Preparation method of alplsutentan and alplsutentan intermediate

Abstract

The invention discloses a preparation method of alplsutentan and an alplsutentan intermediate, alplsutentan is obtained by taking a compound SM1 as a raw material through a one-step method or a multi-step method, and the multi-step method comprises the following steps: reacting the compound SM1 with a compound SM2 to obtain an intermediate I; reacting the intermediate I with 2-[(5-bromo-2-pyrimidinyl) oxy] ethanol to obtain an intermediate II, or reacting the intermediate I with ethylene glycol to obtain an intermediate I-b, and then reacting with 5-bromo-2-chloropyrimidine or 5-fluoro-2-chloropyrimidine to obtain the intermediate II; and finally, removing a protecting group from the intermediate II to obtain alpoxivan. The one-step method comprises the following steps: when X in a compound SM1 is a fluorine atom, the compound SM1 is 5-(4-bromophenyl)-4, 6-difluoropyrimidine, and the compound SM1 reacts with sulfonamide and 2-[(5-bromo-2-pyrimidinyl) oxy] ethanol to directly obtain alpoxivan. The synthesis route is short, and the reaction conditions are mild.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and particularly relates to a preparation method of aprexitentan and an aprexitentan intermediate. Background Art

[0002] Aprocitentan (ACT-132577) is a small molecule oral sulfonamide drug used to treat hypertension and belongs to the antihypertensive drug category. It was jointly developed by the pharmaceutical companies Vifor Pharma and Idorsia Pharmaceuticals. It lowers blood pressure by inhibiting angiotensin II receptors and endothelin receptors, and has a strong antihypertensive effect. Aprocitentan is the first endothelin-1 receptor antagonist approved by the U.S. Food and Drug Administration (FDA) for the treatment of refractory hypertension. It brings a new treatment option to patients with hypertension, especially those with refractory hypertension. It is a milestone and becomes the first antihypertensive drug based on a new mechanism in 30 years. Aprocitentan was launched in the United States in 2024 and has not yet been launched in China.

[0003] Aprexitentan's chemical name is {5-(4-bromophenyl)-6-[2-(5-bromooxazolidin-2-yloxy)-ethoxypyrimidin-4-yl}-sulfonamide, CAS registration number: 1103522-45-7, chemical formula: C16H14Br2N6O4S, molecular weight: 546.19. Aprexitentan is a metabolite of macitentan, a drug for treating pulmonary arterial hypertension. The chemical structures of both are shown below:

[0004]

[0005] The molecular structure of aprexitentan and macitentan is characterized by a phenylpyrimidine substituted with two fragments: a sulfamateamide group and an alkoxy group. Various known routes for the preparation of aprexitentan and macitentan vary in the order in which the sulfamateamide and alkoxy groups are introduced onto the pyrimidine ring. However, regardless of the order in which the two fragments are introduced onto the pyrimidine ring, the sulfamateamide fragment of the target product is introduced via an aromatic nucleophilic substitution reaction of a halogenated pyrimidine using a sulfamateamide compound as a reagent in the presence of a strong base.

[0006] International patent WO 2009024906 (corresponding to Chinese patent CN 101772494B) discloses the use and preparation of aprexitentan and its salts. The method employs a strategy of first introducing sulfamoylamide: in the presence of a strong base, a compound of formula I and a compound of formula II react to obtain an intermediate compound of formula III; finally, the protecting group of compound III is removed using BCl3 or BBr3 to obtain aprexitentan. The reaction formula is shown below:

[0007]

[0008] Wherein, the compound of formula I is a benzyl-protected sulfamoylamide (compound of formula IV_a) or a salt thereof as a nucleophile, which reacts with the compound of formula V under alkaline conditions to prepare the intermediate compound of formula VI, introducing a sulfamoylamide fragment; the compound of formula VI reacts with ethanol in the presence of a strong base to obtain the compound of formula I, as shown in the reaction formula:

[0009]

[0010] In the above-mentioned method for preparing the intermediate compound of Formula I, the hydrogen atoms on the N atom of the sulfonamide group in the intermediate compound of Formula VI (CAS Reg. No. 441797-42-8, predicted pKa = 3.83) are acidic, particularly the hydrogen atoms on the N atom directly attached to the pyrimidine ring. This acidity is stronger than that of ethylene glycol (pKa = 15.1). Consequently, the aromatic nucleophilic substitution reaction of ethylene glycol with the compound of Formula VI under alkaline conditions to prepare the compound of Formula I requires a large excess of strong base. Furthermore, due to the reduced reactivity, the reaction is difficult and requires harsh conditions. Similarly, the aromatic nucleophilic substitution reaction of the compound of Formula I with the compound of Formula 11 to prepare the compound of Formula III also suffers from the disadvantages of requiring a large excess of strong base and producing a large number of byproducts.

[0011] International patent WO 2015121397 (corresponding to Chinese patent CN 105992762B and divisional application CN107162988B) reports an alternative route for producing aprexitentan. This route employs a post-introduction sulfonamide synthesis strategy, comprising 1) reacting a compound of formula VII with a compound of formula V to produce a chloropyrimidine compound of formula VIII; 2) reacting the compound of formula VIII with a fluorinated reagent to produce a fluorinated pyrimidine compound of formula M; and 3) reacting the sulfonamide with a compound of formula IX in the presence of a strong base to produce aprexitentan or a salt thereof. The specific route is as follows:

[0012]

[0013] The preparation method disclosed in International Patent WO 2015121397A1 requires obtaining a high-purity fluorinated pyrimidine compound of Formula IX, which can only be achieved by using an excess of cesium fluoride or tetra-n-butylammonium fluoride. Although this method converts the compound of Formula VIII into the compound of Formula IX, which increases the activity of the pyrimidine in undergoing aromatic nucleophilic substitution reactions, it also adds reaction steps. In particular, the byproducts produced by the fluoride anion after the reaction of the compound of Formula IX with the sulfonamide may affect the quality of the product, aprexitentan. During the post-processing and purification process, it is necessary to overcome the adverse effects of a large amount of related fluorinated byproducts on equipment corrosion and the environment, and the post-processing steps are numerous. In addition, the use of excess non-standard fluorination reagents such as tetra-n-butylammonium fluoride hydrate or cesium fluoride increases the cost of raw materials, which is not conducive to industrial production.

[0014] The defects of the prior art are:

[0015] Existing technologies generally utilize the condensation of a chloropyrimidine compound (Formula VIII) with a sulfonamide to obtain aprexitentan. However, this is due to poorly designed groups in the condensation process, resulting in low conversion efficiency. For example, the preparation of Compound I from Compound VI via an aromatic nucleophilic substitution reaction requires a large excess of a strong base. Furthermore, due to reduced reactivity, the reaction is difficult and requires harsh conditions. Similarly, the preparation of Compound III from Compound I with Compound II via an aromatic nucleophilic substitution reaction also suffers from the disadvantages of requiring a large excess of base and producing a high number of byproducts.

[0016] Pyrimidineamine compound X is generally considered a metabolite of macitentan. However, a suitable scalable forward preparation method is lacking. Existing literature and patented methods all use macitentan as a raw material and are prepared via reverse hydrolysis pathways under alkaline, neutral, and acidic conditions, respectively. This method is clearly unsuitable for the large-scale industrial preparation of pyrimidineamine compound X. Summary of the Invention

[0017] The present invention aims to address the deficiencies in the prior art and to provide a method for preparing aprexitentan and an aprexitentan intermediate that has a short synthetic route, mild reaction conditions, simple operation, high yield, low cost, and is suitable for industrial production.

[0018] To achieve the above object, the present invention adopts the following technical solutions:

[0019] A method for preparing aprexitentan, wherein compound SM1 is used as a raw material and synthesized through a one-step method or a multi-step method to obtain aprexitentan, and the synthesis route is as follows:

[0020]

[0021] The synthetic route of the multi-step method is as follows:

[0022]

[0023] The multi-step method comprises the following steps:

[0024] Compound SM1 reacts with compound SM2 to obtain intermediate I; intermediate I reacts with 2-[(5-bromo-2-pyrimidinyl)oxy]ethanol to obtain intermediate II, or intermediate I first reacts with ethylene glycol to obtain intermediate Ib, and then reacts with 5-bromo-2-chloropyrimidine or 5-fluoro-2-chloropyrimidine to obtain intermediate II; finally, intermediate II is deprotected to obtain aprexitentan;

[0025] The synthetic route of the one-step method is as follows:

[0026]

[0027] The one-step method comprises the following steps:

[0028] When X in compound SM1 is a fluorine atom, compound SM1 is 5-(4-bromophenyl)-4,6-difluoropyrimidine, which reacts with sulfonamide and 2-[(5-bromo-2-pyrimidinyl)oxy]ethanol to directly obtain aprexitentan.

[0029] Preferably, the specific steps of the multi-step method are as follows:

[0030] Step 1, reacting the starting compound SM1 and the compound SM2 with a base to obtain intermediate I;

[0031] Step 2: Intermediate I and 2-[(5-bromo-2-pyrimidinyl)oxy]ethanol are reacted with a base to obtain Intermediate II; or Intermediate I is first reacted with ethylene glycol in the presence of a base, and then reacted with 5-bromo-2-chloropyrimidine or 5-fluoro-2-chloropyrimidine to obtain Intermediate II;

[0032] Step 3: remove the protecting group of intermediate II to obtain the target compound aprexitentan.

[0033] Preferably, in step 1, X of compound SM1 is one of fluorine, chlorine, bromine, iodine, OTs, OMs, and OTf, and X is preferably fluorine, chlorine, or OTf.

[0034] Preferably, in step 1, the base is one of potassium carbonate, potassium phosphate, cesium carbonate, sodium hydride, a metal salt of an alkyl alcohol having 1 to 5 carbon atoms, an amino metal salt, and 1,8-diazobisspiro[5.4.0]undec-7-ene, more preferably one of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamide, and lithium bistrimethylsilylamide.

[0035] Preferably, in step 1, the reaction solvent is one of N-methylpyrrolidone, ethylene glycol dimethyl ether, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0036] Preferably, in step 2, when intermediate I and 2-[(5-bromo-2-pyrimidinyl)oxy]ethanol are reacted with a base to obtain intermediate II, the base is potassium carbonate, potassium phosphate, cesium carbonate, sodium hydride, a metal salt of an alkyl alcohol having 1 to 5 carbon atoms, an amino metal salt, or 1,8-diazobisspiro[5.4.0]undec-7-ene, preferably sodium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamide, or lithium bistrimethylsilylamide. The reaction solvent is any one of tetrahydrofuran, methyltetrahydrofuran, N-methylpyrrolidone, ethylene glycol dimethyl ether, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0037] Preferably, in step 2, when intermediate I first reacts with ethylene glycol and then reacts with 5-bromo-2-chloropyrimidine or 5-fluoro-2-chloropyrimidine to obtain intermediate II, the base is one of potassium carbonate, potassium phosphate, cesium carbonate, sodium hydride, a metal salt of an alkyl alcohol having 1 to 5 carbon atoms, an amino metal salt, 1,8-diazobisspiro[5.4.0]undec-7-ene, preferably one of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamide, and lithium bistrimethylsilylamide; and the reaction solvent is one of tetrahydrofuran, methyltetrahydrofuran, N-methylpyrrolidone, ethylene glycol dimethyl ether, and toluene.

[0038] Preferably, in step 3, the method for removing the protecting group of intermediate II is any one of the following:

[0039] Method 1: using ammonium cerium nitrate and its hydrate or 2,3-dichloro-5,6-dicyanobenzoquinone;

[0040] Method 2: using a strong acid or Lewis acid with a pKa less than 1, wherein the strong acid is selected from trifluoroacetic acid, hydrogen chloride, trifluoromethanesulfonic acid, and methanesulfonic acid, and the Lewis acid is selected from lithium chloride, zinc chloride, aluminum chloride, titanium tetrachloride, and boron trifluoride etherate.

[0041] Preferably, the solvent of method 1 is selected from any one of acetonitrile, dichloromethane, anisole, chloroform, chlorobenzene, tetrahydrofuran, acetic acid, acetone, methanol, ethanol, isopropanol, tert-butanol, trifluoroethanol, hexafluoroisopropanol, water, or a mixed solvent thereof.

[0042] Preferably, the solvent of method 2 is selected from any one of acetonitrile, dichloromethane, chloroform, chlorobenzene, nitromethane, trifluoroethanol, and hexafluoroisopropanol.

[0043] Preferably, the one-step method specifically comprises the following steps:

[0044] Compound SM1 reacts with sulfonamide and 2-[(5-bromo-2-pyrimidinyl)oxy]ethanol in a base and a solvent to obtain the target product.

[0045] Preferably, in the one-step method, the base is one of potassium carbonate, potassium phosphate, cesium carbonate, sodium hydride, an alkyl alcohol metal salt of 1 to 5 carbon atoms, an amino metal salt, and 1,8-diazobisspiro[5.4.0]undec-7-ene, preferably one of potassium carbonate, cesium carbonate, sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium diisopropylamide, and lithium bistrimethylsilylamide.

[0046] Preferably, in the one-step method, the molar ratio of compound SM1, sulfonamide, and 2-[(5-bromo-2-pyrimidinyl)oxy]ethanol is 1:0.5-2:1-5.

[0047] Preferably, in the one-step method, the reaction temperature is 20-80°C.

[0048] Preferably, in the one-step method, the solvent is one of tetrahydrofuran, N-methylpyrrolidone, ethylene glycol dimethyl ether, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0049] A method for preparing an aprexitentan SM1 intermediate, wherein the intermediate is 5-(4-bromophenyl)-4,6-difluoropyrimidine, and the synthetic route is:

[0050]

[0051] The synthesis steps are: using 5-(4-bromophenyl)-4,6-dichloropyrimidine as a raw material, using a fluorination reagent to react in a solvent to obtain 5-(4-bromophenyl)-4,6-difluoropyrimidine.

[0052] Preferably, the fluorination agent is selected from one or both of alkali metal fluorides and organic fluoride salts.

[0053] Preferably, the fluorination agent is selected from any one of lithium fluoride, sodium fluoride, potassium fluoride, potassium bifluoride, cesium fluoride, rubidium fluoride, potassium fluoroborate, ammonium fluoride, tetrabutylammonium fluoride, and tetramethylammonium fluoride, or a mixture of two thereof.

[0054] Beneficial effects: The present invention optimizes the preparation method of aprexitentan, reduces the reaction steps, improves production efficiency and yield, is environmentally friendly, and has a low overall production cost.

[0055] The reaction conditions of the present invention are mild, no special reagents are required, the operation is simple, and the preparation method is suitable for industrial production. The material cost used is low, the yield is high, and the production cost of aprexitentan is greatly reduced. The final product aprexitentan has a high purity of more than 99.5%. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 Liquid phase detection chromatogram of SM2 in Example 1;

[0057] Figure 2 Liquid phase detection chromatogram of intermediate I in Example 1;

[0058] Figure 3 Liquid phase detection chromatogram of intermediate I-b in Example 1;

[0059] Figure 4 Liquid phase detection chromatogram of intermediate II in Example 1;

[0060] Figure 5 Liquid phase detection chromatogram of aprexitentan in Example 1;

[0061] Figure 6 MS+ detection spectrum of aprexitentan in Example 1;

[0062] Figure 7 NMR spectrum of aprexitentan in Example 1 1 HNMR. DETAILED DESCRIPTION

[0063] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0064] Unless otherwise specified, the raw materials and reagents used in the examples can be obtained from commercial sources or prepared according to conventional methods.

[0065] Example 1

[0066] Step 1

[0067]

[0068] Weigh 10.0 g of chlorosulfonyl isocyanate and add it to 36 mL of dichloromethane. Cool it to 0-5 ° C and add tert-butanol (6.8 mL) dropwise. After the addition is complete, react at room temperature. Weigh 9.7 g of 4-methoxybenzylamine and add it to 140 mL of dichloromethane. Add 7.9 g of TEA and add the above reaction solution dropwise. After the addition is complete, warm it to room temperature and react. After the reaction is complete, concentrate the dichloromethane and add 100 mL of ethyl acetate. Extract with water, separate the liquids, concentrate the ethyl acetate, add 77 mL of 4 M hydrochloric acid to the concentrate, heat it to 50-60 ° C and heat it. After the reaction is complete, cool it and crystallize it. Filter to obtain the intermediate SM2, 12.0 g of a yellow solid with a purity of 91.36% and a yield of 78%.

[0069] Step 2

[0070]

[0071] 2.0 g of intermediate SM21 was weighed and added to 120 mL of N,N-dimethylformamide, followed by 8.8 g of potassium tert-butoxide. The mixture was stirred for 0.5 h, and 14.0 g of starting material SM21 was added. The reaction mixture was poured into 120 mL of water and the pH was adjusted to 3-4 with 10% aqueous citric acid. The crude product was filtered and recrystallized from 60 mL of ethyl acetate to obtain intermediate I (18.0 g of a light yellow solid with a purity of 99.20% and a yield of 81%).

[0072] Step 3

[0073]

[0074] 70 mL of ethylene glycol was measured and 6.2 g of sodium methoxide was added in batches. Intermediate I (7.0 g) was added and the temperature was raised to 90°C for reaction. After the reaction was completed, the temperature was lowered and the mixture was added to 70 mL of water. The pH was adjusted to 3-4 with 30% citric acid. The mixture was extracted with 70 mL of ethyl acetate and washed with 70 mL of water. The solid was concentrated to obtain 6.9 g of intermediate Ib as a yellow solid with a purity of 91.2% and a yield of 93.2%.

[0075] Step 4

[0076]

[0077] 6.8 g of intermediate Ib was weighed and added to 122 mL of tetrahydrofuran. 2.3 g of DBU was added. After the addition was complete, the mixture was stirred for 0.5 h, 3.9 g of 5-bromo-2-chloropyrimidine was added, and 10% citric acid was added to adjust the pH to approximately 4. 68 mL of water and 140 mL of ethyl acetate were added, and the mixture was extracted. The ethyl acetate was concentrated, and the crude product was slurried with 50 mL of methanol at 30-40°C to obtain intermediate II as a yellow solid (7.8 g). The purity was 90.6%, and the yield was 88%.

[0078] Step 5

[0079]

[0080] Intermediate II (4.0 g) was weighed and added to 80 mL of acetonitrile, 8 mL of water, and 1.6 g of potassium carbonate. The temperature was lowered by 0-10°C, and 6.6 g of ceric ammonium nitrate was added. The reaction was carried out at 20-30°C. After the reaction was completed, the pH was adjusted to 5-6 with potassium carbonate and filtered to obtain 2.62 g of aprexitentan as an off-white solid with a purity of 97% and a yield of 80%.

[0081] Example 2

[0082] Step 1:

[0083]

[0084] 30.4 g of 5-(4-bromophenyl)-4,6-dichloropyrimidine, 11.6 g of potassium fluoride, and 2.6 g of tetrabutylammonium fluoride were added to 200 g of dimethyl sulfoxide. After stirring at 70-80°C for 24 hours, the reaction solution was poured into 700 mL of water and extracted with 200 mL of toluene. The extract was washed with water, dried, and concentrated to dryness to obtain 24.4 g of solid with a yield of 90%.

[0085] Step 2:

[0086]

[0087] 27.1 g of 5-(4-bromophenyl)-4,6-difluoropyrimidine, 22.0 g of 2-[(5-bromo-2-pyrimidinyl)oxy]ethanol, 20.0 g of sulfonamide, and 30.5 g of potassium carbonate were added to 150 g of dimethyl sulfoxide, and the mixture was reacted at 60-70° C. for 8 hours. The reaction solution was poured into 500 mL of water, and the pH was adjusted to 6-7 by adding 10% citric acid. After stirring for 2 hours, the mixture was filtered, the solid was washed with water, and then dried under reduced pressure at 60° C. to obtain 35.5 g of aprexitentan solid with a yield of 81%.

[0088] Example 3

[0089] Step 1:

[0090]

[0091] 100 g of 5-(4-bromophenyl)-4,6-dichloropyrimidine, 109 g of cesium fluoride, and 800 g of dimethyl sulfoxide were stirred at 60-70°C for 5 hours, and then 1 L of water and 1 L of ethyl acetate were added. The liquids were separated, and the organic phase was washed with 1 L of 30% citric acid aqueous solution, 1 L of water, and 1 L of saturated sodium chloride solution, respectively. The liquids were separated, and the organic phase was concentrated under reduced pressure to dryness to obtain 87.4 g of the product with a yield of 98%.

[0092] Step 2:

[0093]

[0094] 10.0 g of 5-(4-bromophenyl)-4,6-difluoropyrimidine, 7.9 g of 2-[(5-bromo-2-pyrimidinyl)oxy]ethanol, and 15.4 g of potassium carbonate were added to 800 g of dimethyl sulfoxide and reacted at 60-70° C. for 6 hours. Then, 7.12 g of sulfonamide and 15.92 g of potassium carbonate were added and reacted at 60-70° C. for 6 hours. The mixture was filtered and the filter cake was rinsed with 100 mL of ethyl acetate solution. 100 mL of 8% sodium acetate aqueous solution was added to the filtrate, the layers were separated, and the ethanol was extracted from the aqueous phase with 100 mL of ethyl acetate. The layers were separated, and the pH of the water tank was adjusted to 6.0 with 5% sulfuric acid. The mixture was stirred at room temperature for 1 hour, filtered, and the product was rinsed with plenty of water. It was then dried under reduced pressure at 60° C. to obtain 137 g of aprexitentan solid with a yield of 68%.

[0095] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing aprexitentan, characterized in that: Aprexitentan is synthesized using compound SM1 as a raw material through a one-step or multi-step method. The synthetic route is as follows: The synthetic route of the multi-step method is as follows: The multi-step method comprises the following steps: Compound SM1 reacts with compound SM2 to obtain intermediate I; intermediate I reacts with 2-[(5-bromo-2-pyrimidinyl)oxy]ethanol to obtain intermediate II, or intermediate I first reacts with ethylene glycol to obtain intermediate Ib, and then reacts with 5-bromo-2-chloropyrimidine or 5-fluoro-2-chloropyrimidine to obtain intermediate II; finally, intermediate II is deprotected to obtain aprexitentan; The synthetic route of the one-step method is as follows: The one-step method comprises the following steps: When X in compound SM1 is a fluorine atom, compound SM1 is 5-(4-bromophenyl)-4,6-difluoropyrimidine, which reacts with sulfonamide and 2-[(5-bromo-2-pyrimidinyl)oxy]ethanol to directly obtain aprexitentan.

2. The method for preparing aprexitentan according to claim 1, wherein: The specific steps of the multi-step method are as follows: Step 1, reacting the starting compound SM1 and the compound SM2 with a base to obtain intermediate I; Step 2: Intermediate I and 2-[(5-bromo-2-pyrimidinyl)oxy]ethanol are reacted with a base to obtain Intermediate II; or Intermediate I is first reacted with ethylene glycol in the presence of a base, and then reacted with 5-bromo-2-chloropyrimidine or 5-fluoro-2-chloropyrimidine to obtain Intermediate II; Step 3: remove the protecting group of intermediate II to obtain the target compound aprexitentan.

3. The method for preparing aprexitentan according to claim 2, wherein: In step 1, X of compound SM1 is one of fluorine, chlorine, bromine, iodine, OTs, OMs, and OTf; The base is one of potassium carbonate, potassium phosphate, cesium carbonate, sodium hydride, a metal salt of an alkyl alcohol having 1 to 5 carbon atoms, a metal amino salt, and 1,8-diazobisspiro[5.4.0]undec-7-ene; The reaction solvent is one of N-methylpyrrolidone, ethylene glycol dimethyl ether, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

4. The method for preparing aprexitentan according to claim 2, wherein: In step 2, When intermediate I and 2-[(5-bromo-2-pyrimidinyl)oxy]ethanol are reacted with a base to obtain intermediate II, wherein the base is one of potassium carbonate, potassium phosphate, cesium carbonate, sodium hydride, a metal salt of an alkyl alcohol having 1 to 5 carbon atoms, a metal amino salt, or 1,8-diazobisspiro[5.4.0]undec-7-ene; The reaction solvent is any one of tetrahydrofuran, methyltetrahydrofuran, N-methylpyrrolidone, ethylene glycol dimethyl ether, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; When intermediate I first reacts with ethylene glycol and then reacts with 5-bromo-2-chloropyrimidine or 5-fluoro-2-chloropyrimidine to obtain intermediate II, wherein the base is one of potassium carbonate, potassium phosphate, cesium carbonate, sodium hydride, a metal salt of an alkyl alcohol having 1 to 5 carbon atoms, a metal amino salt, or 1,8-diazobisspiro[5.4.0]undec-7-ene; The reaction solvent is one of tetrahydrofuran, methyltetrahydrofuran, N-methylpyrrolidone, ethylene glycol dimethyl ether, and toluene.

5. The method for preparing aprexitentan according to claim 2, wherein: In step 3, the method for removing the protecting group of intermediate II is any one of the following: Method 1: using ammonium cerium nitrate and its hydrate or 2,3-dichloro-5,6-dicyanobenzoquinone; Method 2: using a strong acid or Lewis acid with a pKa less than 1, wherein the strong acid is selected from trifluoroacetic acid, hydrogen chloride, trifluoromethanesulfonic acid, and methanesulfonic acid, and the Lewis acid is selected from lithium chloride, zinc chloride, aluminum chloride, titanium tetrachloride, and boron trifluoride etherate.

6. The method for preparing aprexitentan according to claim 5, wherein: The solvent of method 1 is selected from any one of acetonitrile, dichloromethane, anisole, chloroform, chlorobenzene, tetrahydrofuran, acetic acid, acetone, methanol, ethanol, isopropanol, tert-butanol, trifluoroethanol, hexafluoroisopropanol, water, or a mixed solvent thereof; The solvent of method 2 is selected from any one of acetonitrile, dichloromethane, chloroform, chlorobenzene, nitromethane, trifluoroethanol, and hexafluoroisopropanol.

7. The method for preparing aprexitentan according to claim 1, wherein: The one-step method specifically comprises the following steps: Compound SM1 reacts with sulfonamide and 2-[(5-bromo-2-pyrimidinyl)oxy]ethanol in a base and a solvent to obtain the target product; wherein the base is one of potassium carbonate, potassium phosphate, cesium carbonate, sodium hydride, a metal salt of an alkyl alcohol having 1 to 5 carbon atoms, a metal amino salt, or 1,8-diazobisspiro[5.4.0]undec-7-ene; The molar ratio of compound SM1, sulfonamide, and 2-[(5-bromo-2-pyrimidinyl)oxy]ethanol is 1:0.5-2:1-5; The reaction temperature is 20-80°C; The solvent is one of tetrahydrofuran, N-methylpyrrolidone, ethylene glycol dimethyl ether, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

8. A method for preparing an aprexitentan SM1 intermediate, characterized in that: The intermediate is 5-(4-bromophenyl)-4,6-difluoropyrimidine, and its synthesis route is: The synthesis steps are: using 5-(4-bromophenyl)-4,6-dichloropyrimidine as a raw material, using a fluorination reagent to react in a solvent to obtain 5-(4-bromophenyl)-4,6-difluoropyrimidine.

9. The method for preparing the aprexitentan SM1 intermediate according to claim 8, characterized in that: The fluorination agent is selected from one or both of alkali metal fluorides and organic fluoride salts.

10. The method for preparing the aprexitentan SM1 intermediate according to claim 9, characterized in that: The fluorination agent is selected from any one of lithium fluoride, sodium fluoride, potassium fluoride, potassium bifluoride, cesium fluoride, rubidium fluoride, potassium fluoroborate, ammonium fluoride, tetrabutylammonium fluoride, and tetramethylammonium fluoride, or a mixture of two thereof.

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