Synthesis method of piperonone

Abstract

The invention discloses a synthesis method of piperonone, and relates to the technical field of flavors, fragrances and chemical engineering, and the synthesis method comprises the following steps: taking acrylate as a raw material, and carrying out Michael addition reaction with isobutene under the action of Lewis acid to obtain 5-methyl-5-hexenoic acid ethyl ester; the preparation method comprises the following steps: carrying out nucleophilic substitution reaction on ethyl 5-methyl-5-hexenoate and bromoisopropane under the action of a basic catalyst to obtain ethyl 5-methyl-2-isopropyl-5-hexenoate; carrying out self Friedel-Crafts acylation reaction on the 5-methyl-2-isopropyl-5-hexenoic acid ethyl ester under the action of Lewis acid, so as to obtain 5-methyl-2-isopropyl-5-chloro cyclohexanone; and carrying out elimination reaction on the 5-methyl-2-isopropyl-5-chlorocyclohexanone under the action of alkali to obtain the product piperonone. According to the synthetic route, conventional chemical reagents are used as raw materials, reaction conditions are mild, emission of three wastes is reduced to a great extent, and the synthetic route is more environmentally friendly and suitable for continuous industrial production.

Description

Technical Field

[0001] This invention relates to the fields of fragrance and chemical technology, and in particular to a method for synthesizing piperone. Background Technology

[0002] Piperone, chemically known as 6-isopropyl-3-methyl-2-cyclohexen-1-one, is a naturally occurring cyclic terpenone. It is a characteristic component of peppermint oil and is found in Asian peppermint and peppermint varieties. It has a camphor-like odor and a pungent mint flavor. With wide applications in daily chemicals and food, piperone has significant application value, and its synthesis methods have always attracted considerable attention.

[0003] Khimiya, Prirodnykh, et al. reported a method for synthesizing piperone using thymol methyl ether as a raw material. The method involves Birch reduction (reaction of lithium metal and ethylenediamine-isopropanol), followed by acidic hydrolysis to obtain piperone with a selectivity of 63.5%. However, this Birch reduction method uses highly reactive lithium metal, thus lacking practical industrial applicability.

[0004] Chemische Berichte 82, 112–116, 1949 reported a method using ethyl α-isopropylacetoacetate and methyl vinyl ketone as starting materials, via Michael addition reaction, intramolecular cyclization, and hydrolytic decarboxylation to obtain the product. The disadvantages of this method are that the starting material must be synthesized in-house, as methyl vinyl ketone is not commercially available and requires in-house synthesis; furthermore, it is toxic.

[0005] Tamotsu Fujisawa et al. reported a reaction of 2-methyl-2-pentenyl bromide as a Grignard reagent with methylcyclobutyrolactone to obtain citronellolic acid. Citronellolic acid then reacts with thionyl chloride to obtain citronellol chloride. The product is then obtained by dechlorination with boron trifluoride diethyl ether as a catalyst and dichloromethane as a solvent at room temperature in the presence of potassium carbonate. The disadvantages of this method are that the reaction requires specific experimental conditions, and the Grignard reagent generates a large amount of magnesium salt wastewater.

[0006] BASF reported in US3962341 a method for producing piperonone by reacting 3-methyl-2-butenal with formic acid at high temperature using pentane as a solvent. Takasago reported a metal catalyst for the position-selective hydrogenation of piperonone under high pressure to obtain piperonone.

[0007] CN103755539A reports a four-step synthesis of piperonone. First, methyl isobutyl ketone is reacted with formaldehyde in the presence of hydrogen chloride to obtain the intermediate 3-isopropyl-3-buten-2-one. Then, 3-isopropyl-3-buten-2-one undergoes Michael addition under alkaline catalysis to obtain the intermediate methyl 2-acetyl-4-isopropyl-5-oxo-hexanoate. The methyl 2-acetyl-4-isopropyl-5-oxo-hexanoate undergoes intramolecular condensation under alkaline conditions to obtain the carboxylic ester of piperonone. Finally, the carboxylic ester of piperonone is hydrolyzed and decarboxylated under alkaline conditions to obtain piperonone. The disadvantages of this method are: the hydrogen chloride gas in the first step is highly corrosive, requiring sophisticated production equipment; excessive HCl gas also generates a large amount of acidic wastewater; and the intramolecular condensation reaction in the third step has low selectivity, resulting in a low overall yield.

[0008] In summary, existing methods for synthesizing piperone have the following problems: they use starting materials that are not easy to obtain; or they use expensive and non-recyclable metal catalysts; or they use toxic raw materials and intermediates, resulting in high costs; or they have prominent environmental and safety issues, making them impractical for industrial production. Summary of the Invention

[0009] To address the shortcomings of existing technologies, this invention provides a method for synthesizing piperone that reduces costs, uses mild reaction conditions, is environmentally friendly, and is suitable for industrial production.

[0010] In order to achieve the objective of this invention, the following solution is proposed: A method for synthesizing piperone, comprising the following steps: Step 1: Using acrylate as a raw material, a Michael addition reaction is carried out with isobutylene under the action of Lewis acid to obtain ethyl 5-methyl-5-hexenoate; Step 2: Ethyl 5-methyl-5-hexenoate reacts with isopropane bromide in the presence of a basic catalyst to give ethyl 5-methyl-2-isopropyl-5-hexenoate. Step 3: Ethyl 5-methyl-2-isopropyl-5-hexenoate undergoes its own Friedel-Crafts acylation reaction under the action of a Lewis acid to give 5-methyl-2-isopropyl-5-chlorocyclohexanone; Step 4: 5-Methyl-2-isopropyl-5-chlorocyclohexanone undergoes an elimination reaction under the action of a base to give the product piperonone.

[0011] Furthermore, the Lewis acid used in step one is one or more of aluminum trichloride, boron trifluoride tetrahydrofuran solution, ferric chloride, and zinc chloride. Aluminum trichloride is preferred, and its molar equivalent is 15%-65% of the acrylate. The reaction temperature in step one is 5℃-30℃.

[0012] Furthermore, the alkaline catalyst used in step two is one or more of the following: sodium methoxide (20% methanol solution), sodium ethoxide (20% ethanol solution), potassium tert-butoxide (20% tetrahydrofuran solution), lithium diisopropylamino (20% tetrahydrofuran solution), and lithium hexamethyldisilamino (20% tetrahydrofuran solution). Preferably, lithium hexamethyldisilamino (20% tetrahydrofuran solution) is used, and its weight is 50%-120% of ethyl 5-methyl-5-hexenoate. The reaction temperature in step two is 15℃-65℃.

[0013] Furthermore, the solvent used in step three is one or more of toluene, xylene, tetrahydrofuran, n-heptane, n-hexane, nitrobenzene, and nitrobanane, preferably a mixture of nitrobenzene and nitrobanane. The Lewis acid used in step three is one or more of aluminum trichloride, boron trifluoride tetrahydrofuran solution, ferric chloride, and zinc chloride. Aluminum trichloride is preferred, and its weight is 20%-80% of ethyl 5-methyl-2-isopropyl-5-hexenoate. The reaction temperature in step three is 30℃-80℃.

[0014] Furthermore, the alkali used in step four is one or more of sodium hydroxide, potassium hydroxide, sodium ethoxide, and sodium methoxide. Sodium hydroxide is preferred, and the weight of sodium hydroxide is 50%-120% of 5-methyl-2-isopropyl-5-chlorocyclohexanone. The reaction temperature in step four is 30℃-45℃.

[0015] The beneficial effects of this invention are as follows: the synthetic route of this invention uses conventional chemical reagents as raw materials, the reaction conditions are mild, the emission of waste gas, wastewater, and solid waste is greatly reduced, it is more environmentally friendly, and it is suitable for continuous industrial production. Detailed Implementation

[0016] Example 1 Step 1: At room temperature, add 250.0g of ethyl acrylate and 250.0g of toluene to a 1L three-necked flask, and add 100.0g of aluminum trichloride in batches. Then, control the temperature at -10℃ to -10℃ and, while stirring, pass 168.8g of isobutylene gas below the surface of the reactants. After 1 hour, the gas is completely introduced. Then, control the reaction temperature at 30℃ and react for 2-3 hours. After GC shows that the reaction is complete, add 120.0g of water dropwise to the reaction flask for washing. After washing, separate the liquid and liquid phases. Wash the organic phase again with 120.0g of 10% sodium sulfate solution. After washing, separate the liquid and liquid phases. Distill the organic phase to obtain ethyl 5-methyl-5-hexenoate with a yield of 87%.

[0017] Step 2: First, add 200.0g of ethyl 5-methyl-5-hexenoate and 100.2g of lithium hexamethyldisilamide (20% tetrahydrofuran solution) to a 1L three-necked flask, and control the temperature at -20℃ to 10℃. In another 1L three-necked flask, add 236.4g of bromoisopropane, 300.0g of methanol, and 11.8g of sodium iodide. Heat under reflux for 30 minutes with stirring, then cool to room temperature. While stirring, control the reaction temperature at 0℃ to 5℃, and add the mixture dropwise to the previously prepared mixture of ethyl 5-methyl-5-hexenoate and lithium hexamethyldisilamide over 1 hour. After the addition is complete, react at 15℃ to 25℃ for 2 hours. After GC analysis shows the reaction is complete, add 12.0g of acetic acid to the three-necked flask for neutralization. After neutralization, filter, and then distill the organic phase to obtain ethyl 5-methyl-2-isopropyl-5-hexenoate with a yield of 90%.

[0018] Step 3: First, add 166.7g of nitrobenzene, 333.3g of nitrobanane, and 109.3g of aluminum trichloride to a 1L three-necked flask, maintaining the temperature at 35℃. Then, begin adding 250.0g of ethyl 5-methyl-2-isopropyl-5-hexenoate dropwise over 2 hours. After the addition is complete, react at 65℃ for 2 hours. After GC analysis shows the reaction is complete, add 110.0g of water to the reaction flask for washing. After washing, separate the liquid and liquid phases, and wash the organic phase again with 110.0g of 10% sodium sulfate solution. After washing, separate the liquid and liquid phases, and distill the organic phase to obtain 5-methyl-2-isopropyl-5-chlorocyclohexanone in 86.0% yield.

[0019] Step 4: First, add 500.0g of 5-methyl-2-isopropyl-5-chlorocyclohexanone, 256.5g of 45% sodium hydroxide aqueous solution, and 25.0g of tetrabutylammonium chloride to a 1L three-necked flask, and then react at 30℃ for 3h. After the GC showed that the reaction was complete, separate the liquid to obtain the organic phase, extract the aqueous phase with toluene, combine the organic phases, wash the organic phase twice with 10% sodium sulfate aqueous solution, and distill the organic phase to obtain piperine with a yield of 78%.

[0020] Example 2 Step 1: At room temperature, add 250.0g of ethyl acrylate and 250.0g of toluene to a 1L three-necked flask, and add 133.1g of aluminum trichloride in batches. Then, control the temperature at -10℃ to -10℃ and, while stirring, pass 168.8g of isobutylene gas below the surface of the reactants. After 1 hour, the gas is completely introduced. Then, control the reaction temperature at 30℃ and react for 2-3 hours. After the GC shows that the reaction is complete, add 120.0g of water dropwise to the reaction flask for washing. After washing, separate the liquid and liquid phases. Wash the organic phase again with 120.0g of 10% sodium sulfate solution. After washing, separate the liquid and liquid phases, and distill the organic phase to obtain ethyl 5-methyl-5-hexenoate with a yield of 86.8%.

[0021] Step 2: First, add 200.0g of ethyl 5-methyl-5-hexenoate and 100.1g of lithium diisopropylamino (20% tetrahydrofuran solution) to a 1L three-necked flask, and control the temperature at -15℃ to 0℃. In another 1L three-necked flask, add 236.4g of bromoisopropane, 300.0g of methanol, and 11.8g of sodium iodide. Heat under reflux for 30 minutes with stirring, then cool to room temperature. While stirring, control the reaction temperature at 20℃-30℃ and add the mixture dropwise to the previously prepared mixture of ethyl 5-methyl-5-hexenoate and lithium diisopropylamino at a time of 1 hour. After the addition is complete, react at 30℃-35℃ for 2 hours. GC analysis shows that the reaction is complete. Then, add 12.0g of acetic acid to the three-necked flask at room temperature for neutralization. After neutralization, filter, and then distill the organic phase to obtain ethyl 5-methyl-2-isopropyl-5-hexenoate in 80% yield.

[0022] Step 3: First, add 166.7g of nitrobenzene, 333.3g of nitrobanane, and 84.4g of aluminum trichloride to a 1L three-necked flask, maintaining the temperature at 50℃. Then, begin adding 250.0g of ethyl 5-methyl-2-isopropyl-5-hexenoate dropwise over 2 hours. After the addition is complete, react at 50℃ for 2 hours. After GC analysis shows the reaction is complete, add 80.0g of water to the reaction flask for washing. After washing, separate the liquid and liquid phases, and wash the organic phase again with 80.0g of 10% sodium sulfate solution. After washing, separate the liquid and liquid phases, and distill the organic phase to obtain 5-methyl-2-isopropyl-5-chlorocyclohexanone in 83% yield.

[0023] Step 4: First, add 500.0 g of 5-methyl-2-isopropyl-5-chlorocyclohexanone, 256.5 g of 45% sodium hydroxide aqueous solution, and 25.0 g of tetrabutylammonium chloride to a 1 L three-necked flask, and then react at 45 °C for 3 h. After the GC showed that the reaction was complete, separate the liquid to obtain the organic phase, extract the aqueous phase with toluene, combine the organic phases, wash the organic phase twice with 10% sodium sulfate aqueous solution, and distill the organic phase to obtain piperine with a yield of 75.0%.

[0024] Example 3 Step 1: At room temperature, add 300.0g of ethyl acrylate and 300.0g of toluene to a 1L three-necked flask, and add 80.0g of aluminum trichloride in batches. Then, control the temperature at -10℃ to -10℃ and, while stirring, pass 201.8g of isobutylene gas below the surface of the reactants. After 1 hour, the gas is completely introduced. Then, control the reaction temperature at 25℃ and react for 2-3 hours. After the GC shows that the reaction is complete, add 90.0g of water dropwise to the reaction flask for washing. After washing, separate the liquid and liquid phases. Wash the organic phase again with 90.0g of 10% sodium sulfate solution. After washing, separate the liquid and liquid phases, and distill the organic phase to obtain ethyl 5-methyl-5-hexenoate with a yield of 83%.

[0025] Step 2: First, add 200.0g of ethyl 5-methyl-5-hexenoate and 100.0g of sodium methoxide (20wt%) to a 1L three-necked flask, and control the temperature at 10℃-25℃. In another 1L three-necked flask, add 236.4g of bromoisopropane, 300.0g of methanol, and 11.8g of sodium iodide. Heat under reflux for 30 minutes with stirring, then cool to room temperature. While stirring, control the reaction temperature at 65℃ and add the mixture dropwise to the previously prepared mixture of ethyl 5-methyl-5-hexenoate and sodium methoxide over 1 hour. After the addition is complete, react at 65℃ for 2 hours. GC analysis shows the reaction is complete. Then, add 12.0g of acetic acid to the three-necked flask at room temperature for neutralization. After neutralization, filter the mixture, and then distill the organic phase to obtain ethyl 5-methyl-2-isopropyl-5-hexenoate in 70% yield.

[0026] Step 3: First, add 166.7g of nitrobenzene, 333.3g of nitrobanane, and 50.4g of aluminum trichloride to a 1L three-necked flask, maintaining the temperature at 25℃-30℃. Then, begin adding 250.0g of ethyl 5-methyl-2-isopropyl-5-hexenoate dropwise over 2 hours. After the addition is complete, react at 30℃ for 2 hours. After GC analysis shows the reaction is complete, add 60.0g of water dropwise to the reaction flask. After washing, separate the liquid and liquid phases. Wash the organic phase again with 60.0g of 10% sodium sulfate solution. After washing, separate the liquid and liquid phases, and distill the organic phase to obtain 5-methyl-2-isopropyl-5-chlorocyclohexanone in 75% yield.

[0027] Step 4: First, add 500.0 g of 5-methyl-2-isopropyl-5-chlorocyclohexanone, 291.0 g of 40% sodium hydroxide aqueous solution, and 25.0 g of tetrabutylammonium chloride to a 1 L three-necked flask, and then react at 30 °C for 3 h. After the GC showed that the reaction was complete, add 170.0 g of acetic acid dropwise to the three-necked flask at room temperature to wash and neutralize, then filter, and distill the organic phase to obtain piperonone with a yield of 73%.

[0028] Example 4 Step 1: At room temperature, add 300.0g of ethyl acrylate and 300.0g of toluene to a 1L three-necked flask, and add 60.0g of aluminum trichloride in batches. Then, control the temperature at -10℃ to -10℃ and, while stirring, pass 201.8g of isobutylene gas below the surface of the reactants. After 1 hour, the gas is completely introduced. Then, control the reaction temperature at 5℃ to -15℃ and react for 2 to 3 hours. After the GC shows that the reaction is complete, add 80.0g of water dropwise to the reaction flask for washing. After washing, separate the liquid and liquid phases. Wash the organic phase again with 80.0g of 10% sodium sulfate. After washing, separate the liquid and liquid phases. Distill the organic phase to obtain ethyl 5-methyl-5-hexenoate with a yield of 80%.

[0029] Step 2: First, add 200.0g of ethyl 5-methyl-5-hexenoate and 100.0g of sodium methoxide (30wt%) to a 1L three-necked flask, and control the temperature at -10℃ to 25℃. In another 1L three-necked flask, add 236.4g of bromoisopropane, 300.0g of methanol, and 11.8g of sodium iodide. Heat under reflux for 30 minutes with stirring, then control the reaction temperature at 55℃. Add the previously mixed ethyl 5-methyl-5-hexenoate and sodium methoxide dropwise over 1 hour. After the addition is complete, react at 55℃ for 2 hours. After GC analysis shows the reaction is complete, add 12.0g of acetic acid to the three-necked flask at room temperature for neutralization. After neutralization, filter, and then distill the organic phase to obtain ethyl 5-methyl-2-isopropyl-5-hexenoate in 50% yield.

[0030] Step 3: First, add 500.0g of toluene and 50.4g of aluminum trichloride to a 1L three-necked flask. Control the reaction temperature at 20℃-30℃, and then start adding 250.0g of ethyl 5-methyl-2-isopropyl-5-hexenoate dropwise over 2 hours. After the addition is complete, react at 30℃ for 2 hours. After GC shows that the reaction is complete, add 85.0g of water to the reaction flask for washing. After washing, separate the liquid and liquid phases. Wash the organic phase again with 85.0g of 10% sodium sulfate solution. After washing, separate the liquid and liquid phases, and distill the organic phase to obtain 5-methyl-2-isopropyl-5-chlorocyclohexanone in 60% yield.

[0031] Step 4: First, add 500.0 g of 5-methyl-2-isopropyl-5-chlorocyclohexanone, 265.0 g of 40% sodium hydroxide aqueous solution, and 25.0 g of tetrabutylammonium chloride to a 1 L three-necked flask, and then react at 30 °C for 3 h. After the GC showed that the reaction was complete, add 160.0 g of acetic acid to the three-necked flask at room temperature for washing and neutralization, then filter, and distill the organic phase to obtain piperonone with a yield of 70%.

[0032] Comparative Example 1 The operating steps are the same as in Example 1. Experiments were conducted to compare the types of Lewis acids used in Step 1, and the results are shown in Table 1. Table 1. Effect of Lewis acid type on the purity and yield of the product in step one. It is evident that the Lewis acid solution of aluminum chloride and boron trifluoride tetrahydrofuran yields the highest purity and yield of ethyl 5-methyl-5-hexenoate. Considering both safety and economy, aluminum chloride is the preferred choice.

[0033] Comparative Example 2 The operating steps are the same as in Example 1. Experiments were conducted to compare the types of alkaline catalysts used in step two, and the results are shown in Table 2. Table 2. Effect of alkaline catalyst type on the purity and yield of the product in step two. It is evident that the alkaline catalyst selected in step two, lithium hexamethyldisilamide (20% tetrahydrofuran solution), yielded the highest purity and yield of ethyl 5-methyl-2-isopropyl-5-hexenoate.

[0034] Comparative Example 3 The operating steps are the same as in Example 1. Experiments were conducted to compare the types of solvents used in step three, and the results are shown in Table 3. Table 3. Record of the effect of solvent type on the purity and yield of the product in step three. It is evident that the solvent used in step three, nitropropane and nitroethane, yielded the highest purity and yield of 5-methyl-2-isopropyl-5-chlorocyclohexanone.

[0035] Comparative Example 4 The operating steps are the same as in Example 1. Experiments were conducted to compare the types of Lewis acids used in step three, and the results are shown in Table 4. Table 4. Effect of Lewis acid type on the purity and yield of the product in step three. It is evident that using aluminum trichloride as the Lewis acid in step three yields the highest purity and yield of 5-methyl-2-isopropyl-5-chlorocyclohexanone.

[0036] Comparative Example 5 The operating steps are the same as in Example 1. Experiments were conducted to compare the types of alkali used in step four, and the results are shown in Table 5: Table 5. Record of the effect of alkali type on the purity and yield of the product in step four. It is evident that using sodium hydroxide as the alkali in step four yields the highest purity and yield of piperine.

[0037] The above embodiments are only used to illustrate the technical ideas and features of the present invention, and are not intended to be unique or to limit the present invention. Those skilled in the art should understand that various changes or equivalent substitutions made to the present invention without departing from its scope are all within the scope of protection of the present invention.

Claims

1. A method for synthesizing piperone, characterized in that, Includes the following steps: Step 1: Using acrylate as a raw material, a Michael addition reaction is carried out with isobutylene under the action of Lewis acid to obtain ethyl 5-methyl-5-hexenoate; Step 2: Ethyl 5-methyl-5-hexenoate reacts with isopropane bromide in the presence of a basic catalyst to give ethyl 5-methyl-2-isopropyl-5-hexenoate. Step 3: Ethyl 5-methyl-2-isopropyl-5-hexenoate undergoes its own Friedel-Crafts acylation reaction under the action of a Lewis acid to give 5-methyl-2-isopropyl-5-chlorocyclohexanone; Step 4: 5-Methyl-2-isopropyl-5-chlorocyclohexanone undergoes an elimination reaction under the action of a base to give the product piperonone.

2. The method for synthesizing piperone according to claim 1, characterized in that, In step one, the Lewis acid used is one or more of aluminum trichloride, boron trifluoride tetrahydrofuran solution, ferric chloride, and zinc chloride.

3. The method for synthesizing piperone according to claim 1, characterized in that, In step one, the Lewis acid used is aluminum trichloride, and the molar equivalent of aluminum trichloride is 15%-65% of acrylate.

4. The method for synthesizing piperone according to claim 1, characterized in that, In step two, the alkaline catalyst is one or more of the following: a 20% (w / w) methanol solution of sodium methoxide, a 20% (w / w) ethanol solution of sodium ethoxide, a 20% (w / w) tetrahydrofuran solution of potassium tert-butoxide, a 20% (w / w) tetrahydrofuran solution of lithium diisopropylaminoacetate, and a 20% (w / w) tetrahydrofuran solution of lithium hexamethyldisilaminoacetate.

5. The method for synthesizing piperone according to claim 1, characterized in that, In step two, the alkaline catalyst used is a 20% (w / w) tetrahydrofuran solution of lithium hexamethyldisilamide, which is 50%-120% of ethyl 5-methyl-5-hexenoate by weight.

6. The method for synthesizing piperone according to claim 1, characterized in that, In step three, the solvent used is one or more of toluene, xylene, tetrahydrofuran, n-heptane, n-hexane, nitrobenzene, and nitrobanane.

7. The method for synthesizing piperone according to claim 1, characterized in that, In step three, the Lewis acid used is one or more of aluminum trichloride, boron trifluoride tetrahydrofuran solution, ferric chloride, and zinc chloride.

8. The method for synthesizing piperone according to claim 1, characterized in that, In step three, the Lewis acid used is aluminum trichloride, and the weight of aluminum trichloride is 20%-80% of ethyl 5-methyl-2-isopropyl-5-hexenoate.

9. The method for synthesizing piperone according to claim 1, characterized in that, In step four, the alkali used is one or more of sodium hydroxide, potassium hydroxide, sodium ethoxide, and sodium methoxide.

10. The method for synthesizing piperone according to claim 1, characterized in that, In step four, the alkali used is sodium hydroxide, and the weight of sodium hydroxide is 50%-120% of 5-methyl-2-isopropyl-5-chlorocyclohexanone.

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