Synthetic method of alpoxivan

Abstract

The invention provides a synthesis method of alpoxivan, and belongs to the technical field of heterocyclic compounds. Bromophenyl dichloropyrimidine is used as a raw material, the bromophenyl dichloropyrimidine and excessive sulfonamide are firstly subjected to nucleophilic substitution to prepare sulfadiazine, then amino is protected by chloromethyl benzyl ether to form a sulfadiazine protector, the sulfadiazine protector and ethylene glycol react under the conditions of high temperature and strong alkali to form hydroxyethyl pyrimidine, and the hydroxyethyl pyrimidine is subjected to recrystallization to prepare the sulfadiazine. The preparation method comprises the following steps: reacting hydroxyethyl pyrimidine with 5-bromine-2-chloropyrimidine to generate an alpoxivan protection substance, and carrying out acidic hydrolysis on a chloromethyl benzyl protection group by the alpoxivan protection substance to prepare the alpoxivan. According to the invention, the problems of reaction activity and selectivity of sulfonamide and pyrimidine ring are solved, the whole reaction process is simple, the safety is high, and the product purity is high.

Description

Technical Field

[0001] The present application relates to a method for synthesizing aprexitentan, and belongs to the technical field of heterocyclic compounds. Background Art

[0002] Aprocitentan, formerly known as ACT-132577, is a dual endothelin receptor antagonist. It is a new oral small molecule drug targeting dual endothelin receptors ETA / ETB jointly developed by Idorsia and Janssen. Aprocitentan is one of the metabolites of macitentan, a drug for the treatment of pulmonary arterial hypertension, and is also the first drug to use ETA / ETB inhibitors for hypertension. This drug has a good therapeutic effect in the treatment of refractory hypertension. The results of a Phase III clinical trial (PRECISION) reported in the literature Heidari Nejad, S., Azzam, O. & Schlaich, MP Dual Endothelin Antagonism with Aprocitentan as a Novel Therapeutic Approach for Resistant Hypertension. Curr Hypertens Rep 25, 343-352 (2023). showed that aprocitentan can significantly reduce the diastolic and systolic blood pressure of the subjects, has good tolerability, and has a low rate of adverse reactions with other drugs. It is expected to be used in the treatment of patients with refractory hypertension.

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

[0004]

[0005] Currently, there are several publicly reported synthetic routes for apremilast.

[0006] 1. WO 2009024906 and CN101772494A disclose the use and preparation method of aprexitentan and its salts, adopting the strategy of first introducing sulfamoylamide: in the presence of a strong base, the compound ZJT-3 and 5-bromo-2-chloropyrimidine react to obtain an intermediate ZJT-4; finally, the protective group of the intermediate ZJT-4 is removed with boron trihalide BCl3 or BBr3 to obtain aprexitentan, and the reaction formula is shown below:

[0007]

[0008] This route uses chloroform as a solvent in the final step and boron tribromide for deprotection. The solvent chloroform is used in the final step, and the ICH requires a low residual limit, which is easy to affect the quality of the final product. In addition, when boron tribromide is used for the reaction, there are too many impurities, and the post-treatment requires column elution, which is not conducive to industrialization.

[0009] 2. WO 2015121397, CN105992762A and CN107162988A report an alternative route for preparing aprexitentan, wherein compound 2 and compound 3, namely 5-(4-bromophenyl)-4,6-dichloropyrimidine, are reacted to prepare compound 4, chloropyrimidine; compound 4 is reacted with a fluorinated reagent to prepare compound 5, fluoropyrimidine; in the presence of a strong base, compound 5 is reacted with sulfamoylamide to obtain aprexitentan or its salt. The specific route is as follows:

[0010]

[0011] In this synthetic route, after using compound 3 to replace compound 2 first, the leaving property of the chlorine substituent on the other pyrimidine ring will be greatly reduced, so it is difficult to directly replace the sulfonamide. Therefore, in this route, chlorine is replaced by fluorine to increase the reaction activity of nucleophilic substitution of the pyrimidine ring, which results in the addition of reaction steps such as compound 2→compound 4, compound 4→compound 5 in the above reaction route. At the same time, cesium fluoride and tetrabutylammonium fluoride are used in the process of converting compound 4→compound 5 in the reaction, which are expensive, and the byproduct hydrogen fluoride generated by the reaction can corrode both stainless steel and glass lining, and the metal fluoride dust is more harmful to the human body, resulting in this route being 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 problems of sulfonamide and pyrimidine ring, but also allows the sulfonamide group to be preferentially attached to the pyrimidine ring. The entire reaction process is simple, the conversion rate and selectivity are high, the materials used are green and environmentally friendly, and no corrosive substances such as hydrogen fluoride are generated, which is convenient for industrial scale-up.

[0013] Specifically, the present application is implemented through the following scheme:

[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) and an excess of sulfonamide to nucleophilic substitution 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 base 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., adding p-toluenesulfonic acid monohydrate) to obtain aprexitentan (compound F) by removing the chloromethyl benzyl protecting group.

[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, synthesizing compound B: using bromophenyl dichloropyrimidine as a raw material, reacting with sulfonamide under the action 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, using lower alcohol, water or a mixed solution of lower alcohol and water for slurrying, and separating by crystallization to obtain solid sulfadiazine, i.e., compound B.

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

[0020] Step 3, synthesizing compound D: using sulfadiazine protected substance as raw material, reacting with ethylene glycol under the action of alkaline compound to generate hydroxyethyl pyrimidine, and obtaining solid hydroxyethyl pyrimidine, i.e. compound D, through acid quenching, extraction, concentration, crystallization and separation.

[0021] Step 4, synthesizing compound E: using hydroxyethyl pyrimidine as a raw material, reacting with 5-bromo-2-chloropyrimidine under the action of an alkaline compound to generate an aprexetin protected compound, and obtaining a solid aprexetin protected compound, i.e., compound E, through acid quenching, extraction, concentration, crystallization, and separation.

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

[0023] As preferred:

[0024] In step one,

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

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

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

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

[0029] In step 2,

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

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

[0032] In step three,

[0033] The alkaline compound is an alkaline metal salt such as potassium carbonate, potassium tert-butoxide (t-BuOK), sodium methoxide, sodium ethoxide, sodium hydrogen, etc., preferably potassium tert-butoxide.

[0034] The acid addition refers to adding any one of hydrochloric acid, sulfuric acid, citric acid, etc., preferably hydrochloric acid, and the acid concentration in the acid addition is 1 to 30%, preferably 10 to 20%.

[0035] In step four,

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

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

[0038] In step five,

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

[0040] The above route first replaces sulfonamide, and the selectivity of nucleophilic substitution is ensured by excess sulfonamide, and then the amino group of sulfonamide is protected by chloromethyl benzyl ether to avoid the exposed sulfonamide group from continuing to react with the compound 5-bromo-2-chloropyrimidine under strong alkaline conditions. Finally, the methyl benzyl ether can be removed only by simple acidic conditions, avoiding the use of benzyl and other protective groups that require hydrogenation or boron tribromide and other harsh deprotection conditions. The overall route method is simple to operate, has high selectivity, has good product quality, and no corrosive substances such as hydrogen fluoride are generated during the reaction, and is 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 drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. 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 the technical solution without paying 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 clearer, 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 work are within the scope of protection of this application.

[0045] Example 1

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

[0047] The reaction expression is as follows:

[0048]

[0049] The reaction process is as follows:

[0050] Add dimethyl sulfoxide (DMSO, 25 mL), potassium carbonate (4.92 g), sulfonamide (3.20 g), stir and heat to 65°C, keep stirring for 3 hours. After the heat preservation, cool the liquid to 25°C, quickly drop a mixed solution of bromophenyl dichloropyrimidine (compound A, 5.00 g) and DMSO (15 mL), keep the temperature at 30°C for 21 hours after the dropwise addition. Sample HPLC tracking bromophenyl dichloropyrimidine is less than 1%, and the reaction is over.

[0051] The feed liquid was added to 5% sodium chloride solution (80mL), adjusted to pH = 4.71 with 10g 20% ​​hydrochloric acid, and extracted three times with DCM (70mL, 70ml, 25ml), and the organic layers were combined and recovered under reduced pressure at 45°C to form a yellow oily liquid. Water (20ml) was added and stirred at 20°C for 0.5h for beating crystallization, and separated by suction filtration. The filter cake was washed with water, and the filter cake was placed in an oven and dried under reduced pressure at 50°C. 5.21g of sulfadiazine (compound B) was obtained by powder collection, 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), sulfonamide (12.80 g), stir and heat to 65 ° C, keep warm and stir for 2 hours. After the heat preservation, cool the feed liquid to 25 ° C, quickly add a mixed solution of bromophenyl dichloropyrimidine (compound A, 20.01 g) and DMSO (50 mL), keep warm at 30 ° C for 18 hours after the addition, and the feed liquid becomes clear. Sample HPLC tracking bromophenyl dichloropyrimidine is less than 1%, and the reaction is over.

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

[0061] The reaction expression is 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 into a four-necked flask. The temperature was controlled at 25°C with stirring, and benzyl chloromethyl ether (2.98 g) was added dropwise. After the addition, the mixture was kept warm and stirred for 30 min. The temperature was controlled below 20°C, and DIPEA (3.46 g) was added dropwise. After the addition, the temperature was slowly raised to 50°C. The reaction was carried out for 10 h. Samples were taken for HPLC tracking. The sulfadiazine content was less than 1%, and the reaction was completed.

[0065] The temperature was lowered to 10°C and water (80 mL) was added dropwise to quench. 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 distilled at 50°C. Acetone (10 mL) was added to the residue and stirred at 5°C for 2 h. The residue was slurried and filtered. The filter cake was washed with acetone (2×5 mL), and dried under reduced pressure at 50°C to obtain 4.31 g of sulfadiazine protected compound (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 with stirring. Benzyl chloromethyl ether (15.20 g) was added dropwise. After the addition, the mixture was kept warm and stirred for 30 min. The temperature was controlled at about 20°C and DIPEA (17.10 g) was added dropwise. After the addition, the temperature was slowly raised to 50°C and the reaction was carried out for 8 h. Samples were taken for HPLC detection. The sulfadiazine content was less than 1%, and the reaction was completed.

[0071] The mixture was cooled to 10°C and water (400 mL) was added dropwise to quench the mixture. 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 layers were 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 under stirring. The mixture was filtered, and the filter cake was washed with acetone (2×10 mL). The powder was collected 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 expression is as follows:

[0076]

[0077] The reaction process is as follows:

[0078] Add ethylene glycol (80.00 g) and potassium tert-butoxide (13.46 g) into a four-necked flask, stir and heat to 45°C, insert a drying tube, heat to 45°C, keep warm and stir for 1 hour, add sulfadiazine protected substance (compound C, 16.00 g), heat to 110°C, keep warm and stir for 8 hours, take samples for HPLC tracking, the sulfadiazine protected substance is less than 1%, and the reaction is completed.

[0079] Cool to 20-30°C, add water (200mL), stir, use 15% hydrochloric acid to adjust the pH from 12.72 to 6.51 for quenching, extract three times with dichloromethane (150mL, 100mL, 100mL), combine the organic layers, discard the water layer, wash the organic layer with water (50mL, 50mL) twice, and concentrate under reduced pressure at 40°C to dryness. Add anhydrous methanol (60mL) and heat to reflux to dissolve, cool to below 0°C and stir to crystallize for 4h, filter, and wash the filter cake with pre-cooled anhydrous methanol (10mL). The obtained filter cake is dried under reduced pressure at 60°C for 4h, and 13.96g of hydroxyethyl pyrimidine (compound D) is obtained as powder, with a yield of 82.83% and a purity of 98.386%.

[0080] Example 4

[0081] In this example, compound E: aprexitentan protected compound was prepared.

[0082] The reaction expression is as follows:

[0083]

[0084] The reaction process is as follows:

[0085] Add tetrahydrofuran (THF, 50 mL) and sodium hydrogen (NaH, 3.00 g) to a four-necked flask, stir and cool, introduce nitrogen protection, drop the internal temperature to 10°C, drop a solution of hydroxyethyl pyrimidine (compound D, 10.22 g) in THF (50 mL), start dropping a solution of 5-bromo-2-chloropyrimidine (8.97 g) in THF (40 mL), raise the temperature to 60°C and keep the reaction until the addition is complete. Keep the reaction for 5 hours, take a sample for HPLC tracking, the hydroxyethyl pyrimidine is less than 1%, and the reaction is over.

[0086] 200 mL of water was added dropwise, and after stirring for 0.5 h, the pH of the system was adjusted from 12.07 to 6.35 with 20% hydrochloric acid, and 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] n-heptane (50 mL) was added to the crude product, and the resulting suspension was slurried at 50° C. for 30 min. The suspension was cooled to 15° C. Filtered, and the resulting solid was rinsed with n-heptane and dried under vacuum to obtain 11.56 g of aprexitentan protected compound (Compound E) with a yield of 86.44% and a purity of 99.390%.

[0088] Example 5

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

[0090] The reaction expression is as follows:

[0091]

[0092] The reaction process is as follows:

[0093] Add 10.00 ml of aprexitentan protected substance (Compound E), 50 ml of sec-butyl alcohol, 100 ml of water, and p-toluenesulfonic acid monohydrate (TsOH·H2O) to a four-necked flask, raise the temperature to 60°C, keep stirring for about 8 hours to complete the hydrolysis reaction, take samples for HPLC tracking, and the aprexitentan protected substance (Compound E) is less than 1%, indicating the end of the reaction.

[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 at 50°C under reduced pressure 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] In Examples 1 to 5, bromophenyl dichloropyrimidine (compound A) is subjected to substitution coupling with an excess of sulfonamide, and then the amino group is protected with chloromethyl benzyl ether, and then further substituted with ethylene glycol and 5-bromo-2-chloropyrimidine, respectively, and finally the methoxybenzyl protecting group is hydrolyzed with acid to prepare aprexitentan (compound F). This process takes into account the reactivity and selectivity problems 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 more than 40%, the product quality is excellent, and the purity of aprexitentan reaches a high level of more than 99%.

[0096] Compared with Route 1 in the background technology, its advantages are: the selectivity and conversion rate of the reaction are greatly improved. The overall yield of Route 1 in the background technology is about 1.5%, and repeated purification is required during the process, especially the debenzylation protection step uses 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 includes 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 easy to cause 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 is also likely to 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-mentioned embodiments only express several feasible implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention, and the embodiments are not used to limit the scope of protection in the claims of the present invention. For ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, and all equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.

Claims

1. A method for synthesizing aprexitentan, characterized in that: Using bromophenyl dichloropyrimidine as a raw material, bromophenyl dichloropyrimidine and excess sulfonamide are first subjected to nucleophilic substitution to prepare sulfadiazine, and then chloromethyl benzyl ether is used to protect the amino group to form a sulfadiazine protected substance, the sulfadiazine protected substance reacts with ethylene glycol at 45-110° C. and strong alkaline conditions to form hydroxyethyl pyrimidine, the hydroxyethyl pyrimidine reacts with 5-bromo-2-chloropyrimidine to generate an aprexitentan protected substance, and the aprexitentan protected substance is subjected to acidic hydrolysis of the methoxybenzyl protecting group to prepare an aprexitentan.

2. A method for synthesizing aprexitentan according to claim 1, characterized in that: The molar ratio of bromophenyl dichloropyrimidine to sulfonamide is 1:1~4.

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

4. A method for synthesizing aprexitentan according to claim 1, characterized in that: The reaction temperature for forming the sulfadiazine protected compound is 20~100°C.

5. The method for synthesizing aprexitentan according to claim 1, characterized in that: In the acidic hydrolysis, p-toluenesulfonic acid monohydrate is added to carry out hydrolysis.

6. The method for synthesizing aprexitentan according to any one of claims 1 to 5, characterized in that: Here are the steps: Step 1, using bromophenyl dichloropyrimidine as a raw material, reacting with sulfonamide under the action of an alkaline compound to generate sulfadiazine, adjusting the pH to 4-5 by adding acid, extracting the product with dichloromethane, concentrating the organic layer, beating with lower alcohol, water or a mixed solution of lower alcohol and water, and separating by crystallization to obtain solid sulfadiazine; Step 2, using sulfadiazine as a raw material, in a polar aprotic solvent atmosphere, N,N-diisopropylethylamine as a catalyst, benzyl chloromethyl ether as a protecting agent to carry out a protective reaction to obtain a sulfadiazine protected substance, and then quenching with water, extracting, concentrating, crystallizing, and separating to obtain a solid sulfadiazine protected substance; Step 3, using sulfadiazine protected substance as raw material, reacting with ethylene glycol under the action of alkaline compound to generate hydroxyethyl pyrimidine, and then quenching with acid, extracting, concentrating, crystallizing and separating to obtain solid hydroxyethyl pyrimidine; Step 4, using hydroxyethyl pyrimidine as a raw material, reacting with 5-bromo-2-chloropyrimidine under the action of an alkaline compound to generate an aprexetin protected compound, and then quenching with acid, extracting, concentrating, crystallizing, and separating to obtain a solid aprexetin protected compound; Step 5, using the protected substance of 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.

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

8. The method for synthesizing aprexitentan according to claim 7, characterized in that: 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.

9. The method for synthesizing aprexitentan according to claim 6, characterized in that: The acid addition refers to adding any one of hydrochloric acid, sulfuric acid, and citric acid, and the acid concentration is 1-30%.

10. The method for synthesizing aprexitentan according to claim 6, characterized in that: The lower alcohol is any one of methanol, ethanol, isopropanol, n-butanol, and sec-butanol, or a mixture of more than one of them.

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