Preparation method of (Z)-undec-8-ene-2, 5-diketone

Abstract

The invention belongs to the technical field of synthesis of cis-jasmone, and relates to synthesis of a cis-jasmone intermediate, in particular to a preparation method of (Z)-undec-8-ene-2, 5-diketone. Comprising the step of preparing (Z)-undec-8-ene-2, 5-diketone by taking acetyl propionyl halide and a dihydroxy pyrimidine compound as initial raw materials according to the following reaction route, the preparation method comprises the following steps: uniformly mixing a solution of a (Z)-3-hexene magnesium halide Grignard reagent with a solution of a compound shown in a formula 3 under the condition of-15 to 15 DEG C, heating to 15 to 45 DEG C, reacting for 1 to 3 hours, cooling to 0 to 5 DEG C, carrying out quenching reaction, then adjusting the pH value to 1 to 3, heating to 15 to 45 DEG C, and reacting for 2 to 3 hours; wherein X1 is halogen, X2 is halogen, and R is H or methyl. The preparation method provided by the invention has the characteristics of easily available raw materials, higher isomer Z configuration proportion, simpler operation and the like, and is suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of cis-jasmone synthesis, relates to the synthesis of a cis-jasmone intermediate, and particularly relates to a preparation method of (Z)-undec-8-ene-2,5-dione. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance understanding of the overall background of the invention and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to those skilled in the art.

[0003] Cis-jasmone is an internationally recognized safe synthetic fragrance with an aroma similar to jasmine and is the key aroma component of jasmine oil. There are many methods for synthesizing cis-jasmone, such as: Route 1:

[0004] Route 2:

[0005] Route 3:

[0006] Route 4:

[0007] Among them, in route one, alkylation reaction, Wittig reaction, and acidic ring opening are required, which will produce a large amount of acidic waste liquid, and a large amount of triphenylphosphine oxide is produced as a by-product, and the Z, E isomers of the product are difficult to control. Therefore, the process is not green and environmentally friendly, and the product quality is poor. In route two, catalysts such as tribromide, butyl lithium and Cr(CO)6 are used, which are highly polluting. At the same time, butyl lithium and hydrogen reduction are highly dangerous, which is not conducive to industrial production. Route three has problems such as long route and cumbersome operation, which is not conducive to industrial production. Route four uses chemical reagents such as LDA and sodium amalgam desulfonylation. The reaction conditions are harsh, the pollution is high, and it is not conducive to industrial production. It can be seen from the above reaction routes that most of the synthetic routes require the synthesis of (Z)-undec-8-ene-2,5-dione, as shown in Formula 1:

[0008] Therefore, (Z)-undec-8-ene-2,5-dione is a key intermediate in the synthesis of cis-jasmone. To achieve high-quality industrial production of cis-jasmone, further exploration of the synthesis of (Z)-undec-8-ene-2,5-dione is possible. The existing synthesis route of (Z)-undec-8-ene-2,5-dione is as follows: Route 5:

[0009] Route 6:

[0010] Route 7:

[0011] Among them, in route five, the reagents required are relatively expensive and difficult to obtain. For example, cyclopropenyl lithium is difficult to prepare, which poses a problem of difficulty in industrial scale-up. In route six, 4-heptenoic acid silyl ester needs to be used for the reaction under LDA catalysis. 4-heptenoic acid silyl ester is difficult to prepare, and the use of LDA is relatively dangerous, which is a problem that is difficult to solve in industrialization. Route seven has a complex process, high process difficulty, and high production cost, which limits its industrial production. Therefore, the existing synthesis method of (Z)-undec-8-ene-2,5-dione has industrial problems such as high reagent risk, high cost, high pollution, and complex process. Summary of the Invention

[0012] In order to address the deficiencies of the prior art, the present invention aims to provide a method for preparing (Z)-undec-8-ene-2,5-dione, which has the characteristics of readily available raw materials, a higher proportion of isomer Z configuration, simpler operation, and is suitable for industrial scale-up production.

[0013] In order to achieve the above object, the technical solution of the present invention is: In a first aspect, a method for preparing (Z)-undec-8-ene-2,5-dione comprises the steps of using acetylpropionyl halide and a dihydroxypyrimidine compound as starting materials and preparing (Z)-undec-8-ene-2,5-dione (i.e., the compound shown in Formula 1) according to the following reaction scheme;

[0014] The process for preparing (Z)-undec-8-ene-2,5-dione by reacting the compound represented by Formula 3 with a (Z)-3-hexenylmagnesium halide Grignard reagent is as follows: uniformly mixing a solution of the (Z)-3-hexenylmagnesium halide Grignard reagent and a solution of the compound represented by Formula 3 at -15 to 15° C., heating to 15 to 45° C. and reacting for 1 to 3 hours, cooling to 0 to 5° C. and quenching the reaction, then adjusting the pH to 1 to 3 and heating to 15 to 45° C. and reacting for 2 to 3 hours; Wherein, X1 is halogen, X2 is halogen, and R is H or methyl.

[0015] The reaction principle of the present invention using the compound shown in Formula 3 to react with a (Z)-3-hexenyl magnesium halide Grignard reagent to obtain (Z)-undec-8-ene-2,5-dione is as follows:

[0016] Generally, when a Grignard reagent reacts with a carboxylic acid derivative (ester, acid chloride, amide, etc.), the carboxylic acid derivative will first react with the Grignard reagent to form a ketone. However, the ketone rarely remains in the ketone state and continues to react with the Grignard reagent to form an alcohol. Therefore, the preparation of ketones using Grignard reagents and carboxylic acid derivatives is relatively difficult. In the preparation process of the present invention, the Mg ion of the (Z)-3-hexenylmagnesium halide Grignard reagent forms a six-membered ring intermediate with the nitrogen atom in the compound represented by Formula 3, which prevents further reaction with the Grignard reagent and thus avoids the formation of an alcohol. Acidic hydrolysis then hydrolyzes the complex and simultaneously removes the ketal protecting group under acidic conditions, yielding the ketone in high yield. Furthermore, the present invention utilizes dihydroxypyrimidine compounds in the synthesis process to synthesize (Z)-undec-8-ene-2,5-dione, which can then be recycled and reused, reducing production costs.

[0017] In a second aspect, a method for preparing the above-mentioned (Z)-undec-8-ene-2,5-dione is used in the synthesis of cis-jasmone.

[0018] Specifically, it only requires adding an aldol condensation reaction process to obtain cis-jasmone after the above-mentioned route for synthesizing (Z)-undec-8-ene-2,5-dione.

[0019] The beneficial effects of the present invention are: The raw materials used in the preparation method provided by the present invention, acetyl acryloyl halide, can be synthesized by halogenation of acetyl propionic acid, and (Z)-1-halohexene-3-ene can be synthesized by halogenation of leaf alcohol. Both are convenient to prepare and are available as industrial products. The reagents used are all conventional chemical raw materials, which are inexpensive and readily available. The three wastes are minimal, the reaction yield is high, and isomer selectivity and product indicators are high. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The accompanying drawings, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0021] Figure 1 This is the H NMR spectrum of (Z)-undec-8-ene-2,5-dione prepared in an example of the present invention. DETAILED DESCRIPTION

[0022] It should be noted that the following detailed descriptions are exemplary and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.

[0023] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, they indicate the presence of features, steps, operations, devices, components and / or combinations thereof.

[0024] In view of the fact that the existing methods for preparing (Z)-undec-8-ene-2,5-dione have industrial difficulties such as high reagent risk, high cost, high pollution, and complex process, which affect the high-quality industrialization of cis-jasmone, the present invention proposes a preparation method of (Z)-undec-8-ene-2,5-dione.

[0025] A typical embodiment of the present invention provides a method for preparing (Z)-undec-8-ene-2,5-dione, comprising the steps of preparing (Z)-undec-8-ene-2,5-dione (i.e., the compound shown in Formula 1) using acetylpropionyl halide and a dihydroxypyrimidine compound as starting materials according to the following reaction scheme;

[0026] The process for preparing (Z)-undec-8-ene-2,5-dione by reacting the compound represented by Formula 3 with a (Z)-3-hexenylmagnesium halide Grignard reagent is as follows: uniformly mixing a solution of the (Z)-3-hexenylmagnesium halide Grignard reagent and a solution of the compound represented by Formula 3 at -15 to 15° C., heating to 15 to 45° C. and reacting for 1 to 3 hours, cooling to 0 to 5° C. and quenching the reaction, then adjusting the pH to 1 to 3 and heating to 15 to 45° C. and reacting for 2 to 3 hours; Wherein, X1 is halogen, X2 is halogen, and R is H or methyl.

[0027] In some embodiments, the molar ratio of the compound of Formula 3 to the (Z)-3-hexenyl magnesium halide Grignard reagent is 1:2.0-2.5.

[0028] In some embodiments, a method for uniformly mixing a solution of a (Z)-3-hexenylmagnesium halide Grignard reagent and a solution of the compound represented by Formula 3 is to dropwise add the solution of the (Z)-3-hexenylmagnesium halide Grignard reagent to the solution of the compound represented by Formula 3 and mix them uniformly. Since the (Z)-3-hexenylmagnesium halide Grignard reagent has high reactivity, this addition method can reduce side reactions.

[0029] In some embodiments, the quenching agent added to quench the reaction is ammonium chloride.

[0030] (Z)-3-Hexene magnesium halide Grignard reagent has high activity and is generally prepared on-site. (Z)-1-halogenated-3-hexene is reacted with metallic magnesium to obtain the obtained product. In some embodiments, bromoethane is used to initiate the Grignard reaction during the preparation of (Z)-3-hexene magnesium halide Grignard reagent. Specifically, the molar ratio of (Z)-1-halogenated-3-hexene to metallic magnesium is 2.2:2.4~2.6. Specifically, the process is as follows: under inert atmosphere, a portion of (Z)-1-halogenated-3-hexene is added to a reaction solution containing metallic magnesium, bromoethane is added to initiate the Grignard reaction, and then the remaining (Z)-1-halogenated-3-hexene is added. Specifically, when (Z)-1-halogenated-3-hexene is (Z)-1-bromo-3-hexene, the preparation effect is better.

[0031] Specifically, lithium chloride is added as an auxiliary agent during the preparation of the (Z)-3-hexenyl magnesium halide Grignard reagent. This can promote the Grignard reaction. More specifically, the molar ratio of lithium chloride to magnesium metal is 0.1:2.4-2.6.

[0032] In some embodiments, the solvent used in the reaction of the compound of Formula 3 with a (Z)-3-hexenylmagnesium halide Grignard reagent to prepare (Z)-undec-8-ene-2,5-dione is tetrahydrofuran, 2-methyltetrahydrofuran, or cyclopentyl methyl ether. When tetrahydrofuran is used as the solvent, the preparation effect is better.

[0033] In some embodiments, when preparing the compound represented by Formula 2, a base is used as a catalyst and acid-binding agent to react acetylpropionyl halide with the phenolic hydroxyl group of a dihydroxypyrimidine compound. Specifically, the base is one or a combination of triethylamine, 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIEA), or pyridine, preferably a combination of triethylamine and DMAP. Specifically, the molar ratio of 2-methyl-4,6-dihydroxypyrimidine to base is 1:2.0-3.0.

[0034] In some embodiments, acetylpropionyl chloride and 2-methyl-4,6-dihydroxypyrimidine are used as starting materials. Studies have shown that using these two starting materials results in better preparation results. Specifically, the molar ratio of acetylpropionyl chloride to 2-methyl-4,6-dihydroxypyrimidine is 2.1-2.3:1.

[0035] In some embodiments, the solvent used in preparing the compound represented by Formula 2 is one of dichloromethane, tetrahydrofuran, toluene or xylene, preferably dichloromethane.

[0036] In some embodiments, the compound of Formula 2 and ethylene glycol undergo an alcohol-ketone carbonyl condensation reaction under the catalytic action of an acid to produce the compound of Formula 3. Specifically, the water generated during the reaction is separated and removed. This separation and removal of water can be performed using a water separator. Specifically, the molar ratio of the compound of Formula 2 to ethylene glycol is 1:2.1-2.3.

[0037] The added molar amount of the acid is 1.8-2.2% of the molar amount of the compound represented by Formula 2. Specifically, the acid is p-toluenesulfonic acid or trifluoroacetic acid, preferably p-toluenesulfonic acid.

[0038] In some embodiments, in the preparation of the compound represented by Formula 3 from the compound represented by Formula 2 and ethylene glycol, the solvent used is toluene or xylene, preferably toluene.

[0039] Another embodiment of the present invention provides an application of the preparation method of the above-mentioned (Z)-undec-8-ene-2,5-dione in the synthesis of cis-jasmone.

[0040] Specifically, a preparation method of the above-mentioned (Z)-undec-8-ene-2,5-dione is provided, and the prepared (Z)-undec-8-ene-2,5-dione is subjected to an aldol condensation reaction to obtain cis-jasmone.

[0041] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0042] The reaction scheme involved in the embodiment is as follows:

[0043] Wherein, X1=-Cl or -Br; the compound of formula 2 is the compound of formula 2-1 and the compound of formula 2-2, R in the compound of formula 2-1 is -CH3, and R in the compound of formula 2-2 is -H; the compound of formula 3 is the compound of formula 3-1 and the compound of formula 3-2, R in the compound of formula 3-1 is -CH3, and R in the compound of formula 3-2 is -H; X2=-Cl or -Br.

[0044] Example 1 1. Preparation of the compound represented by formula 2-1 Add 300 ml of toluene to a dry 1L three-necked reaction flask, and then add 50.0 g (1.0 eq) of 2-methyl-4,6-dihydroxypyrimidine, 101.3 g (2.5 eq) of triethylamine, and DMAP. The material liquid was cooled to 15°C in an ice bath under stirring with 2.5g (0.05eq), and acetylpropionyl chloride toluene solution (acetylpropionyl chloride 117.4g (2.2eq) dissolved in toluene 200ml) was slowly added dropwise using a constant pressure dropping funnel. The dropping speed was controlled and the dropping was completed in about 4 hours. Then the temperature was raised to 55°C and stirred to react for 7 hours until the reaction of 2-methyl-2,6-dihydroxypyrimidine was complete. The reaction was stopped and a 5% by mass dilute hydrochloric acid solution was added and stirred to neutralize. The mixture was then allowed to stand and the organic layer was collected. The mixture was then extracted with water and saturated brine. The mixture was allowed to stand and the organic layer was collected. Anhydrous sodium sulfate was added for drying, and the filtrate was filtered and collected. The filtrate was concentrated in vacuo to obtain 115.0g of the compound of formula 2-1 with a yield of 90%. It was directly used in the next reaction without purification.

[0045] 2. Preparation of the compound represented by formula 3-1 Add 650ml of toluene to a dry, 1L, four-necked reaction flask equipped with a water separator. Then, add 100g (1.0eq) of the compound represented by Formula 2-1, 42.3g (2.2eq) of ethylene glycol, and 1.0g (0.02eq) of p-toluenesulfonic acid. Slowly raise the temperature to reflux and maintain the reaction for 18 hours. During the reaction, remove the generated water through the water separator. After the reaction, cool the solution to room temperature and add 200ml of a 5% NaHCO3 solution with stirring for extraction. Then, extract the solution three times with 400ml of saturated sodium chloride. The organic phase is collected, dried over anhydrous magnesium sulfate, filtered, and the filtrate is evaporated under vacuum to obtain 116.9g of the compound represented by Formula 3-1, with a yield of 92%. The crude product can be used directly in the next reaction after solvent removal.

[0046] 3. Preparation of (Z)-undec-8-ene-2,5-dione Add 7.3g (2.5eq) of magnesium turnings to a dry reaction flask. Evacuate the reaction vessel with a vacuum pump and then fill with nitrogen. Repeat this process three times. Add 15g of anhydrous tetrahydrofuran and stir. Dissolve 43.7g (2.2eq) of (Z)-1-bromo-3-hexene in 200g of dry tetrahydrofuran to prepare a (Z)-1-bromo-3-hexene solution. Add 5g of the (Z)-1-bromo-3-hexene solution dropwise using a constant pressure dropping funnel, followed by 0.3g of ethyl bromide to initiate the Grignard reaction. Maintain the temperature of the solution at 15°C, then add the remaining (Z)-1-bromo-3-hexene solution dropwise at a controlled rate over 8 hours. Continue stirring for 0.5 hour while maintaining the temperature, then add 0.5g (0.1eq) of anhydrous lithium chloride to obtain the (Z)-3-hexenylmagnesium bromide Grignard reagent.

[0047] Dissolve 50 g (1.0 eq) of the compound represented by Formula 3-1 in 100 g of dry tetrahydrofuran, cool to -15°C, and add the entire amount of the Grignard reagent prepared above dropwise, controlling the reaction temperature at -15°C. Complete the addition over 5 hours. Insulate and stir for 1 hour, then raise the temperature to 15°C and stir for 3 hours. Cool the reaction solution to 0°C and pour it into 450 g of 10% ammonium chloride solution to quench. Add concentrated hydrochloric acid (38% by mass) dropwise to adjust the pH to 2, raise the temperature to 30°C, and stir for 2 hours. Extract with 400 ml of ethyl acetate, collect the organic phase, and then extract with 200 ml of saturated sodium chloride solution. Collect the organic phase, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate to obtain crude (Z)-undec-8-ene-2,5-dione. Purify the product by distillation to obtain 37.7 g of the product with a yield of 85%. Gas phase purity 97.5%, E isomer 1.8%, (Z)-undec-8-ene-2,5-dione 1 H-NMR spectrum Figure 1 shown.

[0048] The (Z)-undec-8-ene-2,5-dione prepared in this example can be prepared into cis-jasmone through an aldol condensation reaction.

[0049] Example 2 This embodiment is the same as embodiment 1, except that: 1. Preparation of the compound represented by formula 2-1 Add 350ml of dichloromethane to a dry 1L three-necked reaction flask, and then add 50.0g (1.0eq) of 2-methyl-4,6-dihydroxypyrimidine, 81.5g (2.6eq) of pyridine, and DMAP. 7.3g (0.15eq) was stirred and the material liquid was cooled to 10°C in an ice bath. A dichloromethane solution of acetylpropionyl bromide (177.7g (2.5eq) of acetylpropionyl bromide was dissolved in 300ml of dichloromethane) was slowly added dropwise using a constant pressure dropping funnel. The dropping speed was controlled and the dropping was completed in about 3h. Then the temperature was raised to 35°C and stirred for 4 hours to react with 2-methyl-2,6-dihydroxypyrimidine. The reaction was stopped and the temperature was lowered to room temperature. A dilute hydrochloric acid solution with a mass concentration of 5% was added to the reaction solution to adjust the pH to neutral. The reaction was then allowed to stand and the organic layer was collected. The organic phase was extracted with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain 116.9g of the compound of formula 2-1 with a yield of 91.5%. It was used directly in the next reaction without purification.

[0050] Example 3 This embodiment is the same as embodiment 1, except that: 3. Preparation of (Z)-undec-8-ene-2,5-dione Add 7.3g (2.5eq) of magnesium turnings to a dry reaction flask. Evacuate the reaction vessel with a vacuum pump and then fill with nitrogen. Repeat this process three times. Add 15g of anhydrous tetrahydrofuran and stir. Dissolve 43.7g (2.2eq) of (Z)-1-bromo-3-hexene in 200g of dry tetrahydrofuran to prepare a (Z)-1-bromo-3-hexene solution. Add 5g of the (Z)-1-bromo-3-hexene solution dropwise using a constant pressure dropping funnel, followed by 0.3g of ethyl bromide to initiate the Grignard reaction. Maintain the temperature of the solution at 15°C, then add the remaining (Z)-1-bromo-3-hexene solution dropwise at a controlled rate over 10 hours. Continue stirring for 0.5 hour while maintaining the temperature, and then add 0.5g (0.1eq) of anhydrous lithium chloride to obtain the (Z)-3-hexenylmagnesium bromide Grignard reagent.

[0051] Dissolve 50 g (1.0 eq) of the compound represented by Formula 3-1 in 100 g of dry tetrahydrofuran, cool to -15°C, and add the entire amount of the Grignard reagent prepared above dropwise, maintaining the reaction temperature at -15°C. The reaction mixture was stirred for 1 hour, then heated to 20°C and stirred for 3 hours. The reaction mixture was cooled to 5°C and quenched by pouring into 450 g of 10% ammonium chloride solution. Concentrated hydrochloric acid (38%) was then added dropwise to adjust the pH to 3. The mixture was heated to 35°C and stirred for 3 hours. Extraction was then performed with 400 ml of ethyl acetate, and the organic phase was collected. Extraction was then performed with 200 ml of saturated sodium chloride solution, and the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain crude (Z)-undec-8-ene-2,5-dione. Purification by distillation yielded 38.6 g of the product, with a yield of 87%. The gas phase purity was 97.7%, and the E isomer was 1.6%.

[0052] Example 4 This embodiment is the same as embodiment 1, except that: 3. Preparation of (Z)-undec-8-ene-2,5-dione Add 13.2 g (4.5 eq) of magnesium turnings to a dry reaction flask. Evacuate the reaction vessel with a vacuum pump and then fill it with nitrogen. Repeat this process three times. Add 25 g of anhydrous cyclopentyl methyl ether and stir. Dissolve 69.6 g (3.5 eq) of (Z)-1-bromo-3-hexene in 300 g of dry cyclopentyl methyl ether to prepare a (Z)-1-bromo-3-hexene solution. Add 8 g of the (Z)-1-bromo-3-hexene solution dropwise using a constant pressure dropping funnel, followed by 0.5 g of ethyl bromide to initiate the Grignard reaction. Maintain the temperature of the solution at 50°C, then add the remaining (Z)-1-bromo-3-hexene solution dropwise at a controlled rate over 10 hours. Continue stirring at this temperature for 1 hour, then add 1.3 g (0.25 eq) of anhydrous lithium chloride to obtain the (Z)-3-hexenylmagnesium bromide Grignard reagent.

[0053] Dissolve 50 g (1.0 eq) of the compound represented by Formula 3-1 in 200 g of dry cyclopentyl methyl ether, cool to 10°C, and add the entire amount of the Grignard reagent prepared above dropwise. The reaction temperature is controlled at 10°C and the addition is complete over 6 hours. Stir at this temperature for 1 hour, then heat to 40°C and stir for 4 hours. Cool the reaction solution to 0°C and quench it with 450 g of 10% ammonium chloride solution. Adjust the pH to 1 by adding concentrated hydrochloric acid (38%) dropwise, heat to 40°C, and stir for 2 hours. Extract the solution twice with 400 ml of ethyl acetate, collect the organic phase, and then extract it with 500 ml of saturated sodium chloride solution. Collect the organic phase, dry it over anhydrous sodium sulfate, filter it, and concentrate the filtrate to obtain crude (Z)-undec-8-ene-2,5-dione. Purify the solution by distillation to obtain 36.4 g of the product with a purity of 97.1%, including 1.7% of the E isomer, for a yield of 82%.

[0054] Example 5 This embodiment is the same as embodiment 4, except that: 3. Preparation of (Z)-undec-8-ene-2,5-dione Add 13.2 g (4.5 eq) of magnesium turnings to a dry reaction flask. Evacuate the reaction vessel with a vacuum pump and then fill it with nitrogen. Repeat this process three times. Add 25 g of anhydrous cyclopentyl methyl ether and stir. Dissolve 69.6 g (3.5 eq) of (Z)-1-bromo-3-hexene in 300 g of dry cyclopentyl methyl ether to prepare a (Z)-1-bromo-3-hexene solution. Add 8 g of the (Z)-1-bromo-3-hexene solution dropwise using a constant pressure dropping funnel, followed by 0.5 g of ethyl bromide to initiate the Grignard reaction. Maintain the temperature of the solution at 55°C, then add the remaining (Z)-1-bromo-3-hexene solution dropwise at a controlled rate over 10 hours. Continue stirring at this temperature for 1 hour, then add 1.3 g (0.25 eq) of anhydrous lithium chloride to obtain the (Z)-3-hexenylmagnesium bromide Grignard reagent.

[0055] Dissolve 50 g (1.0 eq) of the compound represented by Formula 3-1 in 200 g of dry cyclopentyl methyl ether, cool to 15°C, and add the entire amount of the Grignard reagent prepared above dropwise. The reaction temperature is controlled at 15°C and the addition is complete over 6 hours. Stir at this temperature for 1 hour, then heat to 45°C and stir for 4 hours. Cool the reaction solution to 5°C and pour into 450 g of 10% ammonium chloride solution to quench. Add concentrated hydrochloric acid (38%) dropwise to adjust the pH to 2, heat to 45°C, and stir for 2 hours. Extract twice with 400 ml of ethyl acetate, collect the organic phase, and then extract with 500 ml of saturated sodium chloride solution. Collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain crude (Z)-undec-8-ene-2,5-dione. Purify by distillation to obtain 36.8 g of the product with a purity of 97.6%, including 1.5% of the E isomer, in an 83% yield.

[0056] Example 6 1. Preparation of the compound represented by formula 2-2 Add 250 ml of tetrahydrofuran to a dry 1L three-necked reaction flask, then add 50.0 g (1.0 eq) of 4,6-dihydroxypyrimidine, 135.3 g (3.0 eq) of triethylamine, and 11.5 g (0.2 eq) of DIEA. Cool the solution to 5°C in an ice bath while stirring. Slowly add a solution of acetylpropionyl bromide in tetrahydrofuran (167.7 g (2.1 eq) of acetylpropionyl bromide dissolved in 300 ml of tetrahydrofuran) using a constant pressure dropping funnel. Control the dropping rate and complete the dropwise addition in about 6 hours. Then raise the temperature to 45°C, keep stirring and react for 8 hours until the reaction of 2,6-dihydroxypyrimidine is complete. Stop the reaction, remove tetrahydrofuran in vacuo, add 550 ml of ethyl acetate to the residue, stir and neutralize with a 3% dilute hydrochloric acid solution until neutral, then stand and separate, collect the organic layer, extract the organic phase with water and saturated brine, add anhydrous sodium sulfate and dry, and concentrate in vacuo to obtain compound 119.6 of formula 2-2. g, with a yield of 87%, and was used directly in the next reaction without purification.

[0057] 2. Preparation of the compound represented by formula 3-2 500ml of xylene was added to a dry 1L four-necked reaction flask equipped with a water separator. 100g (1.0eq) of the compound represented by Formula 2-2, 60.5g (3.0eq) of ethylene glycol, and 2.2g (0.06eq) of trifluoroacetic acid were then added to the flask. The temperature was slowly raised to 110°C and maintained for 10 hours. During the reaction, the generated water was separated through the water separator. After the reaction, the liquid was cooled to room temperature and extracted with 250ml of a 5% (mass concentration) NaHCO₃ solution with stirring. The mixture was then extracted three times with 300ml of saturated sodium chloride. The organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the filtrate was collected. The solvent was evaporated under vacuum to yield 114.5g of the compound represented by Formula 3-2, with a yield of 89%.

[0058] 3. Preparation of (Z)-undec-8-ene-2,5-dione Add 10.6 g (3.5 eq) of magnesium turnings to a dry reaction flask. Evacuate the reaction vessel with a vacuum pump, then fill it with nitrogen. Repeat this process three times. Add 20 g of anhydrous 2-methyltetrahydrofuran and stir. Dissolve 37.2 g (2.5 eq) of (Z)-1-chloro-3-hexene in 150 ml of dry 2-methyltetrahydrofuran to prepare a (Z)-1-chloro-3-hexene solution. Add 6 g of the (Z)-1-chloro-3-hexene solution dropwise using a constant pressure dropping funnel, followed by 0.5 g of ethyl bromide to initiate the Grignard reaction. Keep the temperature of the solution at 40°C, and add the remaining (Z)-1-chloro-3-hexene solution dropwise. Continue the addition over a controlled rate of approximately 10 hours. Maintain the temperature and continue stirring for 0.5 hours to obtain the (Z)-3-hexene magnesium chloride Grignard reagent.

[0059] Dissolve 50 g (1.0 eq) of the compound represented by Formula 3-2 in 150 g of dry 2-methyltetrahydrofuran, cool to -5°C, and add the entire amount of the Grignard reagent prepared above dropwise, controlling the reaction temperature at -5°C. Complete the addition over 6 hours. Stir at this temperature for 1 hour, then heat to 30°C and stir for 2 hours. Cool the reaction solution to 0°C and pour into 450 g of 10% ammonium chloride solution to quench. Add concentrated hydrochloric acid (38%) dropwise to adjust the pH to 2, heat to 15°C, and stir for 3 hours. Extract twice with 500 ml of ethyl acetate, collect the organic phase, and then extract with 500 ml of saturated sodium chloride solution. Collect the organic phase, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate to obtain crude (Z)-undec-8-ene-2,5-dione. Purify the product by distillation to obtain 39.9 g of the product with a purity of 97.2%, including 2.4% of the E isomer, for a yield of 87%.

[0060] The (Z)-undec-8-ene-2,5-dione prepared in this example can be prepared into cis-jasmone through an aldol condensation reaction.

[0061] Example 7 This embodiment is the same as embodiment 6, except that: 1. Preparation of the compound represented by formula 2-2 Add 250 ml of tetrahydrofuran to a dry 1L three-necked reaction flask, then add 50.0 g (1.0 eq) of 4,6-dihydroxypyrimidine, 135.3 g (3.0 eq) of triethylamine, and 11.5 g (0.2 eq) of DIEA. Cool the solution to 5°C in an ice bath while stirring. Slowly add a solution of acetylpropionyl bromide in tetrahydrofuran (167.7 g (2.1 eq) of acetylpropionyl bromide dissolved in 300 ml of tetrahydrofuran) using a constant pressure dropping funnel. Control the dropping speed and complete the dropwise addition in about 6 hours. Then raise the temperature to 45°C, keep stirring and react for 10 hours until the reaction of 2,6-dihydroxypyrimidine is complete. Stop the reaction, remove tetrahydrofuran in vacuo, add 550 ml of ethyl acetate to the residue, stir and neutralize with a dilute hydrochloric acid solution with a mass concentration of 3% to neutral, then stand and separate, collect the organic layer, extract the organic phase with water and saturated brine, add anhydrous sodium sulfate and dry, and concentrate in vacuo to obtain compound 126.5 of formula 2-2. The product was used directly in the next reaction without purification.

[0062] Example 8 This embodiment is the same as embodiment 6, except that: 3. Preparation of (Z)-undec-8-ene-2,5-dione Add 10.6g (3.5eq) of magnesium turnings to a dry reaction flask. Evacuate the reaction vessel with a vacuum pump, then fill it with nitrogen. Repeat this process three times. Add 20g of anhydrous 2-methyltetrahydrofuran and stir. Dissolve 37.2g (2.5eq) of (Z)-1-chloro-3-hexene in 150ml of dry 2-methyltetrahydrofuran to prepare a (Z)-1-chloro-3-hexene solution. Add 6g of the (Z)-1-chloro-3-hexene solution dropwise using a constant pressure dropping funnel, followed by 0.5g of ethyl bromide to initiate the Grignard reaction. Keep the temperature of the solution at 45°C, and add the remaining (Z)-1-chloro-3-hexene solution dropwise. Continue the addition over a controlled rate of approximately 10 hours. Maintain the temperature and continue stirring for 0.5 hours to obtain the (Z)-3-hexenemagnesium chloride Grignard reagent.

[0063] Dissolve 50 g (1.0 eq) of the compound represented by Formula 3-2 in 150 g of dry 2-methyltetrahydrofuran, cool to 0°C, and add the entire amount of the Grignard reagent prepared above dropwise. The reaction temperature is maintained at 0°C, and the addition is complete over 6 hours. Stir at this temperature for 1 hour, then heat to 35°C and stir for 2 hours. Cool the reaction solution to 5°C and pour into 450 g of 10% ammonium chloride solution to quench. Add concentrated hydrochloric acid (38%) dropwise to adjust the pH to 3, heat to 20°C, and stir for 3 hours. Extract twice with 500 ml of ethyl acetate, collect the organic phase, and then extract with 500 ml of saturated sodium chloride solution. Collect the organic phase, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate to obtain crude (Z)-undec-8-ene-2,5-dione. Purify the product by distillation to obtain 40.4 g of the product with a purity of 97.5%, including 2.1% of the E isomer, in an 88% yield.

[0064] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A method for preparing (Z)-undec-8-ene-2,5-dione, characterized in that: The method comprises the steps of using acetylpropionyl halide and dihydroxypyrimidine compounds as starting materials and preparing (Z)-undec-8-ene-2,5-dione according to the following reaction scheme; The process for preparing (Z)-undec-8-ene-2,5-dione by reacting the compound represented by Formula 3 with a (Z)-3-hexenylmagnesium halide Grignard reagent is as follows: uniformly mixing a solution of the (Z)-3-hexenylmagnesium halide Grignard reagent and a solution of the compound represented by Formula 3 at -15 to 15° C., heating to 15 to 45° C. and reacting for 1 to 3 hours, cooling to 0 to 5° C. and quenching the reaction, then adjusting the pH to 1 to 3 and heating to 15 to 45° C. and reacting for 2 to 3 hours; Wherein, X1 is halogen, X2 is halogen, and R is H or methyl.

2. The preparation method according to claim 1, wherein The method for uniformly mixing the solution of (Z)-3-hexenylmagnesium halide Grignard reagent and the solution of the compound represented by Formula 3 is as follows: dropwise adding the solution of (Z)-3-hexenylmagnesium halide Grignard reagent to the solution of the compound represented by Formula 3 and mixing them uniformly.

3. The preparation method according to claim 1, wherein The quenching agent added to quench the reaction is ammonium chloride.

4. The preparation method according to claim 1, wherein In the preparation of (Z)-3-hexenyl magnesium halide Grignard reagent, ethyl bromide is used to initiate the Grignard reaction.

5. The preparation method according to claim 1, wherein Lithium chloride is added as an auxiliary agent during the preparation of (Z)-3-hexenyl magnesium halide Grignard reagent.

6. The preparation method according to claim 1, wherein: In the preparation of the compound represented by formula 2, a base is used as a catalyst and an acid-binding agent to react acetylpropionyl halide with the phenolic hydroxyl group of the dihydroxypyrimidine compound.

7. The preparation method according to claim 1, wherein: Acetylpropionyl chloride and 2-methyl-4,6-dihydroxypyrimidine were used as starting materials.

8. The preparation method according to claim 1, wherein The compound shown in Formula 2 and ethylene glycol undergo alcohol and ketone carbonyl condensation reaction under the catalytic action of acid to produce the compound shown in Formula 3.

9. The preparation method according to claim 8, characterized in that: The acid is p-toluenesulfonic acid or trifluoroacetic acid.

10. Use of the preparation method according to any one of claims 1 to 9 in synthesizing cis-jasmone.

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