Process for synthesizing 4-isopropoxy benzene sulfonyl chloride

Abstract

The invention relates to a process for synthesizing 4-isopropoxy benzene sulfonyl chloride. The process comprises the following two steps of: reacting isopropoxy benzene serving as a raw material with pyridine sulfur trioxide to prepare 4-isopropoxy benzene sulfonic acid pyridine, and directly reacting with thionyl chloride by a one-pot method to obtain the 4-isopropoxy benzene sulfonyl chloride. The method is simple and convenient to operate, less in waste solvent and wastewater amount, and beneficial to realizing continuous production; the process is simple, the raw material cost is low, the reaction stability is good, industrialization is easy to realize, and the market competitiveness of the 4-isopropoxy benzene sulfonyl chloride is effectively improved.

Description

Technical Field

[0001] This invention relates to a process for synthesizing 4-isopropoxybenzenesulfonyl chloride, belonging to the field of pharmaceutical intermediates technology. Background Technology

[0002] 4-Isopropoxybenzenesulfonyl chloride is an important organic synthetic intermediate, primarily used as a key starting material in sulfonation and sulfonamide reactions. There are two main known synthetic methods for this product:

[0003] Option 1: An etherification process using sodium 4-hydroxybenzenesulfonate and 2-bromopropane is performed, followed by reaction with thionyl chloride to obtain the product [Bioorganic and Medicinal Chemistry, 2013, vol. 21, #21, pp. 6466-6476]. Problems: The first step, etherification, requires a large excess of 2-bromopropane due to its elimination in a strong base, and the reaction is very slow. The second step yields a low product.

[0004] Option 2: Using sodium 4-hydroxybenzenesulfonate and isopropanol, an ether is formed via photoelectrophoresis, followed by reaction with thionyl chloride under triphenylboron catalysis to obtain product CN118047699,2024,A. Location inpatent: Paragraph0028-0030. The first step, photoelectrophoresis, generates a large amount of waste that cannot be recycled.

[0005] Option 3: Isopropoxybenzene was directly sulfonated with chlorosulfonic acid. However, it was found that the acidity was too strong, and the isopropoxy group was removed. The intermediate 4-isopropoxybenzenesulfonic acid was unstable and deteriorated, making it impossible to generate the next product.

[0006] These unfavorable reaction characteristics limit the scale-up industrial synthesis of 4-isopropoxybenzenesulfonyl chloride, making it essential to find a new green, safe, and environmentally friendly industrial production process. Summary of the Invention

[0007] The purpose of this invention is to overcome the aforementioned shortcomings and provide a process for synthesizing 4-isopropoxybenzenesulfonyl chloride. Using isopropoxybenzene as a raw material, sulfonation with sulfur trioxide pyridine is first performed in pyridine. After distilling off the pyridine, it is directly reacted with thionyl chloride in a one-pot process, followed by post-treatment to obtain sodium 4-isopropoxybenzenesulfonate. This process is green, safe, environmentally friendly, and easy for industrial production.

[0008] The present invention describes a method for synthesizing 4-isopropoxybenzenesulfonyl chloride, which involves two steps, and the reaction route is as follows:

[0009]

[0010] Includes the following steps:

[0011] A. Synthesis of pyridine 4-isopropoxybenzenesulfonic acid: Under nitrogen protection, isopropoxybenzene was reacted with sulfur trioxide pyridine in pyridine at 90-100℃ to obtain pyridine 4-isopropoxybenzenesulfonic acid.

[0012] B. Synthesis of 4-isopropoxybenzenesulfonyl chloride: Using pyridine 4-isopropoxybenzenesulfonic acid as a raw material, it was reacted with thionyl chloride to obtain crude 4-isopropoxybenzenesulfonyl chloride, which was then recrystallized from heptane and tetrahydrofuran to obtain 4-isopropoxybenzenesulfonyl chloride.

[0013] Furthermore, in step A of the above technical solution, the molar ratio of isopropoxybenzene to pyridine trioxide is 1:1.05-1.1.

[0014] Furthermore, in step A of the above technical solution, the pyridine distilled under reduced pressure is reused multiple times.

[0015] Furthermore, in step A of the above technical solution, after vacuum distillation is completed, step B is carried out directly, with the yield calculated as 100%.

[0016] Furthermore, in step A of the above technical solution, after the reaction is completed, the solvent is distilled off under reduced pressure, and step B is carried out directly.

[0017] Furthermore, in step B of the above technical solution, the reaction is carried out in 1,2-dichloroethane or toluene solvent.

[0018] Furthermore, in step B of the above technical solution, the molar ratio of isopropoxybenzene to thionyl chloride is 1:1.3-1.4.

[0019] Furthermore, in step B of the above technical solution, the recrystallization solvent is heptane at twice the weight of the crude product.

[0020] Further, in step B of the above technical solution, after the reaction is completed, water is added to quench the layers at a temperature below 10°C to eliminate separation. The organic layer is dried with sodium sulfate and then evaporated under reduced pressure. Two times its weight of heptane is added, the temperature is raised to 50°C, and then lowered to 0°C for recrystallization to obtain 4-isopropoxybenzenesulfonyl chloride.

[0021] Beneficial effects of the invention

[0022] 1. This route has mild reaction conditions, short cycle, safety and stability, simple operation, and high reaction yield.

[0023] 2. It reduces the generation of wastewater and waste solvents, making the entire process more environmentally friendly, green, and safe.

[0024] 3. The product from step A does not need to be extracted and can be directly processed into step B to achieve continuous production. Attached Figure Description

[0025] Figure 1 The 1H NMR spectrum of 4-isopropylbenzenesulfonyl chloride was obtained in Example 2. Detailed Implementation

[0026] Example 1

[0027] Step 1: Optimization of reaction conditions

[0028] Under nitrogen protection, isopropoxybenzene (0.1 mol) solution, sulfur trioxide pyridine, and pyridine were added to a reaction vessel, and the mixture was stirred and kept at 90-100℃ for 2 hours. The results of the reactions under different conditions are as follows:

[0029]

[0030] Second step: Optimization of reaction conditions

[0031] The reaction solution obtained in the first step was rotary evaporated until it no longer flowed. A solvent (toluene or 1,2-dichloroethane) was added, and thionyl chloride was added dropwise at 60-70°C. After the addition was complete, the mixture was stirred at this temperature for 0.5 h, and a sample was taken for HPLC control. Post-processing was performed by quenching with an aqueous solution. The organic layer was dried with sodium sulfate, evaporated to dryness, recrystallized with solvent, filtered, and dried to obtain 4-isopropoxybenzenesulfonyl chloride. The results under different reaction conditions are as follows:

[0032]

[0033] Number 1 uses dichloromethane, and even with the addition of excess thionyl chloride, the reaction rate is very slow, presumably due to the low boiling point of dichloromethane, which limits the reaction temperature. Numbers 2 and 3 use toluene and 1,2-dichloroethane, and the reaction results are similar. Number 4 does not add solvent and directly uses a large excess of thionyl chloride, and the reaction is normal, but the post-processing generates a large amount of waste. Number 5 uses acetonitrile as solvent, and the reaction results are poor.

[0034] Example 2

[0035] Under nitrogen protection, 1.36 kg of isopropoxybenzene, 4.08 kg of pyridine, and 1.75 kg of sulfur trioxide pyridine were added to a 10 L glass autoclave. The temperature was raised to 90-100 °C and held for 5 h. Normalized HPLC analysis showed isopropoxybenzene < 5% and 4-isopropoxybenzenesulfonic acid pyridine > 95%. Direct post-treatment involved vacuum distillation to remove pyridine, followed by the addition of 2 kg of toluene, and continued vacuum distillation until no liquid flowed. Then, 4.08 kg of toluene was added, and the temperature was raised to 60-70 °C. 1.4 kg of thionyl chloride was added dropwise. After the addition was complete, the temperature was maintained for 4 h. HPLC analysis showed 4-isopropoxybenzenesulfonic acid pyridine < 5% and 4-isopropoxybenzenesulfonyl chloride > 95%. Post-treatment was performed at approximately 0 °C, with the addition of 4 kg of water, resulting in layer separation. The organic layer was evaporated, 2.6 kg of heptane was added, the temperature was lowered to -10 °C and pulped, filtered and dried to obtain 1.95 kg of 4-isopropoxybenzenesulfonyl chloride product, HNMR > 98%.

[0036] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A process for synthesizing 4-isopropoxybenzenesulfonyl chloride, characterized in that, Includes the following steps: A. Synthesis of pyridine 4-isopropoxybenzenesulfonic acid: Under nitrogen protection, isopropoxybenzene was reacted with sulfur trioxide pyridine in pyridine at 90-100℃ to obtain pyridine 4-isopropoxybenzenesulfonic acid. B. Synthesis of 4-isopropoxybenzenesulfonyl chloride: Using pyridine 4-isopropoxybenzenesulfonic acid as a raw material, it was reacted with thionyl chloride to obtain crude 4-isopropoxybenzenesulfonyl chloride, which was then recrystallized from heptane to obtain 4-isopropoxybenzenesulfonyl chloride.

2. The process for synthesizing pyridine 4-isopropoxybenzenesulfonic acid according to claim 1, characterized in that: In step A, the pyridine solvent is recycled and reused multiple times.

3. The process for synthesizing 4-isopropoxybenzenesulfonyl chloride according to claim 1, characterized in that: In step A, the molar ratio of isopropoxybenzene to sulfur trioxide pyridine is 1:1.05-1.

1.

4. The process for synthesizing 4-isopropoxybenzenesulfonyl chloride according to claim 1, characterized in that: After step A is completed, the solvent is distilled off under reduced pressure, and step B is carried out directly.

5. The process for synthesizing 4-isopropoxybenzenesulfonyl chloride according to claim 1, characterized in that: In step B, the reaction is carried out in 1,2-dichloroethane or toluene solvent.

6. The process for synthesizing 4-isopropoxybenzenesulfonyl chloride according to claim 1, characterized in that: In step B, the molar ratio of isopropoxybenzene to thionyl chloride is 1:1.3-1.

4.

7. The process for synthesizing 4-isopropoxybenzenesulfonyl chloride according to claim 1, characterized in that: After the reaction in step B is completed, the aqueous solution is quenched to separate into layers, and the organic layer is evaporated to dryness to obtain a solid crude product.

8. The process for synthesizing 4-isopropoxybenzenesulfonyl chloride according to claim 1, characterized in that: In step B, the recrystallization solvent is heptane at twice the weight of the crude product.

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