Synthesis method of 2-amino-4-chloro-5-(sulfonylamino)-N-(o-tolyl) benzamide

Abstract

The invention provides a synthesis method of 2-amino-4-chloro-5-(sulfonylamino)-N-(o-tolyl) benzamide, and belongs to the technical field of medicine synthesis. According to the method I, according to the property of a substrate 2, 4-dichloro-5-sulfonamido benzoic acid, the reaction temperature is controlled, the substrate reacts with benzylamine, the reaction is promoted to be fully carried out, raw material residues in a mixed solution of a reaction system are reduced, and after a first amidation reaction and benzyl removal, the 2, 4-dichloro-5-sulfonamido benzoic acid is obtained; the 2-amino-4-chloro-5-(sulfonylamino)-N-(o-tolyl) benzamide with high yield is obtained by adding the 2-amino-4-chloro-5-(sulfonylamino)-N-(o-tolyl) benzamide into a solvent; according to the second method, furothiazide is used as an initial raw material, and 2-amino-4-chloro-5-(sulfonylamino)-N-(o-tolyl) benzamide is obtained through a second amidation reaction and methyl furan removal. According to the method, the conversion rate and the yield of the raw materials are improved, raw material residues are effectively controlled, impurities are reduced, the reaction steps are simplified, and the safety during operation is improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and in particular to a method for synthesizing 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide. Background Technology

[0002] Metoprazor is a novel drug that acts on the cardiovascular system through a specific pathway. Its unique pharmacological mechanism lies in its ability to precisely regulate certain key signaling pathways in the body, thereby affecting cardiovascular function at multiple levels. Specifically: (1) Diuretic effect and reduction of cardiac load: Metoprazor mainly achieves its diuretic effect by inhibiting the NCC in the distal part of the renal tubules, increasing the excretion of sodium and chloride ions in the urine. In patients with heart failure, fluid retention is one of the important reasons for increased cardiac load and deterioration of cardiac function. The diuretic effect of metoprazor helps to quickly eliminate excess water in the body, reduce the preload and afterload of the heart, and thus improve cardiac function; (2) Improvement of vascular function: Metoprazor indirectly improves vascular function by affecting the neuroendocrine system in the body. Studies have shown that metoprazor can inhibit the overactivation of the renin-angiotensin system (RAAS), reduce the production of angiotensin II (Ang II), and thus reduce the vasoconstriction caused by Ang II. In addition, metoprazine can promote the production of nitric oxide (NO) and prostacyclin, dilate blood vessels, lower blood pressure, and further improve the blood supply to the heart; (3) reduce myocardial remodeling and improve prognosis. Myocardial remodeling is an important pathophysiological process in the development of heart failure. Metoprazine reduces myocardial fibrosis and inhibits the progression of myocardial remodeling by inhibiting the overactivation of the RAAS system and reducing the secretion of aldosterone. At the same time, metoprazine can also protect myocardial cells from damage by improving coronary blood circulation and increasing myocardial oxygen supply; (4) effectively inhibit inflammatory response and oxidative stress process, reduce vascular wall damage, and prevent the occurrence and development of diseases such as atherosclerosis. Multiple clinical trials have shown that metoprazine has good efficacy in the treatment of cardiovascular diseases such as hypertension and heart failure. After use, patients not only have their blood pressure effectively controlled, but also have significant improvements in cardiac function indicators such as left ventricular ejection fraction and myocardial oxygen consumption. In addition, metoprazine also shows good tolerability and a low incidence of side effects, which provides the possibility for long-term treatment.

[0003] 2-Amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide is a key intermediate in the preparation of metoprazine. Current techniques use 5-chloro-2-methylaniline as a starting material, requiring six reaction steps—acetylation, chlorosulfonation, ammonolysis, oxidation, chlorosulfonation, and ammonolysis—to obtain the 5-chloro-2-methyl-4-aminosulfonylacetanilide intermediate. However, this method results in residual starting materials, cumbersome reaction steps, and potential discomfort during operation. Summary of the Invention

[0004] The purpose of this invention is to provide a method for synthesizing 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide, which improves the conversion rate of raw materials and the yield of products, effectively controls the residue of raw materials, and simplifies the reaction steps.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0006] This invention provides a method for synthesizing 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide, comprising method one and method two;

[0007] The synthesis route of Method 1 is shown in Equation 1 below;

[0008] The first method includes the following steps:

[0009] After mixing 2,4-dichloro-5-sulfonamide benzoic acid and the first solvent, an organic base and benzylamine were added sequentially under an inert atmosphere to carry out a substitution reaction, yielding the first intermediate.

[0010] Using the first intermediate, the second solvent, and o-methylaniline as raw materials, a first amidation reaction is carried out to obtain the second intermediate;

[0011] After mixing the second intermediate, water and the third solvent, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DDQ was added under the condition of cooling to -10℃~0℃ to carry out an oxidative debenzylation reaction to obtain 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide.

[0012]

[0013] The synthesis route of Method 2 is shown in Equation 2 below;

[0014] The second method includes the following steps:

[0015] In an inert atmosphere, furosemide, a fourth solvent, and o-methylaniline were mixed, and phosphorus trichloride was added dropwise under heating conditions to carry out a second amidation reaction, yielding a third intermediate.

[0016] The third intermediate was mixed with concentrated hydrochloric acid and subjected to an oxidative demethylation furan reaction to obtain 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide;

[0017]

[0018] Preferably, the first solvent is at least one of dimethyl sulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone.

[0019] Preferably, the organic base is at least one selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; the organic base is added in batches.

[0020] Preferably, the substitution reaction is carried out under stirring conditions, the temperature of the substitution reaction is 120-140°C, and the time of the substitution reaction is 4-12 hours.

[0021] Preferably, the step of preparing the second intermediate includes: mixing the first intermediate, the second solvent and o-methylaniline, adding phosphorus trichloride dropwise under reflux conditions to carry out a first amidation reaction, and obtaining the second intermediate;

[0022] Alternatively, the steps for preparing the second intermediate may include: mixing the first intermediate and the second solvent, cooling the mixture to -10°C to 10°C, adding triethylamine dropwise, then adding methanesulfonyl chloride dropwise and stirring the mixture, followed by adding o-methylaniline dropwise to carry out the first amidation reaction, thereby obtaining the second intermediate;

[0023] Alternatively, the steps for preparing the second intermediate may include: mixing the first intermediate and the second solvent, cooling the mixture to -10°C to 10°C, adding N,N-carbonyldiimidazole (CDI) in batches, stirring while maintaining the temperature, and then adding o-methylaniline dropwise to carry out the first amidation reaction to obtain the second intermediate;

[0024] Alternatively, the steps for preparing the second intermediate may include: mixing the first intermediate and the second solvent, then sequentially adding 1-hydroxybenzotriazole (HOBT) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), stirring under heat, and then adding o-methylaniline dropwise to carry out the first amidation reaction to obtain the second intermediate.

[0025] Preferably, the temperature of the oxidative debenzylation reaction is -10 to 0°C, and the time of the oxidative debenzylation reaction is 4 to 12 hours.

[0026] Preferably, after the oxidative debenzylation reaction is completed, the method further includes: adding the product of the oxidative debenzylation reaction to an aqueous solution of potassium carbonate for quenching, and then stirring and centrifuging sequentially to obtain a solid; mixing the solid with ethyl acetate, heating and pulping, cooling, centrifuging and drying to obtain 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide.

[0027] Preferably, the temperature at which phosphorus trichloride is added is 95–110°C.

[0028] Preferably, the mass fraction of the concentrated hydrochloric acid is 30% to 36%; the mass ratio of the third intermediate to the volume of the concentrated hydrochloric acid is (80 to 100) g: (560 to 650) mL.

[0029] Preferably, the temperature of the oxidative demethylation of furan is 70–85°C, and the reaction time is 4–12 h.

[0030] This invention provides a method for synthesizing 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide, comprising Method 1 and Method 2. Method 1, based on the properties of the substrate 2,4-dichloro-5-sulfonamidobenzoic acid, controls a specific reaction temperature to selectively react with benzylamine, promoting a complete reaction and reducing raw material residue in the reaction mixture. Following a first amidation reaction and a benzyl group removal reaction (i.e., oxidative debenzylation), 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide with a high yield is obtained. Method 2 uses furosemide as a starting material, undergoing a second amidation reaction and oxidative demethylation of furan to obtain 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide. Compared with existing technologies, the method provided by this invention improves the conversion rate of raw materials and the yield of the product, effectively controls raw material residue, reduces impurity generation, simplifies the reaction steps, and greatly increases operational safety. Meanwhile, the key intermediate for preparing metoprazine, 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzoyl, is of better quality, with higher purity and content, and improved appearance. The production efficiency of API prepared using 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzoamide obtained in this application as a raw material is higher, the product purification difficulty is lower, the product purity is better, the single impurity is smaller, and the impurity distribution is less. Attached Figure Description

[0031] Figure 1 The present invention provides a flowchart for the synthesis of 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide, wherein Formula 1 is Method 1 of the present invention and Formula 2 is Method 2 of the present invention;

[0032] Figure 2 The image shows the LC-MS chromatogram of the first intermediate prepared in Example 1 of this invention, where M+H = 341.04. Figure 2 The upper right image is a mass spectrum;

[0033] Figure 3 The image shows the LC-MS chromatogram of the second intermediate prepared by method ① in Example 1 of this invention, where M+H = 430.07. Figure 3 The upper right image is a mass spectrum;

[0034] Figure 4 The image shows the LC-MS chromatogram of 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide prepared in Example 1 of this invention, where MH = 338.02. Figure 4 The upper right image is a mass spectrum;

[0035] Figure 5 H is the 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide prepared in Example 1 of this invention. 1 NMR spectrum, Figure 5 The image in the upper right corner is a mass spectrum. Detailed Implementation

[0036] Unless otherwise specified, all raw materials used in this invention are commercially available products in the art.

[0037] This invention provides a method for synthesizing 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide, comprising method one and method two;

[0038] The synthesis route of Method 1 is shown in Equation 1 below;

[0039] The first method includes the following steps:

[0040] After mixing 2,4-dichloro-5-sulfonamide benzoic acid and the first solvent, an organic base and benzylamine were added sequentially under an inert atmosphere to carry out a substitution reaction, yielding the first intermediate.

[0041] Using the first intermediate, the second solvent, and o-methylaniline as raw materials, a first amidation reaction is carried out to obtain the second intermediate;

[0042] After mixing the second intermediate, water and the third solvent, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DDQ was added under the condition of cooling to -10℃~0℃ to carry out an oxidative debenzylation reaction to obtain 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide.

[0043]

[0044] In this invention, the first solvent is preferably at least one selected from dimethyl sulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone. In this invention, the organic base is preferably at least one selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; the organic base is preferably added in batches. In this invention, the mass ratio of 2,4-dichloro-5-sulfonamide benzoic acid to the organic base is preferably 1:(0.25-0.5).

[0045] In this invention, the substitution reaction is preferably carried out under stirring conditions, the temperature of the substitution reaction is preferably 120–140°C, more preferably 125–138°C, and the time of the substitution reaction is preferably 2–6 hours, more preferably 3–4 hours. This invention controls the temperature and time of the substitution reaction within the above ranges to ensure that the reactants are completely consumed.

[0046] After the substitution reaction is completed, the product of the substitution reaction is preferably cooled, methyl tert-butyl ether is added, and then mixed with an ice-water mixture. The mixture is stirred at a temperature of <15°C until the system is completely dissolved. Then, concentrated hydrochloric acid with a mass fraction of 30% to 36% is added dropwise at a temperature of <15°C. After centrifugation, a filter cake is obtained. The filter cake is mixed with the ice-water mixture, and concentrated hydrochloric acid with a mass fraction of 30% to 36% is added dropwise at a temperature of <15°C to adjust the pH of the system to 2 to 3. The solid precipitates out and is centrifuged and dried to obtain the first intermediate.

[0047] In this invention, the drying temperature is preferably 50-70°C, and the drying time is preferably 20-28 hours.

[0048] In this invention, the inert atmosphere is preferably a nitrogen atmosphere or an argon atmosphere.

[0049] In this invention, the step of preparing the second intermediate preferably includes: mixing the first intermediate, the second solvent and o-methylaniline, adding phosphorus trichloride dropwise under stirring and reflux conditions to carry out a first amidation reaction to obtain the second intermediate.

[0050] In this invention, the preferred mass ratio of the first intermediate to o-methylaniline is 1:(0.5-1). In this invention, the preferred mass ratio of the first intermediate to phosphorus trichloride is 1:(0.4-0.8). This invention ensures complete reaction of the first intermediate by controlling the proportions of the raw materials used.

[0051] In this invention, the second solvent is preferably at least one selected from toluene, xylene, DMF, and DMSO. In this invention, the first amidation reaction is preferably carried out under stirring and reflux conditions; the duration of the first amidation reaction is preferably 4–12 h, more preferably 6–8 h. This invention controls the temperature and time of the first amidation reaction within the above ranges to ensure complete reaction of the raw materials.

[0052] In this invention, after the first amidation reaction is completed, the process further includes: cooling the product of the first amidation reaction, mixing it with an ice-water mixture, stirring it while controlling the system temperature to be <15°C, and centrifuging it to obtain a filter cake; drying the filter cake, dissolving it in tetrahydrofuran, and then adding it dropwise into a stirred dilute hydrochloric acid solution, stirring at room temperature, and centrifuging and drying it to obtain a second intermediate.

[0053] Alternatively, the steps for preparing the second intermediate preferably include: mixing the first intermediate and the second solvent, cooling the mixture to -10°C to 10°C, adding triethylamine dropwise, then adding methanesulfonyl chloride dropwise and stirring the reaction, then adding o-methylaniline dropwise to carry out the first amidation reaction to obtain the second intermediate;

[0054] In this invention, the mass ratio of the first intermediate, triethylamine, and methanesulfonyl chloride is preferably 1:(1-2.5):(0.2-0.8), more preferably 1:(1.2-2.3):(0.3-0.7), and even more preferably 1:1.74:0.47. This invention promotes the complete reaction of the first intermediate by controlling the ratio of the raw materials. In this invention, the second solvent is preferably at least one selected from DCM, DCE, THF, ethyl acetate, and toluene. In this invention, the first amidation reaction is preferably carried out under stirring at room temperature; the time of the first amidation reaction is preferably 4-12 hours, more preferably 6-8 hours. This invention controls the temperature and time of the first amidation reaction within the above ranges to promote the complete reaction of the raw materials.

[0055] In this invention, after the first amidation reaction is completed, the process further includes: mixing the product of the first amidation reaction with an ice-water mixture, adding concentrated hydrochloric acid dropwise under stirring to adjust the pH of the system to 2-3, allowing it to stand and separate the liquids to obtain a first organic phase; washing the first organic phase sequentially with saturated brine, drying, and concentrating it to obtain a viscous substance; dissolving the viscous substance in ethyl acetate, washing it sequentially with sodium hydroxide solution, and separating the liquids to obtain a second organic phase; and washing the second organic phase sequentially with saturated brine, concentrating it, cooling it to crystallize it, filtering it, and drying it to obtain a second intermediate.

[0056] Alternatively, the steps for preparing the second intermediate preferably include: mixing the first intermediate and the second solvent, cooling to -10°C to 10°C, adding N,N-carbonyldiimidazole CDI in batches, stirring while maintaining the temperature, and then adding o-methylaniline dropwise to carry out the first amidation reaction to obtain the second intermediate.

[0057] In this invention, the mass ratio of the first intermediate to N,N-carbonyldiimidazole CDI is preferably 1:(0.15-1), more preferably 1:(0.3-0.8), and even more preferably 1:0.48. This invention promotes the complete reaction of the first intermediate by controlling the ratio of the raw materials. In this invention, the second solvent is preferably at least one selected from dichloromethane, DCE, THF, ethyl acetate, and toluene. In this invention, the first amidation reaction preferably includes: stirring at -10°C to 0°C for 0.5-2 hours, followed by stirring at room temperature for 4-12 hours. This invention controls the temperature and time of the first amidation reaction within the above ranges to promote the complete reaction of the first intermediate.

[0058] In this invention, after the first amidation reaction is completed, the process further includes: mixing the product of the first amidation reaction with water, and then sequentially separating and drying the organic phase to obtain a solid; mixing the solid with ethyl acetate, and then sequentially heating and pulping, cooling, filtering and drying to obtain a second intermediate.

[0059] Alternatively, the steps for preparing the second intermediate preferably include: mixing the first intermediate and the second solvent, then sequentially adding 1-hydroxybenzotriazole (HOBT) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), maintaining the temperature and stirring, and then adding o-methylaniline dropwise to carry out the first amidation reaction to obtain the second intermediate.

[0060] In this invention, the preferred mass ratio of the first intermediate, 1-hydroxybenzotriazole (HOBT), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) is 1:0.62. This invention ensures complete reaction of the first intermediate by controlling the ratio of the three raw materials.

[0061] In this invention, the second solvent is preferably at least one selected from dichloromethane, DCE, THF, ethyl acetate, and toluene. In this invention, the temperature of the first amidation reaction is preferably -10 to 0°C; the time of the first amidation reaction is preferably 4 to 12 hours. This invention controls the temperature and time of the first amidation reaction within the above ranges to ensure the complete reaction of the first intermediate.

[0062] In this invention, after the first amidation reaction is completed, the process further includes: mixing the product of the first amidation reaction with water, and then sequentially stirring, slurrying and filtering to obtain a viscous solid; mixing the viscous solid with hydrochloric acid, and then sequentially slurrying and filtering at room temperature to obtain a solid; and mixing the solid with ethyl acetate, and then sequentially slurrying, separating the solid from the liquid and drying to obtain a second intermediate.

[0063] In this invention, the mass ratio of the second intermediate to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is preferably 1:(0.8 to 3.5), more preferably 1:(1 to 3), and even more preferably 1:2. This invention controls the amount ratio of the second intermediate to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) within the above range to ensure complete reaction of the second intermediate.

[0064] In this invention, the temperature of the oxidative debenzylation reaction is preferably -10 to 10°C, more preferably -5 to 5°C. The time of the oxidative debenzylation reaction is preferably 4 to 12 hours, more preferably 5 to 6 hours. By controlling the temperature and time of the oxidative debenzylation reaction within the above ranges, this invention promotes the complete reaction of the second intermediate.

[0065] In this invention, after the oxidative debenzylation reaction is completed, it preferably further includes: adding the product of the oxidative debenzylation reaction to an aqueous solution of potassium carbonate for quenching, and then stirring and centrifuging in sequence to obtain a solid; mixing the solid with ethyl acetate, heating and pulping, cooling, centrifuging and drying to obtain 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide.

[0066] In this invention, the synthesis route of method two is shown in Equation 2 below;

[0067] In this invention, method two includes the following steps:

[0068] In an inert atmosphere, furosemide, a fourth solvent, and o-methylaniline were mixed, and phosphorus trichloride was added dropwise under heating conditions to carry out a second amidation reaction, yielding a third intermediate.

[0069] The third intermediate was mixed with concentrated hydrochloric acid and subjected to an oxidative debenzylation reaction to obtain 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide;

[0070]

[0071] In this invention, the inert atmosphere is preferably a nitrogen atmosphere or an argon atmosphere.

[0072] In this invention, the mass ratio of furosemide to phosphorus trichloride is preferably 1:(0.2-0.9), more preferably 1:(0.3-0.7), and even more preferably 1:0.42. This invention controls the mass ratio of furosemide to phosphorus trichloride within the above range to ensure complete reaction of furosemide.

[0073] In this invention, the temperature at which phosphorus trichloride is added is preferably 95–110°C.

[0074] In this invention, the temperature of the second amidation reaction is preferably 95–120°C, more preferably 105–110°C. The time of the second amidation reaction is preferably 4–12 h, more preferably 6–8 h. By controlling the temperature and time of the second amidation reaction within the above ranges, this invention promotes the complete reaction of furosemide.

[0075] In this invention, after the second amidation reaction is completed, the process further includes: cooling the product of the second amidation reaction, mixing it with water, and then stirring, filtering, and drying it sequentially to obtain a third intermediate.

[0076] In this invention, the drying temperature is 78–85°C; the drying time is 22–26 hours.

[0077] In this invention, the mass fraction of the concentrated hydrochloric acid is preferably 30% to 36%; the mass ratio of the third intermediate to the volume of the concentrated hydrochloric acid is (80 to 100) g : (560 to 650) mL. This invention controls the mass ratio of the third intermediate to the volume of the concentrated hydrochloric acid within the above range to ensure complete reaction of the third intermediate.

[0078] In this invention, the temperature of the oxidative debenzylation reaction is preferably 70–85°C, more preferably 78–84°C; the time of the oxidative debenzylation reaction is preferably 0.5–3 h, more preferably 1–2 h. This invention controls the temperature and time of the oxidative debenzylation reaction within the above ranges to ensure the complete reaction of the third intermediate.

[0079] In this invention, after the second amidation reaction is completed, the process further includes: cooling the product of the second amidation reaction, filtering it to obtain a filter cake; mixing the filter cake with water, adding solid sodium hydroxide, adjusting the pH of the system to 9-10, dissolving the filter cake, controlling the temperature to below 40°C, adding concentrated hydrochloric acid with a mass fraction of 36% to adjust the pH of the system to 3-4, a large amount of solid precipitates in the system, filtering to obtain a solid; mixing the solid with DMSO, adding isopropanol dropwise while stirring, keeping the mixture warm and stirring, and gradually precipitating solid in the system, then filtering and drying sequentially to obtain 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide.

[0080] Compared with the prior art, the present invention uses 2,4-dichloro-5-sulfonamide benzoic acid as a raw material in three reaction steps, or furosemide as a starting material in two reaction steps to prepare 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide. Both synthetic routes significantly improve the conversion rate and yield of the raw materials, effectively control the residue of the raw materials, and simplify the reaction steps.

[0081] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0082] Example 1

[0083] The synthetic method for 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide includes the following steps:

[0084] (1) Preparation of the first intermediate, the steps are as follows:

[0085] The first intermediate synthesis equation:

[0086]

[0087] At room temperature, 220 kg of DMSO and 80 kg of 2,4-dichloro-5-sulfonamide benzoic acid were added sequentially to a 500 L enamel reactor and stirred until completely dissolved to obtain a solution of 2,4-dichloro-5-sulfonamide benzoic acid.

[0088] Under nitrogen protection, 25.6 kg of sodium methoxide was added in batches to the 2,4-dichloro-5-sulfonamide benzoic acid solution in the above system, and stirring was continued for 30 min. After the addition was completed, the system temperature was naturally raised to 75°C, and the temperature was maintained above 70°C and stirred for 60 min. Then, 95.23 kg of benzylamine was added directly to the system, and the temperature was raised to 130°C and maintained for 3.5 h for the substitution reaction.

[0089] The product of the substitution reaction was cooled to room temperature, and 59.23 kg of methyl tert-butyl ether was added and stirred for 10 min to obtain a mixture. The mixture was transferred to an 800 kg ice-water mixture, and stirred until the system was clear while maintaining a system temperature <15°C. 20 kg of 36% concentrated hydrochloric acid was added dropwise to the system while maintaining a system temperature <15°C. A large amount of solid precipitated in the system. The mixture was centrifuged to obtain a filter cake. The filter cake was transferred to an enamel-lined reactor, and 320 kg of ice-water was pumped into the reactor. While maintaining a system temperature <15°C, 10 kg of 36% concentrated hydrochloric acid was added dropwise to the system to adjust the pH to ≈2-3. Stirring continued until a large amount of solid precipitated. The solid after centrifugation was dried at 60°C for 24 h to obtain 96.9 kg of the first intermediate, which was directly used in the next production step. HPLC analysis showed that the yield of the first intermediate was 96% (based on 2,4-dichloro-5-sulfonamide benzoic acid).

[0090] (2) The preparation of the second intermediate can be carried out using four different methods, ① to ④, with the following steps:

[0091] The first intermediate synthesis equation:

[0092]

[0093] Method ①:

[0094] At room temperature, 1677 kg of toluene, 241 kg of the first intermediate prepared in step (1), and 227.35 kg of o-methylaniline were added sequentially to an enamel-lined reactor under nitrogen protection. The system was heated to reflux with stirring, and 97.12 kg of phosphorus trichloride was added dropwise. The dropwise addition process was exothermic. After the dropwise addition was completed, the reaction system was kept warm and refluxed for 7 hours to carry out the first amidation reaction.

[0095] The product of the first amidation reaction was cooled to room temperature and added dropwise to 1205 kg of ice-water mixture from a high-level tank. The system temperature was controlled at <15℃, and the mixture was stirred for 1 h. After centrifugation, filter cake was obtained.

[0096] The filter cake was dried at 60°C for more than 24 hours. The dried product solid was dissolved in 643 kg of tetrahydrofuran in an enamel kettle and slowly dripped into 2400 L of 1% dilute hydrochloric acid under rapid stirring. The solid precipitated out. Stirring was continued at room temperature, centrifuged, and dried at 60°C for 24 hours to obtain 211 kg of the second intermediate, which was directly used for the next step of production. HPLC analysis showed that the yield of the second intermediate was 69.54% (based on the first intermediate prepared in step (1)).

[0097] Method 2:

[0098] Add 1.8L of DCM and 200g of the first intermediate prepared in step (1) to a three-necked flask protected by nitrogen. Stir at room temperature for 10min, cool the system to -10℃~10℃, and add 148.5g of triethylamine dropwise. The dropwise addition process is exothermic. After the dropwise addition is completed, continue stirring for 10min. After the stirring is completed, add 94.11g of methanesulfonyl chloride dropwise to the system. After the dropwise addition is completed, continue stirring for 1h. Control the system temperature to -10℃~10℃, and add 188.66g of o-aminotoluene dropwise to the system. After the dropwise addition is completed, continue stirring, and naturally heat to room temperature and keep warm for 7h for the first amidation reaction.

[0099] The first amidation reaction product was transferred to a 1.8L ice-water mixture. 36% concentrated hydrochloric acid was added dropwise to the system with stirring to adjust the pH to 2-3. Stirring was continued, and the mixture was allowed to stand and separate to obtain the first organic phase. The first organic phase was added to 0.9L saturated brine and washed and separated sequentially. After drying with anhydrous sodium sulfate, it was concentrated to obtain a reddish-brown viscous substance. The reddish-brown viscous substance was dissolved in 1.6L ethyl acetate and washed with sodium hydroxide aqueous solution with stirring. After standing and separating, the second organic phase was obtained. It was washed once with saturated brine and then concentrated, cooled to room temperature, crystallized, filtered, and dried sequentially to obtain 140g of the second intermediate, which was directly used in the next production step. HPLC analysis showed that the yield of the second intermediate was 55.49% (based on the first intermediate prepared in step (1)).

[0100] Method ③:

[0101] Add 1000 mL of dichloromethane and 100 g of the first intermediate prepared in step (1) to a three-necked flask. Start stirring and control the system temperature at -10℃ to 0℃. Add 47.58 g of N,N-carbonyldiimidazole CDI in batches. After the addition is completed, continue stirring for 30 min. Then add 94.34 g of o-methylaniline. After the addition is completed, keep stirring at -10℃ to 0℃ for 1 h. Then raise the temperature to 20℃ to 30℃ and continue the first amidation reaction for 2 h.

[0102] The product of the first amidation reaction was transferred to 2000 mL of water, stirred and separated, and the organic phase was dried and concentrated to obtain a yellow solid. The solid was mixed with 800 mL of ethyl acetate, heated and stirred, cooled to room temperature and filtered, and dried to obtain 50.46 g of the second intermediate, which was directly used in the next production step. According to HPLC, the yield of the second intermediate was 40% (based on the first intermediate prepared in step (1)).

[0103] Method 4:

[0104] Add 600 mL of DMF and 100 g of the first intermediate prepared in step (1) to a three-necked flask, and start stirring; at a temperature of 20℃~30℃, add 47.58 g of 1-hydroxybenzotriazole (HOBt) to the system, and then add 61.88 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) in batches. After the addition is completed, keep the reaction at the temperature for 1 h; add 94.38 g of o-methylaniline dropwise to the system. After the dropwise addition is completed, continue the first amidation reaction at room temperature for 3 h.

[0105] The product of the first amidation reaction was transferred to 3000 mL of water and stirred for 1 h. A large amount of solid precipitated in the system. The solid was filtered to obtain a viscous solid. The viscous solid was stirred with 1000 mL of 1 mol / L hydrochloric acid at room temperature for 1 h and filtered to obtain a solid. The solid was stirred with 1000 mL of ethyl acetate, cooled to room temperature, filtered, and dried to obtain 44.2 g of the second intermediate. The yield of the second intermediate was 35% (based on the first intermediate prepared in step (1)) as determined by HPLC.

[0106] (2) Preparation of 2-amino-4-chloro-5-(sulfonylamino)-N-(o-tolyl)benzamide using the second intermediate, the steps are as follows:

[0107] Synthesis equation:

[0108]

[0109] At room temperature, 1022 kg of acetonitrile, 260 kg of water, and 130 kg of the second intermediate prepared by method ① were pumped into an enamel reactor. After stirring for 10 min, the reaction system was cooled to -10℃~0℃. 260 kg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DDQ solid was added to the reaction system in batches. After the addition was completed, the oxidative debenzylation reaction was carried out for 6 h under stirring conditions.

[0110] Add 2000 kg of purified water to the post-treatment vessel, and add 52 kg of potassium carbonate while stirring. After the mixture is completely dissolved, slowly pump the product of the oxidative debenzylation reaction into the post-treatment vessel for quenching. After quenching, continue stirring. A large amount of solid precipitates out of the system. Centrifuge to obtain the solid.

[0111] The solid was mixed with 707 kg of ethyl acetate, heated to 60℃~70℃ and stirred to form a slurry, then cooled to room temperature and stirred continuously. After centrifugation, a solid with a wet weight of 150 kg was obtained. After drying, 69 kg of 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide was obtained. According to HPLC, the yield of the second intermediate was 69.54% (based on the first intermediate prepared in step (1)).

[0112] Figure 2 The LC-MS chromatogram of the first intermediate prepared in Example 1 is shown, where M+H = 341.04. Figure 2 It can be seen that the precise molecular weight of the first intermediate is 340.03, and the MS of the product is M+H=341.04, confirming the correct structure.

[0113] Figure 3 The image shows the LC-MS chromatogram of the second intermediate prepared by method ① in Example 1, where M+H = 430.07. Figure 3 It can be seen that the precise molecular weight of the second intermediate is 429.09, and the MS of the product is M+H=430.07, confirming the correct structure.

[0114] Figure 4 The LC-MS chromatogram of 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide prepared in Example 1 is shown, where MH = 338.02. Figure 4 The precise molecular weight of the target product is 339.04, and the MS value is MH = 338.02, confirming the correct structure.

[0115] Figure 5 H of 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide prepared in Example 1 1 NMR spectrum. (From) Figure 5 As can be seen, the product's proton spectrum is correct, confirming the correct structure.

[0116] Example 2

[0117] The synthetic method for 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide includes the following steps:

[0118] The synthesis equation is:

[0119]

[0120] (1) Preparation of the third intermediate, the steps are as follows:

[0121] Synthesis equation:

[0122]

[0123] At room temperature, 800 mL of toluene, 100 g of furosemide, and 97.2 g of o-methylaniline were added to a three-necked flask under nitrogen protection. The mixture was stirred and heated to 100℃~105℃. 41.52 g of phosphorus trichloride was added dropwise to the system. The addition process was exothermic. The system was refluxed. After the addition was completed, the system was refluxed for the second amidation reaction for 1 h.

[0124] The product of the second amidation reaction was cooled to 15℃~20℃, 400mL of water was added, and after stirring, the mixture was filtered to obtain a filter cake. The filter cake was dried in a forced-air oven at 80℃ for 24h to obtain 95g of the third intermediate. The yield of the third intermediate was 75% (calculated as furosemide) according to HPLC.

[0125] (2) Preparation of 2-amino-4-chloro-5-(sulfonylamino)-N-(o-tolyl)benzamide using a third intermediate, the steps are as follows:

[0126] Synthesis equation:

[0127]

[0128] 95g of the third intermediate prepared in step (1) was mixed with 570mL of concentrated hydrochloric acid with a mass fraction of 36% in a three-necked flask, and the mixture was heated to 80°C with stirring to carry out an oxidative demethylation of furan reaction for 1h.

[0129] The product of the oxidative demethylation of furan was cooled to room temperature and filtered to obtain a filter cake. The filter cake was transferred to 500 mL of water, and sodium hydroxide solid was added to adjust the pH of the system to 9-10. The filter cake dissolved completely. The temperature was controlled below 40°C, and concentrated hydrochloric acid (36% by mass) was added dropwise to adjust the pH of the solution to 3-4. A large amount of solid precipitated in the system. The solid was filtered to obtain a solid. The solid was completely dissolved in 190 mL of DMSO. Isopropanol was added dropwise to the system while stirring. The system was kept warm and stirred, and solid gradually precipitated. The solid was filtered and dried to obtain 38.5 g of 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide.

[0130] HPLC analysis showed that the yield of 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide was 50% (based on a third intermediate).

[0131] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

A method for synthesizing 1,2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide, characterized in that, Including Method 1 and Method 2; The synthesis route of Method 1 is shown in Equation 1 below; The first method includes the following steps: After mixing 2,4-dichloro-5-sulfonamide benzoic acid and the first solvent, an organic base and benzylamine were added sequentially under an inert atmosphere to carry out a substitution reaction, yielding the first intermediate. Using the first intermediate, the second solvent, and o-methylaniline as raw materials, a first amidation reaction is carried out to obtain the second intermediate; After mixing the second intermediate, water and the third solvent, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DDQ was added under the condition of cooling to -10℃~0℃ to carry out an oxidative debenzylation reaction to obtain 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide. The synthesis route of Method 2 is shown in Equation 2 below; The second method includes the following steps: In an inert atmosphere, furosemide, a fourth solvent, and o-methylaniline were mixed, and phosphorus trichloride was added dropwise under heating conditions to carry out a second amidation reaction to obtain a third intermediate. The third intermediate was mixed with concentrated hydrochloric acid and subjected to an oxidative demethylation furan reaction to obtain 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide; 2. The synthesis method according to claim 1, characterized in that, The first solvent is at least one of dimethyl sulfoxide, N,N-dimethylformamide and N-methylpyrrolidone.

3. The synthesis method according to claim 1, characterized in that, The organic base is at least one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; the organic base is added in batches.

4. The synthesis method according to claim 1, characterized in that, The substitution reaction is carried out under stirring conditions, the temperature of the substitution reaction is 120-140°C, and the time of the substitution reaction is 4-12 hours.

5. The synthesis method according to claim 1, characterized in that, The steps for preparing the second intermediate include: mixing the first intermediate, the second solvent and o-methylaniline, adding phosphorus trichloride dropwise under reflux conditions to carry out a first amidation reaction, and obtaining the second intermediate; Alternatively, the steps for preparing the second intermediate may include: mixing the first intermediate and the second solvent, cooling the mixture to -10°C to 10°C, adding triethylamine dropwise, then adding methanesulfonyl chloride dropwise and stirring the mixture, followed by adding o-methylaniline dropwise to carry out the first amidation reaction, thereby obtaining the second intermediate; Alternatively, the steps for preparing the second intermediate may include: mixing the first intermediate and the second solvent, cooling the mixture to -10°C to 10°C, adding N,N-carbonyldiimidazole CDI in batches, stirring while maintaining the temperature, and then adding o-methylaniline dropwise to carry out the first amidation reaction to obtain the second intermediate; Alternatively, the steps for preparing the second intermediate may include: mixing the first intermediate and the second solvent, sequentially adding 1-hydroxybenzotriazole (HOBT) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), maintaining the temperature and stirring, and then adding o-methylaniline dropwise to carry out the first amidation reaction to obtain the second intermediate.

6. The synthesis method according to claim 1, characterized in that, The temperature of the oxidative debenzylation reaction is -10 to 0°C, and the reaction time is 4 to 12 hours.

7. The synthesis method according to claim 1, characterized in that, After the oxidative debenzylation reaction is completed, the process further includes: adding the product of the oxidative debenzylation reaction to an aqueous solution of potassium carbonate for quenching, and then stirring and centrifuging sequentially to obtain a solid; mixing the solid with ethyl acetate, heating and pulping, cooling, centrifuging and drying to obtain 2-amino-4-chloro-5-(sulfonamide)-N-(o-tolyl)benzamide.

8. The synthesis method according to claim 1, characterized in that, The temperature at which phosphorus trichloride is added is 95–110°C.

9. The synthesis method according to claim 1, characterized in that, The mass fraction of the concentrated hydrochloric acid is 30% to 36%; the mass ratio of the third intermediate to the volume of the concentrated hydrochloric acid is (80 to 100) g: (560 to 650) mL.

10. The synthesis method according to claim 1, characterized in that, The temperature of the oxidative demethylation of furan is 70–85°C, and the reaction time is 1–3 h.

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