A method for preparing a brassinolide intermediate

Abstract

This invention belongs to the field of plant growth regulator preparation, and relates to a method for preparing brassinolide intermediates, particularly a method for preparing propionyl brassinolide, 28-homobrassinolide, and 24-epibrassinolide intermediates. The invention provides a novel preparation method comprising the following steps: In a solvent, compound 2 is oxidized with an oxidant under the action of a nitrogen-oxygen free radical catalyst to obtain compound 1. The synthetic route is shown in Figure I below: where R represents a "carbon-carbon single bond" or "carbon-carbon double bond"; R represents: (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C8)cycloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl; preferably methyl or ethyl. This invention is simple to operate, has optimized conditions, is environmentally friendly, has high conversion rate, low cost, and high yield, making it suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of preparation of plant growth regulators, and relates to a method for preparing brassinolide intermediates, particularly to a method for preparing intermediates of propionyl brassinolide, 28-homobrassinolide and 24-epibrassinolide. Background Technology

[0002] In the early 1980s, a research institute under the U.S. Department of Agriculture extracted a compound with a steroidal skeleton structure from rapeseed pollen, which was named brassinolide. Brassinolide is a novel, environmentally friendly plant growth regulator. Through seed soaking and foliar spraying at appropriate concentrations, it can promote the growth of vegetables, melons, and fruits, improve quality, increase yield, enhance color, and thicken leaves. It can also advance the harvesting time for tea leaves, and result in melons and fruits with higher sugar content, larger size, higher yield, and better storage resistance.

[0003] Currently, most plant growth regulators only work for a short period, requiring repeated application and offering only a single effect. In contrast, brassinolides have significant advantages. They can regulate multiple enzymes and hormones required by the plant itself, fully leveraging the plant's inherent potential and growth advantages, enhancing vitality and drought / flood resistance, significantly increasing yield and improving quality. Simultaneously, they reduce the use of pesticides and fertilizers, avoiding environmental pollution and lowering crop cultivation costs, thus significantly increasing economic benefits. Commonly used brassinolides on the market include propionyl brassinolide, 28-homobrassinolide, and 24-epibrassinolide.

[0004] In 1979, Thompson et al. (Thompson, MJ; J. Org. Chem. 1979, 26, 5002) first published the total synthesis of 24-epibrassinolide. They used inexpensive and readily available ergosterol as a starting material, and synthesized it through nine steps: sulfonation, hydrolysis, oxidation, reduction, rearrangement, sulfonation, elimination, dihydroxylation, and lactone formation. This method is lengthy and has a low overall yield. The preparation of intermediate 3, using a chromium trioxide / pyridine oxidation system, generates a large amount of waste liquid and solid waste containing heavy metal ions, causing serious environmental pollution.

[0005] In 1993, McMorris et al. (McMorris, TC; J. Org. Chem. 1993, 58, 2338) reported an improved method for synthesizing 24-epibrassinolide. They optimized the synthetic route based on that of Thompson et al., reducing the number of steps to seven. However, the oxidation step still used a large amount of chromium trioxide / pyridine system to produce intermediate 3, causing serious contamination problems, and the overall yield was only about 10%.

[0006] CN 101812114A discloses the preparation of intermediate 3 using an osmium tetroxide / m-chlorobenzoic acid oxidation system, wherein osmium tetroxide is a volatile and highly toxic solid powder that is expensive, costly, and requires highly skilled operators.

[0007] CN 111004303A discloses the preparation of intermediate 3 using a manganese dioxide / air system, with methanol as the solvent and air introduced for oxidation. Although manganese dioxide can be reused after calcination, the need to introduce air releases a large amount of methanol gas, which may accumulate to the explosive limit, posing a certain safety hazard.

[0008] CN 111518154B discloses the use of tetrabutylammonium bromide (TBAB) and tetrabutylammonium persulfate (n-Bu4NHSO5 or TBAOX) to improve the solubility of intermediate 2 after etherification in order to increase the yield of intermediate 3.

[0009] Current methods for preparing brassinolide intermediates suffer from high costs, environmental pollution, safety hazards, or low yields. Therefore, it is crucial to develop a new, universally applicable method for preparing brassinolide intermediates that is low-cost, environmentally friendly, and safe, particularly methods for preparing propionyl brassinolide, 28-homobrassinolide, and 24-epibrassinolide intermediates. Summary of the Invention

[0010] This invention provides a novel method for preparing brassinolide intermediates, particularly suitable for the preparation of propionyl brassinolide, 28-homobrassinolide and 24-epibrassinolide intermediates. The aim is to improve upon existing methods that suffer from heavy metal pollution, high toxicity, high risk, the need for column chromatography purification of reaction products, high cost and low yield.

[0011] The first aspect of the present invention provides a method for preparing a compound of formula 1, the synthetic route of which is shown in Figure I below:

[0012]

[0013] in The symbol indicates a "carbon-carbon single bond" or a "carbon-carbon double bond"; R indicates (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C8)cycloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl; preferably methyl or ethyl;

[0014] It includes the following steps:

[0015] In a solvent, compound 2 is oxidized with an oxidant under the action of a nitrogen-oxygen free radical catalyst to obtain compound 1.

[0016] As a further improvement of the present invention, the compound of Formula 2 is not limited to being selected from the group consisting of the following compounds:

[0017]

[0018]

[0019] As a further improvement of the present invention, the molar ratio of the compound of Formula 2 to the oxidant is 1:(0.5-3), preferably 1:(1-2).

[0020] As a further improvement of the present invention, the oxidant is selected from sodium hypochlorite, sodium chlorite, sodium perchlorate, sodium periodate, or trichloroisocyanuric acid, preferably sodium hypochlorite.

[0021] As a further improvement of the present invention, the sodium hypochlorite is an aqueous solution, wherein the effective component of sodium hypochlorite in the aqueous solution is 0.1-0.2 mol, preferably 0.1-0.15 mol, and more preferably 0.133 mol, 0.134 mol, 0.135 mol, 0.136 mol, 0.137 mol, 0.138 mol, or 0.139 mol.

[0022] As a further improvement of the present invention, the solvent is selected from one or more combinations of aromatic hydrocarbons, ketones, esters or water; the aromatic hydrocarbon is selected from benzene, toluene or xylene; the ketone is selected from N-methylpiperidone or acetone; the ester is selected from ethyl acetate, butyl acetate or isopropyl acetate; preferably toluene and water, acetone and water or isopropyl acetate and water.

[0023] As a further improvement of the present invention, the solvent is composed of two solvents, preferably an organic solvent and water, wherein the volume ratio of the organic solvent to water is (0.1–10):1, preferably (1–10):1; in some specific embodiments of the present invention, the volume ratio of the organic solvent to water is selected from V 甲苯 V 水 =2:1, V 丙酮 V 水=2:1 or V 醋酸异丙酯 V 水 =2:1.

[0024] As a further improvement of the present invention, the mass-to-volume ratio (g:mL) of the compound of formula 2 to the solvent is 1:6 to 12, preferably 1:8 to 10; in some specific embodiments of the present invention, the mass-to-volume ratio of the compound 2 to the solvent is 1:9.

[0025] As a further improvement of the present invention, the nitrogen-oxygen free radical is preferably ABNO, AZADO, 1-Me-AZADO, 1-Me-ABNO, oxa-AZZDO, TsN-AZZDO, DiAZADO, nortropane-N-oxy, 7-azabicyclo[2.2.1]heptane-N-oxy, 3-BocNH-ABNO, or 3-AcNH-ABNO.

[0026] As a further improvement of the present invention, a co-catalyst is added to the oxidation reaction. The co-catalyst is selected from bromides, preferably sodium hypobromite, hydrogen bromide, potassium bromide or sodium bromide.

[0027] As a further improvement of the present invention, the molar ratio of the nitrogen-oxygen free radical catalyst to the co-catalyst is 1:(0.1-5), preferably 1:(1-2), and more preferably 1:1.

[0028] As a further improvement of the present invention, the molar ratio of the compound of Formula 2 to the nitrogen-oxygen free radical catalyst is 1:(0.001 to 0.1), preferably 1:(0.01 to 0.05), and more preferably 1:(0.02 to 0.05).

[0029] As a further improvement of the present invention, no phase transfer catalyst is added in the oxidation reaction, and the phase transfer catalyst is selected from quaternary ammonium salt phase transfer catalysts, preferably tetrabutylammonium bromide.

[0030] As a further improvement of the present invention, the oxidation reaction is carried out in an alkali, which is preferably a carbonate or bicarbonate of an alkali metal or alkaline earth metal, more preferably sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or calcium bicarbonate.

[0031] As a further improvement of the present invention, the molar ratio of the compound of Formula 2 to the base is 1:(1 to 5), preferably 1:(2 to 2.5).

[0032] As a further improvement of the present invention, the oxidation reaction temperature is ≤30℃, preferably ≤20℃, and more preferably -10~10℃.

[0033] As a further improvement of the present invention, the oxidation reaction yields the compound of formula 1 through simple separation.

[0034] This invention does not specifically limit the separation steps; any separation steps known in the art can be used, as long as they achieve the purpose of this invention. For example, the separation steps may include, but are not limited to: static layering, reduced pressure concentration, cooling, stirring, column chromatography, or filtration. The solvents used in the separation steps can be conventional solvents known in the art.

[0035] A second aspect of the invention provides an application of a method for preparing compounds of Formula 1 to the preparation of propionyl brassinolide, 28-homobrassinolide and 24-epibrassinolide intermediates.

[0036] The abbreviations of the chemical reagents used in this invention are shown in Table 1 below:

[0037] Table 1

[0038]

[0039] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0040] 1. This invention avoids the serious pollution caused by using reagents containing heavy metals, such as chromium trioxide / pyridine (PCC oxidation) and potassium dichromate pyridine (PDC oxidation), making it more environmentally friendly;

[0041] 2. This invention provides a novel method for the oxidative synthesis of brassinolide. This method is simple to operate, has optimized conditions, high conversion rate, low cost, and high yield, making it suitable for industrial production. Detailed Implementation

[0042] To facilitate understanding of the present invention by those skilled in the art, the technical solutions of the present invention are further described below in conjunction with specific embodiments. It should be understood that these embodiments are not intended to limit the scope and spirit of the claims. Unless otherwise specified, all raw materials, reagents, or solvents used in the present invention are commercially available, and experimental methods without specific conditions are generally performed under conventional conditions in the art.

[0043] Option 1:

[0044]

[0045] Compound 2-1 was added to a reaction flask, followed by solvent A, alkali, and the catalyst system. The mixture was cooled and then slowly added dropwise with an aqueous solution of sodium hypochlorite until the reaction was complete. After the reaction was complete, the product was obtained by simple separation.

[0046] Option 2:

[0047]

[0048] Compound 2-2 was added to a reaction flask, followed by solvent A, alkali, and a catalyst. The mixture was cooled and then slowly added dropwise with an aqueous solution of sodium hypochlorite until the reaction was complete. After the reaction was complete, the product was obtained by simple separation.

[0049] Example 1.1

[0050] Compound 2-1 (50 g, 0.121 mol) was added to a 1 L reaction flask, followed by 300 mL of toluene, 150 mL of water, sodium bicarbonate (23.5 g, 0.278 mol), potassium bromide (0.72 g, 0.006 mol), and catalyst ABNO (0.84 g, 0.006 mol). The mixture was cooled to 0–10 °C, and sodium hypochlorite aqueous solution (0.133 mol of active sodium hypochlorite) was slowly added dropwise until the reaction was complete. After the reaction was complete, the mixture was allowed to stand and separate into layers. The aqueous phase was separated, and the organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (n-hexane:ethyl acetate = 5:1) to give 45 g of product, with a yield of 90%.

[0051] 1 H-NMR (400MHz, CDCl3): δ=5.171~5.112(1H,m),5.047–4.988(1H,m),2.436–2.405(1H,d),2.039–2.000(2H,m),1.936–1.863(3H,m) ),1.832–1.659(4H,m),1.560–1.381(7H,m),1.294–1.060(8H,m),1.029–0.996(6H,m),0.845–0.778(9H,m),0.723–0.692(4H,m).

[0052] Example 1.2

[0053] Compound 2-1 (50 g, 0.121 mol) was added to a 1 L reaction flask, followed by 300 mL of acetone, 150 mL of water, sodium bicarbonate (23.5 g, 0.278 mol), potassium bromide (0.72 g, 0.006 mol), and catalyst ABNO (0.84 g, 0.006 mol). The mixture was cooled to 0–10 °C, and an aqueous solution of sodium hypochlorite (0.133 mol of active ingredient) was slowly added dropwise until the reaction was complete. After the reaction was complete, the acetone was concentrated, and the crude product was obtained by filtration. The crude product was subjected to column chromatography (n-hexane:ethyl acetate = 5:1) to give 43 g of product, with a yield of 86%.

[0054] Examples 1.3–1.15 follow the operating method of Scheme 1 and the operating conditions of Example 1.1 or Example 1.2, but with variations in solvent type and amount, reaction temperature, reaction time, type and amount of catalyst system, or type and amount of alkali to prepare product 1-1, as detailed in Table 2 below:

[0055] Table 2

[0056]

[0057]

[0058] Example 2.1

[0059] Compound 2-2 (50 g, 0.126 mol) was added to a 1 L reaction flask, followed by 300 mL of toluene, 150 mL of water, sodium bicarbonate (24.5 g, 0.290 mol), potassium bromide (0.72 g, 0.006 mol), and catalyst ABNO (0.84 g, 0.006 mol). The mixture was cooled to 0–10 °C, and sodium hypochlorite aqueous solution (0.139 mol of active sodium hypochlorite) was slowly added dropwise until the reaction was complete. After the reaction was complete, the mixture was allowed to stand and separate into layers. The aqueous phase was separated, and the organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (n-hexane:ethyl acetate = 5:1) to give 46 g of product, with a yield of 92%.

[0060] 1 H-NMR (400MHz, CDCl3): δ = 5.801 (1H, s), 5.287–5.143 (2H, m), 2.289–2.238 (1H, m), 2.1 48–2.079(3H,m),1.998–1.948(1H,m),1.880–1.811(1H,q),1.800–1.681(10H,m),1.5 62–1,464(2H,m),1.410–1.345(3H,m),1.166–1.132(1H,m),1.099(3H,s),1.064–1.04 7(3H,d),0.939–0.922(3H,d),0.860–0.829(6H,t),0.769–0.746(1H,t),0.688(1H,s).

[0061] Example 2.2

[0062] Compound 2-2 (50 g, 0.126 mol) was added to a 1 L reaction flask, followed by the addition of 300 mL acetone, 150 mL water, sodium bicarbonate (24.5 g, 0.290 mol), potassium bromide (0.72 g, 0.006 mol), and catalyst ABNO (0.84 g, 0.006 mol). The mixture was cooled to 0–10 °C, and an aqueous solution of sodium hypochlorite (0.139 mol of active sodium hypochlorite) was slowly added dropwise until the reaction was complete. After the reaction was complete, the acetone was concentrated, and the crude product was obtained by filtration. The crude product was subjected to column chromatography (n-hexane:ethyl acetate = 5:1) to give 43 g of product, with a yield of 86%.

[0063] Examples 2.3–2.17 follow the operating methods of Scheme 2 and the operating conditions of Example 2.1 or Example 2.2, but with variations in solvent type and amount, reaction temperature, reaction time, type and amount of catalyst system, or type and amount of alkali to prepare products 1–2, as detailed in Table 3 below:

[0064] Table 3

[0065]

[0066]

[0067] Comparative Example 1

[0068] Compound 2-1 (20 g, 0.048 mol) was added to a 1 L reaction flask, followed by 250 mL of isopropyl acetate, 60 mL of water, sodium bicarbonate (9.4 g, 0.111 mol), potassium bromide (0.29 g, 0.0024 mol), and the catalyst TEMPO (0.38 g, 0.00624 mol). The mixture was cooled to -10 to 10 °C, and an aqueous solution of sodium hypochlorite (0.053 mol of active sodium hypochlorite) was slowly added dropwise. The starting materials did not react.

[0069] Comparative Example 2

[0070] Compound 2-1 (50 g, 0.121 mol) was added to a 1 L reaction flask, followed by 300 mL of dichloromethane, 150 mL of water, sodium bicarbonate (23.5 g, 0.278 mol), potassium bromide (0.72 g, 0.006 mol), and catalyst ABNO (0.84 g, 0.006 mol). The mixture was cooled to -10 to 10 °C, and an aqueous solution of sodium hypochlorite (0.133 mol of active sodium hypochlorite) was slowly added dropwise. The starting material deteriorated, and no target product was produced.

Claims

1. A method for preparing a compound of formula 1, characterized in that, The reaction formula is shown in (Ⅰ) below: (Ⅰ)； in" “ represents “carbon-carbon single bond” or “carbon-carbon double bond”; R represents: (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy; It includes the following steps: In a solvent, the compound of formula 2 is oxidized with an oxidant in the presence of a nitrogen-oxygen free radical catalyst to obtain the compound of formula 1. The nitrogen-oxygen free radicals are selected from ABNO, AZADO, 1-Me-AZADO, oxa-AZADO, TsN-AZADO, DiAZADO, nortropane-N-oxy, 7-azabicyclo[2.2.1]heptane-N-oxy, 3-BocNH-ABNO or 3-AcNH-ABNO; The oxidant is selected from sodium hypochlorite, sodium chlorite, sodium perchlorate, sodium periodate, or trichloroisocyanuric acid; The oxidation reaction is carried out in an alkali, wherein the alkali is a carbonate of an alkali metal or an alkaline earth metal or a bicarbonate of an alkali metal or an alkaline earth metal. The solvent consists of an organic solvent and water; The organic solvent is selected from one or more combinations of aromatic hydrocarbons, ketones or esters; The volume ratio of the organic solvent to water is (0.1~10):1; A co-catalyst is added to the oxidation reaction, and the co-catalyst is sodium hypobromite, hydrogen bromide, potassium bromide or sodium bromide.

2. The preparation method according to claim 1, characterized in that, R is methyl or ethyl.

3. The preparation method according to claim 1, characterized in that, The molar ratio of the nitrogen-oxygen radical catalyst to the co-catalyst is 1:(0.1~5).

4. The preparation method according to claim 3, characterized in that, The molar ratio of the nitrogen-oxygen radical catalyst to the co-catalyst is 1:(1~2).

5. The preparation method according to claim 1, characterized in that, The molar ratio of the compound of Formula 2 to the nitrogen-oxygen free radical catalyst is 1: (0.001~0.1).

6. The preparation method according to claim 5, characterized in that, The molar ratio of the compound of Formula 2 to the nitrogen-oxygen free radical catalyst is 1: (0.01~0.05).

7. The preparation method according to claim 6, characterized in that, The molar ratio of the compound of Formula 2 to the nitrogen-oxygen free radical catalyst is 1: (0.02~0.05).

8. The preparation method according to claim 1, wherein the molar ratio of the compound of formula 2 to the oxidant is 1:(0.5~3); And / or, the oxidant is sodium hypochlorite.

9. The preparation method according to claim 8, wherein the molar ratio of the compound of formula 2 to the oxidant is 1:(1~2).

10. The preparation method according to claim 1, characterized in that, The aromatic hydrocarbon is selected from benzene, toluene, or xylene; the ketone is selected from N-methylpiperidone or acetone; and the ester is selected from ethyl acetate, butyl acetate, or isopropyl acetate.

11. The preparation method according to claim 1, characterized in that, The solvent is toluene and water, acetone and water, or isopropyl acetate and water.

12. The preparation method according to claim 1, characterized in that, The mass-to-volume ratio of the compound of Formula 2 to the solvent is 1:(6~12) g:mL.

13. The preparation method according to claim 1, characterized in that, The mass-to-volume ratio of the compound of Formula 2 to the solvent is 1:(8~10) g:mL.

14. The preparation method according to claim 1, characterized in that, The alkali is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or calcium bicarbonate.

15. The preparation method according to claim 1, characterized in that, The molar ratio of the compound of Formula 2 to the base is 1:(1~5).

16. The preparation method according to claim 15, characterized in that, The molar ratio of the compound of Formula 2 to the base is 1:(2~2.5).

17. A method for preparing a brassinolide intermediate, characterized in that, Includes the preparation method described in any one of claims 1 to 16.

18. A method for preparing a brassinolide intermediate, characterized in that, The preparation method according to any one of claims 1 to 16 is included, wherein the brassinolide is propionyl brassinolide, 28-homobrassinolide, or 24-epibrassinolide.

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