A method for synthesizing an organic catalyst and a stilbene derivative

Abstract

The present invention relates to an organic catalyst and a method for synthesizing a diphenylethylene derivative. The method for synthesizing the organic catalyst of the present invention comprises the following steps: reacting compound A with compound B to generate the organic catalyst. The organic catalyst prepared by the method for synthesizing the organic catalyst of the present invention has a high yield. At the same time, the method for synthesizing the organic catalyst of the present invention has simple steps, does not require harsh process conditions, and is suitable for large-scale production. The present invention provides a method for synthesizing an organic catalyst, and at the same time, uses the organic catalyst to synthesize a diphenylethylene derivative with simple raw materials under light conditions. In addition, the present invention provides a method for synthesizing a diphenylethylene derivative using the organic catalyst. The method does not require a transition metal catalyst, has no heavy metal residue, does not require high temperature and high pressure, and produces only water and nitrogen as by-products. The method is green and safe, and is particularly suitable for the synthesis of pharmaceutical and cosmetic active substances.

Description

Technical Field

[0001] The present invention relates to the technical field of organic catalyst synthesis, in particular to a method for synthesizing an organic catalyst and a stilbene derivative. Background Art

[0002] Since stilbene derivatives form a conjugated system with their vinyl bond and benzene ring, they have good chemical properties and are widely used in the pharmaceutical, food, functional materials, dye and other industries.

[0003] For example, resveratrol is a stilbene derivative, an antitoxin produced by many plants when stimulated. It can be synthesized in grape leaves and skins and is a bioactive component in wine and grape juice. It is easily absorbed orally and excreted in urine and feces after metabolism. In vitro and animal studies have shown that resveratrol has antioxidant, anti-inflammatory, anti-cancer, and cardiovascular protective effects. In skin care, resveratrol can be used as a skin whitening agent by inhibiting tyrosinase activity. Resveratrol's antioxidant properties can slow the photoaging process by reducing the expression of AP-1 and NF-kB factors, thereby protecting cells from oxidative damage caused by free radicals and ultraviolet radiation. Resveratrol extracted from natural plants cannot meet the demand for resveratrol. The main source of resveratrol is extracted from the medicinal plant Polygonum cuspidatum, which is mainly concentrated in Hunan and Sichuan, and annual mining has reached saturation. While research on artificial cultivation of Polygonum cuspidatum has begun, large-scale cultivation has not yet been achieved due to technical limitations, the limited supply of wild resources, and the cost of cultivation. At present, natural wild resources of resveratrol are scarce, which creates a huge gap with market demand.

[0004] Oxidized resveratrol is a derivative of resveratrol and a stilbene derivative, primarily found in plants such as mulberry and jackfruit. Oxidized resveratrol is known to have a bioavailability of up to 50%. Pharmacological studies have shown that oxidized resveratrol exhibits excellent tyrosinase inhibition, anti-inflammatory, and antioxidant activities, making it suitable for use as an active ingredient in dermatology. In food, oxidized resveratrol is also used in the food industry as an anti-browning agent, for example, to reduce cloudy apple juice. However, the concentration of this compound in natural plants is very low, and it is only produced in large quantities in response to fungal infection or injury, making it difficult to obtain large quantities of oxidized resveratrol from plant sources.

[0005] The significant biological activities and applications of resveratrol and oxy-resveratrol have garnered widespread attention from the medical community, industry, the press, and the general public. However, their extremely low concentrations have limited their commercialization and application in pharmaceuticals and functional foods. Consequently, researchers have been dedicated to developing rapid and safe synthetic methods to obtain resveratrol and its derivatives.

[0006] Currently, the synthesis process of diphenylethylene derivatives has disadvantages such as lengthy routes, poor raw material economy and high cost, complex operation, expensive and toxic palladium complexes used as transition metal catalysts, unsuitability for large-scale industrial production, and excessively high costs. Therefore, it is of great significance to continue to find an efficient, simple and green synthesis method for diphenylethylene derivatives.

[0007] In view of this, it is indeed necessary to provide a technical solution to the above technical problems. Summary of the Invention

[0008] In order to overcome the defects of the above-mentioned prior art, the first purpose of the present invention is to provide a method for synthesizing an organic catalyst, and the organic catalyst prepared by the method for synthesizing the organic catalyst is used for the synthesis of diphenylethylene derivatives, providing an efficient, simple and green method for synthesizing diphenylethylene derivatives.

[0009] The second object of the present invention is to provide a method for synthesizing stilbene derivatives.

[0010] One of the objectives of the present invention can be achieved by adopting the following technical solutions:

[0011] A method for synthesizing an organic catalyst having a structure shown in Formula I:

[0012]

[0013] The synthesis method comprises the following steps:

[0014] Compound A reacts with compound B to generate the organic catalyst;

[0015] The compound A has the structure shown in formula II:

[0016]

[0017] The compound B has a structure shown in formula III:

[0018]

[0019] Among them, R 1 、R 2 、R 3 、R 4 、R 5 Any one selected from hydrogen, alkyl, aryl, ester, keto or cyano groups.

[0020] Preferably, the R 1 、R 2 、R 3 、R 4、R 5 It is selected from one of methyl, ethyl, n-propyl, n-butyl, tert-butyl, ethoxy, acetyl and substituted phenyl.

[0021] Preferably, compound A reacts with compound B in the presence of a catalyst and an oxygen atmosphere, and the catalyst is cerium ammonium nitrate.

[0022] Preferably, the molar ratio of compound A to compound B is 1:(1.0-1.2), the reaction of compound A and compound B is carried out in an aprotic solvent, and the molar volume ratio of compound A to the aprotic solvent is 1 mol:(1.8-2.2)L.

[0023] Preferably, the reaction temperature is 70-90° C., and the reaction time is 15-17 h.

[0024] Preferably, the method further comprises a pretreatment step, wherein the pretreatment step comprises the following steps: reacting diethyl ethyl phosphate with a pyrrole-2-carboxaldehyde derivative in the presence of a catalyst to generate the compound A, wherein the catalyst is potassium hexamethyldisilazane.

[0025] The second purpose of the present invention can be achieved by adopting the following technical solutions:

[0026] A method for synthesizing a stilbene derivative comprises the following preparation steps:

[0027] S1, mixing compound C and hydrazine hydrate, and reacting to obtain compound D;

[0028] S2. reacting compound D obtained in step S1 with compound E to obtain compound F;

[0029] S3, reacting the compound F obtained in step S2 under light conditions and in the presence of an organic catalyst prepared by the method for synthesizing an organic catalyst according to any one of claims 1 to 6 to obtain the stilbene derivative;

[0030] Wherein compound C has the structure shown in formula IV:

[0031]

[0032] Compound D has the structure shown in Formula V:

[0033]

[0034]

[0035] Compound E has the structure shown in Formula VI:

[0036]

[0037] Compound F has the structure shown in Formula VII:

[0038]

[0039] The stilbene derivative has a structure shown in Formula VIII:

[0040]

[0041] Among them, Ar 1 ,Ar 2 It is phenyl or phenyl substituted by one or more of alkyl, alkoxy, hydroxy, amino or trifluoromethyl.

[0042] Preferably, the molar ratio of compound C, hydrazine hydrate and compound E is 1:(1.0-1.2):(1.0-1.2).

[0043] Preferably, the compound C is 3,5-dihydroxybenzaldehyde, and the compound E is p-hydroxybenzaldehyde or 2,4-dihydroxybenzaldehyde.

[0044] Preferably, the step S1 is carried out in an alcohol solvent, the reaction temperature of the step S1 is 60-70° C., and the reaction time is 3-5 h, and the reaction temperature of the step S2 is 60-70° C., and the reaction time is 5-7 h.

[0045] Compared with the prior art, the present invention has the following beneficial effects:

[0046] 1. The present invention provides a method for synthesizing an organic catalyst. The organic catalyst prepared by the method has a high yield. At the same time, the method for synthesizing the organic catalyst in the present invention has simple steps, does not require harsh process conditions, and is suitable for large-scale production.

[0047] 2. The organic catalyst prepared by the method for synthesizing the organic catalyst provided by the present invention can be used to synthesize stilbene derivatives, including resveratrol and resveratrol oxide, from simple raw materials under light conditions. This provides an efficient, simple, and green method for synthesizing stilbene derivatives.

[0048] 3. The present invention also provides a method for synthesizing stilbene derivatives using the aforementioned novel organic catalyst. This method produces stilbene derivatives in high yield, with simple steps and easily controllable process conditions, making it suitable for large-scale production. Furthermore, this method does not require a transition metal catalyst, produces no heavy metal residues, and does not require high temperature or high pressure. The byproducts are solely water and nitrogen, making it environmentally friendly and safe, making it particularly suitable for the synthesis of pharmaceutical and cosmetic active ingredients. DETAILED DESCRIPTION

[0049] The technical solutions of the present invention will be described clearly and completely below with reference to specific embodiments. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are also within the scope of protection of the present invention.

[0050] A method for synthesizing an organic catalyst having a structure shown in Formula I:

[0051]

[0052] The synthesis method comprises the following steps:

[0053] Compound A reacts with compound B to generate the organic catalyst;

[0054] The reaction formula is shown in formula (1):

[0055]

[0056] The compound A has the structure shown in formula II:

[0057]

[0058] The compound B has a structure shown in formula III:

[0059]

[0060] Among them, R 1 、R 2 、R 3 、R 4 、R 5 Any one selected from hydrogen, alkyl, aryl, ester, keto or cyano groups.

[0061] As one embodiment, the reaction of compound A and compound B to generate the organic catalyst also includes a pretreatment step, wherein diethyl ethyl phosphate and a pyrrole-2-carboxaldehyde derivative are reacted in the presence of a catalyst to generate compound A, and the catalyst is potassium hexamethyldisilazane.

[0062] The reaction formula is shown in formula (2):

[0063]

[0064] As one embodiment, the R 1 、R 2 、R 3 、R 4 、R 5It is selected from one of methyl, ethyl, n-propyl, n-butyl, tert-butyl, ethoxy, acetyl and substituted phenyl.

[0065] In one embodiment, compound A reacts with compound B in the presence of a catalyst and an oxygen atmosphere, wherein the catalyst is ammonium cerium nitrate.

[0066] In one embodiment, the molar ratio of compound A to compound B is 1:(1.0-1.2), the reaction of compound A and compound B is carried out in an aprotic solvent, and the molar volume ratio of compound A to the aprotic solvent is 1 mol:(1.8-2.2) L. Preferably, the molar ratio of compound A to compound B is 1:1.1, the aprotic solvent is acetonitrile, and the molar volume ratio of compound A to the aprotic solvent is 1 mol:2.0 L.

[0067] Aprotic solvents have strong dissolving power and are widely used. The above-mentioned aprotic solvent is acetonitrile, which has good dissolving power for a variety of organic and inorganic compounds.

[0068] In one embodiment, the reaction temperature is 70-90° C., and the reaction time is 15-17 hours. Preferably, the reaction temperature is 80° C., and the reaction time is 16 hours.

[0069] A method for synthesizing a stilbene derivative comprises the following preparation steps:

[0070] S1, mixing compound C and hydrazine hydrate, and reacting to obtain compound D;

[0071] S2. reacting compound D obtained in step S1 with compound E to obtain compound F;

[0072] S3, reacting the compound F obtained in step S2 under light conditions and in the presence of an organic catalyst prepared by the method for synthesizing an organic catalyst according to any one of claims 1 to 6 to obtain the stilbene derivative;

[0073] The reaction formula is shown in formula (3):

[0074]

[0075] Wherein compound C has the structure shown in formula IV:

[0076]

[0077] Compound D has the structure shown in Formula V:

[0078]

[0079] Compound E has the structure shown in Formula VI:

[0080]

[0081] Compound F has the structure shown in Formula VII:

[0082]

[0083] The stilbene derivative has a structure shown in Formula VIII:

[0084]

[0085] Among them, Ar 1 ,Ar 2 is phenyl or phenyl substituted by one or more of alkyl, alkoxy, hydroxyl, amino or trifluoromethyl. 1 ,Ar 2 is a phenyl group with 0-5 substituents, wherein the substituents are selected from one or more of alkyl, alkoxy, hydroxyl, amino or trifluoromethyl; when Ar 1 and / or Ar 2 When there are no substituents, Ar 1 and / or Ar 2 is phenyl; when Ar 1 and / or Ar 2 When Ar is a phenyl group with 1 to 5 substituents, the substituents are selected from alkyl, alkoxy, hydroxyl, amino or trifluoromethyl. 1 and Ar 2 When it is a phenyl group with 1 to 5 substituents, the substituents are selected from methyl, methoxy, hydroxy, dimethylamino, cyano or trifluoromethyl.

[0086] As one embodiment, the molar ratio of compound C, hydrazine hydrate and compound E is 1:(1.0-1.2):(1.0-1.2).

[0087] As one embodiment, the compound C is 3,5-dihydroxybenzaldehyde, and the compound E is p-hydroxybenzaldehyde or 2,4-dihydroxybenzaldehyde.

[0088] In one embodiment, step S1 is carried out in an alcohol solvent, the reaction temperature of step S1 is 60-70°C, the reaction time is 3-5 hours, and the reaction temperature of step S2 is 60-70°C, the reaction time is 5-7 hours. Preferably, the alcohol solvent is methanol, the reaction temperature of step S1 is 65°C, the reaction time is 4 hours, and the reaction temperature of step S2 is 65°C, the reaction time is 6 hours.

[0089] The organic catalyst and its synthesis method, and the synthesis method of stilbene derivatives of the present invention are described below with reference to specific examples.

[0090] Embodiment 1:

[0091] Dissolve 55 mmol of diethyl ethyl phosphate in 100 mL of tetrahydrofuran, cool to 0°C, and dropwise add 60 mL of 1 mol / L potassium hexamethyldisilazane. Remove the cold bath after the solution is added, and allow to rise to room temperature and react for 1 hour to obtain the first mixed solution:

[0092] Add 50 mol of pyrrole-2-carboxaldehyde to the first mixed solution, stir and react for 1 hour, then reflux and react for 2 hours, and cool to room temperature to obtain a second mixed solution;

[0093] 100 mL of ice water was added to the second mixed solution to quench the reaction, and then extracted three times with 150 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate to obtain the concentrated product;

[0094] The concentrated product was dissolved in 100 mL of acetonitrile, and 55 mmol of a cyclohexanone derivative and 5 mmol of ceric ammonium nitrate were added in sequence. Oxygen was introduced and the oxygen pressure was maintained at 1 atmosphere. The temperature was raised to 80°C, and the mixture was reacted for 16 hours. The solvent was then removed by distillation under reduced pressure, and the mixture was diluted to 100 mL with water to obtain a third mixed solution.

[0095] The third mixed liquid was extracted three times with 100 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a product which was recrystallized with ethanol to obtain the organic catalyst.

[0096] In this embodiment, the pyrrole-2-carboxaldehyde derivative is pyrrole-2-carboxaldehyde Cyclohexanone derivatives are cyclohexanone Obtaining the organic catalyst It was named cat.1 and had a yield of 88%.

[0097] 1 H NMR (400MHz, CDCl3): δ8.59 (d J=7.5Hz, 1H), 8.16 (d J=7.5Hz, 1H), 7.97 (ddJ=7.5, 7.5Hz, 1H), 7.69 (dd J=7.5, 7.5Hz, 1H), 7.14 (d J=7.5Hz, 1H), 6.71 (s, 1H), 6.64 (dd J=7.5, 7.5Hz, 1H), 6.28 (d J=7.5Hz, 1H), 2.68 (s, 3H).

[0098] 13C NMR (100MHz, CDCl3): δ144.2,132.9,130.6,129.2,126.5,124.2,122.2,114.1,111.9,99.4,20.0.

[0099] ESI-TOF-HRMS calculation of C 13 H 11 NNa(M+Na) 204.2278 molecular weight, measured 204.2244.

[0100] Example 2:

[0101] Dissolve 55 mmol of diethyl ethyl phosphate in 100 mL of ether, cool to -5°C, and dropwise add 60 mL of 1 mol / L potassium hexamethyldisilazane. Remove the cold bath after the solution is added, and allow to naturally warm to room temperature and react for 0.8 h to obtain the first mixed solution:

[0102] 50 mol of 3-cyanopyrrole-2-carboxaldehyde was added to the first mixed solution, stirred for reaction for 0.8 h, then refluxed for reaction for 2.5 h, and cooled to room temperature to obtain a second mixed solution;

[0103] 100 mL of ice water was added to the second mixed solution to quench the reaction, and then extracted twice with 150 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate to obtain the concentrated product;

[0104] The concentrated product was dissolved in 90 mL of acetonitrile, and 50 mmol of a cyclohexanone derivative and 5 mmol of ceric ammonium nitrate were added in sequence. Oxygen was introduced and the oxygen pressure was maintained at 1 atmosphere. The temperature was raised to 70°C, and the reaction was continued for 17 hours. The solvent was then distilled off under reduced pressure, and the mixture was diluted with water to 100 mL to obtain a third mixed solution.

[0105] The third mixed solution was extracted four times with 100 mL of ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a product which was recrystallized with ethanol to obtain the organic catalyst.

[0106] In this embodiment, the pyrrole-2-carboxaldehyde derivative is 3-cyanopyrrole-2-carboxaldehyde. Cyclohexanone derivative is 4-propylcyclohexanone Obtaining the organic catalyst It was named cat.2 and had a yield of 84%.

[0107] 1H NMR (400MHz, CDCl3): δ7.99(s,1H),7.91(d,J=7.5Hz,1H),7.67(d,J=7.5Hz,1H),7.19(d,J=7.5Hz,1H),7.10 (d,J=7.5Hz,1H),6.63(s,1H),2.68(s,3H),2.61(t,J=7.1Hz,2H),1.62-1.66(m,2H),0.94(t,J=8.0Hz,3H).

[0108] ESI-TOF-HRMS calculation of C 17 H 16 N2Na(M+Na) 271.3188 molecular weight, measured 271.3152.

[0109] Example 3:

[0110] Dissolve 55 mmol of diethyl ethyl phosphate in 100 mL of 1,4-dioxane, cool to 5°C, and dropwise add 60 mL of 1 mol / L potassium hexamethyldisilazane. Remove the cooling bath after the solution is added, and allow the mixture to rise to room temperature and react for 1.2 hours to obtain the first mixed solution:

[0111] 50 mol of 5-methylpyrrole-2-carboxaldehyde was added to the first mixed solution, stirred for reaction for 1.2 h, then refluxed for reaction for 1.5 h, and cooled to room temperature to obtain a second mixed solution;

[0112] 100 mL of ice water was added to the second mixed solution to quench the reaction, and then extracted with 150 mL of ethyl acetate four times. The organic phases were combined and dried over anhydrous sodium sulfate to obtain the concentrated product;

[0113] The concentrated product was dissolved in 110 mL of acetonitrile, and 60 mmol of ethyl 4-cyclohexanonecarboxylate and 5 mmol of ceric ammonium nitrate were added in sequence. Oxygen was introduced and the oxygen pressure was maintained at 1 atmosphere. The temperature was raised to 90°C and the mixture was reacted for 15 hours. The solvent was then distilled off under reduced pressure, and the mixture was diluted to 100 mL with water to obtain a third mixed solution.

[0114] The third mixed liquid was extracted three times with 100 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the product obtained by concentration was recrystallized with ethanol to obtain the organic catalyst.

[0115] In this embodiment, the pyrrole-2-carboxaldehyde derivative is 5-methylpyrrole-2-carboxaldehyde Cyclohexanone derivative is 4-cyclohexanonecarboxylic acid ethyl ester Obtaining the organic catalyst

[0116] It is called cat.3 and has a yield of 80%.

[0117] 1 H NMR (400MHz, CDCl3): δ8.94 (s, 1H), 8.55 (d J = 7.5Hz, 1H), 8.33 (d J = 7.5Hz, 1H), 6.70 (s, 1H), 6.31 (d J = 7.5Hz, 1H), 6.12 (d J=7..5Hz,1H),4.30(q,J=8.0Hz,2H),2.68(s,3H),1.96(s,3H),1.30(t,J=8.0Hz,3H).

[0118] ESI-TOF-HRMS calculation of C 17 H 17 NO2Na(M+Na) molecular weight 290.3178, measured 290.3154.

[0119] Example 4:

[0120] Dissolve 55 mmol of diethyl ethyl phosphate in 100 mL of tetrahydrofuran, cool to -10°C, and dropwise add 60 mL of 1 mol / L potassium hexamethyldisilazane. Remove the cold bath after the solution is added, and allow to naturally warm to room temperature and react for 0.9 h to obtain the first mixed solution:

[0121] 50 mol of 4-butylpyrrole-2-carboxaldehyde was added to the first mixed solution, stirred for reaction for 1 hour, then refluxed for reaction for 2.2 hours, and cooled to room temperature to obtain a second mixed solution;

[0122] 100 mL of ice water was added to the second mixed solution to quench the reaction, and then extracted three times with 150 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate to obtain the concentrated product;

[0123] The concentrated product was dissolved in 100 mL of acetonitrile, and 55 mmol of 4-phenylcyclohexanone and 5 mmol of ceric ammonium nitrate were added in sequence. Oxygen was introduced and the oxygen pressure was maintained at 1 atmosphere. The temperature was raised to 80°C, and the mixture was reacted for 16 hours. The solvent was then distilled off under reduced pressure, and the mixture was diluted to 100 mL with water to obtain a third mixed solution.

[0124] The third mixed solution was extracted twice with 100 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a product which was recrystallized with ethanol to obtain the organic catalyst.

[0125] In this embodiment, the pyrrole-2-carboxaldehyde derivative is 4-butylpyrrole-2-carboxaldehyde. Cyclohexanone derivative is 4-phenylcyclohexanone Obtaining the organic catalyst It was named cat.4 and had a yield of 89%.

[0126] 1 H NMR (400MHz, CDCl3): δ8.30(d,J=7.5Hz,1H),8.04(d,J=7.5Hz,1H),8.00(s,1H),7.75(d,J=7.5Hz,2H),7.40-7.50(m,3H),6.80(s ,1H),6.73(s,1H),6.08(s,1H),2.68(s,3H),2.51(t,J=8.0Hz,2H),1.45-1.49(m,,2H),1.28-1.32(m,2H),0.89(t,J=8.0Hz,3H).

[0127] ESI-TOF-HRMS calculation of C 23 H 23 NNa(M+Na) molecular weight 336.4338, measured 336.4309.

[0128] Example 5:

[0129] Dissolve 55 mmol of diethyl ethyl phosphate in 50 mL of tetrahydrofuran and 50 mL of ether, cool to 0°C, and dropwise add 60 mL of 1 mol / L potassium hexamethyldisilazane. Remove the cooling bath after the solution is added, and allow to rise to room temperature naturally to react for 1.1 hours to obtain the first mixed solution:

[0130] 50 mol of 3-acetyl-4-methylpyrrole-2-carboxaldehyde was added to the first mixed solution, stirred for reaction for 0.9 h, then refluxed for reaction for 2.2 h, and cooled to room temperature to obtain a second mixed solution;

[0131] 100 mL of ice water was added to the second mixed solution to quench the reaction, and then extracted three times with 150 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate to obtain the concentrated product;

[0132] The concentrated product was dissolved in 100 mL of acetonitrile, and 55 mmol of 3-(2-pyridyl)cyclohexanone and 5 mmol of ceric ammonium nitrate were added in sequence. Oxygen was introduced and the oxygen pressure was maintained at 1 atmosphere. The temperature was raised to 80° C. and the mixture was reacted for 16 h. The solvent was then distilled off under reduced pressure, and the mixture was diluted to 100 mL with water to obtain a third mixed solution.

[0133] The third mixed liquid was extracted three times with 100 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a product which was recrystallized with ethanol to obtain the organic catalyst.

[0134] In this embodiment, the pyrrole-2-carboxaldehyde derivative is 3-acetyl-4-methylpyrrole-2-carboxaldehyde. Cyclohexanone derivative is 3-(2-pyridyl)cyclohexanone Obtaining the organic catalyst

[0135] It was named cat.5 and had a yield of 72%.

[0136] 1 H NMR (400MHz, CDCl3): δ8.75(s,1H),8.62(d,J=7.5Hz,1H),8.45(d,J=7.5Hz,1H),8.37(d,J=7.5Hz,1H),7.37-7.39 (m,1H),7.14(d,J=7.5Hz,1H),6.95(s,1H),6.88-6.91(m,1H),6.71(s,1H),2.68(s,3H),2.50(s,3H),2.12(s,3H).

[0137] ESI-TOF-HRMS calculation of C 21 H 18 N2ONa(M+Na) molecular weight 337.3778, measured 337.3751.

[0138] Example 6:

[0139] Dissolve 55 mmol of diethyl ethyl phosphate in 100 mL of ether, cool to 10°C, and dropwise add 60 mL of 1 mol / L potassium hexamethyldisilazane. Remove the cold bath after the solution is added, and allow to rise to room temperature and react for 1 hour to obtain the first mixed solution:

[0140] 50 mol of 4-tert-butylpyrrole-2-carboxaldehyde was added to the first mixed solution, stirred for reaction for 1.1 h, then refluxed for reaction for 1.8 h, and cooled to room temperature to obtain a second mixed solution;

[0141] 100 mL of ice water was added to the second mixed solution to quench the reaction, and then extracted three times with 150 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate to obtain the concentrated product;

[0142] The concentrated product was dissolved in 100 mL of acetonitrile, and 55 mmol of 3-(4-cyanophenyl)cyclohexanone and 5 mmol of ceric ammonium nitrate were added in sequence. Oxygen was introduced and the oxygen pressure was maintained at 1 atmosphere. The temperature was raised to 80°C, and the mixture was reacted for 16 hours. The solvent was then distilled off under reduced pressure, and the mixture was diluted to 100 mL with water to obtain a third mixed solution.

[0143] The third mixed liquid was extracted three times with 100 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a product which was recrystallized with ethanol to obtain the organic catalyst.

[0144] In this embodiment, the pyrrole-2-carboxaldehyde derivative is 4-tert-butylpyrrole-2-carboxaldehyde. Cyclohexanone derivative is 3-(4-cyanophenyl)cyclohexanone Obtaining the organic catalyst

[0145] It was named cat.6 and had a yield of 85%.

[0146] 1 H NMR (400MHz, CDCl3): δ8.51(d,J=7.5Hz,1H),8.22(s,1H),7.89(d,J=7.5Hz,1H),7 .82-7.85(m,4H),6.80(s,1H),6.72(s,1H),6.08(s,1H),2.68(s,3H),1.35(s,9H).

[0147] ESI-TOF-HRMS calculation of C 24 H 22 N2Na(M+Na) molecular weight 361.4438, measured 361.4406.

[0148] Example 7: Synthesis of trans-1,2-phenylethylene

[0149] 100 mmol of benzaldehyde was dissolved in 50 mL of methanol, and the resulting solution was added dropwise to 110 mmol of hydrazine hydrate at room temperature. The temperature was raised to 60°C, and the mixture was refluxed for 4 hours to form a hydrazone to obtain the first system.

[0150] Add 100 mmol of benzaldehyde to the first system, heat to 70°C, reflux for 6 h, remove the solvent by distillation under reduced pressure, and recrystallize from ethanol to obtain a dihydrazone;

[0151] The dihydrazone is reacted in the presence of the organic catalyst and light to generate the stilbene derivative.

[0152] In this embodiment, the organic catalyst is cat.1 obtained in Example 1, and the stilbene derivative trans-1,2-stilbene is obtained with a yield of 96%.

[0153] mp 123.9-124.6℃;

[0154] 1 H NMR (400MHz, CDCl3): δ7.51 (d, J = 7.2Hz, 4H), 7.37-7.33 (m, 4H), 7.27-7.22 (m, 2H), 7.10 (s, 2H);

[0155] 13C NMR (101MHz, CDCl3): δ137.4,128.8,128.7,127.7,126.6;

[0156] EI-MS m / z=180(M + ).

[0157] Example 8: Synthesis of trans-3-methoxystilbene

[0158] 100 mmol of 3-methoxybenzaldehyde was dissolved in 50 mL of methanol. The resulting solution was added dropwise to 100 mmol of hydrazine hydrate at room temperature. The temperature was raised to 65°C and refluxed for 4 hours to form a hydrazone to obtain the first system.

[0159] Add 100 mmol of benzaldehyde to the first system, heat to 60°C, reflux for 6 h, remove the solvent by distillation under reduced pressure, and recrystallize from ethanol to obtain a dihydrazone;

[0160] The dihydrazone is reacted in the presence of the organic catalyst and light to generate the stilbene derivative.

[0161] In this embodiment, the organic catalyst is cat.2 prepared in Example 2 of the present application, and the stilbene derivative trans-3-methoxystilbene is obtained with a yield of 82%.

[0162] 1 H NMR (400MHz, CDCl3): δ7.04-6.97 (m, 4H), 6.74 (d, J = 10.1Hz, 1H), 3.76 (s, 3H);

[0163] 13 C NMR (101MHz, CDCl3) δ160.0,138.8,137.3,129.7,129.1,129.7,128.7,127.7,126.6,119.3,113.4,111.8,55.3;

[0164] EI-MS m / z=210(M + ).

[0165] Example 9: Synthesis of trans-4-methylphenylethylene

[0166] 100 mmol of benzaldehyde was dissolved in 50 mL of methanol, and the resulting solution was added dropwise to 120 mmol of hydrazine hydrate at room temperature. The temperature was raised to 60°C, and the mixture was refluxed for 4 hours to form a hydrazone, thereby obtaining the first system.

[0167] Add 110 mmol of p-tolualdehyde to the first system, heat to 65°C, reflux for 6 hours, remove the solvent by distillation under reduced pressure, and recrystallize from ethanol to obtain a dihydrazone;

[0168] The dihydrazone is reacted in the presence of the organic catalyst and light to generate the stilbene derivative.

[0169] In this embodiment, the organic catalyst is cat.3 prepared in Example 3 of the present application, and the stilbene derivative trans-4-methylstilbene is prepared with a yield of 84%.

[0170] mp 121.7-122.3℃;

[0171] 1 H NMR (400MHz, CDCl3): δ7.48(d,J=7.4Hz,2H),7.39(d,J=8.0Hz,2H),7.33(t,J=7.6Hz,2H),7.24- 7.20(m,1H),7.14(d,J=7.9Hz,2H),7.08(d,J=16.5Hz,1H),7.03(d,J=16.4Hz,1H),2.34(s,3H);

[0172] 13 C NMR (101MHz, CDCl3): δ137.6,137.6,134.6,129.5,128.7,127.8,127.5,126.5,126.5,21.3;

[0173] EI-MS m / z=194(M + ).

[0174] Example 10: Synthesis of trans-4-trifluoromethylphenylethylene

[0175] 100 mmol of benzaldehyde was dissolved in 50 mL of methanol, and the resulting solution was added dropwise to 110 mmol of hydrazine hydrate at room temperature. The temperature was raised to 60°C, and the mixture was refluxed for 4 hours to form a hydrazone to obtain the first system.

[0176] Add 120 mmol of p-trifluoromethylbenzaldehyde to the first system, heat to 60°C, reflux for 6 hours, remove the solvent by distillation under reduced pressure, and recrystallize from ethanol to obtain a dihydrazone;

[0177] The dihydrazone is reacted in the presence of the organic catalyst and light to generate the stilbene derivative.

[0178] In this embodiment, the organic catalyst is cat.4 prepared in Example 4 of the present application, and the stilbene derivative trans-4-trifluoromethylstilbene is obtained with a yield of 87%.

[0179] mp 132.1-133.4℃;

[0180] 1 H NMR (400MHz, CDCl3): δ7.61-7.56(m,4H),7.52(d,J=7.4Hz,2H),7.37(t,J=7.5 Hz,2H),7.29(t,J=7.3Hz,1H),7.18(d,J=16.4Hz,1H),7.10(d,J=16.3Hz,1H);

[0181] 13 C NMR (101MHz, CDCl3): δ140.9,136.7,131.2,129.5,129.1,128.8,128.3,127.2,126.7,126.8,125.7(q,3J(C,F)=3.7Hz),123.0;

[0182] EI-MS m / z=248(M + ).

[0183] Example 11: Synthesis of trans-4-cyanostilbene

[0184] 100 mmol of benzaldehyde was dissolved in 50 mL of methanol, and the resulting solution was added dropwise to 110 mmol of hydrazine hydrate at room temperature. The temperature was raised to 65°C, and the mixture was refluxed for 4 hours to form a hydrazone to obtain the first system.

[0185] Add 100 mmol of p-cyanobenzaldehyde to the first system, heat to 60°C, reflux for 6 hours, remove the solvent by distillation under reduced pressure, and recrystallize from ethanol to obtain a dihydrazone;

[0186] The dihydrazone is reacted in the presence of the organic catalyst and light to generate the stilbene derivative.

[0187] In this embodiment, the organic catalyst is cat.5 prepared in Example 5 of the present application, and the stilbene derivative trans-4-cyanostilbene is obtained with a yield of 78%.

[0188] mp 114.9-115.2℃;

[0189] 1 H NMR (400MHz, CDCl3): δ7.51-7.49(m,2H),7.45-7.41(m,4H),7.28(t,J=7.4Hz,1H),7.24-7.18(m,1H),7.09(d,J=16.3Hz,1H),6.96(d,J=16.3Hz,1H);

[0190] 13C NMR (101MHz, CDCl3): δ141.9,136.3,132.5,132.4,128.9,128.7,127.0,126.9,126.7,119.1,110.6;

[0191] EI-MS m / z=205(M + ).

[0192] Example 12: Synthesis of trans-4-dimethylaminostilbene

[0193] 100 mmol of 4-dimethylaminobenzaldehyde was dissolved in 50 mL of methanol. The resulting solution was added dropwise to 110 mmol of hydrazine hydrate at room temperature. The temperature was raised to 65°C and refluxed for 4 hours to form a hydrazone to obtain the first system.

[0194] Add 100 mmol of benzaldehyde to the first system, raise the temperature to 65°C, reflux for 6 hours, remove the solvent by distillation under reduced pressure, and recrystallize from ethanol to obtain a dihydrazone;

[0195] The dihydrazone is reacted in the presence of the organic catalyst and light to generate the stilbene derivative.

[0196] In this embodiment, the organic catalyst is cat.6 prepared in Example 6 of the present application, and the stilbene derivative trans-4-dimethylaminostilbene is obtained with a yield of 84%.

[0197] mp 144.2-145.6℃;

[0198] 1 H NMR (400MHz, CDCl3): δ7.51(d,J=6.9Hz,2H),7.45(d,J=8.8Hz,2H),7.36(t,J=7.6Hz,2H),7.23(t ,J=7.3Hz,1H),7.09(d,J=16.4Hz,1H),6.95(d,J=16.4Hz,1H),6.76(d,J=8.8Hz,2H),3.02(s,6H);

[0199] 13 C NMR (101MHz, CDCl3): δ150.1,138.2,128.8,128.6,127.6, S22 126.7,126.0,125.8,124.4,112.5,40.5;

[0200] MS (EI) m / z: 223.1.

[0201] Example 13: Synthesis of Resveratrol

[0202] 100 mmol of 3,5-dihydroxybenzaldehyde was dissolved in 50 mL of methanol, and the resulting solution was added dropwise to 110 mmol of hydrazine hydrate at room temperature. The temperature was raised to 70°C, and the mixture was refluxed for 4 hours to form a hydrazone, thereby obtaining the first system.

[0203] Add 120 mmol of p-hydroxybenzaldehyde to the first system, heat to 60°C, reflux for 6 hours, remove the solvent by distillation under reduced pressure, and recrystallize from ethanol to obtain a dihydrazone;

[0204] The dihydrazone is reacted in the presence of the organic catalyst and light to generate the stilbene derivative.

[0205] In this embodiment, the organic catalyst is cat.3 prepared in Example 3 of the present application, and the resveratrol is prepared with a yield of 89%.

[0206] mp 253–255°C;

[0207] 1 H NMR (400MHz, CDCl3): δ4.97 (3H, s, 3×OH), 6.25 (1H, t, J = 2.2, ArH), 6.54 (2H, d, J = 2 .2,2×ArH),6.85,7.44(4H,2d,J=8.6,4×ArH),6.98,7.05(2H,2d,J=16.3,CH=CH);

[0208] 13 C NMR (101MHz, CDCl3): δ102.6, 105.7, 116.4, 126.9, 128.7, 129.3, (7×ArCH, CH=CH), 130.4 141.2 (2×ArC), 158.3, 159.6 (3×ArCO);

[0209] m / z 228(M+,100%),227(37),213(10),211(11),197(10),181(17),157(13),153(13),152(16),151(13),128(14),115(13).

[0210] Example 14: Synthesis of Resveratrol

[0211] 100 mmol of 3,5-dihydroxybenzaldehyde was dissolved in 50 mL of methanol. The resulting solution was added dropwise to 110 mmol of hydrazine hydrate at room temperature. The temperature was raised to 65°C and refluxed for 4 hours to form a hydrazone to obtain the first system.

[0212] Add 110 mmol of p-hydroxybenzaldehyde to the first system, raise the temperature to 65°C, reflux for 6 hours, remove the solvent by distillation under reduced pressure, and recrystallize from ethanol to obtain a dihydrazone;

[0213] The dihydrazone is reacted in the presence of the organic catalyst and light to generate the stilbene derivative.

[0214] In this embodiment, the organic catalyst is cat.6 prepared in Example 6 of the present application, and the resveratrol is obtained with a yield of 91%.

[0215] mp 253–255°C;

[0216] 1 H NMR (400MHz, CDCl3): δ4.97 (3H, s, 3×OH), 6.25 (1H, t, J = 2.2, ArH), 6.54 (2H, d, J = 2 .2,2×ArH),6.85,7.44(4H,2d,J=8.6,4×ArH),6.98,7.05(2H,2d,J=16.3,CH=CH);

[0217] 13 C NMR (101MHz, CDCl3): δ102.6, 105.7, 116.4, 126.9, 128.7, 129.3, (7×ArCH, CH=CH), 130.4 141.2 (2×ArC), 158.3, 159.6 (3×ArCO);

[0218] m / z 228(M+,100%),227(37),213(10),211(11),197(10),181(17),157(13),153(13),152(16),151(13),128(14),115(13).

[0219] Example 15: Synthesis of Oxidized Resveratrol

[0220] 100 mmol of 3,5-dihydroxybenzaldehyde was dissolved in 50 mL of methanol, and the resulting solution was added dropwise to 110 mmol of hydrazine hydrate at room temperature. The temperature was raised to 60°C, and the mixture was refluxed for 4 hours to form a hydrazone, thereby obtaining the first system.

[0221] Add 110 mmol of 2,4-dihydroxybenzaldehyde to the first system, heat to 70°C, reflux for 6 hours, remove the solvent by distillation under reduced pressure, and recrystallize from ethanol to obtain a dihydrazone;

[0222] The dihydrazone is reacted in the presence of the organic catalyst and light to generate the stilbene derivative.

[0223] In this embodiment, the organic catalyst is cat.2 prepared in Example 2 of the present application, and the resveratrol is obtained with a yield of 87%.

[0224] mp 196–198°C;

[0225] 1 H NMR (400MHz, CDCl3): δ6.45(1H,d,J)2.1Hz,H-3),6.37(1H,dd,J)8.4,2.1Hz,H-5),7.3 7(1H,d,J)8.4Hz,H-6),7.30(1H,d,J)16.5Hz,H-7),6.85(1H,d,J)16.5Hz,H-8),6.50;

[0226] m / z 244[M]+,226,110.

[0227] Example 16: Synthesis of Oxidized Resveratrol

[0228] 100 mmol of 3,5-dihydroxybenzaldehyde was dissolved in 50 mL of methanol. The resulting solution was added dropwise to 110 mmol of hydrazine hydrate at room temperature. The temperature was raised to 65°C and refluxed for 4 hours to form a hydrazone to obtain the first system.

[0229] Add 120 mmol of 2,4-dihydroxybenzaldehyde to the first system, heat to 65°C, reflux for 6 hours, remove the solvent by distillation under reduced pressure, and recrystallize from ethanol to obtain a dihydrazone;

[0230] The dihydrazone is reacted in the presence of the organic catalyst and light to generate the stilbene derivative.

[0231] In this embodiment, the organic catalyst is cat.5 prepared in Example 5 of the present application, and the resveratrol is obtained with a yield of 93%.

[0232] mp 196–198°C;

[0233] 1 H NMR (400MHz, CDCl3): δ6.45(1H,d,J)2.1Hz,H-3),6.37(1H,dd,J)8.4,2.1Hz,H-5),7.3 7(1H,d,J)8.4Hz,H-6),7.30(1H,d,J)16.5Hz,H-7),6.85(1H,d,J)16.5Hz,H-8),6.50;

[0234] m / z 244[M]+,226,110.

[0235] As can be seen from Examples 1-6 above, the organic catalysts prepared by the synthesis method of the present invention have high yields, with yields exceeding 72% and reaching as high as 89%. The synthesis method of the organic catalyst of the present invention has simple steps, does not require harsh process conditions, and is suitable for large-scale production. Using the organic catalyst of the present application, stilbene derivatives, including resveratrol and resveratrol oxide, can be synthesized from simple raw materials under illumination conditions, providing a green and simple method for synthesizing stilbene derivatives. Furthermore, as can be seen from Examples 7-12, the stilbene derivatives prepared from simple raw materials under illumination conditions and using one of the organic catalysts in Examples 1-6 above have high yields, reaching over 78% and reaching as high as 96%. As can be seen from Examples 13-14, the resveratrol prepared using the above-mentioned method for preparing stilbene derivatives has high yields, reaching over 89% and reaching as high as 91%. As can be seen from Examples 15-16, the resveratrol oxide prepared using the above-mentioned method for preparing stilbene derivatives has high yields, reaching over 87% and reaching as high as 93%. The method for preparing stilbene derivatives has the advantages of simple preparation process, easy controllable process conditions, low cost and suitability for large-scale production.

[0236] Those skilled in the art can make various other corresponding changes and deformations based on the technical solutions and concepts described above, and all of these changes and deformations should fall within the scope of protection of the claims of the present invention.

Claims

1. A method for synthesizing an organic catalyst, characterized in that: The organic catalyst has a structure shown in Formula I: The synthesis method comprises the following steps: Compound A reacts with compound B to generate the organic catalyst; The compound A has the structure shown in formula II: The compound B has a structure shown in formula III: Among them, R 1 、R 2 、R 3 、R 4 、R 5 Any one selected from hydrogen, alkyl, aryl or cyano; Compound A reacts with compound B in the presence of a catalyst and an oxygen atmosphere, wherein the catalyst is cerium ammonium nitrate.

2. The method for synthesizing an organic catalyst according to claim 1, characterized in that: The R 1 、R 2 、R 3 、R 4 、R 5 One selected from methyl, ethyl, n-propyl, n-butyl and tert-butyl.

3. The method for synthesizing an organic catalyst according to claim 1, characterized in that: The molar ratio of compound A to compound B is 1:(1.0-1.2); the reaction of compound A and compound B is carried out in an aprotic solvent, and the molar volume ratio of compound A to the aprotic solvent is 1 mol:(1.8-2.2)L.

4. The method for synthesizing an organic catalyst according to claim 1, characterized in that: The reaction temperature is 70~90°C, and the reaction time is 15~17h.

5. The method for synthesizing an organic catalyst according to claim 1, characterized in that: The method further comprises a pre-treatment step, which comprises the following steps: reacting diethyl ethyl phosphate with a pyrrole-2-carboxaldehyde derivative in the presence of a catalyst to generate the compound A, wherein the catalyst is potassium hexamethyldisilazane.

6. A method for synthesizing a stilbene derivative, characterized in that: The method comprises the following preparation steps: S1, mixing compound C and hydrazine hydrate, and reacting to obtain compound D; S2. reacting compound D obtained in step S1 with compound E to obtain compound F; S3, reacting the compound F obtained in step S2 under light conditions and in the presence of an organic catalyst prepared by the method for synthesizing an organic catalyst according to any one of claims 1 to 5 to obtain the stilbene derivative; Wherein compound C has the structure shown in formula IV: Compound D has the structure shown in Formula V: Compound E has the structure shown in Formula VI: Compound F has the structure shown in Formula VII: The stilbene derivative has a structure shown in Formula VIII: Among them, Ar 1 ,Ar 2 It is phenyl or phenyl substituted by one or more of alkyl, alkoxy, hydroxy, amino or trifluoromethyl.

7. The method for synthesizing a stilbene derivative according to claim 6, characterized in that: The molar ratio of the compound C, hydrazine hydrate and compound E is 1:(1.0-1.2):(1.0-1.2).

8. The method for synthesizing a stilbene derivative according to claim 6, characterized in that: The compound C is 3,5-dihydroxybenzaldehyde, and the compound E is p-hydroxybenzaldehyde or 2,4-dihydroxybenzaldehyde.

9. The method for synthesizing a stilbene derivative according to claim 6, characterized in that: The step S1 is carried out in an alcohol solvent, the reaction temperature of the step S1 is 60-70° C., and the reaction time is 3-5 hours. The reaction temperature of the step S2 is 60-70° C., and the reaction time is 5-7 hours.

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