Linalool derivative with lasting disinfection function as well as preparation and application of linalool derivative

Abstract

The invention discloses a linalool derivative with a lasting disinfection function as well as preparation and application of the linalool derivative. The structure of the linalool derivative is shown as a formula (I), and the preparation method of the linalool derivative comprises the following steps: adding linalool and sorbic acid into an organic solvent, uniformly mixing, reacting for 2-6 hours under stirring and heating conditions to obtain a mixed product, removing the organic solvent in the mixed product to obtain a crude product, and purifying the crude product to obtain the linalool derivative. The linalool derivative is prepared through the esterification reaction modification of the linalool and the sorbic acid, so that the volatility of the linalool derivative is effectively reduced, and the effectiveness period of the linalool derivative is prolonged. Compared with linalool, the bacteriostatic durability of the cinnamomum camphora sorbic ester is remarkably improved, the bacteriostatic rate can still be higher than 85% within 8 h, and the cinnamomum camphora sorbic ester can be applied to preparation of a long-acting disinfectant. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a linalool derivative and a preparation method thereof, and particularly to a linalool derivative with a long-lasting disinfection function, and its preparation and application. Background Art

[0002] Linalool is a naturally occurring compound with bactericidal and disinfectant functions, widely present in various plants such as lavender and citronella. Due to its natural and low-toxic properties, it shows great application potential in the fields of medical disinfection, food preservation, air purification, etc. However, linalool has a relatively small molecular weight (about 154.25 g / mol) and strong volatility, making it difficult to continuously exert its disinfection effect, affecting the service life and effect of the product, and resulting in its bactericidal effect being difficult to fully play.

[0003] To solve the problem of the long-lasting bactericidal effect of linalool, the existing technology usually adopts the fine powder method. For example, microcapsule fine powder containing linalool is prepared by methods such as spray drying. The wall material can be selected from natural macromolecules such as whey protein isolate, etc., and linalool is wrapped inside. By encapsulating linalool in microcapsules and then making the microcapsules into fine powder through some processes, it can protect linalool from the external environment and achieve slow release, thereby prolonging the bactericidal action time. Linalool can also be made into nanoparticles to form fine powder, or it can be loaded on a nanoscale carrier material, and the formed fine powder preparation may also help improve its stability and bactericidal persistence. For example, the preparation of linalool nanoemulsion with a particle size of 1 - 100 nm, which belongs to a thermodynamically stable system, can improve the solubility of the drug, reduce the enzymatic hydrolysis of the drug in the body, form a protective effect on the drug and achieve slow release. There are also cases of making linalool into nano-liposomes to increase the drug stability and achieve continuous and controllable release. However, these methods often introduce other chemical components, which may not only affect the bactericidal effect of linalool, but also pose potential safety hazards in some application scenarios with extremely high purity requirements, such as the medical and food preservation fields. In addition, the existing methods have limited improvement effects on the bactericidal ability of linalool and are difficult to meet the growing demand for highly efficient bactericidal products. Therefore, developing a method that can effectively improve the service life of linalool, enhance its bactericidal ability, and is green and safe has become an urgent problem to be solved in this field.

[0004] Sorbic acid is a common preservative that inhibits the growth of microorganisms and plays a preservative role by inhibiting the dehydrogenase system in microorganisms. It can effectively inhibit the growth of microorganisms such as molds and yeasts and is widely used in the food industry. However, the antibacterial effect of sorbic acid depends on an acidic environment with a pH lower than 6, and once the pH is higher than 8, it will cause its inactivation. Therefore, sorbic acid has weak and non-persistent antibacterial ability in a neutral to slightly alkaline application environment. Summary of the Invention

[0005] Object of the Invention: The object of the present invention is to provide a linalool derivative with high and lasting antibacterial effect. Another object of the present invention is to propose a preparation method of the linalool derivative to solve the problem of how to modify and prepare the linalool derivative. The third aspect of the present invention provides the application of the linalool derivative in the preparation of a long-acting disinfectant to solve the problem of how to prepare a long-acting disinfectant.

[0006] Technical Solution: A linalool derivative with a structure shown in formula (I) according to the present invention:

[0007]

[0008] The second aspect of the present invention discloses a preparation method of the above linalool derivative, including the following reactions:

[0009]

[0010] During the esterification process, the molecular structure of linalool interacts with sorbic acid, and the electron cloud distribution of linalool changes accordingly, thereby forming a new chemical structure with stronger bactericidal activity, that is, a new disinfection group. This new disinfection group can more effectively destroy the cell wall and cell membrane of bacteria and interfere with the normal metabolic process of bacteria, thus significantly enhancing the bactericidal ability of linalool.

[0011] Preferably, the mass ratio of linalool to sorbic acid is 1 - 2:1 - 2.

[0012] Preferably, the inert atmosphere is a nitrogen atmosphere or a helium atmosphere.

[0013] Preferably, the reaction temperature is 40 - 70 °C.

[0014] This temperature range can not only ensure the smooth progress of the reaction but also avoid the decomposition of linalool and sorbic acid or the occurrence of side reactions due to too high temperature. Continuously stirring the reaction ensures that linalool and sorbic acid are fully contacted and the esterification reaction is completed.

[0015] Preferably, the above preparation method includes the following reaction steps: adding linalool and sorbic acid into an organic solvent, mixing evenly, reacting for 2 - 6 h under stirring and heating conditions to obtain a mixed product, removing the organic solvent from the mixed product to obtain a crude product, and purifying the crude product to obtain the linalool derivative.

[0016] Furthermore, the organic solvent includes at least one of methanol, ethanol, dichloromethane, dimethyl sulfoxide, and tetrahydrofuran.

[0017] Furthermore, the purification method is: adding the crude product into absolute ethanol, heating to slightly boiling to completely dissolve the crude product, then slowly cooling to room temperature, filtering to collect the crystals, and drying the crystals under vacuum to obtain the linalool derivative.

[0018] After the reaction is completed, the organic solvent absolute ethanol is removed by means of vacuum distillation to obtain a crude product containing linalool sorbate. Then, the crude product is recrystallized with absolute ethanol to further improve the purity of the esterified product. Finally, the recrystallized product is placed in a vacuum drying oven for drying to obtain pure linalool sorbate.

[0019] Furthermore, the vacuum drying method is drying at 30 - 50 °C for 4 - 8 h under vacuum conditions.

[0020] The third aspect of the present invention discloses the application of the above linalool derivatives in the preparation of long - acting disinfectants.

[0021] Beneficial effects: Compared with the prior art, the present invention has the following remarkable advantages:

[0022] 1. The present invention prepares linalool derivatives by the esterification reaction modification of linalool and sorbic acid, effectively reducing the volatility of linalool derivatives and increasing the effective period of linalool derivatives. The linalool sorbate in the present invention has a significantly improved antibacterial persistence compared with linalool, and the antibacterial rate can still be higher than 85% at 8 h.

[0023] 2. The bactericidal ability is greatly enhanced: The structure of linalool sorbate contains multiple double bonds and an ester group, with high reactivity. The newly formed bactericidal groups have brought a qualitative leap in the bactericidal effect of linalool. The bactericidal experiment results against common harmful bacteria such as Escherichia coli and Staphylococcus aureus show that at the same concentration, the antibacterial rate of the present invention against Escherichia coli has increased from about 50% to over 90% compared with linalool, and the antibacterial rate against Staphylococcus aureus has increased from about 60% to over 95%. Specific embodiments

[0024] The technical solutions of the present invention will be further described below.

[0025] Example 1: A linalool derivative, whose structure is shown in formula (I):

[0026]

[0027] The preparation method of the above linalool derivative is as follows:

[0028]

[0029] Add 10 g of linalool essential oil, 15 g of sorbic acid, and 100 mL of absolute ethanol to a 250 mL three-necked flask in sequence. Introduce nitrogen into the flask to create an inert gas environment to prevent the oxidation of linalool during the reaction. Turn on the oil bath heating device, control the reaction temperature at 60 °C, and at the same time start the stirrer, set the stirring speed at 300 r / min, and mix and react fully for 4 hours. After the reaction is completed, transfer the mixed product to a rotary evaporator and distill off the absolute ethanol under the conditions of 40 °C and reduced pressure to obtain the crude product of linalool sorbate. Then, add the crude product to an appropriate amount of absolute ethanol, heat it to slightly boiling to completely dissolve the crude product, and then slowly cool it to room temperature to precipitate the linalool sorbate crystals. Filter and collect the crystals, and place the crystals in a vacuum drying oven and dry them at 40 °C for 6 hours to finally obtain high-purity linalool sorbate in the form of a white powder.

[0030] Linalool sorbate derivative 13 C-NMR data (CDCl3, δ / ppm)

[0031] 1. Linalool nucleus part

[0032] δ 135.4 (-CH=, olefin carbon)

[0033] δ 115.3 (=CH2, terminal olefin carbon)

[0034] δ 70.8 (-O-CH2-, methylene group connected by ether bond)

[0035] δ 40.0 - 20.0 (aliphatic ring and -CH3)

[0036] 2. Sorbate part

[0037] δ 165.8 (C=O, ester carbonyl carbon)

[0038] δ 131.5 (-CH=CH-, conjugated double bond carbon)

[0039] δ 129.2 (-CH=CH-, conjugated double bond carbon)

[0040] δ 118.7 (=CH2, terminal olefin carbon)

[0041] δ 61.2 (-COO-CH2-, methylene carbon connected by ester)

[0042] Example 2: The rest are the same as in Example 1, except that:

[0043] The reaction raw materials are: 10 g of linalool essential oil, 20 g of sorbic acid, and 150 mL of absolute ethanol;

[0044] The reaction temperature was controlled at 70 °C and the reaction time was 2 h. The crystals were dried at 50 °C for 4 h under vacuum conditions.

[0045] Example 3: The rest was the same as in Example 1, except that:

[0046] The reaction raw materials were: 10 g of linalool essential oil, 12 g of sorbic acid and 130 mL of absolute ethanol;

[0047] The reaction temperature was controlled at 40 °C and the reaction time was 6 h. The crystals were dried at 30 °C for 8 h under vacuum conditions.

[0048] Comparative Example 1: The rest was the same as in Example 1, except that:

[0049] Sorbic acid was replaced with acetic acid.

[0050] The structure of the final product was as follows:

[0051]

[0052] Linalyl acetate

[0053] 1 1H NMR (400 MHz, CDCl3, δ / ppm)

[0054] 1. 0.95 - 1.00 (d, 3H): Methyl of linalool part (-CH3, adjacent to double bond).

[0055] 2. 1.60 - 1.70 (s, 3H): Methyl of acetate (-COO-CH3).

[0056] 3. 1.75 - 1.85 (m, 2H): Methylene (-CH2-, connected to ester group).

[0057] 4. 2.05 (s, 3H): Methyl of acetate (-COO-CH3, may overlap).

[0058] 5. 4.50 - 4.60 (t, 1H): Methylene adjacent to ester group (-CH-O-CO-).

[0059] 6. 5.10 - 5.20 (m, 1H): Hydrogen of linalool double bond (-CH=).

[0060] 13 13C NMR (100 MHz, CDCl3, δ / ppm)

[0061] 1. 16.5: Methyl carbon of linalool (-CH3).

[0062] 2. 20.8: Methyl carbon of acetate (-COO-CH3).

[0063] 3. 25.5, 27.8: Methylene carbon (-CH2-).

[0064] 4. 60.2: Carbon adjacent to the ester group (-CH-O-).

[0065] 5. 120.5: Carbon of the double bond in linalool (=CH2).

[0066] 6. 170.5: Carbonyl carbon of the ester group (-COO-).

[0067] Comparative Example 2: The rest is the same as in Example 1, except that:

[0068] Sorbic acid was replaced with n - hexanoic acid.

[0069] The structure of the final product is as follows:

[0070]

[0071] Linalool n - hexanoate

[0072] 1 H NMR (400 MHz, CDCl3, δ / ppm)

[0073] 1. 0.90 (t, 3H): Terminal methyl of n - hexanoic acid (-CH3).

[0074] 2. 0.95 - 1.00 (d, 3H): Methyl of linalool (-CH3).

[0075] 3. 1.20 - 1.40 (m, 4H): Methylene in the chain of n - hexanoic acid (-CH2-).

[0076] 4. 1.60 - 1.70 (m, 2H): α - Methylene of n - hexanoic acid (-CH2-COO-).

[0077] 5. 2.30 (t, 2H): Methylene adjacent to the ester group (-CH2-COO-).

[0078] 6. 4.50 - 4.60 (t, 1H): Methylene of linalool (-CH-O-CO-).

[0079] 7. 5.10 - 5.20 (m, 1H): Hydrogen of the double bond in linalool (-CH=).

[0080] 13 C NMR (100 MHz, CDCl3, δ / ppm)

[0081] 1. 13.8: Terminal methyl carbon of n - hexanoic acid (-CH3).

[0082] 2. 16.5: Linalool methyl carbon (-CH3).

[0083] 3. 22.5, 25.5, 27.8, 31.5: Methylene carbons (-CH2-) in the n - hexanoic acid chain.

[0084] 4. 34.2: Methylene carbon adjacent to the ester group (-CH2-COO-).

[0085] 5. 60.2: Linalool methylene carbon (-CH-O-).

[0086] 6. 120.5: Linalool double - bond carbon (=CH2).

[0087] 7. 173.8: Ester - carbonyl carbon (-COO-).

[0088] Comparative Example 3: The rest is the same as in Example 1, except that:

[0089] Sorbic acid was replaced with 2 - hexenoic acid.

[0090] The structure of the final product is as follows:

[0091]

[0092] Linalool - 2 - hexenoate

[0093] 1 H NMR (400 MHz, CDCl3, δ / ppm)

[0094] 1. 0.95 - 1.00 (d, 3H): Linalool methyl (-CH3)

[0095] 2. 1.75 - 1.85 (m, 2H): Methylene (-CH2-)

[0096] 3. 4.50 - 4.60 (t, 1H): Linalool methylene (-CH-O-CO-)

[0097] 4. 5.10 - 5.20 (m, 1H): Linalool double - bond hydrogen (-CH=)

[0098] 5. 5.50 - 6.50 (m, 2H): 2 - hexenoic acid double - bond hydrogen

[0099] 6. 1.0 - 2.5 (m, several H): 2 - hexenoic acid alkyl - chain hydrogen

[0100] 13 C NMR (100 MHz, CDCl3, δ / ppm)

[0101] 1. 16.5: Linalool methyl carbon (-CH3)

[0102] 2. 25.5, 27.8: Methylene carbon (-CH2-)

[0103] 3. 60.2: Linalool methylene carbon (-CH-O-)

[0104] 4. 120.5: Linalool double bond carbon (=CH2)

[0105] 5. 125 - 135: 2-Hexenoic acid double bond carbon (=CH-)

[0106] 6. 166.5: Ester carbonyl carbon (-COO-)

[0107] 7. 10 - 30 (multiple values within the range): 2-Hexenoic acid alkyl chain carbon (-CH2-, -CH3)

[0108] Test the sustained antibacterial performance of the linalool derivatives prepared in Test Example 1 and Comparative Examples 1 - 3 as follows:

[0109] Inoculate Escherichia coli into LB liquid medium (pH 7.2) and Staphylococcus aureus into brain heart infusion broth (pH 7.4) at an initial concentration of 10000 CFU / mL respectively, and add linalool, sorbic acid and different linalool derivatives at a final concentration of 120 mg / L respectively. Incubate with shaking at 37°C, sample every 4 h, perform plate viable cell counting, and calculate the antibacterial rate. The calculation formula is as follows:

[0110] Antibacterial rate = (Initial cell concentration - Viable cell concentration at the sampling time point) / Initial cell concentration × 100%;

[0111] The results are as follows:

[0112] Table 1 Test results of the sustained antibacterial ability of different linalool derivatives

[0113]

[0114] In the above table, negative numbers indicate an increase in the number of bacteria.

[0115] As can be seen from the results in Table 1, the unmodified linalool has poor persistent antibacterial performance due to its strong volatility. Among various organic carboxylic acids, only the linalool derivative modified by sorbic acid can significantly improve the persistent antibacterial performance. The persistent antibacterial performance of the derivatives obtained by modifying linalool with other carboxylic acids such as hexanoic acid is not significantly improved compared with that of unmodified linalool. Instead, the decline rate of the antibacterial performance of some derivatives is much higher than that of unmodified linalool, and they cannot continuously play an antibacterial role. Sorbic acid alone cannot effectively inhibit bacterial proliferation in a neutral environment. Sorbic acid will quickly become ineffective in a neutral environment, and its persistent antibacterial effect is weak. Similarly, acetic acid also does not have a persistent antibacterial effect.

Claims

1. A linalool derivative having a structure represented by formula (I):

2. The preparation method of the linalool derivative according to claim 1, characterized in that, The following reaction is included:

3. The preparation method of the linalool derivative according to claim 2, characterized in that, The mass ratio of the linalool to sorbic acid is 1-2:1-2.

4. The preparation method of the linalool derivative according to claim 2, wherein, The inert atmosphere is a nitrogen atmosphere or a helium atmosphere.

5. The preparation method of the linalool derivative according to claim 2, wherein The reaction temperature is 40-70 °C.

6. The preparation method of the linalool derivative according to claim 2, wherein, The following reaction steps are included: adding linalool and sorbic acid into an organic solvent, mixing evenly, reacting for 2-6 h under stirring and heating conditions to obtain a mixed product, removing the organic solvent in the mixed product to obtain a crude product, and purifying the crude product to obtain a linalool derivative.

7. The preparation method of the linalool derivative according to claim 6, characterized in that, The organic solvent includes at least one of methanol, ethanol, dichloromethane, dimethyl sulfoxide, and tetrahydrofuran.

8. The preparation method of the linalool derivative according to claim 6, wherein, The purification method is as follows: adding the crude product into absolute ethanol, heating to gentle boiling to completely dissolve the crude product, then slowly cooling to room temperature, filtering to collect the crystals, and drying the crystals under vacuum to obtain a linalool derivative.

9. The preparation method of the linalool derivative according to claim 8, characterized in that, The vacuum drying method is drying at 30-50 °C for 4-8 h under vacuum conditions.

10. Use of the linalool derivative according to claim 1 in the preparation of a long-acting disinfectant.

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