A class of ammonium cyclohexane salts and preparation method and application thereof

Abstract

The present invention provides a type of ammonium cyclopentane salt and its preparation method and application. The ammonium cyclopentane salt is represented by the following structural formula (I), wherein the group R is selected from a hydrocarbon group with a carbon number of 1 to 22. The ammonium cyclopentane salt of the present invention can be used in the medical field and the daily chemical field to play the effects of freckle removal, whitening, anti-inflammatory, soothing, repairing, antibacterial and moisturizing; or used as a surfactant to play the functions of cleaning, emulsification, solubilization and dispersion. #imgabs0#

Description

Technical Field

[0001] The invention belongs to the field of chemical medicine raw material products, and in particular relates to a type of ammonium cyclohexane salt and a preparation method and application thereof. Background Art

[0002] Tranexamic acid, also known as tranexamic acid and tranexamic acid, is included in the 2020 edition of the Pharmacopoeia of the People's Republic of China as a hemostatic drug. Tranexamic acid is a synthetic antifibrinolytic drug that has the effects of reducing endothelial damage, anti-inflammatory, and immunomodulatory. It reduces the formation of new blood vessels and melanin by inhibiting plasminogen and inhibiting the activation of tyrosinase. It is often used to treat melasma, angioedema, rosacea, post-inflammatory pigmentation and other diseases. Tranexamic acid also has the effects of repairing the skin barrier, reducing the skin's transepidermal water loss rate, and promoting epidermal renewal.

[0003] Tranexamic acid is mainly taken orally or applied externally, but long-term oral administration can lead to a variety of adverse reactions such as liver and kidney damage, thrombosis, and visual impairment. Topical tranexamic acid essences, creams, and other preparations are relatively safe, but tranexamic acid has strong hydrogen bonding and hydrophilicity, making it difficult to pass through the skin stratum corneum barrier. It is usually necessary to modify tranexamic acid to improve its percutaneous permeability and enhance its efficacy. In addition, when tranexamic acid and sugar compounds are used in the same drug or skin care product formula, browning is likely to occur during production, storage, transportation, and use, seriously affecting the efficacy and quality of the product (Yang Zhen, Yuan Minjia. Study on the inhibition of high-temperature discoloration of tranexamic acid and sugar substances [J]. Daily Chemicals Science, 2021, 44(09): 16-20.).

[0004] The invention patent application with publication number Sho 57-59847 discloses a cycloalkyl acyl tranexamic acid ester; the invention patent application with publication number CN 101253148A discloses an alkyl acyloxyalkyl tranexamic acid ester, which is used as a prodrug of tranexamic acid to treat bleeding or skin diseases; the invention patent application with publication number CN 101925353 A discloses a tranexamic acid amide derivative, which relieves edema or wrinkles by promoting the production of vascular endothelial growth factor; the invention patent application with publication number EP 0604667 A1 discloses an external composition with whitening function, wherein the active ingredient is tranexamic acid ester or tranexamic acid amide; the invention patent application with publication number CN 105085364 A discloses a preparation method of a medicinal compound, maleic tranexamic acid; the invention patent application with publication number CN 113952326 A discloses a PEG acyl tranexamic acid, which can prolong the efficacy time of tranexamic acid; the invention patent application with publication number CN 114751858 A's invention patent application discloses a quinoline tranexamic acid amide with anti-tumor activity. The above invention patent applications all modify the amino group or carboxyl group of tranexamic acid, but no scheme is found to modify the amino group of tranexamic acid into an ammonium group with a short, medium or long chain hydrocarbon group, and to modify the whole tranexamic acid into an inner salt; and the above invention patent applications focus on the drug effect of tranexamic acid, and do not give other effects to tranexamic acid derivatives, such as surface activity, adsorption, moisturizing, etc., thereby avoiding some problems existing in medicines and skin care products.

[0005] Traditional surfactants are widely used in medicines and skin care products, and are indispensable because they have the effects of emulsification, decontamination, dispersion, solubilization, and wetting. However, when using products containing surfactants, there is a problem that the surfactants remain on the skin. For example, when using wash-off products to clean the skin, due to the high content of surfactants, they cannot be completely rinsed and remain. When using resident products, most of the surfactants contained are deposited on the skin; so the frequent use or improper use of medicines and skin care products will cause the surfactants to remain or accumulate on the skin for a long time, thereby causing problems such as skin barrier damage, skin irritation, and skin sensitivity. The invention patent with publication number CN117342971A announces a class of fatty acyl tranexamic acid salts, which have the effects of cleaning, dispersion, and emulsification. Even if they remain on the skin, they will not cause skin problems, but will play the role of whitening, soothing, and repairing the skin. Fatty acyl tranexamic acid salts belong to functional substances and also belong to the category of anionic surfactants, so the pH range of their application is limited and their compatibility with cationic components is poor. Summary of the invention

[0006] In order to solve the above-mentioned shortcomings of tranexamic acid, such as poor skin absorption due to its hydrophilicity and strong hydrogen bonding, browning phenomenon when tranexamic acid is combined with sugar compounds, skin problems caused by residual traditional surfactants, and the shortcomings of anionic tranexamic acid surfactants, such as narrow application pH range and poor compatibility with cations, the present application provides a new type of tranexamic acid derivatives, namely ammonium tranexamic acid salts, which have strong affinity to the skin, have freckle removal and whitening, anti-inflammatory and soothing, repairing, moisturizing, antibacterial effects or surface activity, and have good compatibility in products, so that no additional surfactants need to be added to related medicines and skin care products.

[0007] Therefore, the object of the present invention is to provide a class of ammonium cyclohexane salts and a preparation method and application thereof.

[0008] In order to achieve the above object, the present invention provides the following technical solutions:

[0009] A class of ammonium cyclohexane salts is represented by structural formula (I):

[0010]

[0011] The group R is selected from hydrocarbon groups having 1 to 22 carbon atoms.

[0012] The R is selected from an alkyl group or an alkenyl group having 1 to 22 carbon atoms.

[0013] According to a preferred embodiment of the present invention, the group R in the structural formula (I) is selected from a straight-chain alkyl group having 1 to 6 carbon atoms.

[0014] Preferably, the group R in the structural formula (I) is selected from a straight-chain alkyl group having 7 to 22 carbon atoms.

[0015] Also preferably, the group R in the structural formula (I) is selected from branched alkyl groups having 8 to 22 carbon atoms.

[0016] Also preferably, the group R in the structural formula (I) is selected from straight-chain alkenyl groups having 8 to 22 carbon atoms.

[0017] According to the present invention, the preparation method of the ammonium cyclohexane salt comprises the following steps:

[0018] (1) Add 4-(halomethyl)cyclohexane-1-carboxylic acid to a reaction kettle, maintain the temperature of the reaction kettle at 10 to 30° C., slowly drip an aqueous solution of an alkaline substance into the reaction kettle while stirring, and continue stirring for 1 to 3 hours after the addition is completed;

[0019] (2) slowly dripping the organic solvent solution of N,N-dimethylalkylamine into the reaction kettle while stirring. After the dripping is completed, the temperature is raised to 50-90° C. and stirring is continued for 5-15 hours;

[0020] (3) Transfer the mixture in the reaction kettle to a flask and remove the liquid by rotary evaporation;

[0021] (4) Add organic solvent B to the flask, stir at 50-80° C. for 1-3 h, filter under reduced pressure, transfer the filtrate to a flask, and remove the liquid by rotary evaporation;

[0022] (5) The solid in the flask is placed in an organic solvent C and recrystallized 1 to 3 times to obtain ammonium cyclohexane salt.

[0023] According to the present invention, in the method for preparing ammonium cyclohexane salt, the 4-(halomethyl)cyclohexane-1-carboxylic acid in step (1) is selected from 4-(chloromethyl)cyclohexane-1-carboxylic acid, 4-(bromomethyl)cyclohexane-1-carboxylic acid, and 4-(iodomethyl)cyclohexane-1-carboxylic acid; the alkaline substance in step (1) is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate;

[0024] The organic solvent A in step (2) is selected from methanol, ethanol, propanol, isopropanol, and butanol; the organic solvent B in step (4) is selected from methanol, ethanol, propanol, isopropanol, and butanol; the organic solvent C in step (5) is selected from methanol, ethanol, propanol, isopropanol, butanol, and acetone.

[0025] The ammonium cyclohexane salt is used in the preparation of skin medicines for removing spots, whitening, anti-inflammatory, soothing, repairing or inhibiting bacteria.

[0026] The ammonium cyclopentane salt is used in the field of daily chemicals. The ammonium cyclopentane salt has the effects of moisturizing, removing spots and whitening, anti-inflammatory, soothing and repairing, or is used as a surfactant to play the functions of cleaning, emulsifying, solubilizing and dispersing.

[0027] When the number of carbon atoms of R in the formula (I) is ≥16, the ammonium cyclopentane salt can be used as an emulsifier; when the number of carbon atoms of R in the formula (I) is ≥7 and <16, the ammonium cyclopentane salt can be used as a cleanser; when the number of carbon atoms of R in the formula (I) is ≤6, the ammonium cyclopentane salt can be used as a moisturizer.

[0028] Beneficial effects of the present invention:

[0029] Tranexamic acid is used to treat chloasma, angioedema, post-inflammatory pigmentation, rosacea and other diseases, and has the effects of whitening, soothing and repairing. However, its hydrophilicity and hydrogen bonding are too strong, so it is not easily absorbed by the skin, and it is easy to react with sugar compounds to cause browning. The ammonium cyclopentane salt of the present invention is a derivative of tranexamic acid. By introducing two methyl groups and one hydrocarbon group, the amino group is modified into a quaternary ammonium group with cationic properties, which greatly enhances its lipophilicity and adsorption to the skin. At the same time, the active hydrogen connected to the nitrogen is completely replaced, so that it will not react with the ketone group or carboxyl group in the sugar compound, thereby preventing the occurrence of browning. In addition, the carboxyl group is dehydrogenated and forms an inner salt with the quaternary ammonium group, which greatly weakens the hydrogen bonding effect, is more conducive to skin absorption and the basic efficacy of tranexamic acid. The ammonium cyclopentane salt of the short-chain hydrocarbon group can completely replace tranexamic acid. Traditional surfactants are widely used in medicines and skin care products. Long-term use of related products will cause surfactants to remain or accumulate on the skin, causing skin problems. The medium- and long-chain hydrocarbon ammonium cyclopentane salts have surface activity and antibacterial properties, a wide pH range of application, and good compatibility with cationic substances. They can replace traditional surfactants and play the functions of emulsification, dispersion, solubilization, and cleaning. Therefore, there is no need to add additional surfactants to medicines and skin care products, avoiding skin problems caused by traditional surfactant residues. Ammonium cyclopentane salts have moisturizing, freckle removal and whitening, anti-inflammatory and soothing, repair, and antibacterial effects. Instead of irritating the skin, they will improve skin problems.

[0030] In addition, the preparation method of ammonium cyclohexane salt of the present invention has strong operability, is easy to realize industrial production, can replace tranexamic acid or traditional surfactants, and is widely used in the fields of medicine, daily chemicals, etc. DETAILED DESCRIPTION

[0031] The present invention is further described below in conjunction with specific examples. It should be understood that the following examples are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0032] Unless otherwise specified, the raw materials used in the following examples are commercially available.

[0033] The detection methods of performance efficacy in the following embodiments are as follows:

[0034] References for stability test methods (centrifugation test, heat and cold resistance test, room temperature sample observation): Chen Si, Zhang Yi. Preparation and safety study of Nocardia rubrum cell wall skeleton emulsion[J]. Daily Chemicals Science, 2023, 46(01): 4-8.

[0035] References for moisturizing efficacy test method (transepidermal water loss): Wu Nan, Yuan Ting, Liu Qi, et al. Clinical study on the improvement of sensitive skin by an essence water simulating the skin's natural moisturizing system[J]. Guangdong Chemical Industry, 2024, 51(04): 143-146+68.

[0036] References for emulsification performance test methods: Dong Shuangjian, Li Yunling. Synthesis and properties of unsaturated octadecyl betaine[J]. Printing and Dyeing Auxiliary Agents, 2013, 30(05): 8-10.

[0037] References for the preservative challenge test method (antibacterial performance): Li Zengting, Lv Xin, Li Qian, et al. Evaluation of the efficacy of commercially available preservative-free cosmetic preservative systems[J]. Surfactant Detergent Industry, 2021, 51(10): 975-980.

[0038] References for soothing efficacy test method (redness parameter measurement): Guo Shentao, Xu Wenfeng, Cui Yujiao, et al. Application research on several cosmetic soothing efficacy evaluation methods [J]. Journal of Daily Chemicals Science, 2023, 46(06): 37-40+44.

[0039] References for whitening efficacy test method (human skin whiteness L* measurement): Zhang Lei, Yang Shuqin, Guo Xiuru, et al. Study on efficacy evaluation of raspberry ketone glucoside[J]. Daily Chemicals Science, 2022, 45(03): 43-47.

[0040] References for the test methods of skin repair efficacy (lactic acid stinging test, transepidermal water loss test): Lei Cuiting, Zheng Muchuang, Chen Chuwei. Discussion on the evaluation method of skin repair cosmetics efficacy[J]. Journal of Daily Chemicals, 2021, 44(12): 28-30.

[0041] Example 1

[0042] The structural formula of the ammonium cyclohexane salt of the present embodiment is as follows:

[0043]

[0044] That is, 4-((trimethylammonium)methyl)cyclohexane-1-carboxylate, where the R group is methyl. The preparation method of the ammonium cyclohexane salt is:

[0045] (1) 4-(Chloromethyl)cyclohexane-1-carboxylic acid (61.82 g, 0.3500 mol) was added to a 1 L five-necked interlayer flask equipped with an electromagnetic heating stirrer, a condenser reflux tube, a thermometer, a dropping funnel, and a pH meter. A circulating water bath was turned on to maintain the temperature in the flask at 10°C. A 10% aqueous solution of NaOH (a total of 140.00 g, containing 14.00 g of NaOH, 0.3500 mol) was slowly added dropwise while stirring. After the addition was completed, stirring was continued for 2 h. A solution of ethanol (123.08 g, 2.6716 mol) containing trimethylamine (21.72 g, 0.3674 mol) was slowly dripped into a five-necked interlayer flask through a dropping funnel, and stirring was performed during the dropping process. After the dropping was completed, the temperature was raised to 50° C. and stirring was continued for 12 h. The mixture in the five-necked interlayer flask was transferred to a 0.5 L flask, and evaporated to dryness in a rotary evaporator to obtain a white solid. 300 g of ethanol was added to the above 0.5 L flask, and the mixture was placed in a water bath at 50° C. and stirred for 1 h, and the mixture was filtered under reduced pressure. The filtrate was then transferred to a 0.5 L flask for rotary evaporation. The obtained white solid was recrystallized three times in ethanol, filtered and dried to obtain 4-((trimethylammonium)methyl)cyclohexane-1-carboxylate (64.79 g, 0.3251 mol).

[0046] The prepared 4-((trimethylammonium)methyl)cyclohexane-1-carboxylate was a white solid with a yield of 92.88%.

[0047] 1 H NMR (400MHz, DMSO-d6) δ: 3.38 (s, 9H), 3.25 (d, J = 7.0Hz, 2H), 2.37 (m, 1H), 2.14 (m, 1H), 1.82-1.43 (m, 8H); 13 C NMR(100MHz,DMSO-d6)δ:175.4,61.4,46.5,41.9,31.4,29.1,27.0;[M+H] + m / z:200.16.

[0048] The prepared 4-((trimethylammonium)methyl)cyclohexane-1-carboxylate was applied to the following essence formula, and in the control formula, 4-((trimethylammonium)methyl)cyclohexane-1-carboxylate was replaced with an equal mass of tranexamic acid.

[0049]

[0050]

[0051] The preparation method is as follows: weigh the components of phase A according to their mass fractions into a beaker, heat and stir in a water bath at 80°C to obtain a phase A that is evenly dispersed and has no visible agglomerated particles, cool to room temperature, weigh the components of phase B of corresponding mass, add them to phase A, stir until the solid is completely dissolved, and obtain an essence liquid material that is evenly dispersed and has no visible agglomerated particles.

[0052] The stability, moisturizing effect, soothing effect and whitening effect of the essence were tested according to the methods provided in the references.

[0053] After centrifugation, the essence liquid material did not show precipitation or stratification; after the cold-resistant and heat-resistant material was restored to room temperature, no precipitation, stratification, discoloration, etc. occurred; no precipitation, stratification, discoloration, etc. occurred within 3 months of keeping the sample at room temperature, while the control sample changed color at high temperature. The initial mean transepidermal water loss of 30 subjects with sensitive skin were 20.48 and 21.02, respectively, and the mean transepidermal water loss after using the essence and the control sample for 28 days were 15.04 (significant P < 0.01) and 17.68 (significant P < 0.01), respectively; the initial mean redness of 30 subjects with sensitive skin were 22.17 and 23.39, respectively, and the mean redness after using the essence and the control sample for 28 days were 20.33 (significant P < 0.01) and 21.96 (significant P < 0.01), respectively. <0.01), the ΔL* of the essence sample trial group at the 4th week was 2.56 (significant P<0.05), and the ΔL* of the control sample trial group at the 4th week was 2.61 (significant P>0.05); the above shows that the essence has better high temperature stability, moisturizing effect, and soothing effect than the control sample, and the whitening effect of the two is equivalent; that is, it means that 4-((trimethylammonium)methyl)cyclohexane-1-carboxylate and tranexamic acid have equivalent whitening effects, and the former has better high temperature stability, moisturizing effect, and soothing effect.

[0054] Example 2

[0055] The structural formula of the ammonium cyclohexane salt of the present embodiment is as follows:

[0056]

[0057] That is, 4-((dodecyldimethylammonium)methyl)cyclohexane-1-carboxylate, where the R group is dodecyl. The preparation method of the ammonium cyclohexane salt is:

[0058] (1) 4-(Chloromethyl)cyclohexane-1-carboxylic acid (61.82 g, 0.3500 mol) was added to a 1 L five-necked interlayer flask equipped with an electromagnetic heating stirrer, a condenser reflux tube, a thermometer, a dropping funnel, and a pH meter. A circulating water bath was turned on to maintain the temperature in the flask at 20°C. A 10% aqueous solution of NaHCO3 (a total of 294.10 g, containing 29.41 g of NaHCO3, 0.3501 mol) was slowly added dropwise while stirring. After the addition was completed, stirring was continued for 2 h. A solution of N,N-dimethyldodecylamine (78.42 g, 0.3675 mol) in ethanol (313.68 g, 6.8089 mol) was slowly dripped into a five-necked interlayer flask through a dropping funnel, and stirring was performed during the dropping process. After the dropping was completed, the temperature was raised to 65°C and stirring was continued for 12 hours; the mixture in the five-necked interlayer flask was transferred to a 1L flask, and evaporated to dryness in a rotary evaporator to obtain a white solid; 500 g of isopropanol was added to the above 1L flask, and the mixture was placed in a water bath at 60°C and stirred for 2 hours, and the filtrate was transferred to a 1L flask for rotary evaporation. The obtained white solid was recrystallized three times in isopropanol, filtered and dried to obtain 4-((dodecyldimethylammonium)methyl)cyclohexane-1-carboxylate (111.53 g, 0.3154 mol).

[0059] The prepared 4-((dodecyldimethylammonium)methyl)cyclohexane-1-carboxylate was a white solid with a yield of 90.11%.

[0060] 1 H NMR(400MHz, DMSO-d6)δ:3.32(s,6H),3.27-3.21(m,4H),2.34(m,1H),2.10(m,1H),1.79-1.40(m,10H),1.23-1.28(m,18H),0.89(m,3H); 13 C NMR (100MHz, DMSO-d6)δ:175.3,72.7,62.1,61.9,47.8,42.0,32.5,31.3,30.2,27.0,25.0,23.5,14.2; [M+H] + m / z:354.33.

[0061] The prepared 4-((dodecyldimethylammonium)methyl)cyclohexane-1-carboxylate was applied to the following cleansing formula, and in the control formula, 4-((dodecyldimethylammonium)methyl)cyclohexane-1-carboxylate was replaced with an equal mass of sodium lauroyl sarcosinate.

[0062]

[0063] The preparation method is: weigh the components of phase A according to their mass fraction in a beaker, stir at room temperature to obtain a colorless and transparent phase A; add the corresponding mass of the components of phase B to the mixed phase A in sequence, stir at room temperature until the system is colorless and transparent, and obtain a cleansing foam material.

[0064] The stability and soothing effect of the cleansing foam body, as well as the pH application range test and cationic substance compatibility test were tested according to the methods provided in the reference.

[0065] After centrifugation, the cleansing foam material did not show stratification or precipitation; after the cold-resistant and heat-resistant material was restored to room temperature, no stratification, precipitation, discoloration, etc. occurred; no stratification, precipitation, discoloration, etc. occurred within 3 months of keeping the sample at room temperature, and the control sample material also did not show stratification, precipitation, discoloration, etc. The initial redness averages of 30 sensitive skin subjects were 23.12 and 23.98, respectively, and the redness averages of the cleansing foam and control samples for 28 days were 21.07 (significant P < 0.01) and 22.94 (significant P < 0.01), respectively. The above shows that the cleansing foam material has good stability, and the cleansing foam material has good soothing effect, that is, 4-((dodecyldimethylammonium)methyl)cyclohexane-1-carboxylate has a soothing effect. In addition, the cleansing foam material has abundant foaming during use, which can wash away skin dirt, indicating that 4-((dodecyldimethylammonium)methyl)cyclohexane-1-carboxylate has a cleaning effect.

[0066] pH application range experiment: Glutamic acid and arginine were used to adjust the pH values ​​of the cleansing foam and the control sample to 3.5 and 9.5 respectively, and only the control sample with a pH value of 3.5 showed turbidity, indicating that 4-((dodecyldimethylammonium)methyl)cyclohexane-1-carboxylate has a relatively wide range of applications.

[0067] Cationic substance compatibility test: 0.2% of cetrimonium chloride was added to the cleansing foam and the control sample, respectively, and only the control sample became turbid and had flocculent precipitation, indicating that 4-((dodecyldimethylammonium)methyl)cyclohexane-1-carboxylate has good compatibility with cationic substances.

[0068] Example 3

[0069] The structural formula of the ammonium cyclohexane salt of the present embodiment is as follows:

[0070]

[0071] That is, 4-(((2-ethylhexyl)dimethylammonium)methyl)cyclohexane-1-carboxylate, where the R group is 2-ethylhexyl. The preparation method of the ammonium cyclohexane salt is:

[0072] (1) 4-(Chloromethyl)cyclohexane-1-carboxylic acid (61.82 g, 0.3500 mol) was added to a 1 L five-necked interlayer flask equipped with an electromagnetic heating stirrer, a condenser reflux tube, a thermometer, a dropping funnel, and a pH meter. A circulating water bath was turned on to maintain the temperature in the flask at 20°C. A 10% aqueous solution of NaHCO3 (a total of 294.10 g, containing 29.41 g of NaHCO3, 0.3501 mol) was slowly added dropwise while stirring. After the addition was completed, stirring was continued for 2 h. A methanol (231.32 g, 7.2233 mol) solution containing N,N-dimethyl(2-ethylhexyl)amine (57.83 g, 0.3676 mol) was slowly dripped into a five-necked interlayer flask through a dropping funnel, and stirring was performed simultaneously during the dropping process. After the dropping was completed, the temperature was raised to 70°C and stirring was continued for 15 hours; the mixture in the five-necked interlayer flask was transferred to a 1L flask, and evaporated to dryness in a rotary evaporator to obtain a white solid; 500 g of isopropanol was added to the above 1L flask, and the mixture was placed in a water bath at 60°C and stirred for 2 hours, and the filtrate was filtered under reduced pressure. The filtrate was then transferred to a 1L flask for rotary evaporation, and the obtained white solid was recrystallized three times in isopropanol, filtered and dried to obtain 4-(((2-ethylhexyl)dimethylammonium)methyl)cyclohexane-1-carboxylate (91.22 g, 0.3066 mol).

[0073] The prepared 4-(((2-ethylhexyl)dimethylammonium)methyl)cyclohexane-1-carboxylate was a white solid with a yield of 87.60%.

[0074] 1 H NMR(400MHz,DMSO-d6)δ:3.32(m,6H),3.27-3.01(m,4H),2.31(m,1H),2.13(m,1H),1.94(m,1H),1.7 9-1.39(m,10H),1.33(m,2H),1.26(m,2H),1.20(m,2H),0.98(t,J=8.0Hz,3H),0.90(t,J=8.0Hz,3H); 13 C NMR (100MHz, DMSO-d6)δ:176.2,67.9,48.1,42.3,32.9,32.2,31.4,31.1,30.1,27.4,27.1,23.2,14.3,12.0; [M+H] + m / z:298.27.

[0075] The prepared 4-(((2-ethylhexyl)dimethylammonium)methyl)cyclohexane-1-carboxylate was applied to the following cleansing water formula. In the control formula, 4-(((2-ethylhexyl)dimethylammonium)methyl)cyclohexane-1-carboxylate was replaced with an equal mass of caprylic / capric glycerides polyglyceryl-10 esters.

[0076]

[0077] The preparation method is: weigh the components of phase A according to their mass fraction in a beaker, stir at room temperature to obtain a colorless and transparent phase A; add the corresponding mass of the components of phase B into the mixed phase A in sequence, stir at room temperature until the system is colorless and transparent, and obtain a facial cleansing water body.

[0078] The stability, soothing effect and antibacterial properties of the facial cleanser were tested according to the methods provided in the references.

[0079] After centrifugation, the cleansing water material did not show stratification or precipitation; after the cold-resistant and heat-resistant material was restored to room temperature, no stratification, precipitation, discoloration, etc. occurred; no stratification, precipitation, discoloration, etc. occurred within 3 months of keeping the sample at room temperature, and the control sample material also did not show stratification, precipitation, discoloration, etc. The initial mean redness values ​​of 30 sensitive skin subjects were 23.72 and 23.84, respectively. The mean redness values ​​after using the cleansing water and the control sample for 28 days were 22.07 (significant P < 0.01) and 24.05 (significant P < 0.01), respectively. The antiseptic challenge counts (CFU / g) of the cleansing water material were all <10, and the antiseptic challenge counts (CFU / g) of the control material were >300 for mold and yeast.

[0080] The above shows that the cleansing water has good stability and good soothing effect, that is, 4-(((2-ethylhexyl)dimethylammonium)methyl)cyclohexane-1-carboxylate has a soothing effect. In addition, the cleansing water can remove residual makeup on the skin during use, indicating that 4-(((2-ethylhexyl)dimethylammonium)methyl)cyclohexane-1-carboxylate has a cleansing effect. According to the antiseptic challenge results, 4-(((2-ethylhexyl)dimethylammonium)methyl)cyclohexane-1-carboxylate also has antibacterial properties.

[0081] Example 4

[0082] The structural formula of the ammonium cyclohexane salt of the present embodiment is as follows:

[0083]

[0084] That is, 4-(((9-octadecene)dimethylammonium)methyl)cyclohexane-1-carboxylate, where the R group is 9-octadecene. The preparation method of the ammonium mexacarate is:

[0085] (1) Add 4-(bromomethyl)cyclohexane-1-carboxylic acid (77.39 g, 0.3500 mol) to a 1L five-necked interlayer flask equipped with an electromagnetic heating stirrer, a condenser reflux tube, a thermometer, a dropping funnel, and a pH meter. Turn on a circulating water bath to maintain the temperature in the flask at 20°C. Slowly dropwise add a 16% aqueous solution of KOH (a total of 122.75 g, containing 19.64 g of NaHCO3, 0.3501 mol) while stirring. After the addition is complete, continue stirring for 2.5 h. A solution of N,N-dimethyl(9-octadecenyl)amine (108.60 g, 0.3674 mol) in acetone (615.40 g, 10.5957 mol) was slowly dripped into a five-necked interlayer flask through a dropping funnel, and stirring was performed during the dropping process. After the dropping was completed, the temperature was raised to 75°C and stirring was continued for 15 h. The mixture in the five-necked interlayer flask was transferred to a 1L flask and evaporated to dryness in a rotary evaporator to obtain a light yellow solid. 500 g of isopropanol was added to the above 1L flask, and the mixture was placed in a water bath at 65°C and stirred for 2 h, and the mixture was filtered under reduced pressure. The filtrate was then transferred to a 1L flask for rotary evaporation. The obtained light yellow solid was recrystallized three times in isopropanol, filtered and dried to obtain 4-(((9-octadecenyl)dimethylammonium)methyl)cyclohexane-1-carboxylate (128.11 g, 0.2940 mol).

[0086] The prepared 4-(((9-octadecenyl)dimethylammonium)methyl)cyclohexane-1-carboxylate was a light yellow solid with a yield of 84.00%.

[0087] 1 H NMR(400MHz, DMSO-d6)δ:5.40(m,2H),3.32-3.20(m,10H),2.34-2.13(m,6H),1.80-1.38(m,10H),1.31-1.24(m,22H),0.87(m,3H); 13 C NMR(100MHz,DMSO-d6)δ:175.7,131.4,63.4,62.9,47.8,42.0,32.1,31.2,30.4,30.2,30.0,29.9,29.6,28.2,27.9,27.0,25.5,23.1,14.0; [M+H] + m / z:436.41.

[0088] The prepared 4-(((9-octadecenyl)dimethylammonium)methyl)cyclohexane-1-carboxylate was applied to the following whitening and repairing essence lotion formula, and in the control formula, 4-(((9-octadecenyl)dimethylammonium)methyl)cyclohexane-1-carboxylate was replaced with an equal mass of oleyl betaine.

[0089]

[0090] The preparation method is as follows: weigh the components of phase A according to their mass fractions into a beaker, stir at room temperature to obtain a light yellow transparent phase A; add the components of phase B of corresponding mass into the mixed phase A in sequence, heat to 50°C, emulsify and homogenize at 10,000 rpm for 10 minutes, cool to room temperature, and obtain a milky white whitening and repairing essence liquid material.

[0091] The stability, repairing effect and whitening effect of the whitening and repairing essence were tested according to the method provided in the reference.

[0092] After centrifugation, the whitening and repairing essence liquid did not show stratification, precipitation, or discoloration; after the cold- and heat-resistant material was restored to room temperature, no stratification, precipitation, or discoloration occurred; within 3 months of being kept at room temperature, no stratification, precipitation, or discoloration occurred, while the control sample material showed stratification at high temperature. The initial lactic acid stinging mean values ​​of 30 skin subjects were 2.76 and 2.79, respectively. The lactic acid stinging mean values ​​after using the whitening repair essence and the control sample for 28 days were 0.31 (significant P < 0.01) and 2.59 (significant P < 0.01), respectively. The initial skin TEWL mean values ​​of 30 skin subjects were 18.04 and 17.87, respectively. The skin TEWL mean values ​​after using the whitening repair essence and the control sample for 28 days were 16.21 (significant P < 0.01) and 17.64 (significant P < 0.01), respectively. The ΔL* of the whitening repair essence sample trial group at the 4th week was 2.84 (significant P < 0.01), and the ΔL* of the control sample trial group at the 4th week was 0.09 (significant P < 0.01).

[0093] The above shows that the whitening and repairing essence liquid has good stability, that is, 4-(((9-octadecenyl)dimethylammonium)methyl)cyclohexane-1-carboxylate has good emulsification properties. The whitening and repairing essence liquid has good repairing and whitening effects, indicating that 4-(((9-octadecenyl)dimethylammonium)methyl)cyclohexane-1-carboxylate has repairing and whitening effects.

[0094] Example 5

[0095] The structural formula of the ammonium cyclohexane salt of the present embodiment is as follows:

[0096]

[0097] That is, 4-((alkyldimethylammonium)methyl)cyclohexane-1-carboxylate, wherein the group R is selected from a hydrocarbon group having 1 to 22 carbon atoms.

[0098] 4-((propyldimethylammonium)methyl)cyclohexane-1-carboxylate, 4-((hexyldimethylammonium)methyl)cyclohexane-1-carboxylate, 4-((heptyldimethylammonium)methyl)cyclohexane-1-carboxylate, 4-((tetradecyldimethylammonium)methyl)cyclohexane-1-carboxylate, and 4-((hexadecyldimethylammonium)methyl)cyclohexane-1-carboxylate were prepared according to the method of Example 1.

[0099] According to the method provided in the reference, the emulsifying properties of 4-((trimethylammonium)methyl)cyclohexane-1-carboxylate, 4-((propyldimethylammonium)methyl)cyclohexane-1-carboxylate, 4-((hexyldimethylammonium)methyl)cyclohexane-1-carboxylate, 4-((heptyldimethylammonium)methyl)cyclohexane-1-carboxylate, 4-((dodecyldimethylammonium)methyl)cyclohexane-1-carboxylate, 4-((tetradecyldimethylammonium)methyl)cyclohexane-1-carboxylate, and 4-((hexadecyldimethylammonium)methyl)cyclohexane-1-carboxylate were tested. The addition amount of each component was 2.0%, and the test results are as follows:

[0100]

[0101] The above results indicate that when the number of carbon atoms of the group R is ≥16, the corresponding ammonium cyclohexane salt can be used as an emulsifier; when the number of carbon atoms of the group R is ≥7 and <16, the corresponding ammonium cyclohexane salt can be used as a cleanser; when the number of carbon atoms of the group R is ≤6, the corresponding ammonium cyclohexane salt can be used as a moisturizer like 4-((trimethylammonium)methyl)cyclohexane-1-carboxylate.

Claims

1. A type of ammonium cyclohexane salt, characterized in that: Represented by structural formula (I): The group R is selected from hydrocarbon groups having 1 to 22 carbon atoms.

2. Ammonioxamate according to claim 1, characterized in that The group R in the structural formula (I) is selected from an alkyl group or an alkenyl group having 1 to 22 carbon atoms.

3. Ammonioxamate according to claim 2, characterized in that The group R in the structural formula (I) is selected from a straight-chain alkyl group having 1 to 6 carbon atoms.

4. Amelocyclate according to claim 2, characterized in that The group R in the structural formula (I) is selected from a linear alkyl group having 7 to 22 carbon atoms, a branched alkyl group having 8 to 22 carbon atoms, or a linear alkenyl group having 8 to 22 carbon atoms.

5. The method for preparing the amoxamate according to any one of claims 1 to 4, comprising the following steps: (1) Add 4-(halomethyl)cyclohexane-1-carboxylic acid to a reaction kettle, maintain the temperature of the reaction kettle at 10 to 30° C., slowly drip an aqueous solution of an alkaline substance into the reaction kettle while stirring, and continue stirring for 1 to 3 hours after the addition is completed; (2) slowly dripping the organic solvent solution of N,N-dimethylalkylamine into the reaction kettle while stirring. After the dripping is completed, the temperature is raised to 50-90° C. and stirring is continued for 5-15 hours; (3) Transfer the mixture in the reaction kettle to a flask and remove the liquid by rotary evaporation; (4) Add organic solvent B to the flask, stir at 50-80° C. for 1-3 h, filter under reduced pressure, transfer the filtrate to a flask, and remove the liquid by rotary evaporation; (5) The solid in the flask is placed in an organic solvent C and recrystallized 1 to 3 times to obtain ammonium cyclohexane salt.

6. The preparation method according to claim 5, wherein the 4-(halomethyl)cyclohexane-1-carboxylic acid in step (1) is selected from one of 4-(chloromethyl)cyclohexane-1-carboxylic acid, 4-(bromomethyl)cyclohexane-1-carboxylic acid, and 4-(iodomethyl)cyclohexane-1-carboxylic acid; the alkaline substance in step (1) is selected from one or more of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate; 7. The preparation method according to claim 5, wherein the organic solvent A in step (2) is selected from one or more of methanol, ethanol, propanol, isopropanol, and butanol; the organic solvent B in step (4) is selected from one or more of methanol, ethanol, propanol, isopropanol, and butanol; the organic solvent C in step (5) is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, and acetone.

8. Use of the ammonium cyclohexane salt according to any one of claims 1 to 2 in the preparation of a skin medicine for removing spots, whitening, anti-inflammatory, soothing, repairing or antibacterial effects.

9. The use of any amoxime salt described in claims 1-2 in the field of daily chemicals, wherein the amoxime salt has the effects of moisturizing, removing spots and whitening, anti-inflammatory, soothing and repairing, or is used as a surfactant to have the functions of cleaning, emulsifying, solubilizing and dispersing.

10. The use according to claim 9, wherein when the carbon number of R in the formula (I) is ≥16, the ammonium cyclopentane salt is used as an emulsifier; when the carbon number of R in the formula (I) is ≥7 and <16, the ammonium cyclopentane salt is used as a cleaning agent; when the carbon number of R in the formula (I) is ≤6, the ammonium cyclopentane salt is used as a moisturizer.

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