alkaline compound to generate hydroxyethyl pyrimidine, followed by acid quenching, extraction, concentration, crystallization, and separation to obtain solid hydroxyethyl pyrimidine, i.e., compound D.

[0021] Step 4, synthesizing compound E: using hydroxyethyl pyrimidine as a raw material, reacting with 5-bromo-2-chloropyrimidine in the presence of an alkaline compound to generate aprexitentan protected compound, followed by acid quenching, extraction, concentration, crystallization, and separation to obtain a solid aprexitentan protected compound, namely compound E.

[0022] Step 5, synthesizing compound F: using the protected aprexitentan as a raw material, reacting with an acid in a mixture of an organic solvent and water to generate aprexitentan, and then cooling, crystallizing, and separating to obtain solid aprexitentan, i.e., compound F.

[0023] As preferred:

[0024] In step one,

[0025] The basic compound is any one of potassium carbonate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydride, preferably potassium carbonate.

[0026] The molar ratio of bromophenyl dichloropyrimidine to sulfonamide is 1:1.0-1:4, preferably 1:2-1:3, more preferably 1:2.

[0027] The acid added is any one of hydrochloric acid, sulfuric acid, citric acid, etc., preferably hydrochloric acid. The acid concentration in the acid added is 1-30%, preferably 10-20%.

[0028] The lower alcohol is any one or a mixture of more than one of methanol, ethanol, isopropanol, n-butanol, sec-butanol, etc., and is preferably ethanol. The concentration of the lower alcohol is 10-100%, preferably 50-100%.

[0029] In step two,

[0030] The polar aprotic solvent is preferably DMF and DMAc, more preferably DMAc.

[0031] The reaction temperature is 20-100°C, preferably 40-60°C.

[0032] In step three,

[0033] The basic compound is any one of potassium carbonate, potassium tert-butoxide (t-BuOK), sodium methoxide, sodium ethoxide, sodium hydride, etc., preferably potassium tert-butoxide.

[0034] The acid added is any one of hydrochloric acid, sulfuric acid, citric acid, etc., preferably hydrochloric acid. The acid concentration in the acid added is 1-30%, preferably 10-20%.

[0035] In step four,

[0036] The basic compound is any one of potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydride, etc., preferably sodium hydride.

[0037] The acid added is any one of hydrochloric acid, sulfuric acid, citric acid, etc., preferably hydrochloric acid. The acid concentration in the acid added is 1-30%, preferably 10-20%.

[0038] In step five,

[0039] The organic solvent refers to C1-C4 alcohol, preferably sec-butanol. The volume ratio of the organic solvent to water is 3:1-1:3, preferably 1:1.5-2.

[0040] The above-mentioned route first replaces the sulfonamide, ensuring the selectivity of the nucleophilic substitution through an excess of sulfonamide. The amino group of the sulfonamide is then protected with chloromethyl benzyl ether to prevent the exposed sulfonamide group from reacting with the compound 5-bromo-2-chloropyrimidine under strong alkaline conditions. Finally, the methyl benzyl ether is removed under simple acidic conditions, avoiding the harsh deprotection conditions such as hydrogenation or boron tribromide required by the use of protecting groups such as benzyl. The overall route method is simple to operate, highly selective, and has excellent product quality. Furthermore, no corrosive substances such as hydrogen fluoride are produced during the reaction, making it particularly suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the following briefly introduces the drawings required for use in the embodiments or descriptions of the prior art. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other characterization maps can be obtained according to this technical solution without paying any creative work.

[0042] Figure 1 This is the LC-MS correlation spectrum of sulfadiazine;

[0043] Figure 2 This is the fragmentation diagram of the protected ion of sulfadiazine. DETAILED DESCRIPTION

[0044] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application more clearly understood, the technical solutions in the embodiments of this application will be further described in detail below in conjunction with the drawings in the embodiments of this application. It should be understood that the specific embodiments described herein are only used to explain this application and are not used to limit the technical solutions of this application. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without making creative efforts shall fall within the scope of protection of this application.

[0045] Example 1

[0046] In this example, compound B: sulfadiazine was prepared.

[0047] The reaction is expressed as follows:

[0048]

[0049] The reaction process is as follows:

[0050] Add dimethyl sulfoxide (DMSO, 25 mL), potassium carbonate (4.92 g), and sulfonamide (3.20 g), stir, and heat to 65°C. Maintain stirring for 3 hours. After the incubation, cool the solution to 25°C and quickly add a mixed solution of bromophenyldichloropyrimidine (Compound A, 5.00 g) and DMSO (15 mL) dropwise. After the addition, incubate at 30°C for 21 hours. Sample HPLC analysis indicates that the concentration of bromophenyldichloropyrimidine is less than 1%, indicating the reaction is complete.

[0051] The feed liquid was added to a 5% sodium chloride solution (80 mL), adjusted to pH 4.71 with 10 g of 20% hydrochloric acid, and extracted three times with DCM (70 mL, 70 ml, 25 ml). The organic layers were combined and recovered under reduced pressure at 45 ° C to a yellow oily liquid. Water (20 ml) was added and stirred at 20 ° C for 0.5 h for beating crystallization. The mixture was separated by suction filtration, and the filter cake was washed with water. The filter cake was placed in an oven and dried under reduced pressure at 50 ° C. 5.21 g of sulfadiazine (compound B) was obtained as powder, with a yield of 92.28% and a purity of 96.497%.

[0052] The compound B obtained in the above example was subjected to LC-MS detection (see attached Figure 1 ), where the main ion fragment mass-to-charge ratios m / z in positive ion mode are: [M+H]+=362.8900 (65.59%) 364.8600 (100%) 366.8699 (25.93%), which are consistent with the target structure.

[0053]

[0054] Example 1-1

[0055] The configuration of this embodiment is the same as that of embodiment 1, except that:

[0056] Add DMSO (100 mL), potassium carbonate (19.70 g), and sulfonamide (12.80 g), stir, and heat to 65°C. Maintain stirring for 2 hours. After the incubation period, cool the solution to 25°C and quickly add a mixed solution of bromophenyldichloropyrimidine (Compound A, 20.01 g) and DMSO (50 mL) dropwise. After the addition, incubate at an external temperature of 30°C for 18 hours until the solution becomes clear. Sample HPLC analysis indicates that the concentration of bromophenyldichloropyrimidine is less than 1%, indicating the reaction is complete.

[0057] The feed solution was added to a 5% sodium chloride solution (300 mL), and the pH was measured to be 10.34. The solution was adjusted to pH 4.1 with 20% concentrated hydrochloric acid. DCM (300 mL, 150 mL, 75 mL) was added and extracted three times. The organic layers were combined and recovered under reduced pressure at 45°C to form a yellow oily liquid. 50% ethanol (50 mL) was added and stirred at 0°C for 2 h for beating crystallization. The mixture was separated by suction filtration, and the filter cake was washed with water. The filter cake was placed in an oven and dried under reduced pressure at 50°C. 21.39 g of sulfadiazine (compound B) was obtained as powder, with a yield of 89.36% and a purity of 98.459%.

[0058] In Example 1-1, the slurry solution was replaced with 50% ethanol, and the purity of the product was improved.

[0059] Example 2

[0060] In this example, compound C: a protected form of sulfadiazine was prepared.

[0061] The reaction is expressed as follows:

[0062]

[0063] The reaction process is as follows:

[0064] Under argon protection, sulfadiazine (compound B, 3.99 g) and DMF (10 mL) were added to a four-necked flask with stirring, the temperature was controlled at 25°C, and benzyl chloromethyl ether (2.98 g) was added dropwise. After the addition, the mixture was kept warm and stirred for 30 minutes. DIPEA (3.46 g) was added dropwise while controlling the temperature below 20°C. After the addition, the temperature was slowly raised to 50°C and the reaction was carried out for 10 hours. The sample was taken for HPLC tracking. The sulfadiazine content was less than 1%, and the reaction was completed.

[0065] The mixture was cooled to 10°C and water (80 mL) was added dropwise to quench the mixture. Dichloromethane (80 mL) was added and stirred for extraction. The aqueous layer was extracted with dichloromethane (1×40 mL, 1×20 mL). The combined organic layers were washed with water (2×40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and distilled at 45°C to obtain a light yellow solid. Acetone (5 mL) was added and the mixture was distilled at 50°C. The residue was added with acetone (10 mL) and stirred at 5°C for 2 h, filtered, and the filter cake was washed with acetone (2×5 mL). The powder was collected to obtain 4.31 g of sulfadiazine protected product (Compound C) with a yield of 81.22% and a purity of 98.461%.

[0066] The compound C obtained in the above example was subjected to LC-MS detection (see attached Figure 2 ), where the main ion fragment mass-to-charge ratios m / z in positive ion mode are: [M+H]+=482.9000 (81.46%) 484.9000 (100%) 496.8675 (34.60%), which are consistent with the target structure.

[0067]

[0068] Example 2-1

[0069] The configuration of this embodiment is the same as that of embodiment 2, except that:

[0070] Under argon protection, sulfadiazine (compound B, 20.00 g) and DMAC (100 mL) were added to a four-necked flask, and the temperature was controlled at 20°C. Benzyl chloromethyl ether (15.20 g) was added dropwise. After the addition, the mixture was stirred for 30 minutes. DIPEA (17.10 g) was added dropwise at a temperature of about 20°C. After the addition, the temperature was slowly raised to 50°C and the reaction was carried out for 8 hours. The sample was taken for HPLC detection. The sulfadiazine content was less than 1%, and the reaction was completed.

[0071] The temperature was lowered to 10°C and water (400 mL) was added dropwise to quench the reaction. Dichloromethane (400 mL) was added and stirred for extraction. The aqueous layer was extracted with dichloromethane (1 × 200 mL, 1 × 100 mL). The combined organic layers were washed with water (2 × 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and distilled at 50°C to obtain a light yellow solid. Acetone (10 mL) was added and distilled at 50°C. Acetone (50 mL) was added to the residue and the mixture was kept at 0°C for 4 h. The mixture was filtered and the filter cake was washed with acetone (2 × 10 mL). The mixture was dried under reduced pressure at 50°C to obtain 23.47 g of sulfadiazine protected compound (Compound C) with a yield of 88.47% and a purity of 98.400%.

[0072] This example was expanded under the same reaction conditions as in Example 2, and the yield and purity were good.

[0073] Example 3

[0074] In this example, compound D: hydroxyethyl pyrimidine was prepared.

[0075] The reaction is expressed as follows:

[0076]

[0077] The reaction process is as follows:

[0078] Ethylene glycol (80.00 g) and potassium tert-butoxide (13.46 g) were added to a four-necked flask, the temperature was raised to 45°C with stirring, a drying tube was inserted, the temperature was raised to 45°C, and the mixture was kept warm and stirred for 1 hour. Sulfadiazine protected substance (Compound C, 16.00 g) was added thereto, the temperature was raised to 110°C, and the mixture was kept warm and stirred for 8 hours. Sampling was performed for HPLC tracking. The content of sulfadiazine protected substance was less than 1%, and the reaction was completed.

[0079] The temperature was lowered to 20-30°C, water (200 mL) was added thereto, stirred, quenched by adjusting the pH from 12.72 to 6.51 using 15% hydrochloric acid, extracted with dichloromethane (150 mL, 100 mL, 100 mL) three times, the organic layer was combined, the water layer was discarded, the organic layer was washed with water (50 mL, 50 mL) twice, and concentrated to dryness under reduced pressure at 40°C. Anhydrous methanol (60 mL) was added and the solution was heated to reflux, and the temperature was lowered to below 0°C and stirred for 4 h to crystallize, filtered, and the filter cake was washed with pre-cooled anhydrous methanol (10 mL). The resulting filter cake was dried under reduced pressure at 60°C for 4 h, and the powder was collected to obtain hydroxyethylpyrimidine (compound D) 13.96 g, with a yield of 82.83% and a purity of 98.386%.

[0080] Example 4

[0081] In this example, compound E, an apicigtenan protected product, was prepared.

[0082] The reaction is expressed as follows:

[0083]

[0084] The reaction process is as follows:

[0085] THF (50 mL), sodium hydride (NaH, 3.00 g) was added to a four-necked flask, stirred and cooled, and nitrogen was introduced for protection. The internal temperature was lowered to 10°C, a THF (50 mL) solution of hydroxyethylpyrimidine (compound D, 10.22 g) was added dropwise, and a THF (40 mL) solution of 5-bromo-2-chloropyrimidine (8.97 g) was added dropwise. After the dropwise addition was completed, the temperature was raised to 60°C and the reaction was maintained. After 5 h of maintaining the reaction, a sample was taken for HPLC tracking. The content of hydroxyethylpyrimidine was less than 1%, and the reaction was completed.

[0086] 200 mL of water was added dropwise thereto, stirred for 0.5 h, and then the pH of the system was adjusted from 12.07 to 6.35 using 20% hydrochloric acid. The aqueous phase was extracted twice with ethyl acetate (500 mL). The organic phases were combined, washed with 5% sodium chloride solution (200 mL), and concentrated to dryness to obtain a crude product.

[0087] To the crude product, n-heptane (50 mL) was added, and the resulting suspension was slurried at 50°C for 30 min. It was cooled to 15°C. Filtration was performed, the resulting solid was washed with n-heptane, and vacuum drying was performed to obtain apicigtenan protected product (compound E) 11.56 g, with a yield of 86.44% and a purity of 99.390%.

[0088] Example 5

[0089] In this example, compound F, apicigtenan, was prepared.

[0090] The reaction is expressed as follows:

[0091]

[0092] The reaction process is as follows:

[0093] To a four-necked flask, 10.00 ml of aprexitentan protected compound (Compound E), 50 ml of sec-butanol, 100 ml of water, and p-toluenesulfonic acid monohydrate (TsOH·H2O) were added. The temperature was raised to 60°C and stirred for approximately 8 h to complete the hydrolysis reaction. Sampling was performed for HPLC tracking. The reaction was completed when the content of the aprexitentan protected compound (Compound E) was less than 1%.

[0094] The mixture was cooled to 0°C, stirred for 1 hour to crystallize, filtered, and the filter cake was washed with a small amount of methanol. The filter cake was dried under reduced pressure at 50°C for 8 hours to obtain 8.06 g of aprexitentan (Compound F) with a yield of 80.60% and a purity of 99.210%.

[0095] Examples 1 to 5 prepared aprexitentan (Compound F) by coupling bromophenyldichloropyrimidine (Compound A) with an excess of sulfonamide, then protecting the amino group with chloromethyl benzyl ether, and then further reacting with ethylene glycol and 5-bromo-2-chloropyrimidine, respectively, and finally acidic hydrolysis of the methoxybenzyl protecting group. This process addresses both the reactivity and selectivity issues of the sulfonamide and pyrimidine rings. The entire reaction process is simple, the product purity is high, the synthesis process is simple, the reaction selectivity is high, the total yield is over 40%, the product quality is excellent, and the purity of aprexitentan reaches a high level of over 99%.

[0096] Compared with Route 1 in the background art, this method has the following advantages: the selectivity and conversion rate of the reaction are greatly improved. Route 1 in the background art has an overall yield of approximately 1.5%, and the process requires repeated purification, especially the debenzylation protection step using column separation technology, which is extremely inefficient and has many difficulties and limitations in scale-up.

[0097] Compared with Route 2 in the background technology, its advantages are: although Route 2 contains four steps, it adds the synthesis of Compound 2, Compound 4 and Compound 5 in the process of converting 5-bromo-2-chloropyrimidine to Aprexitentan, resulting in the extension of the conversion route between the two. In particular, the fluorination reaction is introduced in the reaction, and the material cesium fluoride used is expensive and easily causes equipment corrosion and irreversible damage to the human body. The technical solution of the present application is obviously safer in production. In addition, in the actual reaction, the fluorination reaction needs to control the anhydrous environment, otherwise the conversion rate is low, and poor control can easily cause the bromine of the bromophenyl to be further replaced, the purity of the product is reduced, and industrial operation control is more difficult.

[0098] The above-described embodiments only express several possible implementation manners of the present application, the description is relatively specific and detailed, but it cannot be understood as the limitation of the patent scope of the present application, and the embodiments are not used to limit the protection scope in the claims of the present application. For ordinary skilled in the art, without departing from the concept of the present application, several modifications and improvements can be made, and any equivalent implementation or change made without departing from the present application shall be included in the present application.

Claims

1. A method for synthesizing aprexitentan, characterized in that: Compound A is used as a raw material. Compound A and sulfonamide are first subjected to nucleophilic substitution to prepare compound B. Then, chloromethyl benzyl ether is used to protect the amino group to form compound C. Compound C reacts with ethylene glycol at 45-110°C under strong alkaline conditions to form compound D. Compound D reacts with 5-bromo-2-chloropyrimidine to form compound E. Compound E is subjected to acidic hydrolysis of the methoxybenzyl protecting group to prepare compound F, i.e., aprexitentan. During the acidic hydrolysis, p-toluenesulfonic acid monohydrate is added for hydrolysis. The above reaction process is expressed as follows: 。 2. A method for synthesizing aprexitentan according to claim 1, characterized in that: The molar ratio of compound A to sulfonamide is 1:1-4.

3. A method for synthesizing aprexitentan according to claim 1, characterized in that: The molar ratio of compound A to sulfonamide is 1:2~3.

4. The method for synthesizing aprexitentan according to claim 1, wherein: The reaction temperature for forming compound C is 20-100°C.

5. The method for synthesizing aprexitentan according to any one of claims 1 to 4, wherein: Here are the steps: Step 1: Compound A is used as a raw material, reacted with a sulfonamide in the presence of a basic compound to generate a compound B, the pH is adjusted to 4-5 by adding acid, the product is extracted with dichloromethane, and the organic layer is concentrated. A lower alcohol, water, or a mixed solution of a lower alcohol and water is used for beating, and solid compound B is obtained by crystallization and separation, wherein the lower alcohol is any one of methanol, ethanol, isopropanol, n-butanol, and sec-butanol, or a mixture of more than one; Step 2: Using compound B as a raw material, in a polar aprotic solvent atmosphere, N,N-diisopropylethylamine is used as a catalyst, and benzyl chloromethyl ether is used as a protective agent to carry out a protective reaction to obtain compound C, which is then quenched with water, extracted, concentrated, crystallized, and separated to obtain a solid compound C; Step 3: Compound C is reacted with ethylene glycol in the presence of a basic compound to produce Compound D, which is then quenched with acid, extracted, concentrated, crystallized, and separated to obtain a solid Compound D, wherein the basic compound is a strongly basic compound. Step 4: Compound D is reacted with 5-bromo-2-chloropyrimidine in the presence of a basic compound to generate Compound E, which is then quenched with acid, extracted, concentrated, crystallized, and separated to obtain a solid Compound E; Step 5: Compound E is reacted with an acid in a mixture of an organic solvent and water to generate Compound F. After cooling, crystallization, and separation, solid Compound F is obtained, namely, aprexitentan.

6. The method for synthesizing aprexitentan according to claim 5, wherein: The alkaline compound is any one of potassium carbonate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, and sodium hydrogen.

7. The method for synthesizing aprexitentan according to claim 6, wherein: In step 1, the alkaline compound added is potassium carbonate; in step 3, the alkaline compound added is potassium tert-butoxide; in step 4, the alkaline compound added is sodium hydrogen.

8. The method for synthesizing aprexitentan according to claim 5, wherein: The acid addition refers to adding any one of hydrochloric acid, sulfuric acid, and citric acid, with the acid concentration being 1-30%.

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