A process for the synthesis of 24-epibrassinolide

Abstract

The application provides an improved synthesis method of a 24-epibrassilide synthesis process. Through innovative adjustment of a synthesis process condition, significant improvement of reaction yield and selection is realized, and the method has good application value.

Description

Technical Field

[0001] This invention relates to the field of 24-epibrassinolide preparation technology, and in particular to the preparation of 24-epibrassinolide by an improved chemical synthesis method. Background Technology

[0002] Brassinolides are a class of sterol hormones discovered in recent decades, with over 70 structurally similar compounds to date. They are the sixth most important hormone group after auxins, cytokinins, gibberellins, abscisic acid, and ethylene. The first brassinolide was discovered, and it plays a crucial role in multiple aspects of plant development, including stimulating root and stem growth, inhibiting root growth, promoting xylem differentiation, delaying leaf abscission, defending against pathogens, tolerating environmental stress, and promoting reproductive development.

[0003] 24-Epibrassinolide is a phytosterol hormone belonging to the brassinosteroid family. It exhibits strong potential to mitigate the damage to plants caused by heavy metals and pest stress, even at low concentrations (10). -5 -10 -6 At concentrations of mg / L, brassinolide exhibits various activities, increasing vegetative growth and promoting fertilization in plants. Most plant growth regulators only work for a short period, requiring repeated applications, and their effects are singular. In contrast, brassinolide has significant advantages. It can regulate multiple enzymes and hormones required by the plant itself, fully utilizing the plant's inherent potential and growth advantages, enhancing vitality and drought and flood resistance. A single application can achieve multiple goals such as flower and fruit preservation, color enhancement, growth promotion, and dwarfing, significantly increasing yield and improving quality. Simultaneously, it can reduce the use of pesticides and fertilizers, avoiding environmental pollution and lowering crop planting costs, thus significantly increasing economic benefits. 24-Epibrassinolide is also an effective apoptosis inducer in various cancer cells without affecting the growth of normal human cells.

[0004] In 1979, Thompson et al. (Thompson, MJ; J. Org. Chem. 1979, 26, 5002) first published 24 A total synthesis of brassinolide was performed. They used inexpensive and readily available ergosterol as the starting material, and synthesized it via a nine-step reaction involving sulfonation, hydrolysis, oxidation, reduction, rearrangement, sulfonation, elimination, dihydroxylation, and lactone formation. This method is lengthy and has a relatively low overall yield. Currently reported methods for 24... The synthesis of epibrassinolide is complicated by its cumbersome operation, high toxicity, significant environmental pollution, and the need for low-temperature operation, making it difficult to meet the requirements of large-scale production. The industry urgently needs a chemical synthesis method that can obtain 24-epibrassinolide with high yield and purity. Summary of the Invention

[0005] The purpose of this invention is to provide an improved synthetic method for 24-epibrassinolide, in order to solve the technical problems of limited or inefficient chemical synthesis routes in the prior art.

[0006] To address the aforementioned technical problems, this invention provides an improved synthetic method for 24-epibrassinolide, comprising using compound 3 as a reactant and obtaining compound 2 via a Sharpless asymmetric dihydroxylation reaction. The Sharpless asymmetric dihydroxylation reaction includes the following steps: The compound 3, oxidant, dihydroxylating agent, base, ligand and organic solvent are mixed and reacted. After the reaction is completed, the reaction is quenched and separated to obtain the product. The dihydroxylating agent is selected from one or more of OsO4, K2OsO4, OsO4 hydrate, and K2OsO4 hydrate. The oxidant is selected from one or more of K3[Fe(CN)6] or NMO; The alkali is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, NaOH, KOH, LiOH, NH4OH, t-BuONa, t-BuOK, t-BuOLi, cesium carbonate, Et3N, DIPEA, and DBU. The ligand is selected from one or more of (DHQ)2PHAL, (DHQD)2PHAL, DHQ-IND and DHQD-IND; The organic solvent is selected from hexafluoroisopropanol and hexafluoro-2-methylisopropanol; Compound 2 was then subjected to a Baeyer-Villiger oxidative rearrangement reaction to synthesize the target product 24-epibrassinolide. The Baeyer-Villiger oxidative rearrangement reaction used trifluoroperacetic acid as the oxidant and an L-proline derivative as the catalyst. The catalyst was prepared by dissolving 5 mmol of L-proline and 5 mmol of phosphotungstic acid in 100 mL of pure water in a 100 mL flask, stirring overnight at 50-70 °C, removing the solvent under reduced pressure, and drying and grinding the residue under vacuum to obtain a white solid catalyst. The Baeyer-Villiger oxidative rearrangement reaction temperature is room temperature - the boiling point of the reaction solvent, and the reaction time is 5-10 h; The ratio of compound 2, oxidant, and catalyst is 1 mmol: 2-5 mmol: 0.1-100 mg; Its synthetic route is as follows: .

[0007] Furthermore, the reaction temperature of the Sharpless asymmetric dihydroxylation reaction is room temperature - the boiling point of the reaction solvent, and the reaction time is 12-30 h.

[0008] Furthermore, in the Sharpless asymmetric dihydroxylation reaction, the molar ratio of compound 3, oxidant, dihydroxylating agent, base, and ligand is 1:0.01-5:0.01-5:1-5:0.1-0.5, preferably 1:3:0.02:3:0.1.

[0009] Furthermore, the solvent for the Sharpless asymmetric dihydroxylation reaction is preferably hexafluoroisopropanol.

[0010] By adopting the above technical solution, the present invention has the following beneficial effects: using the existing raw material compound 3, under the action of the preferred Sharpless asymmetric bihydroxylation and Baeyer-Villiger oxidative rearrangement reaction system (reaction solvent, catalyst, ligand, etc.), 24-epibrassinolide can be obtained with high reaction yield and purity. Detailed Implementation

[0011] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, 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.

[0012] The present invention will be further explained below with reference to specific embodiments.

[0013] Example 1 In a 100 mL round-bottom flask, 10 mL of hexafluoroisopropanol, 0.02 mmol of catalyst K2OsO4 hydrate K2OsO2(OH)4, 0.1 mmol of chiral ligand (DHQD)2PHAL, 3 mmol of K3[Fe(CN)6], 3 mmol of potassium carbonate, and 2 mmol of methanesulfonamide were added sequentially. The mixture was stirred at room temperature for 20 min. Then, 1 mmol of hexafluoroisopropanol (5 mL) solution of compound 3 was added to the reaction system. The reaction was carried out at room temperature for 24 h. After tert-butanol was removed by evaporation, the mixture was extracted with dichloromethane, washed once with dilute hydrochloric acid and saturated brine, and the solvent was removed by evaporation to obtain the crude product. The crude product was recrystallized from ethyl acetate to obtain compound 2 with a yield of 95% and an HPLC purity of 99.6%.

[0014] Example 2 The reaction solvent hexafluoroisopropanol in Example 1 was replaced with an equal amount of tert-butanol, while the other conditions remained unchanged, to obtain product compound 2 with a yield of 70% and an HPLC purity of 99.3%.

[0015] Example 3 The catalyst K2OsO4 hydrate K2OsO2(OH)4 in Example 1 was replaced with an equal amount of OsO4, and the other conditions remained unchanged, to obtain compound 2 with a yield of 83% and an HPLC purity of 99.5%.

[0016] Example 4 Take 5 mmol L-proline and 5 mmol phosphotungstic acid in a 100 mL flask, add 10 mL of pure water to dissolve them, stir overnight at 50-70 °C, evaporate the solvent under reduced pressure, and obtain an off-white solid catalyst A by vacuum drying and grinding the residue. 300 mL of dichloromethane and 60 mL of TFAA were added to the reaction flask. 0.3 mol of H2O2 was slowly added dropwise under ice bath conditions, and the mixture was stirred for 1 h. Then, 0.1 mol of compound 2 in dichloromethane (150 mL) solution and 0.5 g of catalyst A were added. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the pH of the system was adjusted to 6-7 with sodium carbonate aqueous solution. The mixture was washed with water, separated, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation to obtain the crude product. The crude product was recrystallized from ethyl acetate to obtain compound 1 (24-epibrassinolide), with a yield of 91% and an HPLC purity of 99.9%.

[0017] Example 5 By removing the L-proline catalyst from Example 4 and keeping all other conditions the same, compound 1 was obtained with a yield of 65% and an HPLC purity of 99.2%.

[0018] Example 5 In Example 4, catalyst A was replaced with an equal amount of phosphotungstic acid, and all other conditions remained the same, to obtain compound 1 with a yield of 75% and an HPLC purity of 99.3%.

[0019] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A process for synthesizing 24-epibrassinolide, characterized in that, The process includes preparing compound 2 by using compound 3 as a reactant via a Sharpless asymmetric dihydroxylation reaction, wherein the Sharpless asymmetric dihydroxylation reaction includes the following steps: The compound 3, oxidant, dihydroxylating agent, base, ligand and organic solvent are mixed and reacted. After the reaction is completed, the reaction is quenched and separated to obtain the product. The dihydroxylating agent is selected from one or more of OsO4, K2OsO4, OsO4 hydrate, and K2OsO4 hydrate. The oxidant is selected from one or more of K3[Fe(CN)6] or NMO; The alkali is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, NaOH, KOH, LiOH, NH4OH, t-BuONa, t-BuOK, t-BuOLi, cesium carbonate, Et3N, DIPEA, and DBU. The ligand is selected from one or more of (DHQ)2PHAL, (DHQD)2PHAL, DHQ-IND and DHQD-IND; The organic solvent is selected from hexafluoroisopropanol and hexafluoro-2-methylisopropanol; Compound 2 was then subjected to a Baeyer-Villiger oxidative rearrangement reaction to synthesize the target product 24-epibrassinolide. The Baeyer-Villiger oxidative rearrangement reaction used trifluoroperacetic acid as the oxidant and an L-proline derivative as the catalyst. The catalyst was prepared by dissolving 5 mmol of L-proline and 5 mmol of phosphotungstic acid in 100 mL of pure water in a 100 mL flask, stirring overnight at 50-70 °C, removing the solvent under reduced pressure, and drying and grinding the residue under vacuum to obtain a white solid catalyst. The Baeyer-Villiger oxidative rearrangement reaction temperature is room temperature - the boiling point of the reaction solvent, and the reaction time is 5-10 h; The ratio of compound 2, oxidant, and catalyst is 1 mmol: 2-5 mmol: 0.1-100 mg; Its synthetic route is as follows: .

2. The synthesis method according to claim 1, characterized in that, The reaction temperature for the Sharpless asymmetric dihydroxylation reaction is room temperature - the boiling point of the reaction solvent, and the reaction time is 12-30 h.

3. The synthesis method according to claim 1, characterized in that, The preferred solvent for the Sharpless asymmetric dihydroxylation reaction is hexafluoroisopropanol.

4. The synthesis method according to claim 1, characterized in that, The preferred temperature for the Baeyer-Villiger oxidative rearrangement reaction is room temperature.

5. The synthesis method according to claim 1, characterized in that, The L-proline derivative catalyst can also be prepared using Brønsted acids other than L-proline and phosphotungstic acid.

6. The synthesis method according to claim 5, characterized in that, Other than phosphotungstic acid, the Brønsted acids are sulfuric acid and trifluoromethanesulfonic acid.

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