A preparation method of 3,7-diethyl-3,7-dimethylnonane-4,6-dione

Abstract

The invention discloses a preparation method of 3,7-diethyl-3,7-dimethylnonane-4,6-dione, relates to the technical field of organic synthesis of β-diketone derivatives, and aims to solve the problems of existing methods such as high cost, complex steps, and environmental friendliness that need to be improved. The invention comprises the following steps: reacting malonic acid with N,N'-carbonyldiimidazole in an organic solvent under catalyst conditions to separate and prepare malonyldiimidazole; reacting 3-methyl-3-pentanol with trifluoromethanesulfonic anhydride in an organic solvent under catalyst conditions to separate and prepare 3-methylpentan-3-yl trifluoromethanesulfonate; and coupling reaction of malonyldiimidazole with 3-methylpentan-3-yl trifluoromethanesulfonate under nickel catalysis to separate and prepare 3,7-diethyl-3,7-dimethylnonane-4,6-dione product. The invention has a simple process flow, mild reaction conditions, low raw material cost and production cost, is environmentally friendly, has high product purity and high yield, and is conducive to large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis of beta-diketone derivatives, in particular to a method for preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione. Background Art

[0002] 3,7-Diethyl-3,7-dimethylnonane-4,6-dione, also known as diethyldimethylnonanedione or 2,2,6,6-tetraethyl-3,5-heptanedione, is a class of organic bidentate β-diketone ligand compounds containing a 1,3-dicarbonyl group. It can chelate with almost all metal ions. The metal complexes it forms with metal ions exhibit excellent thermal stabilizer, catalytic, extraction, and luminescence properties, and are widely used in fields such as thermal stabilizers, luminescence, catalysis, and solvent extraction. 3,7-Diethyl-3,7-dimethylnonane-4,6-dione exhibits excellent optical properties and is a good metal chelator. The stable complexes it forms with rare earth metals absorb ultraviolet light and transfer the absorbed energy to the rare earth metal through the β-diketone ligand, causing the rare earth ion to emit characteristic fluorescence. Therefore, its rare earth metal complexes have stable chemical properties and excellent luminescence properties, and have wide application value in organic electroluminescent materials, photoluminescent materials, fluorescent device materials, immunofluorescence analysis and light sensors.

[0003] In the invention patent application with publication number CN106397164A, entitled "A Synthesis Method for 2,2,6,6-Tetramethyl-3,5-Heptanedione", a classic synthesis method for β-diketone compounds is disclosed, namely, the product is prepared by ketoester condensation of an ester and a ketone under strongly alkaline conditions. The reaction is similar to the ester-ester condensation reaction. The α-H activity of the ketone is greater than that of the ester. Under strongly alkaline conditions, the ketone is more likely to remove a proton to form a carbon anion, which then undergoes nucleophilic addition to the ester carbonyl to form a β-diketone compound. However, in general, the more complex the structure of the ketone, the weaker the reaction activity tends to be. Because the structure of 3,7-diethyl-3,7-dimethylnonane-4,6-dione contains three alkyl groups, which greatly increase its steric hindrance, it is very difficult to prepare 3,7-diethyl-3,7-dimethylnonane-4,6-dione by the condensation reaction of ketone and ester.

[0004] The invention patent with announcement number CN110922429B, entitled Organic Light-Emitting Material Containing Auxiliary Ligand, discloses a method for preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione. The method uses ethyl 2-ethylbutyrate as a starting material, firstly extracts α-hydrogen methylation to prepare ethyl 2-ethyl-2-methylbutyrate by lithium diisopropylamide (LDA), then undergoes ester hydrolysis reaction to produce 2-ethyl-2-methylbutyric acid, and 2-ethyl-2-methylbutyric acid is dehydroxymethylated under the action of methyllithium to prepare 3-ethyl-3-methyl-pentane-2 The invention relates to a method for preparing 3-ethyl-3-methyl-pentan-2-one by reacting 2-ethyl-2-methylbutyric acid with oxalyl chloride to prepare 2-ethyl-2-methylbutyryl chloride, and finally condensing 3-ethyl-3-methyl-pentan-2-one and 2-ethyl-2-methylbutyryl chloride under the action of LDA to prepare 3,7-diethyl-3,7-dimethylnonane-4,6-dione, with an overall reaction yield of 21%. The method adopts 2-ethyl-2-methylbutyryl chloride with higher reaction activity instead of 2-ethyl-2-methylbutyric acid methyl ester to carry out condensation reaction with 3-ethyl-3-methyl-pentan-2-one to prepare 3-ethyl-3-methyl-pentan-2-one. The above two methods first synthesize 2-ethyl-2-methylbutyric acid methyl ester or 2-ethyl-2-methylbutyryl chloride and 3-ethyl-3-methyl-pentan-2-one, and require five steps to prepare 3,7-diethyl-3,7-dimethylnonane-4,6-dione. The preparation process requires multiple ultra-low temperature (-78°C) reactions and consumes a large amount of LDA and methyllithium reagents. Therefore, the raw materials are expensive and difficult to obtain, and the synthesis steps are long, the total yield is low, and the production cost is high, resulting in poor economic efficiency.

[0005] The invention patent application with publication number CN112174788A, entitled "A method for preparing 2,2,6,6-tetraethyl-3,5-heptanedione," discloses a method of using malonic acid as a starting material, reacting it with an acyl chloride reagent to prepare malonyl chloride, then reacting it with dimethylhydroxylamine hydrochloride to prepare N,N'-dimethoxy-N,N'-dimethylmalonamide, and finally reacting it with 3-methylpentanemagnesium chloride to prepare 3,7-diethyl-3,7-dimethylnonane-4,6-dione. The maximum total yield of the reaction is approximately 66%. The preparation process is carried out in three steps and the reaction conditions are relatively mild. However, the method uses expensive and difficult-to-obtain 3-methylpentanemagnesium chloride as a reaction raw material. The preparation of malonyl chloride requires specialized equipment, generates a large amount of three wastes, and is highly polluting. Malonyl chloride is highly toxic and corrosive, which does not conform to the development trends of green chemistry. The method also has the disadvantages of high production equipment requirements, high raw material costs, and high pollution.

[0006] In summary, existing synthesis methods generally require multiple reactions, resulting in expensive and difficult-to-obtain raw materials, long preparation steps, low overall yields, and demanding equipment. Organic solvent recovery is difficult, resulting in significant amounts of waste, waste, and other wastes. This creates significant environmental concerns, poor economic efficiency, and high production costs, severely hindering the industrial application of 3,7-diethyl-3,7-dimethylnonane-4,6-dione. Therefore, it is necessary to improve existing preparation methods and develop a new, more economical, green, and efficient synthetic route while ensuring high product yields. Summary of the Invention

[0007] The purpose of the present invention is to provide a method for preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione, so as to solve the problems of the existing method such as high cost, complicated steps, and environmental pollution, which need to be improved.

[0008] To achieve the above object, the present invention provides the following technical solution: a method for preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione, comprising the following specific steps:

[0009] S1. Malonic acid reacts with N,N'-carbonyldiimidazole in an organic solvent under catalyst conditions to separate and prepare malonyldiimidazole. The reaction process is as follows:

[0010]

[0011] S2.3-Methyl-3-pentanol and trifluoromethanesulfonic anhydride react in an organic solvent under catalyst conditions to separate and prepare 3-methylpentan-3-yl trifluoromethanesulfonate. The reaction process is as follows:

[0012]

[0013] S3. The products of step S1 and step S2 are subjected to a nickel-catalyzed coupling reaction to separate and obtain 3,7-diethyl-3,7-dimethylnonane-4,6-dione product, the reaction process of which is:

[0014]

[0015] Preferably, in the above step S1, the organic solvent is one or more of dichloromethane, 1,2-dichloroethane, and 2-methyltetrahydrofuran, and the catalyst is selected from triethylamine or pyridine; and the molar ratio of malonic acid, N,N'-carbonyldiimidazole, and the catalyst is 1:(2.05-2.50):(0.02-0.1).

[0016] Preferably, in the above step S2, the organic solvent is one or more of dichloromethane, 1,2-dichloroethane, and 2-methyltetrahydrofuran, and the catalyst is selected from pyridine, triethylamine, dihydroxy-1,3-dimethyl-4,6-diazacyclooctane or 4-dimethylaminopyridine; the molar ratio of 3-methyl-3-pentanol, trifluoromethanesulfonic anhydride and catalyst is 1:(1.05-1.25):(0.02-0.05).

[0017] Preferably, the separation in steps S1 and S2 includes: after the reaction is completed, neutralizing the reaction system with a weakly acidic aqueous phase extract to neutrality, separating the liquids, washing the oil phase with water several times, drying and removing water, and then distilling under reduced pressure to remove the solvent; the weakly acidic aqueous phase extract is selected from a saturated strong acid and weak base salt solution, an organic weak acid, and a dilute solution of a strong acid, and is used to quench the reaction, adjust the pH to neutrality, and extract the catalyst.

[0018] Preferably, in the above steps S1 and S2, the reaction temperature is 0°C to 30°C, and the reaction time is 2 to 10 hours.

[0019] More preferably, in the above step S2, 3-methyl-3-pentanol and the catalyst are first added to the organic solvent, stirred evenly, and then trifluoromethanesulfonic anhydride is added in batches at 0°C. After the addition is completed, the reaction is carried out at 0°C for a period of time, and then the temperature is raised to 30°C to continue the reaction.

[0020] Preferably, the coupling reaction in step S3 comprises the following steps: under nitrogen protection, adding malonyl diimidazole, 3-methylpentan-3-yl trifluoromethanesulfonate, a catalyst, and a ligand, a reducing agent, and an additive required for the coupling reaction to an organic solvent, heating the mixture to 60-100° C., and reacting the mixture under stirring until sufficient reaction is completed.

[0021] Preferably, in the above step S3, the catalyst is selected from nickel chloride, nickel bromide, nickel iodide, nickel trifluoromethanesulfonate, nickel acetylacetonate, and nickel acetate;

[0022] Preferably, in the above step S3, the ligand is selected from:

[0023]

[0024] Preferably, in the above step S3, the reducing agent is zinc powder;

[0025] Preferably, in the above step S3, the additive is selected from zinc bromide, zinc chloride, zinc iodide, and potassium fluoride;

[0026] Preferably, in the above step S3, the organic solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide or N,N-dimethylacetamide;

[0027] Preferably, in the above step S3, the molar ratio of malonyl diimidazole to 3-methylpentan-3-yl trifluoromethanesulfonate is 1:(2.1-2.5), the molar ratio of malonyl diimidazole to the catalyst is 1:(0.02-0.1), the molar ratio of malonyl diimidazole to the ligand is 1:(0.03-0.15), the molar ratio of malonyl diimidazole to the reducing agent is 1:(1.5-3), and the molar ratio of malonyl diimidazole to the additive is 1:(1.0-1.5).

[0028] Preferably, the separation in step S3 comprises the following steps: after the reaction is completed, cooling to room temperature, rapid silica gel column chromatography, adding water to the chromatographic solution to dilute the liquid, extracting the oil phase, drying, distilling and concentrating to remove the organic solvent, and distilling under reduced pressure to obtain the product; if the organic solvent used in the coupling reaction is easily soluble in water, the organic solvent is first distilled under reduced pressure before chromatography, and then petroleum ether, n-hexane, dichloromethane or 2-methyltetrahydrofuran is added for dilution, and then silica gel column chromatography is performed.

[0029] Preferably, the purity of the 3,7-diethyl-3,7-dimethylnonane-4,6-dione product is greater than 99%, and the total yield is 68-85%.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] 1. The preparation method of 3,7-diethyl-3,7-dimethylnonane-4,6-dione uses malonic acid and 3-methyl-3-pentanol as starting materials to synthesize malonyldiimidazole and 3-methylpentan-3-yl trifluoromethanesulfonate, and then prepares the product through a nickel-catalyzed coupling reaction. Compared with the existing method, the process flow is simple, the reaction conditions are mild, the raw material cost and production cost are low, and it is environmentally friendly. It provides a new method for synthesizing benzene 3,7-diethyl-3,7-dimethylnonane-4,6-dione, which is economical, green and efficient.

[0032] 2. The method for preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione comprises preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione by a coupling reaction of a reaction intermediate malonyldiimidazole and 3-methylpentan-3-yl trifluoromethanesulfonate catalyzed by a nickel salt. The product has high purity, which can reach more than 99%, and a high total reaction yield, which can easily reach about 75%. The addition of a reducing agent and an additive during the reaction can also effectively reduce the formation of by-products and improve the selectivity of the reaction. The reaction by-products are removed during the water washing process, which is more conducive to obtaining a high yield and high purity.

[0033] 3. The preparation method of 3,7-diethyl-3,7-dimethylnonane-4,6-dione: the reaction solvent of the three-step reaction can be recovered and reused through simple treatments such as distillation and drying, which can further effectively control production costs.

[0034] 4. The preparation method of 3,7-diethyl-3,7-dimethylnonane-4,6-dione greatly reduces the cost and has excellent product purity and yield, which is conducive to large-scale production and has industrial feasibility. It is also conducive to expanding the application of 3,7-diethyl-3,7-dimethylnonane-4,6-dione in the fields of optics, medicine, etc. DETAILED DESCRIPTION

[0035] A method for preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione comprises the following specific steps:

[0036] S1. Malonic acid and N,N'-carbonyldiimidazole are reacted in an organic solvent under catalyst conditions. For reference, the reaction temperature can be 0°C to 30°C and the reaction time can be 2 to 10 hours. After the reaction, malonyldiimidazole is separated and obtained. The organic solvent can be one or more of dichloromethane, 1,2-dichloroethane, and 2-methyltetrahydrofuran. The catalyst can be selected from triethylamine or pyridine. Preferably, the molar ratio of malonic acid, N,N'-carbonyldiimidazole, and catalyst is 1:(2.05-2.50):(0.02-0.1).

[0037] S2.3-methyl-3-pentanol and trifluoromethanesulfonic anhydride are reacted in an organic solvent under catalyst conditions. For reference, the reaction temperature can be 0°C to 30°C, and the reaction time can be 2 to 10 hours. More preferably, 3-methyl-3-pentanol and the catalyst can be first added to the organic solvent, stirred evenly, and then trifluoromethanesulfonic anhydride is added in batches at 0°C. After the addition is complete, the reaction is carried out at 0°C for a period of time, and then the temperature is raised to 30°C to continue the reaction. After the reaction, 3-methylpentan-3-yl trifluoromethanesulfonate is separated. The organic solvent can be one or more of dichloromethane, 1,2-dichloroethane, and 2-methyltetrahydrofuran. The catalyst can be selected from pyridine, triethylamine, dihydroxy-1,3-dimethyl-4,6-diazacyclooctane or 4-dimethylaminopyridine. Preferably, the molar ratio of 3-methyl-3-pentanol, trifluoromethanesulfonic anhydride and catalyst is 1:(1.05-1.25):(0.02-0.05);

[0038] S3. The products of step S1 and step S2 are subjected to a nickel-catalyzed coupling reaction. Specifically, the coupling reaction is generally carried out under nitrogen protection, by adding malonyldiimidazole, 3-methylpentan-3-yl trifluoromethanesulfonate, a catalyst, and a ligand, a reducing agent, and an additive required for the coupling reaction to an organic solvent, raising the temperature to 60-100° C. and stirring the reaction until sufficient reaction is completed. For reference:

[0039] The catalyst is selected from nickel chloride, nickel bromide, nickel iodide, nickel trifluoromethanesulfonate, nickel acetylacetonate, and nickel acetate;

[0040] The ligand is selected from:

[0041]

[0042] The reducing agent is zinc powder, which is beneficial to improving the reaction selectivity and reducing the formation of by-products;

[0043] The additive is selected from zinc bromide, zinc chloride, zinc iodide, and potassium fluoride. The additive can improve the stability of the reaction intermediate, reduce the occurrence of side reactions, improve the selectivity of the reaction, increase the reaction conversion rate and product purity, and help improve the yield;

[0044] The organic solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide or N,N-dimethylacetamide, which is used to dissolve organic compounds such as reaction raw materials and ligands, provide a homogeneous reaction environment and facilitate the control of a constant reaction temperature;

[0045] The proportions of the raw materials can be configured as follows: the molar ratio of malonyl diimidazole to 3-methylpentan-3-yl trifluoromethanesulfonate is 1:(2.1-2.5), the molar ratio of malonyl diimidazole to the catalyst is 1:(0.02-0.1), the molar ratio of malonyl diimidazole to the ligand is 1:(0.03-0.15), the molar ratio of malonyl diimidazole to the reducing agent is 1:(1.5-3), and the molar ratio of malonyl diimidazole to the additive is 1:(1.0-1.5);

[0046] After the coupling reaction is completed, the product 3,7-diethyl-3,7-dimethylnonane-4,6-dione can be obtained by separation.

[0047] In a preferred embodiment, the separation in steps S1 and S2 includes: after the reaction is completed, neutralizing the reaction system with a weakly acidic aqueous extract to neutrality, separating the liquids, washing the oil phase with water several times, drying and removing water, and then distilling under reduced pressure to remove the solvent; since the catalysts in steps S1 and S2 are soluble in both organic solvents and water, they are not easy to purify simply, which will affect the third step of the coupling reaction. If a strong base is added, the reaction product may be partially destroyed. Therefore, the use of saturated sodium chloride or strong base for quenching and extraction has limitations; the weakly acidic aqueous extract can be selected from a saturated strong acid and weak base salt solution, an organic weak acid, or a dilute solution of a strong acid, and is used to quench the reaction, adjust the pH to neutrality, and extract the catalyst. Specifically, it can be selected from saturated ammonium chloride, saturated ammonium sulfate, saturated ammonium nitrate, saturated sodium bisulfite, citric acid, gluconic acid, dilute hydrochloric acid, dilute sulfuric acid, etc., preferably a saturated ammonium chloride solution;

[0048] In a preferred embodiment, the separation in step S3 comprises the following steps: after the reaction is completed, cooling to room temperature, rapid silica gel column chromatography, adding water to the chromatographic solution to dilute the separation, extracting the oil phase, drying, distilling and concentrating to remove the organic solvent, and distilling under reduced pressure to obtain the product; if the organic solvent used in the coupling reaction is easily soluble in water, the organic solvent is first distilled under reduced pressure before chromatography, and then petroleum ether, n-hexane, dichloromethane or 2-methyltetrahydrofuran is added for dilution, and then silica gel column chromatography is performed;

[0049] The purity of the 3,7-diethyl-3,7-dimethylnonane-4,6-dione product prepared by the method is greater than 99%, and the total yield is 68-85%.

[0050] Example 1:

[0051] (1) Malonic acid (99%, 104.1 g, 1.0 mol), N,N'-carbonyldiimidazole (99%, 340.5 g, 2.1 mol), triethylamine (98%, 5.1 g, 0.05 mol) and 500 mL of 2-methyltetrahydrofuran were added to a reaction flask, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution was added to neutralize the mixture, and the organic phase was separated. The organic phase was washed with water three times, dried to remove water, and then 2-methyltetrahydrofuran was removed by distillation under reduced pressure to obtain 195 g of malonyldiimidazole;

[0052] (2) 3-Methyl-3-pentanol (99%, 205.0 g, 2.0 mol), 4-dimethylaminopyridine (99%, 7.3 g, 0.06 mol) and 1000 mL of 2-methyltetrahydrofuran were added to the reaction flask, and after stirring evenly, trifluoromethanesulfonic anhydride (99%, 578.4 g, 2.1 mol) was added in batches to the reaction flask at 0°C. After the addition of trifluoromethanesulfonic anhydride, the reaction was carried out at 0°C for 2 hours, and then the temperature of the reaction system was raised to 30°C and the reaction was continued for 8 hours. After the reaction was completed, the reaction system was neutralized to neutrality by dissolving with saturated ammonium chloride, and the liquid was separated. The organic phase was washed with water 3 times, dried to remove water, and then 2-methyltetrahydrofuran was removed by distillation under reduced pressure to obtain 438.0 g of 3-methylpentan-3-yl trifluoromethanesulfonate.

[0053] (3) Under nitrogen protection, malonyl diimidazole (102.1 g, 0.5 mol) and 3-methylpentan-3-yl trifluoromethanesulfonate (257.4 g, 1.1 mol) prepared in steps (1) and (2), 5.5 g nickel bromide (99%, 25 mmol), 16.8 g ligand L1 (99%, 37.5 mmol), 55.0 g zinc powder (99%, 1.0 mol), 112.6 g zinc bromide (99%, 0.5 mol) and 1000 mL of ethanol were added to the reaction flask. After the addition of the materials, the temperature was raised to 60° C., the stirring speed was 550 rpm, and the reaction was kept warm for 16 hours. After the reaction, the mixture was cooled to room temperature and subjected to rapid silica gel column chromatography. The chromatographic solution was diluted with water and separated. The organic liquid was extracted with a saturated sodium chloride aqueous solution and dried. The 2-methyltetrahydrofuran was removed by distillation and concentrated. Then, 188.7 g of 3,7-diethyl-3,7-dimethylnonane-4,6-dione was obtained by vacuum distillation. The high performance gas chromatography (GC) content was 99.1%, and the total yield of the three-step reaction was 78.5%.

[0054] Example 2:

[0055] (1) Malonic acid (99%, 104.1 g, 1.0 mol), N,N'-carbonyldiimidazole (99%, 405.5 g, 2.5 mol), pyridine (98%, 7.9 g, 0.1 mol) and 500 mL of dichloromethane were added to a reaction flask and stirred at room temperature for 2 hours. After the reaction was completed, saturated ammonium chloride aqueous solution was added to neutralize the mixture and separate the liquids. The organic phase was washed with water three times, dried to remove water, and then dichloromethane was removed by vacuum distillation to obtain 198 g of malonyldiimidazole;

[0056] (2) 3-Methyl-3-pentanol (99%, 205.0 g, 2.0 mol), dihydroxy-1,3-dimethyl-4,6-diazacyclooctane (99%, 20.6 g, 0.1 mol) and 1000 mL of 2-methyltetrahydrofuran were added to the reaction flask, and after stirring evenly, trifluoromethanesulfonic anhydride (99%, 661.0 g, 2.4 mol) was added in batches to the reaction flask at 0°C. After the addition of trifluoromethanesulfonic anhydride, the reaction was carried out at 0°C for 2 hours, and then the temperature of the reaction system was raised to 30°C and the reaction was continued for 8 hours. After the reaction was completed, the reaction system was neutralized to neutrality with saturated ammonium chloride, and the liquid was separated. The organic phase was washed with water 3 times, dried to remove water, and then distilled under reduced pressure to remove dichloromethane to obtain 446.0 g of 3-methylpentan-3-yl trifluoromethanesulfonate.

[0057] (3) Under nitrogen protection, malonyl diimidazole (102.1 g, 0.5 mol) and 3-methylpentan-3-yl trifluoromethanesulfonate (245.7 g, 1.05 mol) prepared in steps (1) and (2), 3.1 g nickel iodide (99%, 10 mmol), 16.8 g ligand L1 (99%, 37.5 mmol), 55.0 g zinc powder (99%, 1.0 mol), 159.6 g zinc iodide (99%, 0.5 mol) and 1000 mL After the addition of the materials, the temperature was raised to 60° C., the stirring speed was 550 rpm, and the reaction was kept warm for 16 hours. After the reaction, the mixture was cooled to room temperature and subjected to rapid silica gel column chromatography. The chromatographic solution was diluted with water and separated. The organic liquid was extracted with a saturated sodium chloride aqueous solution and dried. The 2-methyltetrahydrofuran was removed by distillation and concentrated. Then, 176.0 g of 3,7-diethyl-3,7-dimethylnonane-4,6-dione was obtained by distillation under reduced pressure. The high performance gas chromatography (GC) content was 99.2%, and the total yield of the three-step reaction was 73.2%.

[0058] Example 3:

[0059] Step (1) and step (2) are the same as those in Example 1 in terms of reaction conditions and treatment methods; (3) under nitrogen protection, malonyl diimidazole (102.1 g, 0.5 mol) and 3-methylpentan-3-yl trifluoromethanesulfonate (292.5 g, 1.25 mol) prepared in steps (1) and (2), 5.5 g nickel bromide (99%, 25 mmol), 18.3 g ligand L2 (99%, 37.5 mmol), 82.5 g zinc powder (99%, 1.5 mol), 112.6 g zinc bromide (99%, 0.5 mol) and 6 00mL of N,N-dimethylformamide; after the addition, the temperature was raised to 80°C, the stirring speed was 550rpm, and the reaction was kept warm for 16 hours; after the reaction, N,N-dimethylformamide was removed by distillation under reduced pressure, and the mixture was cooled to room temperature and petroleum ether was added for rapid silica gel column chromatography. The chromatographic liquid was diluted with water and separated, and the organic liquid was extracted with a saturated sodium chloride aqueous solution and dried. The petroleum ether was removed by distillation and then 193.4g of 3,7-diethyl-3,7-dimethylnonane-4,6-dione was obtained by distillation under reduced pressure, with a high performance gas chromatography (GC) content of 99.1%. The total yield of the three-step reaction was 80.6%.

[0060] Example 4:

[0061] Step (1) and step (2) are the same as those in Example 1 in terms of reaction conditions and treatment methods;

[0062] (3) Under nitrogen protection, malonyl diimidazole (102.1 g, 0.5 mol) and 3-methylpentan-3-yl trifluoromethanesulfonate (257.4 g, 1.1 mol) prepared in steps (1) and (2), 8.9 g nickel acetate (99%, 50 mmol), 41.0 g ligand L3 (99%, 75.0 mmol), 82.5 g zinc powder (99%, 1.5 mol), 43.6 g potassium fluoride (99%, 0.75 mol) and 1000 mL of tetrahydrofuran were added to the reaction flask; after the addition of the materials, , heating to 60°C, stirring at 550 rpm, and keeping warm for 16 hours; after the reaction, cooling to room temperature, adding petroleum ether for rapid silica gel column chromatography, adding water to the chromatographic liquid to dilute the liquid, extracting the organic liquid with a saturated sodium chloride aqueous solution, washing the inorganic liquid with dichloromethane, mixing the organic liquids and drying them, distilling and concentrating to remove 2-methyltetrahydrofuran, and then distilling under reduced pressure to obtain 190.5 g of 3,7-diethyl-3,7-dimethylnonane-4,6-dione, with a high-performance gas chromatography (GC) content of 99.0%, and a total yield of 79.4% for the three-step reaction.

[0063] Example 5:

[0064] Step (1) and step (2) are the same as those in Example 1 in terms of reaction conditions and treatment methods;

[0065] (3) Under nitrogen protection, malonyl diimidazole (102.1 g, 0.5 mol) and 3-methylpentan-3-yl trifluoromethanesulfonate (240.0 g, 1.025 mol) prepared in steps (1) and (2), 17.8 g nickel trifluoromethanesulfonate (99%, 50 mmol), 8.8 g ligand L4 (99%, 15 mmol), 42.3 g zinc powder (99%, 0.75 mol), 29.0 g potassium fluoride (99%, 0.5 mol) and 1000 m L of 2-methyltetrahydrofuran; after the addition of the materials, the temperature was raised to 80° C., the stirring speed was 550 rpm, and the reaction was kept warm for 24 hours; after the reaction, the mixture was cooled to room temperature and subjected to rapid silica gel column chromatography, the chromatographic liquid was diluted with water and separated, the organic liquid was extracted with a saturated sodium chloride aqueous solution, dried, and distilled and concentrated to remove 2-methyltetrahydrofuran, and then distilled under reduced pressure to obtain 163.6 g of 3,7-diethyl-3,7-dimethylnonane-4,6-dione, with a high-performance gas chromatography (GC) content of 99.3%, and a total yield of 68.2% for the three-step reaction.

[0066] Example 6:

[0067] Step (1) and step (2) are the same as those in Example 1 in terms of reaction conditions and treatment methods;

[0068] (3) Under nitrogen protection, malonyl diimidazole (102.1 g, 0.5 mol) and 3-methylpentan-3-yl trifluoromethanesulfonate (240.0 g, 1.025 mol) prepared in steps (1) and (2), 5.5 g nickel bromide (99%, 25 mmol), 22 g ligand L4 (99%, 37.5 mmol), 82.5 g zinc powder (99%, 1.5 mol), 29.0 g potassium fluoride (99%, 0.5 mol) and 1000 mL of 2-methyltetrahydrofuran; after the addition of the materials, the temperature was raised to 80°C, the stirring speed was 550rpm, and the reaction was kept warm for 16 hours; after the reaction was completed, the mixture was cooled to room temperature and subjected to rapid silica gel column chromatography, the chromatographic solution was diluted with water and separated, the organic liquid was extracted with a saturated sodium chloride aqueous solution, dried, and distilled and concentrated to remove 2-methyltetrahydrofuran, and then distilled under reduced pressure to obtain 176.5g of 3,7-diethyl-3,7-dimethylnonane-4,6-dione, with a high-performance gas chromatography (GC) content of 99.1%, and a total yield of 73.5% for the three-step reaction.

[0069] The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included in the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection defined by the claims.

[0070] Any matters not described in detail in the present invention are well-known technologies to those skilled in the art.

Claims

1. A method for preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione, characterized in that: The specific steps include: S1. reacting malonic acid with N,N'-carbonyldiimidazole in an organic solvent under catalyst conditions to separate and obtain malonyldiimidazole, wherein the catalyst is selected from triethylamine or pyridine; S2. 3-Methyl-3-pentanol is reacted with trifluoromethanesulfonic anhydride in an organic solvent in the presence of a catalyst to separate and prepare 3-methylpentan-3-yl trifluoromethanesulfonate, wherein the catalyst is selected from pyridine, triethylamine, dihydroxy-1,3-dimethyl-4,6-diazacyclooctane or 4-dimethylaminopyridine; S3. The products of step S1 and step S2 are subjected to a nickel-catalyzed coupling reaction to separate and obtain 3,7-diethyl-3,7-dimethylnonane-4,6-dione product, wherein the nickel-catalyzed catalyst is selected from nickel chloride, nickel bromide, nickel iodide, nickel trifluoromethanesulfonate, nickel acetylacetonate, and nickel acetate; The ligand required for the coupling reaction is selected from: The additive required for the coupling reaction is selected from zinc bromide, zinc chloride, zinc iodide, and potassium fluoride; The reducing agent required for the coupling reaction is zinc powder.

2. The method for preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione according to claim 1, wherein: In step S1, the organic solvent is one or more of dichloromethane, 1,2-dichloroethane, and 2-methyltetrahydrofuran; the molar ratio of malonic acid, N,N'-carbonyldiimidazole, and the catalyst is 1:(2.05-2.50):(0.02-0.1).

3. The method for preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione according to claim 1, wherein: In step S2, the organic solvent is one or more of dichloromethane, 1,2-dichloroethane, and 2-methyltetrahydrofuran; the molar ratio of 3-methyl-3-pentanol, trifluoromethanesulfonic anhydride, and the catalyst is 1:(1.05-1.25):(0.02-0.05).

4. The method for preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione according to claim 1, wherein: The separation in steps S1 and S2 includes: after the reaction is completed, neutralizing the reaction system to neutrality with a weakly acidic aqueous phase extract, separating the liquids, washing the oil phase with water several times, drying and removing water, and then distilling under reduced pressure to remove the solvent; the weakly acidic aqueous phase extract is selected from a saturated strong acid and weak base salt solution, an organic weak acid, and a dilute solution of a strong acid, and is used to quench the reaction, adjust the pH to neutrality, and extract the catalyst.

5. The method for preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione according to claim 1, wherein: In the steps S1 and S2, the reaction temperature is 0° C. to 30° C., and the reaction time is 2 to 10 hours.

6. The method for preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione according to claim 5, wherein: In step S2, 3-methyl-3-pentanol and a catalyst are first added to an organic solvent and stirred evenly, and then trifluoromethanesulfonic anhydride is added in batches at 0° C. After the addition is complete, the mixture is reacted at 0° C. for a period of time, and then the temperature is raised to 30° C. to continue the reaction fully.

7. The method for preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione according to claim 1, wherein: The coupling reaction of step S3 comprises the following steps: under nitrogen protection, adding malonyl diimidazole, 3-methylpentan-3-yl trifluoromethanesulfonate, a catalyst, and a ligand, a reducing agent, and an additive required for the coupling reaction to an organic solvent, heating the solvent to 60-100° C., and reacting the solvent under stirring until the reaction is complete.

8. The method for preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione according to claim 7, wherein: In step S3, the organic solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide or N,N-dimethylacetamide; In step S3, the molar ratio of malonyl diimidazole to 3-methylpentan-3-yl trifluoromethanesulfonate is 1:(2.1-2.5), the molar ratio of malonyl diimidazole to the catalyst is 1:(0.02-0.1), the molar ratio of malonyl diimidazole to the ligand is 1:(0.03-0.15), the molar ratio of malonyl diimidazole to the reducing agent is 1:(1.5-3), and the molar ratio of malonyl diimidazole to the additive is 1:(1.0-1.5).

9. The method for preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione according to claim 1, wherein: The separation in step S3 The method comprises the following steps: cooling to room temperature after the reaction is completed, performing rapid silica gel column chromatography, adding water to the chromatography liquid to dilute and separate the liquid, extracting the oil phase, drying, distilling and concentrating to remove the organic solvent, and performing reduced pressure distillation to obtain the product; if the organic solvent used in the coupling reaction is easily soluble in water, the organic solvent is first removed by reduced pressure distillation before chromatography, and then petroleum ether, n-hexane, dichloromethane or 2-methyltetrahydrofuran is added for dilution, and then silica gel column chromatography is performed.

10. The method for preparing 3,7-diethyl-3,7-dimethylnonane-4,6-dione according to any one of claims 1 to 9, characterized in that: The purity of the 3,7-diethyl-3,7-dimethylnonane-4,6-dione product is greater than 99%, and the total yield is 68-85%.

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