Deep eutectic solvent

Abstract

To provide a novel deep eutectic solvent capable of reducing concern for irritation to a biological body.SOLUTION: A deep eutectic solvent comprises: (A) one or two selected from components (A1) and (A2), (A1) being phosphocholine and (A2) being glycerophosphocholine; and (B) one or more selected from components (B1) to (B8), (B1) being polyhydric alcohols, (B2) being saccharides, (B3) being organic acids, (B4) being dibasic acids, (B5) being aromatic alcohols or aromatic carboxylic acids, (B6) being ascorbic acids, (B7) being organic amines, and (B8) being organic amides.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to deep eutectic solvents. [Background technology]

[0002] Deep eutectic solvents are a general term for compositions that are liquid at room temperature and are obtained by mixing a hydrogen bond acceptor compound and a hydrogen bond donor compound. Even if one or both of the hydrogen bond acceptor compound and the hydrogen bond donor compound are solid at room temperature, mixing them causes a depression of the eutectic melting point, creating a liquid state at room temperature. Deep eutectic solvents are known to have similar characteristics to ionic liquids, but are superior in that they can be obtained at lower cost than ionic liquids and can be obtained from compounds that are less environmentally hazardous and toxic than ionic liquids. Therefore, they are expected to be used as new solvents to replace ionic liquids. Specific known uses of deep eutectic solvents include reaction solvents (e.g., Reference 1), extraction solvents (e.g., Reference 2), dispersion media (e.g., Patent Document 3), electrolytes (e.g., Reference 4), resin additives (e.g., Reference 5), lubricants (e.g., Patent Document 6), fire-fighting foams (e.g., Patent Document 7), deicing agents (e.g., Patent Document 8), cryopreservatives (e.g., Patent Document 9), vaccine preparations (e.g., Patent Document 10), pharmaceuticals (e.g., Patent Document 11), skin cosmetics (e.g., Patent Document 12), and hair cosmetics (e.g., Patent Document 13).

[0003] Choline chloride is a commonly used hydrogen-bond acceptor compound for deep eutectic solvents. However, its potential biological irritation raises concerns about its use in various applications. Phosphocholine, a compound in which one choline group is bound to a phosphoric acid via a phosphate ester bond, is known to function as an intermediate in the biosynthetic pathway of phosphatidylcholine and sphingomyelin in vivo, and is also known to be involved in immune responses as one of the binding targets of C-reactive protein. Glycerophosphocholine, a compound in which a phosphocholine group is bound to the hydroxyl group at the 1-position of glycerol via a phosphate ester bond, is used in pharmaceuticals and supplements as a source of choline, a nutrient essential for brain function and cell membrane formation. Thus, phosphocholine and glycerophosphocholine are biocompatible compounds, and are less likely to be irritating to the body than choline chloride. However, the use of phosphocholine and glycerophosphocholine as deep eutectic solvents has not been reported. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Special Publication No. 2022-523192 [Patent Document 2] Japanese Patent Application Publication No. 2023-119164 [Patent Document 3] Japanese Patent Application Publication No. 2017-082063 [Patent Document 4] Japanese Patent Publication No. 2020-149923 [Patent Document 5] Japanese Patent Application Publication No. 2020-105336 [Patent Document 6] Japanese Patent Publication No. 2023-151663 [Patent Document 7] Special Publication No. 2019-528814 [Patent Document 8] Special Publication No. 2021-510760 [Patent Document 9] Special Publication No. 2020-520253 [Patent Document 10] Special Publication No. 2021-508680 [Patent Document 11] Special Publication No. 2023-539699 [Patent Document 12] Special Publication No. 2023-516367 [Patent Document 13] Special Publication No. 2021-534103 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a new deep eutectic solvent that is less likely to irritate the body. [Means for solving the problem]

[0006] As a result of extensive research into solving the above problems, the present inventors discovered that a deep eutectic solvent consisting of the following components (A) and (B) solves the above problems, and thus completed the present invention. (A) One or two selected from the following components (A1) and (A2): (A1) Phosphocholine (A2) Glycerophosphocholine (B) One or more selected from the following components (B1) to (B8): (B1) Polyhydric alcohols (B2) Saccharides (B3)Organic acids (B4) Dibasic acids (B5) Aromatic alcohols or aromatic carboxylic acids (B6) Ascorbic acids (B7) Organic amines (B8) Organic amides [Effects of the Invention]

[0007] The deep eutectic solvent of the present invention has little risk of irritation to living organisms, and can therefore be preferably used in a variety of applications of conventionally known deep eutectic solvents, such as synthetic solvents, extraction solvents, dispersion media, electrolytes, resin additives, lubricants, fire-extinguishing foams, deicing agents, cryopreservatives, vaccine preparations, pharmaceuticals, skin cosmetics, and hair cosmetics. DETAILED DESCRIPTION OF THE INVENTION

[0008] In the present invention, a deep eutectic solvent refers to a composition obtained by mixing a hydrogen bond acceptor compound and a hydrogen bond donor compound, in which one or both of the hydrogen bond acceptor compound and the hydrogen bond donor compound are solid at room temperature, and mixing these compounds causes a eutectic melting point depression, resulting in a liquid composition at room temperature. In the present invention, room temperature refers to 15 to 30°C.

[0009] The deep eutectic solvent of the present invention comprises the following components (A) and (B): (A) One or two selected from the following components (A1) and (A2): (A1) Phosphocholine (A2) Glycerophosphocholine (B) One or more selected from the following components (B1) to (B8): (B1) Polyhydric alcohols (B2) Saccharides (B3)Organic acids (B4) Dibasic acids (B5) Aromatic alcohols or aromatic carboxylic acids (B6) Ascorbic acids (B7) Organic amines (B8) Organic amides

[0010] Component (A) used in the deep eutectic solvent of the present invention is used as a hydrogen bond acceptor compound. The phosphocholine of component (A1) used in the present invention is a compound in which one choline group molecule is bonded to phosphoric acid via a phosphate ester bond. Its melting point is approximately 110°C and it is a solid compound at room temperature. The phosphocholine used in the present invention may be in the form of a salt. The method for producing phosphocholine is not particularly limited, and products produced by known methods can be used. Phosphocholines are generally commercially available, and such commercially available products can be preferably used in the present invention. Furthermore, the glycerophosphocholine of component (A2) used in the present invention is a compound in which a phosphocholine group is bonded to the hydroxyl group at the 1-position of glycerin via a phosphate ester bond. Its melting point is approximately 143°C and it is a solid compound at room temperature. The glycerophosphocholine used in the present invention may be an optically active substance or a racemic substance, or may be in the form of a salt. The method for producing glycerophosphocholine is not particularly limited, and products produced by known methods can be used. Glycerophosphocholine is generally commercially available, and such commercially available products can be preferably used in the present invention.

[0011] Component (B) used in the deep eutectic solvent of the present invention is one or more selected from the following components (B1) to (B8), and is used as a hydrogen bond donor compound. (B1) Polyhydric alcohols (B2) Saccharides (B3)Organic acids (B4) Dibasic acids (B5) Aromatic alcohols or aromatic carboxylic acids (B6) Ascorbic acids (B7) Organic amines (B8) Organic amides

[0012] More specifically, the polyhydric alcohols of component (B1) include ethylene glycol, propylene glycol, 1,3-propanediol, 1,2-butylene glycol, 1,3-butylene glycol, 2,3-butylene glycol, tetramethylene glycol, hexylene glycol, octylene glycol, 1,2-pentanediol, 1,2-hexanediol, 1,2-heptanediol, 1,2-octanediol, 1,2-decanediol, glycerin, trimethylolpropane, 1,2,6-hexanetrimethylolpropane, and 1,2,6-hexanetrimethylolpropane. Examples of suitable glycerols include glycerol, sorbitol, xylitol, erythritol, inositol, maltitol, mannitol, ethylglycerin, butylglycerin, hexylglycerin, ethylhexylglycerin, cyclohexylglycerin, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, dipropylene glycol, tripropylene glycol, polypropylene glycol, diglycerin, triglycerin, tetraglycerin, polyglycerin, and isosorbide. These may be used alone or in combination of two or more. Among these, from the viewpoint of further enhancing the effects of the present invention, preferred are propylene glycol, 1,3-propanediol, 1,3-butylene glycol, 1,2-pentanediol, glycerin, sorbitol, xylitol, erythritol, inositol, maltitol, mannitol, dipropylene glycol, diglycerin, and isosorbide.

[0013] More specifically, examples of the sugars of component (B2) include xylose, galactose, glucose, mannose, fructose, maltose, trehalose, lactose, sucrose, glucosamine, N-acetylglucosamine, alkyl glucosides, glyceryl glucosides, and arbutin. These may be used alone or in combination of two or more. Of these, glucose, fructose, maltose, trehalose, lactose, sucrose, alkyl glucosides, glyceryl glucosides, and arbutin are preferred from the viewpoint of further enhancing the effects of the present invention.

[0014] More specifically, examples of organic acids of component (B3) include acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, gluconic acid, levulinic acid, glutamic acid, aspartic acid, and phytic acid. These may be used alone or in combination of two or more. Of these, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, gluconic acid, and levulinic acid are preferred from the viewpoint of further enhancing the effects of the present invention.

[0015] More specifically, dibasic acids of component (B4) include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, cyclohexanedicarboxylic acid, etc. These may be used alone or in combination of two or more. Of these, succinic acid, glutaric acid, adipic acid, azelaic acid, sebacic acid, etc. are preferred from the viewpoint of further exerting the effects of the present invention.

[0016] More specifically, examples of the aromatic alcohol or aromatic carboxylic acid of component (B5) include phenol, cresol, benzyl alcohol, phenethyl alcohol, phenoxyethanol, dibutylhydroxytoluene, butylhydroxyanisole, thymol, hinokitiol, isopropylmethylphenol, vanillin, propyl gallate, parahydroxybenzoic acid esters, benzoic acid, salicylic acid, gallic acid, phthalic acid, cinnamic acid, hydroxycinnamic acid, ferulic acid, and caffeic acid. These may be used alone or in combination of two or more. Of these, from the viewpoint of further exerting the effects of the present invention, phenoxyethanol, thymol, hinokitiol, isopropylmethylphenol, vanillin, propyl gallate, parahydroxybenzoic acid esters, benzoic acid, salicylic acid, gallic acid, ferulic acid, and caffeic acid are preferred.

[0017] More specific examples of the ascorbic acids of component (B6) include ascorbic acid, ascorbic acid phosphate, ascorbic acid glucoside, ascorbic acid monostearate, ascorbic acid monopalmitate, ascorbic acid dipalmitate, and other ascorbic acid fatty acid esters, ascorbic acid alkyl ethers such as 2-O-ethyl ascorbic acid, 3-O-ethyl ascorbic acid, 3-O-cetyl ascorbic acid, 2-O-glyceryl ascorbic acid, 3-O-glyceryl ascorbic acid, and 2,3-O-glyceryl ascorbic acid, etc. These may be used alone or in combination of two or more. Of these, from the viewpoint of further exerting the effects of the present invention, ascorbic acid, ascorbic acid phosphate, ascorbic acid glucoside, 2-O-ethyl ascorbic acid, 3-O-ethyl ascorbic acid, 3-O-cetyl ascorbic acid, 2-O-glyceryl ascorbic acid, 3-O-glyceryl ascorbic acid, 2,3-O-glyceryl ascorbic acid, and the like are preferred.

[0018] More specifically, examples of the organic amines of component (B7) include monoethanolamine, diethanolamine, triethanolamine, lysine, arginine, histidine, ornithine, creatine, guanidine, and trishydroxymethylaminomethane. These may be used alone or in combination of two or more. Among these, from the viewpoint of further exerting the effects of the present invention, monoethanolamine, diethanolamine, triethanolamine, and trishydroxymethylaminomethane are preferred.

[0019] More specifically, examples of the organic amides of component (B8) include urea, dimethylurea, hydroxyethylurea, allantoin, and nicotinamide. These may be used alone or in combination of two or more. Among these, urea, hydroxyethylurea, and nicotinamide are preferred from the viewpoint of further enhancing the effects of the present invention.

[0020] The blending ratio of component (A) and component (B) in the deep eutectic solvent of the present invention is not particularly limited, as long as they are blended so as to become liquid at room temperature due to the depression of the eutectic melting point. Specifically, the blending ratio is preferably 0.1 to 15 moles, and more preferably 0.1 to 10 moles, of component (B) per mole of component (A). A more preferable blending ratio range varies depending on the types of components (A) and (B). More preferable blending ratios for each type of component are described below.

[0021] When component (A) is component (A1), the following applies. When component (B) is component (B1), component (B1) is preferably blended in an amount of 0.15 to 15 moles, and more preferably 0.2 to 10 moles, per mole of component (A1). When component (B) is component (B2), component (B2) is preferably blended in an amount of 0.1 to 1.7 mol, and more preferably 0.1 to 1.5 mol, per 1 mol of component (A1). When component (B) is component (B3), component (B3) is preferably blended in a ratio of 0.15 to 7 moles, and more preferably 0.2 to 5 moles, per mole of component (A1). When component (B) is component (B4), component (B4) is preferably blended in a ratio of 0.25 to 1.8 mol, and more preferably 0.33 to 1.5 mol, per 1 mol of component (A1). When component (B) is component (B5), component (B5) is preferably blended in a ratio of 0.25 to 2.5 moles, and more preferably 0.33 to 2 moles, per mole of component (A1). When component (B) is component (B6), component (B6) is preferably blended in an amount of 0.15 to 7 moles, and more preferably 0.2 to 5 moles, per mole of component (A1). When component (B) is component (B7), component (B7) is preferably blended in a ratio of 0.15 to 7 moles, and more preferably 0.2 to 5 moles, per mole of component (A1). When component (B) is component (B8), component (B8) is preferably blended in an amount of 0.1 to 3.5 mol, and more preferably 0.1 to 3 mol, per 1 mol of component (A1).

[0022] When component (A) is component (A2), the following applies. When component (B) is component (B1), component (B1) is preferably blended in an amount of 0.1 to 15 moles, and more preferably 0.1 to 10 moles, per mole of component (A2). When component (B) is component (B2), component (B2) is preferably blended in an amount of 0.1 to 1.7 mol, and more preferably 0.1 to 1.5 mol, per 1 mol of component (A2). When component (B) is component (B3), component (B3) is preferably blended in a ratio of 0.1 to 7 moles, and more preferably 0.1 to 5 moles, per mole of component (A2). When component (B) is component (B4), component (B4) is preferably blended in a ratio of 0.25 to 1.8 mol, and more preferably 0.33 to 1.5 mol, per 1 mol of component (A2). When component (B) is component (B5), component (B5) is preferably blended in an amount of 0.1 to 2.5 moles, and more preferably 0.1 to 2 moles, per mole of component (A2). When component (B) is component (B6), component (B6) is preferably blended in a ratio of 0.1 to 7 moles, and more preferably 0.1 to 5 moles, per mole of component (A2). When component (B) is component (B7), component (B7) is preferably blended in an amount of 0.1 to 2.5 mol, and more preferably 0.1 to 2 mol, per 1 mol of component (A2). When component (B) is component (B8), component (B8) is preferably blended in an amount of 0.1 to 1.7 mol, and more preferably 0.1 to 1.5 mol, per 1 mol of component (A2).

[0023] The method for producing the deep eutectic solvent of the present invention is not particularly limited, and it can be produced by a generally known method. Specifically, it can be produced by heating and mixing the respective components as they are, or by dissolving the respective components in a solvent and then distilling off the solvent.

[0024] The deep eutectic solvent of the present invention obtained as described above can be used in various applications in which deep eutectic solvents have traditionally been used, such as reaction solvents, extraction solvents, dispersion media, electrolytes, resin additives, lubricants, fire-extinguishing foams, deicing agents, cryopreservatives, vaccine preparations, pharmaceuticals, skin cosmetics, and hair cosmetics.

[0025] The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples in any way.

[0026] <Confirmation of deep eutectic solvent formation 1> Using phosphocholine as component (A1) and various components (B) listed in Table 1, the presence or absence of formation of a deep eutectic solvent was confirmed by the following method. The results are also shown in Table 1. How to check whether deep eutectic solvents are formed Components (A) and (B) were weighed into a recovery flask in the ratios shown in the table, and ethanol in an amount three times the total mass of components (A) and (B) was added. The mixture was then heated and dissolved at 70°C. The ethanol was then removed using an evaporator, and the resulting composition was cooled to room temperature. The appearance of the resulting composition was visually inspected. Those that were liquid at room temperature were judged to have formed a deep eutectic solvent, while those that were not were judged not to have formed a deep eutectic solvent (in the table, cases where a deep eutectic solvent was formed are indicated by ○, and cases where a deep eutectic solvent was not formed are indicated by ×).

[0027] [Table 1]

[0028] From the results in Table 1, it was confirmed that component (A1) and component (B) shown in Table 1 both form deep eutectic solvents.

[0029] <Confirmation of deep eutectic solvent formation 2> Using phosphocholine as component (A1) and various components (B) listed in Table 2, the formation of a deep eutectic solvent was confirmed by changing the blending ratio of components (A1) and (B) in the same manner as above.

[0030] [Table 2]

[0031] From the results in Table 2, it was possible to confirm the range of the blending ratio of component (B) that forms a deep eutectic solvent when component (A1) is used.

[0032] <Confirmation of deep eutectic solvent formation 3> The formation of a deep eutectic solvent was confirmed in the same manner as above using glycerophosphocholine as component (A2) and various components (B) listed in Table 3. The results are also shown in Table 3.

[0033] [Table 3]

[0034] From the results in Table 3, it was confirmed that component (A2) and the compound of component (B) listed in Table 3 both form deep eutectic solvents.

[0035] <Confirmation of deep eutectic solvent formation 4> Using glycerophosphocholine as component (A2) and various components (B) listed in Table 4, whether or not a deep eutectic solvent was formed when the blending ratio of components (A2) and (B) was changed was confirmed in the same manner as above.

[0036] [Table 4]

[0037] From the results in Table 4, it was possible to confirm the range of the blending ratio of component (B) that forms a deep eutectic solvent when component (A2) is used.

[0038] Various active ingredients of pharmaceuticals or cosmetics were dissolved by heating using the deep eutectic solvents of the present invention with the compositions shown in Tables 5 and 6. After cooling to room temperature, the dissolution of the active ingredients was judged visually (in the tables, clear dissolution is indicated by ○, and indissolution is indicated by ×).

[0039] [Table 5]

[0040] [Table 6]

[0041] The results in Tables 5 and 6 demonstrate that the deep eutectic solvent of the present invention can dissolve various active ingredients in pharmaceuticals or cosmetics. Because the deep eutectic solvent of the present invention is less likely to cause irritation, it can be preferably used as a base or additive for pharmaceuticals or cosmetics. It is also expected to have the effect of promoting the penetration of active ingredients.

Claims

1. A deep eutectic solvent consisting of the following components (A) and (B): (A) One or two selected from the following components (A1) and (A2): (A1) Phosphocholine (A2) Glycerophosphocholine (B) One or more selected from the following components (B1) to (B8): (B1) Polyhydric alcohols (B2) Saccharides (B3) Organic acids (B4) Dibasic acids (B5) Aromatic alcohols or aromatic carboxylic acids (B6) Ascorbic acids (B7) Organic amines (B8) Organic amides

2. Component (B) is component (B1), and component (B1) is ethylene glycol, propylene glycol, 1,3-propanediol, 1,2-butylene glycol, 1,3-butylene glycol, 2,3-butylene glycol, tetramethylene glycol, hexylene glycol, octylene glycol, 1,2-pentanediol, 1,2-hexanediol, 1,2-heptanediol, 1,2-octanediol, 1,2-decanediol, glycerin, trimethylolpropane, 1,2,6-hexanetriol, sorbitol, xylitol, The deep eutectic solvent according to claim 1, which is one or more selected from the group consisting of ethanol, erythritol, inositol, maltitol, mannitol, ethylglycerin, butylglycerin, hexylglycerin, ethylhexylglycerin, cyclohexylglycerin, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, dipropylene glycol, tripropylene glycol, polypropylene glycol, diglycerin, triglycerin, tetraglycerin, polyglycerin and isosorbide.

3. Component (B) is component (B2), and component (B2) is one or more selected from xylose, galactose, glucose, mannose, fructose, maltose, trehalose, lactose, sucrose, glucosamine, N-acetylglucosamine, alkyl glucoside, glyceryl glucoside, and arbutin. The deep eutectic solvent according to claim 1.

4. Component (B) is component (B3), and component (B3) is one or more selected from acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, gluconic acid, levulinic acid, glutamic acid, aspartic acid, and phytic acid. The deep eutectic solvent according to claim 1.

5. Component (B) is component (B4), and component (B4) is one or more selected from oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, and cyclohexanedicarboxylic acid. The deep eutectic solvent according to claim 1.

6. Component (B) is component (B5), and component (B5) is one or more selected from phenol, cresol, benzyl alcohol, phenethyl alcohol, phenoxyethanol, dibutylhydroxytoluene, butylhydroxyanisole, thymol, hinokitiol, isopropylmethylphenol, vanillin, propyl gallate, parahydroxybenzoic acid ester, benzoic acid, salicylic acid, gallic acid, phthalic acid, cinnamic acid, hydroxycinnamic acid, ferulic acid, and caffeic acid. The deep eutectic solvent according to claim 1.

7. 2. The deep eutectic solvent according to claim 1, wherein component (B) is component (B6), and component (B6) is one or more selected from ascorbic acid, ascorbic acid phosphate ester, ascorbic acid fatty acid ester, ascorbic acid glucoside, and ascorbic acid alkyl ether.

8. Component (B) is component (B7), and component (B7) is one or more selected from monoethanolamine, diethanolamine, triethanolamine, lysine, arginine, histidine, ornithine, creatine, guanidine, and trishydroxymethylaminomethane. The deep eutectic solvent according to claim 1.

9. Component (B) is component (B8), and component (B8) is one or more selected from urea, dimethyl urea, hydroxyethyl urea, allantoin, and nicotinamide. The deep eutectic solvent according to claim 1.

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