Acylating agent and a method of producing thereof

Abstract: A sugar derivative wherein a hydroxy-carboxylic acid is introduced to position 1 of a sugar via an ether linkage, and other hydroxyl groups are protected with protective groups. A method of producing the sugar derivative, comprising allowing glycolic ester to react with a compound so as to introduce said glycolic ester at position 1 of the sugar skeleton, followed by saponification, said compound having on position 1 anyone of a hydroxyl group, a halogen atom and a sulfur atom as a substituent group, and having other hydroxyl groups protected with protective groups.

Description: The present invention relates to an acylating agent and a method of manufacturing thereof, and in more detail, it relates to an acylating agent comprising a sugar derivative and to a method of manufacturing said sugar derivative. For the purpose of improving the stability of physiologically active substances and the water solubility of fat-soluble substances, extensive studies have gone into the technology of making glycosides via an ether linkage, and it is general knowledge to convert physiologically active substances to glycosides by making an ether linkage by organic synthesis or enzymatic reaction (see published methods of glycosidation; for example, Chapter 3 in Series of Experimental Chemistry, 4th Edition, Volume 26 (Organic Synthesis VIII), edited by The Chemical Society of Japan). However, since the hydroxyl groups in sugars have relatively low reactivity, one problem is that the yield of the desired products is low in organic synthesis. On the other hand, in enzymatic reactions the obtainable products are limited by the substrate specificity of enzymes and in addition plural reaction products may be formed. In previous methods of manufacturing glycosides, matching of aglycone and sugar was an important factor, and particularly when the aglycone is a compound containing a hydroxyl, amino or other radicals it was difficult to synthesize the glycoside. Monatshefte für Chemie 126, 923-931 (1995) describes the synthesis of symetric multivalent molecules containing four carbohydrate substituents WO95/14028 discloses similar pharmaceutical compositions for the treatment and prophylaxis of bacterial infection and methods for producing them. G. Petersson et al., Svensk Papperstining, vol 72, no. 7 (1969) pertains to the formation of glucopyranosylglycolic acids during the hydrolysis of cellulose. Also many cases have been reported, where synthesized glycosides do not satisfactorily contribute to the improvement of physical properties of substances, and so establishment of a more effective technique of glycosylation is desirable. Meanwhile, acylating agents, that have been used for introducing an acyl group to an organic compound, have been generally halogenated acyl or carboxylic acid anhydrides, but other active acylating agents such as other carboxylic acid derivatives and imidazolides have also been the target of development. No acylating agent containing sugar has yet been reported to date and it has not been utilized in the synthesis of glycosides. Extensive studies have led to a novel technique of synthesizing glycosides by using an acylating agent. A novel acylating agent was developed that allows a sugar readily to be combined with a compound containing a hydroxyl, amino or other radicals. As a result, the present inventors have found that the compound, obtained by combining acetic acid to a sugar at the position 1 via an ether linkage and by protecting other hydroxyl groups with a protective group, can be combined with a compound containing a hydroxyl, amino or other radicals, and that the product contributes to the improvement of physical properties of the original compound as desired. The present invention relates to a sugar derivative wherein a hydroxycarboxylic acid is introduced to position 1 of a sugar via an ether linkage, and other hydroxyl groups are protected with protective groups. Further the present invention provides an acetyloxyglycoside represented by the formula. 1 (wherein, R 1 is a group of hydroxyl protective group) Another aspect of the present invention is a method of producing a sugar derivative of Claim 1, which comprises allowing glycolic ester to react with a compound so as to introduce said glycolic ester at position 1 of the sugar skeleton, followed by saponification, said sugar having on position 1 anyone of a hydroxyl group or halogen atom as a substituent group, and having other hydroxyl groups protected with a denzyl or acetyl group. The present invention relates to an acylating agent comprising the sugar derivative of Claim 1. A sugar derivative that constitutes the acylating agent of the present invention is, as described above, a compound wherein a hydroxycarboxylic acid is introduced to position 1 of a sugar via an ether linkage, and other hydroxyl groups are protected with protective groups, and it is manufactured mainly from a monosaccharide or its glycoside as the starting material. Examples of such a sugar are glucose, mannose, allose, altrose, gulose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, psicose, fructose, sorbose, tagatose and fucose. Maltose and other disaccharides may also be employed. The acetyloxy glycoside that is represented by the above formula may be produced by the following reactions: (wherein, R 1 is hydrogen or a hydroxyl protective group ordinarily employed, which is described, for example, in New Series of Experimental Chemistry, Vol. 14 (Organic Synthesis V), Chapter 11-1, edited by The Chemical Society of Japan. Y is OR 1 or a halogen atom or a sulfur atom as a substituent group. R 2 is a carboxylic protective acid, and examples thereof are methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl, monochloroethyl, monobromoethyl, trichloroethyl, benzyl, p-methylbenzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl and allyl groups in addition to those that groups described in p. 152-192, Chapter 5, of "Protective Groups in Organic Synthesis" by Theodora W. Green.) Below is explained in detail a typical embodiment of the present invention by using glucose as a sugar. The sugar derivatives of the present invention may be produced by the following reaction steps: 2, 3, 4, 6-Tetrabenzyl-glucose (Compound (3), molecular weight 540.65) which is obtained, according to conventional methods, by starting with glucose via methyl-α-glucoside (Compound (1)) and Compound (2) whose hydroxyl groups except that on position 1 are benzylated, is allowed to react with ethyl glycolate together with p-toluenesulfonic acid in benzene at 0-150°C, preferably at 110°C, for 0.5-50 hours, preferably for 8 hours, so as to introduce ethyl glycolate to the position 1 of glucose, and an ethyl ester (Compound (4), molecular weight 626.76) is obtained. Then, after the said compound (4) is treated with an alkali (for example, 6N NaOH) in methanol-dioxane solution at from room temperature to 100°C for 0.5-50 hours, preferably for 3 hours, the reaction mixture is saponified by making it acidic with hydrochloric acid (for example, 1N HCl) to obtain a corresponding carboxylic acid compound (Compound (5)). This is tetrabenzyl acetyloxy-glucoside, a sugar derivative of the present invention, which is obtained when glucose is employed as the starting material. When another sugar is employed in place of glucose, the corresponding sugar derivative with a different sugar skeleton may be obtained by similar reaction steps. The sugar derivative is useful as an acylating agent and it undergoes an acylating reaction readily with a compound having a hydroxyl or amino group, for example, and gives a combined product. Hydrolysis of the product with a paradium catalyst removes the protective benzyl groups on the sugar moiety to yield desired free glycoside. By the method described below, tetraacetyl acetyloxy-glucoside, another sugar derivative of the present invention may be manufactured. Ethyl glycolate is allowed to react with 1-chloro-3-hydroxy-tetrabutyldistanoxane and allyl alcohol at 0-150°C, preferably at 120°C, for 0.5-50 hours, preferably for 11 hours, to obtain Compound (6). To a mixture of this compound (6) and pentaacetyl-glucose (Compound (7)), boron trifluoride-diethyl ether complex is added, and the mixture is allowed to react at 0-100°C, preferably at 30°C, for 0.5-50 hours, preferably for 20 hours, to obtain Compound (8). To this compound (8), paradium acetate, triphenyl-phosphine, triethylamine and formic acid are added, and the mixture is allowed to react at 0-100°C, preferably at 30 °C, for 0.5-50 hours, preferably for 20 hours, to obtain Compound (9). This compound is tetraacetyl acetyloxy-glucoside, another sugar derivative of the present invention when glucose is used as the starting sugar. In this case also, by similar reactions with a sugar other than glucose, the corresponding sugar derivative with a different sugar moiety may be obtained. The sugar derivative is useful as an acylating agent, and it can be readily combined with a compound having a hydroxyl or amino group by undergoing an acylating reaction. Hydrolysis of the product in alkaline solution removes the modifying acetyl groups in the sugar moiety and the desired free glycoside is obtained. A variety of compounds may be used for the conversion to glycosides by the reaction with the acylating agent of the present invention. Particularly, physiologically active substances such as paclitaxel and vitamin D, and fat-soluble compounds such as perfumes may be mentioned. The conversion of these compounds to glycosides contributes to the improvement of their stability and water solubility. For the improvement of water solubility of fat-soluble compounds, the adequate length of the acyl group is an acetyl group as described in the above acylating agent. Longer acyl chains cannot contribute to the improvement of water solubility of the compounds. However, in order to improve other physical properties, employment of another substance, in place of glycolic ester that serves as a spacer, will produce another acylating agent with a different acyl chain length, and it is recommended to select an acylating agent suitable for the specific purpose. In this way, the use of the acylating agent of the present invention produces glycosides readily in which a sugar is combined via a spacer. The glycosylation greatly contributes to the improvement of physical properties such as water solubility and stability. By the present invention, a sugar derivative is provided, which introduces a hydroxycarboxylic acid on the position 1 of the sugar via an ether linkage and whose other hydroxyl groups are protected. This compound may be used as an acylating agent for allowing to react with various substances to convert them into glycosides, and by this process, it can be used for the improvement of physical properties of the said substances. EXAMPLE The present invention will be described in more detail by means of the following examples, which however are not intended to restrict the scope of the invention. Example 1 2,3,4,6-Tetrabenzyl-glucose (Compound (3), C 34 H 36 O 6 , molecular weight 540.65) (1.62 g) which was obtained by the conventional method, ethyl glycolate (1.56 g), p-toluene-sulfonic acid (0.10 g) and benzene (80 ml) were allowed to react at 110°C under refluxing for 8 hours to obtain the ethyl ester (Compound (4), C 38 H 42 O 8 , molecular weight 626.74). Then, this compound (1.88 g) was allowed to react with 6N NaOH (10 ml) in methanol (10 ml) and dioxane (15 ml) at room temperature-100°C for 3 hours, and its deethylation by bringing it into 1N HCl (80 ml) produced the carboxylic acid compound (Compound (5), C 36 H 38 O 8 , molecular weight 598.69). Compound (5) was dissolved in deuterium chloroform for subjecting to analysis by 1 H-NMR and each peak was assigned for the determination of structure, confirming that it is represented correctly by the above-described structure. Data are given below. 1 H-NMR (500 MHz, CDCl 3 ) of the carboxylic compound: 3.35-3.80 (m, 5H), 3.90-4.95 (m, 10H), 7.00-7.40 (m, 20H, Ar) Example 2 To ethyl glycolate (10 mmol), 1-chloro-3-hydroxytetrabutyldistanox ane (30 mg) and allyl alcohol (5 ml) were added and stirring of the mixture at 120°C for 11 hours gave Compound (6). Then this compound (3 mmol) and pentaacetyl-glucose (2 mmol) were dissolved in methylene chloride (8 ml), and after dropping boron trifluoride-diethyl ether complex (2.4 mmol) the mixture was stirred at room temperature for 20 hours to obtain Compound (8). This compound (1.1 mmol) was dissolved in tetrahydrofuran (THF) (5 ml) and then paradium acetate (0.1 mmol), triphenylphosphine (0.3 mmol), triethylamine (5 mmol) and formic acid (4 mmol) were added successively, and the mixture was stirred at room temperature for 20 hours to obtain Compound (9), namely the carboxylic acid compound (tetraacetyl acetyloxy-glucoside). This carboxylic acid compound was dissolved in deuterium chloroform and subjected to analysis by 1 H-NMR. By assigning each peak the structure was determined and it was confirmed to be represented correctly by the above shown structure. Data are shown below. 1 H-NMR (500 MHz, CDCl 3 ) of the carboxylic compound: 2.02-2.10 (m, 12H), 3.69-3.77 (m, 1H), 4.10-4.18 (m, 1H), 4.22-4.40 (m, 3H), 4.67 (d, J=7.6, 1H), 5.01-5.15 (m, 2H), 5.23-5 28 (m, 1H) Example 3 By using benzyl acetyloxy-glucoside which is represented by Compound (5) and obtained in Example 1 as an acylating agent, 1-menthol was converted into glucoside. Reaction steps are as shown below. 1-Menthol (1 mmol) was dissolved in methylene chloride (5 ml) and dicyclohexylcarbodiimide (DCC) (2 ml) and 4-N,N-dimethylaminopyridine (DMAP) (2 mmol) were added. Then benzyl acetyloxy-glucoside (2 mmol) was added and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into saturated aqueous sodium chloride solution, extracted with ethyl acetate and treated by the conventional method to obtain 1-menthol-glucoside. Then the reaction product was debenzylated by using paradium/carbon in ethanol to obtain free glucoside. 1-Menthol-glucoside thus obtained was found to have about 200 times higher water solubility than 1-menthol itself. Example 4 By using tetraacetyl acetyloxy-glucoside obtained in Example 2 as an acylating agent, glucosylation of 1-menthol was performed. The reaction steps are as follows: 1-Menthol (1 mmol) was dissolved in methylene chloride (5 ml) and DCC (2 ml) and DMAP (2 mmol) were added. Then tetraacetyl acetyloxy-glucoside (2 mmol) was added and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into saturated aqueous solution of sodium chloride, and after extracting with ethyl acetate, 1-menthol-glucoside was obtained by the treatment of the conventional method. The reaction product was deacetylated in ethanol with 0.1N sodium hydroxide to obtain free glucoside. 1-Menthol glucoside thus obtained was found to have about 200 times higher solubility in water than 1-menthol itself.

Claims: A method of producing a sugar derivative wherein a hydroxy-carboxylic acid is introduced to position 1 of a sugar via an ether linkage, and other hydroxyl groups of the sugar are protected with benzyl or acetyl groups, which comprises allowing glycolic ester to react with a sugar so as to introduce said glycolic ester at position 1 of the sugar skeleton, followed by saponification, said sugar having in position 1 a hydroxyl group or a halogen atom as a substituent group, and having other hydroxyl groups being protected with benzyl or acetyl groups.

Inventors: HAMADA HIROKI, HARA KOJI, HARA KOZO, MANDAI TADAKATSU, MIKUNI KATSUHIKO, OKUMOTO HIROSHI, HAMADA, HIROKI, HARA, KOJI, HARA, KOZO, MANDAI, TADAKATSU, MIKUNI, KATSUHIKO, OKUMOTO, HIROSHI, Hamada, Hiroki, Okayamarika-Daigaku, Hara, Koji, Ensuiko Sugar Refining Co., Ltd., Hara, Kozo, Ensuiko Sugar Refining Co., Ltd., Mandai, Tadakatsu, Kurashiki Univ. of Sci. &amp; Arts, Mikuni, Katsuhiko, Ensuiko Sugar Refining Co., Ltd, Okumoto, Hiroshi, Kurashiki Univ. of Sci. &amp; Arts
Applicants: ENSUIKO SUGAR REFINING, MANDAI TADAKATSU, ENSUIKO SUGAR REFINING COMPANY, LIMITED, MANDAI, TADAKATSU
Application year: 1997
Main classification: C07H15
IPC codes: C07H15, C07H1