CYCLODEXTRIN DERIVATIVE

Abstract: A cyclodextrin derivative having at least one group selected from the group consisting of sulfonic acid, sulfonic acid salt, ammonium salt, phosphoric acid, carboxyl, carboxylic acid salt and hydroxyl groups and a remarkably high water solubility.

Description: Technical Field This invention relates to cyclodextrin derivatives, more particularly to cyclodextrin derivatives having extremely high water solubility. Background Art Chemicals such as pharmaceuticals and agrichemicals are generally required to have water solubility because of the nature of their use. One of the means of improving the water solubility of those chemicals that have been proposed in recent years is by including them in cyclodextrin. However, because of the limited solubility of cyclodextrin in water, the cyclodextrin inclusion compounds have had the problem that their water solubility is still insufficient for practical applications. Under these circumstances, efforts have been made to improve the solubility of cyclodextrin in water by various methods such as methylating, hydroxyethylating or hydroxypropylating cyclodextrin, or synthesizing polymers crosslinked with epichlorohydrin, but no satisfactory results have yet been achieved. The US-A-3 453 259 discloses a cyclodextrin derivative containing a glycol group as well as a 1-hydroxymethyl-2,3-dihydroxypropyl ether of cyclodextrin. Therefore, an object of the present invention is to provide cyclodextrin derivatives having extremely high solubility in water. Disclosure of Invention The present inventor conducted intensive studies in order to achieve the above-stated object and found that it could be attained by providing a cyclodextrin derivative which contains at least one group represented by the formula: -C(CH 2 -OH) 3 . The present invention is described below in greater detail. In accordance with the present invention, the water solubility of cyclodextrin (hereunder abbreviated as CD) is improved significantly by positively introducing a trihydroxymethyl-tert.-butyl group into the molecule of CD. The CD to be used in the present invention may be of any type such as α-CD, β-CD or γ-CD. In the following, we describe exemplary reaction schemes for the synthesis of claimed CD derivatives. (A) Mono-(trishydroxy) β-CD (B) Di-(trishydroxy) β-CD (C) Hepta-(trishydroxy) β-CD In (A) - (C), n represents 6 - 8. The reactions for synthesis described above can specifically be carried out in accordance with the following schemes. (A) Synthesis of mono-(trishydroxy)β-CD β-CD is dissolved in dehydrated pyridine at room temperature and, to the resulting system, p-toluenesulfonyl chloride dissolved in pyridine is added dropwise at 20°C or below. After the end of the dropwise addition, the mixture is further stirred overnight at room temperature. After the end of the reaction, pyridine is distilled off under vacuum at 40°C or below and the residue is reprecipitated from a large volume of acetone, with the precipitate being collected and recrystallized three times from water (yield: ca. 25%). The thus obtained β-CD monotosylate is dissolved in DMF and reacted with KI overnight at 70 - 80°C. After the end of the reaction, DMF is distilled off under vacuum and the residue is reprecipitated from a large volume of acetone, with the precipitate being collected and recrystallized from an n-butanol/ethanol/water system (yield: ca. 60%). Subsequently, 2-phenyl-5-benzyloxymethyl-5-hydroxymethyl-1,3-dioxane and NaII are reacted in DMF at room temperature in a nitrogen stream and, one hour later, the system is heated to 30 - 40°C, whereupon β-CD monoiodide dissolved in DMF is added dropwise and, after the end of the dropwise addition, the mixture is subjected to reaction overnight at 90 - 100°C. After the end of the reaction, DMF is distilled off under vacuum and the residue is reprecipitated from a large volume of acetone, with the precipitate being dissolved in hot ethanol, filtered and subjected to another reprecipitation from a large volume of acetone. The precipitate is collected and recrystallized with ethanol (yield: ca. 15%). Further, the precipitate is dissolved in acetic acid and hydrogenated by addition of 5% Pd/C (under pressure of 5 kg/cm 3 at room temperature). After 24-h reaction, Pd/C is separated by filtration and acetic acid is distilled off under vacuum, with the residue being reprecipitated from a large volume of acetone. The precipitate is washed thoroughly with acetone and methanol and vacuum dried to obtain the end compound (yield: ca. 80%). (B) Synthesis of di-(trishydroxy)β-CD β-CD is dissolved in pyridine at room temperature and, to the resulting solution, diphenylmethane, p,p'-disulfonyl chloride dissolved in pyridine is added dropwise at 5°C. After the end of the dropwise addition, the mixture is stirred overnight at 20°C or below. After the end of the reaction, pyridine is distilled off under vacuum at 40°C or below and the residue is reprecipitated from a large volume of acetone. The precipitate is collected and purified by repeated recrystallization from water (yield: ca. 15%). The thus obtained compound is reacted with KI in DMF overnight at 70 - 80°C and, after the end of the reaction, DMF is distilled off under vacuum, with the residue being reprecipitated from a large volume of acetone. The precipitate is collected and purified by recrystallization from an n-butanol/ethanol/water system (yield: ca. 55%). The synthesis of compound 1 ○ and end compound 2 ○ is performed in the same manner as described in "Synthesis of mono-(trishydroxy)β-CD under (A). 1 ○: (yield: ca. 5%) 2 ○ : (yield: ca. 80%) (C) Synthesis of hepta-(trishydroxy)β-CD β-CD is dissolved in DMF at room temperature and, after the addition of methanesulfonyl bromide, the mixture is stirred at 60 - 70°C for 24 h. After the end of the reaction, DMF is distilled off under vacuum and the residue is reprecipitated from a large volume of methanol. After neutralization, the precipitate is added to ice cooled water, filtered, washed with ice cooled water thoroughly and dried to obtain β-CD heptabromide (yield: ca. 80%). The synthesis of compound 3 ○ and end compound 4 ○ is performed as follows. Subsequently, 2,2-dimethyl-1,3-dioxolane-4-methanol and NaH are reacted in DMF at room temperature in a nitrogen atmosphere and, one hour later, the system is heated to 30 - 40°C, whereupon the precipitate dissolved in DMF is added dropwise and, after the end of the dropwise addition, the mixture is subjected to reaction overnight at 90 - 100°C. After the end of the reaction, DMF is distilled off under vacuum and the residue is reprecipitated from a large volume of acetone, with the precipitate being dissolved in hot ethanol, filtered and subjected to another reprecipitation from a large volume of acetone. The precipitate is collected and recrystallized with ethanol (yield: ca. 20%). Further, the precipitate is dissolved in acetic acid and, to the resulting solution, a hydrochloric acid/acetic acid (1/1) solution is added dropwise at room temperature and the mixture is stirred for ca. 1 h, followed by concentrating the solvent under vacuum and reprecipitating the residue from a large volume of diethyl ether. The reprecipitation is followed by vacuum drying. 3 ○ : (yield: ca. 5%) 4 ○ : (yield: ca. 60%) The end compounds are identified by suitable methods such as NMR spectroscopy, mass spectroscopy and elemental analysis. Other CD derivatives can be synthesized by similar procedures based on the above-described methods. The water solubility of the CD derivatives obtained in the manner described above was checked and the results are shown below. Water Solubility (g/100 ml H 2 O) Material Name Solubility (25°C, g/100 ml H 2 O) β-CD (comparison) 1.85 From "Japanese Food Processing Data" Dimethyl β-CD (comparison) 57 Hydroxypropyl β-CD (comparison) 115 Mono-(trishydroxy) β-CD >200 - Di-(trishydroxy) β-CD >250 Hepta-(trishydroxy) β-CD >380 As described in detail on the foregoing pages at least one tri-hydroxymethyl-tert.-butyl group is introduced positively into CD in accordance with the present invention and this achieves a substantial improvement in the solubility of CD in water, thereby providing CD inclusion compounds of high water solubility. Industrial Applicability The CD derivatives of the present invention which have high water solubility may be useful as chemicals (e.g. pharmaceuticals and agrichemicals), aromatics, fragrances, cosmetics, detergents, paints, dyes, food additives in foodstuffs, etc.

Claims: A cyclodextrin derivative which contains at least one group represented by the formula: -C-(CH 2 -OH) 3 .

Inventors: YOSHINAGA MASANOBU, YOSHINAGA, MASANOBU, YOSHINAGA, MASANOBU, TOPPAN PRINTING CO., LTD.
Applicants: TOPPAN PRINTING CO LTD, TOPPAN PRINTING CO. LTD.
Application year: 1991
Main classification: C08B37
IPC codes: C08B37