A process for the production of 2,2'-(propane-2,2'-diylbis(sulfonamid-diyl))diamin and its hydrochloride salt

Abstract

The application discloses a production process of 2,2'-(propane-2,2'-diylbis(sulfonamidyl))diethylamine and its hydrochloride. 2,2'-(propane-2,2'-diylbis(sulfonamidyl))diethylamine is a common active oxygen response small molecule. At present, the synthesis process of the molecule has the problems of complex synthesis steps, multi-step post-treatment, difficult reuse of solvent, low reaction rate and low reaction yield, and high-pollution gas purification. The application adopts a new production process. Cysteamine hydrochloride and acetone are reacted in a reaction system by one-step method to prepare 2,2'-(propane-2,2'-diylbis(sulfonamidyl))diethylamine dihydrochloride product. After alkaline washing, 2,2'-(propane-2,2'-diylbis(sulfonamidyl))diethylamine product is obtained. The production process does not need high-pollution hydrogen chloride gas catalysis, has high reaction efficiency and yield, the involved solvent can be recycled and reused, the reactants and products are easy to separate, the product has high purity, the reaction device is simple, the process is environment-friendly, and the reaction end point is easy to monitor.

Description

Technical Field

[0001] This invention relates to a production process for 2,2'-(propane-2,2'-dimethylbis(sulfonamide dimethyl))diethylamine and its hydrochloride, which has reactive oxygen species responsiveness and can be used for the synthesis of pharmaceutical intermediates and novel polymers, belonging to the field of chemical synthesis. Background Technology

[0002] Reactive oxygen species (ROS) are essential active substances for cellular life activities. As signaling or regulatory molecules, they participate in a series of physiological processes within the body. Under normal physiological conditions, ROS maintain homeostasis. However, in some diseases, ROS levels are abnormally elevated, leading to oxidative stress. Excessively high ROS levels can damage proteins, nucleic acids, and lipids, resulting in tissue dysfunction and cell death. Therefore, reducing tissue ROS levels is beneficial for alleviating inflammation and promoting tissue regeneration. Currently, the functional group reaction mechanisms of ROS responses can be divided into two categories: first, ROS responses cause changes in hydrophilicity and hydrophobicity, such as thioether bonds, selenium, and tellurium functional groups; second, ROS induce the breaking of chemical bonds, including phenylboronic acid / ester bonds and ketethiocyanate bonds.

[0003] The structural formula of 2,2'-(propane-2,2'-dimethylbis(sulfonamide diethyl))diethylamine is shown below. It is a small molecule with amino groups at both ends, and its bonds can be broken in response to ROS, thereby achieving polymer degradation or drug release. It has been applied in the synthesis of biodegradable biomaterials and drug precursors. The oxidative degradation product of 2,2'-(propane-2,2'-dimethylbis(sulfonamide diethyl))diethylamine—acetone—participates in human metabolism and is therefore non-toxic and harmless, showing promise for applications in disease treatment.

[0004]

[0005] Currently, there are two main synthesis techniques. Method one is as follows: Cysteine ​​hydrochloride and acetone are placed in a container and stirred, with hydrogen chloride gas continuously introduced. After reacting for 1-2 days, 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine dihydrochloride is obtained. The hydrochloride is then subjected to alkaline washing and other steps to obtain 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine. This method is a heterogeneous reaction, with low reaction efficiency and yield, and the reaction endpoint is difficult to determine. Secondly, the generated product will coat the starting material, forming a mixture of the two, resulting in an impure product. In addition, this method requires the introduction of hydrogen chloride gas, which has a high risk factor, and also requires additional tail gas treatment processes, resulting in high production costs.

[0006]

[0007] Method 2 is as follows: Cysteine ​​or cysteine ​​hydrochloride, ethyl trifluoroacetate, and triethylamine are dissolved in methanol and reacted for 8-12 hours. The reaction solution is then neutralized with acetic acid to remove the organic solvent. The mixture is extracted with ethyl acetate, and the organic layer is dried with anhydrous magnesium sulfate to obtain compound 1. Under nitrogen protection, compound 1 and acetone are dissolved in acetonitrile, and boron trifluoride diethyl ether is added. The mixture is then reacted at 0-4°C for 2-6 hours. The reaction system is then poured into a 5%-15% sodium carbonate solution and extracted with ethyl acetate. The combined organic layers are washed with sodium carbonate solution, dried with anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain compound 2. The compound is dissolved in 6M sodium hydroxide solution and reacted for 2-6 hours, then extracted with dichloromethane to obtain 2,2'-(propane-2,2'-dimethylbis(sulfonamide dimethyl))diethylamine. This method involves multiple steps and requires multiple post-processing steps, making it impossible to obtain the product in a single reaction.

[0008]

[0009] Based on this, the present invention provides a more environmentally friendly and efficient method for preparing 2,2'-(propane-2,2'-dimethylbis(sulfonamide dimethyl))diethylamine and its hydrochloride, which is more conducive to large-scale production and application. Summary of the Invention

[0010] The purpose of this invention is to address the shortcomings of existing synthetic processes by providing a production process for 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine and its hydrochloride. This process involves a one-step reaction of cysteine ​​hydrochloride and acetone under non-hydrogen chloride gas catalysis to generate 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine dihydrochloride, followed by alkali washing to obtain 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine. This process is simple to operate, highly efficient, environmentally friendly, low-cost, and requires a simple reaction apparatus.

[0011] The production process of 2,2'-(propane-2,2'-diylbis(sulfonamide diyl))diethylamine and its hydrochloride according to the present invention comprises the following steps:

[0012] The first step involves continuously stirring and dissolving cysteine ​​hydrochloride, solvent, and catalyst until a homogeneous solution of a certain concentration is formed, followed by the addition of a certain amount of acetone.

[0013] The second step involves stirring the above system for 2-6 hours under certain conditions until a white precipitate is formed.

[0014] The third step involves separating the white precipitate by vacuum filtration, which yields 2,2'-(propane-2,2'-dimethylbis(sulfonamide dimethyl))diethylamine dihydrochloride, which is then stored at room temperature.

[0015] Furthermore, the organic solvent used in the first step is one or more of chloroform and organic acids, and the organic acids are liquid acids, including formic acid, acetic acid, etc.

[0016] Furthermore, the concentration of cysteine ​​hydrochloride in the solution in the first step is 0.1-1.3 g / mL.

[0017] Furthermore, in the first step, the mass-to-volume ratio of cysteine ​​hydrochloride to acetone is from 5g:1mL to 1g:5mL, and the catalyst used can be one or more of the following: p-toluenesulfonic acid, boron trifluoride diethyl ether complex, proline, trifluoroacetic acid, etc., and the molar ratio of the catalyst to cysteine ​​hydrochloride is 0.001:1-0.1:1.

[0018] Furthermore, the reaction conditions in the second step are a temperature of 0-50℃.

[0019] Furthermore, the hydrochloride product obtained in the third step is washed with alkali and dried to obtain 2,2'-(propane-2,2'-diylbis(sulfanilamide))diethylamine. The concentrated alkali solution used for alkali washing is one or more of sodium hydroxide, potassium hydroxide, ammonium hydroxide, etc., with a concentration of 8-15M. The mass-to-volume ratio of 2,2'-(propane-2,2'-diylbis(sulfanilamide))diethylamine dihydrochloride to alkali solution is 1g:1mL to 1g:10mL.

[0020] The beneficial effects of the present invention include the following:

[0021] This invention addresses the problems of complex synthesis steps, multiple post-processing steps, difficulty in reusing solvents, low reaction rates and yields, and the need for highly polluting gas purification in the synthesis of 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine. A novel production process is designed to obtain the desired product in one step, without requiring highly polluting hydrogen chloride gas catalysis. This process boasts high reaction efficiency and yield, recyclable and reusable solvents, easy separation of reactants and products, high product purity, a simple reaction apparatus, environmental friendliness, and easy monitoring of the reaction endpoint. Attached Figure Description

[0022] Figure 1 The 1H NMR spectrum of 2,2'-(propane-2,2'-dimethylbis(sulfonamide dimethyl))diethylamine dihydrochloride prepared in Example 1 of this invention.

[0023] Figure 2 The image shows the 1H NMR spectrum of 2,2'-(propane-2,2'-dimethylbis(sulfonamide dimethyl))diethylamine prepared in Example 1 of this invention.

[0024] Figure 3The image shows the carbon NMR spectrum of 2,2'-(propane-2,2'-dimethylbis(sulfonamide dimethyl))diethylamine prepared in Example 1 of this invention.

[0025] Figure 4 The mass spectrum of 2,2'-(propane-2,2'-dimethylbis(sulfonamide dimethyl))diethylamine prepared in Example 1 of this invention.

[0026] Figure 5 The image shows the 1H NMR spectrum of the bulk solid product described in the comparative example. Detailed Implementation

[0027] The present invention will be further described below with reference to the accompanying drawings and specific embodiments.

[0028] Example 1

[0029] At 25°C, 3L of formic acid, 2kg of cysteine ​​hydrochloride, and 2g of p-toluenesulfonic acid were added to a reaction vessel equipped with a thermometer and a stirrer. After stirring and dissolving, 700mL of acetone was added, and the mixture was stirred thoroughly for 2 hours. The product 2,2'-(propane-2,2'-dimethylbis(sulfonamide dimethyl))diethylamine dihydrochloride was then separated. Its theoretical mass was 2353g, and the mass of the product obtained was 1880g, with a hydrochloride product yield of 79.9%.

[0030] Weigh 10 mg of hydrochloride into 600 μL of deuterated methanol solvent and perform a 1H NMR spectrum, as follows: Figure 1 As shown.

[0031] 1000 g of 2,2'-(propane-2,2'-diylbis(sulfadimidine))diethylamine dihydrochloride was added to 1000 mL of 12 M sodium hydroxide solution and stirred thoroughly. The organic layer product was then placed in a beaker, and anhydrous sodium sulfate was added to cover the bottom of the beaker. After stirring overnight and filtering, 2,2'-(propane-2,2'-diylbis(sulfadimidine))diethylamine was obtained, with a theoretical mass of 727 g and a product mass of 690 g, yielding a yield of 94.9%. The calculated yield of 2,2'-(propane-2,2'-diylbis(sulfadimidine))diethylamine was 75.5%. 10 mg of 2,2'-(propane-2,2'-diylbis(sulfadimidine))diethylamine was weighed into 600 μL of deuterated methanol solvent, and 1H and 1C NMR spectra were performed. The results are as follows. Figure 2 and Figure 3 As shown, the NMR spectrum showed no impurity peaks, proving that 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine was successfully synthesized with high purity. A methanol solution of 20 mg of 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine was then analyzed by mass spectrometry, and the results are as follows. Figure 4 As shown, this further proves its successful synthesis.

[0032] Example 2

[0033] At 45℃, 3L of formic acid, 2kg of cysteine ​​hydrochloride, and 2g of p-toluenesulfonic acid were added to a reactor equipped with a thermometer and a stirrer. After stirring and dissolving, 700mL of acetone was added, and the mixture was stirred thoroughly for 2 hours. The product 2,2'-(propane-2,2'-dimethylbis(sulfonamide dimethyl))diethylamine dihydrochloride was then separated. The theoretical mass was 2353g, the product mass was 1906g, and the yield was 81.0%. 1000g of 2,2'-(propane-2,2'-diylbis(sulfanilamide))diethylamine dihydrochloride was added to 1000mL of 12M sodium hydroxide solution and stirred thoroughly. The organic layer product was then placed in a beaker, and anhydrous sodium sulfate was added to cover the bottom of the beaker. After stirring overnight and filtering, 2,2'-(propane-2,2'-diylbis(sulfanilamide))diethylamine was obtained with a theoretical mass of 727g and a product mass of 698g, yielding a yield of 96.0%. The calculated yield of 2,2'-(propane-2,2'-diylbis(sulfanilamide))diethylamine was 77.8%.

[0034] Example 3

[0035] At 25°C, 2L of formic acid, 2kg of cysteine ​​hydrochloride, and 2g of trifluoroacetic acid were added to a reaction vessel equipped with a thermometer and a stirrer. After stirring and dissolving, 700mL of acetone was added, and the mixture was stirred thoroughly for 2 hours. The product 2,2'-(propane-2,2'-dimethylbis(sulfonamide dimethyl))diethylamine dihydrochloride was then separated. The theoretical mass was 2353g, the product mass was 1929g, and the yield was 82.0%. 1000g of 2,2'-(propane-2,2'-diylbis(sulfanilamide))diethylamine dihydrochloride was added to 1000mL of 12M sodium hydroxide solution and stirred thoroughly. The organic layer product was then placed in a beaker, and anhydrous sodium sulfate was added to cover the bottom of the beaker. After stirring overnight and filtering, 2,2'-(propane-2,2'-diylbis(sulfanilamide))diethylamine was obtained with a theoretical mass of 727g and a product mass of 691g, yielding a yield of 95.0%. The calculated yield of 2,2'-(propane-2,2'-diylbis(sulfanilamide))diethylamine was 77.9%.

[0036] Comparative Example

[0037] According to the synthetic route disclosed in the prior art, as shown below, the reactants were added in the proportions of Example 1 of this invention. Specifically, 2 kg of cysteine ​​hydrochloride and 700 mL of acetone were added to a reaction vessel equipped with a thermometer and a stirrer. Then, dry HCl gas was introduced and the mixture was stirred. After 8 hours, the blocky solid product was removed, and 10 mg of the solid powder was dissolved in 600 μL of deuterated methanol. The resulting proton nuclear magnetic resonance (NMR) spectrum was analyzed. The results are as follows: Figure 5The product contains a significant amount of the reactant cysteine ​​hydrochloride. Specifically, it yields a mixture containing 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine hydrochloride and cysteine ​​hydrochloride. 1000 g of this solid was added to 1000 mL of 12 M sodium hydroxide solution and stirred thoroughly. The organic layer product was then placed in a beaker, and anhydrous sodium sulfate was added to cover the bottom of the beaker. After stirring overnight and filtering, 510 g of 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine was obtained. The theoretical yield calculated based on the reaction was 855 g, resulting in a total yield of 59.6%.

[0038] It can be seen that, on the one hand, the yield of the product prepared by the method disclosed in the prior art is significantly lower than that of 2,2'-(propane-2,2'-diylbis(sulfonamide diyl))diethylamine prepared by the technical route disclosed in this invention. On the other hand, the technology used in this invention has a shorter reaction time. The scheme of this invention has significant advantages and is more conducive to large-scale production and application.

[0039]

Claims

1. A production process for 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine and its hydrochloride, characterized in that, Cysteine ​​hydrochloride and acetone are reacted in a step-by-step process under the catalysis of non-hydrogen chloride gas to produce 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine dihydrochloride; the production process includes the following steps: The first step involves continuously stirring and dissolving cysteamine hydrochloride, solvent, and catalyst until a homogeneous solution of a certain concentration is formed, and then adding a certain amount of acetone. The solvent is formic acid, and the catalyst is either p-toluenesulfonic acid or trifluoroacetic acid. The mass-to-volume ratio of cysteamine hydrochloride to acetone is from 5 g:1 mL to 1 g:5 mL. The second step involves the formation of a white precipitate after 2-6 hours of reaction. The third step involves separating the white precipitate using vacuum filtration. The precipitate is the product 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine dihydrochloride, which is stored at room temperature. Further processing of 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine dihydrochloride yields 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine, with the following structural formula: .

2. The production process of 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine and its hydrochloride according to claim 1, characterized in that, The amount of cysteamine hydrochloride is 0.1-1.3 g / mL solvent.

3. The production process of 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine and its hydrochloride according to claim 1, characterized in that, The molar ratio of the catalyst to cysteine ​​hydrochloride is 0.001:1 to 0.1:

1.

4. The production process of 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine and its hydrochloride according to claim 1, characterized in that, The reaction temperature is 0-50℃.

5. The production process of 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine and its hydrochloride according to claim 1, characterized in that, The obtained hydrochloride product was washed with alkali and dried to obtain 2,2'-(propane-2,2'-dimethylbis(sulfonamide dimethyl))diethylamine.

6. The production process of 2,2'-(propane-2,2'-diylbis(sulfonamide diel))diethylamine and its hydrochloride according to claim 5, characterized in that, Alkaline washing uses a concentrated alkaline solution, which is one or more of sodium hydroxide, potassium hydroxide, and ammonium hydroxide, with a concentration of 8-15 M. The mass-to-volume ratio of 2,2'-(propane-2,2'-dimethylbis(sulfonamide dimethyl))diethylamine dihydrochloride to the concentrated alkaline solution is from 1 g:1 mL to 1 g:10 mL.

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