MC2297A1 - NEW F-ALKYL SUGARS AND NUCLEOSIDES - Google Patents

Description

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patent for invention of new f-alkyl sugars and nucleosides by François Szônyi

The present invention relates to the synthesis of bisequenced compounds comprising a totally or partially fluorinated sequence and a hydrocarbon sequence derived from a monosaccharide or a nucleoside, some representatives of which are usable as surfactants, others being capable of exhibiting biological activity.

The compounds according to the invention can be represented by the general formula:

where Rl= rf(CH2)mnhco with Rf equal to a poly or perfluorinated radical and m equal to an integer, r2=r3=r4= qh when n = 0 or 1, or r^= oh, r^= hypoxanthine, 20 thymine or uracil in position (3, R^= h or oh when R^= hypoxanthine or uracil and r4= h when R^= thymine when n = 0, or R^= R^= oh, R^= aldohexose linked at C-6 when n = 1.

Perfluorinated compounds are well known for their ability to significantly lower the surface tension of the liquids in which they are dissolved, even at very low concentrations.

For about ten years the synthesis of non-ionic F-alkylated surfactants with a well-defined structure has been of great interest due to their possible use in dispersed systems intended for the biomedical and biotechnological fields.

Two types of approach can be distinguished in the preparation of such compounds.

Firstly, the preparation of amphiphilic compounds whose hydrophilic part is represented by one or more polyoxyethylated chains [T. GARTISER, C. SELVE, L. MANSUY, A. ROBERT and J.J. DELPUECH, J. Chem. Research (M), 2672 (1984); J. AFZAL, B.M. FUNG and E.O'REAR, J. Fluorine Chem., M, 385 (1987); F.SZÔNYI and A. CAMBON, J. Fluorine Chem., M, 195 (1987); C. SELVE, M. MOUMNI and J.J. DELPUECH, J. Chem. Soc. Chem. Commun., 1437 (1987); J. BOMMELAER, F.SZÔNYI and A. CAMBON, J. Fluorine Chem., 47, 235 (1990)] and whose synthesis is based on a strategy of selective activation of polyethylene glycols.

More recently, the grafting of a perfluoroalkyl chain onto a carbohydrate-type polyhydroxylated substrate has developed [S. COHEN and C. M. SHARTS, 12th Intl. Symp. Fluorine Chem., Santa Cruz, USA (1988); J. GREINER, A. MILIUS and J.G. RIESS, Tetrahedron Lett., 29, 2193 (1988); J. GREINER, A. MANFREDI and J.G. RIESS, New J. Chem., 13, 247 (1989)] due to the difficulty of accessing long defined polyoxyethylated chains on the one hand, and the low cost of carbohydrate raw materials on the other.

However, this latter approach requires the use of protecting groups in order to perfluoroalkylate only one of the hydroxyl functions present in the molecule, which increases the complexity of the synthesis.

Recently we have developed the preparation of 2-F-alkylethyl isocyanates from 2-F-alkylethyl iodides with good yields [M. A. JOUANI, F.SZÔNYI and A. CAMBON, J. Fluorine Chem. (to appear)], but it has been shown in hydrocarbon series that alkyl or aryl isocyanates could lead to monocarbamates by reacting selectively on the primary hydroxyl function of a monosaccharide [S. KOMORI and T. AGAWA, Technol. Repts. Osaka Univ., 8, 487 (1958); I. HIRAO, K. ITOH, N. SAKAIRI, Y. ARAKI and Y. ISHIDO, Carbohydr. Res., J09, 181 (1982); D. PLUSQUELLEC and M. LEFEUVRE, Tetrahedron Lett., 2^ 4165 (1987); D. PLUSQUELLEC, F. ROULEAU, M. LEFEUVRE and E. BROWN, Tetrahedron, 46, 465 (1990)].

In the present invention we report that 2-F-alkylethyl isocyanates lead to new F-alkylated monocarbamates without requiring special protection of sugars coupled or not with chosen purine or pyrimidine bases.

Compounds with R^ = RF(CH2)mNFI(X), where Rf and m have the same meaning as before, r2 = r3 = r4 = OH, and n = 0 or 1, as well as those with R^ having the same meaning as before, R^ = r4 = OH, r3 = C-6-linked aldohexose, and n = 1, are obtained by reacting ribose, an aldohexose, or a C-6-linked disaccharide (e.g., melibiose or gentiobiose) in excess with an isocyanate of the general formula RF(CH2)mNCO, where Rf and m have the same meaning as before. This reaction is advantageously carried out at a temperature

between 0 and 10°C, in the presence of an anhydrous aprotic organic solvent such as pyridine, DMF, DMSO or N-Methylpyrrolidone.

The regioselectivity of the reaction of F-alkylated isocyanates with saccharides, according to the invention, has also found a remarkable application with regard to nucleosides. Indeed, it is known that to prepare monofunctionalized nucleosides it is often necessary to use selective protecting groups; F-alkylated isocyanates react selectively with the primary hydroxyl group of nucleosides to give a new nucleoside possessing a 2-F-alkylethylcarbamate function at the 5' position, without requiring the use of protecting groups.

The compounds with R^= RF(CH2)mNHCO where Rf and m have the same meaning as before, R^= OH, R^= hypoxanthine, thymine or uracil in position P, R4= H or OH when R^= hypoxanthine or uracil and r4= H when R^= thymine and n = 0, are therefore obtained by reacting inosine, thymidine or uridine with an isocyanate of general formula RF(CH2)mNCO where Rp and m have the same meaning as before.

This reaction is advantageously carried out at a temperature between 0 and 20°C, in the presence of an anhydrous aprotic organic solvent such as pyridine, DMF, DMSO or N-Methylpyrrolidone.

All the products obtained are new and as such form part of the present invention.

Water-soluble compounds exhibit remarkable surface activity, exceeding that of known F-alkylated carbohydrate surfactants (ys = 23 to 36 mN.m⁻¹ at a concentration of 0.1%). As an example, the surface tension range obtained with D-glucose 2-F-alkylethylcarbamates is 17.1 to 23.4 mN.m⁻¹ at a concentration of 0.1%.

The following examples are intended to illustrate the present invention, but are in no way limiting.

EXAMPLES I to III

In a ground-glass flask equipped with a magnetic stirrer, a bromine funnel, and a condenser, 15 mmol of D-glucose and 20 mL of anhydrous pyridine are placed. The flask is placed in an ice-water bath under an inert atmosphere. Then, 10 mmol of freshly distilled isocyanate is added dropwise through the bromine funnel while stirring, and the reaction mixture is allowed to return to room temperature while stirring for 20 hours. The solvent is evaporated, and the residue is mixed with 30 mL of water and 30 mL of n-butanol or 2-butanol. The mixture is then allowed to settle, and the two phases are separated. The aqueous phase is extracted again with n-butanol or 2-butanol (2 x 30 mL). The compound is then recrystallized from acetonitrile. C4F9C2H4NHCO-C6H11O6 iF°C = 126-30°C Yield = 63%

C6F13C2H4NCO-C6H11O6 F°C = 137-41 °C Yield = 67%

C8F17C2H4NCO-C6H11O6 F°C = 146-50°C Yield =70%

EXAMPLE IV

In a ground-glass flask equipped with a magnetic stirrer, a bromine bulb, and a condenser, 5 mmol of thymidine solution is placed in 30 mL of anhydrous pyridine. The system is placed under an inert atmosphere at 15°C; 5 mmol of 2-F-octylethyl isocyanate is added. The reaction mixture is stirred for 36 hours, allowing it to return to room temperature. It is then slowly poured into 200 mL of ice-cold water while stirring vigorously. The precipitate is filtered, washed thoroughly with cold water, and stored under vacuum overnight in a desiccator containing P₂O₅. The product is solubilized in n-butanol and then released by the addition of petroleum ether. The resulting precipitate is then recovered by filtration through a sintered pore size of 4 and dried under vacuum.

F°C = 158°C Yield = 70%

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Claims (3)

DEMANDS 1) Fluorinated compounds possessing a carbohydrate residue and corresponding to the formula: CH2OR1 (CHOH)n CHR4 in which R^ represents a radical of general formula RF(CH2)mNHCO where Rf denotes a poly- or perfluorinated radical and m an integer, 10 r2, r3, r4 an OH group when n = 0 or 1, or R^ an OH group, R3 a hypoxanthine, thymine or uracil group at position j3, R^ a hydrogen atom or an OH group when r3 denotes a hypoxanthine or uracil group and r^ a hydrogen atom when r3 denotes a thymine group when n = 0, or r^ and r4 an OH group, r3 an aldohexose linked at C-6 when n = 1. 15 2) A process for manufacturing the compounds according to claim 1 where R* denotes a radical of general formula RF(CH2)mNHCO in which Rf and m are such as defined in claim 1 and R^, r3, r4 have the meanings defined in claim 1 and dependent on the value of n being equal to h 0 or 1, characterized by the reaction of an F-alkylated isocyanate of general formula RF(CH2)mNCO with ribose, an aldohexose, a C-6 linked disaccharide or a nucleoside selected from inosine, thymidine and uridine. 3) Application of the compounds according to claim 1 where R^ represents a radical of general formula RF(CH2)mNHCO in which Rf denotes a poly or perfluorinated radical whose number of carbon atoms does not exceed 12 and m as defined in claim 1, and R^, r3, r4 an OH group when n = 0 or 1, as a surfactant.