Method for preparing carvacrol from p-cymene

Abstract

The invention provides a preparation method of carvacrol, which breaks the inherent route of preparing carvacrol from limonene and then preparing carvacrol from carvacrol in the traditional preparation method, and comprises the following steps: nitrating p-cymene to obtain an intermediate 1, and reacting the intermediate 1 with a reducing reagent to obtain an intermediate 2. And finally, carrying out diazotization hydrolysis reaction on the intermediate 2 in a two-phase system of water and an organic phase to obtain carvacrol. The preparation method does not need a process of preparing carvone under harsh conditions, does not need to be carried out at high temperature and high pressure, does not need an expensive catalyst, and is high in yield, high in product purity, simple in step and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of carvacrol preparation, and specifically relates to a method for preparing carvacrol from p-cymene. Background Art

[0002] Carvacrol, with the chemical formula C10H14O, CAS number: 499-75-2, is easily soluble in alcohol and ether, insoluble in water, has the smell of thymol, is a colorless to light yellow thick oily liquid, can evaporate with water vapor, and is used in spices, food additives, and feed additives.

[0003] In the prior art, the synthesis process of carvacrol mainly includes the following routes: (1) Dichloromethane is used as a solvent to dissolve o-benzophenol, and after dissolution, aluminum chloride is added as a catalyst, and 2-chloropropane is added dropwise at -15±5°C, and the reaction is completed after 4 hours. The reaction process generates hydrogen chloride, which is easy to corrode equipment, and the use of halogenated hydrocarbons is not environmentally friendly, especially after the reaction, it is difficult to completely remove the halogenated hydrocarbons, so the use of the products produced by this process is limited.

[0004] (2) Chinese patent CN101475448A discloses: using L-carvone as raw material, organic acid or inorganic acid as main catalyst, and PEG-400 or PEG-600 as co-catalyst, a high content of carvacrol is obtained by reaction. This method uses acid as main catalyst and the amount added is large, which has high requirements on equipment. Post-treatment also requires alkaline solution neutralization, which will inevitably produce a large amount of wastewater and bring high environmental pressure. In particular, the biggest problem is that the price of L-carvone is higher than that of carvacrol, so this process has no practical significance.

[0005] (3) Sulfonation of p-cymene with sulfuric acid is then performed, and the sulfonated p-cymene is then converted into carvacrol using molten sodium hydroxide at 300°C. This process requires excessively high temperatures, places high demands on equipment, and is highly dangerous, which can bring significant risks to the reaction.

[0006] (4) Chinese patent CN115448819B discloses: using para-cymene as raw material, using a self-made copper compound as a catalyst, and using tetramethylpiperidine as a co-catalyst, carvacrol is obtained by reaction. This method uses a copper compound as a catalyst and tetramethylpiperidine as a co-catalyst. Although the copper catalyst exhibits good catalytic activity in catalytic oxidation, it will lead to poor selectivity in practical applications. Secondly, the copper compound will lose some activity during long-term use, affecting the sustainability and reusability of the catalytic process. Although using air as an oxidant is green and environmentally friendly, it has the defect of over-oxidation leading to the production of by-products. Secondly, using air as an oxidant has high requirements for equipment and brings certain risks to the reaction. Summary of the invention

[0007] In view of the above problems, the present invention provides a method for efficiently preparing carvacrol from p-cymene. The method has high yield and simple preparation method, thereby reducing the production cost of carvacrol and being suitable for industrial production.

[0008] To achieve the above object, the present invention provides the following technical solutions: The present invention provides a method for preparing carvacrol from p-cymene, comprising the following steps: (1) 4-Cymene is subjected to nitration reaction to obtain intermediate 1.

[0009] Preferably, the nitrating agent used in the nitrating reaction is concentrated nitric acid or nitrate, and the molar ratio of p-cymene to the nitrating agent is 1:(0.5-3).

[0010] Preferably, concentrated sulfuric acid and glacial acetic acid are also added in the nitration reaction to form a mixed acid emulsion with p-cymene, and the mass ratio of p-cymene to concentrated sulfuric acid and glacial acetic acid is 1: (0.5-5): (0.3-3); the mass concentration of the concentrated sulfuric acid is more preferably 90%-100%.

[0011] More preferably, in the nitration reaction, the nitrating agent is mixed with concentrated sulfuric acid and then added dropwise to the mixed acid solution containing p-cymene: the mass ratio of the nitrating agent to sulfuric acid is 1: (0.5-4).

[0012] More preferably, the dropwise addition is completed within 0.5 h to 5 h, and the reaction is continued for 0.5 h to 2 h after the dropwise addition is completed.

[0013] Preferably, after the nitration reaction is completed, appropriate amounts of ice water and ether are added, the mixture is allowed to stand for stratification, the organic phase is subjected to reduced pressure distillation at 150 Pa-160 Pa, and a fraction at 120° C.-130° C. is collected to obtain Intermediate 1.

[0014] By controlling the amount of the nitrating agent, p-cymene, glacial acetic acid and concentrated sulfuric acid, the reaction is made to proceed in a direction that is favorable for the formation of intermediate 1, thereby increasing the yield of the reaction.

[0015] (2) The intermediate 1 is subjected to a reduction reaction to obtain the intermediate 2.

[0016] Preferably, the reducing agent used in the reduction reaction is iron powder or zinc powder, and the molar ratio of the intermediate 1 to the reducing agent is 1:(4-40).

[0017] Preferably, the solvent system in the reduction reaction is a water / ethanol / glacial acetic acid mixed solvent, the mass ratio of the intermediate 1 to ethanol is 1: (2-40), the mass ratio of the intermediate 1 to water is 1: (2-40), and the mass ratio of the intermediate 1 to glacial acetic acid is 1: (2-40).

[0018] Preferably, the reduction reaction conditions are: the intermediate 1 is added to a water / ethanol / glacial acetic acid solution, and then a reducing agent is added in batches, and the reaction is carried out at 0-130° C. for 1-6 hours.

[0019] Preferably, after the reduction reaction is completed, the mixture is filtered with diatomaceous earth, and water and ethyl acetate are added to wash and separate the layers. The organic phase is subjected to reduced pressure distillation at 150 Pa-160 Pa, and a fraction at 120° C.-130° C. is collected to obtain Intermediate 2.

[0020] By controlling the amount of reducing agent, water, ethanol and acetic acid, the reaction is made to proceed in a direction that is favorable for the formation of intermediate 2, thereby increasing the yield of the reaction.

[0021] (3) The intermediate 2 is subjected to a diazotization hydrolysis reaction to obtain carvacrol.

[0022] Preferably, the diazotizing agent used in the diazotizing hydrolysis reaction is sodium nitrite, and the molar ratio of the intermediate 2 to the diazotizing agent is 1: (0.5-4).

[0023] Preferably, in the diazotization hydrolysis reaction, the solvent system is an organic / water mixed solvent, the organic phase solvent is: at least one of p-nitrotoluene, nitrobenzene and cyclopentyl methyl ether, and the aqueous phase solvent is: at least one of aqueous sulfuric acid solution and aqueous phosphoric acid solution, with a mass fraction of 10%-80%; the mass ratio of the organic phase solvent to the aqueous phase solvent is 1: (1-50).

[0024] Preferably, in the diazotization hydrolysis reaction, the intermediate 2 is dissolved in an organic / water mixed solvent, a diazotization reagent or its aqueous solution (the mass fraction of sodium nitrite is 20%-80%) is added in 0.2-1h, and the reaction is continued for 0.5-4h at a reaction temperature of 0-100°C.

[0025] Preferably, after the diazotization hydrolysis reaction is completed, ice water and ethyl acetate are added to wash and separate the layers, the organic phase is subjected to reduced pressure distillation at 150Pa-160Pa, and the fraction at 120°C-130°C is collected to obtain carvacrol.

[0026] By controlling the dosage of the diazotizing agent, water, sulfuric acid, and organic solvent, the reaction is made to proceed in a direction that is favorable for the formation of carvacrol, thereby improving the yield of the reaction.

[0027] The present invention has the following positive and beneficial effects: The present invention breaks the inherent route of the traditional preparation method that limonene needs to be prepared into carvone first, and then carvone is used to prepare carvacrol. The intermediate 1 is creatively obtained by nitration of p-cymene, and the intermediate 1 is then reduced to obtain the intermediate 2. Finally, the intermediate 2 is subjected to a diazotization hydrolysis reaction in a two-phase system to obtain carvacrol. The preparation method of the present invention does not need to go through a process of preparing carvone under harsh conditions, does not need to be carried out under high temperature and high pressure, does not need expensive catalysts, has high yield, high product purity, and simple steps, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the HNMR chart of intermediate 1 in Example 1 of the present invention.

[0029] Figure 2 This is the HNMR chart of intermediate 2 in Example 1 of the present invention.

[0030] Figure 3 This is the HNMR chart of intermediate 3 in Example 1 of the present invention. DETAILED DESCRIPTION

[0031] The present invention will be further described in detail below in conjunction with specific embodiments. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present invention more thoroughly understood.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0033] The traditional preparation method often uses limonene as a raw material to first prepare carvone, and then performs aromatic ring isomerization on carvone to obtain carvacrol. This technical process has many steps, high preparation cost, and high requirements for reaction conditions. Industrialization has great safety risks. After a large number of experimental explorations, the technicians of the present invention have obtained a method of the present invention with high yield, simple process, and suitable for industrial production of carvacrol.

[0034] Example 1 A method for preparing carvacrol from p-cymene comprises the following steps: Preparation of intermediate 1: 10 g (0.0746 mol) of p-cymene, 21.5 g of concentrated sulfuric acid (98%) and 6 g of glacial acetic acid were placed in a 250 ml three-necked flask and stirred to form a mixed acid emulsion, which was cooled to -15°C. At the same time, a mixed solution of 21.5 g of concentrated sulfuric acid (98%) and 8.12 g of concentrated nitric acid (0.0812 mol, mass fraction of 65%) was prepared and cooled to -5°C. The mixed solution was added dropwise to the mixed acid emulsion containing p-cymene within 2 h. After the addition was completed, the reaction was continued for 15 min, during which the temperature was maintained at -10°C (with dry ice). The obtained product was diluted with water and allowed to stand for stratification (2 h). The upper organic layer was extracted, and the lower aqueous layer was extracted with ether. The organic layers were combined and distilled under reduced pressure at 150 Pa-160 Pa. The fraction of 120°C-130°C was received to obtain 11.07 g of intermediate 1 with a yield of 85%. Chemical shift of intermediate 1: 1H NMR (600 MHz, DMSO) δ 7.82 (s, 1H), 7.53 (s, 2H), 7.42 (s, 1H), 3.00(s, 1H), 2.46 (s, 4H), 1.21 (s, 8H).

[0035] Preparation of intermediate 2: 5g (0.033mol) of intermediate 1, 20g of ethanol, 20g of water and 35g of glacial acetic acid were placed in a 250ml three-necked flask, 10g of reduced zinc powder (0.153mol) was added in batches, heated to 80°C, refluxed and stirred for 2 hours, filtered on diatomaceous earth and extracted three times with ethyl acetate, washed with water, the organic phase was distilled under reduced pressure at 150Pa-160Pa, and the fraction at 120°C-130°C was collected to obtain 4.11g of intermediate 2 with a yield of 87%. Chemical shift of intermediate 2: 1H NMR (600 MHz, DMSO) δ 6.47 (s, 1H), 6.34 (s, 1H), 4.66 (s, 3H), 1.99 (s, 4H), 1.13 (s, 6H).

[0036] Preparation of carvacrol: 0.92 g (0.00617 mol) of intermediate 2 was dissolved in sulfuric acid (30%, 50 g) solution, 30 g of cyclopentyl methyl ether was added, and then an aqueous solution containing 0.5 g (0.0072 mol) of sodium nitrite was added dropwise over 15 minutes. After the addition was completed, the mixture was heated to 80 ° C for 90 minutes and then cooled to ambient temperature. The mixture was then distributed between water (50 ml) and ethyl acetate (50 ml), and the aqueous layer was separated and washed with other portions of ethyl acetate (2×25 ml). The combined organic material was washed with brine (50 ml) and dried, and vacuum distilled at 150 Pa-160 Pa, and the fraction at 120 ° C-130 ° C was received to obtain 0.698 g of carvacrol with a yield of 75%. Chemical shift of carvacrol: 1H NMR (600 MHz, DMSO) δ 9.04 (s, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H), 6.55 (dd, J =7.6, 1.8 Hz, 1H), 2.74 (dq, J = 13.8, 6.9 Hz, 1H), 2.05 (s, 3H), 1.26 – 1.21 (m, 1H), 1.14 (d, J = 6.9 Hz, 6H).

[0037] Example 2 A method for preparing carvacrol from p-cymene comprises the following steps: Preparation of intermediate 1: 5 g (0.0373 mol) of p-cymene, 21.5 g of concentrated sulfuric acid (98%) and 6 g of glacial acetic acid were placed in a 250 ml three-necked flask and stirred to form a mixed acid emulsion, which was cooled to -15°C. At the same time, a mixed solution of 21.5 g of concentrated sulfuric acid and 8.12 g of concentrated nitric acid (0.0812 mol, mass fraction of 65%) was prepared and cooled to 0°C. The mixed solution was added dropwise to the mixed acid emulsion containing p-cymene within 2.5 h. After the addition was completed, the reaction was continued for 15 min, during which the temperature was maintained at -15°C (with dry ice). The obtained product was diluted with water and allowed to stand for stratification (2 h). The upper organic layer was extracted, and the lower aqueous layer was extracted with ether. The organic layers were combined and distilled under reduced pressure at 150 Pa-160 Pa. The fraction of 120°C-130°C was received to obtain 11.72 g of intermediate 1 with a yield of 90%.

[0038] Preparation of intermediate 2: 5 g (0.033 mol) of intermediate 1, 20 g of ethanol, 20 g of water and 35 g of glacial acetic acid were placed in a 250 ml three-necked flask, 20 g of reducing zinc powder (0.306 mol) was added in batches, heated to 100 ° C, refluxed with stirring for 2 hours, filtered on diatomaceous earth and extracted three times with ethyl acetate, washed with clean water, and the organic phase was distilled under reduced pressure at 150 Pa-160 Pa, and the distillate at 120 ° C-130 ° C was collected to obtain 4.36 g of intermediate 2 with a yield of 92%.

[0039] Preparation of carvacrol: 0.92 g (0.00617 mol) of intermediate 2 was dissolved in a solution of sulfuric acid (40%, 50 g), 30 g of cyclopentyl methyl ether was added, and then an aqueous solution containing 1 g (0.0144 mol) of sodium nitrite was added dropwise over 15 minutes. After the addition was completed, the mixture was heated to 80°C for 90 minutes and then cooled to ambient temperature. The mixture was then distributed between water (50 ml) and ethyl acetate (50 ml), and the aqueous layer was separated and washed with the remaining portion of ethyl acetate (2×25 ml). The combined organic material was washed with brine (50 ml) and dried, and vacuum distilled at 150 Pa-160 Pa, and the fraction at 120°C-130°C was received to obtain 0.665 g of carvacrol with a yield of 70%.

[0040] Example 3 A method for preparing carvacrol from p-cymene comprises the following steps: Preparation of intermediate 1: 20 g (0.1492 mol) of p-cymene, 21.5 g of concentrated sulfuric acid (98%) and 6 g of glacial acetic acid were placed in a 250 ml three-necked flask and stirred to form a mixed acid emulsion, which was cooled to -15 °C. At the same time, a mixed solution of 21.5 g of concentrated sulfuric acid and 8.12 g of concentrated nitric acid (0.0812 mol, mass fraction of 65%) was prepared and cooled to -5 °C. The mixed solution was added dropwise to the mixed acid emulsion containing p-cymene within 3 h. After the addition was completed, the reaction was continued for 15 min, during which the temperature was maintained at -20 °C (with dry ice). The obtained product was diluted with water and allowed to stand for stratification (2 h). The upper organic layer was extracted, and the lower aqueous layer was extracted with ether. The organic layers were combined and distilled under reduced pressure at 150 Pa-160 Pa. The fraction of 120 °C-130 °C was received to obtain 22.14 g of intermediate 1 with a yield of 83%.

[0041] Preparation of intermediate 2: 5 g (0.033 mol) of intermediate 1, 20 g of ethanol, 20 g of water and 35 g of glacial acetic acid were placed in a 250 ml three-necked flask, 18.5 g (0.33 mol) of reduced iron powder was added in batches, heated to 90 ° C, refluxed with stirring for 2 hours, filtered on diatomaceous earth and extracted three times with ethyl acetate, washed with clean water, and distilled under reduced pressure at 150 Pa-160 Pa, and the distillate at 120 ° C-130 ° C was received to obtain 3.77 g (light yellow liquid) of intermediate 2 with a yield of 80%.

[0042] Preparation of carvacrol: 0.92 g (0.00617 mol) of intermediate 2 was dissolved in a sulfuric acid solution (30%, 50 g), 30 g of cyclopentyl methyl ether was added, and then an aqueous solution containing 0.5 g (0.0072 mol) of sodium nitrite was added dropwise over 30 minutes. After the addition was completed, the mixture was heated to 100°C for 90 minutes and then cooled to ambient temperature. The mixture was then distributed between water (50 ml) and ethyl acetate (50 ml), and the aqueous layer was separated and washed with the remaining portion of ethyl acetate (2×25 ml). The combined organic material was washed with brine (50 ml) and dried, and vacuum distilled at 150 Pa-160 Pa, and the fraction at 120°C-130°C was received to obtain 0.71 g of carvacrol with a yield of 78%.

[0043] It should be understood that the attached claims summarize the scope of the present invention. Under the guidance of the concept of the present invention, those skilled in the art should realize that certain changes made to the various embodiments of the present invention will be covered by the spirit and scope of the claims of the present invention.

Claims

1. A method for preparing carvacrol from p-cymene, characterized in that: The following steps are involved: (1) nitrifying p-cymene to obtain intermediate 1; (2) subjecting the intermediate 1 to a reduction reaction to obtain the intermediate 2; (3) The intermediate 2 is subjected to a diazotization hydrolysis reaction to obtain carvacrol.

2. The method for preparing carvacrol from p-cymene according to claim 1, characterized in that: The nitrating agent used in the nitrating reaction is concentrated nitric acid or nitrate, and the molar ratio of p-cymene to the nitrating agent is 1:(0.5-3).

3. The method for preparing carvacrol from p-cymene according to claim 1, characterized in that: Concentrated sulfuric acid and glacial acetic acid are also added in the nitration reaction to form a mixed acid emulsion with p-cymene. The mass ratio of p-cymene to concentrated sulfuric acid and glacial acetic acid is 1: (0.5-5): (0.3-3).

4. The method for preparing carvacrol from p-cymene according to claim 3, characterized in that: In the nitration reaction, the nitration reagent is first mixed with concentrated sulfuric acid and then added dropwise to a mixed acid solution containing para-cymene: the mass ratio of the nitration reagent to sulfuric acid is 1: (0.5-4).

5. The method for preparing carvacrol from p-cymene according to claim 1, characterized in that: After the nitration reaction is completed, appropriate amounts of ice water and ether are added, the mixture is allowed to stand for stratification, the organic phase is distilled under reduced pressure at 150 Pa-160 Pa, and the fraction at 120° C.-130° C. is collected to obtain intermediate 1.

6. The method for preparing carvacrol from p-cymene according to claim 1, characterized in that: The reducing agent used in the reduction reaction is iron powder or zinc powder, and the molar ratio of the intermediate 1 to the reducing agent is 1:(4-40).

7. The method for preparing carvacrol from p-cymene according to claim 1, characterized in that: The solvent system in the reduction reaction is a water / ethanol / glacial acetic acid mixed solvent, and the mass ratio of the intermediate 1 to ethanol, water and glacial acetic acid is 1:(2-40):(2-40):(2-40).

8. The method for preparing carvacrol from p-cymene according to claim 1, characterized in that: After the reduction reaction is completed, the mixture is filtered with diatomaceous earth, and water and ethyl acetate are added to wash and separate the layers. The organic phase is distilled under reduced pressure at 150 Pa-160 Pa, and the fraction at 120° C.-130° C. is collected to obtain intermediate 2.

9. The method for preparing carvacrol from p-cymene according to claim 1, characterized in that: The diazotization reagent used in the diazotization hydrolysis reaction is sodium nitrite, and the molar ratio of the intermediate 2 to the diazotization reagent is 1: (0.5-4).

10. The method for preparing carvacrol from p-cymene according to claim 1, characterized in that: In the diazotization hydrolysis reaction, the solvent system is an organic / water mixed solvent, the organic phase solvent is: at least one of p-nitrotoluene, nitrobenzene and cyclopentyl methyl ether, and the aqueous phase solvent is: at least one of aqueous sulfuric acid solution and aqueous phosphoric acid solution, with a mass fraction of 10%-80%; the mass ratio of the organic phase solvent to the aqueous phase solvent is 1: (1-50).

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