Synthesis method of sulfachloropyrimidine

Abstract

The invention discloses a synthesis method of sulfachloropyrimidine, which comprises the following steps: taking paranitroaniline and 4, 6-dichloropyrimidine as raw materials, synthesizing acyl chloride by diazotization and sulfonylation of paranitroaniline, generating aminopyrimidine by ammonification of 4, 6-dichloropyrimidine, condensing aminopyrimidine and acyl chloride, and then synthesizing sulfachloropyrimidine by reduction. According to the method, chlorosulfonic acid is not used in the reaction process, the reaction treatment is simple, and the safety risk is reduced. Acid used in the chlorosulfonation process and ammonia used in the ammonification process can be recycled and reused, the product yield reaches 76.2%, and the quality meets the standard requirement. The process can improve the yield and reduce the production cost, the production process is easy to control, less three wastes are generated, and the environmental pollution is small.

Description

Technical Field

[0001] This invention relates to a method for synthesizing a compound, and more particularly to a method for synthesizing sulfachloropyrimidine. Background Technology

[0002] Sulfachloropyrimidine (6-chlorosulfadiazine) is an important organic synthesis intermediate, mainly used in the pharmaceutical industry to synthesize sulfamethoxypyrimidine sodium, which is a commonly used antibiotic in clinical practice. This drug can effectively inhibit the growth and reproduction of Gram-positive and Gram-negative bacteria, and bacteria develop resistance to this drug relatively slowly.

[0003] Currently, the commonly used method for synthesizing sulfachloropyrimidine is the condensation reaction of 4,6-dichloropyrimidine with sodium sulfamethoxam (p-aminobenzenesulfonamide) (Hu Meiling et al., Research Progress in the Synthesis of Sulfadiazine, ZHEJIANG CHEMICAL INDUSTRY, Vol.53 No.5 (2022)). Most industrial production methods for sulfonamides use acetanilide as a raw material, which undergoes sulfonation, chlorination, amination, hydrolysis, neutralization, and crystallization with chlorosulfonic acid, ultimately yielding sulfonamides with a yield of 72-74%. Sulfonamides are then condensed with 4,6-dichloropyrimidine to obtain sulfachloropyrimidine, with an overall product yield of approximately 68%-70%. In the synthesis of p-acetaminobenzenesulfonyl chloride (P-ASC), the excess chlorosulfonic acid method was used. Acetanilide was added to chlorosulfonic acid at 12-15 °C (chlorosulfonic acid / acetanilide = 4.97-6.10:1, molar ratio), and the mixture was heated to 60 °C and reacted for 2 hours. After that, the mixture was diluted in ice water and filtered to obtain the product. The yield was 77.0%-81.01%.

[0004] In existing sulfonamide synthesis processes, chlorosulfonic acid is a key reagent, but it is highly corrosive and hygroscopic. It reacts violently with water, causing an explosion and generating large amounts of waste acid. While most of the hydrochloric acid tail gas can be recycled, the sulfuric acid must be discharged as wastewater along with water. Unreacted chlorosulfonic acid, through hydrolysis and product washing, generates large amounts of acidic wastewater, causing significant environmental pollution and increasing production and subsequent treatment costs. Furthermore, existing sulfonamide synthesis processes suffer from low raw material utilization, leading to resource waste. This increases the production cost of sulfonamides, further increasing the cost and safety risks of synthesizing sulfachloropyrimidine from 4,6-dichloropyrimidine. Summary of the Invention

[0005] To address the aforementioned problems, this invention provides a method for synthesizing sulfachloropyrimidine. This method uses p-nitroaniline and 4,6-dichloropyrimidine as raw materials to prepare sulfachloropyrimidine. The reaction process is simple, and the total yield of sulfachloropyrimidine products reaches 76.2%. At the same time, it avoids the use of sulfonamides, thereby avoiding the use of chlorosulfonic acid, thus reducing safety risks and environmental pollution.

[0006] Specifically, the technical solution protected by this invention is as follows: A method for synthesizing sulfachloropyrimidine, comprising the following steps: Synthesis of 4-nitro-sulfonamide-6-chloropyrimidine: p-nitroaniline was synthesized from p-nitrobenzenesulfonyl chloride via diazotization and sulfonation reactions; Synthesis of 4-amino-6-chloropyrimidine: 4,6-dichloropyrimidine was synthesized by reacting it with ammonia water through an ammoniation reaction. Synthesis of 4-nitro-sulfonamide-6-chloropyrimidine: p-Nitrobenzenesulfonyl chloride and 4-amino-6-chloropyrimidine are refluxed under the action of an alkaline catalyst to undergo a condensation reaction to synthesize 4-nitro-sulfonamide-6-chloropyrimidine; Synthesis of sulfachloropyrimidine: 4-nitro-sulfa-6-chloropyrimidine and hydrogen undergo a reduction reaction in the presence of a noble metal catalyst to synthesize sulfachloropyrimidine.

[0007] To obtain p-nitrobenzenesulfonyl chloride with higher yield and higher purity, the diazotization reaction step in the synthesis of p-nitrobenzenesulfonyl chloride includes: first reacting concentrated hydrochloric acid and p-nitroaniline at below 15°C for 20-40 min, then adding a 20 wt%-40 wt% sodium nitrite aqueous solution dropwise, and after the addition is completed, maintaining the temperature for 45-75 min to obtain p-nitrobazo-diazotized benzene chloride solution A; The steps of the sulfonation reaction include: first, stirring and mixing the copper salt catalyst and glacial acetic acid, and then passing SO2 gas through the mixture at a temperature below 20°C until saturation is achieved, to obtain solution B; then, at a temperature below 15°C, adding the p-nitrodiazotized chlorobenzene solution A to solution B, and stirring the reaction for 1.5 to 2.5 h, diluting with twice the amount of ice water, filtering, washing the filter cake with a small amount of ice water, and drying to a moisture content ≤0.1%, to obtain p-nitrobenzenesulfonyl chloride, and recovering the glacial acetic acid and SO2 therein.

[0008] To improve the recovery rate of acetic acid and SO2, the method for recovering glacial acetic acid and SO2 includes: first, transferring the mother liquor from which p-nitrobenzenesulfonyl chloride has been separated into an enamel-lined reactor, connecting it to an absorption device filled with acetic acid, heating it to boiling until all SO2 evaporates, and obtaining an acetic acid solution containing SO2; then, neutralizing the remaining acetic acid solution in the mother liquor from which p-nitrobenzenesulfonyl chloride has been separated with an alkaline solution; then, distilling to obtain an aqueous acetic acid fraction; and finally, rectifying the aqueous acetic acid fraction to recover the acetic acid therein.

[0009] To obtain 4-amino-6-chloropyrimidine with high yield and high purity, the steps for synthesizing 4-amino-6-chloropyrimidine include: first, reacting 4,6-dichloropyrimidine with an aqueous ammonia solution of 23 wt% to 30 wt% at 60 to 80°C for 2 to 3 h to synthesize 4-amino-6-chloropyrimidine; then, recovering the ammonia by atmospheric distillation; then, cooling to room temperature to precipitate the solid; filtering; drying the filter cake to obtain purified 4-amino-6-chloropyrimidine.

[0010] To improve the ammonia recovery rate, the method of recovering ammonia by atmospheric distillation includes: after the reaction for synthesizing 4-amino-6-chloropyrimidine is completed, a distillation apparatus is connected, which is connected to an ammonia absorption device. After atmospheric distillation is completed, the absorbed and recovered ammonia water is transferred to an ammonia water preparation tank, and ammonia gas is introduced to prepare an ammonia water solution with a concentration of 23wt%~30wt%.

[0011] To improve the yield of 4-nitro-sulfonamide-6-chloropyrimidine, in the step of synthesizing 4-nitro-sulfonamide-6-chloropyrimidine, the molar ratio of p-nitrobenzenesulfonyl chloride, 4-amino-6-chloropyrimidine and the alkaline catalyst is 1:1.03~1.1:1.1~1.25.

[0012] To improve the reaction efficiency of the synthesis of 4-nitro-sulfanilamide-6-chloropyrimidine, the alkaline catalyst is one or more of pyridine, triethylamine, potassium carbonate, and sodium carbonate.

[0013] To improve the yield and purity of 4-nitro-sulfanilamide-6-chloropyrimidine, the steps for synthesizing 4-nitro-sulfanilamide-6-chloropyrimidine include: adding p-nitrobenzenesulfonyl chloride, 4-amino-6-chloropyrimidine, and the alkaline catalyst to a first solvent, stirring and heating to reflux, maintaining the temperature for 3-5 hours, then adding drinking water, stirring to dissolve the solid, allowing the aqueous layer to separate, adding activated carbon, maintaining the temperature at 80-90°C for 2-4 hours, and filtering while hot; adjusting the pH of the filtrate obtained from hot filtration to 2-6 with hydrochloric acid, filtering by suction, washing the filter cake with hot water, and drying to obtain 4-nitro-sulfanilamide-6-chloropyrimidine. To improve the yield of sulfachloropyrimidine, the synthesis step of sulfachloropyrimidine includes: adding 4-nitro-sulfa-6-chloropyrimidine and a noble metal catalyst to an alcohol solvent, introducing hydrogen gas, and reacting at 100~130℃ and 0.6~0.8MPa for 3~5h to synthesize sulfachloropyrimidine.

[0014] To further purify sulfachloropyrimidine, the steps of synthesizing sulfachloropyrimidine include, after the reaction is completed, the following steps: first, distilling to recover the alcohol solvent, then adding purified water, cooling to 0-5°C for crystallization for 1.5-2.5 hours, filtering, and drying the filter cake to obtain the purified sulfachloropyrimidine product.

[0015] A method for synthesizing sulfachloropyrimidine, comprising the following steps: Diazotization: p-Nitroaniline is used as the starting material and reacts with concentrated hydrochloric acid and sodium nitrite to synthesize p-nitrodiazochlorobenzene; Sulfonation: In a copper salt catalyst and glacial acetic acid, p-nitrodiazochlorobenzene undergoes a sulfonation reaction with SO2 gas to synthesize 4-nitro-sulfonamide-6-chloropyrimidine; Ammoniation: 4,6-Dichloropyrimidine undergoes an ammoniation reaction with ammonia to give 4-amino-6-chloropyrimidine; Condensation: Nitrobenzenesulfonyl chloride and 4-amino-6-chloropyrimidine undergo a condensation reaction under reflux in the presence of an alkaline catalyst to synthesize 4-nitro-sulfonamide-6-chloropyrimidine; Reduction: 4-Nitro-sulfanilamide-6-chloropyrimidine and hydrogen undergo a reduction reaction in the presence of a noble metal catalyst to synthesize sulfachloropyrimidine.

[0016] Therefore, compared with the prior art, the present invention uses p-nitroaniline and 4,6-dichloropyrimidine as raw materials to prepare sulfachloropyrimidine through diazotization, sulfonation, ammoniation, condensation and reduction reactions. This process can improve product yield, reduce safety risks, and the acid used in the chlorosulfonation process and the ammoniation process can be recycled and reused, resulting in less waste, less environmental pollution, reduced production costs, and improved economic benefits, making it suitable for industrial production. Attached Figure Description

[0017] Figure 1 This is a flowchart of the sulfachloropyrimidine synthesis process provided in Example 1 of the present invention; Figure 2 The infrared spectrum of sulfachloropyrimidine synthesized in Example 1 of this invention; Figure 3 The sulfachloropyrimidine synthesized in Example 1 of this invention 1 H NMR spectrum. Detailed Implementation

[0018] To reduce the safety risks and production costs of synthesizing sulfachloropyrimidine, this invention develops a synthetic route for sulfachloropyrimidine that avoids sulfonamides and chlorosulfonic acid, as shown below: .

[0019] The specific implementation scheme of the present invention based on the above synthetic route is as follows: A method for synthesizing sulfachloropyrimidine, comprising the following steps: 1) Diazotization: Concentrated hydrochloric acid is cooled to below 15°C, p-nitroaniline is added, and the reaction is stirred for 20-40 min. A 20 wt%-40 wt% sodium nitrite aqueous solution is then added dropwise. After the addition is complete, the reaction is maintained at this temperature for 45-75 min to obtain p-nitrodiazotized chlorobenzene solution A. Specifically, in this step, the molar ratio of p-nitroaniline to sodium nitrite is 1:1.02-1:1.1, preferably 1:1.02-1:1.05; the molar ratio of p-nitroaniline to concentrated hydrochloric acid is 1:2.5-1:5, preferably 1:3.5-1:4; and the dropping temperature of the sodium nitrite aqueous solution is no more than -15°C to 5°C, such as -15°C, -10°C, -5°C, 0°C, 5°C, etc., preferably -10°C to 0°C.

[0020] 2) Sulfonation: Add copper salt catalyst to glacial acetic acid, stir and cool to below 20°C, then introduce SO2 gas until saturated to obtain solution B; below 15°C, add p-nitrodiazotized chlorobenzene solution A to solution B, then stir and react for 1.5~2.5h, dilute with 2 times the amount of ice water, filter, wash the filter cake with a small amount of ice water, and dry to a moisture content ≤0.1% to obtain intermediate 1: p-nitrobenzenesulfonyl chloride. In this step, the copper salt catalyst is copper sulfate pentahydrate, and the mass ratio of p-nitroaniline, glacial acetic acid, and copper sulfate pentahydrate is 1:5~6:0.15~0.20, such as 1:5:0.15, 1:5:0.20, 1:5.5:0.15, 1:5.5:0.20, 1:6:0.15, 1:6:0.20, etc.; the SO2 introduction temperature is 3~15℃, such as 3℃, 5℃, 8℃, 10℃, 12℃, 15℃, etc., preferably 8~10℃; the sulfonation reaction temperature is -15~10℃, such as -15℃, -10℃, -5℃, 0℃, 5℃, 10℃, etc., preferably -10~-5℃.

[0021] Step 2) sulfonation further includes the step of recovering glacial acetic acid and SO2. The specific recovery method includes: transferring the mother liquor from intermediate 1 into an enamel-lined reactor, connecting it to an absorption device filled with acetic acid, and heating it to boiling until all SO2 evaporates. This allows the acetic acid solution containing SO2 to be reused, recovering 70-80% of the SO2. The remaining acetic acid solution is neutralized with sodium hydroxide solution, and then distilled at a temperature slightly above the azeotropic point of acetic acid and water (102-107°C) to obtain a relatively pure aqueous acetic acid fraction. This fraction is then purified using a distillation column filled with Raschig rings and dichloromethane as an azeotropic agent, ultimately recovering approximately 80% of the acetic acid.

[0022] 3) Ammoniation: 4,6-Dichloropyrimidine and an ammonia solution with a concentration of 23 wt%~30 wt% are added to a high-pressure reactor, stirred and heated, and the reaction is maintained at this temperature for 2~3 hours. Ammonia is recovered by distillation under normal pressure, and the solid is precipitated at room temperature. The solid is filtered, and the filter cake is dried at 70~90℃ for 1~3 hours to obtain the intermediate 2:4-amino-6-chloropyrimidine. To optimize the parameters, the mass ratio of 4,6-dichloropyrimidine to the ammonia solution is 1:5~1:20, such as 1:5, 1:8, 1:10, 1:12, 1:15, 1:18, 1:20, etc., preferably 1:8~1:10.

[0023] In addition, step 3) ammoniation also includes a step of recovering ammonia. Specifically: after the synthesis reaction of intermediate 2 is completed, a distillation apparatus is connected, and an ammonia absorption apparatus is connected to the tail end. After distillation, the recovered ammonia water is transferred to an ammonia water preparation tank, and ammonia gas is introduced to prepare an ammonia water solution with a concentration of 23 wt%~30 wt%, which is then ready for use. The ammonia recovery rate is 75~85%.

[0024] 4) Condensation: Intermediate 1, Intermediate 2, and alkaline catalyst are added to the first solvent, stirred, and heated to reflux. The reaction is maintained at this temperature for 3-5 hours. Then, drinking water is added, the solid is dissolved by stirring, and the aqueous layer is separated by standing. Activated carbon is added, and the reaction is maintained at 80-90℃ for 2-4 hours. The mixture is then filtered while hot. The filtrate is adjusted to pH 2-6 with hydrochloric acid, filtered under vacuum, and the filter cake is washed with a small amount of hot water and dried at 70-90℃ for 1-3 hours to obtain Intermediate 3: 4-nitro-sulfanilamide-6-chloropyrimidine. In this step, the purpose of the two-step heat treatment is as follows: the first heat treatment is for the condensation reaction, and the second heat treatment is for decolorization and impurity removal. The temperature at which activated carbon is added for the second heat treatment is 80-90℃, which is the most effective temperature for decolorization and impurity removal. During the purification of 4-nitro-sulfanilamide-6-chloropyrimidine, hot filtration is necessary to prevent the precipitation of 4-amino-6-chloropyrimidine and some byproducts at low temperatures.

[0025] If the amount of the first solvent is too small, the raw materials will not dissolve completely, affecting the reaction; if the amount is too large, the cost will increase. Therefore, the mass ratio of p-nitrobenzenesulfonyl chloride to the first solvent is 1:4~6, such as 1:4, 1:4.5, 1:5, 1:5.5, 1:6, etc. If the amount of activated carbon is too small, the purity of 4-nitro-sulfanilamide-6-chloropyrimidine will be affected; if the amount is too large, the yield of 4-nitro-sulfanilamide-6-chloropyrimidine will be affected. Therefore, the mass ratio of p-nitrobenzenesulfonyl chloride to activated carbon is 1:0.1~0.2, such as 1:0.1, 1:0.12, 1:0.14, 1:0.15, 1:0.16, 1:0.18, 1:0.2, etc. 5) Reduction: Intermediate 3 and the noble metal catalyst are added to an alcohol solvent, hydrogen gas is introduced, and the reaction is maintained at 100-130℃ and 0.6-0.8MPa for 3-5 hours. After the reaction is completed, the alcohol solvent is recovered by distillation, purified water is added, and the mixture is cooled to 0-5℃ for crystallization for 1.5-2.5 hours. The mixture is then filtered, and the filter cake is dried at 70-90℃ for 1-3 hours to obtain sulfachloropyrimidine.

[0026] The alcohol solvent is methanol or ethanol. The noble metal catalyst can be Pd / C, Pt / C, Ni, etc. Further optimization of parameters is needed. If the amount of alcohol solvent is too small, the raw material cannot be completely dissolved, affecting the product yield; if the amount is too large, the cost increases. Therefore, the mass ratio of 4-nitro-sulfanilamide-6-chloropyrimidine to the alcohol solvent is 1:4~8, such as 1:4, 1:5, 1:6, 1:7, 1:8, etc.; the mass ratio of 4-nitro-sulfanilamide-6-chloropyrimidine to the noble metal catalyst is 1:0.05~0.15, such as 1:0.05, 1:0.07, 0.10, 0.12, 0.15, etc.

[0027] The present invention will be further described below with reference to examples. It should be noted that the following description is only for explaining the present invention and does not limit its content.

[0028] Example 1 Please see Figure 1 This embodiment provides a method for synthesizing sulfachloropyrimidine, including the following steps: Synthetic intermediate 1: 405 g (4.0 mol) of 36% hydrochloric acid was cooled to -8℃, and 138.12 g (1 mol) of p-nitroaniline was added. The mixture was stirred for 30 min, and the temperature was maintained. A 30% sodium nitrite aqueous solution (1.03 mol) containing 71 g (1.03 mol) of sodium nitrite was added dropwise. After the addition was completed, the mixture was kept at this temperature for 1 h to obtain p-nitrodiazotized chlorobenzene solution A. 24.86 g of copper sulfate was added to 690 g of glacial acetic acid, and the mixture was stirred and cooled to 8-10℃. 306 g of SO2 gas was introduced until saturation to obtain solution B. The mixture was cooled to -5℃, and p-nitrodiazotized chlorobenzene solution A was added to solution B. The mixture was then stirred and reacted for 2 h. The mixture was diluted with twice the amount of ice water, filtered, and the filter cake was washed with a small amount of ice water. The mixture was dried until the moisture content was ≤0.1% to obtain 204 g (0.92 mol) of intermediate 1, with a molar yield of 92%. Simultaneously, glacial acetic acid and sulfur dioxide are recovered: the mother liquor from intermediate 1 is transferred to an enamel-lined reactor, connected to an absorption device filled with acetic acid, and heated to boiling until all SO2 evaporates. This allows the acetic acid solution containing SO2 to be reused, recovering approximately 230g of SO2. The remaining acetic acid solution is neutralized with sodium hydroxide, then distilled at approximately 104°C to obtain an aqueous acetic acid fraction. This fraction is then purified using a Raschig ring-filled distillation column with dichloromethane as an azeotropic agent, ultimately yielding approximately 552g of acetic acid.

[0029] Synthetic intermediate 2: 169 g of 4,6-dichloropyrimidine (1.134 mol) and 845 g of 25% ammonia solution were added to an autoclave, stirred, and heated to 55-60°C. The reaction was maintained at this temperature for approximately 2.5 h. Ammonia was recovered by atmospheric distillation. The mixture was cooled to room temperature to precipitate a solid, which was then filtered. The filter cake was dried at 80°C for 2 h to obtain 126.3 g of intermediate 2 (0.97 mol), with a molar yield of 86%. The ammonia recovery method included: after the reaction, the distillation apparatus was connected to an ammonia absorption device at the tail end. After distillation, the recovered ammonia solution was transferred to an ammonia solution preparation tank, and ammonia gas was introduced to prepare a 25% ammonia solution for later use. The ammonia recovery rate was approximately 80%.

[0030] Synthetic intermediate 3: 204 g of intermediate 1 (0.92 mol), 126.3 g of intermediate 2 (0.97 mol), and 107.06 g of triethylamine (1.058 mol) were added to 1020 ml of dichloromethane, stirred and heated to reflux, and the reaction was maintained at this temperature for about 4 h. Then, 500 ml of drinking water was added, the solid was stirred and dissolved, and the aqueous layer was separated by standing. 30.6 g of activated carbon was added, and the reaction was maintained at about 85 °C for 3 h. The mixture was filtered while hot. The filtrate was adjusted to pH=4 with hydrochloric acid, filtered by suction, and the filter cake was washed with a small amount of hot water and dried at 80 °C for 2 h to obtain 261 g of intermediate 3, with a molar yield of 90%.

[0031] Synthesis of sulfachloropyrimidine: 261 g of intermediate 3 (0.83 mol) and 21 g of Pd / C were added to 1300 g of methanol, and hydrogen gas was introduced. The reaction was carried out at approximately 115 °C and 0.7 MPa for about 4 h. After the reaction was completed, the methanol solvent was recovered by distillation, 100 g of purified water was added, and the mixture was kept at 0–5 °C for 2 h to crystallize. The mixture was filtered, and the filter cake was dried at 80 °C for 2 h to obtain 226.7 g of sulfachloropyrimidine, with a molar yield of 96%.

[0032] The sulfachloropyrimidine prepared in this embodiment was subjected to infrared and nuclear magnetic resonance detection, and the results are as follows: Figures 2-3 As shown. Among them, Figure 2 Indicates: 3465 and 3379cm -1 The absorption peaks at 1630 cm⁻¹ are due to the asymmetric and symmetric stretching vibrations of aniline, indicating the presence of an amino group within the molecule; -1 The absorption peaks at 1567 and 1488 cm⁻¹ are due to the bending vibration of the amino group, further indicating the presence of an amino group within the molecule; -1 The absorption peaks at 1343, 1152, and 1086 cm⁻¹ are absorption peaks of the C=C stretching vibration of the benzene ring. -1 The absorption peak at 1306 cm⁻¹ is the vibrational absorption peak of sulfonamide. -1 The absorption peak is the stretching vibration peak of CN; 825 cm⁻¹ -1 The absorption peak is due to the out-of-plane bending vibration of the CH group of the 1,4-substituted aromatic ring in the molecule.

[0033] Figure 3 As shown 1 The sum of the integrated areas (from high field to low field) of all peaks given by the 1H NMR spectrum is 8.73, indicating that there are a total of 9 protons in the sample molecule, which is equal to the number of protons in the molecular formula. Among them: δ=11.77ppm (1H, s) is 1 hydrogen on the N atom of the sulfonamide group, i.e., H-4; δ=8.59ppm (1H, m) is 1 hydrogen on the 2nd carbon of the pyridine ring, i.e., H-6; δ=7.59ppm (2H, m) is 2 hydrogens on the benzene ring near the sulfonamide group, i.e., H-3; δ=6.96ppm (1H, m) is 1 hydrogen on the 5th carbon of the pyridine ring, i.e., H-5; δ=6.60ppm (2H, m) is 2 hydrogens on the benzene ring near the amino group, i.e., H-2; δ=6.18ppm (2H, m) is 2 hydrogens on the benzene ring of the amino group, i.e., H-1.

[0034] Therefore, combining Figure 1 and Figure 2 This indicates that sulfachloropyrimidine was successfully synthesized in this embodiment.

[0035] Example 2 This embodiment provides a method for synthesizing sulfachloropyrimidine, including the following steps: Synthetic Intermediate 1: 385 g (3.8 mol) of 36% hydrochloric acid was cooled to -5°C, and 138.12 g (1.0 mol) of p-nitroaniline was added. The mixture was stirred for 30 min, and the temperature was maintained. A 30% sodium nitrite aqueous solution containing 71 g (1.03 mol) of sodium nitrite was added dropwise. After the addition was completed, the mixture was kept at this temperature for 1 h to obtain p-nitrodiazotized chlorobenzene solution A. 24.86 g of copper sulfate was added to 690 g of glacial acetic acid, and the mixture was stirred and cooled to 8-10°C. SO2 gas was introduced until saturation was achieved to obtain solution B. The mixture was cooled to -5°C, and p-nitrodiazotized chlorobenzene solution A was added to solution B. The mixture was then stirred and reacted for 2 h. The solution was diluted with twice the amount of ice water, filtered, and the filter cake was washed with a small amount of ice water. The solution was dried until the moisture content was ≤0.1% to obtain 202 g of intermediate 1, with a molar yield of 91%. At the same time, the glacial acetic acid and sulfur dioxide in the mother liquor from the separation of intermediate 1 in this example were recovered using the same method as in Example 1.

[0036] Synthetic intermediate 2: 186.5 g of 4,6-dichloropyrimidine and 1492 g of 25% ammonia water were added to a high-pressure reactor, stirred and heated to 55-60°C, and the reaction was maintained at this temperature for about 2.5 h. Ammonia was recovered by atmospheric distillation, and the solid was precipitated at room temperature. The solid was filtered, and the filter cake was dried at 80°C for 2 h to obtain 125 g of intermediate 2, with a molar yield of 88%. At the same time, the ammonia in this step was recovered by the same atmospheric distillation method as in Example 1.

[0037] Synthetic intermediate 3: 202 g of intermediate 1 (0.91 mol), 125 g of intermediate 2 (0.96 mol), and 148.4 g of potassium carbonate (1.07 mol) were added to 1010 ml of dichloromethane. The mixture was stirred and heated to reflux, and the reaction was maintained at this temperature for about 4 h. Then, 500 ml of drinking water was added, and the solid was stirred to dissolve. The mixture was allowed to stand and the aqueous layer was separated. 30.3 g of activated carbon was added, and the reaction was maintained at about 85 °C for 3 h. The mixture was then filtered while hot. The filtrate was adjusted to pH=5 with hydrochloric acid, filtered by suction, and the filter cake was washed with a small amount of hot water and dried at 80 °C for 2 h to obtain 260 g of intermediate 3 (0.82 mol), with a molar yield of 90%.

[0038] Synthesis of sulfachloropyrimidine: 260 g of intermediate 3 (0.82 mol) and 26 g of Pd / C were added to 1560 g of ethanol, hydrogen gas was introduced, and the reaction was maintained at approximately 105 °C and 0.6 MPa for about 5 h. After the reaction was completed, the solvent was recovered by distillation, 100 g of purified water was added, and the mixture was kept at 0–5 °C for 2 h to crystallize. After filtration, the filter cake was dried at 80 °C for 2 h to obtain 221.1 g of sulfachloropyrimidine, with a molar yield of 94%.

[0039] Example 3 This embodiment provides a method for synthesizing sulfachloropyrimidine, including the following steps: Synthetic intermediate 1: 405 g (4.0 mol) of 36% concentrated hydrochloric acid was cooled to -10℃, and 138.12 g (1.0 mol) of p-nitroaniline was added. The mixture was stirred for 30 min, and the temperature was maintained. 1.02 mol of 30% sodium nitrite aqueous solution containing 70.3 g of sodium nitrite was added dropwise. After the addition was completed, the mixture was kept at this temperature for 1 h to obtain p-nitrodiazotized chlorobenzene solution A. 27.62 g of copper sulfate was added to 828 g of glacial acetic acid, and the mixture was stirred and cooled to 8-10℃. SO2 gas was introduced until saturation was achieved to obtain solution B. The temperature was lowered to -10℃, and p-nitrodiazotized chlorobenzene solution A was added to solution B. The mixture was stirred for 2 h, diluted with twice the amount of ice water, filtered, and the filter cake was washed with a small amount of ice water. The solution was dried until the moisture content was ≤0.1% to obtain 208.3 g of intermediate 1 (0.94 mol), with a molar yield of 94%. Simultaneously, using the same method as in Example 1, glacial acetic acid and sulfur dioxide were recovered from the mother liquor of intermediate 1 in this example.

[0040] Synthetic intermediate 2: 192 g (1.128 mol) of 4,6-dichloropyrimidine and 1536 g of 25% ammonia solution were added to an autoclave, stirred and heated to 55-60°C, and kept at this temperature for 2-3 h. Ammonia was recovered by atmospheric distillation, and the solid was precipitated at room temperature. The solid was filtered, and the filter cake was dried at 80°C for 2 h to obtain 131.5 g (1.015 mol) of intermediate 2, with a molar yield of 90%. At the same time, the ammonia in this step was recovered by the same atmospheric distillation method as in Example 1.

[0041] Synthetic intermediate 3: 208.3 g of intermediate 1 (0.94 mol), 131.5 g of intermediate 2 (1.015 mol), and 85.50 g of pyridine (1.081 mol) were added to 1040 ml of dichloromethane. The mixture was stirred and heated to reflux, and the reaction was maintained at this temperature for about 5 h. Then, 500 ml of drinking water was added, and the solid was stirred to dissolve. The mixture was allowed to stand and the aqueous layer was separated. 31.2 g of activated carbon was added, and the reaction was maintained at about 85 °C for 3 h. The mixture was filtered while hot. The filtrate was adjusted to pH=3 with hydrochloric acid, filtered under vacuum, and the filter cake was washed with a small amount of hot water and dried at 80 °C for 2 h to obtain 272.1 g of intermediate 3 (0.865 mol), with a molar yield of 92%.

[0042] Synthesis of sulfachloropyrimidine: 272.1 g of intermediate 3 (0.865 mol) and 27.2 g of Pd / C were added to 2176 g of methanol, and hydrogen gas was introduced. The reaction was carried out at approximately 130 °C and 0.8 MPa for about 3 h. After the reaction was completed, the methanol solvent was recovered by distillation, and 100 g of purified water was added. The mixture was kept at 0–5 °C for 2 h to crystallize. After filtration, the filter cake was dried at 80 °C for 2 h to obtain 241.3 g of sulfachloropyrimidine (0.8475 mol), with a molar yield of 98%.

[0043] Example 4 This embodiment provides a method for synthesizing sulfachloropyrimidine, including the following steps: Synthetic intermediate 1: 405 g (4.0 mol) of 36% concentrated hydrochloric acid was cooled to -8℃, and 138.12 g (1.0 mol) of p-nitroaniline was added. The mixture was stirred for 30 min, and the temperature was maintained. A 30% sodium nitrite aqueous solution (1.02 mol) containing 70.3 g of sodium nitrite was added dropwise. After the addition was completed, the mixture was kept at this temperature for 1 h to obtain p-nitrodiazotized chlorobenzene solution A. 27.62 g of copper sulfate was added to 690 g of glacial acetic acid, and the mixture was stirred and cooled to 8-10℃. SO2 gas was introduced until saturation was achieved to obtain solution B. The temperature was lowered to -8℃, and p-nitrodiazotized chlorobenzene solution A was added to solution B. The mixture was then stirred for 2 h, diluted with twice the amount of ice water, filtered, and the filter cake was washed with a small amount of ice water. The solution was dried until the moisture content was ≤0.1% to obtain 206.1 g of intermediate 1 (0.93 mol), with a molar yield of 93%. Simultaneously, using the same method as in Example 1, glacial acetic acid and sulfur dioxide were recovered from the mother liquor of intermediate 1 in this example.

[0044] Synthetic intermediate 2: 160g (1.075mol) of 4,6-dichloropyrimidine and 1600g of 25% ammonia solution were added to an autoclave, stirred and heated to 55-60℃, and kept at this temperature for 2-3h. Ammonia was recovered by atmospheric distillation, and the solid was precipitated at room temperature. The solid was filtered, and the filter cake was dried at 80℃ for 2h to obtain 129.5g (1.0mol) of intermediate 2, with a molar yield of 93%. At the same time, the ammonia in this step was recovered by the same atmospheric distillation method as in Example 1.

[0045] Synthetic intermediate 3: 206.1 g of intermediate 1 (0.93 mol), 129.5 g of intermediate 2 (1.0 mol), and 88.27 g (1.116 mol) of pyridine were added to 1030 ml of dichloromethane. The mixture was stirred and heated to reflux, and the reaction was maintained at this temperature for 3 h. Then, 500 ml of drinking water was added, and the solid was stirred to dissolve. The mixture was allowed to stand and the aqueous layer was separated. 31 g of activated carbon was added, and the reaction was maintained at 90 °C for 3 h. The mixture was then filtered while hot. The filtrate was adjusted to pH=4 with hydrochloric acid, filtered under vacuum, and the filter cake was washed with a small amount of hot water and dried at 80 °C for 2 h to obtain 272.2 g of intermediate 3 (0.865 mol), with a molar yield of 93%.

[0046] Synthesis of sulfachloropyrimidine: 272.2 g of intermediate 3 (0.865 mol) and 40.8 g of Pd / C were added to 1633 g of methanol, and hydrogen gas was introduced. The reaction was carried out at approximately 120 °C and 0.7 MPa for about 4 h. After the reaction was completed, the methanol solvent was recovered by distillation, 100 g of purified water was added, and the mixture was kept at 0–5 °C for 2 h to crystallize. After filtration, the filter cake was dried at 80 °C for 2 h to obtain 236.40 g of sulfachloropyrimidine (0.8303 mol), with a molar yield of 96%.

[0047] Example 5 (Recycling and reuse of solvent): This embodiment provides a method for synthesizing sulfachloropyrimidine, including the following steps: Synthetic intermediate 1: 405 g (4.0 mol) of 36% concentrated hydrochloric acid was cooled to -8℃, and 138.12 g (1.0 mol) of p-nitroaniline was added. The mixture was stirred for 30 min, and the temperature was maintained. A 30% sodium nitrite aqueous solution (1.02 mol) containing 7.03 g of sodium nitrite was added dropwise. After the addition was completed, the mixture was kept at this temperature for 1 h to obtain p-nitrodiazotized chlorobenzene solution A. 27.62 g of copper sulfate was added to 700 g of glacial acetic acid containing SO2, and the mixture was stirred and cooled to 8-10℃. SO2 gas was introduced until saturation was achieved to obtain solution B. The temperature was lowered to -8℃, and p-nitrodiazotized chlorobenzene solution A was added to solution B. The mixture was then stirred for 2 h, diluted with twice the amount of ice water, filtered, and the filter cake was washed with a small amount of ice water. The solution was dried until the moisture content was ≤0.1% to obtain 206 g of intermediate 1 (0.93 mol), with a molar yield of 93%. In this embodiment, the 700 g of SO2-containing glacial acetic acid was composed of the 552 g of SO2-containing glacial acetic acid recovered in Example 1 and 138 g of newly added SO2-containing glacial acetic acid. Furthermore, this embodiment used the same method as in Example 1 to recover glacial acetic acid and sulfur dioxide from the mother liquor of intermediate 1.

[0048] Synthetic intermediate 2: 160 g (1.075 mol) of 4,6-dichloropyrimidine and 1600 g of 25% ammonia solution were added to an autoclave, stirred, and heated to 55-60°C. The reaction was maintained at this temperature for approximately 2.5 h. Ammonia was recovered by atmospheric distillation, and the mixture was cooled to room temperature to precipitate a solid. The solid was filtered, and the filter cake was dried at 80°C for 2 h to obtain 129.5 g (1.0 mol) of intermediate 2, with a molar yield of 93%. Simultaneously, the ammonia in this step was recovered using the same atmospheric distillation method as in Example 1. The 1600 g ammonia solution used in this step was prepared from the ammonia recovered in Example 1 and the newly added ammonia.

[0049] Synthetic intermediate 3: 206 g of intermediate 1 (0.93 mol), 129.5 g of intermediate 2 (1.0 mol), and 88.27 g (1.116 mol) of pyridine were added to 1030 ml of dichloromethane. The mixture was stirred and heated to reflux, and the reaction was maintained at this temperature for about 4 h. Then, 500 ml of drinking water was added, and the solid was stirred to dissolve. The mixture was allowed to stand and the aqueous layer was separated. 31 g of activated carbon was added, and the reaction was maintained at about 85 °C for 3 h. The mixture was then filtered while hot. The filtrate was adjusted to pH 4 with hydrochloric acid, filtered under vacuum, and the filter cake was washed with a small amount of hot water and dried at 80 °C for 2 h to obtain 272.2 g of intermediate 3 (0.865 mol), with a molar yield of 93%.

[0050] Synthesis of sulfachloropyrimidine: 272.2 g of intermediate 3 (0.865 mol) and 40.8 g of Pd / C were added to 1633 g of methanol, and hydrogen gas was introduced. The reaction was carried out at approximately 120 °C and 0.7 MPa for about 4 h. After the reaction was completed, the methanol solvent was recovered by distillation, 100 g of purified water was added, and the mixture was kept at 0–5 °C for 2 h to crystallize. After filtration, the filter cake was dried at 80 °C for 2 h to obtain 236.40 g of sulfachloropyrimidine (0.8303 mol), with a molar yield of 96%.

[0051] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications can still be made to the specific implementation of the present invention or equivalent substitutions can be made to some technical features without departing from the spirit of the technical solutions of the present invention, and all such modifications and substitutions should be covered within the scope of the technical solutions claimed in the present invention.

Claims

1. A method for synthesizing sulfachloropyrimidine, comprising the steps of: Synthesis of 4-nitro-sulfonamide-6-chloropyrimidine: p-nitroaniline was synthesized from p-nitrobenzenesulfonyl chloride via diazotization and sulfonation reactions; Synthesis of 4-amino-6-chloropyrimidine: 4,6-dichloropyrimidine was synthesized by reacting it with ammonia water through an ammoniation reaction. Synthesis of 4-nitro-sulfonamide-6-chloropyrimidine: p-Nitrobenzenesulfonyl chloride and 4-amino-6-chloropyrimidine are refluxed under the action of an alkaline catalyst to undergo a condensation reaction to synthesize 4-nitro-sulfonamide-6-chloropyrimidine; Synthesis of sulfachloropyrimidine: 4-nitro-sulfa-6-chloropyrimidine and hydrogen undergo a reduction reaction in the presence of a noble metal catalyst to synthesize sulfachloropyrimidine.

2. The synthesis method according to claim 1, characterized in that, In the step of synthesizing p-nitrobenzenesulfonyl chloride, the diazotization reaction step includes: first reacting concentrated hydrochloric acid and p-nitroaniline at below 15°C for 20-40 min, then adding a sodium nitrite aqueous solution with a concentration of 20 wt%-40 wt%, and after the addition is completed, maintaining the temperature for 45-75 min to obtain p-nitrobazo-diazotized benzene chloride solution A; The steps of the sulfonation reaction include: first, stirring and mixing the copper salt catalyst and glacial acetic acid, and then introducing SO2 gas at a temperature below 20°C until saturation to obtain solution B; then, adding the p-nitrodiazotized chlorobenzene solution A to solution B at a temperature below 15°C, stirring and reacting for 1.5~2.5 h, diluting with twice the amount of ice water, filtering, washing the filter cake with a small amount of ice water, and drying to a moisture content ≤0.1% to obtain p-nitrobenzenesulfonyl chloride, and recovering the glacial acetic acid and SO2 therein.

3. The synthesis method according to claim 2, characterized in that, The method for recovering glacial acetic acid and SO2 includes: first, transferring the mother liquor from which p-nitrobenzenesulfonyl chloride was separated into an enamel-lined reactor, connecting it to an absorption device filled with acetic acid, heating it to boiling until all SO2 evaporates, and obtaining an acetic acid solution containing SO2; then, neutralizing the remaining acetic acid solution in the mother liquor from which p-nitrobenzenesulfonyl chloride was separated with an alkaline solution; then, distilling to obtain an aqueous acetic acid fraction; and finally, rectifying the aqueous acetic acid fraction to recover the acetic acid therein.

4. The synthesis method according to claim 1, 2, or 3, characterized in that, The steps for synthesizing 4-amino-6-chloropyrimidine include: first, reacting 4,6-dichloropyrimidine with an aqueous ammonia solution of 23wt%~30wt% at 60~80℃ for 2~3 h to synthesize 4-amino-6-chloropyrimidine; then, recovering the ammonia by atmospheric distillation; then, cooling to room temperature to precipitate the solid; filtering; drying the filter cake to obtain purified 4-amino-6-chloropyrimidine.

5. The synthesis method according to claim 4, characterized in that, The method for recovering ammonia by atmospheric distillation includes: after the reaction for synthesizing 4-amino-6-chloropyrimidine is completed, a distillation apparatus is connected, which is connected to an ammonia absorption device. After atmospheric distillation is completed, the recovered ammonia water is transferred to an ammonia water preparation tank, and ammonia gas is introduced to prepare an ammonia water solution with a concentration of 23 wt% to 30 wt%.

6. The synthesis method according to claim 1, 2, or 3, characterized in that, In the step of synthesizing 4-nitro-sulfanilamide-6-chloropyrimidine, the molar ratio of p-nitrobenzenesulfonyl chloride, 4-amino-6-chloropyrimidine, and the alkaline catalyst is 1:1.03~1.1:1.1~1.25; wherein the alkaline catalyst is one or more of pyridine, triethylamine, potassium carbonate, and sodium carbonate.

7. The synthesis method according to claim 6, characterized in that, The steps for synthesizing 4-nitro-sulfonamide-6-chloropyrimidine include: adding p-nitrobenzenesulfonyl chloride, 4-amino-6-chloropyrimidine, and the alkaline catalyst to a first solvent, stirring and heating to reflux, maintaining the temperature for 3-5 hours, then adding drinking water, stirring to dissolve the solid, allowing it to stand to separate the aqueous layer, adding activated carbon, maintaining the temperature at 80-90°C for 2-4 hours, and filtering while hot; adjusting the pH of the filtrate obtained from the hot filtration to 2-6 with hydrochloric acid, filtering by suction, washing the filter cake with hot water, and drying to obtain 4-nitro-sulfonamide-6-chloropyrimidine.

8. The synthesis method according to claim 1, 2, or 3, characterized in that, The steps for synthesizing sulfachloropyrimidine include: adding 4-nitro-sulfa-6-chloropyrimidine and a noble metal catalyst to an alcohol solvent, introducing hydrogen gas, and reacting at 100~130℃ and 0.6~0.8MPa for 3~5 hours to synthesize sulfachloropyrimidine.

9. The synthesis method according to claim 8, characterized in that, In the step of synthesizing sulfachloropyrimidine, after the reaction for synthesizing sulfachloropyrimidine is completed, the following steps are also included: first, the alcohol solvent is recovered by distillation, then purified water is added, the mixture is cooled to 0~5℃ for 1.5~2.5 h to crystallize, filtered, and the filter cake is dried to obtain the purified sulfachloropyrimidine product.

10. A method for synthesizing sulfachloropyrimidine, comprising the steps of: Diazotization: p-Nitroaniline is used as the starting material and reacts with concentrated hydrochloric acid and sodium nitrite to synthesize p-nitrodiazochlorobenzene; Sulfonation: In a copper salt catalyst and glacial acetic acid, p-nitrodiazochlorobenzene undergoes a sulfonation reaction with SO2 gas to synthesize 4-nitro-sulfonamide-6-chloropyrimidine; Ammoniation: 4,6-Dichloropyrimidine undergoes an ammoniation reaction with ammonia to give 4-amino-6-chloropyrimidine; Condensation: Nitrobenzenesulfonyl chloride and 4-amino-6-chloropyrimidine undergo a condensation reaction under reflux in the presence of an alkaline catalyst to synthesize 4-nitro-sulfonamide-6-chloropyrimidine; Reduction: 4-Nitro-sulfanilamide-6-chloropyrimidine and hydrogen undergo a reduction reaction in the presence of a noble metal catalyst to synthesize sulfachloropyrimidine.

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