Process for the preparation of a diaminophenoxyethanol sulfate

Abstract

This invention relates to the field of pharmaceutical intermediate synthesis technology, and discloses a preparation process for diaminophenoxyethanol sulfate, comprising the following steps: Step S1, preparing chitosan-supported nickel nanoparticles: using chelated cross-linked chitosan microspheres to chelate nickel salt, and then adding a reducing agent to reduce nickel ions to obtain chitosan-supported nickel nanoparticles; Step S2, using 2,4-dinitrochlorobenzene and ethylene glycol as raw materials, synthesizing 2,4-dinitrophenoxyethanol under the action of an alkaline catalyst; Step S3, using 2,4-dinitrophenoxyethanol as raw material and 1,4-dioxane as solvent, the prepared chitosan-supported nickel nanoparticles have a higher loading capacity for nickel nanoparticles. As a catalyst, in the process of catalyzing the hydrogenation of 2,4-dinitrophenoxyethanol to prepare 2,4-diaminophenoxyethanol, the nickel nanoparticles are not prone to agglomeration, and after repeated use, they still maintain good catalytic activity and excellent stability.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, and in particular to a preparation process for diaminophenoxyethanol sulfate. Background Technology

[0002] 2,4-Diaminophenoxyethanol sulfate is a chemically synthesized substance with corrosion inhibitory, bactericidal, and antioxidant properties. It is also a phenoxyethanol-based plant growth regulator that can promote plant growth and increase plant yield. It has wide applications in medicine, dyes, and agriculture.

[0003] In existing technologies, there are two main methods for synthesizing 2,4-diaminophenoxyethanol sulfate: The first method involves condensing 2,4-dinitrophenyl halobenzene and ethylene glycol, or 2,4-dinitrophenol and haloethanol, under alkaline conditions to form 2,4-dinitrophenoxyethanol, followed by chemical reduction or catalytic hydrogenation, and finally treatment with concentrated sulfuric acid to obtain the target product. The second method uses 2,4-diaminophenyl halobenzene and ethylene glycol, or 2,4-diaminophenol and haloethanol, as raw materials, condensing them under alkaline conditions to form 2,4-diaminophenoxyethanol, and then treating with concentrated sulfuric acid to obtain the target product. The first method not only has lower raw material costs and wider availability, but also fewer side reactions. Furthermore, the catalytic hydrogenation reaction used to convert 2,4-dinitrophenoxyethanol to 2,4-diaminophenoxyethanol results in less pollution and higher yields.

[0004] Catalytic hydrogenation typically requires a catalyst, usually a nickel-based or palladium-based catalyst. Palladium-based catalysts are expensive and difficult to use in large-scale, low-cost industrial production, while nickel-based catalysts are prone to agglomeration during catalysis, leading to a decrease in specific surface area, reduced active sites, decreased stability, and reduced activity. Therefore, this invention modifies nickel-based catalysts to increase the number of active sites and improve catalytic performance.

[0005] Chitosan is a natural polymer compound containing hydroxyl and amino groups in its molecule. It has a good chelating effect on nickel ions. Chitosan was modified and used to support nickel nanoparticles. Chitosan-supported nickel nanoparticles were prepared as a catalyst for the hydrogenation of 2,4-dinitrophenoxyethanol to 2,4-diaminophenoxyethanol. Summary of the Invention

[0006] This invention proposes a preparation process for diaminophenoxyethanol sulfate, which prepares chitosan-supported nickel nanoparticles that can be used as a catalyst. In the process of catalyzing the hydrogenation of 2,4-dinitrophenoxyethanol to 2,4-diaminophenoxyethanol, the nickel nanoparticles are not prone to agglomeration and maintain good catalytic activity and excellent stability after repeated use.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] A process for preparing diaminophenoxyethanol sulfate includes the following steps:

[0009] Step S1: Preparation of chitosan-supported nickel nanoparticles: Nickel salts are chelated using chelated cross-linked chitosan microspheres, and then a reducing agent is added to reduce nickel ions to obtain chitosan-supported nickel nanoparticles.

[0010] Step S2: Using 2,4-dinitrochlorobenzene and ethylene glycol as raw materials, 2,4-dinitrophenoxyethanol is synthesized under the action of an alkaline catalyst.

[0011] Step S3: Using 2,4-dinitrophenoxyethanol as raw material, 1,4-dioxane as solvent, and chitosan-supported nickel nanoparticles as catalyst, 2,4-diaminophenoxyethanol sulfate is synthesized by catalytic hydrogenation.

[0012] Furthermore, the preparation method of the chelated cross-linked chitosan microspheres is as follows: chelated cross-linked chitosan microspheres are obtained by a substitution reaction between a chelating agent and the cross-linked chitosan microspheres.

[0013] Furthermore, the chelating agent is prepared by:

[0014] One mole equivalent of diethylene glycol undergoes a substitution reaction with one mole equivalent of 6-bromo-3-pyridinecarboxaldehyde to give hydroxyglycopyridinecarboxaldehyde.

[0015] One molar equivalent of hydroxyglycolpyridine carboxaldehyde reacts with one molar equivalent of tetraethylenepentamine in a Schiff base reaction to yield a chelating agent.

[0016] Furthermore, the preparation method of cross-linked chitosan microspheres is as follows:

[0017] Chitosan microspheres were prepared by capillary droplet method, and cross-linked chitosan microspheres were prepared by using epichlorohydrin as cross-linking agent and perchloric acid as catalyst.

[0018] Further, in step S1, the nickel salt is any one of nickel sulfate, nickel nitrate, or nickel acetate.

[0019] Further, in step S1, the reducing agent is sodium borohydride or hydrazine hydrate.

[0020] Further, in step S2, the alkaline catalyst is any one of sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate.

[0021] Furthermore, in step S3, the temperature for catalytic hydrogenation is 60-90℃.

[0022] Furthermore, the pressure for catalytic hydrogenation is 0.1-0.5 MPa.

[0023] The beneficial effects of this invention are as follows:

[0024] This invention uses epichlorohydrin as a crosslinking agent and chitosan microspheres as raw material to obtain crosslinked chitosan microspheres. By preparing a chelating agent, the crosslinked chitosan microspheres are modified by introducing pyridine groups, amino groups, and Schiff base groups into the crosslinked chitosan microspheres, which can improve the chelating ability of the crosslinked chitosan microspheres for nickel ions. Then, the nickel ions are reduced to nano-nickel to prepare chitosan-supported nano-nickel, which has a higher loading capacity for nano-nickel. As a catalyst, in the process of catalyzing the hydrogenation of 2,4-dinitrophenoxyethanol to prepare 2,4-diaminophenoxyethanol, the nano-nickel is not prone to agglomeration and still maintains good catalytic activity and excellent stability after repeated use. Detailed Implementation

[0025] Natural chitosan can chelate nickel ions, but it has relatively few chelating sites. By preparing a chelating agent and modifying cross-linked chitosan microspheres, chelated cross-linked chitosan microspheres are obtained, which then chelate nickel ions. The nickel ions are then reduced with sodium borohydride to obtain chitosan-supported nickel nanoparticles. The chelating agent increases the chelation amount of nickel ions by chitosan, thereby increasing the loading capacity of the chitosan-supported nickel nanoparticles. Cross-linked chitosan prevents the aggregation of nickel nanoparticles and ensures good overall stability of the catalyst. The resulting chitosan-supported nickel nanoparticles exhibit high catalytic activity and good stability, and can be reused multiple times.

[0026] Experimental Example 1:

[0027] The method for preparing chitosan-supported nickel nanoparticles is as follows:

[0028] One mole equivalent of diethylene glycol undergoes a substitution reaction with one mole equivalent of 6-bromo-3-pyridinecarboxaldehyde to give hydroxyglycopyridinecarboxaldehyde.

[0029] One mole equivalent of hydroxyglycolpyridine carboxaldehyde reacts with one mole equivalent of tetraethylenepentamine in a Schiff base reaction to yield a chelating agent.

[0030] Chitosan microspheres were prepared by capillary droplet droplet formation. Under the catalysis of perchloric acid, the chitosan microspheres were modified with epichlorohydrin to obtain cross-linked chitosan microspheres. Then, they were subjected to a substitution reaction with a chelating agent to obtain chelated cross-linked chitosan microspheres.

[0031] Nickel sulfate was chelated using chelated cross-linked chitosan microspheres, and then sodium borohydride was added to reduce the nickel ions, resulting in chitosan-loaded nickel nanoparticles.

[0032] Experimental Example 2:

[0033] The specific steps for preparing chitosan-supported nickel nanoparticles are as follows:

[0034] Step 1: Add 1.1g of diethylene glycol to 40mL of toluene, mix well, add 0.3g of tetrabutylammonium bromide and 2g of potassium hydroxide, stir and heat, add 1.9g of 6-bromo-3-pyridinecarboxaldehyde dropwise, reflux, replace with an oil-water separator after 2h, react for another 6h, filter and distill under reduced pressure to obtain hydroxyglycolpyridinecarboxaldehyde;

[0035] Step 2: Add 1.9g of tetraethylenepentamine to 50mL of anhydrous ethanol, mix well, purge with nitrogen for protection, add 2.1g of hydroxyglycolpyridine carboxaldehyde dropwise, heat to reflux, react for 3h, cool to room temperature, precipitate, filter, wash, and vacuum dry to obtain chelating agent.

[0036] Step 3: Add 0.5g of chitosan to 20mL of 2% acetic acid, sonicate for 20min, remove air bubbles to form a chitosan solution, and add 5mL of the chitosan solution to 25mL of a mixed solution (95% ethanol / 7.5% sodium hydroxide solution, V / V=1:4) through a capillary dropper to form chitosan microspheres. Filter the solution, wash it with deionized water until neutral, add it to 50mL of isopropanol to suspend the chitosan microspheres, then add 1mL of epichlorohydrin and 0.2mL of perchloric acid, raise the temperature to 60℃, and react for 3h to obtain cross-linked chitosan microspheres. Wash the microspheres with deionized water until neutral, add them to deionized water, add 2g of chelating agent, raise the temperature to 60℃, react for 5h, and then vacuum dry to obtain chelated cross-linked chitosan microspheres.

[0037] Step 4: Add 1g of chelated cross-linked chitosan microspheres to 20mL of 0.5mol / L NiSO4 solution, stir magnetically at room temperature for 2h for adsorption, filter, rinse with deionized water, and then remove the adsorbed Ni... 2+ Chelated cross-linked chitosan microspheres were added to 10 mL of a 1 mol / L sodium borohydride solution, the temperature was set to 10 °C, the reaction was carried out for 3 h, filtered, and vacuum dried to obtain chitosan-supported nickel nanoparticles.

[0038] Example 1:

[0039] A 2,4-diaminophenoxyethanol sulfate, comprising the following raw materials in parts by weight:

[0040] 40.5 parts of 2,4-dinitrochlorobenzene;

[0041] 62 parts ethylene glycol;

[0042] 10.4 parts sodium hydroxide;

[0043] 2.3 parts chitosan-supported nickel nanoparticles;

[0044] The preparation process of 2,4-diaminophenoxyethanol sulfate is as follows:

[0045] Step 1: Mix 2,4-dinitrochlorobenzene and sodium hydroxide evenly, then add ethylene glycol while stirring. Raise the temperature to 65°C and keep the reaction at this temperature for 6 hours. Distill off the unreacted ethylene glycol under reduced pressure. Add distilled water to the distilled material, stir thoroughly, filter, and wash the solid material with water three times. Recrystallize the washed material with methanol, decolorize with activated carbon, and vacuum dry to obtain 2,4-dinitrophenoxyethanol.

[0046] Step 2: Add 46 parts by weight of 2,4-dinitrophenoxyethanol, 500 parts by weight of 1,4-dioxane, and chitosan-supported nickel nanoparticles to a reactor. After sealing the reactor, purge with nitrogen five times, then purge with hydrogen five times. Raise the temperature to 75°C and continue purging with hydrogen to 0.2 MPa. React at this temperature and pressure for 5 hours. After the reaction, cool the reactor, purge with nitrogen five times, and discharge the mixture. Separate the reactants under nitrogen protection. Wash the chitosan-supported nickel nanoparticles with 1,4-dioxane and recover them. Continue to treat the filtrate with concentrated sulfuric acid under nitrogen protection to make the pH of the mixture less than 2. After sulfuric acid treatment, filter the mixture and wash the filter residue five times with methanol. After thorough filtration, place the mixture in a vacuum dryer and dry for 24 hours to obtain 2,4-diaminophenoxyethanol sulfate.

[0047] The determination method for 2,4-diaminophenoxyethanol sulfate was as follows: HPLC analysis was performed under the following conditions: mobile phase CH3OH / H2O (volume ratio 60:40); measurement wavelength 220 nm; mobile phase flow rate 0.5 mL / min; measurement temperature 25 ℃; Kronisil C18 column; the content of 2,4-diaminophenoxyethanol sulfate was found to be 98.7%, and the calculated yield was 68.6%.

[0048] Example 2:

[0049] Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation process was carried out according to the formulation and preparation process in Example 1. The only difference between the preparation process and that in Example 1 was that 4.6 parts by weight of chitosan-supported nickel nanoparticles were used instead of 2.3 parts by weight of chitosan-supported nickel nanoparticles.

[0050] The results of HPLC analysis of 2,4-diaminophenoxyethanol sulfate were as follows: the content of 2,4-diaminophenoxyethanol sulfate was 98.9%, and the calculated yield was 74.3%.

[0051] Example 3:

[0052] Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation process was carried out according to the formulation and preparation process in Example 1. The only difference between the preparation process in Example 1 and the preparation process in Example 1 is that 6.9 parts by weight of chitosan-supported nickel nanoparticles were used instead of 2.3 parts by weight of chitosan-supported nickel nanoparticles.

[0053] The results of HPLC analysis of 2,4-diaminophenoxyethanol sulfate were as follows: the content of 2,4-diaminophenoxyethanol sulfate was 99.1%, and the calculated yield was 80.1%.

[0054] Example 4:

[0055] Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation process was carried out according to the formulation and preparation process in Example 1. The only difference between the preparation process and that in Example 1 was that 9.2 parts by weight of chitosan-supported nickel nanoparticles were used instead of 2.3 parts by weight of chitosan-supported nickel nanoparticles.

[0056] The results of HPLC analysis of 2,4-diaminophenoxyethanol sulfate were as follows: the content of 2,4-diaminophenoxyethanol sulfate was 99.4%, and the calculated yield was 83.5%.

[0057] Example 5:

[0058] Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation process was carried out according to the formulation and preparation process in Example 1. The only difference between the preparation process and that in Example 1 was that 11.5 parts by weight of chitosan-supported nickel nanoparticles were used instead of 2.3 parts by weight of chitosan-supported nickel nanoparticles.

[0059] The results of HPLC analysis of 2,4-diaminophenoxyethanol sulfate were as follows: the content of 2,4-diaminophenoxyethanol sulfate was 99.4%, and the calculated yield was 85.8%.

[0060] Example 6:

[0061] Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation process was carried out according to the formulation and preparation process in Example 1. The only difference between the preparation process in Example 1 and the preparation process in Example 1 is that 11.5 parts by weight of chitosan-supported nano-nickel (used once) was used instead of 2.3 parts by weight of chitosan-supported nano-nickel.

[0062] The results of HPLC analysis of 2,4-diaminophenoxyethanol sulfate were as follows: the content of 2,4-diaminophenoxyethanol sulfate was 99.2%, and the calculated yield was 85.7%.

[0063] Example 7:

[0064] Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation process was carried out according to the formulation and preparation process in Example 1. The only difference between the preparation process in Example 1 and the preparation process in Example 1 is that 11.5 parts by weight of chitosan-supported nano-nickel (used 3 times) was used instead of 2.3 parts by weight of chitosan-supported nano-nickel.

[0065] The results of HPLC analysis of 2,4-diaminophenoxyethanol sulfate were as follows: the content of 2,4-diaminophenoxyethanol sulfate was 99%, and the calculated yield was 85.2%.

[0066] Example 8:

[0067] Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation process was carried out according to the formulation and preparation process in Example 1. The only difference between the preparation process in Example 1 and the preparation process in Example 1 is that 11.5 parts by weight of chitosan-supported nano-nickel (used 5 times) was used instead of 2.3 parts by weight of chitosan-supported nano-nickel.

[0068] The results of HPLC analysis of 2,4-diaminophenoxyethanol sulfate were as follows: the content of 2,4-diaminophenoxyethanol sulfate was 98.8%, and the calculated yield was 84.5%.

[0069] Example 9:

[0070] Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation process was carried out according to the formulation and preparation process in Example 1. The only difference between the preparation process in Example 1 and the preparation process in Example 1 is that 11.5 parts by weight of chitosan-supported nano-nickel (used 5 times) was used instead of 2.3 parts by weight of chitosan-supported nano-nickel.

[0071] The results of HPLC analysis of 2,4-diaminophenoxyethanol sulfate were as follows: the content of 2,4-diaminophenoxyethanol sulfate was 98.4%, and the calculated yield was 84.1%.

[0072] Example 10:

[0073] Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation process was carried out according to the formulation and preparation process in Example 1. The only difference between the preparation process in Example 1 and the preparation process in Example 1 is that 11.5 parts by weight of chitosan-supported nano-nickel (used 10 times) was used instead of 2.3 parts by weight of chitosan-supported nano-nickel.

[0074] The results of HPLC analysis of 2,4-diaminophenoxyethanol sulfate were as follows: the content of 2,4-diaminophenoxyethanol sulfate was 98%, and the calculated yield was 83.7%.

[0075] Comparative Example 1:

[0076] Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation process was carried out according to the formulation and preparation process in Example 1. The only difference between the preparation process and that in Example 1 was that 4.6 parts by weight of RTH-411 Raney nickel was used instead of 2.3 parts by weight of chitosan-supported nano nickel.

[0077] The results of HPLC analysis of 2,4-diaminophenoxyethanol sulfate were as follows: the content of 2,4-diaminophenoxyethanol sulfate was 98.5%, and the calculated yield was 68.9%.

[0078] Comparative Example 2:

[0079] Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation process was carried out according to the formulation and preparation process in Example 1. The only difference between the preparation process in Example 1 and the preparation process in Example 1 is that 4.6 parts by weight of RTH-411 Raney nickel (used once) was used instead of 2.3 parts by weight of chitosan-supported nano nickel.

[0080] The results of HPLC analysis of 2,4-diaminophenoxyethanol sulfate were as follows: the content of 2,4-diaminophenoxyethanol sulfate was 97.8%, and the calculated yield was 65.7%.

[0081] Comparative Example 3:

[0082] Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation process was carried out according to the formulation and preparation process in Example 1. The only difference between the preparation process in Example 1 and the preparation process in Example 1 is that 4.6 parts by weight of RTH-411 Raney nickel (used 3 times) was used instead of 2.3 parts by weight of chitosan-supported nano nickel.

[0083] The results of HPLC analysis of 2,4-diaminophenoxyethanol sulfate were as follows: the content of 2,4-diaminophenoxyethanol sulfate was 97.1%, and the calculated yield was 62.5%.

[0084] Comparative Example 4:

[0085] Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation process was carried out according to the formulation and preparation process in Example 1. The only difference between the preparation process in Example 1 and the preparation process in Example 1 is that 4.6 parts by weight of RTH-411 Raney nickel (used 5 times) was used instead of 2.3 parts by weight of chitosan-supported nano nickel.

[0086] The results of HPLC analysis of 2,4-diaminophenoxyethanol sulfate were as follows: the content of 2,4-diaminophenoxyethanol sulfate was 96.2%, and the calculated yield was 51.9%.

[0087] Comparative Example 5:

[0088] Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation process was carried out according to the formulation and preparation process in Example 1. The only difference between the preparation process in Example 1 and the preparation process in Example 1 is that 4.6 parts by weight of RTH-411 Raney nickel (used 8 times) was used instead of 2.3 parts by weight of chitosan-supported nano nickel.

[0089] The results of HPLC analysis of 2,4-diaminophenoxyethanol sulfate were as follows: the content of 2,4-diaminophenoxyethanol sulfate was 93.4%, and the calculated yield was 28.3%.

[0090] Comparative Example 6:

[0091] Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation process was carried out according to the formulation and preparation process in Example 1. The only difference between the preparation process in Example 1 and the preparation process in Example 1 is that 4.6 parts by weight of RTH-411 Raney nickel (used 10 times) was used instead of 2.3 parts by weight of chitosan-supported nano nickel.

[0092] The results of HPLC analysis of 2,4-diaminophenoxyethanol sulfate were as follows: the content of 2,4-diaminophenoxyethanol sulfate was 92.5%, and the calculated yield was 20.4%.

Claims

1. A preparation process for diaminophenoxyethanol sulfate, characterized in that, Includes the following steps: Step S1, preparing chitosan-supported nickel nanoparticles, the specific process is as follows: One molar equivalent of diethylene glycol undergoes a substitution reaction with one molar equivalent of 6-bromo-3-pyridinecarboxaldehyde to give hydroxyglycopyridinecarboxaldehyde; One molar equivalent of hydroxyglycopyridine carboxaldehyde reacts with one molar equivalent of tetraethylenepentamine in a Schiff base reaction to yield a chelating agent; Chitosan microspheres were prepared by capillary droplet droplet formation. Under the catalysis of perchloric acid, the chitosan microspheres were modified with epichlorohydrin to obtain cross-linked chitosan microspheres. Then, they were subjected to a substitution reaction with a chelating agent to obtain chelated cross-linked chitosan microspheres. Nickel salts were chelated using chelated cross-linked chitosan microspheres, and then nickel ions were reduced by adding a reducing agent to obtain chitosan-loaded nickel nanoparticles. Step S2: Using 2,4-dinitrochlorobenzene and ethylene glycol as raw materials, 2,4-dinitrophenoxyethanol is synthesized under the action of an alkaline catalyst. In step S3, 2,4-diaminophenoxyethanol sulfate is synthesized by catalytic hydrogenation using 2,4-dinitrophenoxyethanol as raw material, 1,4-dioxane as solvent, and chitosan-supported nickel nanoparticles as catalyst, followed by sulfuric acid acidification.

2. The preparation process of diaminophenoxyethanol sulfate according to claim 1, characterized in that, The nickel salt is one of nickel sulfate, nickel nitrate, or nickel acetate.

3. The preparation process of diaminophenoxyethanol sulfate according to claim 1, characterized in that, The reducing agent is sodium borohydride or hydrazine hydrate.

4. The preparation process of diaminophenoxyethanol sulfate according to claim 1, characterized in that, The alkaline catalyst is any one of sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate.

5. The preparation process of diaminophenoxyethanol sulfate according to claim 1, characterized in that, The reaction temperature for catalytic hydrogenation is 60-90℃.

6. The preparation process of diaminophenoxyethanol sulfate according to claim 1, characterized in that, The reaction pressure for catalytic hydrogenation is 0.1-0.5 MPa.