Preparation process of diamino phenoxyethanol sulfate

Abstract

The invention relates to the technical field of synthesis of medical intermediates, and discloses a preparation process of diamino phenoxyethanol sulfate.The preparation process comprises the following steps that S1, chitosan-loaded nano nickel is prepared, specifically, chelating type cross-linked chitosan microspheres are used for chelating nickel salt, then a reducing agent is added for reducing nickel ions, and the chitosan-loaded nano nickel is obtained; s2, 2, 4-dinitrochlorobenzene and ethylene glycol are used as raw materials, and 2, 4-dinitrophenoxy ethanol is synthesized under the action of a basic catalyst; s3, with 2, 4-dinitrophenoxy ethanol as a raw material and 1, 4-dioxane as a solvent, the prepared chitosan is loaded with nano-nickel, the loading capacity of the nano-nickel is higher, the nano-nickel is not prone to agglomeration in the process of catalyzing hydrogenation of 2, 4-dinitrophenoxy ethanol to prepare 2, 4-diamino phenoxy ethanol by using the chitosan as a catalyst, and the nano-nickel is not prone to agglomeration after being repeatedly used for many times, so that the yield of the 2, 4-dinitrophenoxy ethanol is increased. Good catalytic activity is still maintained, and the stability is excellent.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediate synthesis, in particular to a preparation process of diaminophenoxyethanol sulfate. Background Art

[0002] 2,4-Diaminophenoxyethanol sulfate is a chemically synthesized substance with corrosion inhibition, bactericidal, and antioxidant effects. It is also a phenoxyethanol plant growth regulator that can promote plant growth and increase plant yield. It is widely used in medicine, dyes, agriculture and other fields.

[0003] In the prior art, there are two main methods for synthesizing 2,4-diaminophenoxyethanol sulfate: the first is to condense 2,4-dinitrohalobenzene and ethylene glycol or 2,4-dinitrophenol and haloethanol under alkaline conditions to form 2,4-dinitrophenoxyethanol, which is then chemically reduced or catalytically hydrogenated and finally treated with concentrated sulfuric acid to obtain the target product; the second is to condense 2,4-diaminohalobenzene and ethylene glycol or 2,4-diaminophenol and haloethanol under alkaline conditions to form 2,4-diaminophenoxyethanol, which is then treated with concentrated sulfuric acid to obtain the target product. The first method not only has lower raw material costs and wider sources, but also has fewer side reactions. When 2,4-dinitrophenoxyethanol is converted into 2,4-diaminophenoxyethanol, a catalytic hydrogenation reaction is used, which is less polluting and has higher returns.

[0004] Catalytic hydrogenation usually requires a catalyst, generally a nickel-based catalyst or a palladium-based catalyst. Palladium-based catalysts are expensive and difficult to use in large-scale, low-cost industrial production. Nickel-based catalysts easily agglomerate during the catalytic process, resulting in a decrease in specific surface area, a reduction in active sites, a decrease in stability, and a decrease in activity. Therefore, the present invention modifies the nickel-based catalyst to increase the active sites of the catalyst and improve the catalytic effect.

[0005] Chitosan is a natural polymer compound containing hydroxyl and amino groups in its molecules. It has a good chelating effect on nickel ions. Chitosan is modified and used to load nano-nickel to prepare chitosan-loaded nano-nickel as a catalyst for catalyzing the hydrogenation of 2,4-dinitrophenoxyethanol to prepare 2,4-diaminophenoxyethanol. Summary of the Invention

[0006] The invention proposes a preparation process of diaminophenoxyethanol sulfate, wherein chitosan-loaded nano-nickel is prepared as a catalyst. During the process of catalyzing the hydrogenation of 2,4-dinitrophenoxyethanol to prepare 2,4-diaminophenoxyethanol, the nano-nickel is not prone to agglomeration and maintains good catalytic activity and excellent stability after repeated use.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions: A preparation process of diaminophenoxyethanol sulfate comprises the following steps: Step S1, preparing chitosan-loaded nano-nickel: using chelated cross-linked chitosan microspheres to chelate nickel salt, and then adding a reducing agent to reduce nickel ions to obtain chitosan-loaded nano-nickel; Step S2, using 2,4-dinitrochlorobenzene and ethylene glycol as raw materials, in the presence of a basic catalyst, to synthesize 2,4-dinitrophenoxyethanol; Step S3: using 2,4-dinitrophenoxyethanol as a raw material, 1,4-dioxane as a solvent, and chitosan-supported nano-nickel as a catalyst to synthesize 2,4-diaminophenoxyethanol sulfate through a catalytic hydrogenation method.

[0008] Furthermore, the preparation method of the chelated cross-linked chitosan microspheres is as follows: the chelated cross-linked chitosan microspheres are prepared by a substitution reaction between a chelating agent and the cross-linked chitosan microspheres.

[0009] Furthermore, the preparation method of the chelating agent is: One mole equivalent of diethylene glycol and one mole equivalent of 6-bromo-3-pyridinecarboxaldehyde undergo a substitution reaction to obtain hydroxyglycol pyridinecarboxaldehyde; One mole equivalent of hydroxyglycol pyridine carboxaldehyde reacts with one mole equivalent of tetraethylene pentamine to form a chelating agent.

[0010] Furthermore, the preparation method of cross-linked chitosan microspheres is: Chitosan microspheres were prepared by capillary dropper droplet spheroidization method, using epichlorohydrin as crosslinking agent and perchloric acid as catalyst to prepare crosslinked chitosan microspheres.

[0011] Furthermore, in step S1, the nickel salt is any one of nickel sulfate, nickel nitrate or nickel acetate.

[0012] Furthermore, in step S1, the reducing agent is sodium borohydride or hydrazine hydrate.

[0013] Furthermore, in step S2, the alkaline catalyst is any one of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

[0014] Furthermore, in step S3, the temperature of the catalytic hydrogenation method is 60-90°C.

[0015] Furthermore, the pressure of the catalytic hydrogenation method is 0.1-0.5 MPa.

[0016] The beneficial effects of the present invention are as follows: The present invention uses epichlorohydrin as a cross-linking agent and chitosan microspheres as raw materials to obtain cross-linked chitosan microspheres. A chelating agent is prepared and modified by using the chelating agent to introduce pyridine groups, amino groups and Schiff base groups into the cross-linked chitosan microspheres, thereby improving the chelating ability of the cross-linked chitosan microspheres for nickel ions. The nickel ions are then reduced to nano-nickel to prepare chitosan-loaded nano-nickel. The nano-nickel has a higher loading amount for the 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 easy to agglomerate, and after repeated use, it still maintains good catalytic activity and excellent stability. DETAILED DESCRIPTION

[0017] Natural chitosan can chelate nickel ions, but natural chitosan has few chelate sites for nickel ions. By preparing a chelating agent and using it to modify cross-linked chitosan microspheres, chelated cross-linked chitosan microspheres are obtained. These microspheres then chelate nickel ions, which are then reduced with sodium borohydride to produce chitosan-supported nano-nickel. The chelating agent increases the ability of chitosan to chelate nickel ions, thereby increasing the loading capacity of the chitosan-supported nano-nickel. Cross-linked chitosan prevents the aggregation of nano-nickel while also improving the overall stability of the catalyst. The resulting chitosan-supported nano-nickel exhibits high catalytic activity and excellent stability, making it reusable.

[0018] Experimental Example 1: The method for preparing chitosan-loaded nano-nickel is: One mole equivalent of diethylene glycol and one mole equivalent of 6-bromo-3-pyridinecarboxaldehyde undergo a substitution reaction to obtain hydroxyglycol pyridinecarboxaldehyde; One molar equivalent of hydroxyglycol pyridine formaldehyde reacts with one molar equivalent of tetraethylene pentamine to produce a chelating agent; Chitosan microspheres were prepared by capillary dropper droplet spheroidization method, and then modified with ethylene chloride oxide under the catalytic action of perchloric acid to obtain cross-linked chitosan microspheres, which were then subjected to substitution reaction with a chelating agent to obtain chelated cross-linked chitosan microspheres. Nickel sulfate was chelated by chelating cross-linked chitosan microspheres, and sodium borohydride was added to reduce nickel ions to obtain chitosan-loaded nano-nickel.

[0019] Experimental Example 2: The specific steps for preparing chitosan-loaded nano-nickel are: Step 1: Add 1.1 g of diethylene glycol to 40 mL of toluene, mix well, add 0.3 g of tetrabutylammonium bromide and 2 g of potassium hydroxide, stir and heat, add 1.9 g of 6-bromo-3-pyridinecarboxaldehyde dropwise, reflux, replace the oil-water separator after 2 hours, react for another 6 hours, filter and distill under reduced pressure to obtain hydroxyglycol pyridinecarboxaldehyde; Step 2: Add 1.9 g of tetraethylenepentamine to 50 mL of anhydrous ethanol, mix well, introduce nitrogen protection, add 2.1 g of hydroxyglycolpyridine formaldehyde dropwise, heat to reflux, react for 3 h, cool to room temperature, precipitate, filter, wash, and vacuum dry to obtain a chelating agent; Step 3, 0.5 g of chitosan was added to 20 mL of 2% acetic acid, and after ultrasonication for 20 min, the bubbles were removed to form a chitosan solution. 5 mL of chitosan solution was drawn through a capillary dropper and added dropwise to 25 mL of a mixed solution of 95% ethanol / 7.5% sodium hydroxide solution (V / V=1:4) to form chitosan microspheres. The mixture was filtered and washed with deionized water until neutral. The mixture was added to 50 mL of isopropanol to suspend the chitosan microspheres. 1 mL of epichlorohydrin and 0.2 mL of perchloric acid were added, the temperature was raised to 60 ° C, and the reaction was carried out for 3 h to obtain cross-linked chitosan microspheres. The mixture was washed with deionized water until neutral, and the mixture was added to deionized water. 2 g of a chelating agent was added, the temperature was raised to 60 ° C, and the reaction was carried out for 5 h. The mixture was vacuum dried to obtain chelated cross-linked chitosan microspheres. Step 4: Add 1 g of chelated cross-linked chitosan microspheres to 20 mL of 0.5 mol / L NiSO4 solution, adsorb with magnetic stirring at room temperature for 2 h, filter, rinse with deionized water, and then remove the adsorbed Ni 2+ The chelated cross-linked chitosan microspheres were added to 10 mL of 1 mol / L sodium borohydride solution, the temperature was set to 10°C, the reaction was carried out for 3 h, the mixture was filtered, and vacuum dried to obtain chitosan-loaded nano-nickel.

[0020] Example 1: A 2,4-diaminophenoxyethanol sulfate, comprising the following raw materials in parts by weight: 40.5 parts of 2,4-dinitrochlorobenzene; 62 parts of ethylene glycol; 10.4 parts of sodium hydroxide; 2.3 parts of chitosan loaded with nano-nickel; A preparation process of 2,4-diaminophenoxyethanol sulfate is as follows: Step 1: 2,4-dinitrochlorobenzene and sodium hydroxide are mixed evenly, and ethylene glycol is added under stirring. The temperature is raised to 65° C., and the mixture is kept warm for 6 hours. Unreacted ethylene glycol is evaporated under reduced pressure, and distilled water is added to the distilled material. The mixture is fully stirred, filtered, and the solid material is washed with water three times. The washed material is recrystallized with methanol, decolorized with activated carbon, and vacuum dried to obtain 2,4-dinitrophenoxyethanol. Step two, 46 parts by weight of 2,4-dinitrophenoxyl ethanol, 500 parts by weight of 1,4-dioxane and chitosan loaded nanometer nickel are added into the reaction kettle, the reaction kettle is sealed, replaced with nitrogen for 5 times, then hydrogen is introduced and replaced for 5 times, the temperature is increased to 75℃, hydrogen is continuously introduced to 0.2MPa, the reaction is carried out for 5h under the temperature and pressure, after the reaction is finished, the temperature is cooled, replaced with nitrogen for 5 times and discharged, the reaction material is separated under the protection of nitrogen, the chitosan loaded nanometer nickel is washed with 1,4-dioxane and recovered, the obtained filtrate is continuously treated with concentrated sulfuric acid under the protection of nitrogen and the pH of the mixture is less than 2, the material treated with sulfuric acid is suction filtered, the filter residue is washed with methanol for 5 times, the material is sufficiently suction filtered and placed in vacuum drying for 24h, 2,4-diamino phenoxyl ethanol sulfate is obtained.

[0021] The determination method of 2,4-diamino phenoxyl ethanol sulfate is: HPLC method is used for analysis, the analysis conditions are: mobile phase CH3OH / H2O (volume ratio 60:40); determination wavelength 220nm, mobile phase flow rate 0.5mL / min, determination temperature 25℃, Kronisil C18 column, the content of 2,4-diamino phenoxyl ethanol sulfate is 98.7%, the calculated yield is 68.6%.

[0022] Example 2: Preparation of 2,4-diamino phenoxyl ethanol sulfate: according to the formula and preparation process in example 1, the preparation process is prepared, and the difference between the preparation process of example 1 is only that 4.6 parts by weight of chitosan loaded nanometer nickel is used instead of 2.3 parts by weight of chitosan loaded nanometer nickel; The results of using HPLC method to analyze 2,4-diamino phenoxyl ethanol sulfate are: the content of 2,4-diamino phenoxyl ethanol sulfate is 98.9%, and the calculated yield is 74.3%.

[0023] Example 3: Preparation of 2,4-diamino phenoxyl ethanol sulfate: according to the formula and preparation process in example 1, the preparation process is prepared, and the difference between the preparation process of example 1 is only that 6.9 parts by weight of chitosan loaded nanometer nickel is used instead of 2.3 parts by weight of chitosan loaded nanometer nickel; The results of using HPLC method to analyze 2,4-diamino phenoxyl ethanol sulfate are: the content of 2,4-diamino phenoxyl ethanol sulfate is 99.1%, and the calculated yield is 80.1%.

[0024] Example 4: Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation was carried out according to the formula and preparation process in Example 1, with the only difference from the preparation process in Example 1 being that 9.2 parts by weight of chitosan-loaded nano-nickel was used instead of 2.3 parts by weight of chitosan-loaded nano-nickel; Among them, the result of analyzing 2,4-diaminophenoxyethanol sulfate using the HPLC method was: the content of 2,4-diaminophenoxyethanol sulfate was 99.4%, and the calculated yield was 83.5%.

[0025] Example 5: Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation was carried out according to the formula and preparation process in Example 1, with the only difference from the preparation process in Example 1 being that 11.5 parts by weight of chitosan-loaded nano-nickel was used instead of 2.3 parts by weight of chitosan-loaded nano-nickel; Among them, the result of analyzing 2,4-diaminophenoxyethanol sulfate using the HPLC method was: the content of 2,4-diaminophenoxyethanol sulfate was 99.4%, and the calculated yield was 85.8%.

[0026] Example 6: Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation was carried out according to the formula and preparation process in Example 1, except that 11.5 parts by weight of chitosan-loaded nano-nickel (used once) was used instead of 2.3 parts by weight of chitosan-loaded nano-nickel. Among them, the result of analyzing 2,4-diaminophenoxyethanol sulfate using the HPLC method was: the content of 2,4-diaminophenoxyethanol sulfate was 99.2%, and the calculated yield was 85.7%.

[0027] Example 7: Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation was carried out according to the formula and preparation process in Example 1, except that 11.5 parts by weight of chitosan-loaded nano-nickel (used 3 times) was used instead of 2.3 parts by weight of chitosan-loaded nano-nickel. The results of analyzing 2,4-diaminophenoxyethanol sulfate using the HPLC method showed that the content of 2,4-diaminophenoxyethanol sulfate was 99%, and the calculated yield was 85.2%.

[0028] Example 8: Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation was carried out according to the formula and preparation process in Example 1, except that 11.5 parts by weight of chitosan-loaded nano-nickel (used 5 times) was used instead of 2.3 parts by weight of chitosan-loaded nano-nickel. Among them, the result of analyzing 2,4-diaminophenoxyethanol sulfate using the HPLC method was: the content of 2,4-diaminophenoxyethanol sulfate was 98.8%, and the calculated yield was 84.5%.

[0029] Example 9: Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation was carried out according to the formula and preparation process in Example 1, except that 11.5 parts by weight of chitosan-loaded nano-nickel (used 5 times) was used instead of 2.3 parts by weight of chitosan-loaded nano-nickel. Among them, the result of analyzing 2,4-diaminophenoxyethanol sulfate using the HPLC method was: the content of 2,4-diaminophenoxyethanol sulfate was 98.4%, and the calculated yield was 84.1%.

[0030] Example 10: Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation was carried out according to the formula and preparation process in Example 1, except that 11.5 parts by weight of chitosan-loaded nano-nickel (used 10 times) was used instead of 2.3 parts by weight of chitosan-loaded nano-nickel. Among them, the result of analyzing 2,4-diaminophenoxyethanol sulfate using the HPLC method was: the content of 2,4-diaminophenoxyethanol sulfate was 98%, and the calculated yield was 83.7%.

[0031] Comparative Example 1: Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation was carried out according to the formula and preparation process in Example 1, with the only difference from the preparation process in Example 1 being that 4.6 parts by weight of RTH-411 Raney nickel was used instead of 2.3 parts by weight of chitosan-loaded nano-nickel; The results of analyzing 2,4-diaminophenoxyethanol sulfate using the HPLC method showed that the content of 2,4-diaminophenoxyethanol sulfate was 98.5%, and the calculated yield was 68.9%.

[0032] Comparative Example 2: Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation was carried out according to the formula and preparation process in Example 1, except that 4.6 parts by weight of RTH-411 Raney nickel (used once) was used instead of 2.3 parts by weight of chitosan-loaded nano-nickel. Among them, the result of analyzing 2,4-diaminophenoxyethanol sulfate using the HPLC method was: the content of 2,4-diaminophenoxyethanol sulfate was 97.8%, and the calculated yield was 65.7%.

[0033] Comparative Example 3: Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation was carried out according to the formula and preparation process in Example 1, except 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-loaded nano-nickel. The results of analyzing 2,4-diaminophenoxyethanol sulfate using the HPLC method showed that the content of 2,4-diaminophenoxyethanol sulfate was 97.1%, and the calculated yield was 62.5%.

[0034] Comparative Example 4: Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation was carried out according to the formula and preparation process in Example 1, except 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-loaded nano-nickel. Among them, the result of analyzing 2,4-diaminophenoxyethanol sulfate using the HPLC method was: the content of 2,4-diaminophenoxyethanol sulfate was 96.2%, and the calculated yield was 51.9%.

[0035] Comparative Example 5: Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation was carried out according to the formula and preparation process in Example 1, except 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-loaded nano-nickel. Among them, the result of analyzing 2,4-diaminophenoxyethanol sulfate using the HPLC method was: the content of 2,4-diaminophenoxyethanol sulfate was 93.4%, and the calculated yield was 28.3%.

[0036] Comparative Example 6: Preparation of 2,4-diaminophenoxyethanol sulfate: The preparation was carried out according to the formula and preparation process in Example 1, except 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-loaded nano-nickel. The results of analyzing 2,4-diaminophenoxyethanol sulfate using the HPLC method showed that 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: The following steps are involved: Step S1, preparing chitosan-loaded nano-nickel: using chelated cross-linked chitosan microspheres to chelate nickel salt, and then adding a reducing agent to reduce nickel ions to obtain chitosan-loaded nano-nickel; Step S2, using 2,4-dinitrochlorobenzene and ethylene glycol as raw materials, in the presence of a basic catalyst, to synthesize 2,4-dinitrophenoxyethanol; Step S3: using 2,4-dinitrophenoxyethanol as a raw material, 1,4-dioxane as a solvent, and chitosan-supported nano-nickel as a catalyst to synthesize 2,4-diaminophenoxyethanol sulfate through a catalytic hydrogenation method.

2. The preparation process of diaminophenoxyethanol sulfate according to claim 1, characterized in that: The preparation method of the chelated cross-linked chitosan microspheres comprises the following steps: a chelating agent is reacted with the cross-linked chitosan microspheres to produce the chelated cross-linked chitosan microspheres.

3. The preparation process of diaminophenoxyethanol sulfate according to claim 2, characterized in that: The preparation method of the chelating agent is: One mole equivalent of diethylene glycol and one mole equivalent of 6-bromo-3-pyridinecarboxaldehyde undergo a substitution reaction to obtain hydroxyglycol pyridinecarboxaldehyde; One mole equivalent of hydroxyglycol pyridine carboxaldehyde reacts with one mole equivalent of tetraethylene pentamine to form a chelating agent.

4. The preparation process of diaminophenoxyethanol sulfate according to claim 2, characterized in that: The preparation method of cross-linked chitosan microspheres is as follows: Chitosan microspheres were prepared by capillary dropper droplet spheronization method, using epichlorohydrin as crosslinking agent and perchloric acid as catalyst to prepare crosslinked chitosan microspheres.

5. The preparation process of diaminophenoxyethanol sulfate according to claim 1, characterized in that: In step S1, the nickel salt is any one of nickel sulfate, nickel nitrate or nickel acetate.

6. The preparation process of diaminophenoxyethanol sulfate according to claim 1, characterized in that: In step S1, the reducing agent is sodium borohydride or hydrazine hydrate.

7. The preparation process of diaminophenoxyethanol sulfate according to claim 1, characterized in that: In step S2, the alkaline catalyst is any one of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

8. The process for preparing diaminophenoxyethanol sulfate according to claim 1, wherein: In step S3, the temperature of the catalytic hydrogenation method is 60-90°C.

9. The process for preparing diaminophenoxyethanol sulfate according to claim 1, wherein: The pressure of the catalytic hydrogenation method is 0.1-0.5 MPa.