FR2696467A1 - Chemical prepn. of fatty acid mono-ester(s) of D-fructose - useful amphiphile(s) in cosmetic, buccal, dental, pharmaceutical and food compsns. - Google Patents

Abstract

Prepn. of fatty acid monoesters of D-fructose comprises formation of a mixed anhydride of formula (I) in an organic solvent. This is reacted with D-fructose in the same solvent, in the presence of a base to give the required monoesters. R = 7-21C alkyl or alkenyl, or a defined mixt. of these; R' = 2-10C alkyl. Also claimed are fatty acid monoesters of D-fructose of formulas (II) and (III). R1 = H or -C(=O)R; only one R1 is -C(=O)R. USE/ADVANTAGE - Use of (II) and (III) in cosmetic, buccal, dental, pharmaceutical and food compsns. is claimed. (II) and (III) are amphiphiles. Some of them can form vesicles, useful as vehicles in cosmetic, pharmaceutical and food compsns..Others readily foam, useful in cosmetic and dental compsns.. Octanoic esters of D-fructose are able to restore the permeability barrier of delipidised skin, useful in treating dry and damaged skin. The method gives good yields (better than 60%).

Description

 The subject of the present invention is a new process for the preparation of D-fructose fatty acid monoesters and their use in various fields of industry and in particular in the cosmetic, oral, pharmaceutical and food fields.

 It has already been proposed in the article by Von E. Reinefeld et al., Zucker, No. 9, p. 236-241, 1968, the preparation of fatty acid monoesters of D-fructose by reaction of a chloride of fatty acid on D-fructose. This method has the disadvantage of leading to relatively low yields of monoesters (<51%) and to the formation of quantities of di- and tri-esters (> 39% especially in the case of the decanoate ester), not allowing not to perform under good conditions purification by silica gel plate chromatography.

As another process for the preparation of fatty acid esters of D-fructose, mention may also be made of the process described in French Patent No. 74,292,40 (2,270,321) by cultivation of a microorganism using fructose, belonging to the genera Arthrobacter,
Corynebacterium, Nocardia or Mycobacterium, and capable of producing fructose fatty acid esters in a medium containing fructose as a carbon source, forming fructose fatty acid esters intracellularly and recovering the esters from microbial cells.

After various studies, it has now been unexpectedly found that it is possible to obtain, with good yields (> 60%) of monoesters of
D-fructose via the mixed carboxylic-carbonic anhydride method.

dans laquelle:
R représente un radical allyle, linéaire ou ramifié, ou alcényle, ayant de 7 à 21 atomes de carbone ou R représente un mélange défini de tels radicaux allyle ou alcényle, et R' représente un radical allyle, linéaire ou ramifié ayant de 2 à 10 atomes de carbone, par réaction, en présence d'une première base, d'un acide R-COOH, R ayant la même signification que ci-dessus, et d'un chloroformiate d'alkyle ClCOOR', R' ayant la même signification que ci-dessus, et dans un deuxième temps, à faire réagir ledit anhydride mixte de formule (I) en solution dans ledit solvant organique, avec du D-fructose, éventuellement en présence d'une deuxième base.The subject of the present invention is therefore a process for the preparation of D-fructose fatty acid monoesters, the latter consisting in a first step of forming in an organic solvent a mixed anhydride of formula (I):

in which:
R represents a linear or branched allyl radical, or alkenyl, having from 7 to 21 carbon atoms, or R represents a defined mixture of such allyl or alkenyl radicals, and R 'represents a linear or branched allyl radical having from 2 to 10 carbon atoms. carbon atoms, by reaction, in the presence of a first base, an R-COOH acid, R having the same meaning as above, and an alkyl chloroformate ClCOOR ', R' having the same meaning than above, and in a second step, reacting said mixed anhydride of formula (I) dissolved in said organic solvent with D-fructose, optionally in the presence of a second base.

 The first and second base may be the same or different.

As the reaction organic solvent, it is possible to use according to the invention tetrahydrofuran, N, N-dimethylformamide, pyridine, N-methylpyrrolidone,
N, N-dimethylacetamide or a mixture of these solvents.

 The base for the activation of the fatty acid is preferably an organic base selected from triethylamine, pyridine, 4-dimethylaminopyridine, tributylamine or N-methylmorpholine.

 The second step, or esterification step, may optionally be carried out after dewatering the salts formed in the first step and the D-fructose is preferably in solution in pyridine, or optionally in N-methylpyrrolidone, N, N dimethylformamide or N, N-dimethylacetamide.

To the solution of D-fructose, it is optionally possible to add a base chosen from triethylamine, pyridine, 4-dimethylaminopyridine, tributylamine or else
N-methyl.

 At least three equivalents of D-fructose with respect to the fatty acid reacted in the first step are preferably used according to the invention.

 According to the invention, the alkyl chloroformate is preferably chosen from ethyl chloroformate and isopropyl chloroformate.

 After the end of the reaction, the solvents are evaporated and the resulting product can either be chromatographed on a column of silica gel using preferably a mixture of solvents based on methylene chloride and methanol, or extracted using a mixture of water-ethyl acetate solvents.

 The reaction temperature of the process according to the invention is generally between -25 and + 400C and the reaction time between 3 and 15 hours.

 The fatty acid R-COOH is preferably selected from octanoic acid, dodecanoic acid, hexadecanoic acid and oleic acid.

dans lesquelles:
R1 représente un atome d'hydrogène ou le radical

The monoesters of fatty acids of D-fructose obtained by the process according to the invention can be represented by the following formulas:

in which:
R1 represents a hydrogen atom or the radical

R represents a linear or branched allyl radical, or alkenyl having 7 to 21 carbon atoms, or R represents a defined mixture of such allyl or alkenyl radicals, provided that only one of the radicals R 1 represents the radical;

 The monoesters of fatty acids of D-fructose are obtained by the process according to the invention with a yield greater than 60% after purification, operation by which the unreacted starting materials and the diesters (<10 %) and triesters (<1%).

 The determination of the structures of the products obtained was carried out by 13 C-NMR in deuterated dimethylsulfoxide (DMSO) and by mass spectroscopy.

The process according to the invention with respect to known processes such as the process involving a fatty acid chloride allows a very rapid activation of the fatty acid, and the use "in situ" of its activated form giving a high yield in monoesters of
D-fructose.

 The interest of obtaining a high yield of monoesters is absolutely essential for the valorization and the use of these D-fructose derivatives as amphiphiles in the cosmetic, pharmaceutical, oral and food fields.

 The monoesters of fatty acids of D-fructose as defined above have very interesting properties and find particular application in the cosmetic, pharmaceutical and food.

 Among these properties, mention should be made especially of the possibility, especially for monoesters of D-fructose in which R represents an allyl radical between 11 and 21 carbon atoms, to form in the hydrated state and in combination with cholesterol and sodium diketylphosphate, dispersible lamellar phases in the form of vesicles. The respective proportions between the monoesters of D-fructose, cholesterol and sodium diketylphosphate can be for example 47.5 / 47.5 / 5 or 62.5 / 32.5 / 5. These vesicles may in particular allow the carrier of various active ingredients known in the cosmetic, pharmaceutical and food fields.

 Furthermore, certain monoesters of D-fructose such as octanoic and decanoic monoesters (R = C7 and Cg) can be incorporated in water at a concentration of 1 to 5% and thus form very foaming solutions with foam compactness important.

This property is particularly sought after in the context of application in the cosmetic and oral fields.

 Finally, the monoesters of fatty acids of D-fructose such as octanoic monoesters have an activity of restoration of the water permeability barrier (reduction of insensible water loss of 18%) on a Stratum Corneum previously delipidated. This unexpected activity is essential especially in the cosmetic and pharmaceutical fields in the search for the rehydration of dry and damaged skin.

 The present invention therefore also relates to a cosmetic, oral, pharmaceutical or food composition containing in a suitable carrier at least one fatty acid monoester D-fructose as obtained and defined above.

 In the compositions according to the invention, the monoesters of fatty acids of D-fructose are generally present at a concentration of between 0.01 and 30% by weight relative to the total weight of the composition, and preferably between 0.5 and 15% by weight.

 The compositions according to the invention may be in various forms, in particular in the form of foaming or non-foaming lotions, of emulsions of liquid or semi-liquid consistency, such as milks obtained by dispersion of a fatty phase in an aqueous phase. or conversely, suspensions or emulsions of soft consistency of the cream or ointment type, gels or solid preparations such as sticks, cleaning breads, impregnated pads or in the form of moisturizing masks.

 As the carrier of the compositions according to the invention, it is possible to use water, organic solvents which are compatible with a topical application, such as acetone, glycerol, isopropyl alcohol, ethyl alcohol or triglycerides of fatty acids. at C6-C24, glycol ethers such as lower alkyl ethers of mono- or diethylene glycol, the alkyl radical of which has from 2 to 4 carbon atoms.

 It is also possible to use polycarbonyl esters of short chain C1-C4 acids or volatile silicones as solvents.

 The compositions according to the invention may also contain fatty substances such as natural or synthetic oils.

 The compositions according to the invention may also contain thickening or gelling agents such as cellulose or cellulose derivatives. The thickeners may also be acrylic polymers, alginates, gums such as xanthan gum, guar, locust bean or gum arabic or polyethylene glycols, bentonites and montmorillonites.

 The compositions according to the invention may also contain active substances such as moisturizing agents as well as adjuvants such as antioxidants, preservatives, perfumes or dyes.

 The compositions according to the invention may also be in the form of solutions or dispersions containing the fatty acid monoesters of D-fructose in vesicular form, the vesicles then being able to serve as an encapsulating agent for lipophilic or hydrophilic active ingredients. .

GENERAL PROCESS FOR THE PREPARATION OF MONOESTERS
FATTY ACIDS OF D-FRUCTOSE
The carboxylic acid R-COOH is dissolved in an organic solvent such as tetrahydrofuran at 25 g (W / V). To this solution, 1.05 eq. of triethylamine and the medium is stirred at ambient temperature for one hour. The solution of the triethylamine salt obtained is then added to a solution of alkyl chloroformate ClCOOR ', preferably isopropyl chloroformate (1 eq.) In tetrahydrofuran (10% w / v) cooled to -200C with a bath alcohol / dry ice.

 After addition, the medium is stirred for at least three hours.

 The D-fructose (3 eq.) Is in parallel dissolved in a basic solvent such as for example anhydrous pyridine (8 g per 100 ml) and the medium, optionally filtered, is added to the solution of D-fructose to room temperature for at least 3 hours.

 After evaporation of the solvents, the product is either chromatographed on a column of silica gel using a mixture of solvents based on methylene chloride and methanol, or extracted using a mixture of solvents based on of water and ethyl acetate.

According to this general method, the following D-fructose fatty acid monoesters were prepared
EXAMPLE 1 Octanoic monoesters of D-fructose
Yield 80% (amber paste)
Elemental analysis: C14H2607; M = 306.4
C%
Calc. 54.89 8.55
Tr. 54.85 8.64
The 13C NMR and mass spectrometry spectra are consistent with the expected structure.

EXAMPLE 2 Dodecanoic monoesters of D-fructose
Yield = 95% (amber paste)
Elemental analysis: Cl8H3407; M = 362.5
C%
Calc. 59.65 9.45
Tr. 59.72 9.63
The 13C NMR and mass spectrometry spectra are consistent with the expected structure.

EXAMPLE 3 Hexadecano Monoesters of D-Fructose
Yield = 65%
Melting point = 610C
Elemental analysis: C22M42O7; M = 418.6
C%
Calc. 63.13 10.11
Tr. 63.85 10.45
The 13C NMR and mass spectrometry spectra are consistent with the expected structure.

EXAMPLE 4 Oleic monoesters of D-fructose
Yield = 87% (amber paste)
Elemental analysis: C24H4407; M = 444.6
C% H%
Calc. 62.30 10.02
Tr. 62.19 9.99
The 13C NMR and mass spectrometry spectra are consistent with the expected structure.

EXAMPLES OF COMPOSITIONS
EXAMPLE 1: Vesicular preparation in the form of cream
A lipid phase is first prepared by mixing the following ingredients: hexadecanoic monoesters of D-fructose
obtained according to Example 3 47.5 g - Cholesterol 47.5 g - Sodium diketylphosphate 5g
This lipid phase, in a proportion of 5%, is then used in the preparation of the vesicular composition according to conventional methods, the remainder of the composition being constituted by water, optionally supplemented with preserving agents and / or antioxidant and possibly oil.

EXAMPLE 2: Vesicular preparation in the form of cream
A lipid phase is first prepared by mixing the following ingredients: Dodecanoic monoesters of D-fructose
obtained according to Example 2 62.5 g - Cholesterol 32.5 g - Sodium diketylphosphate 5g
This lipid phase, in a proportion of 10% by weight, is used in the preparation of the vesicular composition according to conventional methods, the remainder of the composition being constituted by water, optionally supplemented with preserving agents and / or antioxidant and possibly oil.

EXAMPLE 3 Foaming Preparation - Octanoic Monoesters of D-Fructose
obtained according to Example 2 5g - 40% triethanolamine Laurysulfate in water 40 g - Cocoylbétaïne 4g - Copra fatty acid diethanolamide 3g - Preservatives 0.2 g - Water qs 100 g
This preparation is particularly suitable for the manufacture of a product for the shower.

EXAMPLE 4 Preparation of a moisturizing fluid-in-water emulsion - Octanoic monoesters of D-fructose
obtained according to Example 1 5g - cetyl alcohol 0.2 g - stearic acid 0.5 g - glyceryl stearate-stearate
Polyethylene Glycol (100 EO) (50/50) 0.4 g - Volatile Silicone (Cyclomethicone) 5g - Polyisobutylene 2g - Olycerol 4g - Carboxyvinyl polymer 0.4 g - Sodium hydroxide 0.3 g - Preservatives 0.1 g - Fragrance 0.2 g - Distilled water qs 100 g

Claims (11)

 Process for the preparation of fatty acid monoesters of D-fructose, characterized in that it consists, in a first step, in forming in an organic solvent, a mixed anhydride of formula (1):

 in which: R represents a linear or branched allyl radical, or alkenyl, having from 7 to 21 carbon atoms, or R represents a defined mixture of such alkyl or alkenyl radicals, and R 'represents a linear or branched alkyl radical having from 2 to 10 carbon atoms; carbon atoms, by reaction, in the presence of a base, an R-COOH acid, R having the same meaning as above, and an alkyl chloroformate C1COOR ', R' having the same meaning as above, and in a second step, reacting said mixed anhydride of formula (I) in solution in said organic solvent essentially in the presence of a base, with D-fructose.  2. Process according to Claim 1, characterized in that the organic solvent is chosen from tetrahydrofuran, N, N-dimethylformamide, pyridine, N-methylpyrrolidone, N, N-dimethylacetamide or a mixture of these solvents.  3. Process according to Claim 1, characterized in that the base is chosen from triethylamine, pyridine, 4-aminopyridine, tributylamine or N-methyl.  4. Process according to claim 1, characterized in that the D-fructose is reacted in solution in pyridine, N-methylpyrrolidone, N, N-dimethylformamide or N, N-dimethylacetamide.  5. Method according to any one of the preceding claims, characterized in that about 3 eq are reacted. of D-fructose relative to the fatty acid.  6. Process according to any one of the preceding claims, characterized in that, after the end of the reaction and evaporation of the solvents, silica gel column chromatography is carried out using a mixture of solvents based on chloride. methylene and methanol.  7. Process according to any one of Claims 1 to 5, characterized in that, after the end of the reaction and the evaporation of the solvents, extraction is carried out using a mixture of water-acetate solvents. 'ethyl.  8. Monoesters of fatty acids of D-fructose, characterized in that they correspond to the following formulas:

 in which: R1 represents a hydrogen atom or the radical

R represents a linear or branched allyl radical, or alkenyl having 7 to 21 carbon atoms, or R represents a defined mixture of such allyl or alkenyl radicals, provided that only one of the radicals R 1 represents the radical;  - Oleic monoesters of D-fructose.  hexadecano monoesters of D-fructose, and  dodecanoic monoesters of D-fructose,  octanoic monoesters of D-fructose,  9. Monoesters of fatty acids of D-fructose according to claim 8, characterized in that they are chosen from:  Cosmetic, oral, pharmaceutical or food composition, characterized in that it contains in a suitable carrier at least one fatty acid monoester of D-fructose according to claims 8 and 9 or obtained according to any one of Claims 1 to 7.  11. Composition according to Claim 10, characterized in that the fatty acid monoester of D-fructose is present in a concentration of between 0.01 and 30% and preferably between 0.5 and 15% by weight relative to to the total weight of the composition.