Application of curcumol derivatives in the preparation of drugs for preventing and treating phytopathogenic fungi

Abstract

The present invention provides a curcumol derivative, a preparation method thereof, and an application thereof in the preparation of drugs for preventing and treating wheat head blight, sheath blight of rice, black shank of tobacco, Phomopsis disease and rice blast. It has good antibacterial activity against Rhizoctonia solani of rice, Phytophthora parasitica var. nicotianae of tobacco, Phomopsis sp. and Magnaporthe oryzae, and has good control effects on plant pathogenic fungal diseases such as Rhizoctonia solani of rice, Phytophthora parasitica var. nicotianae of tobacco, Phomopsis sp. and Magnaporthe oryzae, and has broad application prospects and development potential.

Description

Technical Field

[0001] The present invention relates to the technical field of the application of compounds, and particularly relates to the application of a curcumol derivative in the preparation of a drug for preventing and treating phytopathogenic fungi. Background Art

[0002] Phytopathogenic bacteria are the number one killer causing the reduction of the yields of major food and cash crops. Wheat, rice, tobacco, kiwifruit, etc. are all invaded by phytopathogenic bacteria. Among them, wheat, as one of the main food crops in China, has a planting area second only to rice. Wheat scab (Fusarium graminearum, commonly known as ear blight, rotten wheat head, red wheat head) is one of the most harmful diseases in the high-quality production of wheat in China.

[0003] The pathogen of rice sheath blight (T. cucumeris) belongs to fungi of the Deuteromycota phylum and has strong parasitism. It mainly uses sclerotia surviving in the soil as the primary infection source and is one of the most destructive fungal diseases worldwide. The sclerotia in the soil still have a germination rate of 12% for those over 11 years old. When crops are infected with rice sheath blight, the leaves, leaf ears, and roots and stems will all be damaged. In the initial stage, dark green small markings appear on the leaves and then evolve into cloud patterns, with brown in the middle of the markings. In the later stage, the internal tissues of the rice are damaged, and semi-transparent leaves with dark brown edges appear, and finally the leaves turn yellow and wither. After being infected with rice sheath blight, rice will have difficulty in heading, an increase in empty grains during heading, and a decrease in the weight of produced grains.

[0004] Rice blast is caused by the infection of the filamentous ascomycete fungus Magnaporthe oryzae. It infects rice at different stages to form seedling blast, leaf blast, panicle neck blast, and grain blast. Among them, panicle neck blast has the greatest impact on the yield loss of rice and is one of the main diseases seriously threatening the safe production of rice globally. Magnaporthe oryzae can parasitize more than 50 gramineous plants including rice, wheat, millet, and other cash crops. This disease has regional epidemicity and is extremely likely to break out and cause disasters in a suitable environment. The yield loss caused by rice blast every year accounts for 10% - 30% of the total rice yield, and in severely affected areas and years, the yield loss even reaches more than 80%.

[0005] Tobacco black shank, commonly known as "tobacco black root" and "black stalk madness", is an important soil-borne fungal disease that harms tobacco caused by Phytophthora parasitica. Since it was first reported in the Huanghuai tobacco-growing area of China in 1950, it has become one of the main soil-borne diseases in China. When it is severe, the incidence rate reaches more than 75%, seriously affecting the yield and quality of tobacco in China.

[0006] Phomopsis is a large genus of fungi in the family Sphaeropsidaceae of the class Coelomycetes, containing more than 100 different species, and can parasitize more than 70 plants of different families. The pathogens of this genus are widely distributed geographically, causing serious diseases such as leaf blight, twig blight, stem rot, canker and fruit rot of plants, resulting in significant economic losses. The pathogen Phomopsis sp. was isolated and purified from kiwifruit.

[0007] At present, the control of plant pathogenic bacteria mainly relies on chemical pesticides, but they have many side effects. For example, prochloraz is a widely used chemical fungicide, but some studies have found that some of its metabolites such as 2,4,6-trichlorophenoxyacetic acid are carcinogenic, mutagenic, carcinogenic and toxic, and are environmental pollutants. In addition, long-term use of chemical pesticides such as carbendazim and thiophanate-methyl is likely to increase the drug resistance of pathogenic bacteria, resulting in pesticide residues, environmental pollution and ecological balance destruction.

[0008] With the proposal of the concept of "green plant protection", plant-derived pesticides can decompose naturally and are not prone to produce drug resistance. The development of environmentally friendly, safe, low-toxic and highly effective plant-derived pesticides has been increasingly emphasized. In the prior art, Chinese patent documents with application numbers 202110225360.1 and 202010090869.5 reported the application of sesquiterpene derivatives in the preparation of drugs for controlling wheat scab. Using curcumol in curcuma oil as a precursor, a pseudo-natural product can be used to control wheat scab.

[0009] The present inventors considered that as a chiral compound, curcumol was modified, and the obtained derivatives might have a selective inhibitory effect on pathogenic bacteria of different genera. Therefore, we continued to carry out the preparation of a series of derivatives with other acyl groups introduced after introducing a chloroacetyl group at the 8-position hydroxyl group in the early stage, and explored whether it also had good control effects on plant pathogenic fungal diseases such as Rhizoctonia solani (T. cucumeris), Phytophthora parasitica var. nicotianae (P. var nicotianae), Phomopsis sp. and Magnaporthe oryzae (P. oryzae). Summary of the Invention

[0010] The technical problem solved by the present invention is to provide a curcumol derivative, its preparation method and its application in the preparation of drugs for controlling wheat scab, sheath blight of rice, black shank of tobacco, Phomopsis disease and rice blast, which has good control effects on plant pathogenic fungal diseases such as Rhizoctonia solani, Phytophthora parasitica var. nicotianae, Phomopsis sp. and Magnaporthe oryzae.

[0011] In view of this, the present invention provides an application of a curcumol derivative in the preparation of a drug for controlling wheat scab, and the curcumol derivative has the structure shown in Formula 1:

[0012]

[0013] Among them, R is any one of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27.

[0014]

[0015]

[0016] The present invention also provides an application of a curcumol derivative in the preparation of a drug for preventing and treating sheath blight of rice. The curcumol derivative has the structure shown in Formula 1:

[0017]

[0018] Among them, R is any one of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27.

[0019]

[0020] The present invention also provides an application of a curcumol derivative in the preparation of a drug for preventing and treating black shank of tobacco. The curcumol derivative has the structure shown in Formula 1:

[0021]

[0022] Among them, R is any one of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27.

[0023]

[0024] The present invention also provides an application of a curcumol derivative in the preparation of a drug for preventing and treating Phomopsis disease. The curcumol derivative has the structure shown in Formula 1:

[0025]

[0026] Among them, R is any one of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27.

[0027]

[0028] The present invention also provides an application of a curcumol derivative in the preparation of a rice blast drug, and the curcumol derivative has the structure shown in Formula 1:

[0029]

[0030] Among them, R is any one of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27.

[0031]

[0032] Preferably, the dosage form of the drug is one of powder, suspending agent, granule, water dispersible agent and microemulsion.

[0033] The present invention also provides a preparation method of a curcumol derivative, comprising the following steps: performing an oxidation reaction on curcumol under the action of a complex oxidant composed of ruthenium trichloride, sodium periodate and 2,6-dimethylpyridine to obtain a colorless transparent liquid Z-1, then introducing a double bond to obtain an intermediate M, and finally performing acylation to obtain the curcumol derivative.

[0034] Preferably, the colorless transparent liquid Z-1 is prepared as follows: take curcumol, ruthenium trichloride, sodium periodate and 2,6-dimethylpyridine and add them into a reaction flask, then add an acetonitrile dichloromethane water mixed solution, stir at room temperature, track by TLC until the reaction is complete, wash successively with saturated sodium bisulfite and saturated brine, simultaneously add DCM for extraction successively, dry the DCM with anhydrous sodium sulfate and then concentrate under reduced pressure, and obtain the colorless transparent liquid Z-1 after column chromatography.

[0035] Preferably, the intermediate M is prepared as follows: react the colorless transparent liquid Z-1, 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, paraformaldehyde and the catalyst i-Pr2NH·TFA at 70 °C, track by TLC until the reaction is complete, wash with saturated tartaric acid and saturated brine, dry with anhydrous sodium sulfate and then concentrate under reduced pressure, scrape, and obtain the intermediate M after column chromatography.

[0036] The present invention also provides a curcumol derivative, which has the structure shown in Formula 1:

[0037]

[0038] Wherein, R is any one of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27;

[0039]

[0040] The present invention provides a curcumol derivative, its preparation method, and its application in the preparation of drugs for preventing and treating wheat head blight, rice sheath blight, tobacco black shank, Phomopsis disease, and rice blast. It has good antibacterial activity against Rhizoctonia solani, Phytophthora parasitica var. nicotianae, Phomopsis sp., and Magnaporthe oryzae, and has good control effects on plant pathogenic fungal diseases such as Rhizoctonia solani, Phytophthora parasitica var. nicotianae, Phomopsis sp., and Magnaporthe oryzae, and has broad application prospects and development potential. Detailed Embodiments

[0041] To further understand the present invention, the preferred embodiments of the present invention will be described below in conjunction with examples. However, it should be understood that these descriptions are only for further explaining the features and advantages of the present invention, rather than limiting the claims of the present invention.

[0042] The present invention uses the sesquiterpene extract contained in curcuma oil, and the isolated and identified curcumol (Curcumol, CAS: 4871-97-0, molecular formula: C 15 H 24 O 2 , molecular weight: 236.3, structural formula as follows) as the raw material to synthesize a series of sesquiterpene derivatives, and screen out compounds with better antifungal activity against crops.

[0043]

[0044] As a preferred scheme, the curcumol derivative is prepared according to the following method: Curcumol is oxidized under the action of a complex oxidant composed of RuCl 3 (ruthenium trichloride), NaIO 4 (sodium periodate) and 2,6-Lutidine (2,6-dimethylpyridine), then a double bond is introduced, and finally acylation is carried out. The synthetic route and general formula are as follows.

[0045]

[0046]

[0047] Among them,

[0048]

[0049] The five pathogenic bacteria of plant pathogenic fungi, namely Rhizoctonia solani of rice, Phytophthora parasitica var. nicotianae of tobacco, Phomopsis sp., Magnaporthe oryzae of rice and Gibberella zeae of wheat, belong to plant pathogenic bacteria of different genera. Since curcumol is a chiral compound, derivatives obtained by modifying it have selective inhibitory effects on pathogenic bacteria of different genera.

[0050] To further understand the present invention, the technical solutions provided by the present invention will be described in detail below in conjunction with embodiments, and the protection scope of the present invention is not limited by the following embodiments.

[0051] The raw materials used in the embodiments of the present invention are all commercially available.

[0052] Example 1

[0053] Preparation of Intermediate Z-1 and M

[0054] Take 100 mg (0.424 mmol) of curcumol, RuCl 3 (ruthenium trichloride), NaIO 4 (sodium periodate) and 2,6-Lutidine (2,6-dimethylpyridine) and add them to a 50 mL reaction flask, then add 20 mL of a mixed solution of acetonitrile dichloromethane water (CH 3 CN:DCM:H 2 O = 0.75:0.75:1), stir at room temperature, and monitor the reaction by TLC until it is complete. After the reaction is complete, wash it successively with saturated sodium bisulfite and saturated brine, extract it with DCM at the same time successively, dry the DCM with anhydrous sodium sulfate, and then concentrate it under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain a colorless transparent liquid Z-1 (85 mg, yield 84.3%).

[0055] 1 1H-NMR(CDCl 3 , 400 MHz) δ: 2.71 (2H, m, H-7), 2.30 (2H, m, H-4), 1.04 (3H, d, J = 6.8 Hz, H-12), 0.98 (3H, d, J = 6.4 Hz, H-13), 0.89 (3H, d, J = 6.4 Hz, H-11). 13 13C-NMR(CDCl 3, 100 MHz) δ: 211.2 (C-10), 104.8 (C-8), 86.7 (C-5), 60.7 (C-1), 56.1 (C-7), 46.6 (C-4), 40.0 (C-9), 35.1 (C-6), 30.9 (C-3), 30.0 (C-11), 26.6 (C-2), 22.7 (C-12), 21.0 (C-13), 11.8 (C-14); ESI MS m / z: 238.1 [M+Na] + 。

[0056] Take Z-1 (100 mg, 0.420 mmol), 3 - 4 mL of 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, paraformaldehyde (0.840 mmol) and catalyst i-Pr2NH·TFA (0.420 mmol), react at 70 °C, monitor the reaction by TLC until completion, wash with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, scrape, and obtain white solid M (90 mg, yield 85.7%) by column chromatography (petroleum ether: ethyl acetate = 10:1).

[0057] 1 1H NMR (600 MHz, Chloroform-d) δ 6.25 (d, J = 1.3 Hz, 1H, H-1’), 5.72 (d, J = 1.3 Hz, 1H, H-1’), 0.98 (d, J = 6.5 Hz, 3H, H-11), 0.86 (d, J = 6.3 Hz, 3H, H-10), 0.82 (d, J = 6.6 Hz, 3H, H-13); 13 13C NMR (150 MHz, CDCl 3 ) δ 200.75 (C-10), 144.63 (C-9), 121.86 (C-14), 105.43 (C-8), 86.18 (C-5), 59.93 (C-7), 56.45 (C-1), 40.87 (C-4), 35.38 (C-6), 30.97 (C-3), 29.79 (C-11), 27.12 (C-2), 22.41 (C-12), 20.56 (C-13), 11.61 (C-15); ESI MS m / z: 273.1 [M+Na] + , 523.2 [2M+Na] + 。

[0058] Example 2

[0059] Preparation of Derivative C1

[0060] In a 50 mL reaction flask, intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol) were added. Then 20 mL of DCM was added, and the mixture was stirred at room temperature for 30 min. Subsequently, p-toluoyl chloride (0.8 - 1.2 mmol) was added, and the mixture was stirred at room temperature. The reaction was monitored by TLC until completion. The reaction was quenched with water, washed successively with saturated tartaric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. White powder C1 was obtained by column chromatography (petroleum ether: ethyl acetate = 100:1).

[0061] 1 H NMR (600 MHz, Chloroform-d) δ 7.94 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 7.7 Hz, 2H), 6.39 (s, 1H), 5.58 (s, 1H), 2.63–2.51 (m, 2H), 2.42 (s, 3H), 2.38 (t, J = 12.8 Hz, 1H), 2.13–2.05 (m, 1H), 2.01–1.92 (m, 3H), 1.67–1.57 (m, 1H), 1.45–1.38 (m, 2H), 1.07 (d, J = 6.1 Hz, 3H), 1.01 (d, J = 6.2 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.77, 163.04, 144.19, 141.67, 129.96, 129.36, 127.93, 121.65, 108.23, 87.75, 59.99, 54.45, 41.21, 34.07, 31.05, 29.45, 27.26, 22.49, 21.83, 21.17, 11.59; ESI-MS m / z: 391.2 [M+Na] + , 759.3 [2M+Na] + .

[0062] Example 3

[0063] Preparation of Derivative C2

[0064] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add cyclopropanecarbonyl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C2 by column chromatography (petroleum ether:ethyl acetate = 100:1).

[0065] 1 H NMR (600 MHz, Chloroform - d) δ 6.32 (s, 1H), 5.53 (s, 1H), 2.51–2.44 (m, 2H), 2.31 (t, J = 12.5 Hz, 1H), 2.04 (dddd, J = 12.9, 10.4, 8.4, 5.9 Hz, 1H), 1.97–1.90 (m, 2H), 1.89–1.81 (m, 1H), 1.65 (td, J = 8.1, 4.0 Hz, 1H), 1.57 (tdd, J = 11.0, 5.4, 3.3 Hz, 1H), 1.38–1.29 (m, 2H), 1.05–1.01 (m, 5H), 0.92 (d, J = 6.3 Hz, 3H), 0.88 (dd, J = 7.5, 2.5 Hz, 5H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.87, 171.24, 141.81, 121.39, 107.83, 87.58, 59.95, 53.58, 41.10, 34.07, 31.01, 29.38, 27.23, 22.44, 20.85, 14.00, 11.53, 8.78, 8.68; ESI - MS m / z: 341.2 [M + Na] + , 659.3 [2M + Na] + .

[0066] Example 4

[0067] Preparation of Derivative C3

[0068] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add 4-chlorobenzoyl chloride (4-Chlorobenzoyl Chloride, 0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C3 by column chromatography (petroleum ether:ethyl acetate = 100:1).

[0069] 1 H NMR (600 MHz, Chloroform-d) δ 7.98 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 6.40 (s, 1H), 5.55 (s, 1H), 2.60–2.52 (m, 2H), 2.38 (t, J = 12.4 Hz, 1H), 2.09 (ddd, J = 14.1, 9.2, 4.6 Hz, 1H), 1.96 (dddt, J = 17.0, 12.3, 7.4, 4.2 Hz, 3H), 1.65–1.57 (m, 2H), 1.45–1.38 (m, 2H), 1.06 (d, J = 6.1 Hz, 3H), 1.00 (d, J = 6.3 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.52, 162.10, 141.46, 139.95, 131.26, 129.09, 129.03, 121.68, 108.47, 87.89, 59.93, 54.53, 41.21, 34.03, 31.05, 29.40, 27.25, 22.45, 21.19, 11.57; ESI-MS m / z: C 22 H 25 ClO 4 : 388.89, found 411.5 [M+Na] + , 799.7 [2M+Na] + .

[0070] Example 5

[0071] Preparation of Derivative C4

[0072] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add acryloyl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate and concentrate under reduced pressure. Obtain white powder C4 by column chromatography (petroleum ether: ethyl acetate = 100:1).

[0073] 1 H NMR (600 MHz, Chloroform - d) δ 6.42 (d, J = 17.3 Hz, 1H), 6.35 (s, 1H), 6.13 (dd, J = 17.3, 10.5 Hz, 1H), 5.88 (d, J = 10.5 Hz, 1H), 5.52 (s, 1H), 2.52 (td, J = 10.8, 10.2, 8.0 Hz, 2H), 2.34 (t, J = 12.5 Hz, 1H), 2.10–2.03 (m, 1H), 1.98–1.91 (m, 2H), 1.88 (ddd, J = 13.6, 9.7, 3.8 Hz, 1H), 1.57 (ddd, J = 16.3, 9.1, 3.9 Hz, 1H), 1.36 (ddd, J = 23.8, 12.4, 7.0 Hz, 2H), 1.05 (d, J = 6.2 Hz, 3H), 0.92 (d, J = 6.3 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.72, 162.50, 141.58, 131.58, 129.22, 121.59, 108.14, 87.73, 59.94, 53.82, 41.15, 34.05, 31.04, 29.38, 27.25, 22.43, 20.86, 11.54; ESI - MS m / z: 327.1 [M + Na] + ,631.3 [2M + Na] + 。

[0074] Example 6

[0075] Preparation of Derivative C5

[0076] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add 4-chlorobutanoyl chloride (4-Chlorobutanoyl Chloride, 0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C5 by column chromatography (petroleum ether: ethyl acetate = 100:1).

[0077] 1 H NMR (600 MHz, Chloroform-d) δ 6.33 (s, 1H), 5.52 (s, 1H), 3.61 (td, J = 6.4, 1.4 Hz, 2H), 2.58 (t, J = 7.2 Hz, 2H), 2.52–2.45 (m, 2H), 2.33 (t, J = 12.4 Hz, 1H), 2.12–2.04 (m, 3H), 1.98–1.91 (m, 2H), 1.88–1.82 (m, 1H), 1.55 (tdd, J = 13.6, 10.6, 6.9 Hz, 1H), 1.39–1.29 (m, 2H), 1.04 (d, J = 6.2 Hz, 3H), 0.90 (dd, J = 10.2, 6.5 Hz, 6H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.70, 169.12, 141.72, 121.49, 108.10, 87.68, 59.87, 53.55, 44.06, 41.11, 34.06, 32.24, 31.03, 29.34, 27.36, 27.23, 22.40, 20.88, 11.53; ESI-MS m / z: 377.1 [M+Na] + , 731.2 [2M+Na] + .

[0078] Example 7

[0079] Preparation of Derivative C6

[0080] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add trans-crotonoyl chloride (E-Crotonoyl chloride, 0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C6 by column chromatography (petroleum ether: ethyl acetate = 100:1).

[0081] 1 H NMR (600 MHz, Chloroform-d) δ 7.00 (m, 1H), 6.34 (s, 1H), 5.86 (dd, J = 15.6, 1.7 Hz, 1H), 5.52 (s, 1H), 2.53–2.47 (m, 2H), 2.33 (t, J = 12.5 Hz, 1H), 2.09–2.02 (m, 1H), 1.94 (td, J = 7.4, 3.1 Hz, 2H), 1.93–1.84 (m, 5H), 1.60–1.52 (m, 1H), 1.40–1.29 (m, 2H), 1.05 (d, J = 6.1 Hz, 3H), 0.92 (d, J = 6.3 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.76, 162.69, 145.70, 141.63, 123.30, 121.39, 107.77, 87.46, 59.83, 53.71, 41.01, 33.93, 30.91, 29.27, 27.11, 22.32, 20.76, 18.08, 11.42; ESI-MS m / z: 341.1 [M+Na] + , 659.3 [2M+Na] + .

[0082] Example 8

[0083] Preparation of Derivative C7

[0084] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add 3,5 - dimethylisoxazole - 4 - carboxylic acid (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C7 by column chromatography (petroleum ether: ethyl acetate = 100:1).

[0085] 1 H NMR (600 MHz, Chloroform - d) δ 6.41 (s, 1H), 5.50 (s, 1H), 2.67 (s, 3H), 2.56–2.49 (m, 1H), 2.45 (s, 3H), 2.44 - 2.48 (m, 1H), 2.36 (t, J = 12.4 Hz, 1H), 2.14–2.05 (m, 1H), 2.00–1.91 (m, 3H), 1.63 - 1.56 (m, 1H), 1.42 (dd, J = 12.9, 7.3 Hz, 2H), 1.05 (d, J = 6.0 Hz, 3H), 0.97 (d, J = 6.3 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.27, 175.67, 159.94, 158.81, 141.29, 121.69, 109.14, 108.69, 87.80, 59.70, 55.00, 41.21, 34.04, 31.04, 29.46, 27.26, 22.34, 21.60, 13.90, 12.30, 11.54; ESI - MS m / z: 396.1 [M + Na] + , 769.2 [2M + Na] + .

[0086] Example 9

[0087] Preparation of Derivative C8

[0088] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add 2-furoyl chloride (2-Furoyl Chloride, 0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C8 by column chromatography (petroleum ether:ethyl acetate = 100:1).

[0089] 1 H NMR (600 MHz, Chloroform-d) δ 7.60 (d, J = 1.0 Hz, 1H), 7.19 (d, J = 3.2 Hz, 1H), 6.52 (dd, J = 3.5, 1.7 Hz, 1H), 6.39 (s, 1H), 5.65 (s, 1H), 2.63 (td, J = 11.6, 7.4 Hz, 1H), 2.53 (t, J = 9.9 Hz, 1H), 2.38 (t, J = 12.5 Hz, 1H), 2.13–2.03 (m, 1H), 2.00–1.92 (m, 3H), 1.94–1.86 (m, 1H), 1.60 (td, J = 5.5, 2.8 Hz, 2H), 1.45–1.33 (m, 2H), 1.07 (d, J = 6.1 Hz, 3H), 0.97 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.63, 154.96, 146.91, 144.95, 141.56, 121.88, 118.58, 112.04, 108.65, 87.88, 59.99, 53.89, 41.15, 34.04, 31.06, 29.44, 27.27, 22.44, 20.87, 11.56; ESI-MS m / z: 367.2 [M+Na] + ,711.3 [2M+Na] + 。

[0090] Example 10

[0091] Preparation of Derivative C9

[0092] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add 3-chlorobenzoyl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C9 by column chromatography (petroleum ether:ethyl acetate = 100:1).

[0093] 1 H NMR (600 MHz, Chloroform-d) δ 8.01 (t, J = 1.9 Hz, 1H), 7.93 (dt, J = 7.8, 1.4 Hz, 1H), 7.56 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 6.41 (s, 1H), 5.56 (s, 1H), 2.61–2.52 (m, 2H), 2.39 (t, J = 12.5 Hz, 1H), 2.15–2.06 (m, 1H), 2.02–1.89 (m, 3H), 1.65–1.55 (m, 1H), 1.46–1.38 (m, 2H), 1.06 (d, J = 6.1 Hz, 3H), 1.01 (d, J = 6.3 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.46, 161.71, 141.37, 134.82, 133.45, 132.39, 129.99, 128.00, 121.72, 108.58, 87.92, 59.93, 54.52, 41.20, 34.02, 31.05, 29.41, 27.26, 22.44, 21.18, 11.56; ESI-MS m / z: 411.1 [M+Na] + ,799.3 [2M+Na] + 。

[0094] Example 11

[0095] Preparation of Derivative C10

[0096] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add benzoyl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor by TLC until the reaction is complete, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C10 by column chromatography (petroleum ether:ethyl acetate = 100:1).

[0097] 1 H NMR (600 MHz, Chloroform - d) δ8.06 (d, J = 6.8 Hz, 1H), 7.59 (t, J = 7.4 Hz, 0H), 7.46 (t, J = 7.8 Hz, 1H), 6.40 (s, 1H), 5.59 (s, 1H), 2.63–2.52 (m, 2H), 2.39 (t, J = 12.4 Hz, 1H), 2.09 (ddd, J = 13.1, 9.2, 4.5 Hz, 1H), 2.00–1.92 (m, 3H), 1.67–1.57 (m, 1H), 1.46–1.38 (m, 2H), 1.07 (d, J = 6.1 Hz, 3H), 1.02 (d, J = 6.3 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ199.72, 162.94, 141.58, 133.42, 130.66, 129.91, 128.65, 121.70, 108.34, 87.81, 59.98, 54.52, 41.21, 34.07, 31.06, 29.45, 27.27, 22.49, 21.19, 11.58; ESI - MS m / z: 377.2 [M+Na] + ,731.5 [2M+Na] + 。

[0098] Example 12

[0099] Preparation of Derivative C11

[0100] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add 2-chlorobenzoyl chloride (2-Chlorobenzoyl Chloride, 0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C11 by column chromatography (petroleum ether: ethyl acetate = 100:1).

[0101] 1 H NMR (600 MHz, Chloroform-d) δ 7.87 (dd, J = 7.8, 1.7 Hz, 1H), 7.48–7.42 (m, 2H), 7.33 (td, J = 7.5, 1.5 Hz, 1H), 6.40 (s, 1H), 5.66 (s, 1H), 2.68 (td, J = 11.6, 7.2 Hz, 1H), 2.55 (t, J = 9.48 Hz 1H), 2.41 (t, J = 12.6 Hz, 1H), 2.14–2.04 (m, 1H), 2.01–1.90 (m, 3H), 1.66–1.54 (m, 1H), 1.47–1.34 (m, 2H), 1.08 (d, J = 6.2 Hz, 3H), 0.96 (d, J = 6.3 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.68, 161.72, 141.48, 134.12, 132.89, 131.64, 131.42, 130.41, 126.79, 121.82, 109.10, 87.91, 59.95, 53.87, 41.17, 34.14, 31.09, 29.49, 27.33, 22.44, 21.17, 11.58; ESI-MS m / z: 411.1 [M+Na] + ,799.3 [2M+Na] + 。

[0102] Example 13

[0103] Preparation of Derivative C12

[0104] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add cinnamoyl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C12 by column chromatography (petroleum ether: ethyl acetate = 100:1).

[0105] 1 H NMR (600 MHz, Chloroform - d) δ 7.71 (d, J = 16.0 Hz, 1H), 7.53 (dd, J = 6.7, 2.9 Hz, 2H), 7.40 (p, J = 3.4, 2.9 Hz, 3H), 6.45 (d, J = 16.0 Hz, 1H), 6.38 (s, 1H), 5.59 (s, 1H), 2.60–2.50 (m, 2H), 2.37 (t, J = 12.4 Hz, 1H), 2.13–2.04 (m, 1H), 2.01–1.87 (m, 3H), 1.65–1.56 (m, 1H), 1.44–1.33 (m, 2H), 1.07 (d, J = 6.1 Hz, 3H), 0.97 (d, J = 6.3 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.69, 163.26, 145.77, 141.59, 134.21, 130.56, 128.95, 128.22, 121.50, 118.50, 108.03, 87.56, 59.84, 53.82, 41.05, 33.96, 30.94, 29.31, 27.14, 22.34, 20.84, 11.45; ESI - MS m / z: 403.1 [M + Na] + , 783.3 [2M + Na] + .

[0106] Example 14

[0107] Preparation of Derivative C13

[0108] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add octanoyl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C13 by column chromatography (petroleum ether: ethyl acetate = 100:1).

[0109] 1 H NMR (600 MHz, Chloroform - d) δ 6.32 (d, J = 1.1 Hz, 1H), 5.52 (d, J = 1.1 Hz, 1H), 2.54–2.46 (m, 2H), 2.38–2.29 (m, 3H), 2.05 (tdd, J = 10.3, 8.3, 5.9 Hz, 1H), 1.97–1.89 (m, 2H), 1.90–1.81 (m, 1H), 1.63 (p, J = 7.5 Hz, 2H), 1.40–1.23 (m, 11H), 1.04 (d, J = 6.2 Hz, 3H), 0.92–0.85 (m, 9H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.92, 170.22, 141.95, 121.33, 107.89, 87.56, 59.94, 53.41, 41.12, 35.50, 34.15, 31.79, 31.06, 29.39, 29.14, 29.06, 27.26, 24.77, 22.73, 22.44, 20.87, 14.20, 11.54; ESI - MS m / z: 399.2 [M + Na] + ,775.5 [2M + Na] + 。

[0110] Example 15

[0111] Preparation of Derivative C14

[0112] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add myristoyl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography (petroleum ether: ethyl acetate = 100:1) to obtain white powder CU-15.

[0113] 1 H NMR (600 MHz, Chloroform-d) δ 6.32 (d, J = 1.1 Hz, 1H), 5.52 (d, J = 1.1 Hz, 1H), 2.54–2.46 (m, 2H), 2.38–2.29 (m, 3H), 2.10–2.01 (m, 1H), 1.97–1.90 (m, 2H), 1.91–1.81 (m, 1H), 1.56 (dtt, J = 11.2, 5.4, 2.4 Hz, 1H), 1.40–1.23 (m, 24H), 1.04 (d, J = 6.2 Hz, 3H), 0.91–0.86 (m, 9H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.92, 170.22, 141.95, 121.33, 107.89, 87.56, 59.94, 53.41, 41.12, 35.51, 34.15, 32.06, 31.06, 29.81, 29.79, 29.74, 29.60, 29.50, 29.41, 29.39, 29.19, 27.27, 24.77, 22.83, 22.44, 20.88, 14.26, 11.55; ESI-MS m / z: 483.4 [M+Na] + , 943.5 [2M+Na] + .

[0114] Example 16

[0115] Preparation of Derivative C15

[0116] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add 3-fluorobenzoyl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C15 by column chromatography (petroleum ether: ethyl acetate = 100:1).

[0117] 1 H NMR (600 MHz, Chloroform-d) δ 7.84 (dt, J = 7.8, 1.3 Hz, 1H), 7.72 (ddd, J = 9.3, 2.7, 1.6 Hz, 1H), 7.44 (td, J = 8.0, 5.5 Hz, 1H), 7.29 (tdd, J = 8.1, 2.5, 0.8 Hz, 1H), 6.41 (s, 1H), 5.57 (s, 1H), 2.61–2.52 (m, 2H), 2.39 (t, J = 12.4 Hz, 1H), 2.15–2.07 (m, 1H), 2.02–1.91 (m, 3H), 1.66–1.56 (m, 1H), 1.46–1.37 (m, 2H), 1.06 (d, J = 6.2 Hz, 3H), 1.02 (d, J = 6.3 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.51, 163.52, 161.78, 141.36, 132.79, 130.32, 125.64, 121.75, 120.54, 116.78, 108.53, 87.91, 59.92, 54.54, 41.19, 34.01, 31.03, 29.41, 27.25, 22.45, 21.18, 11.56; ESI-MS m / z: 395.1 [M+Na] + ,767.4 [2M+Na] + 。

[0118] Example 17

[0119] Preparation of Derivative C16

[0120] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add 2-fluorobenzoyl chloride (2-Fluorobenzoyl chloride, 0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C16 by column chromatography (petroleum ether:ethyl acetate = 100:1).

[0121] 1 H NMR (600 MHz, Chloroform-d) δ 7.98 (td, J = 7.6, 1.9 Hz, 1H), 7.57–7.52 (m, 1H), 7.22 (td, J = 7.6, 1.1 Hz, 1H), 7.15 (ddd, J = 10.9, 8.3, 1.1 Hz, 1H), 6.40 (s, 1H), 5.73 (s, 1H), 2.70 (td, J = 11.7, 7.2 Hz, 1H), 2.55 (t, J = 12.6 Hz, 1H), 2.41 (dd, J = 13.0, 12.0 Hz, 1H), 2.14–2.04 (m, 1H), 2.01–1.88 (m, 3H), 1.66–1.54 (m, 1H), 1.47–1.34 (m, 2H), 1.08 (d, J = 6.2 Hz, 3H), 0.97 (d, J = 6.3 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.51, 163.52, 161.77, 141.36, 132.77, 130.34, 125.65, 121.75, 120.61, 116.70, 108.53, 87.91, 59.92, 54.54, 41.19, 34.01, 31.03, 29.41, 27.25, 22.45, 21.18, 11.56; ESI-MS m / z: 395.1 [M+Na] + , 767.3 [2M+Na] + .

[0122] Example 18

[0123] Preparation of Derivative C17

[0124] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add 4-fluorobenzoyl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C17 by column chromatography (petroleum ether: ethyl acetate = 100:1).

[0125] 1 H NMR(600MHz,Chloroform-d)δ8.08–8.05(m,2H),7.13(t,J=8.6Hz,2H),6.40(s,1H),5.56(s,1H),2.61–2.52(m,2H),2.38(t,J=12.4Hz,1H),2.10(td,J=13.5,11.8,6.2Hz,1H),2.02–1.91(m,3H),1.66–1.55(m,1H),1.46–1.37(m,2H),1.06(d,J=6.0Hz,3H),1.01(d,J=6.4Hz,3H),0.94(d,J=6.6Hz,3H); 13 C NMR(150MHz,CDCl 3 )δ199.78,163.08,161.35,141.60,135.02,132.57,124.24,121.96,119.15,117.36,109.10,87.91,59.98,53.56,41.16,34.22,31.08,29.56,27.33,22.50,20.87,11.60;ESI-MS m / z:395.1[M+Na] + ,767.3[2M+Na] + 。

[0126] Example 19

[0127] Preparation of Derivative C18

[0128] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add 3,3-dimethylacryloyl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate and concentrate under reduced pressure. Obtain white powder C18 by column chromatography (petroleum ether: ethyl acetate = 100:1).

[0129] 1 H NMR (600 MHz, Chloroform-d) δ 6.33 (s, 1H), 5.71 (s, 1H), 5.51 (s, 1H), 2.53–2.45 (m, 2H), 2.36–2.28 (m, 1H), 2.16 (s, 3H), 2.09–2.02 (m, 1H), 1.97–1.91 (m, 3H), 1.91 (s, 3H), 1.60–1.54 (m, 1H), 1.39–1.29 (m, 2H), 1.05 (d, J = 6.1 Hz, 3H), 0.91 (d, J = 6.2 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 200.09, 162.85, 158.81, 141.87, 121.57, 116.39, 107.63, 87.47, 59.97, 53.89, 41.14, 34.05, 31.03, 29.43, 27.65, 27.24, 22.48, 20.87, 20.48, 11.59; ESI-MS m / z: 355.1 [M+Na] + , 687.3 [2M+Na] + 。

[0130] Example 20

[0131] Preparation of Derivative C19

[0132] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add 2-thiophenecarbonyl chloride (2-ThiophenecarbonylChloride, 0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C19 by column chromatography (petroleum ether: ethyl acetate = 100:1).

[0133] 1 H NMR (600 MHz, Chloroform-d) δ 7.83 (dd, J = 3.8, 1.3 Hz, 2H), 7.58 (dd, J = 4.9, 1.3 Hz, 2H), 7.12 (dd, J = 5.0, 3.7 Hz, 2H), 6.40 (s, 1H), 5.63 (s, 1H), 2.66–2.50 (m, 4H), 2.37 (t, J = 12.6 Hz, 1H), 2.12–2.05 (m, 2H), 2.01–1.89 (m, 5H), 1.66–1.56 (m, 3H), 1.40 (ddd, J = 15.8, 12.9, 7.0 Hz, 4H), 1.07 (d, J = 6.2 Hz, 5H), 0.99 (d, J = 6.3 Hz, 6H), 0.93 (d, J = 6.6 Hz, 6H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.62, 158.48, 141.48, 134.16, 133.02, 128.07, 121.85, 108.58, 87.85, 59.96, 54.19, 41.14, 34.00, 31.01, 29.43, 27.23, 22.46, 21.02, 11.58; ESI-MS m / z: 383.1 [M+Na] + , 743.2 [2M+Na] + 。

[0134] Example 21

[0135] Preparation of Derivative C20

[0136] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add acetyl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C20 by column chromatography (petroleum ether: ethyl acetate = 100:1).

[0137] 1 H NMR (600 MHz, Chloroform-d) δ 6.32 (s, 1H), 5.54 (s, 1H), 2.56–2.46 (m, 2H), 2.33 (t, J = 12.4 Hz, 1H), 2.11 (s, 3H), 2.09–2.01 (m, 1H), 1.99–1.88 (m, 2H), 1.90–1.80 (m, 1H), 1.59–1.51 (m, 1H), 1.40–1.27 (m, 2H), 1.04 (d, J = 6.2 Hz, 3H), 0.89 (dd, J = 9.8, 6.5 Hz, 6H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.82, 167.39, 141.83, 121.43, 108.01, 87.62, 59.93, 53.20, 41.11, 34.11, 31.06, 29.36, 27.25, 22.47, 22.42, 20.77, 11.53; ESI-MS m / z: 293.1 [M+H] + , 315.1 [M+Na] + .

[0138] Example 22

[0139] Preparation of Derivative C21

[0140] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add 5-chlorothiophene-2-carbonyl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C21 by column chromatography (petroleum ether: ethyl acetate = 100:1).

[0141] 1 1H NMR (600 MHz, Chloroform-d) δ 7.61 (d, J = 4.0 Hz, 1H), 6.95 (d, J = 4.0 Hz, 1H), 6.39 (s, 1H), 5.59 (s, 1H), 2.58–2.50 (m, 2H), 2.37 (t, J = 12.6 Hz, 1H), 2.13–2.04 (m, 1H), 2.01–1.85 (m, 3H), 1.63–1.56 (m, 1H), 1.44–1.33 (m, 2H), 1.06 (d, J = 6.2 Hz, 3H), 0.97 (d, J = 6.3 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H); 13 13C NMR (150 MHz, CDCl 3 ) δ 199.39, 157.43, 141.32, 138.03, 133.79, 132.11, 127.63, 121.85, 108.74, 87.96, 59.92, 54.26, 41.15, 33.97, 31.01, 29.40, 27.23, 22.43, 21.04, 11.56; ESI-MS m / z: 417.4 [M+Na] + 。

[0142] Example 23

[0143] Preparation of Derivative C22

[0144] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, then add 4-nitrobenzoyl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The white powder C22 is obtained by column chromatography (petroleum ether:ethyl acetate = 100:1).

[0145] 11H NMR (600 MHz, Chloroform-d) δ 8.31 (d, J = 8.9 Hz, 2H), 8.21 (d, J = 8.8 Hz, 2H), 6.42 (s, 1H), 5.55 (s, 1H), 2.62–2.53 (m, 2H), 2.40 (t, J = 12.6 Hz, 1H), 2.16–2.07 (m, 1H), 2.03–1.89 (m, 3H), 1.63–1.55 (m, 1H), 1.48–1.39 (m, 2H), 1.06 (d, J = 6.2 Hz, 3H), 1.01 (d, J = 6.4 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H); 13 13C NMR (150 MHz, CDCl 3 ) δ 199.19, 161.03, 150.82, 141.15, 135.94, 130.97, 123.84, 121.76, 108.89, 88.10, 59.85, 54.59, 41.20, 33.97, 31.03, 29.36, 27.23, 22.40, 21.21, 11.54; ESI-MS m / z: 422.2 [M+Na] + 。

[0146] Example 24

[0147] Preparation of Derivative C23

[0148] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, then add nicotinoyl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The white powder C23 is obtained by column chromatography (petroleum ether:ethyl acetate = 100:1).

[0149] 11H NMR (600 MHz, Chloroform-d) δ 9.25 (s, 1H), 8.80 (d, J = 3.2 Hz, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.42 (dd, J = 7.9, 4.8 Hz, 1H), 6.41 (s, 1H), 5.57 (s, 1H), 2.70–2.52 (m, 2H), 2.39 (t, J = 12.4 Hz, 1H), 2.16–2.06 (m, 1H), 2.03–1.88 (m, 3H), 1.63–1.57 (m, 1H), 1.43 (td, J = 11.9, 10.7, 6.7 Hz, 2H), 1.06 (d, J = 5.9 Hz, 3H), 1.01 (d, J = 6.3 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H); 13 13C NMR (150 MHz, CDCl 3 ) δ 199.36, 161.65, 153.87, 151.12, 141.28, 137.44, 126.54, 123.60, 121.78, 108.67, 88.01, 59.89, 54.61, 41.20, 33.98, 31.03, 29.39, 27.24, 22.43, 21.21, 11.56; ESI-MS m / z: 356.4 [M+H] + , 378.5 [M+Na] + , 733.8 [2M+Na] + 。

[0150] Example 25

[0151] Preparation of Derivative C24

[0152] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, then add hexanoyl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The white powder C24 is obtained by column chromatography (petroleum ether:ethyl acetate = 100:1).

[0153] 11H NMR (600 MHz, Chloroform-d) δ 6.32 (s, 1H), 5.52 (s, 1H), 2.54–2.46 (m, 2H), 2.38–2.29 (m, 3H), 2.10–2.01 (m, 1H), 1.99–1.89 (m, 2H), 1.90–1.81 (m, 1H), 1.68–1.60 (m, 2H), 1.58–1.51 (m, 1H), 1.40–1.27 (m, 6H), 1.04 (d, J = 6.1 Hz, 3H), 0.92–0.87 (m, 9H); 13 13C NMR (150 MHz, CDCl 3 ) δ 199.83, 170.11, 141.79, 121.24, 107.75, 87.44, 59.80, 53.27, 40.98, 35.33, 34.00, 31.20, 30.92, 29.26, 27.13, 24.31, 22.34, 22.32, 20.74, 13.92, 11.42; ESI-MS m / z: 371.1 [M+Na] + , 719.5 [2M+Na] + 。

[0154] Example 26

[0155] Preparation of Derivative C25

[0156] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, then add valeryl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain white powder C25 by column chromatography (petroleum ether:ethyl acetate = 100:1).

[0157] 1 1H NMR (600 MHz, Chloroform-d) δ 6.32 (d, J = 1.1 Hz, 1H), 5.52 (d, J = 1.1 Hz, 1H), 2.54–2.46 (m, 2H), 2.39–2.29 (m, 3H), 2.10–2.01 (m, 1H), 1.99–1.89 (m, 2H), 1.90–1.81 (m, 1H), 1.62 (m, 2H), 1.59–1.53 (m, 1H), 1.40–1.27 (m, 4H), 1.04 (d, J = 6.2 Hz, 3H), 0.95–0.86 (m, 9H);13 C NMR (150 MHz, CDCl 3 ) δ 199.82, 170.08, 141.80, 121.23, 107.76, 87.44, 59.80, 53.25, 40.98, 35.08, 34.01, 30.92, 29.26, 27.13, 26.68, 22.32, 22.19, 20.73, 13.75, 11.42; ESI-MS m / z: 335.5 [M+H] + , 357.5 [M+Na] + , 691.8 [2M+Na] + 。

[0158] Example 27

[0159] Preparation of Derivative C26

[0160] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, then add butyryl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate and concentrate under reduced pressure. Column chromatography (petroleum ether: ethyl acetate = 100:1) gives white powder C26.

[0161] 1 H NMR (600 MHz, Chloroform-d) δ 6.32 (s, 1H), 5.52 (s, 1H), 2.49 (td, J = 10.7, 9.9, 3.7 Hz, 2H), 2.37–2.29 (m, 3H), 2.10–2.01 (m, 1H), 1.98–1.90 (m, 2H), 1.90–1.81 (m, 1H), 1.71–1.62 (m, 2H), 1.61–1.51 (m, 1H), 1.39–1.27 (m, 2H), 1.04 (d, J = 6.1 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H), 0.89 (dd, J = 8.5, 6.4 Hz, 6H); 13 C NMR (150 MHz, CDCl 3) δ 199.91, 170.02, 141.95, 121.33, 107.90, 87.56, 59.94, 53.41, 41.11, 37.41, 34.14, 31.06, 29.38, 27.26, 22.44, 20.86, 18.26, 13.76, 11.53; ESI-MS m / z: 343.1 [M+Na] + , 663.3 [2M+Na] + 。

[0162] Example 28

[0163] Preparation of Derivative C27

[0164] In a 50 mL reaction flask, add intermediate M (100 mg, 0.4 mmol) and sodium hydride (NaH, 1.2 - 2.0 mmol), then add 20 mL of DCM, stir at room temperature for 30 min, subsequently add propionyl chloride (0.8 - 1.2 mmol), stir at room temperature, monitor the reaction by TLC until completion, quench with water, wash successively with saturated tartaric acid and saturated brine, dry over anhydrous sodium sulfate and concentrate under reduced pressure, and obtain white powder C27 by column chromatography (petroleum ether: ethyl acetate = 100:1).

[0165] 1 H NMR (600 MHz, Chloroform-d) δ 6.32 (d, J = 1.1 Hz, 1H), 5.52 (d, J = 1.1 Hz, 1H), 2.54–2.47 (m, 2H), 2.40 (q, J = 7.6 Hz, 2H), 2.33 (t, 1H), 2.10–2.01 (m, 1H), 1.99–1.89 (m, 2H), 1.90–1.81 (m, 1H), 1.60–1.52 (m, 1H), 1.40–1.27 (m, 2H), 1.15 (t, J = 7.5 Hz, 3H), 1.05 (d, J = 6.4 Hz, 3H), 0.89 (t, J = 6.8 Hz, 6H); 13 C NMR (150 MHz, CDCl 3 ) δ 199.90, 170.84, 141.89, 121.36, 107.88, 87.58, 59.93, 53.25, 41.09, 34.11, 31.02, 29.37, 28.81, 27.23, 22.43, 20.81, 11.54, 8.92; ESI-MS m / z: 329.1 [M+Na] + , 635.3 [2M+Na] + 。

[0166] Example 29

[0167] Activity determination of a series of derivatives against phytopathogenic fungi

[0168] Wheat gibberella zeae, Thanatephorus cucumeris, Phytophthora parasitica varnicotianae, Phomopsis sp., and Pyricularia oryzae used in the following examples were provided by the Key Laboratory of Natural Products Chemistry, Guizhou Academy of Sciences, China. The activation of the bacterial strains was as follows: Using an inoculation loop, scrape 3 loops of the bacterial strains and inoculate them onto a potato dextrose agar medium (PDA), and incubate at a constant temperature of 28 ± 1°C for 72 hours.

[0169] The bacteriostatic effect of the compound was evaluated by the virulence plate method. Use a punch (with a diameter of Ф4 mm) to punch out 5-mm-diameter bacterial cakes on the PDA plate of the activated wheat gibberella zeae, and then add them to the center of the poisoned and control plates with the active substance, with 5 replicates for each treatment. Incubate at a constant temperature of 28 ± 1°C, and observe the bacteriostatic situation. Measure the diameter of the bacterial cake by the cross method, and calculate the specific inhibition rate.

[0170] Inhibition rate (I, %) = (C - T) / (C - 5 mm) × 100%

[0171] I is the inhibition rate of the active substance, C is the growth diameter of the blank control bacterial cake, and T is the growth diameter of the bacterial cake on the virulence plate.

[0172] According to the different inhibition rates at gradient concentrations, calculate the IC 50 value, and the results are shown in Tables 1 - 5. The positive control drugs are pyrimethanil (CAS: 53112 - 28 - 0, molecular weight: 199) and thiophanate-methyl (CAS: 23564 - 05 - 8, molecular weight: 342).

[0173]

[0174] The activity results are shown in Tables 1, 2, 3, 4, 5, and 6.

[0175] Table 1 Activity evaluation of derivatives against Phomopsis sp., the pathogen of kiwifruit soft rot*

[0176]

[0177]

[0178] *means ± sd, n = 3.

[0179] Table 2 Control effect experiment of compound C3 against Phomopsis sp. on kiwifruit (3 days)

[0180]

[0181]

[0182] The activity of the compound against Phomopsis sp. Among them, preferably,

[0183]

[0184] Its IC against Phomopsis sp 50 is less than 2 μg / mL;

[0185] Secondly,

[0186]

[0187] Its IC against Phomopsis sp 50 is greater than 2 μg / mL and less than 6 μg / mL; Again,

[0188]

[0189] Its IC against Phomopsis sp 50 is greater than 6 μg / mL and less than 11 μg / mL; Then,

[0190]

[0191] Its IC against Phomopsis sp 50 is greater than 12 μg / mL and less than 20 μg / mL;

[0192] Finally,

[0193]

[0194] Its IC against Phomopsis sp 50 is greater than 21 μg / mL and less than 40 μg / mL; The above derivatives IC 50 is less than 50 μg / mL and has the potential for development as an antibacterial agent.

[0195]

[0196] Summary: The half-maximal inhibitory concentrations of derivatives C3 (3.06 μM), C21 (3.07 μM), and C22 (3.16 μM) were 1 / 44 of that of pyrimethanil (134 μM). The inhibition rates of C3 (93.56%), C21 (84.61%), and C22 (79.30%) against Phomopsis sp. were achieved at 50 μg / mL. Therefore, C3 is the most valuable for developing into an antibacterial agent against Phomopsis sp.

[0197] Therefore, we conducted a preliminary efficacy study on C3. At a low concentration of 10-fold IC 50 , the efficacy reached 15.42%, and pyrimethanil had no effect; at a medium concentration of 50-fold IC 50 , the efficacy reached 26.94%, and that of pyrimethanil was 9.18%, which was 2.9 times that of pyrimethanil; at a high concentration of 100-fold EC 50 , the efficacy reached over 50.59%, which was 1.5 times that of pyrimethanil (37.68%).

[0198] Table 3 Evaluation of the activities of derivatives against Rhizoctonia solani*

[0199]

[0200]

[0201] *means±sd, n = 3.

[0202] Activities of compounds against Rhizoctonia solani

[0203] Derivatives C2, C4, C5, C6, C8, and C20 showed inhibition rates of over 90% against Rhizoctonia solani at 50 μg / mL.

[0204] First, C4 was preferred.

[0205]

[0206] Its anti-IC 50 was greater than 2 μg / mL and less than 6 μg / mL;

[0207] Secondly, C2, C6, C8, and C20 were preferred.

[0208]

[0209] Its anti-IC 50 was greater than 6 μg / mL and less than 11 μg / mL;

[0210] Finally, C5 was preferred.

[0211]

[0212] Its anti-IC 50 is greater than 12 μg / mL and less than 20 μg / mL.

[0213] Summary: At 50 μg / mL, the inhibition rate C4 (100%) against the pathogen of rice sheath blight (Rhizoctonia solani), and the half-maximal inhibitory concentration of compound C4 (IC 50 8.81 μM) is 1 / 3 of that of the positive control thiophanate-methyl (IC 50 24.74 μM). Therefore, compound C4 has the greatest value in developing into an antibacterial agent against the pathogen of rice sheath blight (Rhizoctonia solani).

[0214] Table 4 Activity evaluation of derivatives against the pathogen of wheat head blight (Wheat gibberella zeae)*

[0215]

[0216]

[0217] *means±sd, n=3.

[0218] Preferred activity of the compound against the pathogen of wheat head blight (Wheatgibberella zeae)

[0219]

[0220] For the derivatives at 50 μg / mL, C2 (99.64%), C4 (79.85%), C5 (76.89%), C6 (87.74%), C8 (74.92%) and C10 (75.62%). For the positive control thiophanate-methyl, the inhibition rate at 50 μg / mL is 91.35%, and the half-maximal inhibitory concentration (IC 50 40.86 μM). For derivatives C2 (IC 50 43.43 μM), C4 (IC 50 33.21 μM), C5 (IC 50 46.60 μM), C6 (IC 50 49.58 μM), C8 (IC 50 32.22 μM) and C10 (IC 50 30.86 μM).

[0221] Summary: From the maximum inhibition rate and the half-maximal inhibitory concentration IC50 Overall, the inhibition rate of compound C2 was 99.64% at 50 μg / mL, and the IC 50 was 13.82 μg / mL, which was comparable to that of thiophanate-methyl. Therefore, compound C2 has the potential to be developed into an antibacterial agent.

[0222] Table 5. Activity evaluation of derivatives against Phytophthora parasitica var nicotianae*

[0223]

[0224]

[0225]

[0226] *means±sd, n = 3.

[0227] Activity of compounds against Phytophthora parasitica var nicotianae

[0228] Among them, the preferred ones are

[0229]

[0230] Derivatives C2 (96.14%), C4 (98.23%), C6 (94.96%), C20 (90.30%), C26 (96.13%) and C27 (94.49%) at 50 μg / mL, with inhibition rates above 90%.

[0231] Positive control thiophanate-methyl (IC 50 185.43 μM); C2 (IC 50 41.83 μM), C4 (IC 50 42.65 μM), C6 (IC 50 32.88 μM), C20 (IC 50 52.31 μM), C26 (IC 50 25.46 μM) and C27 (IC 50 39.95 μM).

[0232] Summary: From the maximum inhibition rate and half-effective inhibition concentration IC 50 Overall, the inhibition rate of compound C26 was 96.13% at 50 μg / mL, and the IC 50It is approximately 1 / 7 of the positive control thiophanate-methyl (185.43 μM) at 25.46 μM. Therefore, compound C26 has the potential to be developed into an antibacterial agent.

[0233] Table 6 Evaluation of the activities of derivatives against Magnaporthe oryzae *

[0234]

[0235]

[0236] *means ±sd, n = 3. Activities of the compounds against Magnaporthe oryzae

[0237] Among them, preferably

[0238]

[0239] Derivatives C2 (100%), C4 (100%), C20 (100%), C23 (100%), C26 (100%) and C23 (100%) had inhibition rates of over 100% at 50 μg / mL.

[0240] Positive control thiophanate-methyl (IC 50 8.29 ± 0.09 μM), C2 (IC 50 43.62 ± 9.99 μM), C5 (IC 50 86.39 ± 8.53 μM), C8 (IC 50 37.57 ± 3.81 μM), C20 (IC 50 57.14 ± 6.78 μM), C23 (IC 50 29.37 ± 3.21 μM) and C27 (IC 50 54.62 ± 8.92 μM).

[0241] Summary: Considering the maximum inhibition rate at 50 μg / mL and the half-maximal inhibitory concentration IC 50 Overall, compound C23 had an inhibition rate of 100% at 50 μg / mL. Although the IC 50 of C23 was 29.37 μM, approximately 3.5 times that of the positive control thiophanate-methyl (8.29 μM), as a plant-derived pesticide, C23 has the potential to be developed into a fungicide against Magnaporthe oryzae.

[0242] The description of the above embodiments is only used to help understand the method and its core idea of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

[0243] The above description of the disclosed embodiments enables those skilled in the art to implement or use the present invention. Various modifications to these embodiments will be obvious to those skilled in the art, and the general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to these embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A curcumol derivative, characterized in that, it has the structure shown in Formula 1: wherein, R is any one of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, 2. Use of a curcumol derivative in the preparation of a drug for preventing and treating wheat head blight, characterized in that, the curcumol derivative has the structure shown in Formula 1: wherein, R is any one of C2, C3, C4, C5, C6, C7, C8, C10, C11, C12, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, 3. Use of a curcumol derivative in the preparation of a drug for preventing and treating sheath blight of rice, characterized in that, the curcumol derivative has the structure shown in Formula 1: wherein, R is any one of C2, C3, C4, C5, C6, C8, C10, C12, C17, C18, C19, C20, C23, C26, C27, 4. Use of a curcumol derivative in the preparation of a drug for preventing and treating tobacco black shank, characterized in that, the curcumol derivative has the structure shown in Formula 1: wherein, R is any one of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, 5. Use of a curcumol derivative in the preparation of a drug for preventing and treating Phomopsis disease, characterized in that, the curcumol derivative has the structure shown in Formula 1: wherein, R is any one of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, 6. Use of a curcumol derivative in the preparation of a drug for preventing and treating rice blast, characterized in that, the curcumol derivative has the structure shown in Formula 1: wherein, R is any one of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, 7. The use according to any one of claims 2-6, characterized in that, the dosage form of the drug is one of powder, suspension, granule, water dispersible granule and microemulsion.

8. A preparation method of the curcumol derivative according to claim 1, characterized in that, it includes the following steps: Curcumol is subjected to an oxidation reaction under the action of a complex oxidant composed of ruthenium trichloride, sodium periodate and 2,6-dimethylpyridine to obtain a colorless transparent liquid Z-1. Then, a double bond is introduced to obtain an intermediate M. Finally, the intermediate M is subjected to acylation with an acyl chloride or an acid under the action of NaH to obtain a curcumol derivative. The colorless transparent liquid Z-1 is prepared according to the following method: Take curcumol, ruthenium trichloride, sodium periodate and 2,6-dimethylpyridine and add them into a reaction flask. Then add a mixed solution of acetonitrile, dichloromethane and water, stir at room temperature, and track the reaction by TLC until it is complete. Wash successively with saturated sodium bisulfite and saturated brine, extract with DCM simultaneously, dry the DCM with anhydrous sodium sulfate, and then concentrate under reduced pressure. After column chromatography, a colorless transparent liquid Z-1 is obtained. The intermediate M is prepared according to the following method: React the colorless transparent liquid Z-1, 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, paraformaldehyde and the catalyst i-Pr2NH·TFA at 70 °C, track the reaction by TLC until it is complete, wash with saturated tartaric acid and saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, scrape, and obtain the intermediate M after column chromatography.

Images