A process for the preparation of alpha-terpinone

Abstract

The application discloses a preparation method of alpha-tuliketone, relates to organic synthesis technology utilization, and the preparation is that 4,8-dimethyl-3,7-nonadiene-2-ketone and triacetal are subjected to aldol condensation reaction under the action of acid-base bifunctional catalyst to generate alpha-tuliketone; the acid-base bifunctional catalyst is obtained by grafting organic base onto carboxylic acid functionalized mesoporous material.The acid-base bifunctional catalyst is simple in preparation, good in stability and reusable, is used for catalyzing the reaction of 4,8-dimethyl-3,7-nonadiene-2-ketone and triacetal, can directly generate target product alpha-tuliketone by one-pot method, is high in reaction activity, short in reaction period, simple in post-treatment, simplifies process, is high in yield, and the yield can reach more than 95%.

Description

A method for preparing α-draconone Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing α-turatone. Background Technology

[0002] α-Turkeyone, also known as α-damascone, is a precious fragrance. Its unique aroma has always been loved by people. Adding this substance to some expensive cosmetics can make the fragrance more delicate and the taste more mellow.

[0003] Current research on the synthesis of α-damascone began in the 1970s. In 1973, Cooks et al. designed a method for synthesizing α-damascone, in which CH2=CHCMe=CHCOMe and Me2C=CH2 undergo a Diels-Alder reaction under AlCl3 catalysis, and then the resulting compound is condensed with acetaldehyde aldol to obtain α-damascone. However, the raw materials for this synthetic route need to be prepared in-house, and the reaction conditions are relatively harsh, making it difficult to achieve industrial production. In addition, the condensation reaction of the Diels-Alder reaction product with acetaldehyde aldol requires complex operating techniques, resulting in unstable product quality and yield.

[0004] Marek and Schule et al. used allyl magnesium bromide and chain-like citral as raw materials to first prepare long-chain ketones, and finally synthesized damasones via a ring-closing reaction. In this route, the displacement of double bonds usually yields different isomers, and the purification technology of the product is not easily adopted industrially.

[0005] Citral is the preferred raw material for the synthesis of damascone due to its low cost and easy availability, and its ability to readily form the backbone required for α-turatones during the reaction. The synthesis route involves the reaction of citral with a Grignard reagent, followed by Des Martin oxidation, aldol condensation, and dehydration cyclization to finally synthesize the target product. In this route, the aldol condensation of the Des Martin oxidation product with acetaldehyde is difficult to achieve using conventional base-catalyzed methods due to its significant steric hindrance. It requires prior treatment with N-methylaniline magnesium bromide or N-methylaniline magnesium chloride to form an active intermediate before aldol condensation with acetaldehyde (J. Chem. Soc. Perkin I, 1975, 1735).

[0006] US Patent 4198309 discloses a method for synthesizing hydroxyketones from acetaldehyde using ethyl magnesium bromide and N-methylaniline as catalysts, followed by dehydration with p-toluenesulfonic acid to obtain the final product. The disadvantages of this process are its complexity, the inability to recycle the catalyst, and the demanding reaction conditions requiring an anhydrous and oxygen-free environment. It also results in high overall costs, significant waste generation, and environmental unfriendliness. Summary of the Invention

[0007] Based on the technical problems existing in the background art, the present invention proposes a method for preparing α-Turkestanone.

[0008] The present invention proposes a method for preparing α-turatone, and the synthetic route is as follows:

[0009]

[0010] The synthesis steps are as follows: Compound 3 and triacetaldehyde undergo an aldol condensation reaction in the presence of the acid-base bifunctional catalyst Pro-proximal-CA-SBA-15 or Pro-maximum-CA-SBA-15 to generate compound 4, namely α-turatone.

[0011] Furthermore, the acid-base bifunctional catalyst is obtained by grafting an organic base onto a carboxylic acid-functionalized mesoporous material; the organic base refers to an amine compound or its hydrochloride salt containing an amino group in its molecule;

[0012] Preferably, the amount of the organic base used is 3-10% of the mass of the carboxyl-functionalized mesoporous material.

[0013] The above-mentioned organic base structure contains nitrogen-containing organic groups, which provide basic sites.

[0014] Furthermore, the carboxyl-functionalized mesoporous material is a carboxyl-functionalized silicon mesoporous material;

[0015] The organic base is Boc-Lys-OMe.HCl or / and H-Lys-OMe.HCl.

[0016] Furthermore, the acid-base bifunctional catalyst is prepared as follows: tetraethyl orthosilicate and 2-cyanopropyltriethoxysilane are co-condensed, then hydrolyzed under acidic conditions to obtain a carboxyl-functionalized mesoporous material, which is then reacted with an organic base to obtain an organic base-grafted carboxyl-functionalized mesoporous material.

[0017] Furthermore, the amount of the acid-base bifunctional catalyst used is 1-5% of the mass of compound 3;

[0018] The molar ratio of compound 3 to triacetaldehyde is 1:2.

[0019] Furthermore, the solvent for the aldol condensation reaction is selected from one or more of acetonitrile, ethyl acetate, ethanol, n-hexane, cyclohexane, n-heptane, methyl tert-butyl ether, and toluene;

[0020] Preferably, the mass ratio of the solvent to compound 3 is 4-8:1.

[0021] The synthesis of α-draconone can proceed smoothly in the above solvents, especially when toluene is chosen as the solvent, the synthesis of α-draconone has excellent reaction yield.

[0022] Furthermore, the aldol condensation reaction is carried out at a temperature of 80-120°C for a reaction time of 3-7 hours.

[0023] In this invention, the synthesis temperature of α-turatone is 80-120℃, and the reaction time is 3-7 h. The optimal temperature and time parameters vary within the above range depending on the choice of different catalysts and solvents, and those skilled in the art can make selections according to the specific circumstances of this invention.

[0024] Furthermore, after the aldol condensation reaction is completed, the reaction solution is filtered, and the filtrate is distilled under reduced pressure to recover unreacted compound 3 and α-turatone, respectively.

[0025] Furthermore, the synthetic route for compound 3 is as follows:

[0026]

[0027] 1) Compound 1 undergoes a nucleophilic addition reaction with the Grignard reagent methylmagnesium bromide to generate compound 2;

[0028] 2) Compound 2 undergoes oxidation under the action of Des Martin oxidant to produce compound 3.

[0029] Further, in step 1), the solvent for the nucleophilic addition reaction is tetrahydrofuran, the reaction temperature is 0°C, and the reaction time is 30 min;

[0030] In step 2), the solvent for the oxidation reaction is dichloromethane, the reaction temperature is 20-30℃, and the reaction time is 2-3h.

[0031] Preferably, in step 1), after the nucleophilic addition reaction is completed, the reaction solution is further quenched by adding NH4Cl solution, rotary evaporated, and then extracted with ethyl acetate. The extracted organic phase is then concentrated to obtain compound 2.

[0032] Preferably, in step 2), after the oxidation reaction is completed, sodium thiosulfate solution is added to the reaction solution to separate the organic phase 1 and the aqueous phase; dichloromethane is added to the aqueous phase for extraction, and the extracted organic phase 2 and the separated organic phase 1 are combined and concentrated to obtain compound 3.

[0033] Currently, bifunctional acid-base catalysts applicable to aldol condensation reactions can be classified into three categories based on the nature of the acid and base sites they provide. The first category consists of inorganic materials (such as hydrotalcite, supported metal oxides, mixed metal oxides, and ion-exchanged montmorillonite), characterized by the presence of both acid and base sites on the catalyst surface. The second category comprises organic materials that inherently possess both acid and base sites (mainly amino acids). The third category involves introducing acid sites (phosphate groups, carboxylic acid groups, etc.) and base sites (such as amines) onto the surface of mesoporous materials. However, all of the catalysts reported above suffer from the drawback of being prone to deactivation.

[0034] The inventors discovered through their research that the choice of catalyst has a significant impact on the reaction process. The carboxyl-functionalized mesoporous material used in this invention is selected from the silicon-based support SBA-COOH. The inventors had also attempted to use non-silicon-based mesoporous materials, mainly including metal oxides, phosphates, and sulfides. However, their research revealed that these mesoporous materials have poor thermal stability and their pore structure easily collapses after calcination. In particular, non-silicon-based mesoporous molecular sieves are difficult to modify with both acids and bases. In contrast, the inventors found that mesoporous silicon molecular sieves possess excellent mechanical and thermal stability, and acid-base modification is easily achieved and performed.

[0035] Furthermore, the inventors discovered in their research that the distance between the acid-base active centers distributed on the catalyst surface is crucial for the aldol condensation reaction of this invention. Too close a distance may cause neutralization between the active centers; too far a distance will prevent multiple active centers from simultaneously activating the reactants and achieving synergistic catalysis. In particular, when applying the catalyst of this invention to the reaction of 4,8-dimethyl-3,7-nonadien-2-one and paraldehyde, the best catalytic effect is achieved using acid-base bifunctional mesoporous materials with mutually isolated acid-base active centers, such as H-lys(boc)-OMe.HCl and Boc-Lys-OMe.HCl grafted with SBA-COOH.

[0036] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0037] 1. The acid-base bifunctional catalyst of the present invention is simple to prepare and has good stability. When used to catalyze the reaction of 4,8-dimethyl-3,7-nonadien-2-one and triacetaldehyde, the target product α-turatone can be directly generated in a one-pot process. It has high reactivity, short reaction cycle, simple post-processing, simplified process, and high yield, which can reach more than 95%.

[0038] 2. The acid-base bifunctional catalyst of the present invention has good stability and can be reused. Without any treatment (including regeneration or simple cleaning), the catalyst can still have good catalytic activity after being reused 20 times. Under the same catalytic conditions, its reaction conversion rate and product yield are almost unchanged compared with the first reuse. The change range is within the allowable error range of manual operation or equipment, and the yield can still reach more than 95%.

[0039] 3. This invention directly uses metaldehyde to participate in the reaction, eliminating the need for pretreatment steps, thus simplifying the operation process. At the same time, metaldehyde is more stable and easier to store as a raw material, which also saves costs.

[0040] This invention provides a simpler and more industrially suitable method for synthesizing α-turatones, which simplifies the process steps, reduces production costs, and achieves high product yield and purity. Detailed Implementation

[0041] The technical solution of the present invention will now be described in detail through specific embodiments. Embodiments

[0042] Preparation of carboxyl-functionalized mesoporous material SBA-15-COOH

[0043] 2-Cyanopropyltriethoxysilane (CTES) was dissolved in the triblock polymer P123 (EO) 20 PO 70 EO 20 In an aqueous solution of hydrochloric acid, the mixture was stirred for 50 min in a water bath at 40°C. Then, a certain amount of tetraethyl orthosilicate (TEOS) was added dropwise, controlling the molar composition of the reaction mixture to be (1-x)TEOS:xCTES:0.017P123:5.9HCl:193H2O, where x = 0.05. The reaction mixture was stirred at 40°C for another 20 h, then loaded into a reactor and reacted at 100°C for 24 h. After cooling and filtration, the mixture was dried at 60°C to obtain the SBA-15-CN sample.

[0044] To remove the template agent and hydrolyze the cyano group to the carboxyl group, dried SBA-15-CN was dissolved in 48% sulfuric acid solution, stirred at 95°C for 24 h, then washed with deionized water, filtered, and dried at 60°C to finally obtain sample SBA-15-COOH. Example

[0045] Preparation of acid-base bifunctional catalyst 1 (Pro-proximal-CA-SBA-15)

[0046] Dissolve 0.5 g of boc-lys-OMe.HCl (excess) in 10 ml of deionized water; dissolve 0.19 g of NHS and 0.31 g of EDC in a mixture of 1.2 g of SBA-15-COOH and 2 ml of dimethyl sulfoxide (DMSO). Then, mix the two solutions and adjust the pH of the mixture to 8.0 using triethylamine. Stir at 38°C for 8 hours, centrifuge, wash with ethanol and excess water, and dry to obtain the Pro-proximal-CA-SBA-15 sample, an acid-base bifunctional catalyst with isolated acid-base active centers. Example

[0047] Preparation of acid-base bifunctional catalyst 2 (Pro-maximum-CA-SBA-15)

[0048] Dissolve 0.5 g of H-lys(boc)-OMe.HCl (excess) in 10 ml of deionized water; dissolve 0.19 g of NHS and 0.31 g of EDC in a mixture of 1.2 g of SBA-15-COOH and 2 ml of dimethyl sulfoxide (DMSO). Then, mix the two solutions and adjust the pH of the mixture to 8.0 using triethylamine. Continue stirring at 38°C for 8 h, centrifuge, wash with ethanol and excess water, and dry to obtain the Pro-maximum-CA-SBA-15 sample, an acid-base bifunctional catalyst with isolated acid-base active centers. Example

[0049] Preparation of compound 3

[0050]

[0051] 6.835 ml of citral and 20 ml of THF were mixed, and 20 ml of methyl magnesium bromide was added dropwise to the reaction system under ice-water bath conditions. After stirring in an ice-water bath for 30 min, the mixture was quenched with NH4Cl solution, and then extracted with ethyl acetate. The extracted organic phase was concentrated to obtain compound 2.

[0052] The obtained compound 2 was mixed with Desmartin oxidant at a molar ratio of 1:1 with dichloromethane. After stirring at room temperature for 2.5 h, a saturated sodium thiosulfate solution was added, and the mixture was separated into organic phase 1 and aqueous phase. Dichloromethane was added to the aqueous phase for extraction. The extracted organic phase 2 and the separated organic phase 1 were combined and concentrated to obtain compound 3. Example

[0053] Preparation of α-Turkeyone

[0054] 5.4 g of compound 3 prepared in Example 4, 5 times its mass of acetonitrile, 1.5% by mass of acid-base bifunctional catalyst 1 (Pro-proximal-CA-SBA-15, prepared in Example 2), and 8.8 g of metaldehyde were added to a reaction vessel. The mixture was stirred, then heated to 110 °C and reacted for 4 hours. After cooling, the reaction solution was discharged. The catalyst was recovered by filtration, and the filtrate was distilled under reduced pressure to recover unreacted compound 3 and α-turazone, yielding 7.29 g of α-turazone product with a purity (gas phase content) of 99.5% and a yield of 95%. Example

[0055] 5.4 g of compound 3 prepared in Example 4, 4 times its mass of toluene, 2% by mass of acid-base bifunctional catalyst 2 (Pro-maximum-CA-SBA-15, prepared in Example 3), and 8.8 g of paraldehyde were added to a reaction vessel. The mixture was stirred, then heated to 100°C and reacted. After maintaining the temperature for 5 hours, the mixture was cooled and the reaction liquid was discharged. The catalyst was recovered by filtration, and the filtrate was distilled under reduced pressure to recover unreacted compound 3 and α-turazone, respectively. 7.45 g of α-turazone was obtained, with a purity (gas phase content) of 99.5% and a yield of 97%.

[0056] The acid-base bifunctional catalysts recovered in Examples 5 and 6 were recycled and reused. Results showed that even after more than 35 consecutive uses, the reaction conversion rate and product yield remained almost unchanged compared to the initial use, with the yield still exceeding 95%. Based on its excellent stability and simple processing method, the catalyst of this invention can be used continuously in industrial applications, simplifying the process flow and significantly reducing process costs.

[0057] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing α-drakone, characterized in that, The synthesis route is as follows: The synthesis steps are as follows: Compound 3 and triacetaldehyde undergo an aldol condensation reaction in the presence of the acid-base bifunctional catalyst Pro-proximal-CA-SBA-15 or Pro-maximum-CA-SBA-15 to generate compound 4, namely α-turatone.

2. The method for preparing α-drakone according to claim 1, characterized in that, The acid-base bifunctional catalyst is obtained by grafting an organic base onto a carboxylic acid-functionalized mesoporous material; the organic base refers to an amine compound containing an amino group or its hydrochloride salt; the amount of the organic base is 3-10% of the mass of the carboxylic acid-functionalized mesoporous material.

3. The method for preparing α-drakone according to claim 2, characterized in that, The carboxyl-functionalized mesoporous material is a carboxyl-functionalized silicon mesoporous material; the organic base is Boc-Lys-OMe.HCl or / and H-Lys-OMe.HCl.

4. The method for preparing α-drakone according to claim 3, characterized in that, The acid-base bifunctional catalyst is prepared as follows: tetraethyl orthosilicate and 2-cyanopropyltriethoxysilane are co-condensed, and then hydrolyzed under acidic conditions to obtain a carboxyl-functionalized mesoporous material, which is then reacted with an organic base to obtain an organic base-grafted carboxyl-functionalized mesoporous material.

5. The method for preparing α-drakone according to claim 4, characterized in that, The amount of the acid-base bifunctional catalyst is 1-5% of the mass of compound 3; the molar ratio of compound 3 to triacetaldehyde is 1:

2.

6. The method for preparing α-drakone according to claim 5, characterized in that, The solvent for the aldol condensation reaction is selected from one or more of acetonitrile, ethyl acetate, ethanol, n-hexane, cyclohexane, n-heptane, methyl tert-butyl ether, and toluene; the mass ratio of the solvent to compound 3 is 4-8:

1.

7. The method for preparing α-drakone according to claim 6, characterized in that, The aldol condensation reaction is carried out at a temperature of 80-120℃ for 3-7 hours.

8. The method for preparing α-drakone according to claim 7, characterized in that, After the aldol condensation reaction is completed, the reaction solution is filtered, and the filtrate is distilled under reduced pressure to recover unreacted compound 3 and α-turatone, respectively.

9. The method for preparing α-drakone according to claim 8, characterized in that, The synthetic route for compound 3 is as follows: 1) Compound 1 undergoes a nucleophilic addition reaction with Grignard reagent methyl magnesium bromide to generate compound 2; 2) Compound 2 undergoes an oxidation reaction with Des Martin oxidant to generate compound 3.

10. The method for preparing α-drakone according to claim 9, characterized in that, In step 1), the solvent for the nucleophilic addition reaction is tetrahydrofuran, the reaction temperature is 0℃, and the reaction time is 30 min; in step 2), the solvent for the oxidation reaction is dichloromethane, the reaction temperature is 20-30℃, and the reaction time is 2-3 h; in step 1), after the nucleophilic addition reaction is completed, NH4Cl solution is added to the reaction solution for quenching, rotary evaporation is performed, and then ethyl acetate is added for extraction. The extracted organic phase is concentrated to obtain compound 2; in step 2), after the oxidation reaction is completed, sodium thiosulfate solution is added to the reaction solution, the layers are separated, and organic phase 1 and aqueous phase are obtained; dichloromethane is added to the aqueous phase for extraction, and the extracted organic phase 2 and the separated organic phase 1 are combined and concentrated to obtain compound 3.

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