A process for the preparation of (z)-undec-8-ene-2,5-dione

Abstract

The application belongs to the technical field of cis-jasmone synthesis, and relates to synthesis of a cis-jasmone intermediate, in particular to a preparation method of (Z)-undec-8-ene-2,5-dione. The preparation method comprises the following steps: acetylpropionyl halide and a dihydroxypyrimidine compound are used as starting materials, and (Z)-undec-8-ene-2,5-dione is prepared according to the following reaction route; a solution of (Z)-3-hexenyl magnesium bromide Grignard reagent is uniformly mixed with a solution of a compound shown in formula 3 under the condition of-15-15 DEG C, the temperature is increased to 15-45 DEG C, reaction is carried out for 1-3 hours, the temperature is decreased to 0-5 DEG C and the reaction is quenched, then the pH is adjusted to 1-3 and the temperature is increased to 15-45 DEG C, and reaction is carried out for 2-3 hours; wherein X1 is halogen, X2 is halogen, and R is H or methyl. The preparation method has the characteristics of easy-to-obtain starting materials, higher proportion of isomer Z configuration, simpler operation and the like, and is suitable for industrialized scale production.

Description

Technical Field

[0001] This invention belongs to the field of cis-jasmone synthesis technology, and relates to the synthesis of cis-jasmone intermediates, specifically to a method for preparing (Z)-undec-8-ene-2,5-dione. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] cis-jasmone is an internationally recognized safe synthetic fragrance compound with a scent similar to jasmine flowers and is a key aroma component of jasmine oil. There are numerous methods for synthesizing cis-jasmone, such as:

[0004] Route 1:

[0005]

[0006] Route 2:

[0007]

[0008] Route 3:

[0009]

[0010] Route 4:

[0011]

[0012] Route 1 involves alkylation, Wittech reaction, and acid ring-opening, generating large amounts of acidic waste liquid and producing significant amounts of triphenylphosphine oxide as a byproduct. The Z and E isomers of the product are also difficult to control. Therefore, the process is not environmentally friendly, and the product quality is poor. Route 2 uses catalysts such as phosphine tribromide, butyllithium, and Cr(CO)6, resulting in high pollution levels. Furthermore, butyllithium and hydrogen reduction are highly hazardous, hindering industrial production. Route 3 suffers from long routes and cumbersome operations, making it unsuitable for industrial production. Route 4 uses chemical reagents such as LDA and sodium amalgam desulfonylation, requiring harsh reaction conditions and generating high pollution levels, also unfavorable for industrial production. From the above reaction routes, it can be seen that most synthetic routes require the synthesis of (Z)-undec-8-ene-2,5-dione, as shown in Formula 1:

[0013]

[0014] Therefore, (Z)-undec-8-en-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-en-2,5-dione is warranted. The existing routes for synthesizing (Z)-undec-8-en-2,5-dione are shown below:

[0015] Route 5:

[0016]

[0017] Route Six:

[0018]

[0019] Route 7:

[0020]

[0021] Among these methods, Route 5 requires expensive and difficult-to-obtain reagents; for example, cyclopropenyllithium is difficult to prepare, posing a challenge for industrial scale-up. Route 6 requires the reaction using 4-heptenoic acid silane ester under LDA catalysis. 4-heptenoic acid silane ester is difficult to prepare, and the use of LDA is highly hazardous, presenting a significant challenge for industrialization. Route 7 involves a complex process, high technological difficulty, and high production costs, limiting its industrial production. Therefore, existing methods for synthesizing (Z)-undec-8-en-2,5-dione face industrialization challenges due to the high risk and expense of reagents, high pollution levels, and complex processes. Summary of the Invention

[0022] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing (Z)-undec-8-ene-2,5-dione. This method features readily available raw materials, a higher proportion of Z-isomer configurations, and simpler operation, making it suitable for industrial-scale production.

[0023] To achieve the above objectives, the technical solution of the present invention is as follows:

[0024] In a first aspect, a method for preparing (Z)-undec-8-ene-2,5-dione includes the steps of preparing (Z)-undec-8-ene-2,5-dione (i.e., the compound shown in Formula 1) by using acetylpropionyl halide and dihydroxypyrimidine compounds as starting materials according to the following reaction route.

[0025]

[0026] The process for preparing (Z)-undec-8-ene-2,5-dione by reacting the compound shown in Formula 3 with (Z)-3-hexene magnesium halide Grignard reagent is as follows: the solution of (Z)-3-hexene magnesium halide Grignard reagent is mixed evenly with the solution of the compound shown in Formula 3 at -15~15℃, the temperature is raised to 15~45℃ and reacted for 1~3 hours, the temperature is lowered to 0~5℃ and the reaction is quenched, then the pH is adjusted to 1~3 and the temperature is raised to 15~45℃ and reacted for 2~3 hours;

[0027] Where X1 is a halogen, X2 is a halogen, and R is H or methyl.

[0028] The reaction principle of this invention, which involves reacting the compound shown in Formula 3 with a (Z)-3-hexene magnesium halide Grignard reagent to obtain (Z)-undec-8-en-2,5-dione, is as follows:

[0029]

[0030] Generally, when Grignard reagents react with carboxylic acid derivatives (esters, acyl chlorides, amides, etc.), the carboxylic acid derivatives initially react with the Grignard reagent to form ketones. However, it is difficult for these derivatives to remain in the ketone position and continue reacting with the Grignard reagent to form alcohols. Therefore, preparing ketones using Grignard reagents and carboxylic acid derivatives is challenging. In this invention, the Mg ions of the (Z)-3-hexene magnesium halide Grignard reagent form a six-membered ring intermediate with the N atom in the compound shown in Formula 3, preventing further reaction of the Grignard reagent and thus avoiding alcohol formation. Then, through acidic hydrolysis, the complex is hydrolyzed while simultaneously removing the ketal protecting group under acidic conditions, resulting in a high-yield ketone. Furthermore, this invention utilizes dihydroxypyrimidine compounds in the synthesis process to synthesize (Z)-undec-8-en-2,5-dione, which can then be recycled, reducing production costs.

[0031] Secondly, the application of the above-mentioned method for preparing (Z)-undec-8-ene-2,5-dione in the synthesis of cis-jasmone.

[0032] Specifically, it only requires adding a process via aldol condensation after the above-mentioned route for synthesizing (Z)-undec-8-ene-2,5-dione to obtain cis-jasmone.

[0033] The beneficial effects of this invention are as follows:

[0034] The preparation method provided by this invention uses acetylacryloyl halide, which can be synthesized by halogenation of acetylpropionic acid, and (Z)-1-halohexene-3-ene, which can be synthesized by halogenation of leaf alcohol. The preparation is convenient and both are available in industrial products. The reagents used are all conventional chemical raw materials, which are inexpensive and readily available, produce less waste, have high reaction yield, and exhibit high isomer selectivity and product indicators. Attached Figure Description

[0035] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0036] Figure 1 The 1H NMR spectrum of (Z)-undec-8-ene-2,5-dione prepared in an embodiment of the present invention. Detailed Implementation

[0037] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0038] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0039] Given that existing methods for preparing (Z)-undec-8-ene-2,5-dione face industrialization challenges such as high-risk and expensive reagents, high pollution, and complex processes, which hinder the high-quality industrialization of cis-jasmone, this invention proposes a method for preparing (Z)-undec-8-ene-2,5-dione.

[0040] 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) by using acetylpropionyl halide and dihydroxypyrimidine compounds as starting materials according to the following reaction route;

[0041]

[0042] The process for preparing (Z)-undec-8-ene-2,5-dione by reacting the compound shown in Formula 3 with (Z)-3-hexene magnesium halide Grignard reagent is as follows: the solution of (Z)-3-hexene magnesium halide Grignard reagent is mixed evenly with the solution of the compound shown in Formula 3 at -15~15℃, the temperature is raised to 15~45℃ and reacted for 1~3 hours, the temperature is lowered to 0~5℃ and the reaction is quenched, then the pH is adjusted to 1~3 and the temperature is raised to 15~45℃ and reacted for 2~3 hours;

[0043] Where X1 is a halogen, X2 is a halogen, and R is H or methyl.

[0044] In some embodiments, the molar ratio of the compound shown in Formula 3 to the (Z)-3-hexene magnesium halide Grignard reagent is 1:2.0~2.5.

[0045] In some embodiments, the method for uniformly mixing the solution of (Z)-3-hexene magnesium halide Grignard reagent with the solution of the compound shown in Formula 3 is as follows: the solution of (Z)-3-hexene magnesium halide Grignard reagent is added dropwise to the solution of the compound shown in Formula 3 and mixed uniformly. Since the (Z)-3-hexene magnesium halide Grignard reagent has high reactivity, this addition method can reduce side reactions.

[0046] In some embodiments, the quenching agent added to the quenching reaction is ammonium chloride.

[0047] (Z)-3-hexene magnesium halide Grignard reagents are highly reactive and are generally prepared fresh for immediate use. They are obtained by reacting (Z)-1-halo-3-hexene with metallic magnesium. In some embodiments, bromoethane is used to initiate the Grignard reaction during the preparation of (Z)-3-hexene magnesium halide Grignard reagents. Specifically, the molar ratio of (Z)-1-halo-3-hexene to metallic magnesium is 2.2:2.4~2.6. The process is as follows: under an inert atmosphere, a portion of (Z)-1-halo-3-hexene is added to a reaction solution containing metallic magnesium, followed by the addition of bromoethane to initiate the Grignard reaction, and then the remaining (Z)-1-halo-3-hexene is added. Specifically, the preparation effect is better when (Z)-1-halo-3-hexene is (Z)-1-bromo-3-hexene.

[0048] Specifically, lithium chloride is added as an auxiliary agent in the preparation of (Z)-3-hexene magnesium halide Grignard reagent to promote the Grignard reaction. More specifically, the molar ratio of lithium chloride to metallic magnesium is 0.1:2.4~2.6.

[0049] In some embodiments, during the reaction of the compound shown in Formula 3 with a (Z)-3-hexene magnesium halide Grignard reagent to prepare (Z)-undec-8-en-2,5-dione, the solvent used is tetrahydrofuran, 2-methyltetrahydrofuran, or cyclopentyl methyl ether. The preparation effect is better when tetrahydrofuran is used as the solvent.

[0050] In some embodiments, in preparing the compound shown in 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 two of triethylamine, 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIEA), and pyridine, preferably a combination of triethylamine and DMAP. Specifically, the molar ratio of 2-methyl-4,6-dihydroxypyrimidine to the base is 1:2.0~3.0.

[0051] In some embodiments, acetylpropionyl chloride and 2-methyl-4,6-dihydroxypyrimidine are used as starting materials. Studies have shown that the preparation results are better when using these two starting materials. Specifically, the molar ratio of acetylpropionyl chloride to 2-methyl-4,6-dihydroxypyrimidine is 2.1~2.3:1.

[0052] In some embodiments, the solvent used in preparing the compound shown in Formula 2 is one of dichloromethane, tetrahydrofuran, toluene, or xylene, preferably dichloromethane.

[0053] In some embodiments, the compound shown in Formula 2 reacts with ethylene glycol under acid catalysis to undergo an alcohol-ketone carbonyl condensation reaction to generate the compound shown in Formula 3. Specifically, the water generated during the reaction is separated and removed. Water separation can be performed using a water separator. Specifically, the molar ratio of the compound shown in Formula 2 to ethylene glycol is 1:2.1~2.3.

[0054] The amount of acid added is 1.8 to 2.2% of the molar amount of the compound shown in Formula 2. Specifically, the acid is p-toluenesulfonic acid or trifluoroacetic acid, preferably p-toluenesulfonic acid.

[0055] In some embodiments, when the compound of Formula 2 is reacted with ethylene glycol to prepare the compound of Formula 3, the solvent used is toluene or xylene, preferably toluene.

[0056] Another embodiment of the present invention provides the application of the above-mentioned method for preparing (Z)-undec-8-ene-2,5-dione in the synthesis of cis-jasmone.

[0057] Specifically, a method for preparing the above-mentioned (Z)-undec-8-ene-2,5-dione is provided, and the obtained (Z)-undec-8-ene-2,5-dione is subjected to an aldol condensation reaction to obtain cis-jasmone.

[0058] To enable those skilled in the art to better 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.

[0059] The reaction routes involved in the embodiments are shown below:

[0060]

[0061] Wherein, X1 = -Cl or -Br; Compound 2 is Compound 2-1 and Compound 2-2, R in Compound 2-1 is -CH3, and R in Compound 2-2 is -H; Compound 3 is Compound 3-1 and Compound 3-2, R in Compound 3-1 is -CH3, and R in Compound 3-2 is -H; X2 = -Cl or -Br.

[0062] Example 1

[0063] I. Preparation of the compound shown in Formula 2-1

[0064] Add 300 ml of toluene to a dry 1 L three-necked reaction flask, then add 50.0 g (1.0 eq) of 2-methyl-4,6-dihydroxypyrimidine, 101.3 g (2.5 eq) of triethylamine, and DMAP. 2.5 g (0.05 eq) of the feed solution was cooled to 15 °C in an ice bath with stirring. Acetylpropionyl chloride toluene solution (117.4 g (2.2 eq) of acetylpropionyl chloride dissolved in 200 ml of toluene) was slowly added dropwise using a constant pressure dropping funnel. The addition was controlled and completed in about 4 hours. Then the temperature was raised to 55 °C and the reaction was maintained at this temperature with stirring for 7 hours until the 2-methyl-2,6-dihydroxypyrimidine reaction was complete. The reaction was stopped, and 5% (w / w) dilute hydrochloric acid solution was added and stirred to neutralize. The mixture was then allowed to stand and the organic layer was collected. The organic layer was extracted with water and saturated brine with stirring. The mixture was then allowed to stand and the organic layer was collected. Anhydrous sodium sulfate was added to dry the mixture. The mixture was filtered, and the filtrate was collected and concentrated under vacuum to obtain 115.0 g of the compound shown in Formula 2-1, with a yield of 90%. The compound was used directly in the next reaction without purification.

[0065] II. Preparation of the compound shown in Formula 3-1

[0066] Add 650 ml of toluene to a dry 1 L four-necked reaction flask equipped with a water separator. Then add 100 g (1.0 eq) of the compound shown in Formula 2-1, 42.3 g (2.2 eq) of ethylene glycol, and 1.0 g (0.02 eq) of p-toluenesulfonic acid to the reaction flask. Slowly heat to reflux and maintain reflux for 18 hours. During the reaction, remove the water produced through the water separator. After the reaction is complete, cool the solution to room temperature and add 200 ml of 5% NaHCO3 solution for extraction. Then extract three times with 400 ml of saturated sodium chloride. Collect the organic phase, dry with anhydrous magnesium sulfate, filter, collect the filtrate, and remove the solvent under vacuum to obtain 116.9 g of the compound shown in Formula 3-1, with a yield of 92%. The crude product can be directly used for the next reaction after solvent removal.

[0067] III. Preparation of (Z)-Undec-8-ene-2,5-dione

[0068] Add 7.3 g (2.5 eq) of magnesium shavings to a dry reaction flask, evacuate the reaction apparatus with a vacuum pump, and then purge with nitrogen. Repeat this operation three times. Add 15 g of anhydrous tetrahydrofuran and start stirring. Dissolve 43.7 g (2.2 eq) of (Z)-1-bromo-3-hexene in 200 g of dry tetrahydrofuran to prepare a (Z)-1-bromo-3-hexene solution. Add 5 g of the (Z)-1-bromo-3-hexene solution dropwise using a constant pressure dropping funnel, and then add 0.3 g of bromoethane to initiate the Grignard reaction. Maintain the temperature of the solution at 15 °C, and then add the remaining (Z)-1-bromo-3-hexene solution dropwise, controlling the dropping rate. The reaction is completed in 8 hours. Keep the solution at the temperature and continue stirring for 0.5 hours. Then add 0.5 g (0.1 eq) of anhydrous lithium chloride to obtain the (Z)-3-hexene magnesium bromide Grignard reagent.

[0069] 50 g (1.0 eq) of the compound shown in Formula 3-1 was dissolved in 100 g of dry tetrahydrofuran. The solution was cooled to -15 °C, and the Grignard reagent prepared above was added dropwise, maintaining the reaction temperature at -15 °C. The addition was completed over 5 hours. The mixture was kept at this temperature and stirred for 1 hour, then heated to 15 °C and stirred for 3 hours. The reaction solution was cooled to 0 °C and quenched in a 10% ammonium chloride solution (450 g). Concentrated hydrochloric acid (38% by mass) was added dropwise to adjust the pH to 2, and the mixture was heated to 30 °C and stirred for 2 hours. The solution was then extracted with 400 ml of ethyl acetate, and the organic phase was collected. The organic phase was then extracted with 200 ml of saturated sodium chloride solution, and the organic phase was collected. Anhydrous magnesium sulfate was added for drying, and the solution was filtered. The filtrate was collected and concentrated to obtain crude (Z)-undec-8-ene-2,5-dione. The product was purified 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 as follows Figure 1 As shown.

[0070] The (Z)-undec-8-ene-2,5-dione prepared in this embodiment can be used to prepare cis-jasmone via aldol condensation.

[0071] Example 2

[0072] This embodiment is the same as Embodiment 1, except that:

[0073] I. Preparation of the compound shown in Formula 2-1

[0074] Add 350 ml of dichloromethane to a dry 1 L three-necked reaction flask, then add 50.0 g (1.0 eq) of 2-methyl-4,6-dihydroxypyrimidine, 81.5 g (2.6 eq) of pyridine, and DMAP. 7.3 g (0.15 eq) of the feed solution was cooled to 10 °C in an ice bath with stirring. Acetylpropionyl bromide solution (177.7 g (2.5 eq) of acetylpropionyl bromide dissolved in 300 ml of dichloromethane) was slowly added dropwise using a constant pressure dropping funnel. The addition rate was controlled and the addition was completed in about 3 hours. Then the temperature was raised to 35 °C and the reaction was stirred and maintained for 4 hours until the 2-methyl-2,6-dihydroxypyrimidine reaction was complete. The reaction was stopped and the temperature was cooled to room temperature. A 5% (w / w) dilute hydrochloric acid solution 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 and dried with anhydrous sodium sulfate. The solution was concentrated under vacuum to obtain 116.9 g of the compound shown in Formula 2-1, with a yield of 91.5%. The compound was used directly in the next reaction without purification.

[0075] Example 3

[0076] This embodiment is the same as Embodiment 1, except that:

[0077] III. Preparation of (Z)-Undec-8-ene-2,5-dione

[0078] Add 7.3 g (2.5 eq) of magnesium shavings to a dry reaction flask, evacuate the reaction apparatus with a vacuum pump, and then purge with nitrogen. Repeat this operation three times. Add 15 g of anhydrous tetrahydrofuran and start stirring. Dissolve 43.7 g (2.2 eq) of (Z)-1-bromo-3-hexene in 200 g of dry tetrahydrofuran to prepare a (Z)-1-bromo-3-hexene solution. Add 5 g of the (Z)-1-bromo-3-hexene solution dropwise using a constant pressure dropping funnel, and then add 0.3 g of bromoethane to initiate the Grignard reaction. Maintain the temperature of the solution at 15 °C, and then add the remaining (Z)-1-bromo-3-hexene solution dropwise, controlling the dropping rate. The reaction is completed in 10 hours. Keep the solution at the temperature and continue stirring for 0.5 hours. Then add 0.5 g (0.1 eq) of anhydrous lithium chloride to obtain the (Z)-3-hexene magnesium bromide Grignard reagent.

[0079] 50 g (1.0 eq) of the compound shown in Formula 3-1 was dissolved in 100 g of dry tetrahydrofuran. The solution was cooled to -15 °C, and the Grignard reagent prepared above was added dropwise, maintaining the reaction temperature at -15 °C. The addition was completed over 5 hours. The mixture was kept at this temperature and stirred for 1 hour, then heated to 20 °C and stirred for 3 hours. The reaction solution was cooled to 5 °C and quenched in a 10% ammonium chloride solution (450 g). Concentrated hydrochloric acid (38% by mass) was added dropwise to adjust the pH to 3. The mixture was heated to 35 °C and stirred for 3 hours. The solution was then extracted with 400 ml of ethyl acetate, and the organic phase was collected. The organic phase was then extracted with 200 ml of saturated sodium chloride solution, and the organic phase was collected. Anhydrous magnesium sulfate was added for drying, and the solution was filtered. The filtrate was collected and concentrated to obtain crude (Z)-undec-8-ene-2,5-dione. The product was purified by distillation to obtain 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%.

[0080] Example 4

[0081] This embodiment is the same as Embodiment 1, except that:

[0082] III. Preparation of (Z)-Undec-8-ene-2,5-dione

[0083] Add 13.2 g (4.5 eq) of magnesium shavings to a dry reaction flask, evacuate the reaction apparatus with a vacuum pump, and then purge with nitrogen. Repeat this operation three times. Add 25 g of anhydrous cyclopentyl methyl ether and start stirring. 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, and then add 0.5 g of bromoethane to initiate the Grignard reaction. Maintain the temperature of the solution at 50 °C, and then add the remaining (Z)-1-bromo-3-hexene solution dropwise, controlling the dropping rate. The reaction is completed in 10 hours. Keep the solution at the temperature and continue stirring for 1 hour. Add 1.3 g (0.25 eq) of anhydrous lithium chloride to obtain the (Z)-3-hexene magnesium bromide Grignard reagent.

[0084] 50 g (1.0 eq) of the compound shown in Formula 3-1 was dissolved in 200 g of dry cyclopentyl methyl ether. The mixture was cooled to 10 °C, and the Grignard reagent prepared above was added dropwise over 6 hours while maintaining the reaction temperature at 10 °C. The mixture was kept at this temperature and stirred for 1 hour, then heated to 40 °C and stirred for 4 hours. The reaction solution was cooled to 0 °C and quenched in 450 g of 10% ammonium chloride solution. Concentrated hydrochloric acid (38% by mass) was added dropwise to adjust the pH to 1, and the mixture was heated to 40 °C and stirred for 2 hours. The mixture was then extracted twice with 400 ml of ethyl acetate, and the organic phase was collected. The organic phase was then extracted again with 500 ml of saturated sodium chloride solution, and the organic phase was collected. The mixture was dried with anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated to obtain crude (Z)-undec-8-ene-2,5-dione. After distillation purification, 36.4 g of the product was obtained with a purity of 97.1%, containing 1.7% of the E isomer, and the yield was 82%.

[0085] Example 5

[0086] This embodiment is the same as embodiment 4, except that:

[0087] III. Preparation of (Z)-Undec-8-ene-2,5-dione

[0088] Add 13.2 g (4.5 eq) of magnesium shavings to a dry reaction flask, evacuate the reaction apparatus with a vacuum pump, and then purge with nitrogen. Repeat this operation three times. Add 25 g of anhydrous cyclopentyl methyl ether and start stirring. 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, and then add 0.5 g of bromoethane to initiate the Grignard reaction. Maintain the temperature of the solution at 55 °C, and then add the remaining (Z)-1-bromo-3-hexene solution dropwise, controlling the dropping rate. The reaction is completed in 10 hours. Keep the solution at the temperature and continue stirring for 1 hour. Add 1.3 g (0.25 eq) of anhydrous lithium chloride to obtain the (Z)-3-hexene magnesium bromide Grignard reagent.

[0089] 50 g (1.0 eq) of the compound shown in Formula 3-1 was dissolved in 200 g of dry cyclopentyl methyl ether. The mixture was cooled to 15 °C, and the Grignard reagent prepared above was added dropwise over 6 hours while maintaining the reaction temperature at 15 °C. The mixture was stirred at this temperature for 1 hour, then heated to 45 °C and stirred for 4 hours. The reaction solution was cooled to 5 °C and quenched in 450 g of 10% ammonium chloride solution. Concentrated hydrochloric acid (38% by mass) was added dropwise to adjust the pH to 2, and the mixture was heated to 45 °C and stirred for 2 hours. The mixture was then extracted twice with 400 ml of ethyl acetate, and the organic phase was collected. The organic phase was then extracted again with 500 ml of saturated sodium chloride solution, and the organic phase was collected. The mixture was dried with anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated to obtain crude (Z)-undec-8-ene-2,5-dione. After distillation purification, 36.8 g of the product was obtained with a purity of 97.6%, including 1.5% of the E isomer, and a yield of 83%.

[0090] Example 6

[0091] I. Preparation of the compound shown in Formula 2-2

[0092] Add 250 ml of tetrahydrofuran to a dry 1 L 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 with stirring. Slowly add acetylpropionyl bromide tetrahydrofuran solution (167.7 g (2.1 eq) of acetylpropionyl bromide dissolved in 300 ml of tetrahydrofuran) using a constant pressure dropping funnel, controlling the dropping rate. The addition should be completed in approximately 6 hours. Then raise the temperature to 45 °C and maintain the temperature with stirring for 8 hours until the 2,6-dihydroxypyrimidine has completely reacted. Stop the reaction, remove the tetrahydrofuran under vacuum, and add 550 ml of ethyl acetate and 3% hydrochloric acid solution to the residue. Stir to neutralize, then allow to stand and separate the layers. Collect the organic layer, extract the organic phase with water and saturated brine, dry with anhydrous sodium sulfate, and concentrate under vacuum to obtain compound 119.6 as shown in Formula 2-2. g, yield 87%, used directly in the next reaction without purification.

[0093] II. Preparation of the compound shown in Formula 3-2

[0094] Add 500 ml of xylene to a dry 1 L four-necked reaction flask equipped with a water separator. Then add 100 g (1.0 eq) of the compound shown in Formula 2-2, 60.5 g (3.0 eq) of ethylene glycol, and 2.2 g (0.06 eq) of trifluoroacetic acid to the reaction flask. Slowly raise the temperature to 110 °C and maintain the temperature for 10 hours. During the reaction, remove the water produced through the water separator. After the reaction is complete, cool the solution to room temperature and add 250 ml of 5% NaHCO3 solution for extraction. Then extract three times with 300 ml of saturated sodium chloride. Collect the organic phase, dry it with anhydrous magnesium sulfate, filter, collect the filtrate, and remove the solvent under vacuum to obtain 114.5 g of the compound shown in Formula 3-2, with a yield of 89%.

[0095] III. Preparation of (Z)-Undec-8-ene-2,5-dione

[0096] Add 10.6 g (3.5 eq) of magnesium shavings to a dry reaction flask, evacuate the reaction apparatus with a vacuum pump, and then purge with nitrogen. Repeat this operation three times. Add 20 g of anhydrous 2-methyltetrahydrofuran and start stirring. 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, and then add 0.5 g of bromoethane to initiate the Grignard reaction. Maintain the temperature of the solution at 40 °C, and add the remaining (Z)-1-chloro-3-hexene solution dropwise over approximately 10 hours, controlling the dropping rate. Continue stirring for 0.5 hours to obtain the (Z)-3-hexene magnesium chloride Grignard reagent.

[0097] 50 g (1.0 eq) of the compound shown in Formula 3-2 was dissolved in 150 g of dry 2-methyltetrahydrofuran. The mixture was cooled to -5 °C, and the Grignard reagent prepared above was added dropwise, maintaining the reaction temperature at -5 °C. The addition was completed over 6 hours. The mixture was kept at this temperature and stirred for 1 hour, then heated to 30 °C and stirred for 2 hours. The reaction solution was cooled to 0 °C and quenched in a 10% ammonium chloride solution (450 g). Concentrated hydrochloric acid (38% by mass) was added dropwise to adjust the pH to 2, and the mixture was heated to 15 °C and stirred for 3 hours. The mixture was then extracted twice with 500 ml of ethyl acetate, and the organic phase was collected. The organic phase was then extracted again with 500 ml of saturated sodium chloride solution, and the organic phase was collected. Anhydrous magnesium sulfate was added and the mixture was dried. The solution was filtered, and the filtrate was collected and concentrated to obtain crude (Z)-undec-8-ene-2,5-dione. The product was purified by distillation to obtain 39.9 g of product with a purity of 97.2%, containing 2.4% of the E isomer, and a yield of 87%.

[0098] The (Z)-undec-8-ene-2,5-dione prepared in this embodiment can be used to prepare cis-jasmone via aldol condensation.

[0099] Example 7

[0100] This embodiment is the same as embodiment 6, except that:

[0101] I. Preparation of the compound shown in Formula 2-2

[0102] Add 250 ml of tetrahydrofuran to a dry 1 L 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 with stirring. Slowly add acetylpropionyl bromide tetrahydrofuran solution (167.7 g (2.1 eq) of acetylpropionyl bromide dissolved in 300 ml of tetrahydrofuran) using a constant pressure dropping funnel, controlling the dropping rate. The addition should be completed in approximately 6 hours. Then raise the temperature to 45 °C and maintain the temperature with stirring for 10 hours until the 2,6-dihydroxypyrimidine has completely reacted. Stop the reaction, remove the tetrahydrofuran under vacuum, and add 550 ml of ethyl acetate and 3% hydrochloric acid solution to the residue. Stir to neutralize, then allow to stand and separate the layers. Collect the organic layer, extract the organic phase with water and saturated brine, dry with anhydrous sodium sulfate, and concentrate under vacuum to obtain compound 126.5 as shown in Formula 2-2. g, yield 92%, used directly in the next reaction without purification.

[0103] Example 8

[0104] This embodiment is the same as embodiment 6, except that:

[0105] III. Preparation of (Z)-Undec-8-ene-2,5-dione

[0106] Add 10.6 g (3.5 eq) of magnesium shavings to a dry reaction flask, evacuate the reaction apparatus with a vacuum pump, and then purge with nitrogen. Repeat this operation three times. Add 20 g of anhydrous 2-methyltetrahydrofuran and start stirring. 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, and then add 0.5 g of bromoethane to initiate the Grignard reaction. Maintain the temperature of the solution at 45 °C, and add the remaining (Z)-1-chloro-3-hexene solution dropwise over approximately 10 hours, controlling the dropping rate. Continue stirring for 0.5 hours to obtain the (Z)-3-hexene magnesium chloride Grignard reagent.

[0107] 50 g (1.0 eq) of the compound shown in Formula 3-2 was dissolved in 150 g of dry 2-methyltetrahydrofuran. The solution was cooled to 0 °C, and the Grignard reagent prepared above was added dropwise, maintaining the reaction temperature at 0 °C. The addition was completed over 6 hours. The mixture was kept at this temperature and stirred for 1 hour, then heated to 35 °C and stirred for 2 hours. The reaction solution was cooled to 5 °C and quenched in a 10% ammonium chloride solution (450 g). Concentrated hydrochloric acid (38% by mass) was added dropwise to adjust the pH to 3, and the mixture was heated to 20 °C and stirred for 3 hours. The mixture was then extracted twice with 500 ml of ethyl acetate, and the organic phase was collected. The organic phase was then extracted again with 500 ml of saturated sodium chloride solution, and the organic phase was collected. The mixture was dried with anhydrous magnesium sulfate, filtered, and the filtrate was collected and concentrated to obtain crude (Z)-undec-8-ene-2,5-dione. The crude product was purified by distillation to obtain 40.4 g of product with a purity of 97.5%, containing 2.1% of the E isomer, and a yield of 88%.

[0108] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included 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 process includes the steps of preparing (Z)-undec-8-ene-2,5-dione using acetylpropionyl halide and dihydroxypyrimidine compounds as starting materials according to the following reaction route; The process for preparing (Z)-undec-8-ene-2,5-dione by reacting the compound shown in Formula 3 with (Z)-3-hexene magnesium halide Grignard reagent is as follows: the solution of (Z)-3-hexene magnesium halide Grignard reagent is mixed evenly with the solution of the compound shown in Formula 3 at -15~15℃, the temperature is raised to 15~45℃ and reacted for 1~3 hours, the temperature is lowered to 0~5℃ and the reaction is quenched, then the pH is adjusted to 1~3 and the temperature is raised to 15~45℃ and reacted for 2~3 hours; Where X1 is a halogen, X2 is a halogen, and R is H or methyl; Lithium chloride is added as an auxiliary agent during the preparation of (Z)-3-hexene magnesium halide Grignard reagent. The compound shown in Formula 2 reacts with ethylene glycol under acid catalysis to undergo an alcohol-ketone carbonyl condensation reaction to produce the compound shown in Formula 3.

2. The preparation method according to claim 1, characterized in that, The method for uniformly mixing the solution of (Z)-3-hexene magnesium halide Grignard reagent with the solution of the compound shown in Formula 3 is as follows: the solution of (Z)-3-hexene magnesium halide Grignard reagent is added dropwise to the solution of the compound shown in Formula 3 and mixed uniformly.

3. The preparation method according to claim 1, characterized in that, The quenching agent added to the quenching reaction is ammonium chloride.

4. The preparation method according to claim 1, characterized in that, The Grignard reaction is initiated by bromoethane in the preparation of (Z)-3-hexene magnesium halide Grignard reagent.

5. The preparation method according to claim 1, characterized in that, In the preparation of the compound shown in 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.

6. The preparation method according to claim 1, characterized in that, Acetylpropionyl chloride and 2-methyl-4,6-dihydroxypyrimidine were used as starting materials.

7. The preparation method according to claim 1, characterized in that, The acid is p-toluenesulfonic acid or trifluoroacetic acid.

8. The application of the preparation method according to any one of claims 1 to 7 in the synthesis of cis-jasmone.

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