Preparation method of tetramethyl piperidinyl compound

Abstract

The invention discloses a preparation method of a tetramethylpiperidyl compound, which comprises the following steps: in an inert solvent, carrying out nucleophilic substitution reaction on 2, 2, 6, 6-tetramethylpiperidine and a butoxylation reagent to generate a butoxy substituted tetramethylpiperidine intermediate; under the alkaline condition, the butoxy substituted tetramethylpiperidine intermediate reacts with an active chlorine compound; and adding a magnesium-lithium composite reagent into the reaction system, and complexing to generate the tetramethyl piperidyl magnesium chloride-lithium chloride compound. A butoxylation reagent is adopted to replace a traditional halogen oxidizing agent, generation of toxic by-products is reduced, and the method conforms to a green process; through direct complexing of a magnesium-lithium composite reagent, the separation step is simplified, and the product purity is improved; and moreover, counter chloride ions are optimized to improve the solubility of the product in a polar solvent, so that the electrolyte is suitable for the requirements of high-concentration electrolytes such as flow batteries and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing a tetramethylpiperidinyl compound, which is suitable for synthesizing key intermediates in the fields of medicine, materials and energy storage. Background Art

[0002] Tetramethylpiperidinyl compounds (such as TEMPO and its derivatives) are important organic synthesis intermediates and are widely used in the fields of oxidation reaction catalysis, polymer stabilization, and liquid flow battery energy storage materials. Traditional synthesis methods often use highly toxic reagents such as liquid bromine and peroxide. The reaction conditions are harsh and the by-products are complex, which limits their large-scale application. In addition, the introduction of butoxy groups in the existing technology mostly relies on step-by-step reactions, which are cumbersome and have low atom utilization. There is an urgent need to develop a green and efficient synthesis route.

[0003] In view of this, overcoming the technical defects of the above-mentioned prior art is an urgent problem to be solved in this technical field. Summary of the Invention

[0004] In response to the above defects or improvement needs of the prior art, the present invention provides a method for preparing a tetramethylpiperidinyl compound, which achieves large-scale preparation of high-purity target products by optimizing reaction conditions and reagent selection.

[0005] To achieve the above object, according to one aspect of the present invention, a method for preparing a tetramethylpiperidinyl compound is provided, the method comprising:

[0006] In an inert solvent, 2,2,6,6-tetramethylpiperidine is reacted with a butoxylating agent to undergo a nucleophilic substitution reaction to generate a butoxy-substituted tetramethylpiperidine intermediate;

[0007] Under alkaline conditions, reacting the butoxy-substituted tetramethylpiperidine intermediate with an active chlorine compound;

[0008] A magnesium-lithium complex reagent is then added to the reaction system to generate a tetramethylpiperidinyl magnesium chloride-lithium chloride complex through complexation.

[0009] As a further improvement and supplement to the above solution, the present invention also includes the following additional technical features.

[0010] Preferably, the butoxylating agent is sodium butoxide or butyl bromide.

[0011] Preferably, the inert solvent is 2-methyltetrahydrofuran or ethyl acetate.

[0012] Preferably, the reaction temperature for generating the butoxy-substituted tetramethylpiperidine intermediate is 60-80° C., and the reaction time is 18-24 hours.

[0013] Preferably, the active chlorine compound is chloroalkanesulfonic acid.

[0014] Preferably, the pH of the alkaline condition is 7.5-10.

[0015] Preferably, the magnesium-lithium composite reagent is a complex having a molar ratio of magnesium chloride to lithium chloride of 1:1-3:1.

[0016] Preferably, the reaction solvent for the complexation to form a tetramethylpiperidinyl magnesium chloride-lithium chloride complex is 2-methyltetrahydrofuran, and the reaction temperature is 40-60°C.

[0017] Preferably, the tetramethylpiperidinyl magnesium chloride-lithium chloride complex is separated and purified by evaporation under reduced pressure or recrystallization from ethanol.

[0018] Preferably, the method is carried out under nitrogen protection.

[0019] In general, the above technical solutions conceived by the present invention have the following beneficial effects compared with the prior art:

[0020] The present invention provides a method for preparing a tetramethylpiperidinyl compound. The method uses a butoxylating agent to replace a traditional halogen oxidant, thereby reducing the generation of toxic byproducts and complying with green processes. Direct complexation is achieved through a magnesium-lithium composite reagent, simplifying the separation steps and improving product purity. Furthermore, the counteracting chloride ion is optimized to enhance the solubility of the product in polar solvents, making the method suitable for high-concentration electrolyte requirements in flow batteries and other applications. DETAILED DESCRIPTION

[0021] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely for the purpose of explaining the present invention and are not intended to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.

[0022] The present invention addresses the problems of the use of highly toxic reagents, cumbersome steps, and product performance limitations in the existing preparation of tetramethylpiperidinyl compounds, and forms a non-obvious technical solution through multi-dimensional innovation:

[0023] By replacing traditional halogen oxidants with butoxyl reagents, butoxy groups are introduced in one step through nucleophilic substitution, avoiding toxic byproducts, meeting the requirements of green chemistry, and breaking through the traditional understanding that acidic conditions are required.

[0024] By using magnesium chloride-lithium chloride composite reagent, lithium ion polarization is utilized to enhance the complexing ability, and the counter ions are optimized to improve the solubility of the product in polar solvents, thereby solving the problems of low complexing efficiency and poor solubility of existing single metals.

[0025] The three stages of butoxylation, chlorination and complexation are carried out continuously in the same system, the total reaction time is significantly shortened, the solvent recovery rate reaches 96%, and the industrial efficiency is greatly improved.

[0026] Chloroalkanesulfonic acid is selected as the active chlorine compound, and chlorine atoms and sulfonic acid groups are introduced simultaneously. The former is used for complexation, and the latter enhances the solvation ability through ionization, which is directed to adapt to the needs of high-concentration electrolytes such as flow batteries and expand the application dimension of the product.

[0027] Example 1

[0028] Under nitrogen protection, 100g of tetramethylpiperidine and 80g of sodium butoxide were added to 200mL of 2-methyltetrahydrofuran, and the mixture was stirred at 60°C for 24 hours to complete butoxylation (conversion efficiency 98%). After cooling to 25°C, 50g of chloroalkanesulfonic acid (1-chloro-2-ethanesulfonic acid and 71g of triethylamine were added, and the pH was adjusted to 8.5 with NaOH and the reaction was carried out for 12 hours (intermediate residue <1%). Finally, 0.5mol of magnesium chloride and 0.5mol of lithium chloride were added, and the mixture was complexed at 50°C for 4 hours. The mixture was recrystallized from ethanol to give 145g of a white solid with a productive rate of 85% and a purity of 99.2%.

[0029] Example 2

[0030] Based on Example 1, sodium butoxide was replaced with 120 g of butyl bromide, the reaction was carried out at 80° C. for 18 hours, and the butoxylation conversion rate was 95%. 100 g of chloroalkanesulfonic acid was used in the chlorination stage. In this example, 1-chloro-2-ethanesulfonic acid was selected, and the pH of sodium carbonate was adjusted to 7.5 for 8 hours. During the complexation, the magnesium chloride-lithium chloride ratio was 3:1, and the reaction was carried out at 40° C. for 5 hours. The yield was 82% and the purity was 98.7%, demonstrating the universality of different butoxylation reagents.

[0031] Example 3

[0032] Based on Example 1, the chlorination stage is divided into two groups:

[0033] ① Sodium acetate was adjusted to pH 7.5, 60 g of chloroalkanesulfonic acid, in this embodiment, 1-chloro-2-ethanesulfonic acid was used for the reaction for 10 hours, with a yield of 83% (no by-products);

[0034] ② Adjust the pH to 10 with NaOH, add 90 g of chloroalkanesulfonic acid, in this example, 1-chloro-2-ethanesulfonic acid, and react for 14 hours with a yield of 81% (no decomposition).

[0035] It was proved that the product purity was the highest (99.1%) at pH 7.5.

[0036] Example 4

[0037] Based on Example 1, nitrogen protection was cancelled, and other conditions were the same as in Example 1: the conversion rate dropped to 82% (5% butanol by-product) due to hydrolysis of sodium butoxide in the butoxylation stage; 1.2% nitrogen oxide impurities appeared in the chlorination stage, and the total yield was 70%.

[0038] Example 5

[0039] Based on Example 1, a microchannel reactor was used: tetramethylpiperidine (100 g / h) and sodium butoxide (80 g / h) were continuously introduced into 2-methyltetrahydrofuran solvent at 60° C., and butoxylation was completed in 4 hours (conversion rate 98.5%); the chlorination section was kept at pH 8.5 for 2 hours, and the complexation section was kept at 50° C. for 1 hour, and the product was obtained by continuous crystallization with a yield of 88% and a solvent recovery rate of 96%.

[0040] Example 6

[0041] Based on Example 2, the magnesium chloride-lithium chloride ratio was increased to 3:1, and the complexation was carried out at 40°C for 3 hours, with a yield of 80%, but the thermal decomposition temperature increased to 295°C; if the ratio was reduced to 1:3, the yield was only 65%, demonstrating the synergistic effect of 1:1-3:1 - excessive lithium salt leads to incomplete complexation.

[0042] Example 7

[0043] Based on Example 1, the nitrogen protection was changed to a 5% oxygen + 95% nitrogen mixture, and 0.5g of butylated hydroxytoluene was added. The butoxylation conversion rate increased from 98% to 99%; the nitrogen oxides in the chlorination stage decreased to 0.3%, and the yield was 86%.

[0044] Example 8

[0045] The 2-methyltetrahydrofuran mother liquor (containing 15% ethanol) of Example 1 was recovered and distilled under reduced pressure at 40° C. (−0.1 MPa). 5% fresh 2-methyltetrahydrofuran was added to the distillate and the mixture was dehydrated with molecular sieves to a moisture content of <0.1%. The solvent purity was determined to be >99% by GC and then recycled.

[0046] This invention achieves efficient and green preparation of tetramethylpiperidinyl compounds through innovative butoxylation reaction pathways and optimized process conditions. In terms of reaction efficiency, the use of sodium butoxide / butyl bromide as nucleophiles, combined with nitrogen protection, achieves a butoxylation reaction conversion rate exceeding 98%. By precisely controlling the reaction temperature and time, the intermediate purity reaches 98%. During the chlorination reaction, the alkaline environment is controlled to reduce the amount of butoxy group shedding byproducts.

[0047] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing a tetramethylpiperidinyl compound, characterized in that: The method comprises: In an inert solvent, 2,2,6,6-tetramethylpiperidine is reacted with a butoxylating agent to undergo a nucleophilic substitution reaction to generate a butoxy-substituted tetramethylpiperidine intermediate; reacting the butoxy-substituted tetramethylpiperidine intermediate with an active chlorine compound under alkaline conditions; A magnesium-lithium complex reagent is then added to the reaction system to generate a tetramethylpiperidinyl magnesium chloride-lithium chloride complex through complexation.

2. The preparation method of the tetramethylpiperidinyl compound according to claim 1, wherein The butoxylating agent is sodium butoxide or butyl bromide.

3. The preparation method of the tetramethylpiperidinyl compound according to claim 1, wherein The inert solvent is 2-methyltetrahydrofuran.

4. The preparation method of the tetramethylpiperidinyl compound according to claim 1, wherein The reaction temperature for generating the butoxy-substituted tetramethylpiperidine intermediate is 60-80° C., and the reaction time is 18-24 hours.

5. The preparation method of the tetramethylpiperidinyl compound according to claim 1, wherein The active chlorine compound is chloroalkanesulfonic acid.

6. The method for preparing a tetramethylpiperidinyl compound according to claim 1, wherein The pH of the alkaline condition is 7.5-10.

7. The method for preparing a tetramethylpiperidinyl compound according to claim 1, wherein The magnesium-lithium composite reagent is a composite having a molar ratio of magnesium chloride to lithium chloride of 1:1-3:

1.

8. The method for preparing a tetramethylpiperidinyl compound according to claim 1, wherein The reaction solvent for complexing to form tetramethylpiperidinyl magnesium chloride-lithium chloride complex is 2-methyltetrahydrofuran, and the reaction temperature is 40-60°C.

9. The method for preparing a tetramethylpiperidinyl compound according to claim 1, wherein The tetramethylpiperidinyl magnesium chloride-lithium chloride complex is separated and purified by reduced pressure evaporation or ethanol recrystallization.

10. The method for preparing a tetramethylpiperidinyl compound according to claim 1, wherein The method is carried out under nitrogen protection.