A method for preparing 28-homobrassinolide
A one-pot synthesis of 28-homobrassinolide was achieved using water and ethyl acetate as solvents, with the addition of carboxylic acid and tin Beta molecular sieves, followed by the dropwise addition of hydrogen peroxide solution to carry out the lactonization reaction. This method solves the problems of complex operation, high solvent toxicity, and low yield in existing technologies, and realizes an efficient, green, and environmentally friendly preparation process.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JIANGXI XINLILAI BIOCHEMICAL CO LTD
- Filing Date
- 2026-05-12
- Publication Date
- 2026-07-17
AI Technical Summary
Existing methods for preparing 28-homobrassinolide have problems such as multiple operation steps, high solvent toxicity, long reaction time, low yield and high energy consumption, and are also harmful to the environment and the health of operators.
28-homobrassinolide was synthesized in a one-pot process using water and ethyl acetate as a mixed solvent. Carboxylic acid and tin Beta molecular sieve were added, and hydrogen peroxide solution was added dropwise to carry out the lactonization reaction. After the reaction, the product was separated by static layering. A green solvent system was used and the operation steps were simplified.
This method enables the efficient, green, and environmentally friendly preparation of 28-homobrassinolide, improving product purity and yield, reducing side reactions, and lowering energy consumption and operational steps.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical synthesis technology, specifically to a method for preparing 28-homobrassinolide. Background Technology
[0002] 28-Homobrassinolide is a highly active brassinolide plant growth regulator that promotes cell elongation and division, enhances photosynthesis, improves crop stress resistance, and increases yield. It is widely used in agriculture and horticulture. Its preparation typically involves a Baeyer-Villiger lactone reaction using a compound of formula I as a raw material. In existing technologies, this lactone reaction usually involves first reacting trifluoroacetic anhydride with hydrogen peroxide in dichloromethane solvent below 0°C to generate peroxyacid, followed by the addition of the compound of formula I for the reaction.
[0003]
[0004] This method requires step-by-step operations, resulting in a long overall reaction time and high energy consumption. It also involves side reactions, with an overall yield of approximately 75%. Furthermore, the process uses highly toxic dichloromethane and trifluoroacetic anhydride as reagents, posing significant health hazards to operators and the environment. Therefore, developing a method for preparing 28-homobrassinolide with fewer operational steps, a greener solvent system, and higher yield and purity is of great importance. Summary of the Invention
[0005] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing 28-homobrassinolide. This method uses a one-pot synthesis of 28-homobrassinolide, employs a green and environmentally friendly solvent system, and produces 28-homobrassinolide with high purity and high yield.
[0006] To achieve the above objectives, the present invention adopts the following technical solution: This application provides a method for preparing 28-homobrassinolide, comprising the following steps: S1. Using the compound of formula I as raw material, water and ethyl acetate as mixed solvents, carboxylic acid and tin Beta molecular sieve are added and mixed, and hydrogen peroxide solution is added dropwise to carry out lactonization reaction to generate 28-homobrassinolide. S2. Filter the liquid, let the filtrate stand to separate into layers, extract the aqueous phase with ethyl acetate, combine the organic phases and wash them with potassium carbonate solution and sodium chloride solution in sequence, and let them stand to separate into layers. S3. The organic phase was washed sequentially with sodium bisulfite solution and sodium chloride solution, allowed to stand and separate into layers, concentrated, crystallized, and filtered to obtain crude 28-homobrassinolide. S4. The obtained crude 28-homobrassinolide is recrystallized with ethyl acetate to obtain the final product.
[0007]
[0008] This application uses compound of formula I as a raw material. In the presence of carboxylic acid and tin Beta molecular sieve, water and ethyl acetate are used as a mixed solvent. Hydrogen peroxide solution is added dropwise. Hydrogen peroxide and carboxylic acid have good solubility in water. In the presence of a dispersed tin Beta molecular sieve catalyst, they react to generate peroxycarboxylic acid. Ethyl acetate can dissolve compound of formula I. The generated peroxycarboxylic acid reacts with compound of formula I at the two-phase interface. The generated 28-brassinolide is mainly present in the ethyl acetate phase. Compared with the existing technology, the reaction of this application is more stable and controllable, with fewer side reactions. At the same time, it realizes the one-pot lactone reaction. After the reaction is completed, by standing and separating the layers, the organic phase is on the top, and the aqueous phase can be separated to achieve product separation from the aqueous phase. The overall reaction steps are fewer, the reaction yield is higher, and the reaction raw materials are more green and environmentally friendly than those of the existing technology.
[0009] Furthermore, in S1, the molar ratio of compound I, carboxylic acid, and hydrogen peroxide is 1:1-3:2-4; an appropriate excess of carboxylic acid and hydrogen peroxide can ensure the formation rate of peroxycarboxylic acid, thereby ensuring the complete reaction of the raw materials; the amount of tin Beta molecular sieve used is 2-10% of the weight of compound I, and excessive use will increase the cost and increase the yield and purity of side reactions.
[0010] It should be noted that the volume ratio of water to ethyl acetate in the mixed solvent is very important in the method of this application. Specifically, in S1, the volume ratio of water to ethyl acetate in the mixed solvent is 30-40:60-70; the mass-volume ratio of the compound of Formula I to the mixed solvent is 1g:20-50ml. At this ratio, the aqueous phase is sufficient to dissolve hydrogen peroxide and carboxylic acid to generate peroxycarboxylic acid, ensuring a good solubility of the raw materials. Simultaneously, the higher proportion of ethyl acetate also facilitates the smooth lactone reaction between the peroxycarboxylic acid and the raw materials.
[0011] Furthermore, the lactone formation reaction described in S1 is carried out at a temperature of 0-20°C for a reaction time of 4-6 hours. The lactone formation reaction of this application can be carried out over a wide temperature range, does not require cooling with refrigerated brine, and has low energy consumption.
[0012] Furthermore, the mass concentration of the hydrogen peroxide solution in S1 is 25-30%; the time for adding the hydrogen peroxide solution is 30-60 minutes. By adding hydrogen peroxide of the above concentration dropwise, it is possible to control the local concentration of hydrogen peroxide in the feed solution from being too high, thus ensuring a stable reaction.
[0013] Furthermore, the carboxylic acid in S1 is selected from at least one of formic acid, acetic acid, and propionic acid; preferably, the carboxylic acid is acetic acid. Experiments have shown that acetic acid has good reactivity and a moderate boiling point, and is safe and environmentally friendly under experimental conditions.
[0014] Furthermore, the tin Beta molecular sieve described in S1 has a tin content of 6-10%, which can effectively activate hydrogen peroxide and carbonyl groups, promoting the Baeyer-Villiger reaction. Simultaneously, the tin Beta molecular sieve is in solid form and can be recovered by filtration after the reaction, enabling reuse. The specific recovery method is as follows: filter the reaction product, wash the filter cake with a small amount of ethyl acetate, and then vacuum dry at 50°C for 2 hours.
[0015] Furthermore, the potassium carbonate solution in S2 is an aqueous solution of potassium carbonate with a mass concentration of 30-35%; the sodium chloride solution is a saturated aqueous solution of sodium chloride. Potassium carbonate can be used to neutralize residual carboxylic acids, while saturated sodium chloride washes away impurities and helps to clearly separate the two phases.
[0016] Further, the sodium bisulfite solution in S3 is a sodium bisulfite aqueous solution with a mass concentration of 15-25%; the sodium chloride solution is a sodium chloride aqueous solution with a mass concentration of 10-20%. Sodium bisulfite reduces and decomposes residual peroxides, and dilute brine further washes away impurities.
[0017] Further, the specific recrystallization operation described in S4 is as follows: crude 28-homobrassinolide is added to ethyl acetate, heated to 50-70°C to completely dissolve the crude product, cooled to room temperature, and allowed to stand at 0-10°C for 4-12 hours to crystallize. After filtration, the product is washed with cold ethyl acetate and dried under vacuum to constant weight.
[0018] The reaction solvent and post-processing of this application consist only of water and ethyl acetate. The ethyl acetate can be recovered by conventional desolvation and condensation methods. Since the organic solvent system is simple, the recovered ethyl acetate can be reused without distillation.
[0019] Compared with the prior art, the beneficial effects of the present invention are as follows: This application uses the compound of formula I as raw material, and in the presence of carboxylic acid and tin Beta molecular sieve, hydrogen peroxide solution is added dropwise in a mixed solvent of water and ethyl acetate. Compared with the methods of the prior art, the reaction is more efficient and there are fewer side reactions. The lactone reaction is completed in one pot. After the reaction is completed, the organic phase is on the upper layer. The product can be separated from the aqueous phase by standing and separating the layers. The overall reaction operation steps are fewer and the reaction yield is higher. Detailed Implementation
[0020] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. The described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0021] In this embodiment and comparative example, the tin content of the tin Beta molecular sieve is 8%, provided by Zhuoran Environmental Protection Technology (Dalian) Co., Ltd. Unless otherwise specified, all methods described are conventional methods. Unless otherwise specified, all concentrations refer to mass concentrations. Unless otherwise specified, all raw materials described are obtainable from publicly available commercial sources.
[0022] Example 1 1. In a three-necked flask, add 50g of compound I, 12g of acetic acid, 2.5g of tin Beta molecular sieve, and 1500mL of a mixed solvent of water and ethyl acetate, wherein the volume ratio of water to ethyl acetate is 30:70. Stir at 50rpm and cool to 10°C. Add 34g of 30% hydrogen peroxide solution dropwise over 45min. After the addition is complete, continue the reaction at this temperature for 4.5h.
[0023] 2. After the reaction is complete, filter under reduced pressure. Wash the filter cake with 20 mL of ethyl acetate. Dry the filter cake under vacuum at 50°C for 2 h to recover the tin Beta molecular sieve. Transfer the filtrate to a separatory funnel and let it stand for 30 min to separate the layers. Extract the lower aqueous phase with 100 mL of ethyl acetate. Combine the organic phases and wash them successively with 150 mL of 30% potassium carbonate aqueous solution and 150 mL of saturated sodium chloride aqueous solution. Let them stand to separate the layers.
[0024] 3. Transfer the organic phase to a separatory funnel, wash with 100 mL of 20% sodium bisulfite aqueous solution, and then wash with 100 mL of 15% sodium chloride aqueous solution. Evaporate the organic phase under reduced pressure to 20% of its original volume at 50°C, allow to cool naturally to room temperature, and let it crystallize at 0°C for 3 hours. Filter the solution and wash with 20 mL of cold ethyl acetate to obtain crude 28-homobrassinolide.
[0025] 4. Crude 28-homobrassinolide was added to 400 mL of ethyl acetate, heated to 60°C with stirring to dissolve, filtered while hot, and the filtrate was allowed to cool naturally to room temperature and crystallized at 4°C for 8 hours. The solution was then filtered, washed with 20 mL of cold ethyl acetate, and dried under vacuum at 50°C to constant weight to obtain 28-homobrassinolide. The HPLC purity of the obtained 28-homobrassinolide was 99.1%, and the yield was 87.6%.
[0026] Example 2 1. In a three-necked flask, add 50g of compound I, 14.8g of propionic acid, 5g of tin Beta molecular sieve, and 1500mL of a mixed solvent of water and ethyl acetate, wherein the volume ratio of water to ethyl acetate is 30:70. Stir at 50rpm and cool to 20°C. Add 34g of 30% hydrogen peroxide solution dropwise over 45min. After the addition is complete, continue the reaction at this temperature for 6h.
[0027] 2. After the reaction is complete, filter under reduced pressure. Wash the filter cake with 20 mL of ethyl acetate. Dry the filter cake under vacuum at 50°C for 2 h to recover the tin Beta molecular sieve. Transfer the filtrate to a separatory funnel and let it stand for 30 min to separate the layers. Extract the lower aqueous phase with 100 mL of ethyl acetate. Combine the organic phases and wash them successively with 150 mL of 30% potassium carbonate aqueous solution and 150 mL of saturated sodium chloride aqueous solution. Let them stand to separate the layers.
[0028] 3. Transfer the organic phase to a separatory funnel, wash with 100 mL of 20% sodium bisulfite aqueous solution, and then wash with 100 mL of 15% sodium chloride aqueous solution. Evaporate the organic phase under reduced pressure to 20% of its original volume at 50°C, allow to cool naturally to room temperature, and let it crystallize at 0°C for 3 hours. Filter the solution and wash with 20 mL of cold ethyl acetate to obtain crude 28-homobrassinolide.
[0029] 4. Crude 28-homobrassinolide was added to 400 mL of ethyl acetate, heated to 60°C with stirring to dissolve, filtered while hot, and the filtrate was allowed to cool naturally to room temperature and crystallized at 0°C for 8 hours. The solution was then filtered, washed with 20 mL of cold ethyl acetate, and dried under vacuum at 50°C to constant weight to obtain 28-homobrassinolide. The HPLC purity of the obtained 28-homobrassinolide was 97.3%, and the yield was 84.4%.
[0030] Example 3 1. In a three-necked flask, add 50g of compound I, 13.8g of 88% formic acid, 1.5g of tin Beta molecular sieve, and 1500mL of a mixed solvent of water and ethyl acetate, wherein the volume ratio of water to ethyl acetate is 40:60. Stir at 50rpm and cool to 5°C. Add 34g of 30% hydrogen peroxide solution dropwise over 45min. After the addition is complete, continue the reaction at this temperature for 5h.
[0031] 2. After the reaction is complete, filter under reduced pressure. Wash the filter cake with 20 mL of ethyl acetate. Dry the filter cake under vacuum at 50°C for 2 h to recover the tin Beta molecular sieve. Transfer the filtrate to a separatory funnel and let it stand for 30 min to separate the layers. Extract the lower aqueous phase with 100 mL of ethyl acetate. Combine the organic phases and wash them successively with 150 mL of 30% potassium carbonate aqueous solution and 150 mL of saturated sodium chloride aqueous solution. Let them stand to separate the layers.
[0032] 3. Transfer the organic phase to a separatory funnel, wash with 100 mL of 20% sodium bisulfite aqueous solution, and then wash with 100 mL of 15% sodium chloride aqueous solution. Evaporate the organic phase under reduced pressure to 20% of its original volume at 50°C, allow to cool naturally to room temperature, and let it crystallize at 0°C for 3 hours. Filter the solution and wash with 20 mL of cold ethyl acetate to obtain crude 28-homobrassinolide.
[0033] 4. Crude 28-homobrassinolide was added to 400 mL of ethyl acetate, heated to 60°C and stirred to dissolve. The mixture was filtered while hot, and the filtrate was allowed to cool naturally to room temperature and crystallized at 0°C for 8 hours. The solution was then filtered, washed with 20 mL of cold ethyl acetate, and dried under vacuum at 50°C to constant weight to obtain 28-homobrassinolide. The HPLC purity of the obtained 28-homobrassinolide was 97.6%, and the yield was 86.3%.
[0034] Example 4 1. In a three-necked flask, add 50g of compound I, 18g of acetic acid, 3.5g of tin Beta molecular sieve, and 1500mL of a mixed solvent of water and ethyl acetate, wherein the volume ratio of water to ethyl acetate is 35:65. Stir at 50rpm and cool to 10°C. Add 34g of 30% hydrogen peroxide solution dropwise over 45min. After the addition is complete, continue the reaction at this temperature for 4.5h.
[0035] 2. After the reaction is complete, filter under reduced pressure. Wash the filter cake with 20 mL of ethyl acetate. Dry the filter cake under vacuum at 50°C for 2 h to recover the tin Beta molecular sieve. Transfer the filtrate to a separatory funnel and let it stand for 30 min to separate the layers. Extract the lower aqueous phase with 100 mL of ethyl acetate. Combine the organic phases and wash them successively with 150 mL of 30% potassium carbonate aqueous solution and 150 mL of saturated sodium chloride aqueous solution. Let them stand to separate the layers.
[0036] 3. Transfer the organic phase to a separatory funnel, wash with 100 mL of 20% sodium bisulfite aqueous solution, and then wash with 100 mL of 15% sodium chloride aqueous solution. Rotary evaporate the organic phase under reduced pressure at 50°C to 20% of its original volume, allow it to cool naturally to room temperature, and let it crystallize at 0°C for 3 hours. Filter the solution and wash with 20 mL of cold ethyl acetate to obtain crude 28-homobrassinolide.
[0037] 4. Crude 28-homobrassinolide was added to 400 mL of ethyl acetate, heated to 60°C with stirring to dissolve, filtered while hot, and the filtrate was allowed to cool naturally to room temperature and crystallized at 0°C for 8 hours. The solution was then filtered, washed with 20 mL of cold ethyl acetate, and dried under vacuum at 50°C to constant weight to obtain 28-homobrassinolide. The HPLC purity of the obtained 28-homobrassinolide was 99.3%, and the yield was 89.2%.
[0038] The recovered tin Beta molecular sieve was repeated under the conditions of this embodiment. The results showed that after the fifth application, the yield was 82.5% and the purity was 98.1%.
[0039] Comparative Example 1 The method of Example 1 was followed, except that the amount of tin Beta molecular sieve added was 7.5 g, and the HPLC purity of the obtained 28-homobrassinolide was 87.5%, with a yield of 74.1%.
[0040] Comparative Example 2 The method of Example 1 was followed, except that the reaction solvent was replaced with pure ethyl acetate. The obtained 28-homobrassinolide had an HPLC purity of 85.4% and a yield of 63.7%.
[0041] Comparative Example 3 The method of Example 1 was followed, except that the reaction solvent was replaced with pure water. The obtained 28-homobrassinolide had an HPLC purity of 76.2% and a yield of 13.7%.
[0042] Comparative Example 4 The method was followed in Example 1, except that the volume ratio of water to ethyl acetate in the mixed solvent was 50:50. The obtained 28-homobrassinolide had an HPLC purity of 95.9% and a yield of 70.4%. Comparative Example 5 The method of Example 1 was followed, except that the lactone reaction temperature was 30°C, and the HPLC purity of the obtained 28-homobrassinolide was 82.5%, with a yield of 62.6%. Comparative Example 6 The method of Example 1 was followed, except that hydrogen peroxide was added at once, and the HPLC purity of the obtained 28-homobrassinolide was 92.8%, with a yield of 71.5%. Comparative Example 7 The method of Example 1 was followed, except that ethyl acetate was replaced with dichloromethane in the mixed solvent in step 1, and ethyl acetate was replaced with dichloromethane in steps 2-3. The HPLC purity of the obtained 28-homobrassinolide was 93.1%, and the yield was 53.8%. Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application and not to limit them; although this application has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications can still be made to the specific implementation of this application or equivalent substitutions can be made to some technical features, all of which should be covered within the scope of the technical solutions claimed in this application.
Claims
1. A method for preparing 28-homobrassinolide, characterized in that, Includes the following steps: S1. Using the compound of formula I as raw material, water and ethyl acetate as mixed solvents, carboxylic acid and tin Beta molecular sieve are added and mixed, and hydrogen peroxide solution is added dropwise to carry out lactonization reaction to generate 28-homobrassinolide. S2. Filter the liquid, let the filtrate stand to separate into layers, extract the aqueous phase with ethyl acetate, combine the organic phases and wash them with potassium carbonate solution and sodium chloride solution in sequence, and let them stand to separate into layers. S3. The organic phase was washed sequentially with sodium bisulfite solution and sodium chloride solution, allowed to stand and separate into layers, concentrated, crystallized, and filtered to obtain crude 28-homobrassinolide. S4. The obtained crude 28-homobrassinolide is recrystallized with ethyl acetate to obtain the final product.
2. The method for preparing 28-homobrassinolide according to claim 1, characterized in that, In S1, the molar ratio of compound I, carboxylic acid, and hydrogen peroxide is 1:1-3:2-4; The amount of tin beta molecular sieve used is 2-10% of the weight of the compound of formula I.
3. The method for preparing 28-homobrassinolide according to claim 1, characterized in that, The volume ratio of water to ethyl acetate in the mixed solvent in S1 is 30-40:60-70; the mass-volume ratio of the compound of Formula I to the mixed solvent is 1g:20-50ml.
4. The method for preparing 28-homobrassinolide according to claim 1, characterized in that, The lactone reaction temperature described in S1 is 0-20℃, and the reaction time is 4-6h.
5. The method for preparing 28-homobrassinolide according to claim 1, characterized in that, The mass concentration of the hydrogen peroxide solution mentioned in S1 is 25-30%; the time for adding the hydrogen peroxide solution is 30-60 min.
6. The method for preparing 28-homobrassinolide according to claim 1, characterized in that, The carboxylic acid in S1 is selected from at least one of formic acid, acetic acid, and propionic acid; preferably, the carboxylic acid is acetic acid.
7. The method for preparing 28-homobrassinolide according to claim 1, characterized in that, The tin content of the tin beta molecular sieve described in S1 is 6-10%.
8. The method for preparing 28-homobrassinolide according to claim 1, characterized in that, The potassium carbonate solution mentioned in S2 is a potassium carbonate aqueous solution with a mass concentration of 30-35%; the sodium chloride solution is a saturated sodium chloride aqueous solution.
9. The method for preparing 28-homobrassinolide according to claim 1, characterized in that, The sodium bisulfite solution mentioned in S3 is an aqueous solution of sodium bisulfite with a mass concentration of 15-25%; the sodium chloride solution is an aqueous solution of sodium chloride with a mass concentration of 10-20%.
10. The method for preparing 28-homobrassinolide according to claim 1, characterized in that, The specific recrystallization operation described in S4 is as follows: crude 28-homobrassinolide is added to ethyl acetate, heated to 50-70°C to completely dissolve the crude product, cooled to room temperature, and allowed to stand at 0-10°C for 4-12 hours to crystallize. After filtration, the product is washed with cold ethyl acetate and dried under vacuum to constant weight.