A method for synthesizing a carboxyl-unprotected dihydrogibberellin plant growth regulator

Abstract

The application discloses a new method for synthesizing dihydrogibberellin without protecting carboxyl. The application provides a new method for synthesizing dihydrogibberellin without protecting carboxyl, which comprises the following steps: 1) mixing a compound shown in formula II with a catalyst A in an organic solvent B, and carrying out a hydrogen reduction reaction under a hydrogen atmosphere to obtain a compound shown in formula III; 2) mixing the compound shown in formula III with a saturated aqueous solution of a base in an organic solvent C, and carrying out a selective deacetylation reaction to obtain a compound shown in formula IV; and 3) mixing the compound shown in formula IV with triphenyl phosphine and an elimination reagent in an organic solvent D, and carrying out a dehydration elimination reaction to obtain dihydrogibberellin shown in formula V. The application can simplify the synthesis method of dihydrogibberellin and is more beneficial to large-scale production and synthesis.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology and relates to a method for synthesizing the plant growth regulator dihydrogibberellin without carboxyl protection. Background Technology

[0002] Dihydrogibberellin is a derivative synthesized from gibberellin A3 (GA3), with the chemical structure exo-16,17-dihydro-13-acetyl-GA5. Dihydrogibberellin is a biodegradable and environmentally friendly plant growth regulator. For example, in greenhouse conditions, applying 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 effect on improving lodging in crops. Applying 25 g of dihydrogibberellin per hectare is approximately equivalent to applying 200 g of calcium cyclamate or 1000 g of chlormequat chloride per hectare (Can. J. Chem. 2004, 82, 293-300.). The mechanism of action of dihydrogibberellin is through competitive inhibition of the substrate of GA3ox (2-ketoglutarate-dependent dioxygenase). Structurally, dihydrogibberellin is similar to GA9 and GA3. 20 They are extremely similar and can bind tightly to the enzyme's binding site, thus enabling GA9 to interact with GA. 20 If the plant cannot be successfully oxidized to produce GA4 and GA1, which have growth-promoting activities, the stem elongation will be inhibited and the plant height will be reduced (Annual review of plantbiology 2008, 59, 225-251; Plant Physiol .2004, 135, 1000-1007.).

[0003] Given the advantages of dihydrogibberellin, such as its high efficiency, low toxicity, plant growth-regulating activity, and environmental friendliness, research on its efficient preparation methods has been receiving continuous attention.

[0004] The synthetic methods reported in the literature are mainly chemical synthesis, which uses gibberellic acid as a raw material and protects the carboxyl group with methyl ester and the hydroxyl group with acetyl group through a series of chemical reactions to obtain the final product dihydrogibberellin (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 synthetic route is long (at least 7 steps), with low overall yield (maximum 30%), poor reproducibility (the ZnCl2-catalyzed reaction for protecting the carboxyl group used by Lewis N. Mander et al. is difficult to reproduce), harsh and dangerous conditions (demethyl ester protection and elimination of methanesulfonate require high-temperature reflux, resulting in significant losses and very low yield), and difficult purification (demethyl ester protection requires a strong base, and harsh conditions lead to the formation of many impurities in the product). Therefore, it cannot be used as a method for the large-scale preparation of dihydrogibberellin. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing dihydrogibberellin, a plant growth regulator, without carboxyl protection. This invention simplifies the synthesis process of dihydrogibberellin and is more conducive to large-scale production synthesis.

[0006] This invention involves acetylation of gibberellic acid to obtain acetylgibberellic acid, followed by hydrogenation reduction of the acetylgibberellic acid double bond in the presence of a specific catalyst without protecting the carboxyl group. The method achieves efficient elimination of the hydroxyl group under unprotected carboxyl conditions, directly yielding the target product. This method is the first to achieve a highly efficient four-step synthesis of dihydrogibberellin with an overall yield of 90% without carboxyl group protection.

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

[0008]

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

[0010]

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

[0012] In this invention, in step 3), the pH of the reaction solution is adjusted by the saturated aqueous solution of the alkali to remove the C3 acetyl group;

[0013] In step 3), the hydroxyl group at the C3 position of the compound shown in formula IV forms an olefin bond.

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

[0015] .

[0016] In this invention, the gibberellic acid of Formula I reacts with acetic anhydride, thereby replacing the hydrogen in C3-OH and C13-OH of Formula I with acetyl groups.

[0017] In the above method, in the step of preparing the compound shown in Formula II, the organic solvent A is pyridine; the organic base includes 4-dimethylaminopyridine;

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

[0019] The reaction temperature can be 10℃~80℃, preferably 30℃~60℃, more preferably 40℃~50℃, and the time can be 4~24 hours, preferably 6~8 hours.

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

[0021] Based on the compound represented by Formula II per kilogram, the amount of organic solvent B can be 1 to 100 L, preferably 2 to 10 L, and more preferably 3 to 5 L;

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

[0023] Based on 1 part by weight of the compound represented by Formula II, the amount of catalyst A 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;

[0024] The hydrogenation reduction reaction is carried out at room temperature and for a duration of 2 to 12 hours, preferably 4 to 6 hours.

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

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

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

[0028] In the above method, in step 2), the pH of the system is adjusted to 9-10 using the saturated aqueous solution of the alkali.

[0029] The selective deacetylation reaction is carried out at room temperature and for a time of 0.2 to 2 hours, preferably 0.5 to 1 hour.

[0030] In this invention, after the reaction in step 2) is completed, the system is post-processed 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, anhydrous sodium sulfate is dried, and the system is concentrated to obtain the compound shown in Formula IV.

[0031] In the above method, in step 3), the organic solvent D is selected from at least one of dichloromethane, trichloromethane, 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, trichloromethane, and 1,2-dichloroethane, and most preferably dichloromethane;

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

[0033] In the above method, in step 3), the amount of organic solvent D used per kilogram of the compound represented by formula IV can be 1~100 L, preferably 2~10 L, more preferably 3~5 L; the amount of triphenylphosphine used can be 0.5~5 mol, preferably 0.8~3 mol, more preferably 1~1.5 mol; and the amount of eliminator used can be 0.5~5 mol.

[0034] The dehydration elimination reaction can take 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 this invention is gibberellic acid (Formula I). ​​The dihydrogibberellin product shown in Formula V is obtained through a four-step reaction, which simplifies the synthesis steps and reduces the production cycle.

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

[0038] (3) The reagents used in this invention are inexpensive, which greatly reduces production costs.

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

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

[0041] In summary, this invention presents a simple, safe, high-yield, and short synthetic route for dihydrogibberellin using readily available and inexpensive gibberellic acid as a raw material. Attached Figure Description

[0042] Figure 1 The 1H NMR spectrum is shown in Example 2.

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

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

[0045] Figure 4 The 1H NMR spectrum is shown in Example 3.

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

[0047] Figure 6 The 1H NMR spectrum is shown in Example 4. Detailed Implementation

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

[0049] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0050] The specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.

[0051] In this invention, unless otherwise stated, the volume values ​​of gases and liquids used are those at one standard atmosphere at 25°C.

[0052] Example 1: Synthesis of Compound II:

[0053]

[0054] 100 g (0.289 mol) of gibberellic acid of Formula I was added to a 1000 mL round-bottom flask, and 400 mL of pyridine was added to dissolve it. 150 g (1.469 mol) of acetic anhydride was slowly added, and the mixture was stirred and heated to 50 °C for 8 hours. After the reaction was completed, the reaction solution was slowly poured into 2 M ice-cold hydrochloric acid solution, and a white solid product precipitated. The pH was adjusted to about 3 with 2 M hydrochloric acid solution, and the mixture was stirred for 1 hour. The mixture was filtered, and the filter cake was washed with water until the pH was about 6. The filter cake was dried to obtain 123.4 g of the compound of 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 shown in Formula II was dissolved in 600 mL of ethyl acetate. After complete dissolution, 7 g (0.05 parts by weight) of 5% Pd / C was added. The mixture was then shaken in a hydrogenation reactor for 6 hours. After the reaction was completed, Pd / C was removed by filtration. Pd / C was washed clean with 100 mL of ethyl acetate and recovered. The filtrate was directly concentrated to obtain 124.7 g of product III, with a final yield of 99.3%.

[0058] The structural verification data is as follows:

[0059] like Figure 1 As shown, 1 H NMR (500 MHz, DMSO) δ 13.07 – 11.69 (m, 1H, COOH), 4.76(q, J = 1.7 Hz, 1H, CH), 3.00 (d, J = 10.7 Hz, 1H, CH), 2.44 (d, J = 10.7 Hz, 1H,CH), 2.20 (q, J = 6.9 Hz, 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 = 4.3 Hz, 1H, CH), 1.92 – 1.89 (m, 1H, CH), 1.88 – 1.84 (m, 1H, CH), 1.83 (d, J= 6.6 Hz, 1H,CH), 1.80 – 1.74(m, 1H,CH), 1.73 (d, J = 5.4 Hz, 1H, CH), 1.70 (s, 1H, CH), 1.69 – 1.65 (m, 1H, CH), 1.63 (dd, J = 10.1, 3.0 Hz, 1H, CH), 1.61 – 1.55 (m, 1H, CH), 1.06 (dd, J =12.6, 5.8 Hz, 1H, CH), 0.94 (d, J = 3.3 Hz, 3H, CH3), 0.84 (d, J = 7.0 Hz, 3H,CH3).

[0060] like Figure 2 As shown, 13 C NMR (126 MHz, DMSO) δ 176.82, 173.37, 170.36, 170.13,93.70, 85.06, 71.25, 53.44, 53.13, 52.26, 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 IV:

[0063]

[0064] 129.4 g (0.289 mol) of the substance shown in Formula III was dissolved in 500 mL of methanol. After complete dissolution, a saturated potassium carbonate aqueous solution was slowly added dropwise to adjust the pH of the reaction system 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 to adjust the pH of the system to between 6 and 7. Methanol was removed by vacuum distillation, followed by extraction with dichloromethane and water, drying with anhydrous sodium sulfate, and concentration to obtain 115.2 g of product IV, with a final yield of 98.6%.

[0065] like Figure 4 As shown, the structural confirmation data is as follows: 1H NMR (500 MHz, DMSO) δ 12.47 (s, 1H,COOH), 5.33 (d, J = 4.5 Hz, 1H, OH), 3.34 (s, 1H, CH), 3.01 (d, J = 10.7 Hz, 1H, CH), 2.39 (d, J = 10.7 Hz, 1H, CH), 2.20 (q, J = 7.0 Hz, 1H, CH), 2.05 (ddd, J =13.8, 7.7, 2.5 Hz, 1H, CH), 2.02 – 1.97 (m, 1H, CH), 1.96 (s, 3H, CH3), 1.90(dd, J = 10.8, 2.1 Hz, 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 = 6.9 Hz, 1H, CH), 1.68 (d, J = 5.9 Hz,1H, CH), 1.67 (s, 1H, CH), 1.64 – 1.59 (m, 1H, CH), 1.58 (dd, J = 7.3, 4.5 Hz,1H, CH), 1.56 – 1.49 (m, 1H, CH), 1.04 (dd, J = 12.6, 5.9 Hz, 1H, CH), 0.98 (s,3H, CH3), 0.83 (d, J = 6.9 Hz, 3H, CH3). Specifically, as follows: Figure 6 As 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 shown in Formula IV undergoes a dehydration elimination reaction at the C3 position of the compound shown in Formula IV in the presence of triphenylphosphine and an elimination reagent to form an olefin bond, thereby obtaining dihydrogibberellin shown in Formula V.

[0069]

[0070] Under nitrogen protection, 113.4 g (0.289 mol) of the substance shown in formula (Ⅳ) was dissolved in 400 mL of dichloromethane. After complete dissolution, 75.8 g (0.289 mol) of triphenylphosphine was added, followed by dropwise addition of 50.3 g (0.289 mol) of diethyl azodicarbonate. 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 mixture was cooled to 0 °C, stirred, and a solid precipitated. The solid was filtered, washed with 100 mL of dichloromethane, and the filtrate was extracted with water, dried over anhydrous sodium sulfate, and concentrated to obtain 106.8 g of the compound shown in formula (Ⅳ), with a final yield of 98.7%.

[0071] like Figure 6 As shown, the structural confirmation data is as follows: 1 H NMR (300 MHz, DMSO) δ 12.59 (s, 1H,COOH), 5.88 – 5.81 (m, 1H, =CH), 5.67 (dd, J = 9.3, 2.1 Hz, 1H, =CH), 2.62 (d, J = 10.4 Hz, 1H, CH), 2.48 – 2.45 (m, 1H, CH), 2.37 (d, J = 10.3 Hz, 1H, CH), 2.19 (q, J = 6.8 Hz, 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 = 9.7 Hz, 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 = 10.8 Hz, 1H, CH), 1.23 (s, 1H, CH), 1.10 (s, 3H, CH3), 0.83 (d, J = 6.9Hz, 3H, CH3).

Claims

1. A method for synthesizing dihydrogibberellin, a plant growth regulator, without carboxyl protection, comprising the following steps: 1) In an organic solvent B, the compound shown in Formula II is mixed with catalyst A, and under a hydrogen atmosphere, a hydrogenation reduction reaction is carried out to obtain the compound shown in Formula III; ； 2) In organic solvent C, the compound shown in Formula III is mixed with a saturated aqueous solution of a base to carry out a selective deacetylation reaction to obtain the compound shown in Formula IV; ； In step 2), the organic solvent C is selected from at least one of methanol, ethanol, tetrahydrofuran, acetone, and acetonitrile; Based on the amount of organic solvent C added per kilogram of the compound represented by formula III in step 1), the amount of organic solvent C used is 1~100L; The alkali is selected from at least one of potassium carbonate, sodium carbonate, and potassium bicarbonate; In step 2), the pH of the system is adjusted to 9-10 using the saturated aqueous solution of the alkali; The selective deacetylation reaction was carried out at room temperature for 0.2 to 2 hours. 3) In organic solvent D, the compound shown in formula IV undergoes a dehydration elimination reaction in the presence of triphenylphosphine and an elimination reagent to obtain dihydrogibberellin shown in formula V.

2. The method according to claim 1, characterized in that, The compound shown in Formula II is prepared by the following steps: in organic solvent A, in the presence of an organic base, gibberellic acid of Formula I reacts with acetic anhydride to obtain the compound shown in Formula II; 。 3. The method according to claim 2, characterized in that, In the steps 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 of 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 mol, and the amount of acetic anhydride used is 1 to 15 mol. The reaction temperature is 10℃~80℃, and the time is 4~24 hours.

4. The 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 organic solvent B used is 1 to 100 L per kilogram of the compound represented by Formula II; The catalyst A is selected from Pd / C or PtO2; The amount of catalyst A is 0.001 to 0.5 parts by weight per 1 part by weight of the compound represented by Formula II; The hydrogenation reduction reaction is carried out at room temperature for 2 to 12 hours.

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

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

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