A method for preparing a pyrimidine sulfamide compound

Abstract

The application provides a preparation method of a pyrimidine sulfamide compound, and the method overcomes the defects of the prior art, such as the need of using an excessive strong base, low conversion efficiency, and more by-products, and the like, and the method is characterized in that the pyrimidine sulfamide is generated through the reaction of the combined action of a molecular sieve and a catalyst, the reaction condition is mild, the step is economical, the environment is friendly, the comprehensive production cost is low, the raw material is easy to obtain, the environment is friendly and economical, and the method is beneficial to the industrialized production of the pyrimidine sulfamide compound.

Description

Technical Field

[0001] This invention belongs to the technical field of drug synthesis methods, and relates to a method for preparing pyrimidine sulfonamide compounds. Background Technology

[0002] In March 2024, Tryvio, an oral antagonist targeting dual endothelin A / B receptors (ETA / ETB) co-developed by Idorsia and Johnson & Johnson, was approved by the FDA for use in combination with other antihypertensive drugs to treat patients with refractory hypertension. It effectively inhibits the binding of ET-1 to both ETA and ETB, controlling blood pressure by inhibiting the endothelin signaling pathway. In the Phase III PRECISION study, combination therapy significantly reduced blood pressure in patients with refractory hypertension, with efficacy lasting up to 48 weeks.

[0003] Tryvio is characterized by a phenylpyrimidine with an aminosulfonamide group substituted, as shown in the following formula.

[0004]

[0005] Those skilled in the art know that sulfonamides are undesirable nucleophiles (the mediating effect leads to the delocalization of sulfur by the lone pair electrons of N). The reaction of compound II with sulfonamide does not occur at 70°C in DMSO. It is known that sulfonamides can undergo nucleophilic reactions to yield pyrimidine sulfonamides in the presence of a strong base, but the presence of a large amount of base results in numerous nucleophilic byproducts, incomplete reaction, and ultimately low purity and yield of the final product. Existing techniques typically use potassium carbonate as a base to enable nucleophilic reactions of sulfonamides; however, potassium carbonate is insoluble in the reaction solvent, and adding large amounts of potassium carbonate to the reaction system causes the nucleophilic reaction to occur in a solid-liquid two-phase state. This operation is not conducive to industrial-scale production. Furthermore, the use of large amounts of potassium carbonate not only fails to ensure complete reaction between sulfonamide and compound II but also generates numerous byproducts, resulting in low purity and low yield of the final product.

[0006]

[0007] Patent CN117736152A provides a method that involves adding a step of ammonolysis of the chlorine on the pyrimidine ring to obtain a pyrimidine amine, followed by substitution with a sulfonamide compound or Burgess reagent to remove the protecting group from the sulfonamide, thus yielding apxitentan. The specific steps are shown in the reaction formula below. This route is relatively long, and the yield of the final product decreases due to the added reaction steps after ammonolysis, substitution, and deprotection. Furthermore, the intermediate ammonolysis requires high pressure, and the sulfonated Burgess reagent is expensive, making this route difficult to scale up for industrial production.

[0008] Summary of the Invention

[0009] The problem the invention aims to solve

[0010] To address the existing problems, this invention aims to provide a method for preparing pyrimidine sulfonamide compounds of formula I. This method is green, efficient, safe, environmentally friendly, and low-cost, with mild reaction conditions, simple operation, high product yield, and good purity, making it suitable for large-scale industrial production.

[0011] Technical solution

[0012] A first aspect of the present invention provides a method for preparing a compound of formula I, comprising the following steps:

[0013]

[0014] In the presence of a catalyst and zeolite, the compound of formula II is reacted with a sulfonamide compound to obtain the compound of formula I.

[0015] The sulfonamide compound can be represented by the following formula:

[0016] R1 and R2 are independently selected from H or a protecting group, wherein the protecting group is selected from -CO2Me, -CO2t-Bu, -CO2Bn or benzyl; at least one of R1 and R2 is H.

[0017] In some embodiments of the present invention, R1 and R2 of the sulfonamide compound may both be H.

[0018] In some embodiments of the present invention, the molar ratio of the compound of formula II to the sulfonamide compound is 1:1 to 1:4, preferably 1.0:1.2 to 1.0:3.0, more preferably 1.0:1.6 to 1.0:2.4, and even more preferably 1.0:1.6, 1.0:1.7, 1.0:1.8, 1.0:1.9, 1.0:2.0, 1.0:2.1, 1.0:2.2, 1.0:2.3 or 1.0:2.4.

[0019] In some embodiments of the present invention, the catalyst may be a fluorinated quaternary ammonium salt, which is selected from one or more of tetrabutylammonium fluoride, tetramethylammonium fluoride, trimethylphenylammonium fluoride, trimethylbenzylammonium fluoride, benzyltripropylammonium fluoride, methyltriethylammonium fluoride, phenyltributylammonium fluoride and benzyltributylammonium fluoride, or one or more hydrates of the above fluorinated quaternary ammonium salts, preferably tetrabutylammonium fluoride and / or tetramethylammonium fluoride and their hydrates.

[0020] In some embodiments of the present invention, the molar ratio of the compound of formula II to the catalyst is not greater than 1.0:2.5, preferably 1.0:2.5 to 1.0:10.0, more preferably 1.0:2.5 to 1.0:5.0, and more preferably 1.0:2.5, 1.0:3.0, 1.0:3.5, 1.0:4.0, 1.0:4.5, or 1.0:5.0.

[0021] In some embodiments of the present invention, the zeolite may be an artificial zeolite or a molecular sieve, preferably one or more of type 3A, type 4A, type 5A, type 13X and type Y molecular sieves, and more preferably type 4A and / or type 3A molecular sieves.

[0022] In some embodiments of the present invention, the molecular sieve may be spherical or powdered. The spherical molecular sieve preferably has a particle size of 2-3 mm or 3-5 mm, and the powdered molecular sieve may be 10-400 mesh, preferably 20-325 mesh, and more preferably 325 mesh.

[0023] In some embodiments of the present invention, the mass ratio of the zeolite to the compound of formula II is ≥2, preferably 2-10, more preferably 2-4, and even more preferably 2:1, 2.25:1, 2.5:1, 2.75:1, 3:1, 3.25:1, 3.5:1, 3.75:1, or 4:1.

[0024] In some embodiments of the present invention, the mass ratio of the zeolite to the catalyst is not less than 1.2, i.e., m 沸石 :m 催化剂 The value is not less than 1.2, preferably m. 沸石 :m 催化剂 The value is 1.2-5.0, and m is further optimized. 沸石 :m 催化剂 The value is 1.2-3.5, more preferably m. 沸石 :m 催化剂 The values ​​are 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or 3.5.

[0025] In some embodiments of the present invention, the solvent used for the reaction of the compound of formula II with the sulfonamide compound is a polar aprotic solvent, or a mixture of a polar aprotic solvent and other solvents. The solvent may be selected from one or more of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO, and sulfolane, or a mixture of two solvents: the first solvent is selected from toluene and / or DCM, and the second solvent is selected from one or more of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO, and sulfolane, or a mixture of the first solvent and the second solvent. Preferably, the solvent used in the reaction contains dimethyl sulfoxide; more preferably, dimethyl sulfoxide is used as the solvent in the reaction.

[0026] In some embodiments of the present invention, the volume-to-mass ratio (V / m) of the solvent volume V to the mass m of compound of formula II is ≥4V, preferably 4V-16V, more preferably 5V-14V, more preferably 8V-12V, and even more preferably 8V, 10V or 12V.

[0027] In some embodiments of the present invention, the reaction temperature is ≥30°C, preferably 30-75°C, more preferably 40-70°C, and even more preferably 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, or 70°C.

[0028] In some embodiments of the present invention, the reaction time is ≥2 hours, preferably ≥4 hours, and more preferably 4-6 hours.

[0029] In some embodiments of the present invention, if one of R1 or R2 of the sulfonamide compound is a protecting group, the method further includes the step of deprotecting the compound of formula I.

[0030] Another aspect of the present invention provides a method for preparing a compound of formula I, comprising the following steps:

[0031] (1) In the presence of a catalyst and zeolite, the compound of formula II is reacted with a sulfonamide compound to obtain the compound of formula I;

[0032] (2) Cool the compound of Formula I, filter it, and add water to the filtrate until a solid precipitates out;

[0033] (3) Crystallize and filter to obtain compound of formula I.

[0034] In some embodiments of the present invention, the sulfonamide compound in step (1) of the method has the same definition as described above.

[0035] In some embodiments of the present invention, R1 and R2 of the sulfonamide compound may both be H.

[0036] In some embodiments of the present invention, step (1) of the method does not use alkali or alkaline salt.

[0037] In some embodiments of the present invention, step (1) of the method does not use potassium carbonate.

[0038] In some embodiments of the present invention, the molar ratio of the compound of formula II to the sulfonamide compound in step (1) of the method is 1:1 to 1:4, preferably 1.0:1.2 to 1.0:3.0, more preferably 1.0:1.6 to 1.0:2.4, and more preferably 1.0:1.6, 1.0:1.7, 1.0:1.8, 1.0:1.9, 1.0:2.0, 1.0:2.1, 1.0:2.2, 1.0:2.3 or 1.0:2.4.

[0039] In some embodiments of the present invention, the catalyst in step (1) of the method may be a fluorinated quaternary ammonium salt, which is selected from one or more of tetrabutylammonium fluoride, tetramethylammonium fluoride, trimethylphenylammonium fluoride, trimethylbenzylammonium fluoride, benzyltripropylammonium fluoride, methyltriethylammonium fluoride, phenyltributylammonium fluoride and benzyltributylammonium fluoride, or one or more hydrates of the above fluorinated quaternary ammonium salts, preferably tetrabutylammonium fluoride and / or tetramethylammonium fluoride and their hydrates.

[0040] In some embodiments of the present invention, the molar ratio of the compound of formula II to the catalyst in step (1) of the method is not greater than 1.0:2.5, preferably a molar ratio of 1.0:2.5 to 1.0:10.0, more preferably a molar ratio of 1.0:2.5 to 1.0:5.0, and more preferably a molar ratio of 1.0:2.5, 1.0:3.0, 1.0:3.5, 1.0:4.0, 1.0:4.5 or 1.0:5.0.

[0041] In some embodiments of the present invention, the zeolite in step (1) of the method can be artificial zeolite or molecular sieve, preferably one or more of type 3A, type 4A, type 5A, type 13X and type Y molecular sieve, and more preferably type 4A and / or type 3A molecular sieve.

[0042] In some embodiments of the present invention, the molecular sieve may be spherical or powdered. The spherical molecular sieve preferably has a particle size of 2-3 mm or 3-5 mm, and the powdered molecular sieve may be 10-400 mesh, preferably 20-325 mesh, and more preferably 325 mesh.

[0043] In some embodiments of the present invention, the mass ratio of the zeolite to the compound of formula II in step (1) of the method is ≥2, preferably 2-10, more preferably 2-4, and even more preferably 2:1, 2.25:1, 2.5:1, 2.75:1, 3:1, 3.25:1, 3.5:1, 3.75:1 or 4:1.

[0044] In some embodiments of the present invention, the mass ratio of the zeolite to the catalyst in step (1) of the method is not less than 1.2, i.e., m 沸石 :m 催化剂 The value is not less than 1.2, preferably m. 沸石 :m 催化剂 The value is 1.2-5.0, and m is further optimized. 沸石 :m 催化剂 The value is 1.2-3.5, more preferably m. 沸石 :m 催化剂 The values ​​are 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or 3.5.

[0045] In some embodiments of the present invention, the solvent used for the reaction of compound II with sulfonamide in step (1) of the method is a polar aprotic solvent or a mixture of a polar aprotic solvent and other solvents. It may be selected from one or more of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO and sulfolane, or the first of two solvents is selected from toluene and / or DCM, and the second is selected from one or more of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO and sulfolane, or a mixture of the first solvent and the second solvent. Preferably, the solvent used for the reaction contains dimethyl sulfoxide. More preferably, dimethyl sulfoxide is used as the solvent for the reaction.

[0046] In some embodiments of the present invention, the volume-to-mass ratio (V / m) of the solvent volume V to the mass m of compound II in step (1) of the method is ≥4V, preferably 4V-16V, more preferably 5V-14V, more preferably 8V-12V, and even more preferably 8V, 10V or 12V.

[0047] In some embodiments of the present invention, the reaction temperature of step (1) of the method is ≥30°C, preferably 30-75°C, more preferably 40-70°C, and even more preferably 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, or 70°C.

[0048] In some embodiments of the present invention, the reaction time in step (1) of the method is ≥2 hours, preferably ≥4 hours, and more preferably 4-6 hours.

[0049] In some embodiments of the present invention, the zeolite in step (1) of the method can be a molecular sieve, preferably a type 4A molecular sieve and / or a type 3A molecular sieve.

[0050] In some embodiments of the present invention, if one of R1 or R2 of the sulfonamide compound is a protecting group, step (1) of the method further includes the step of deprotecting the compound of formula I.

[0051] In some embodiments of the present invention, the solution cooling temperature in step (2) of the method is 10-35°C, preferably cooled to room temperature, more preferably cooled to 15-35°C, and even more preferably cooled to 20-30°C.

[0052] In some embodiments of the present invention, the amount of water added in step (2) of the method is 0.5 to 3 times the volume ratio of the solvent used in step (1) above, preferably 1.0 to 2.0 times.

[0053] In some embodiments of the present invention, step (3) of the method includes a stirring crystallization step.

[0054] In some embodiments of the present invention, step (3) of the method includes a drying step after filtration.

[0055] In some embodiments of the present invention, the stirring and crystallization time in step (3) of the method is 0.5-5h, preferably 1-3h.

[0056] Another aspect of the present invention provides a method for preparing a compound of formula I, comprising the following steps:

[0057] (1) In the presence of a catalyst and zeolite, the compound of formula II is reacted with a sulfonamide compound to obtain the compound of formula I;

[0058] (2) Cool the compound of Formula I, filter it, add an alkaline aqueous solution to the filtrate as the aqueous phase, add an organic solvent that is immiscible with water as the organic phase, and extract it;

[0059] (3) Neutralize the aqueous phase with an acidic aqueous solution until a solid precipitates out, crystallize, and filter to obtain compound I.

[0060] In some embodiments of the present invention, the sulfonamide compound in step (1) of the method has the same definition as described above.

[0061] In some embodiments of the present invention, R1 and R2 of the sulfonamide compound may both be H.

[0062] In some embodiments of the present invention, step (1) of the method does not use alkali or alkaline salt.

[0063] In some embodiments of the present invention, step (1) of the method does not use potassium carbonate.

[0064] In some embodiments of the present invention, the molar ratio of the compound of formula II to the sulfonamide compound in step (1) of the method is 1:1 to 1:4, preferably 1.0:1.2 to 1.0:3.0, more preferably 1.0:1.6 to 1.0:2.4, and more preferably 1.0:1.6, 1.0:1.7, 1.0:1.8, 1.0:1.9, 1.0:2.0, 1.0:2.1, 1.0:2.2, 1.0:2.3 or 1.0:2.4.

[0065] In some embodiments of the present invention, the catalyst in step (1) of the method may be a fluorinated quaternary ammonium salt, which is selected from one or more of tetrabutylammonium fluoride, tetramethylammonium fluoride, trimethylphenylammonium fluoride, trimethylbenzylammonium fluoride, benzyltripropylammonium fluoride, methyltriethylammonium fluoride, phenyltributylammonium fluoride and benzyltributylammonium fluoride, or one or more hydrates of the above fluorinated quaternary ammonium salts, preferably tetrabutylammonium fluoride and / or tetramethylammonium fluoride and their hydrates.

[0066] In some embodiments of the present invention, the molar ratio of the compound of formula II to the catalyst in step (1) of the method is not greater than 1.0:2.5, preferably a molar ratio of 1.0:2.5 to 1.0:10.0, more preferably a molar ratio of 1.0:2.5 to 1.0:5.0, and more preferably a molar ratio of 1.0:2.5, 1.0:3.0, 1.0:3.5, 1.0:4.0, 1.0:4.5 or 1.0:5.0.

[0067] In some embodiments of the present invention, the zeolite in step (1) of the method can be artificial zeolite or molecular sieve, preferably one or more of type 3A, type 4A, type 5A, type 13X and type Y molecular sieve, and more preferably type 4A and / or type 3A molecular sieve.

[0068] In some embodiments of the present invention, the molecular sieve may be spherical or powdered. The spherical molecular sieve preferably has a particle size of 2-3 mm or 3-5 mm, and the powdered molecular sieve may be 10-400 mesh, preferably 20-325 mesh, and more preferably 325 mesh.

[0069] In some embodiments of the present invention, the mass ratio of the zeolite to the compound of formula II in step (1) of the method is ≥2, preferably 2-10, more preferably 2-4, and even more preferably 2:1, 2.25:1, 2.5:1, 2.75:1, 3:1, 3.25:1, 3.5:1, 3.75:1 or 4:1.

[0070] In some embodiments of the present invention, the mass ratio of the zeolite to the catalyst in step (1) of the method is not less than 1.2, i.e., m 沸石 :m 催化剂 The value is not less than 1.2, preferably m. 沸石 :m 催化剂 The value is 1.2-5.0, and m is further optimized. 沸石 :m 催化剂 The value is 1.2-3.5, more preferably m. 沸石 :m 催化剂 The values ​​are 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or 3.5.

[0071] In some embodiments of the present invention, the solvent used for the reaction of compound II with sulfonamide in step (1) of the method is a polar aprotic solvent or a mixture of a polar aprotic solvent and other solvents. It may be selected from one or more of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO and sulfolane, or the first of two solvents is selected from toluene and / or DCM, and the second is selected from one or more of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO and sulfolane, or a mixture of the first solvent and the second solvent. Preferably, the solvent used for the reaction contains dimethyl sulfoxide. More preferably, dimethyl sulfoxide is used as the solvent for the reaction.

[0072] In some embodiments of the present invention, the volume-to-mass ratio (V / m) of the solvent volume V to the mass m of compound II in step (1) of the method is ≥4V, preferably 4V-16V, more preferably 5V-14V, more preferably 8V-12V, and even more preferably 8V, 10V or 12V.

[0073] In some embodiments of the present invention, the reaction temperature of step (1) of the method is ≥30°C, preferably 30-75°C, more preferably 40-70°C, and even more preferably 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, or 70°C.

[0074] In some embodiments of the present invention, the reaction time in step (1) of the method is ≥2 hours, preferably ≥4 hours, and more preferably 4-6 hours.

[0075] In some embodiments of the present invention, the zeolite in step (1) of the method may be a molecular sieve, preferably a 4A molecular sieve and / or a 3A molecular sieve.

[0076] In some embodiments of the present invention, if one of R1 or R2 of the sulfonamide compound is a protecting group, step (1) of the method further includes the step of deprotecting the compound of formula I.

[0077] In some embodiments of the present invention, the solution cooling temperature in step (2) of the method is 10-35°C, preferably cooled to room temperature, more preferably cooled to 15-35°C, and even more preferably cooled to 20-30°C.

[0078] In some embodiments of the present invention, the addition of an aqueous alkali solution in step (2) of the method is preferably an aqueous alkali solution, wherein the inorganic alkali may be one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and lithium hydroxide.

[0079] In some embodiments of the present invention, in step (2) of the method, an alkaline aqueous solution is added to adjust the pH of the aqueous phase to 8.0-12.0, preferably to 9.0-11.0.

[0080] In some embodiments of the present invention, the organic solvent in step (2) of the method is one or more organic solvents that are immiscible with water, preferably one or more organic solvents selected from esters, haloalkanes, and aromatic hydrocarbons, more preferably one or more of isopropyl acetate, ethyl acetate, butyl acetate, dichloromethane, trichloromethane, and toluene, and more preferably one or more of isopropyl acetate, ethyl acetate, and butyl acetate.

[0081] In some embodiments of the present invention, the acid aqueous solution in step (3) of the method can be an aqueous solution of inorganic acid or organic acid, preferably an aqueous solution of sulfuric acid, hydrochloric acid, acetic acid or formic acid, more preferably an aqueous solution of sulfuric acid with a concentration of less than 10%, and even more preferably a 5% aqueous solution of sulfuric acid.

[0082] In some embodiments of the present invention, the aqueous phase in step (3) of the method is neutralized with an acidic aqueous solution to a pH value of 5.5-7.5, preferably a pH value of 6.2-6.8.

[0083] In some embodiments of the present invention, step (3) of the method includes a stirring crystallization step.

[0084] In some embodiments of the present invention, step (3) of the method includes a drying step after filtration.

[0085] In some embodiments of the present invention, the stirring and crystallization time in step (3) of the method is 0.5-5h, preferably 1-3h.

[0086] Beneficial effects

[0087] The key advantages of this invention compared to existing technologies are:

[0088] 1. The reaction conditions are mild, the overall production cost is lower, the scale-up feasibility is good, and the production is more economical and friendly;

[0089] 2. No inorganic alkali was used in the reaction process to avoid solid-liquid two-phase reaction. At the same time, the addition of zeolite made the production more stable and the conversion rate was high, which greatly improved the process yield.

[0090] 3. The product has high purity. The addition of zeolite during the reaction process effectively reduces the generation of hydrolysis impurities and lowers the reaction temperature, thus effectively reducing the generation of deetherification impurities caused by high temperature. Detailed Implementation

[0091] Terminology Definition

[0092] Unless otherwise stated, the terms “molecular sieve” and “zeolite” as used in this invention are classified by the International Zeolite Association Structural Committee in accordance with the I UPAC Committee’s rules for the nomenclature of zeolites. The term “zeolite” includes various natural and synthetic crystalline aluminosilicate materials containing positive ions. Another definition is “zeolite-type molecular sieve” or “artificial zeolite” which includes molecular sieves to cover the content that can be used in the definition of “zeolite” disclosed in this invention.

[0093] Unless otherwise stated, the term "V" as used in this invention may refer to a unit of volume-to-mass ratio of a solvent to a substance. For example, the terms "4V", "8V", "10V" or "12V" may refer to a volume-to-mass ratio of solvent volume V to the mass m of compound of formula II that is "4", "8", "10" or "12", and the unit is V. For example, if the mass of compound of formula II is 1g and the amount of solvent added is 4ml, 8ml, 10ml or 12ml, the mass-to-volume ratio of solvent to compound of formula II is 4V, 8V, 10V or 12V.

[0094] Unless otherwise stated, the terms “room temperature” or “ambient temperature” as used in this invention refer to temperatures in the range of 15°C to 35°C, such as, for example, 20°C to 30°C.

[0095] Unless otherwise stated, the term "conversion rate" or "conversion of reaction" as used in this invention refers to the yield of a given reactant into a product in a specific reaction. For example, the HPLC detection of the purity of compound I in the reaction solution can reflect the amount of compound I obtained by the reaction of compound II with sulfonamide compounds, and can reflect the degree of reaction of compound II to obtain compound I, that is, the conversion rate of compound II to compound I.

[0096] The preparation method involved in this invention will be further described in detail below through examples, but it should not be construed as limiting the scope of the above-mentioned subject matter of this invention to the following examples. All technologies implemented based on the above content of this invention fall within the scope of this invention.

[0097] If specific conditions for experimental methods are not described in the embodiments of this disclosure, they are generally performed under conventional conditions or as recommended by the manufacturers of the raw materials and products. Materials or reagents whose specific source is not specified are commercially available.

[0098] The purity of the compounds and the purity of the reaction solution of compound I were determined by high performance liquid chromatography (HPLC).

[0099] High performance liquid chromatography conditions:

[0100] Instrument: Agilent 1260-6125B

[0101] Column: 937#, CST CHROM C18, 5μm, 4.6×50mm

[0102] Mobile phase A (mPA): 0.1% formic acid solution

[0103] Mobile phase B (mPB): Acetonitrile

[0104] Flow rate: 2.0 ml / min

[0105] Column temperature: 40℃

[0106] Elution gradient:

[0107] T / min 0 2.7 3.6 3.61 4.2 mPA / % 90 10 10 90 90 mPB / % 10 90 90 10 10

[0108] Example 1

[0109] Compound II (200 g; 411 mmol), sulfonamide (79 g; 822 mmol; 2 equivalents), tetramethylammonium fluoride tetrahydrate (169 g; 1027 mmol; 2.5 equivalents), and 4A molecular sieve (2-3 mm, 450 g) were suspended in DMSO (2000 mL). The mixture was heated to 55 °C and maintained for 5 h. The reaction mixture was cooled to 25 °C, filtered, and 2000 mL of water was added dropwise to the filtrate. A solid precipitated out, which was filtered and dried to give apxitentan (205 g; 92% yield, 98.67% purity).

[0110] Example 2

[0111] Compound II (10 g; 21 mmol), sulfonamide (3.95 g; 42 mmol; 2 equivalents), tetramethylammonium fluoride tetrahydrate (13.8 g; 84 mmol; 4.0 equivalents), and 4A molecular sieve (325 mesh powder, 25 g) were suspended in DMSO (100 mL). The mixture was heated to 45 °C and maintained for 4 h. The reaction mixture was cooled to 25 °C, filtered with diatomaceous earth, and the filtrate was added dropwise with 100 mL of aqueous solution containing potassium carbonate (4.25 g). 100 mL of isopropyl acetate was added, and the mixture was extracted and separated. The aqueous phase was neutralized with 5% sulfuric acid aqueous solution to 6.8, and a solid precipitated. The solid was filtered and dried to give apxitentan (10.1 g; 90% yield, 99.56% purity).

[0112] Example 3

[0113] Compound II (10 g; 21 mmol), sulfonamide (3.95 g; 42 mmol; 2 equivalents), tetrabutylammonium fluoride trihydrate (26.5 g; 84 mmol; 4.0 equivalents), and 3A molecular sieve (40 g) were suspended in DMSO (100 mL). The mixture was heated to 65 °C and maintained for 4 h. The reaction mixture was cooled to 25 °C, filtered with diatomaceous earth, and the filtrate was added dropwise with 100 mL of aqueous solution containing potassium carbonate (4.25 g). 100 mL of isopropyl acetate was added, and the mixture was extracted and separated. The aqueous phase was neutralized with 5% sulfuric acid aqueous solution to pH 6.2, and a solid precipitated. The solid was filtered and dried to give apxitentan (9.02 g; 80% yield, 99.30% purity).

[0114] Comparative Example 1

[0115] Compound II (1.99 g; 4.1 mmol), sulfonamide (0.49 g; 4.9 mmol; 1.2 equivalents), and tetramethylammonium fluoride tetrahydrate (2.35 g; 14.4 mmol; 3.5 equivalents) were suspended in DMSO (10 mL). The mixture was heated to 65 °C and maintained for 8 h. HPLC analysis of the reaction solution showed a purity of 58.01% for apxitentan.

[0116] Comparative Example 2

[0117] Compound II (1.99 g; 4.1 mmol), sulfonamide (0.49 g; 4.9 mmol; 1.2 equivalents), and tetramethylammonium fluoride tetrahydrate (2.35 g; 14.4 mmol; 3.5 equivalents) were added to potassium carbonate (1.13 g, 8.2 mmol, 2 equivalents) and suspended in 10 mL of DMSO. The mixture was heated to 65 °C and maintained for 8 h. HPLC analysis of the reaction solution showed that the purity of apxitentan was 78.98%.

[0118] Comparative Example 3

[0119] Compound II (2.0 g; 4.1 mmol), sulfonamide (0.49 g; 4.9 mmol; 1.2 equivalents), and tetrabutylammonium fluoride trihydrate (1.98 g; 14.4 mmol; 3.5 equivalents) were added to potassium carbonate (1.13 g, 8.2 mmol, 2 equivalents) and suspended in 10 mL of DMSO. The mixture was heated to 65 °C and maintained for 8 h. HPLC analysis of the reaction solution showed a purity of 76.36% for apxitentan.

[0120] Example 4

[0121] Following the reaction steps of Example 2, the reaction was carried out with compound II as 1 equivalent, DMSO as 10V as the reaction solvent, 4A molecular sieve as 2.5 equivalents (w / w), tetramethylammonium fluoride as 4.0 equivalents (molar ratio), reaction temperature as 50-60℃, reaction time as 4-6h. The purity of the reaction solution was determined by HPLC when the amount of sulfonamide added (molar ratio) was 1.6, 2.0 and 2.4 equivalents. The results are shown in Table 1 below.

[0122] Table 1

[0123] Example sulfonamide equivalent Apcitentan (%) 4-1 1.6 88.25 4-2 2.0 93.16 4-3 2.4 87.41

[0124] Conclusion: When the reaction conditions described above are met and the amount of sulfonamide added is 1.6-2.4 equivalents, the purity of alprazolam is greater than 85%.

[0125] Example 5

[0126] Following the reaction steps of Example 2, the reaction was carried out with compound II as 1 equivalent, sulfonamide as 2.0 equivalents (molar ratio), DMSO as 10V as the reaction solvent, 4A molecular sieve as 2.5 equivalents (w / w), reaction temperature as 50-60℃, and reaction time as 4-6h. The reaction was investigated when the amount of tetramethylammonium fluoride (TMAF) added (molar ratio) was 4.0 and 5.0 equivalents. The purity of the reaction solution was detected by HPLC and is shown in Table 2 below.

[0127] Table 2

[0128] Example TMAF Apcitentan (%) 5-1 4.0 93.16 5-2 5.0 92.19

[0129] Conclusion: When the reaction conditions described above are met and the molar ratio of tetramethylammonium fluoride (TMAF) is 4.0-5.0 equivalents, the purity of alprazotentan is greater than 90%.

[0130] Example 6

[0131] Following the reaction steps of Example 2, the reaction was carried out with compound II as 1 equivalent, sulfonamide as 2.0 equivalents (molar ratio), tetramethylammonium fluoride (TMAF) as 4.0 equivalents (molar ratio), 4A molecular sieve as 2.5 equivalents (w / w), reaction temperature as 50-60℃, and reaction time as 4-6h. The purity of the reaction solution was investigated by HPLC when DMSO was used as the reaction solvent and its volume-to-mass ratio relative to compound II was 8V, 10V, and 12V. The results are shown in Table 3 below.

[0132] Table 3

[0133] Example DMSO dosage Apcitentan (%) 6-1 8V 93.18 6-2 10V 95.17 6-3 12V 95.62

[0134] Conclusion: When the above reaction conditions are followed and 8-12V of DMSO is used as the reaction solvent, the purity of alpracitentan is greater than 90%.

[0135] Example 7

[0136] Following the reaction steps of Example 2, the reaction was carried out with compound II as 1 equivalent, sulfonamide as 2.0 equivalents (molar ratio), tetramethylammonium fluoride as 4.0 equivalents (molar ratio), and DMSO as 10V as the reaction solvent. The reaction temperature was 50-60℃, and the reaction time was 4-6h. The purity of the reaction solution was determined by HPLC when the amount of 4A molecular sieve was 2.0, 2.5, and 3.0 equivalents (w / w). The results are shown in Table 4 below.

[0137] Table 4

[0138] Example 4A molecular sieve dosage Apcitentan (%) 7-1 2.0 95.32 7-2 2.5 96.06 7-3 3.0 94.47

[0139] Conclusion: When the above reaction conditions are followed and the amount of 4A molecular sieve is 2.0-3.0 equivalents (w / w), the purity of alprasitetentan is greater than 90%.

[0140] Example 8

[0141] Following the reaction steps of Example 2, the reaction was carried out with compound II as 1 equivalent, sulfonamide as 2.0 equivalents (molar ratio), tetramethylammonium fluoride as 4.0 equivalents (molar ratio), DMSO as 10V as the reaction solvent, and 4A molecular sieve as 2.5 equivalents (w / w). The reaction time was 4-6 h. The purity of the reaction solution was determined by HPLC at reaction temperatures of 40℃, 50℃, 60℃, and 70℃, as shown in Table 5 below.

[0142] Table 5

[0143] Example Reaction temperature (°C) Apcitentan (%) 8-1 40 95.64 8-2 50 95.90 8-3 60 95.93 8-4 70 96.01

[0144] Conclusion: When the reaction conditions described above are met and the reaction temperature is above 40°C, the purity of alpracitentan is greater than 95%.

[0145] Examples 9-10

[0146] Following the reaction steps of Example 2, the reaction was carried out with compound of formula II as 1 equivalent, sulfonamide as 2.0 equivalent (molar ratio), tetramethylammonium fluoride as 4.0 equivalent (molar ratio), DMSO as 10V as the reaction solvent, and 4A molecular sieve as 2.5 equivalent (w / w). The purity of the reaction solution was determined by HPLC under different reaction times at reaction temperatures of 50℃ and 60℃, as shown in Tables 6 and 7 below.

[0147] Table 6 Selection of reaction time at 50℃

[0148] Example Reaction time (h) Apcitentan (%) 9-1 4 94.27 9-2 6 95.90 9-3 10 96.20 9-4 24 96.17

[0149] Table 7 Selection of reaction time at 60℃

[0150] Example Reaction time (h) Apcitentan (%) 10-1 2 93.93 10-2 4 96.02 10-3 6 95.93 10-4 10 96.03 10-5 24 96.00

[0151] Conclusion: When the above reaction conditions are met, the purity of apraxitentan is greater than 90% when the reaction temperature is 50℃ and the reaction time is greater than 4h, and the purity of apraxitentan is greater than 90% when the reaction temperature is 60℃ and the reaction time is greater than 2h.

[0152] Based on the results of Examples 4-10 and Comparative Examples 1-3, it can be seen that the purity of alpracitentan in the reaction solution of Comparative Example 1 is 58.01%. The reaction conversion rate of Comparative Examples 2-3 is improved after the addition of potassium carbonate, but the purity of alpracitentan in the reaction solution still does not reach 80%. Examples 4-10 use the process of the present invention, which does not use alkaline salts in the reaction process. After adding molecular sieves and catalysts to participate in the reaction, the reaction conversion rate is significantly improved, and the purity of alpracitentan in the reaction solution can reach greater than 85%. In some examples, the purity of alpracitentan in the reaction solution is even greater than 95%.

[0153] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention. Furthermore, the technical solutions of the various embodiments can be combined with each other, but this must be based on the ability of those skilled in the art to implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be considered that such a combination of technical solutions does not exist and is not within the protection scope claimed by the present invention.

Claims

1. A method for preparing a compound of formula I, comprising the following steps: In the presence of a catalyst and zeolite, the compound of formula II is reacted with a sulfonamide compound to obtain the compound of formula I. The sulfonamide compound can be represented by the following formula: R1 and R2 are independently selected from H or a protecting group, wherein the protecting group is selected from -CO2Me, -CO2t-Bu, -CO2Bn or benzyl; at least one of R1 and R2 is H.

2. The preparation method according to claim 1, characterized in that... The zeolite can be an artificial zeolite or a molecular sieve.

3. The preparation method according to claims 1-2, characterized in that... The molecular sieve can be selected from one or more of the following types: 3A, 4A, 5A, 13X, and Y.

4. The preparation method according to claims 1-3, characterized in that... The molecular sieve can be spherical or powdered. The spherical molecular sieve preferably has a particle size of 2-3 mm or 3-5 mm, and the powdered molecular sieve can be 10-400 mesh, preferably 20-325 mesh, more preferably 100-325 mesh, and even more preferably 200-325 mesh.

5. The preparation method according to claims 1-4, characterized in that... The mass ratio of the zeolite to the compound of formula II is ≥2.

6. A method for preparing a compound of formula I, comprising the following steps: (1) In the presence of a catalyst and zeolite, the compound of formula II is reacted with a sulfonamide compound to obtain the compound of formula I; (2) Cool the compound of Formula I, filter it, and add water to the filtrate until a solid precipitates out; (3) Crystallize and filter to obtain compound of formula I.

7. The preparation method according to claim 6, characterized in that... The amount of water added in step (2) is 0.5 to 3 times the volume ratio of the solvent used in step (1).

8. A method for preparing a compound of formula I, comprising the following steps: (1) In the presence of a catalyst and zeolite, the compound of formula II is reacted with a sulfonamide compound to obtain the compound of formula I; (2) Cool the compound of Formula I, filter, add an alkaline aqueous solution to the filtrate as the aqueous phase, add an organic solvent that is immiscible with water as the organic phase, and extract; (3) Neutralize the aqueous phase with an acidic aqueous solution until a solid precipitates out, crystallize, and filter to obtain compound I.

9. The preparation method according to claim 8, characterized in that... In step (2), an alkaline aqueous solution is added to adjust the pH of the aqueous phase to 8.0-12.0, preferably to 9.0-11.

0.

10. The preparation method according to claims 8-9, characterized in that... In step (3), the aqueous phase is neutralized with an acidic aqueous solution to a pH value of 5.5-7.5, preferably 6.2-6.8.

Images