A method for synthesizing menthol amine compounds and application thereof in cigarettes

Abstract

The invention discloses a method for synthesizing menthol amine compounds and their application in cigarettes. In an air environment, menthol and bromoacetyl bromide are placed in a reaction container, a first additive is added, a first step reaction is carried out in a first solvent, and then an amine derivative and a second additive are added, and a reaction is carried out in a second reaction solvent to prepare menthol amine compounds, wherein the reaction formula is: The menthol amine compound prepared by the invention is a common biologically active molecular structure and has a wide range of biological properties, including antibacterial, anti-inflammatory and antiviral activities. In particular, the menthol amine compound prepared by the invention has a more penetration-promoting effect, promotes the transdermal penetration of drugs, and is non-irritating and non-toxic to the skin.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a one-pot preparation method of menthol amine compounds with simple method and mild reaction conditions. Background Art

[0002] Menthol (also known as L-menthol) is a simple cyclic monoterpene alcohol with remarkable biological properties. Menthol is an important essential oil component of mint oil. L-menthol and menthol-rich peppermint oil have a variety of biological properties, including antibacterial, antifungal, anesthetic and penetration-enhancing effects, as well as chemopreventive and immunomodulatory effects. One of the main effects of menthol is the cooling sensation produced when chewed, inhaled or applied to the skin. Used in traditional medicine to treat a variety of diseases including infections, menthol has now been widely used in various fields from the pharmaceutical and cosmetic industries to the tobacco and food industries.

[0003] Amines are widely present in the biological world and have extremely important physiological and biological activities. For example, proteins, nucleic acids, many hormones, antibiotics and alkaloids are all derivatives of amines. Most drugs used clinically are also amines or amine derivatives. Understanding the properties and synthesis methods of amines is a prerequisite for studying these complex natural products and better maintaining human health.

[0004] Therefore, it is of great practical value to develop a method for synthesizing menthol amine compounds. At present, there are few synthetic methods for constructing such compounds. For example, menthol can react with amine compounds in an alkaline environment of a strong base (such as KOH, NaOH, etc.). Usually, menthol first forms a corresponding salt in a suitable solvent (commonly alcohol or ether is used as a solvent) under strong alkaline conditions, and then post-processes it. Finally, menthol amine compounds should be formed with amine derivatives; or menthol amine compounds can be synthesized and prepared under the action of heavy metal salts or transition metals. In summary, the synthesis of menthol amine compounds now requires strong bases or precious metal salts for catalysis, and these heavy metal salts and strong bases will pollute the ecological environment, the post-processing is relatively cumbersome, the substrate range is limited, and the atomic economy of the synthetic strategy is often not high. These shortcomings do not conform to the concept of green synthesis and are difficult to adapt to the requirements of industrial production.

[0005] In order to solve the above problems, the present invention is proposed. Summary of the invention

[0006] The object of the present invention is to provide a method for preparing menthol amine compounds by a multi-component one-pot method involving menthol, bromoacetyl bromide and amine derivatives under mild conditions. The method has mild conditions, is transition metal-free, and uses cheap raw materials to efficiently prepare menthol amine compounds. To achieve the above object, the technical solution adopted by the present invention is:

[0007] Menthol, bromoacetyl bromide and amine derivatives were used as reaction raw materials and menthol amine derivatives were obtained by a multi-component one-pot method in the presence of inorganic metal salts Na2CO3 and Na2SO4.

[0008] The specific synthesis method is: in an air environment, menthol and bromoacetyl bromide are placed in a reaction container, a first additive is added, a first step reaction is carried out in a first solvent, and then an amine derivative and a second additive are added, and a reaction is carried out in a second reaction solvent to prepare a menthol amine compound, and the reaction formula is:

[0009] Preferably, after the first step reaction is carried out for 4 hours, the second step reactant is added continuously, and after the temperature is raised for reaction for 6 hours, post-treatment is carried out.

[0010] Preferably, the mentholamine compound includes 2-isopropyl-5-methylcyclohexylpropylglycine, 2-isopropyl-5-methylcyclohexylpentylglycine, 2-isopropyl-5-methylcyclohexylcyclobutylglycine, 2-isopropyl-5-methylcyclohexylcycloheptylglycine, 2-isopropyl-5-methylcyclohexylN-methyl-N-phenylglycine or tert-butyl 3-((2-((2-isopropyl-5-methylcyclohexyl)oxy)-2-oxoethyl)amino)azetidine-1-carboxylate.

[0011] Preferably, the amine derivatives are various amine compounds such as propylamine, pentylamine and N-methylaniline.

[0012] Preferably, the first additive and the second additive are inorganic salts, wherein the first additive is Na2CO3, and the second additive is Na2CO3 and Na2SO4.

[0013] Preferably, the first reaction solvent is dichloromethane, and the second reaction solvent is tetrahydrofuran.

[0014] Preferably, the molar ratio of menthol, bromoacetyl bromide and amine derivatives is 1:0.5:5 to 1:2:5.

[0015] Preferably, the first step reaction temperature is 10-50°C, the reaction time is 2-5 hours, and the second step reaction temperature is 50-100°C, the reaction time is 4-10 hours.

[0016] The second aspect of the present invention provides an application of the mentholamine compound prepared by the synthesis method described in the first aspect of the present invention in cigarettes, which is added to cigarettes as an additive to enrich the aroma, increase the moistness, and improve the softness of the smoke. Specifically, the product is dissolved in food-grade ethanol and added to shredded tobacco in a certain proportion of the specific gravity of the shredded tobacco to make cigarettes.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] 1. The present invention provides a green, economical and practical method for synthesizing menthol amine compounds. The method uses menthol, bromoacetyl bromide and amine derivatives as raw materials in a multi-component one-pot method under the conditions of the participation of inorganic metal salts Na2CO3 and Na2SO4. The method has mild conditions, no transition metals, and uses cheap raw materials to efficiently prepare menthol amine compounds. The method of the present invention is green, novel and has good substrate adaptability.

[0019] 2. Adding the mentholamine compounds synthesized by the present invention as additives into cigarettes can enrich the aroma, increase the moistness, and improve the softness of the smoke. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The general reaction formula of the present invention is: wherein the general formula of the amine compound is RNH2, and R is a substituent such as an alkyl group. DETAILED DESCRIPTION

[0021] The following examples will help to understand the present invention, but the content of the present invention is not limited thereto. The reaction formula in the following examples is:

[0022]

[0023] Embodiment 1:

[0024]

[0025] Dissolve DL-menthol (1.0eq) in 5mL DCM, add Na2CO3, wait for the solution to cool to 0°C, slowly drop bromoacetyl bromide (1.0eq), remove the cold bath reactor, react at room temperature for 4h, and concentrate under vacuum to obtain a crude product. Dissolve the crude product in 5ml THF, add propylamine (1.5eq), then add anhydrous Na2CO3 (2.5eq) and anhydrous Na2SO4, reflux at 70°C for 6h, after the reaction, filter the solution to remove anhydrous Na2SO4, extract three times with EtOAc (3×10ml), dry the organic layer with anhydrous Na2SO4, concentrate under reduced pressure, and separate with silica gel column (petroleum ether / ethyl acetate) to obtain the target product as a colorless oil.

[0026] 1HNMR (400MHz, CDCl3): δ4.71 (td, J=10.92Hz, 4.00Hz, 1H), 3.45 (S, 2H), 1.96-1.93 (m, 1H), 1.82-1.78 (m, 1H ),1.66-1.61(m,2H),1.49-1.31(m,3H),1.03-0.94(m,2H),0.86(t,J=6.12Hz,7H),0.72(d,J=6.96Hz,3H);

[0027] 13 CNMR (100MHz, CDCl3): δ170.32,74.37,57.18,46.86,40.90,34.14,31.34,26.23,23.29,21.98,20.73,16.20,16.20.

[0028] MS: m / z, found: 255.2198.

[0029] The obtained product was dissolved in food-grade ethanol and added to shredded tobacco at a ratio of 0.0001%-1% of the specific gravity of the shredded tobacco to make heated cigarettes. After smoking evaluation, it was found that compared with the control, the compound can enrich the aroma, increase the moistness, and improve the softness of the smoke.

[0030] Embodiment 2:

[0031]

[0032] Dissolve DL-menthol (1.0eq) in 5mL DCM, add Na2CO3, wait for the solution to cool to 0°C, slowly drop bromoacetyl bromide (1.0eq), remove the cold bath reactor, react at room temperature for 4h, and concentrate under vacuum to obtain a crude product. Dissolve the crude product in 5ml THF, add pentylamine (1.5eq), then add anhydrous Na2CO3 (2.5eq) and anhydrous Na2SO4, reflux at 70°C for 6h, after the reaction, filter the solution to remove anhydrous Na2SO4, extract three times with EtOAc (3×10ml), dry the organic layer with anhydrous Na2SO4, concentrate under reduced pressure, and separate with silica gel column (petroleum ether / ethyl acetate) to obtain the target product as a colorless oil.

[0033] 1HNMR (400MHz, CDCl3): δ4.74(td,J=10.88Hz,4.32Hz,1H),3.56(S,2H),2.73-2.68(m,1H),2.02- 1.97(m,1H),1.87-1.83(m,1H),1.71-0.98(m,11H),0.94-0.89(m,11H),0.77(d,J=6.96Hz,3H);

[0034] 13 CNMR (100MHz, CDCl3): δ170.83,74.41,55.21,53.96,46.94,40.95,34.19,31.38,26.27,23.33,22.02,20.77,20.40,16.25,13.99.

[0035] MS: m / z, found: 283.2511.

[0036] The obtained product was dissolved in food-grade ethanol and added to shredded tobacco at a ratio of 0.0001%-2% of the weight of the shredded tobacco to make traditional cigarettes. After smoking evaluation, it was found that compared with the control, the compound can increase the aroma, improve the smoking quality, and have a slightly cool taste.

[0037] Embodiment 3:

[0038]

[0039] Dissolve DL-menthol (1.0eq) in 5mL DCM, add Na2CO3, wait for the solution to cool to 0°C, slowly drop bromoacetyl bromide (1.0eq), remove the cold bath reactor, react at room temperature for 4h, and concentrate under vacuum to obtain a crude product. Dissolve the crude product in 5ml THF, add cyclobutylamine (1.5eq), then add anhydrous Na2CO3 (2.5eq) and anhydrous Na2SO4, reflux at 70°C for 6h, after the reaction, filter the solution to remove anhydrous Na2SO4, extract three times with EtOAc (3×10ml), dry the organic layer with anhydrous Na2SO4, concentrate under reduced pressure, and separate with silica gel column (petroleum ether / ethyl acetate) to obtain the target product as a colorless oil.

[0040] 1HNMR (400MHz, CDCl3): δ4.73 (td, J=10.88Hz, 4.36Hz, 1H), 3.53 (S, 3H), 2.06-1.80 (m, 5H), 1.71- 1.57(m,4H),1.51-1.26(m,4H),1.07-0.96(m,2H),0.90(t,J=6.4Hz,7H),0.76(d,J=6.96Hz,3H);

[0041] 13 CNMR (101MHz, CDCl3): δ170.84,74.29,57.00,51.02,46.94,34.19,31.37,30.30,27.88,26.27,23.36,22.02,20.76,20.76,16.27;

[0042] MS: m / z, found: 267.2198.

[0043] The obtained product was dissolved in food-grade ethanol and added to shredded tobacco at a ratio of 0.0001%-2% of the weight of the shredded tobacco to make traditional cigarettes. After smoking evaluation, it was found that compared with the control, the compound can increase the smoothness and improve the smoking quality.

[0044] Embodiment 4:

[0045]

[0046] Dissolve DL-menthol (1.0eq) in 5mL DCM, add Na2CO3, wait for the solution to cool to 0°C, slowly drop bromoacetyl bromide (1.0eq), remove the cold bath reactor, react at room temperature for 4h, and concentrate under vacuum to obtain a crude product. Dissolve the crude product in 5ml THF, add cycloheptylamine (1.5eq), then add anhydrous Na2CO3 (2.5eq) and anhydrous Na2SO4, reflux at 70°C for 6h, after the reaction, filter the solution to remove anhydrous Na2SO4, extract three times with EtOAc (3×10ml), dry the organic layer with anhydrous Na2SO4, concentrate under reduced pressure, and separate with silica gel column (petroleum ether / ethyl acetate) to obtain the target product as a colorless oil.

[0047] 1HNMR (400MHz, CDCl3): δ4.73(td,J=10.88Hz,4.36Hz,1H),3.50(S,2H),2.06-1.98(m,2H),1.91-1.85( m,2H),1.70-1.66(m,4H),1.54-1.35(m,7H),1.29-1.25(m,1H),1.11-0.96(m,3H),0.92-0.76(m,13H);

[0048] 13 CNMR (101MHz, CDCl3): δ171.84,74.22,63.35,60.40,52.73,46.99,40.87,3 4.23,31.66,31.38,27.74,26.23,25.14,23.35,22.03,20.80,16.27,14.20.

[0049] MS: m / z, found: 309.2668.

[0050] The obtained product was dissolved in food-grade ethanol and added to cigarette paper at a ratio of 0.001%-1% of the weight of tobacco to make traditional cigarettes. After smoking evaluation, it was found that compared with the control, the compound can increase the amount of smoke aroma and improve the smoothness and softness of the smoke.

[0051] Embodiment 5:

[0052]

[0053] Dissolve DL-menthol (1.0eq) in 5mL DCM, add Na2CO3, wait for the solution to cool to 0°C, slowly drop bromoacetyl bromide (1.0eq), remove the cold bath reactor, react at room temperature for 4h, and concentrate under vacuum to obtain a crude product. Dissolve the crude product in 5ml THF, add N-methylaniline (1.5eq), then add anhydrous Na2CO3 (2.5eq) and anhydrous Na2SO4, reflux at 70°C for 6h, after the reaction, filter the solution to remove anhydrous Na2SO4, extract three times with EtOAc (3×10ml), dry the organic layer with anhydrous Na2SO4, concentrate under reduced pressure, and separate with silica gel column (petroleum ether / ethyl acetate) to obtain the target product as a light brown oil.

[0054] 1HNMR (400MHz, CDCl3): δ7.28-7.23 (m, 2H), 6.76 (t, J = 7.28Hz, 1H), 6.70 (d, J = 8.2Hz, 2H),4.70(td,J=10.88Hz,4.40Hz,1H),4.07(q,J=30.72Hz,18.04Hz,2H),3.09(S,3H ),2.01-1.96(m,1H),1.69-1.63(m,3H),1.51-1.42(m,1H),1.35-1.28(m,1H),1.05- 0.99(m,1H),0.91(d,J=6.52Hz,4H),0.83(d,J=7.04Hz,4H),0.68(d,J=6.96Hz,3H).

[0055] 13 CNMR (101MHz, CDCl3): δ170.89,148.91,129.14,129.14,117.25,112.28,112.28,7 4.97,54.91,46.93,40.81,39.77,34.15,31.36,25.96,23.15,22.01,20.81,16.02.

[0056] MS: m / z, found: 303.2198.

[0057] The obtained product was dissolved in food-grade ethanol and added to shredded tobacco at a ratio of 0.0005%-3% of the specific gravity of the shredded tobacco to make traditional cigarettes. After smoking evaluation, it was found that compared with the control, the compound can increase the amount of smoke aroma, increase the smoothness of the smoke, and improve comfort.

[0058] Embodiment 6:

[0059]

[0060] Dissolve DL-menthol (1.0eq) in 5mL DCM, add Na2CO3, wait for the solution to cool to 0°C, slowly drop bromoacetyl bromide (1.0eq), remove the cold bath reactor, react at room temperature for 4h, and concentrate under vacuum to obtain a crude product. Dissolve the crude product in 5ml THF, add 1-tert-butyloxycarbonyl-3-aminocyclobutylamine (1.5eq), then add anhydrous Na2CO3 (2.5eq) and anhydrous Na2SO4, reflux at 70°C for 6h, after the reaction, filter the solution to remove anhydrous Na2SO4, extract three times with EtOAc (3×10ml), dry the organic layer with anhydrous Na2SO4, concentrate under reduced pressure, and separate with silica gel column (petroleum ether / ethyl acetate) to obtain the target product as a colorless oil.

[0061] 1 HNMR (400MHz, CDCl3): δ4.74 (td, J=9.64Hz, 3.16Hz, 1H), 4.74 (td, J=9.64Hz, 3.16Hz, 1H), 3.98-3.86 (m, 2H), 3.62-3 .56(m,2H),2.28-1.59(m,7H),1.51-1.26(m,11H),1.08-0.89(m,3H),0.81(t,J=6.24Hz,7H),0.76(d,J=6.96Hz,3H).

[0062] 13 CNMR (101MHz, CDCl3): δ170.48,156.26,125.53,79.50,74.81,46.92,46.92,40.89, 34.14,31.39,30.31,28.38,28.38,28.38,26.37,23.36,22.02,20.76,20.76,16.29.

[0063] MS: m / z, found: 368.2675.

[0064] The obtained product was dissolved in food-grade ethanol and added to shredded tobacco at a ratio of 0.0002%-2% of the weight of the shredded tobacco to make traditional cigarettes. After smoking evaluation, it was found that compared with the control, the compound can increase the amount of smoke aroma, increase the moistness, and make the smoke more comfortable.

Claims

1. An application of a menthol amine compound in cigarettes, wherein the structural formula of the menthol amine compound is: ， It is characterized in that The mentholamine compound is dissolved in food-grade ethanol and added into cigarette tobacco in a proportion of 0.0002%-2% of the weight of the tobacco.

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