Synthesis method for dual endothelin receptor antagonist aprocitentan

Abstract

Provided in the present invention is a synthesis method for aprocitentan, comprising the following steps: 1) a compound of formula X and a sulfonylation reagent compound of formula XI undergoing a sulfonylation reaction to prepare a compound of formula XII; and 2) removing an R protective group on the pyrimidine sulfonamide compound of formula XII obtained in the previous step, so as to obtain aprocitentan. The synthesis method of the present invention overcomes the problem in the prior art that preparing macitentan by means of condensation of chloropyrimidine and sulfonamide needs to use an excessive amount of a strong base and involves a relatively low conversion efficiency, relatively many side products and other defects. The synthesis method does not need using a fluorine reagent for fluorination, involves economical steps, is environmentally-friendly, and has a relatively low comprehensive production cost. Compared with existing methods for preparing aprocitentan, the method of the present invention has characteristics of easily available raw materials, being environmentally-friendly and economical, and the like, thereby facilitating the industrial production of aprocitentan.

Description

A method for synthesizing a dual endothelin receptor antagonist aprexitentan Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a method for synthesizing aprexitentan, a dual endothelin receptor antagonist. Background Art

[0002] Aprocitentan, formerly known as ACT-132577, is a dual endothelin receptor antagonist jointly developed by Idorsia Pharmaceuticals and Janssen. Results from a Phase III clinical trial (PRECISION) reported in Lancet 2022;400:1927-37 demonstrated that aprocitentan significantly reduced both diastolic and systolic blood pressure in participants, was well tolerated, and had a low rate of adverse reactions with other medications, suggesting potential for the treatment of patients with refractory hypertension.

[0003] The chemical name of aprexitentan is: {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy-pyrimidin-4-yl}-sulfonamide, CAS registration number: 1103522-45-7, chemical formula: C 16 H 14 Br2N6O4S, molecular weight: 546.19. Aprexitentan is a metabolite of macitentan, a drug for the treatment of pulmonary arterial hypertension. The chemical structures of the two are shown below:

[0004] 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.

[0005] 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:

[0006] 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 ethylene glycol in the presence of a strong base to obtain the compound of formula I, as shown in the reaction formula:

[0007] 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 Registry 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 II 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.

[0008] International patent WO 2015121397 (corresponding to Chinese patent CN 105992762B and divisional application CN 107162988B) reports an alternative route for producing aprexitentan. This route employs a post-introduction sulfonamide fragment synthesis strategy, comprising 1) reacting a compound of formula VII with a compound of formula V to prepare a chloropyrimidine compound of formula VIII; 2) reacting the compound of formula VIII with a fluorinated reagent to prepare a fluorinated pyrimidine compound of formula IX; and 3) reacting a sulfonamide (compound of formula IV-b) with a compound of formula IX in the presence of a strong base to obtain aprexitentan or a salt thereof. The specific route is as follows:

[0009] 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, after the compound of Formula IX reacts with the compound of Formula IV-b, the byproducts produced by the fluoride anion 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.

[0010] In addition, in the quality study of the raw material of macitentan, as reported in the literature Xenobiotica 2012; 42: 901-910, the compound of formula X is a major metabolite of macitentan, and its name in the literature is ACT-080803, as shown below

[0011] Other public documents and patents also utilize methods for degrading macitentan to obtain a standard sample of Compound X to meet the quality control requirements of the macitentan API. Chinese patents CN 106478520B and CN 106279043B, and the publication Monash Chem 2018;149:653-661, respectively, report methods for preparing Compound X by hydrolyzing macitentan under alkaline, neutral, and acidic conditions. However, these methods are only suitable for preparing small quantities of impurity standards required for quality control studies of macitentan and are not suitable for large-scale industrial production of Compound X.

[0012] The defects of the prior art are:

[0013] 1) The prior art generally uses condensation of a chloropyrimidine compound of Formula VIII with a sulfonamide to obtain aprexitentan. However, due to poor group design during the condensation process, the conversion efficiency is low. For example, when using a compound of Formula VI to prepare a compound of Formula I via an aromatic nucleophilic substitution reaction, a large excess of strong base is required. Furthermore, due to reduced reactivity, the reaction is difficult and requires harsh conditions. Similarly, the aromatic nucleophilic substitution reaction of a compound of Formula I with a compound of Formula II to prepare a compound of Formula III also suffers from the disadvantages of requiring a large excess of base and producing a large number of byproducts.

[0014] 2) The conversion rate of the condensation reaction of the chloropyrimidine compound of formula VIII with sulfonamide is low. The chlorine substituent of the pyrimidine needs to be converted to fluorine in advance using a fluorine reagent to enhance the reaction activity and improve the condensation conversion efficiency. However, there are disadvantages such as increased synthesis steps, severe corrosion of equipment by the fluorine reagent, and higher overall production costs.

[0015] 3) 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 starting 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.

[0016] Summary of the Invention

[0017] In view of the shortcomings of the prior art, the object of the present invention is to provide an improved synthesis method of aprexitentan to better meet the requirements of industrialization.

[0018] To achieve the above-mentioned object of the invention, the core of the present invention is to provide a method for preparing aprexitentan by sulfonylation reaction of pyrimidineamine, and at the same time provide a large-scale preparation method of the pyrimidineamine required by the method.

[0019] In a first aspect, the present invention provides a method for synthesizing aprexitentan using a pyrimidineamine compound of formula X. The technical solution is as follows:

[0020] 1) Compound X is reacted with a sulfonylating agent, compound XI, to prepare compound XII

[0021] The sulfonylating agent compound of formula XI can be the following sulfonamide:

[0022] Wherein: X represents a leaving group selected from: Cl, or -OC6F5; R represents H, or a protecting group CO2Me, CO2t-Bu, CO2Bn;

[0023] Alternatively, the sulfonylating agent compound of formula XI may also be the following Burgess reagent:

[0024] Wherein: R' can be an alkyl group such as methyl, ethyl, tert-butyl, benzyl, etc.;

[0025] 2) Removing the R protecting group of the pyrimidine sulfonamide compound of formula XII obtained in the previous step to obtain aprexitentan

[0026] According to the method of the present invention, in step 1), the amount of the sulfonylating agent compound of formula XI is 1 to 2 equivalents of the raw material compound of formula X, preferably 1.0 to 1.5 equivalents.

[0027] According to the method of the present invention, wherein, in step 1), the sulfonylation reaction is carried out in the presence of a base, and the base is an organic base or an inorganic base; wherein the organic base is selected from one of triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine; the inorganic base is selected from one of sodium carbonate, potassium carbonate, or sodium hydroxide; and the amount of the base used is 1 to 5 equivalents of the compound of formula X, preferably 2.5 to 3.0 equivalents.

[0028] According to the method of the present invention, wherein, in step 1), the solvent used in the reaction is selected from one or more of dichloromethane, tetrahydrofuran, and toluene; wherein the sulfonylating agent formula XI compound is In the case of, the solvent used in the reaction can also be selected from acetonitrile and / or dimethylformamide.

[0029] According to the method of the present invention, wherein, in step 1), the reaction temperature is 0-60°C.

[0030] According to the method of the present invention, in step 1), in particular, when X=Cl and R=H, aprexitentan can be directly obtained by the above reaction.

[0031] Under this process condition,

[0032] The base is selected from triethylamine, pyridine, diisopropylethylamine, or 2,6-lutidine;

[0033] The solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene, acetonitrile and dimethylformamide;

[0034] The reaction temperature range is 0-60°C.

[0035] According to the method of the present invention, in step 2),

[0036] Method A: When R = CO2tBu, R = CO2Bn, remove the protecting group under acidic conditions;

[0037] The acid is a protonic acid or a Lewis acid, the protonic acid is selected from HCl, H2SO4 or trifluoroacetic acid, and the Lewis acid is selected from boron tribromide or boron trichloride;

[0038] The acidic removal reaction solvent is selected from THF or dichloromethane.

[0039] According to the method of the present invention, in step 2),

[0040] Method B: When R = CO2CH3, remove the protecting group under alkaline conditions;

[0041] The base is selected from one of sodium carbonate, potassium carbonate, lithium hydroxide and sodium hydroxide;

[0042] The alkaline removal reaction solvent is selected from THF, toluene, dichloromethane or a mixed solvent of C1-C4 alcohol and water.

[0043] In another aspect, the present invention provides three methods for large-scale preparation of pyrimidine amine compounds of formula X to meet the requirements of the present invention for manufacturing aprexitentan. The synthetic routes are shown in the figure below:

[0044] Wherein: Route 1 comprises: step a) condensing a dichloropyrimidine compound of formula V with a pyrimidinol compound of formula VII under alkaline conditions to obtain an ether compound of formula VIII; step b) aminolyzing the ether compound of formula VIII in the presence of a base and a phase transfer catalyst to obtain a pyrimidinamine compound of formula X.

[0045] The equivalent ratio of the dichloropyrimidine compound of formula V, the pyrimidinol compound of formula VII and the base in step a) is 1:1.1-1.3:1.1-1.3, preferably 1:1.2:1.2;

[0046] The base in step a) is selected from potassium tert-butoxide or potassium carbonate;

[0047] The solvent of step a) is selected from toluene;

[0048] The reaction temperature of step a) is in the range of 0 to 5°C;

[0049] The ammonia source in step b) is selected from ammonia gas or ammonia water;

[0050] The phase transfer catalyst in step b) is selected from tetrabutylammonium fluoride, tetrabutylammonium chloride or tetrabutylammonium bromide;

[0051] The base in step b) is selected from sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate;

[0052] The equivalent ratio of the ether compound VIII, ammonia source, base and phase transfer catalyst is 1:2.5-3.5:1.2-1.7:0.2-1.2, preferably 1:3.0:1.5:0.5;

[0053] The solvent of step b) is selected from tetrahydrofuran (THF), acetonitrile, ethanol, dimethyl sulfoxide (DMSO) or dimethylformamide (DMF);

[0054] The reaction temperature of step b) is in the range of 80-100°C;

[0055] Route 2 comprises: step c) aminolysis of a dichloropyrimidine compound of formula V to obtain a pyrimidineamine compound of formula X-1; step d) condensing the pyrimidineamine compound of formula X-1 with ethylene glycol under alkaline conditions to obtain an ether compound of formula X-2; and step e) condensing the ether compound of formula X-2 with 5-bromo-2-chloropyrimidine under alkaline conditions to obtain the pyrimidineamine compound of formula X.

[0056] The ammonia source in step c) is selected from ammonia gas or ammonia water;

[0057] The solvent in step c) is selected from one or two of tetrahydrofuran (THF), ethanol, or toluene;

[0058] The reaction temperature of step c) is in the range of 10 to 60°C;

[0059] The base in step d) is selected from sodium hydroxide, lithium hydroxide or potassium hydroxide;

[0060] The solvent of step d) is selected from toluene;

[0061] The reaction temperature of step d) is in the range of 90-110°C;

[0062] The base in step e) is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide or potassium carbonate;

[0063] The equivalent ratio of the ether X-2 compound, 5-bromo-2-chloropyrimidine and base is 1:1.1-1.4:2.0-5.0, preferably 1:1.2:4.0;

[0064] The solvent in step e) is selected from THF, toluene, acetonitrile, DMF or dioxane;

[0065] The reaction temperature of step e) is in the range of 20 to 60°C;

[0066] Route 3 comprises: step c) subjecting a dichloropyrimidine compound of formula V to aminolysis to obtain a pyrimidineamine compound of formula X-1; and step f) directly condensing the pyrimidineamine compound of formula X-1 with a pyrimidinol compound of formula VII in the presence of a base and a phase transfer catalyst to obtain the pyrimidineamine compound of formula X.

[0067] The base in step f) is selected from potassium tert-butoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide;

[0068] The phase transfer catalyst in step f) is selected from one of the quaternary ammonium salt catalysts tetrabutylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium fluoride;

[0069] The equivalent ratio of the pyrimidineamine compound of formula X-1, the pyrimidine alcohol compound of formula VII, the base and the phase transfer catalyst in step f) is 1:1.1-1.3:1.5-3.0:0.2-0.6, preferably 1:1.2:2.5:0.5;

[0070] The solvent in step f) is selected from toluene, acetonitrile, dioxane or DMF;

[0071] The reaction temperature of step f) is in the range of 70-110°C; Beneficial effects

[0072] The outstanding advantages of the present invention compared to the prior art are:

[0073] 1) The present invention designs and implements a sulfonylation reaction of a pyrimidineamine compound of formula X with a sulfonylation agent to prepare aprecitentan. The conversion efficiency of the sulfonylation reaction is significantly improved, overcoming the shortcomings of the prior art of using a chloropyrimidine compound of formula VIII and a sulfonamide for condensation to obtain macitentan, which requires the use of an excess of strong base, has low conversion efficiency, and produces a large number of by-products.

[0074] 2) The present invention designs and implements a sulfonylation reaction of a pyrimidineamine compound of formula X with a sulfonylation agent to prepare aprexitentan, without the need for fluorination using a fluorine agent. The process is economical, environmentally friendly, and has a low overall production cost.

[0075] 3) The method for preparing the pyrimidineamine compound of formula X, which is the raw material of aprexitentan, and the method for preparing aprexitentan by sulfonylation using the compound of the present invention have the advantages of readily available raw materials, environmental protection, and economy compared to existing methods for preparing aprexitentan, and are conducive to the industrial production of aprexitentan. DETAILED DESCRIPTION

[0076] The present invention will be described in detail below in conjunction with specific embodiments and examples, and the advantages and various effects of the present invention will be more clearly presented. It should be understood by those skilled in the art that these specific embodiments and examples are for illustrating the present invention, rather than limiting the present invention.

[0077] The analysis conditions of the compounds of the present invention are as follows: 1 H NMR, 13 C NMR was measured using a Bruker Avance 400 nuclear magnetic resonance instrument; HRMS was measured using a Waters Xevo G2-XS QTof high-resolution mass spectrometer, and the ion source was an ESI source.

[0078] Example 1: Preparation of Compound VIII

[0079] Under nitrogen, a reaction flask was charged with 5-(4-bromophenyl)-4,6-dichloropyrimidine (Formula V, 30.4 g; 100.0 mmol) and 2-((5-bromopyrimidin-2-yl)oxy)ethanol VII (26.3 g; 120.1 mmol; 1.2 equivalents) in toluene (200 mL). The mixture was cooled to 0-5°C and finely powdered potassium carbonate (15.9 g; 115.1 mmol; 1.15 equivalents) was added portionwise over 1 hour with stirring. The reaction was continued with stirring at 0-5°C for 2 hours. Upon completion of the reaction, the mixture was acidified by adding 40% aqueous citric acid to adjust the pH to approximately 2-3. The organic phase was separated, washed twice with water (100 mL), and concentrated to dryness under reduced pressure to obtain the crude title compound. Methanol was added to the oil and refluxed to precipitate a solid. The solid was slowly cooled to 10-15°C with stirring and filtered. The filter cake was washed with a small amount of methanol and dried under vacuum to obtain the title compound 5-(4-bromophenyl)-4-[2-[(5-bromopyrimidinyl)-2-oxy]ethoxy]-6-chloropyrimidine VIII (42.3 g; 87% yield). HRMS m / z (ESI): C 16 H 12 Br2ClN4O2[M+H +]Theoretical calculated value: 484.9010, measured value: 484.9016.

[0080] Example 2: Preparation of Compound X-1

[0081] Under nitrogen protection, 5-(4-bromophenyl)-4,6-dichloropyrimidine V (2.7 g, 9.0 mmol, 1 equivalent), ammonia (23 g, 180 mmol, 20 equivalents), and THF (15 mL) were added to the reaction flask. The mixture was heated to 50 ° C and stirred for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature and water (50 mL) and dichloromethane (20 mL) were added. The organic phase was separated, washed twice with water (100 mL), and concentrated to dryness under reduced pressure to obtain pyrimidineamine X-1 (2.2 g, 87% yield). HRMS m / z (ESI): C 10 H8BrClN3[M+H + ]Theoretical calculated value: 283.9585, measured value: 283.9589.

[0082] Example 3: Preparation of Compound X-1

[0083] Under nitrogen protection, 5-(4-bromophenyl)-4,6-dichloropyrimidine V (2.7 g, 9.0 mmol, 1 equivalent) and 20% ammonia in ethanol (15 g, 180 mmol, 20 equivalents) were added to a pressure vessel at room temperature. The mixture was heated to 50 ° C and stirred in a closed container for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature and water (50 mL) and dichloromethane (20 mL) were added. The organic phase was separated, washed twice with water (100 mL), and concentrated to dryness under reduced pressure to obtain pyrimidineamine X-1 (2.0 g, 82% yield). HRMS m / z (ESI): C 10 H8BrClN3[M+H + ]Theoretical calculated value: 283.9585, measured value: 283.9581.

[0084] Example 4: Preparation of Compound X-2

[0085] Pyrimidineamine X-1 (1.43 g, 5 mmol, 1.0 eq), toluene (15 mL, 10 V), sodium hydroxide (0.4 g, 10 mmol, 2.0 eq), and ethylene glycol (2.8 ml, 50 mmol, 10.0 eq) were added to a reaction flask. The mixture was heated to 100°C and stirred for 10 hours. After the reaction was completed, 15 mL of saturated brine was added, extracted, and the organic phase was separated and concentrated to dryness under reduced pressure to obtain compound X-2 (1.43 g; 92% yield). HRMS m / z (ESI): C 12 H13 BrN3O2[M+H + ]Theoretical calculated value: 310.0186, measured value: 310.0182.

[0086] Example 5: Preparation of Compound X

[0087] In a sealed pressure reactor, compound VIII (24.3 g; 50.0 mmol) was added to 30% aqueous ammonia (8.5 g; 150 mmol; 3 equivalents), potassium carbonate (10.35 g; 75.0 mmol, 1.5 equivalents), tetrabutylammonium fluoride (6.5 g; 25 mmol, 0.5 equivalents) and THF (120 mL) at room temperature, and the temperature was raised to 80°C for 7 hours. After the reaction, the reaction solution was concentrated to dryness under reduced pressure, dissolved in dichloromethane (250 mL), washed twice with 5% aqueous sodium chloride solution, and the organic layer was concentrated to dryness under reduced pressure. The residue was added with methanol (200 mL), heated to reflux, slowly cooled to 0-5°C, stirred to crystallize, filtered, and the filter cake was washed with ethanol and dried under vacuum to obtain the title compound X (20.9 g; 90% yield). HRMS m / z (ESI): C 16 H 14 Br2N5O2[M+H + ]Theoretical calculated value: 465.9509, measured value: 465.9502; 1 H-NMR (400MHz, CD3OD) δ: 8.71 (s, 2H), 8.11 (s, 1H), 7.50 (d, J = 7.6Hz, 2H), 7.18 (d, 2H), 6.27 (br, 2H), 3.97 (m, 4H).

[0088] According to the operation process and material ratio of Example 5, only the ammonia source, solvent type, base type, and reaction temperature were changed. The synthesis of pyrimidineamine X is shown in the following table:

[0089] Example 12: Preparation of Compound X

[0090] Ether X-2 (1.86 g, 6 mmol, 1.0 eq) and THF (18 ml, 10 V) were added to the reaction flask, followed by sodium hydroxide (0.96 g, 240 mmol, 4.0 eq). 5-Bromo-2-chloropyrimidine (1.39 g, 7.2 mmol, 1.2 eq) was added with stirring and the mixture was stirred at room temperature (25 ° C) for 12 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, dissolved in ethyl acetate (25 mL), washed twice with 5% sodium chloride aqueous solution, and the organic layer was concentrated to dryness under reduced pressure. The residue was added with ethanol (15 mL), heated to dissolve, slowly cooled to 0-5 ° C, stirred to crystallize, filtered, and the filter cake was washed with ethanol and dried under vacuum to obtain pyrimidine amine X (2.52 g, 90%). HRMS m / z (ESI): C 16 H 14 Br2N5O2[M+H + ]Theoretical calculated value: 465.9509, measured value: 465.9504.

[0091] According to the operation process and material ratio of Example 12, only the type of base, the type of solvent, and the equivalent of 5-bromo-2-chloropyrimidine were changed. The synthesis of pyrimidinamine X is shown in the following table:

[0092] Example 20: Preparation of Compound X

[0093] Under nitrogen protection, compound X-1 (28.5 g; 100 mmol), compound VII (26.3 g; 120 mmol; 1.2 equivalents), sodium hydroxide (8.0 g; 200 mmol; 2.0 equivalents), tetrabutylammonium chloride (13.9 g; 50 mmol; 0.5 equivalents) and toluene (200 mL) were added to the reaction flask. The reaction was stirred at 80 ° C for 8 h. After the reaction was completed, the synthetic solution was cooled to room temperature and acidified by adding 30% citric acid aqueous solution to adjust the pH to about 2-3. The organic phase was separated and washed twice with saturated sodium chloride aqueous solution (100 mL). The organic layer was concentrated to dryness under reduced pressure. 300 mL of ethanol was added to the residue, the temperature was raised to dissolve, and the mixture was slowly cooled to 10-15 ° C with stirring. The solid precipitated and the solid was filtered. The filter cake was washed with a small amount of ethanol and dried under vacuum to obtain pyrimidine amine X (41.1 g; 88% yield). HRMS m / z (ESI): C 16 H 14 Br2N4O2[M+H + ]Theoretical calculated value: 465.9509, measured value: 465.9502.

[0094] According to the operation process and material ratio of Example 20, only the type of base, the type of solvent, and the reaction temperature were changed. The synthesis of pyrimidineamine X is shown in the following table:

[0095] Example 27: Synthesis of pyrimidinesulfonamide XII-a when X=Cl, R=CO2tBu:

[0096] To a reaction flask at 0°C, pyrimidineamine X (2.34 g, 5 mmol, 1.0 eq), Et3N (1.5 g, 1.5 mmol, 3.0 eq), and 30 mL of dichloromethane were added. A solution of tert-butyloxycarbonyl chlorosulfonamide (1.29 g, 6 mmol, 1.2 eq) in dichloromethane (10 mL) (1.29 g, 6 mmol, 1.2 eq) was slowly added dropwise over 1 hour. After complete addition, the mixture was heated to 25°C and stirred for 3 hours. Upon completion of the reaction, saturated aqueous ammonium chloride (20 mL) was added. The layers were separated and washed twice with saturated aqueous sodium chloride (20 mL). The organic layer was concentrated to dryness under reduced pressure. 15 mL of ethanol was added to the residue, and the mixture was heated to a clear solution. The mixture was slowly cooled to 10-15°C with stirring to precipitate a solid. The solid was filtered, the filter cake was washed with a small amount of ethanol, and dried under vacuum to afford sulfonamide XII-a (2.8 g, 88% yield). HRMS m / z (ESI): C 21 H 23 Br2N6O6S[M+H + ]Theoretical calculated value: 644.9761, measured value: 644.9768. 1 H-NMR (400MHz, DMSO-d6) δ: 12.96 (br, 1H), 10.83 (br, 1H), 8.68 (s, 2H), 8.53 (s, 1H), 7.48 (d, J=8.4Hz, 2H), 7.20 (d, J=8.4Hz, 2H), 4.71 (m, 2H), 4.59 (m, 2H), 1.36 (s, 9H). 13 C-NMR (100MHz, CDCl3) δ: 165.42, 163.06, 159.63, 156.18, 154.62, 151.01, 1 32.50, 130.68, 129.60, 120.92, 111.84, 105.91, 81.09, 65.41, 65.37, 27.68.

[0097] According to the operation process and material ratio of Example 27, only the X and R substituents of reagent XI were changed. The synthesis of compound XII is shown in the following table:

[0098] NMR data of XII-b: 1H-NMR (400MHz, DMSO-d6) δ: 12.90 (br, 1H), 11.30 (br, 1H), 8.68 (s, 2H), 8.55 (s, 1H), 7.49 (d, J=8.4Hz, 2H), 7.19 (d, J=8.4Hz, 2H), 4.70 (m, 2H), 4.59 (m, 2H), 3.62 (s, 3H). 13 C-NMR (100MHz, CDCl3) δ: 165.59, 163.06, 159.64, 157.18, 154.64, 152.68, 132.57, 130.69, 129.51, 120.96, 111.85, 106.15, 65.48, 65.35, 52.52.

[0099] Example 33: Synthesis of pyrimidinesulfonamide XII-b when sulfonylation reagent XI is Burgess reagent:

[0100] To a reaction flask at 0°C, pyrimidineamine X (2.34 g, 5 mmol, 1.0 eq), Et3N (1.1 g, 11 mmol, 2.2 eq), and 30 mL of dichloromethane were added. A solution of Burgess reagent methyl N-(triethylammoniumsulfonyl)carbamate (1.44 g, 6 mmol, 1.2 eq) in dichloromethane (10 mL) (1.29 g, 6 mmol, 1.2 eq) was slowly added dropwise over 1 hour. After complete addition, the mixture was stirred at 25°C for 3 hours. After completion of the reaction, saturated aqueous ammonium chloride (20 mL) was added. The layers were separated and washed twice with saturated aqueous sodium chloride (20 mL). The organic layer was concentrated to dryness under reduced pressure. 15 mL of ethanol was added to the residue, and the mixture was heated to a clear solution. The mixture was slowly cooled to 10-15°C with stirring to precipitate a solid. The solid was filtered, the filter cake was washed with a small amount of ethanol, and dried under vacuum to afford sulfonamide XII-a (2.7 g, 86% yield). HRMS m / z(ESI):C 18 H 17 Br2N6O6S[M+H + ]Theoretical calculated value: 602.9292, measured value: 602.9296.

[0101] According to the operation process and material ratio of Example 33, only the R' substituent of the Burgess reagent was changed. The synthesis of the compound of Formula XII is shown in the following table:

[0102] Example 37: Preparation of Aprocitentan

[0103] To a reaction flask at 0°C, pyrimidineamine X (2.34 g, 5 mmol, 1.0 eq), Et3N (1.1 g, 11 mmol, 2.2 eq), and 30 mL of dichloromethane were added. A solution of chlorosulfonamide (0.693 g, 6 mmol, 1.2 eq) in dichloromethane (10 mL) (1.29 g, 6 mmol, 1.2 eq) was slowly added dropwise over 1 hour. After complete addition, the mixture was heated to 25°C and stirred for 3 hours. After the reaction was complete, saturated aqueous ammonium chloride (20 mL) was added. The layers were separated and washed twice with saturated aqueous sodium chloride (20 mL). The organic layer was concentrated to dryness under reduced pressure. 15 mL of ethanol was added to the residue, and the mixture was heated to dissolve. The mixture was slowly cooled to 10-15°C with stirring to precipitate a solid. The solid was filtered, the filter cake was washed with a small amount of ethanol, and dried under vacuum to obtain aprexitentan (2.43 g, 89% yield). HRMS m / z (ESI): C 16 H 15 Br2N6O4[M+H + ]Theoretical calculated value: 544.9237, measured value: 544.9232.

[0104] According to the operating procedures and material ratios of Example 37, only the type of base and the type of solvent were changed. The synthesis of aprexitentan is shown in the following table:

[0105] Example 46: When R = CO2tBu: Synthesis of Aprexitentan from XII-a:

[0106] At 0°C, methyl carbamate raw material XII-a (646 mg, 1 mmol, 1.0 eq) and THF (20 ml) were added to the reaction flask, and then a solution of boron tribromide (300 mg, 1.2 mmol, 1.2 eq) in THF (20 ml) was slowly added dropwise. After the addition was complete, the reaction was kept warm for 8 hours. After the reaction was complete, 1% aqueous sodium hydroxide solution was added at 0°C to quench the reaction. The mixture was extracted twice with dichloromethane (20 ml). The organic phases were combined and the organic layer was concentrated to dryness under reduced pressure. 10 mL of ethanol was added to the residue, the temperature was raised to dissolve the clear solution, and the mixture was slowly cooled to 10-15°C with stirring to precipitate a solid. The solid was filtered, and the filter cake was washed with a small amount of ethanol and dried in vacuo to obtain 480 mg of aprexitentan (yield 88%).

[0107] According to the operating procedures and material ratios of Example 46, only the type of acid and solvent were changed. The synthesis of aprexitentan is shown in the following table:

[0108] Example 50: When R = CO2Bn: Synthesis of Aprexitentan from XII-c

[0109] At 0°C, methyl carbamate raw material XII-c (680 mg, 1 mmol, 1.0 eq) and THF (20 ml) were added to the reaction flask, and then a solution of boron tribromide (300 mg, 1.2 mmol, 1.2 eq) in THF (20 ml) was slowly added dropwise. After the addition was complete, the reaction was kept warm for 8 hours. After the reaction was complete, 1% aqueous sodium hydroxide solution was added at 0°C to quench the reaction. The mixture was extracted twice with dichloromethane (20 ml). The organic phases were combined and the organic layer was concentrated to dryness under reduced pressure. 10 mL of ethanol was added to the residue, the temperature was raised to dissolve the clear solution, and the mixture was slowly cooled to 10-15°C with stirring to precipitate a solid. The solid was filtered, and the filter cake was washed with a small amount of ethanol and dried in vacuo to obtain 464 mg of aprexitentan (yield 85%).

[0110] Example 51: When R = CO2CH3: Synthesis of Aprexitentan from XII-b

[0111] To a reaction flask, methyl carbamate starting material XII-b (646 mg, 1 mmol, 1.0 eq) and sodium carbonate (424 mg, 4.0 mmol, 4.0 eq) were added, followed by H₂O-THF (10 mL-10 mL). The reaction mixture was heated to 80°C and stirred for 10 h. After completion of the reaction, saturated aqueous NH₄Cl solution (20 mL) was added, and the mixture was extracted twice with DCM (20 mL). The organic phases were combined and concentrated to dryness under reduced pressure. 10 mL of ethanol was added to the residue, and the mixture was heated to dissolve. The mixture was then slowly cooled to 10-15°C with stirring to precipitate a solid. The solid was filtered, and the filter cake was washed with a small amount of ethanol and dried under vacuum to obtain 480 mg of aprexitentan (88% yield).

[0112] According to the operating procedures and material ratios of Example 51, only the type of base and solvent were changed. The synthesis of aprexitentan is shown in the following table:

[0113] The above is only a preferred embodiment of the present invention. From a technical perspective, based on the conceptual framework of the synthetic route of the present invention, several optimizations of the reaction conditions in the implementation steps and method improvements made to obtain the intermediates involved in the present invention should also be considered as the scope of protection of the present invention.

Claims

1. A method for synthesizing aprexitentan, comprising the following steps: 1) Compound X and compound XI are reacted by sulfonylation to prepare compound XII The sulfonylating agent compound of formula XI is a sulfonamide represented by the following formula: in: X represents a leaving group selected from: Cl, or -OC 6 F 5 ; R represents H, or a protecting group CO 2 Me, CO 2 t-Bu,CO 2 Bn; Alternatively, the sulfonylating agent compound of formula XI is a Burgess reagent of the following formula: Wherein: R' is methyl, ethyl, tert-butyl, or benzyl; 2) Removing the R protecting group of the pyrimidine sulfonamide compound XII obtained in the previous step to obtain aprexitentan 2. The method for synthesizing aprexitentan according to claim 1, Features: The amount of the sulfonylating agent compound of formula XI used in step 1) is 1.0 to 2.0 equivalents of the pyrimidine amine compound of formula X.

3. The method for synthesizing aprexitentan according to claim 1, Features: Step 1) is carried out in the presence of an organic base or an inorganic base; wherein the organic base is selected from one of triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine; and the inorganic base is selected from one of sodium carbonate, potassium carbonate, or sodium hydroxide.

4. The method for synthesizing aprexitentan according to claim 1, Features: In the reaction of removing the protecting group of the compound of formula XII in step 2), when R=CO 2 tBu,R=CO 2 When Bn, the protecting group is removed under acidic conditions, and the acid is a protonic acid or a Lewis acid, and the protonic acid is selected from HCl, H 2 SO 4 or trifluoroacetic acid, the Lewis acid is selected from boron tribromide or boron trichloride; when R=CO 2 CH 3 When the protecting group is removed under alkaline conditions, the base is selected from one of sodium carbonate, potassium carbonate, lithium hydroxide and sodium hydroxide.

5. The method for synthesizing aprexitentan as claimed in claim 1, wherein when X = Cl and R = H, aprexitentan is obtained directly by the above reaction under alkaline conditions.

6. The method for synthesizing aprexitentan according to claim 5, wherein the base is selected from one of triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine.

7. A method for synthesizing a pyrimidineamine compound of formula X, include: Step a) condensing a dichloropyrimidine compound of formula V with a pyrimidinol compound of formula VII under alkaline conditions to obtain an ether compound of formula VIII; Step b) In the presence of a base and a phase transfer catalyst, the ether compound VIII is subjected to aminolysis to obtain the pyrimidine amine compound X 8. The method for synthesizing the pyrimidineamine compound of formula X according to claim 7, Features: The equivalent ratio of the dichloropyrimidine compound of formula V, the pyrimidinol compound of formula VII and the base in step a) is 1:1.1-1.3:1.1-1.

3.

9. The method for synthesizing the pyrimidineamine compound of formula X according to claim 7, Features: The ammonia source in step b) is selected from ammonia gas or ammonia water.

10. The method for synthesizing the pyrimidineamine compound of formula X according to claim 7, Features: The phase transfer catalyst in step b) is selected from one of tetrabutylammonium fluoride, tetrabutylammonium chloride or tetrabutylammonium bromide.

11. The method for synthesizing the pyrimidineamine compound of formula X according to claim 7, Features: The base in step b) is selected from one of sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.

12. The method for synthesizing the pyrimidineamine compound of formula X according to claim 7, Features: The equivalent ratio of the ether compound VIII, the ammonia source, the base and the phase transfer catalyst in step b) is 1:2.5-3.5:1.2-1.7:0.2-1.

2.

13. The method for synthesizing the pyrimidineamine compound of formula X according to claim 7, Features: The solvent of step b) is selected from tetrahydrofuran (THF), acetonitrile, ethanol, dimethyl sulfoxide (DMSO) or dimethylformamide (DMF).

14. A method for synthesizing a pyrimidineamine compound of formula X, include: Step c) subjecting the dichloropyrimidine compound of formula V to aminolysis to obtain the pyrimidineamine compound of formula X-1; Step d) under alkaline conditions, condensing the pyrimidine amine compound X-1 with ethylene glycol to obtain the ether compound X-2; Step e) under alkaline conditions, condensing the ether compound X-2 with 5-bromo-2-chloropyrimidine to obtain the pyrimidine amine compound X 15. The method for synthesizing the pyrimidineamine compound of formula X according to claim 14, Features: The ammonia source in step c) is selected from ammonia gas or ammonia water.

16. The method for synthesizing the pyrimidineamine compound of formula X according to claim 14, Features: The reaction temperature of step c) is in the range of 10 to 60°C.

17. The method for synthesizing the pyrimidineamine compound of formula X according to claim 14, Features: The base in step d) is selected from sodium hydroxide, lithium hydroxide or potassium hydroxide.

18. The method for synthesizing the pyrimidineamine compound of formula X according to claim 14, Features: The reaction temperature of step d) is in the range of 90-110°C.

19. The method for synthesizing the pyrimidineamine compound of formula X according to claim 14, Features: The base in step e) is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide or potassium carbonate.

20. The method for synthesizing the pyrimidineamine compound of formula X according to claim 14, Features: The equivalent ratio of the ether X-2 compound, 5-bromo-2-chloropyrimidine and the base in step e) is 1:1.1-1.4:2.0-5.

0.

21. A method for synthesizing a pyrimidineamine compound of formula X, include: Step f) directly condensing the pyrimidineamine compound of formula X-1 with the pyrimidine alcohol compound of formula VII in the presence of a base and a phase transfer catalyst to obtain the pyrimidineamine compound of formula X 22. The method for synthesizing the pyrimidineamine compound of formula X according to claim 21, Features: The base in step f) is selected from potassium tert-butoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide.

23. The method for synthesizing the pyrimidineamine compound of formula X according to claim 21, Features: The phase transfer catalyst in step f) is selected from one of the quaternary ammonium salt catalysts tetrabutylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium fluoride.

24. The method for synthesizing the pyrimidineamine compound of formula X according to claim 21, Features: In the step f), the equivalent ratio of the pyrimidineamine compound of formula X-1, the pyrimidine alcohol compound of formula VII, the base and the phase transfer catalyst is 1:1.1-1.3:1.5-3.0:0.2-0.

6.

25. The method for synthesizing the pyrimidineamine compound of formula X according to claim 21, Features: The solvent in step f) is selected from toluene, acetonitrile, dioxane or dimethylformamide (DMF).

26. The method for synthesizing the pyrimidineamine compound of formula X according to claim 21, Features: The reaction temperature of step f) is in the range of 70-110°C.

27. A compound of formula XII-a as shown below 28. A compound of formula XII-b as shown below

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