Novel method for synthesizing plant growth regulator dihydrogibberellin without protecting carboxyl

Abstract

The invention discloses a novel method for synthesizing a plant growth regulator dihydrogibberellin without protecting carboxyl. The invention provides a novel method for synthesizing a plant growth regulator dihydrogibberellin without protecting carboxyl, which comprises the following steps: 1) in an organic solvent B, mixing a compound as shown in a formula II with a catalyst A, and carrying out hydrogenation reduction reaction in a hydrogen atmosphere to obtain a compound as shown in a formula III; 2) in an organic solvent C, mixing the compound as shown in the formula III with a saturated aqueous solution of alkali, and carrying out selective deacetylation reaction to obtain a compound as shown in a formula IV; and 3) in an organic solvent D, carrying out a dehydration elimination reaction on the substance as shown in the formula IV in the presence of triphenylphosphine and an elimination reagent to obtain the dihydrogibberellin as shown in a formula V. The synthesis method of dihydrogibberellin can be simplified, and large-scale production and synthesis are facilitated. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a new method for synthesizing dihydrogibberellin, a plant regulator, without protecting the carboxyl group. Background Art

[0002] Dihydrogibberellin is a derivative synthesized from gibberellin A3 (GA3) with the chemical structure of exo-16,17-dihydro-13-acetyl-GA5. Dihydrogibberellin is a degradable, environmentally friendly plant growth regulator. For example, in a greenhouse environment, the use of 500 mg of dihydrogibberellin per hectare can significantly reduce the plant height of wheat, barley and many grasses. In field experiments, dihydrogibberellin has a significant improvement on crop lodging. The use of 25 grams of dihydrogibberellin per hectare is approximately equivalent to the use of 200 grams of calcium cyclohexane per hectare or 1000 grams of chlormequat per hectare (Can.J.Chem.2004,82,293-300.). The mechanism of action of dihydrogibberellin is through the competitive inhibition of the substrate of GA3ox (2-ketoglutarate-dependent dioxygenase). Dihydrogibberellin is structurally similar to GA9 and GA 20 Very similar, can tightly bind to the action site of the enzyme, so that GA9 and GA 20 It cannot be smoothly oxidized to generate GA4 and GA1 with growth-promoting activity, which ultimately hinders the elongation of the plant stem and reduces the plant height (Annual review of plant biology 2008, 59, 225-251; Plant Physiol. 2004, 135, 1000-1007.).

[0003] In view of the advantages of dihydrogibberellins such as high efficiency, low toxicity, plant growth regulating activity and environmental friendliness, the research on its efficient preparation method has been receiving continuous attention.

[0004] The synthesis method reported in the literature is mainly chemical synthesis, that is, using gibberellic acid as a raw material, protecting the carboxyl group with methyl ester and the hydroxyl group with acetyl group, and converting the final product dihydrogiberyl through a series of chemical reactions to obtain the final product dihydrogiberyl (Can.J.Chem., 2004, 82, 293-300.; Phytochemistry, 1998, 49, 2195-2206). This method has a long reaction route, high industrialization cost, and low final yield. The synthesis method has a long route (at least 7 steps of reaction), low total yield (up to 30%), poor repeatability (the ZnCl2-catalyzed reaction of protecting the carboxyl group used by Lewis N.Mander et al. is difficult to repeat the result), severe conditions are dangerous (demethyl ester protection and elimination of mesylate require reflux under high temperature conditions, with more losses and very low yields), and great purification difficulty (demethyl ester protection requires strong bases, and severe conditions will lead to the generation of many impurities in the product), and cannot be used as a method for the large-scale preparation of dihydrogiberyl. Summary of the invention

[0005] The purpose of the present invention is to provide a novel method for synthesizing dihydrogibberellin, a plant regulator, without protecting the carboxyl group. The present invention can simplify the synthesis process of dihydrogibberellin and is more conducive to large-scale production and synthesis.

[0006] According to the invention, after acetylation of gibberellic acid to obtain acetylgibberellic acid, a hydrogenation reduction reaction of the double bond of the acetylgibberellic acid is carried out without protecting the carboxyl group in the presence of a specific catalyst; and efficient elimination of the hydroxyl group is achieved without protecting the carboxyl group to directly obtain the target product. The method realizes for the first time a 4-step efficient synthesis method of dihydrogiberellic acid without protecting the carboxyl group throughout the process, and the total yield reaches 90%.

[0007] The present invention provides a novel method for synthesizing dihydrogibberellin, a plant regulator, without protecting the carboxyl group, comprising the following steps: 1) in an organic solvent B, a compound represented by formula II is mixed with a catalyst A, and a hydrogenation reduction reaction is carried out in a hydrogen atmosphere to obtain a compound represented by formula III;

[0008]

[0009] 2) In an organic solvent C, the compound represented by formula III is mixed with a saturated aqueous solution of a base to carry out a selective deacetylation reaction to obtain a compound represented by formula IV;

[0010]

[0011] 3) In an organic solvent D, the substance represented by formula IV undergoes a dehydration elimination reaction in the presence of triphenylphosphine and an elimination reagent to obtain the dihydrogibberellin represented by formula V.

[0012] In the present invention, in step 3), the saturated aqueous solution of the base is used to adjust the pH of the reaction solution to remove the acetyl group of C3;

[0013] In step 3), the hydroxyl group at the C3 position of the compound represented by formula IV forms an olefinic bond.

[0014] In the above-mentioned synthesis method, the compound represented by formula II is prepared according to the following steps: in an organic solvent A, in the presence of an organic base, the gibberellic acid represented by formula I reacts with acetic anhydride to obtain the compound represented by formula II;

[0015]

[0016] In the present invention, the gibberellic acid represented by formula I reacts with acetic anhydride, so that the hydrogen in C3-OH and C13-OH in formula I is replaced by acetyl.

[0017] In the above-mentioned synthesis method, in the step of preparing the compound represented by formula II, the organic solvent A is pyridine; the organic base includes 4-dimethylaminopyridine;

[0018] For each mole of gibberellic acid represented by formula I, the volume of the organic solvent used may be 1 to 100 L, preferably 2 to 10 L, and more preferably 3 to 5 L; the molar amount of the organic base may be 0.001 to 0.1 mole, and the amount of acetic anhydride may be 1 to 15 moles, preferably 3 to 10 moles, and more preferably 5 to 8 moles;

[0019] The reaction temperature may be 10°C to 80°C, preferably 30°C to 60°C, more preferably 40°C to 50°C, and the reaction time may be 4 to 24 hours, preferably 6 to 8 hours.

[0020] In the above-mentioned synthesis method, in step 1), the organic solvent B is selected from at least one of ethyl acetate, acetone, methanol, ethanol, tetrahydrofuran and acetonitrile;

[0021] The amount of the organic solvent B used per kilogram of the compound represented by formula II may be 1 to 100 L, preferably 2 to 10 L, and more preferably 3 to 5 L;

[0022] The catalyst A may be selected from Pd / C or PtO2;

[0023] The amount of the catalyst A used may be 0.001 to 0.5 parts by weight, preferably 0.01 to 0.3 parts by weight, and more preferably 0.05 to 0.1 parts by weight, per 1 part by weight of the compound represented by formula II;

[0024] The temperature of the hydrogenation reduction reaction is room temperature; the time can be 2 to 12 hours, preferably 4 to 6 hours.

[0025] In the above-mentioned synthesis method, in step 2), the organic solvent C is selected from at least one of methanol, ethanol, tetrahydrofuran, acetone, and acetonitrile;

[0026] The amount of the organic solvent C used is 1 to 100 L, preferably 2 to 10 L, and more preferably 3 to 5 L, per kilogram of the compound represented by formula III put into step 1);

[0027] The base is selected from at least one of potassium carbonate, sodium carbonate and potassium bicarbonate, preferably potassium carbonate.

[0028] In the above-mentioned synthesis method, in step 2), the saturated aqueous solution of the base is used to adjust the pH of the system to 9-10;

[0029] The temperature of the selective deacetylation reaction is room temperature; the time can be 0.2 to 2 hours, preferably 0.5 to 1 hour.

[0030] In the present invention, after the reaction in step 2) is completed, the system is post-treated as follows: dilute hydrochloric acid water is added dropwise to adjust the pH of the system to between 6 and 7, methanol is removed by vacuum distillation, dichloromethane and water are extracted, dried over anhydrous sodium sulfate, and concentrated to obtain the compound represented by formula IV.

[0031] In the above-mentioned synthesis method, in step 3), the organic solvent D is selected from at least one of dichloromethane, chloroform, 1,2-dichloroethane, toluene, benzene, xylene, isopropyl acetate, ethyl acetate, n-hexane, tetrachloromethane, petroleum ether, chlorobenzene, dioxane and tetrahydrofuran, preferably selected from at least one of dichloromethane, chloroform and 1,2-dichloroethane, and most preferably dichloromethane;

[0032] The elimination reagent is selected from at least one of diethyl azodicarboxylate, dimethyl azodicarboxylate and diisopropyl azodicarboxylate, preferably diethyl azodicarboxylate.

[0033] In the above-mentioned synthesis method, in step 3), per kilogram of the compound represented by formula IV, the amount of the organic solvent D can be 1 to 100 L, preferably 2 to 10 L, and more preferably 3 to 5 L; the amount of the triphenylphosphine can be 0.5 to 5 moles, preferably 0.8 to 3 moles, and more preferably 1 to 1.5 moles; the amount of the elimination reagent can be 0.5 to 5 moles;

[0034] The dehydration elimination reaction time may be 1 to 24 hours, preferably 6 to 8 hours.

[0035] The present invention has the following beneficial effects:

[0036] (1) The starting material used in the present invention is gibberellic acid (Formula I), and the dihydrogiberellic acid product shown in Formula V is obtained through a four-step reaction, thereby simplifying the synthesis steps and reducing the production cycle.

[0037] (2) Compared with the reported synthetic steps, the present invention can obtain the product more efficiently and in higher yield. The post-treatment of each step is simple and easy to operate. The obtained product has high purity and can be put into the next step of production without further treatment.

[0038] (3) The reagents used in the present invention are cheap, which greatly reduces the production cost.

[0039] (4) The production conditions of the present invention are mild and safe.

[0040] (5) The final product of the present invention has high purity, not less than 98%, and the total production yield is not less than 95%.

[0041] In summary, the present invention designs a dihydrogibberellic acid synthesis route with simple operation, safety, high yield and short route using cheap and easily available gibberellic acid as raw material. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 This is the H NMR spectrum of Example 2.

[0043] Figure 2 This is the NMR carbon spectrum of Example 2.

[0044] Figure 3 This is the NMR mass spectrum of Example 2.

[0045] Figure 4 This is the H NMR spectrum of Example 3.

[0046] Figure 5 This is the NMR mass spectrum of Example 3.

[0047] Figure 6 This is the H NMR spectrum of Example 4. DETAILED DESCRIPTION

[0048] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0049] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0050] The specific implementation of the present invention is described in detail below in conjunction with the accompanying drawings. It should be understood that the specific implementation described here is only used to illustrate and explain the present invention, and is not used to limit the present invention.

[0051] In the present invention, unless otherwise specified, the volume values ​​of gases and liquids used are those at a standard atmospheric pressure at 25°C.

[0052] Example 1, Synthesis of Compound Formula II:

[0053]

[0054] In a 1000ml round-bottom flask, add 100g (0.289mol) of gibberellic acid shown in formula I, add 400ml of pyridine to dissolve, slowly add 150g (1.469mol) of acetic anhydride, stir and heat to 50°C, react for 8 hours. After the reaction is completed, slowly pour the reaction solution into 2M icy hydrochloric acid water to precipitate a white solid product, adjust the pH to about 3 with 2M hydrochloric acid water, stir for 1 hour, filter, wash the filter cake with water to about pH = 6, and dry the filter cake to obtain 123.4g of the compound shown in formula II, with a yield of 99.3%.

[0055] Example 2, Synthesis of Compound Formula III:

[0056]

[0057] 124.4 g (0.289 mol) of the substance represented by formula II was dissolved in 600 mL of ethyl acetate. After sufficient dissolution, 7 g (0.05 weight portion) of 5% Pd / C was added and the mixture was shaken in a hydrogenation reactor for 6 hours. After the reaction was completed, Pd / C was filtered out and washed with 100 ml of ethyl acetate. Pd / C was recovered and the filtrate was directly concentrated to obtain 124.7 g of product III with a final yield of 99.3%.

[0058] The structural confirmation data are as follows:

[0059] like Figure 1 As shown, 1H NMR (500MHz, DMSO) δ13.07-11.69(m,1H,COOH),4.76(q,J=1.7Hz,1H,CH),3.00(d,J=10.7Hz,1H,CH),2.44(d,J=10.7Hz,1H,CH),2.20(q,J= 6.9Hz,1H,CH),2.09(s,3H,CH3),2.07-1.99(m,1H,CH),1.97(s,3H,CH3),1.95(s,1H,CH),1.93(d,J=4.3Hz,1H,CH),1.92-1.89(m,1H,CH),1 .88-1.84(m,1H,CH),1.83(d,J=6.6Hz,1H,CH),1.80-1.74(m,1H,CH),1.73(d,J=5.4Hz,1H,CH),1.70(s,1H,CH),1.69-1.65(m,1H,CH),1.6 3(dd,J=10.1,3.0Hz,1H,CH),1.61-1.55(m,1H,CH),1.06(dd,J=12.6,5.8Hz,1H,CH),0.94(d,J=3.3Hz,3H,CH3),0.84(d,J=7.0Hz,3H,CH3).

[0060] like Figure 2 As shown, 13 C NMR (126MHz, DMSO) δ176.82,173.37,170.36,170.13,93.70,85.06,71.25,53.44,53.13,52.2 6,51.85,48.62,44.42,41.30,37.56,27.21,25.44,21.78,21.41,19.16,17.35,14.83,14.81.

[0061] like Figure 3 As shown, LC-MS [M + Na] + :457.1841.

[0062] Example 3, Synthesis of Compound Formula IV:

[0063]

[0064] 129.4 g (0.289 mol) of the substance represented by formula III was dissolved in 500 mL of methanol. After sufficient dissolution, a saturated potassium carbonate aqueous solution was slowly added dropwise, and the pH of the reaction system was adjusted to between 9 and 10. The reaction was stirred for 0.5 hours. After the reaction was completed, 2 M dilute hydrochloric acid was added dropwise, and the pH of the system was adjusted to between 6 and 7. Methanol was removed by distillation under reduced pressure, and the mixture was extracted with dichloromethane and water, dried over anhydrous sodium sulfate, and concentrated to obtain 115.2 g of product IV with a final yield of 98.6%.

[0065] like Figure 4 The structural confirmation data are as follows: 1 H NMR (500MHz, DMSO) δ12.47(s,1H,COOH),5.33(d,J=4.5Hz,1H,OH),3.34(s,1H,CH),3.01(d,J=10.7Hz,1H,CH),2.39(d,J=10.7Hz,1H,CH),2.2 0(q,J=7.0Hz,1H,CH),2.05(ddd,J=13.8,7.7,2.5Hz,1H,CH),2.02-1.97(m,1H,CH),1.96(s,3H,CH3),1.90(dd,J=10.8,2.1Hz,1H,CH),1.88-1 .84(m,1H,CH),1.83-1.81(m,1H,CH),1.80-1.74(m,1H,CH),1.72(d,J=6.9Hz,1H,CH),1.68(d,J=5.9Hz,1H,CH),1.67(s,1H,CH),1.64-1.59(m ,1H,CH),1.58(dd,J=7.3,4.5Hz,1H,CH),1.56-1.49(m,1H,CH),1.04(dd,J=12.6,5.9Hz,1H,CH),0.98(s,3H,CH3),0.83(d,J=6.9Hz,3H,CH3). Specifically as Figure 6 shown.

[0066] like Figure 5 As shown, LC-MS [M + Na] + :415.1738.

[0067] Example 4, Synthesis of Compound V:

[0068] (4) In an organic solvent, the substance represented by Formula IV is subjected to a dehydration elimination reaction in the presence of triphenylphosphine and an elimination agent to form an olefinic bond at the hydroxyl group at the C3 position of the compound represented by Formula IV, thereby obtaining a dihydrogibberellin represented by Formula V;

[0069]

[0070] Under nitrogen protection, 113.4 g (0.289 mol) of the substance represented by formula (Ⅳ) was dissolved in 400 mL of dichloromethane. After sufficient dissolution, 75.8 g (0.289 mol) of triphenylphosphine was added, and 50.3 g (0.289 mol) of diethyl azodicarboxylate was added dropwise. The mixture was stirred at room temperature for 8 hours. After the reaction was completed, 60.92 g (0.448 mol) of zinc chloride was added, the temperature was lowered to 0°C, and the solid was precipitated by stirring. The solid was filtered and washed with 100 ml of dichloromethane. The filtrate layer was extracted with water, dried over anhydrous sodium sulfate, and concentrated to obtain 106.8 g of the compound represented by formula V. The final yield was 98.7%.

[0071] like Figure 6 The structural confirmation data are as follows: 1 H NMR (300MHz, DMSO) δ12.59 (s, 1H, COOH), 5.88-5.81 (m, 1H, = CH), 5.67 (dd, J = 9.3, 2.1Hz, 1H, = CH), 2.62 (d, J = 10.4Hz, 1H,CH),2.48-2.45(m,1H,CH),2.37(d,J=10.3Hz,1H,CH),2.19(q,J=6.8Hz,1H,CH),2.09-2.03(m,1H,CH),2.01(s,1H ,CH),1.96(s,3H,CH3),1.91(s,1H,CH),1.85(d,J=9.7Hz,1H,CH),1.81-1.75(m,1H,CH),1.71(s,1H,CH),1.67(s,1H ,CH),1.65-1.59(m,1H,CH),1.55(d,J=10.8Hz,1H,CH),1.23(s,1H,CH),1.10(s,3H,CH3),0.83(d,J=6.9Hz,3H,CH3).

Claims

1. A novel method for synthesizing dihydrogibberellin, a plant regulator, without protecting the carboxyl group, comprising the following steps: 1) mixing a compound represented by formula II with a catalyst A in an organic solvent B, and reacting them with hydrogenation reduction reaction under a hydrogen atmosphere to obtain a compound represented by formula III; 2) In an organic solvent C, the compound represented by formula III is mixed with a saturated aqueous solution of a base to carry out a selective deacetylation reaction to obtain a compound represented by formula IV; 3) In an organic solvent D, the compound represented by formula IV undergoes a dehydration elimination reaction in the presence of triphenylphosphine and an elimination reagent to obtain the dihydrogibberellin represented by formula V.

2. The synthesis method according to claim 1, characterized in that The compound represented by formula II is prepared according to the following steps: in an organic solvent A, in the presence of an organic base, the gibberellic acid represented by formula I reacts with acetic anhydride to obtain the compound represented by formula II; 3. The synthesis method according to claim 2, characterized in that In the step of preparing the compound represented by formula II, the organic solvent A is pyridine; the organic base includes 4-dimethylaminopyridine; For each mole of gibberellic acid represented by formula I, the volume of the organic solvent used is 1 to 100 L, the molar amount of the organic base is 0.001 to 0.1 mole, and the amount of acetic anhydride can be 1 to 15 moles; The reaction temperature is 10° C. to 80° C., and the reaction time is 4 to 24 hours.

4. The synthesis method according to claim 1 or 2, characterized in that In step 1), the organic solvent B is selected from at least one of ethyl acetate, acetone, methanol, ethanol, tetrahydrofuran and acetonitrile; The amount of the organic solvent B is 1 to 100 L per kilogram of the compound represented by formula II; The catalyst A may be selected from Pd / C or PtO2; The amount of the catalyst A is 0.001 to 0.5 parts by weight per 1 part by weight of the compound represented by formula II; The temperature of the hydrogenation reduction reaction is room temperature; the time is 2 to 12 hours.

5. The synthesis method according to any one of claims 1 to 4, characterized in that In step 2), the organic solvent C is selected from at least one of methanol, ethanol, tetrahydrofuran, acetone, and acetonitrile; The amount of the organic solvent C is 1 to 100 L per kg of the compound represented by formula III added in step 1); The base is selected from at least one of potassium carbonate, sodium carbonate and potassium bicarbonate.

6. The synthesis method according to any one of claims 1 to 5, characterized in that In step 2), the saturated aqueous solution of the base adjusts the pH of the system to 9-10; The temperature of the selective deacetylation reaction is room temperature; the time is 0.2 to 2 hours.

7. The synthesis method according to any one of claims 1 to 6, characterized in that In step 3), the organic solvent D is selected from at least one of dichloromethane, chloroform, 1,2-dichloroethane, toluene, benzene, xylene, isopropyl acetate, ethyl acetate, n-hexane, tetrachloromethane, petroleum ether, chlorobenzene, dioxane and tetrahydrofuran; The elimination reagent is selected from at least one of diethyl azodicarboxylate, dimethyl azodicarboxylate and diisopropyl azodicarboxylate.

8. The synthesis method according to any one of claims 1 to 7, characterized in that In step 3), the amount of the organic solvent D is 1 to 100 L per kilogram of the compound represented by formula IV; the amount of the triphenylphosphine is 0.5 to 5 moles; and the amount of the elimination reagent is 0.5 to 5 moles; The dehydration elimination reaction time is 1 to 24 hours.

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