A process for the preparation of alpirotenan and intermediates

Abstract

The application relates to the technical field of organic chemistry, and provides a preparation method of aprocitentan or a salt thereof and an intermediate. The application takes a structure shown in formula C or a salt thereof as raw material, carries out a sulfonation reaction with sodium benzenesulfinate to obtain a compound or a salt thereof shown in formula G, carries out a substitution reaction between the compound or the salt thereof shown in formula G and a compound shown in formula B to generate a compound or a salt thereof shown in formula H, and finally carries out a reaction with a sulfonamide to obtain aprocitentan (Aprocitentan) or a salt thereof. The application ingeniously replaces fluorination reagents with cheap and easily obtained sodium benzenesulfinate, utilizes the reactivity of a benzene sulfone group to synthesize Aprocitentan, the raw material is easy to obtain, the cost is lower, the yield is higher, the generated fluorine by-products in the reaction are avoided, the reaction kettle is not corroded by fluorine reagents in industrial production, and the application is particularly suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic chemistry, and particularly relates to a preparation method of aprocitentan and an intermediate. BACKGROUND

[0002] Aprocitentan (CAS: 1103522-45-7) is a kind of oral antagonist targeting dual endothelin receptors, which is jointly developed by Idorsia and Janssen, is an innovative drug with a new antihypertensive mechanism, and has excellent antihypertensive effect and good tolerance, is suitable for a refractory hypertension patient group, can significantly reduce the blood pressure of patients, and the antihypertensive effect can be maintained for nearly one year. In addition to the potential inhibition of the endothelin pathway, the probability of drug-drug interaction of aprocitentan with other drugs is low, and these characteristics make aprocitentan have the potential to become a drug for treating refractory hypertension.

[0003] The synthesis route of aprocitentan reported in the patent (CN105992762A) is as follows:

[0004]

[0005] In the synthesis route, compound D or a salt thereof is reacted with tetra-n-butylammonium fluoride hydrate or cesium fluoride in the presence of a base in a polar aprotic organic solvent or a polar mixture of aprotic organic solvents to generate compound E, and then compound E is used to prepare aprocitentan (i.e. compound F). The cesium fluoride and tetrabutylammonium fluoride used in the synthesis route are expensive, and the generated hydrogen fluoride can corrode stainless steel and enamel, which is not suitable for industrial mass production. SUMMARY

[0006] Therefore, the present application provides a preparation method of aprocitentan and an intermediate. In the present application, the cheap and easily available sodium benzenesulfinate is used to replace the fluorination reagent, and the reactivity of the benzene sulfone group is used to synthesize aprocitentan, so that the yield is higher, the cost is lower, and no corrosive substances such as hydrogen fluoride are generated in the reaction process, which is particularly suitable for industrial production.

[0007] In order to achieve the above-mentioned application purposes, the present application provides the following technical solutions:

[0008] A preparation method of aprocitentan or a salt thereof, comprising the following steps:

[0009] Step I: performing a sulfonation reaction on a compound or a salt thereof shown in the structure of formula C, sodium benzenesulfinate, an acid and a solvent to obtain a compound or a salt thereof shown in the structure of formula G;

[0010] Step II: substituting the compound or salt thereof represented by the structure of formula G, the compound or salt thereof represented by the structure of formula B, a first basic compound and a solvent to obtain a compound or salt thereof represented by the structure of formula H;

[0011] Step III: sulfonamidating the compound or salt thereof represented by the structure of formula H, a sulfonamide, a second basic compound and a solvent to obtain the aprocitentan or salt thereof;

[0012]

[0013] Preferably, the acid in step I includes one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, hydrogen bromide and hydrogen iodide;

[0014] The molar ratio of the compound or salt thereof represented by the structure of formula C and the acid is 1: (0.5-4);

[0015] The molar ratio of the compound or salt thereof represented by the structure of formula C and sodium benzenesulfinate is 1: (1-5);

[0016] The solvent for the sulfonation reaction includes one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide.

[0017] Preferably, the temperature for the sulfonation reaction in step I is 70-150°C, and the reaction time is 10-30h.

[0018] Preferably, the molar ratio of the compound or salt thereof represented by the structure of formula G and the compound or salt thereof represented by the structure of formula B in step II is 1: (1-3);

[0019] The molar ratio of the compound or salt thereof represented by the structure of formula G and the first basic compound is 1: (1-4).

[0020] Preferably, the first basic compound in step II includes one or more of alkali metal hydroxides, alkali metal carbonates, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, potassium tert-butoxide and sodium hydride;

[0021] The solvent for the substitution reaction includes one or more of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide,

[0022] Preferably, the temperature for the substitution reaction in step II is 0-60°C, and the reaction time is 12-28h.

[0023] Preferably, the molar ratio of the compound or salt thereof having the structure shown in formula H to sulfonamide in step III is 1:(1-4); and the molar ratio of the compound or salt thereof having the structure shown in formula H to the second basic compound is 1:(1-3).

[0024] Preferably, the second basic compound in step III comprises one or more of alkali metal hydroxide, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, sodium methoxide, potassium tert-butoxide, and alkali metal carbonate.

[0025] The solvent for the sulfonamidation reaction in step III comprises one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0026] Preferably, the sulfonamidation reaction is carried out at a temperature of 50-150°C for 8-22 hours.

[0027] Preferably, the compound has the structure shown in formula G or formula H.

[0028]

[0029] The present application provides a preparation method of aprocitentan or a salt thereof, comprising the following steps: step I: subjecting a compound or a salt thereof having the structure shown in formula C, sodium benzenesulfinate, an acid, and a solvent to a sulfonation reaction to obtain a compound or a salt thereof having the structure shown in formula G; step II: subjecting the compound or the salt thereof having the structure shown in formula G, a compound or a salt thereof having the structure shown in formula B, a first basic compound, and a solvent to a substitution reaction to obtain a compound or a salt thereof having the structure shown in formula H; and step III: subjecting the compound or the salt thereof having the structure shown in formula H, sulfonamide, a second basic compound, and a solvent to a sulfonamidation reaction to obtain the aprocitentan or the salt thereof. The raw materials used in the present application are easy to obtain and inexpensive, and the production cost is relatively low. The use of expensive fluorine reagents is avoided. The introduction of the phenyl sulfone group avoids the generation of fluorine by-products in the reaction, and avoids the corrosion of the reaction kettle by fluorine reagents in industrial production. The reaction conditions of the present application are mild, the yield is high, the post-treatment is simple, and the present application is particularly suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 The hydrogen nuclear magnetic resonance spectrum of the compound G prepared in Example 1 of the present application;

[0031] Figure 2 The hydrogen nuclear magnetic resonance spectrum of the compound H prepared in Example 3 of the present application;

[0032] Figure 3The hydrogen nuclear magnetic resonance spectrum of Aprocitentan prepared for the embodiment 5 of the present application. DETAILED DESCRIPTION

[0033] The present application provides a preparation method of Aprocitentan or its salt, comprising the following steps:

[0034] Step I: sulfonating the compound or its salt of the structure shown in formula C, sodium benzene sulfinate, an acid and a solvent to obtain a compound or its salt of the structure shown in formula G;

[0035] Step II: substituting the compound or its salt of the structure shown in formula G, the compound or its salt of the structure shown in formula B, a first basic compound and a solvent to obtain a compound or its salt of the structure shown in formula H;

[0036] Step III: sulfonamidating the compound or its salt of the structure shown in formula H, a sulfonamide, a second basic compound and a solvent to obtain the Aprocitentan or its salt;

[0037]

[0038] The route for synthesizing Aprocitentan or its salt of the present application is as follows:

[0039]

[0040] The preparation method of the present application is described in detail below in combination with the synthesis route.

[0041] Step I: the present application carries out a sulfonation reaction by mixing a compound or salt thereof having a structure shown in formula C, sodium benzenesulfinate, an acid and a solvent, to obtain a compound or salt thereof having a structure shown in formula G. In the present application, the acid preferably includes one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, hydrogen bromide and hydrogen iodide, more preferably hydrochloric acid or acetic acid, the hydrochloric acid is preferably used in the form of concentrated hydrochloric acid, and the acetic acid is preferably used in the form of glacial acetic acid; the molar ratio of the compound or salt thereof having a structure shown in formula C to the acid is preferably 1:(0.5-4), more preferably 1:(1-2); the molar ratio of the compound or salt thereof having a structure shown in formula C to sodium benzenesulfinate is preferably 1:(1-5), more preferably 1:(2-3); the salt of the compound having a structure shown in formula C is preferably a hydrochloride or acetate of formula C, and correspondingly, the salt of the compound having a structure shown in formula G and the salt of the compound having a structure shown in formula H obtained subsequently are also preferably hydrochlorides or acetates; the solvent for the sulfonation reaction preferably includes one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide, more preferably acetonitrile or N,N-dimethylformamide; the temperature for the sulfonation reaction is preferably 70-150°C, more preferably 80-100°C, and the reaction time is preferably 10-30h, more preferably 12-18h.

[0042] In a specific embodiment of the present application, the compound having a structure shown in formula C is first dissolved in a solvent, then sodium benzenesulfinate is added, the system is stirred for 10 min, and then the acid is added dropwise, after the acid addition is completed, the system is heated to 70-150°C for reaction.

[0043] After the sulfonation reaction is completed, the present application preferably mixes the obtained reaction solution with water and stirs to separate the product, the separated solid product is filtered and separated, and then washed and dried in sequence, to obtain the compound or salt thereof having a structure shown in formula G; the washing is preferably washing with water and n-hexane in sequence.

[0044] After obtaining the compound or salt thereof shown in the structure of formula G, the present application mixes the compound or salt thereof shown in the structure of formula G, the compound or salt thereof shown in the structure of formula B, a first basic compound and a solvent to perform a substitution reaction, thereby obtaining a compound or salt thereof shown in the structure of formula H. In the present application, the chemical name of the compound shown in the structure of formula B is 2-((5-bromopyrimidin-2-yl)oxy)ethanol; the molar ratio of the compound or salt thereof shown in the structure of formula G to the compound or salt thereof shown in the structure of formula B is preferably 1:(1-3), more preferably 1:(1-2); the molar ratio of the compound or salt thereof shown in the structure of formula G to the first basic compound is preferably 1:(1-4), more preferably 1:(1.5-2.5); the first basic compound preferably comprises one or more of alkali metal hydroxide, alkali metal carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, potassium tert-butoxide and sodium hydride, and the alkali metal hydroxide is preferably potassium hydroxide or sodium hydroxide; the alkali metal carbonate is preferably potassium carbonate, sodium carbonate or cesium carbonate; in a specific embodiment of the present application, the first basic compound is most preferably potassium tert-butoxide or K2CO3; and the solvent for the substitution reaction preferably comprises one or more of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide, more preferably toluene or chlorobenzene.

[0045] In the present application, the temperature for the substitution reaction is preferably 0-60°C, more preferably 30-40°C, and the reaction time is preferably 12-28h, more preferably 15-20h.

[0046] In a specific embodiment of the present application, the compound shown in the structure of formula G, the compound shown in the structure of formula B and the solvent are mixed first, then the first basic compound is added in batches at 0°C, and the reaction is performed at the temperature of the substitution reaction.

[0047] After the substitution reaction is completed, the present application preferably quenches the reaction solution with water, separates the layers to obtain an aqueous phase, extracts the aqueous phase with ethyl acetate, washes the obtained organic phase with brine and then concentrates it to obtain a crude product; the crude product is added to methanol and heated to reflux, then cooled to room temperature, and the solid is precipitated under the condition of an ice water bath, the solid is filtered, washed and dried to obtain the compound or salt thereof shown in the structure of formula H; the time for heating to reflux is preferably 30min, and the washing agent for washing is preferably n-hexane.

[0048] After obtaining the compound of formula H, the present application mixes the compound of formula H or its salt, sulfonamide, a second basic compound and a solvent to perform a sulfonamide reaction to obtain the aprocitentan or its salt. In the present application, the molar ratio of the compound of formula H or its salt to sulfonamide is preferably 1:(1-4), more preferably 1:(1-2); the molar ratio of the compound of formula H or its salt to the second basic compound is preferably 1:(1-3), more preferably 1:(1-2); the second basic compound preferably comprises one or more of alkali metal hydroxide, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, sodium methoxide, potassium tert-butoxide and alkali metal carbonate; the alkali metal hydroxide is preferably potassium hydroxide or sodium hydroxide; the alkali metal carbonate is preferably potassium carbonate, sodium carbonate or cesium carbonate; in a specific embodiment of the present application, the second basic compound is most preferably sodium methoxide or K2CO3; the solvent for the sulfonamide reaction preferably comprises one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide, more preferably dimethyl sulfoxide or N,N-dimethylformamide.

[0049] In the present application, the temperature for the sulfonamide reaction is preferably 50-150°C, more preferably 60-90°C, and the reaction time is preferably 8-22h, more preferably 10-16h.

[0050] After the sulfonamide reaction is completed, the present application preferably adds water to quench the reaction, mixes the obtained reaction liquid with hydrochloric acid solution to obtain an acidified reaction liquid, performs a first extraction on the acidified reaction liquid using ethyl acetate to obtain a first organic phase and a first aqueous phase; adjusts the pH value of the first aqueous phase to 9 and performs a second extraction using ethyl acetate to obtain a second organic phase and a second aqueous phase; adjusts the pH value of the second aqueous phase to 14 and performs a third extraction using ethyl acetate to obtain a third organic phase and a third aqueous phase; combines the first organic phase, the second organic phase and the third organic phase, concentrates, dries the concentrated residue to obtain the aprocitentan or its salt, and the structure of the aprocitentan is shown in formula F in the synthesis route.

[0051] The present application also provides an intermediate for preparing aprocitentan, having a structure shown in formula G or formula H.

[0052]

[0053] The preparation method of the compound having a structure shown in formula G or formula H is not described here again.

[0054] The technical solutions in the present application will be described clearly and completely below in combination with the embodiments in the present application. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by those skilled in the art without creative work belong to the scope of protection of the present application.

[0055] In the following examples, the compounds having the structures shown in Formula C, Formula G and Formula H are referred to as Compound C, Compound G and Compound H respectively.

[0056] Synthesis of Compound G in Example 1

[0057] Compound C (20 g, 65.80 mmol, 1.0 eq) was dissolved in 200 mL of acetonitrile in a 500 mL reaction bottle, sodium benzenesulfinate (32.41 g, 197.4 mmol, 3.0 eq) was added, stirred for 10 min, glacial acetic acid (3.95 g, 65.80 mmol, 1.0 eq) was added dropwise, the reaction liquid was heated to 90°C, after 18 hours of reaction, 600 mL of water was added and stirred for 2 hours to precipitate, the precipitated solid was suction filtered, washed with water and n-hexane in turn and dried to obtain white solid Compound G (24.26 g, 90% yield). 1 H NMR (400 MHz, CDCI3) δ 7.60-7.53 (m, 3H), 7.50-7.44 (m, 1H), 7.44-7.38 (m, 2H), 7.37-7.30 (m, 4H). The hydrogen nuclear magnetic resonance spectrum of Compound G is shown in Figure 1 .

[0058] Synthesis of Compound G in Example 2

[0059] Compound C (20 g, 65.80 mmol, 1.0 eq) was dissolved in 200 mL of N,N- dimethylformamide in a 500 mL reaction bottle, sodium benzenesulfinate (32.41 g, 197.4 mmol, 2.5 eq) was added, stirred for 10 min, concentrated hydrochloric acid (36% concentration, 6.67 g, 65.80 mmol, 1.0 eq) was added dropwise, the reaction liquid was heated to 100°C, after 12 hours of reaction, 600 mL of water was added and stirred for 2 hours to precipitate, the precipitated solid was suction filtered, washed with water and n-hexane in turn and dried to obtain white solid Compound G (24.83 g, 92% yield).

[0060] Synthesis of Compound H in Example 3

[0061] In a reaction flask was added compound G (20 g, 48.82 mmol, 1.0 eq) and 2-((5- bromopyrimidin-2-yl)oxy)ethanol (10.69 g, 48.82 mmol, 1.0 eq), chlorobenzene (200 mL), K2CO3 (7.91 g, 73.23 mmol, 1.5 eq) was added portion wise at 0 °C, followed by incubation at 20 °C for 20 h, quenched with water, separated the layers, extracted the aqueous phase with ethyl acetate 50 mL three times, combined the organic phases, washed with brine and concentrated, dried under vacuum, added methanol (50 mL) and heated to reflux for half an hour, slowly decreased to room temperature, ice water bath for 2 h to precipitate the solid, filtered, the solid obtained was washed with a small amount of n-hexane and dried to obtain compound H as a white solid (25.81 g, 89% yield). 1 H NMR (400 MHz, CDC13) δ 8.71 (s, 1H), 8.47 (s, 2H), 7.75-7.68 (m, 2H), 7.64-7.58 (m, 1H), 7.50-7.42 (m, 4H), 7.08-7.03 (m, 2H), 4.77-4.68 (m, 2H), 4.63-4.56 (m, 2H). The hydrogen nuclear magnetic resonance spectrum of compound H is shown in Figure 2

[0062] Synthesis of compound H of example 4

[0063] In a reaction flask was added compound G (20 g, 48.82 mmol, 1.0 eq) and 2-((5- bromopyrimidin-2-yl)oxy)ethanol (10.69 g, 48.82 mmol, 1.0 eq), chlorobenzene (200 mL), K2CO3 (7.91 g, 73.23 mmol, 1.5 eq) was added portion wise at 0 °C, followed by incubation at 20 °C for 20 h, quenched with water, separated the layers, extracted the aqueous phase with ethyl acetate 50 mL three times, combined the organic phases, washed with brine and concentrated, dried under vacuum, added methanol (50 mL) and heated to reflux for half an hour, slowly decreased to room temperature, ice water bath for 2 h to precipitate the solid, filtered, the solid obtained was washed with a small amount of n-hexane and dried to obtain compound H as a white solid (25.81 g, 89% yield).

[0064] Synthesis of aprocitentan of example 5

[0065] ​A mixture of compound H (50 g, 84.42 mmol, 1.0 eq), sulfonamide (12.17 g, 126.63 mmol, 1.5 eq), K2CO3(13.67 g, 126.63 mmol, 1.5 eq) and N,N-dimethylformamide (200 mL) was heated to 90 °C, after 10 hours of reaction, quenched with water, first added 2 mol / L hydrochloric acid (100 mL) to acidify the reaction solution, extracted with 600 mL of ethyl acetate, then the pH of the aqueous phase was adjusted to 9, extracted with 600 mL of ethyl acetate once, finally the pH of the aqueous phase was adjusted to 14, extracted with 600 mL of ethyl acetate once again, the organic phase was combined, concentrated and dried to obtain white solid compound as Aprocitentan (41.90 g, 91% yield). 1 H NMR (400 MHz, CDC13) δ 8.48 (s, 2H), 8.23 (s, 1H), 7.54-7.50 (m, 2H), 7.23-7.17 (m, 2H), 4.91 (s, 1H), 4.70-4.65 (m, 2H), 4.63-4.59 (m, 2H). The hydrogen nuclear magnetic resonance spectrum of Aprocitentan is shown in Figure 3

[0066] Example 6 Synthesis of Aprocitentan

[0067] A mixture of compound H (50 g, 84.42 mmol, 1.0 eq), sulfonamide (12.17 g, 126.63 mmol, 1.5 eq), K2CO3(13.67 g, 126.63 mmol, 1.5 eq) and N,N-dimethylformamide (200 mL) was heated to 90 °C, after 10 hours of reaction, quenched with water, first added 2 mol / L hydrochloric acid (100 mL) to acidify the reaction solution, extracted with 600 mL of ethyl acetate, then the pH of the aqueous phase was adjusted to 9, extracted with 600 mL of ethyl acetate once, finally the pH of the aqueous phase was adjusted to 14, extracted with 600 mL of ethyl acetate once again, the organic phase was combined, concentrated and dried to obtain white solid compound as Aprocitentan (41.90 g, 91% yield).

[0068] ​The above embodiment results show that the preparation method of procitentan provided by the application uses compound C or a salt thereof as raw material, reacts with sodium benzenesulfinate to obtain compound G or a salt thereof, compound G or a salt thereof is subjected to substitution reaction with compound B to generate compound H or a salt thereof, the obtained compound H is similar in structure to compound E, and is subjected to reaction with sulfonamide to obtain Aprocitentan or a salt thereof. The application ingeniously uses cheap and readily available sodium benzenesulfinate to replace fluorination reagents, and uses the reactivity of a benzene sulfone group to synthesize Aprocitentan, so that the yield is higher, the cost is lower, and the application is particularly suitable for industrial production.

[0069] The above only describes the preferred embodiments of the application, and it should be noted that those skilled in the art can make several improvements and refinements without departing from the principles of the application, and these improvements and refinements should also be considered as the protection scope of the application.

Claims

1. A method for preparing apxitentan or a salt thereof, characterized in that, Includes the following steps: Step I: The compound with the structure shown in Formula C or its salt, sodium benzenesulfonate, acid and solvent are mixed and subjected to a sulfonation reaction to obtain the compound with the structure shown in Formula G or its salt. The acid in step I is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, hydrogen bromide, and hydrogen iodide; Step II: Mix the compound with the structure shown in Formula G or its salt, the compound with the structure shown in Formula B or its salt, the first basic compound and the solvent to carry out a substitution reaction to obtain the compound with the structure shown in Formula H or its salt. The first basic compound in step II is selected from one or more of alkali metal hydroxides, alkali metal carbonates, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, potassium tert-butoxide, and sodium hydrogen. Step III: The compound with the structure shown in Formula H or its salt, sulfonamide, second basic compound and solvent are mixed and subjected to a sulfonation reaction to obtain alpracententan or its salt; The second basic compound in step III is selected from one or more of alkali metal hydroxides, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, sodium methoxide, potassium tert-butoxide, and alkali metal carbonates; Formula C; Formula G; Formula B; Formula H.

2. The preparation method according to claim 1, characterized in that, In step I, the molar ratio of the compound with the structure shown in formula C or its salt to the acid is 1:(0.5~4). The molar ratio of the compound with the structure shown in Formula C or its salt to sodium benzenesulfinate is 1:(1~5); The solvent for the sulfonation reaction includes one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide.

3. The preparation method according to claim 1 or 2, characterized in that, In step I, the sulfonation reaction temperature is 70℃~150℃, and the reaction time is 10~30h.

4. The preparation method according to claim 1, characterized in that, In step II, the molar ratio of the compound or its salt with the structure shown in formula G to the compound or its salt with the structure shown in formula B is 1:(1~3); The molar ratio of the compound with the structure shown in Formula G or its salt to the first basic compound is 1:(1~4).

5. The preparation method according to claim 1 or 4, characterized in that, The solvent for the substitution reaction in step II includes one or more of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide.

6. The preparation method according to claim 1 or 4, characterized in that, The temperature of the substitution reaction in step II is 0℃~60℃, and the reaction time is 12~28h.

7. The preparation method according to claim 1, characterized in that, In step III, the molar ratio of the compound with the structure shown in formula H or its salt to the sulfonamide is 1:(1~4); the molar ratio of the compound with the structure shown in formula H or its salt to the second basic compound is 1:(1~3).

8. The preparation method according to claim 1 or 7, characterized in that, The solvent for the sulfonation reaction in step III includes one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide.

9. The preparation method according to claim 1 or 7, characterized in that, The sulfonamide reaction in step III is carried out at a temperature of 50℃ to 150℃ for a reaction time of 8 to 22 hours.

10. An intermediate for the preparation of apraxitentan, characterized in that, It has the structure shown in formula G or formula H: Formula G; Formula H.

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