JP5100160B2 - Sugar-branched cyclodextrin derivatives and process for producing the same - Google Patents

Description

  The present invention relates to a sugar-branched cyclodextrin that is attracting attention as a drug carrier of a target drug delivery system. Specifically, a sugar compound chemically modified using a derivative of 2- (4-hydroxyphenyl) ethyl alcohol and 2-chloroethanol as a raw material and a cyclodextrin derivative are subjected to coupling condensation, and then the sugar hydroxyl protecting group is removed. The present invention relates to a sugar-branched cyclodextrin derivative obtained by protection and a production method thereof.

  A sugar-branched cyclodextrin is expected to be used as a target drug transport system because it has both the ability to recognize a lectin protein in a living body of a sugar molecule and the drug inclusion ability of a cyclodextrin. From such a viewpoint, many methods for producing sugar-branched cyclodextrins have been reported (see, for example, Non-Patent Documents 1-5). Since sugar-branched cyclodextrins take the drug into the cavity of the cyclodextrin and send it to the target cells, it is not necessary to bind the drug to the carrier, and if it is a drug that can be included, easy drug preparation is possible. Make it possible. On the other hand, since the drug is transported non-covalently, there is a risk of drug leakage during transport. Cyclodextrins originally have the ability to incorporate hydrophobic drug molecules, but the development of more efficient drug carrier molecules requires high drug retention and a high association constant for the drug. There is. As a cyclodextrin derivative having such a function, it has been reported that doxorubicin, an anthracycline anticancer agent, is retained at a very high association constant by introducing an aromatic group into a spacer that binds cyclodextrin and a sugar molecule. (See Non-Patent Document 4). However, since this reported method uses 4-hydroxyphenyl β-glucopyranoside obtained from nature, only glucose can be used as the sugar molecule. Furthermore, although it has already been reported in Non-Patent Document 5, in these reports, since the spacer between the sugar molecule and the aromatic group is short, it cannot be expected to show a high association with the target lectin protein. Therefore, it is necessary to design a sugar-branched cyclodextrin derivative having a high degree of freedom, and high applicability to a target drug delivery system is required.

T. Furuike et al., `` Chemical and Enzymatic synthesis of Glycocluster Having Sialyl Lewis X Arrays Using -Cyclodexytrin As a Key Scaffold Material '', Tetrahedron, 2005, 61, 1737. R. Roy et al., `` Synthesis of Persialylated ・ -Cyclodextrins '', Journal of Organic Chemistry, 2000, 65, 8743. H. Abe et al., `` Structural Effects of Oligosaccharide-branched Cyclodextrins on The Dual Recognition Toward Lectin and Drug '', Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2002, 44, 39. T. Yamanoi et al., `` Synthesis of mono-Glucose-branched Cyclodextrins With a High Inclusion Ability For Doxorubicin And Their Efficient Glycosylation Using Mucor hiemalis Endo- ・ -N-acetylglucosaminidase, Bioorganic & Medicinal Chemistry Letters, 2005, 15, Vol. 1009 page. Yamanoi et al., `` Synthesis and Evaluation of Galactose Branched Cyclodextrins Aimed at Development of Drug Carrier Molecules '', Abstracts of the 86th Annual Meeting of the Chemical Society of Japan, 2006, 1PA-140, p. 1433.

  An object of the present invention is to provide a cyclodextrin derivative in which various sugar molecules are branched which have a high association constant for anthracycline drugs and the like and are expected to have a high association constant for a target lectin protein. It is.

As a result of diligent research on cyclodextrin derivatives branched from various sugar molecules that have high association constants for drugs such as anthracyclines and that are expected to have high association constants for target lectin proteins, Since 2- (4-hydroxyphenyl) ethyl alcohol is used as a spacer material for binding sugar molecules and has a high association constant with lectin proteins, it is used as a spacer material between sugar molecules and aromatic groups. By using 2-chloroethanol, cyclodextrin derivatives branched from various sugar molecules can be produced, and the present invention has been achieved.
That is, the present invention utilizes an alcohol derivative such as 2- (4-hydroxyphenyl) ethyl alcohol and 2-chloroethanol as a raw material for a spacer when cyclodextrin and various sugar molecules are bonded, and an aromatic group is formed in the spacer. The present invention relates to a sugar-branched cyclodextrin derivative (1 to 4) characterized in that it has a method for producing the same.

またnは1から5までの整数、mは1から5までの整数、Rはグリコシド結合で結合したグルコース、マンノース、ガラクトース、N-アセチル-グルコサミン、グルコサミン、フコース、N-アセチルノイラミン酸、あるいは、グルコース、マンノース、ガラクトース、N-アセチル-グルコサミン、グルコサミン、フコース、N-アセチルノイラミン酸から構成される二糖または三糖。）

N is an integer from 1 to 5, m is an integer from 1 to 5, R is glucose, mannose, galactose, N-acetyl-glucosamine, glucosamine, fucose, N-acetylneuraminic acid bonded by a glycosidic bond, or Disaccharides or trisaccharides composed of glucose, mannose, galactose, N-acetyl-glucosamine, glucosamine, fucose and N-acetylneuraminic acid. )

  Anthracyclines are known as doxorubicin, idamycin, daunomycin, rubirubicin, and the like, and act as antibiotics, anticancer agents, and anticancer agents. The sugar-branched cyclodextrin derivative of the present invention is expected to have a strong inclusion force with respect to these anthracycline drugs, and further, by introducing a spacer between the aromatic group and the sugar molecule, the sugar-branched cyclodextrin derivative is highly effective against lectin proteins. Since the association constant is expected, use of the target drug delivery system as a drug carrier is expected. In addition, since various sugar molecules can be introduced, it can be considered that it can act as a receptor for enzyme reaction and can be used as a drug carrier after the sugar molecule is constructed.

Hereinafter, the present invention will be described in detail.
The present invention uses 2- (4-hydroxyphenyl) ethyl alcohol having an aromatic group as a raw material for inclusion of anthracycline antibiotics and the like with a high association constant, and further includes a sugar molecule and an aromatic group. A high association constant is expected for the target lectin protein by using an alcohol derivative such as 2-chloroethanol as a raw material for spacers, and it is related to the production of cyclodextrin derivatives in which various sugar molecules are branched. It is.

  In the sugar-branched cyclodextrin derivative [1] of the present invention, the presence of an aromatic group in the spacer that connects the cyclodextrin and the branched sugar molecule improves the hydrophobicity in the cavity of the cyclodextrin and increases the sugar molecule. In the case of a derivative having two or more branches, this aromatic group causes a stacking phenomenon that sandwiches the aromatic part of the anthracycline drug, and a strong pi-electron interaction occurs, thereby increasing the anthracycline drug and the like. It is presumed that the inclusion constant can be included. Furthermore, by introducing a spacer between the sugar molecule and the aromatic group, the degree of freedom of the sugar molecule is increased, and it is presumed that it interacts with the lectin protein with a high association constant. The device of the present invention uses an alcohol derivative such as 2- (4-hydroxyphenyl) ethyl alcohol and 2-chloroethanol as a raw material for a spacer connecting cyclodextrin and a sugar molecule, so that an anthracycline or the like is used in the spacer. It is a sugar-branched cyclodextrin derivative capable of introducing various sugar molecules, which has an aromatic group that is expected to include an antibiotic with a high association constant and is expected to have a high association constant with a lectin protein.

  Next, the cyclodextrin derivative will be described. The method described in W. Wang et al. (Tetrahedron Asymmetry, 2001, Vol. 12, p. 517), that is, reductive treatment using perbenzyl-α or β or γ-cyclodextrin with diisobutylaluminum hydride. By this method, various cyclodextrins in which the 6-position benzyl group of cyclodextrin is converted into one or two hydroxyl groups are obtained. Furthermore, after introducing an appropriate protecting group into this hydroxyl group, reductive treatment with diisobutylaluminum hydride is performed again to obtain various cyclodextrins in which a number of benzyl groups at the 6-position of cyclodextrin are converted into hydroxyl groups. It is known that The preparation of these cyclodextrin derivatives can be adjusted by the reaction temperature and the amount of diisobutylaluminum hydride.

  As the sugar molecule of the sugar-branched cyclodextrin derivative, well-known monosaccharides such as glucose, mannose, galactose, N-acetylglucosamine, fucose, glucosamine, N-acetylneuraminic acid can be used. In addition, known disaccharides and trisaccharides composed of glucose, mannose, galactose, N-acetylglucosamine, fucose, glucosamine and N-acetylneuraminic acid can be used. Monosaccharides, disaccharides or trisaccharides are introduced into the primary hydroxyl group derived from 2-chloroethanol via glycosidic bonds, but the glycosidic bonds are either α or β bonds or glycosidic bonds in which α and β are mixed. I do not care.

The spacer connecting the cyclodextrin derivative and the sugar molecule will be described. By reacting 2- (4-hydroxyphenyl) ethyl alcohol with an equivalent amount of an alkali reagent such as sodium hydroxide to form a sodium salt and an alkyl halide reagent such as allyl bromide, the phenolic hydroxyl group is allylated. 2- (4-allyloxyphenyl) ethanol produced. Then, 2-chloroethanol is reacted with a hydroxyl-protecting group such as tetrahydropyran-2-ene under alkaline conditions to synthesize 2-O- (2-chloroethoxy) -tetrahydropyran, using sodium hydride. 1-hydroxy-3-oxa-5- (4-allyl) in which n is 1 shown in the figure below by preparing 2- (4-allyloxyphenyl) ethyl alcohol after treatment with sodium salt and treating with 1N hydrochloric acid Oxyphenyl) pentane is manufactured. This was further reacted with 2-O- (2-chloroethoxy) -tetrahydropyran, and the same conditions were repeated, whereby 1-hydroxy-3,6-dioxa-8- (4-allyl) in which n is 2 as shown in the figure below. Oxyphenyl) octane can be produced. In the same manner, it is possible to manufacture a spacer with an increased value of n shown in the figure below. Moreover, when manufacturing the spacer shown in the following figure, it is not limited to 2-chloroethanol.

  Next, the glycosylation to spacer and pentaacetyl-β-D-galactose will be described. Well-known sugar donors such as thioglycosides, glycosyl imidates, glycosyl fluorides, 1-O-acylate sugars can be used. It goes without saying that the reaction conditions are the well-known glycosylation reaction conditions (activator, solvent, temperature, molar ratio) specific to these sugar donors.

  The terminal olefin of the spacer of mono-, di- or trisaccharide glycosides in which the sugar hydroxyl group is converted to a benzyl group as needed is from Yamanoi et al. (Bioorganic & Medicinal Chemistry Letters, 2005, 15th volume, 1009) In the same manner as described, a hydroboration reaction using 9-borabicyclo [3.3.1] nonane, followed by hydrolysis with an aqueous hydrogen peroxide solution, which is converted to alcohol and obtained using iodine and triphenylphosphine. Glycosides with iodinated terminal ends of sugar, disaccharide or trisaccharide spacers can be produced.

  The sugar-branched cyclodextrin derivative will be described. For coupling reactions with various cyclodextrins in which the benzyl group at the 6-position of cyclodextrin obtained by reductive treatment of perbenzyl-α, β, or γ-cyclodextrin is converted to a hydroxyl group, dimethylformamide Among them, a hydroxyl group alkylation reaction using an alkali reagent such as potassium hydroxide is utilized. Glycosides with iodinated spacer ends are not particularly limited with respect to these cyclodextrins, but are preferably used in an amount of 2 to 5 equivalents. In addition, an alkaline reagent such as potassium hydroxide can be used in an amount of 10 to 1000 times, preferably 20 to 200 times that of a glycoside in which the end of the spacer is iodinated. In this alkylation reaction, it goes without saying that a well-known Williamson ether synthesis method using sodium hydroxide or sodium hydride in dimethylformamide or tetrahydrofuran can be used.

  Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to the following examples.

[Example 1]
(Step 1) Spacer synthesis
2- (4-Hydroxyphenyl) ethyl alcohol (5.0 g / 36.1 mmol) was placed in an eggplant flask, methanol (30.0 mL) was added, and 0.5 M aqueous sodium hydroxide solution (72.0 mL / 36.1 mmol) was added. After 1 hour, the residue was evaporated under reduced pressure, and N, N-dimethylformamide (50.0 mL) and allyl bromide (3.7 mL / 43.4 mmol) were added. After 3 hours, N, N-dimethylformamide was removed by distillation under reduced pressure, and purification was performed by flash column chromatography (developing solvent ratio hexane: ethyl acetate = 2: 1) to obtain 2- (4-allyloxyphenyl) ethyl alcohol. (5.5 g) was obtained with oil in 98% yield.

  Meanwhile, 2-chloroethanol (12.01 g / 0.15 mol) and 3,4-dihydro-2H-pyran (16.3 mL / 0.18 mol) were dissolved in dichloromethane (3.5 mL), and p-toluenesulfonic acid (42.0 mg / 0.22) was dissolved. mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour and a half under an argon gas atmosphere. After stopping the reaction with an aqueous sodium hydrogen carbonate solution (5.0 ml), the organic layer was extracted with dichloromethane and an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. Purification was performed by flash column chromatography (developing solvent ratio hexane: ethyl acetate = 6: 1), and 2-chloroethyltetrahydropyran-2-yl ether (22.6 g) was obtained in an oil yield of 92%.

  Then 2- (4-allyloxyphenyl) ethyl alcohol (513.6 mg / 2.88 mmol) was dissolved in N, N-dimethylformamide (10.0 mL) and sodium hydride (600 mg / 25.0 mmol) was added at 0 ° C. Stir for 1 hour. Thereafter, 2-chloroethyltetrahydropyran-2-yl ether (1.14 g / 6.92 mmol) was dissolved in N, N-dimethylformamide (5.0 mL) and added. After 118 hours, the organic layer was extracted with dichloromethane and brine and dried over anhydrous sodium sulfate.

Purification by flash column chromatography (developing solvent ratio hexane: ethyl acetate = 4: 1), 2- {2-O- [2- (4-allyloxyphenyl) ethyl] ethoxy} -tetrahydropyran (546.2 mg) Was obtained as an oil in 62% yield, and 2- {2-O- [2- (4-allyloxyphenyl) ethyl] ethoxy} -tetrahydropyran (501.2 mg / 1.64 mmol) was added to tetrahydrofuran (11.0 mL). Dissolved, 1N hydrochloric acid (6.0 mL) was added, and the mixture was stirred for 1.5 hr. The organic layer was extracted with dichloromethane and brine and dried over anhydrous sodium sulfate. Purified by thin layer chromatography (developing solvent ratio chloroform: methanol = 20: 1), 1-hydroxy-3-oxa-5- (4-allyloxyphenyl) pentane (342.0 mg) was obtained in 94% yield, oil Was obtained.
¹ H NMR (150 MHz, CDCl ₃ ): δ 35.30 (C-4), 61.72 (C-1 or 2 or 3), 68.80 (C-5), 71.79 (C-1 or 2 or 3), 72.22 ( C-1 or 2 or 3), 114.67 (Ph), 117.52 (C-7), 129.72 (Ph), 130.97 (Ph), 133.38 (C-6), 157.11 (Ph).

(Step 2) Synthesis of glycoside Pentaacetyl-β-D-galactose (150.2 mg / 0.38 mmol) and 1-hydroxy-3-oxa-5- (4-allyloxyphenyl) pentane (114.8 mg / 0.52 mmol) Dissolved in propiononitrile (3.0 mL), boron trifluoride diethyl ether complex (97.0 μL / 0.77 mmol) was added in an argon gas atmosphere at 0 ° C., and the mixture was stirred for 20 hours. The reaction was stopped with an aqueous sodium hydrogen carbonate solution (5.0 mL), and then the organic layer was extracted with ethyl acetate and an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. Purified by thin layer chromatography (developing solvent ratio chloroform: methanol = 20: 1), 2,3,4,6-tetra-O-acetyl-1-O- [3-oxa-5- (4-allyl) Oxyphenyl) pentyl] -β-D-galactopyranoside (139.1 mg) was obtained in an oil yield of 65%.

Next, 2,3,4,6-tetra-O-acetyl-1-O- [3-oxa-5- (4-allyloxyphenyl) pentyl] -β-D-galactopyranoside (132.6 mg / 0.24 mmol) was dissolved in methanol (5.0 mL), sodium methoxide (0.2 mL) was added, and the mixture was stirred for 2 hours. Methanol was removed under reduced pressure, and the residue was dissolved in N, N-dimethylformamide (10.0 mL). Sodium hydride (183.0 mg / 7.63 mmol) was added at 0 ° C., and the mixture was stirred for 30 minutes. Then benzyl bromide (239.0 μL / 2.01 mmol) was added. After 24 hours at room temperature, the organic layer was extracted with ethyl acetate and brine and dried over anhydrous sodium sulfate.
Purification by thin layer chromatography (developing solvent ratio hexane: ethyl acetate = 3: 1), 2,3,4,6-tetra-O-benzyl-1-O- [3-oxa-5- (4- Allyloxyphenyl) pentyl] -β-D-galactopyranoside (260.6 mg) was obtained in 84% yield as an oil.
In addition, 2,3,4,6-tetra-O-benzyl-1-O- [3-oxa-5- (4-allyloxyphenyl) pentyl] -β-D-galactopyranoside (293.8 mg / 0.39 mmol) was dissolved in tetrahydrofuran (2.0 mL), 9-borabicyclo- [3.3.1] -nonane 0.5 M tetrahydrofuran solution (4.7 mL / 2.35 mmol) was added in an argon gas atmosphere at 0 ° C., and the mixture was stirred for 6 hours. Then, 30% hydrogen peroxide solution (447.0 μL / 3.90 mmol) and 0.5 M aqueous sodium hydroxide solution (2.4 mL / 1.17 mmol) were added at room temperature, stirred for 13 hours, and the organic layer was washed with ethyl acetate and brine. Extracted and dried over anhydrous sodium sulfate. Purification was performed by thin layer chromatography (developing solvent ratio hexane: ethyl acetate = 1: 1), and 2,3,4,6-tetra-O-benzyl-1-O- {3-oxa-5- [4- (3-Hydroxypropyloxy) phenyl] pentyl} -β-D-galactopyranoside (290.2 mg) was obtained in an oil yield of 96%.
Then 2,3,4,6-tetra-O-benzyl-1-O- {3-oxa-5- [4- (3-hydroxypropyloxy) phenyl] pentyl} -β-D-galactopyranoside (207.7 mg / 0.27 mmol), triphenylphosphine (298.0 mg / 1.14 mmol), and iodine (290.3 mg / 1.14 mmol) are dissolved in N, N-dimethylformamide (6.0 mL), and 70 ° C under argon gas atmosphere Stir for 24 hours. Thereafter, the organic layer was extracted with ethyl acetate and brine and dried over anhydrous sodium sulfate. Purification was performed by thin layer chromatography (developing solvent ratio hexane: ethyl acetate = 2: 1), and 2,3,4,6-tetra-O-benzyl-1-O- {3-oxa-5- [4- (3-iodoxypropyloxy) phenyl] pentyl} -β-D-galactopyranoside (177.3 mg) was obtained as an oil in 75% yield.
¹ H NMR (150 MHz, CDCl ₃ ): δ 2.57 (C-8 ').

(Step 3) Synthesis of cyclodextrin derivative [2]
2,3,4,6-tetra-O-benzyl-1-O- {3-oxa-5- [4- (3-iodoxypropyloxy) phenyl] pentyl} -β-D-galactopyranoside ( 152.2 mg / 0.17 mmol) and heptakis- (2,3-di-O-benzyl) -6 ^B , 6 ^C , 6 ^E , 6 ^F , 6 ^G -penta-O-benzyl-β-cyclodextrin (131.8 mg /0.046 mmol) into an eggplant flask, N, N-dimethylformamide (7.0 mL) is added, and potassium hydroxide (316.5 mg / 5.64 mmol) and tetra-n-butyl-ammonium iodide (1.8 mg / 0.006 mmol) was added, a calcium chloride tube was attached, and the mixture was stirred at room temperature for 2 days. The organic layer was extracted with ethyl acetate and brine and dried over anhydrous sodium sulfate. Purified by thin layer chromatography (developing solvent ratio hexane: ethyl acetate: methanol = 6: 1: 0.5), heptakis (2,3-di-O-benzyl) -6 ^B , 6 ^C , 6 ^E , 6 ^F , 6 ^G -penta-O-benzyl-6 ^A or 6 ^D -mono-O- {3- [4- (2,3,4,6-tetra-O-benzyl-β-D-galactopyranose-1- Ile-1,4-dioxa-hexane-6-yl) phenyloxy] propyl} -β-cyclodextrin (86.4 mg) was obtained in an oil yield of 52%.
Further, heptakis (2,3-di-O-benzyl) -6 ^B , 6 ^C , 6 ^E , 6 ^F , 6 ^G -penta-O-benzyl-6 ^A or 6 ^D -mono-O- {3- [ 4- (2,3,4,6-Tetra-O-benzyl-β-D-galactopyranose-1-yl-1,4-dioxa-hexane-6-yl) phenyloxy] propyl} -β-cyclodextrin (72.5 mg / 0.020 mmol) is placed in a bifurcated eggplant flask, and further palladium hydroxide (104.9 mg / 0.67 mmol) is added and dissolved in N, N-dimethylformamide (15 mL). Hydrogenation with was carried out for 24 hours. The reaction was traced by TLC, and further solvent was added as necessary. Palladium hydroxide was removed by pleat filtration, further filtered through a membrane filter, and lyophilized. Next, it was purified by gel filtration (LH-20) and freeze-dried. As a result, 6-mono-O- {3- [4- (β-D-galactopyranose-1-yl-1,4-dioxa- Hexane-6-yl) phenyloxy] propyl} -β-cyclodextrin [2] (27.7 mg) was obtained as white crystals in a yield of 90%.
MALDI-TOF MS; Found: m / z [M + Na] ⁺ 1541.8: Calcd for [M + Na] ⁺ 1541.5.

[Example 2]
(Synthesis of cyclodextrin derivative [3])
Heptakis (2,3-di-O-benzyl) -6 ^B , 6 ^C , 6 ^E , 6 ^F , 6 ^G -penta-O-benzyl-6 ^A simultaneously under the conditions of Example 1 (Step 3) , 6 ^D -Bis-O- {3- [4- (2,3,4,6-tetra-O-benzyl-β-D-galactopyranose-1-yl-1,4-dioxa-hexane-6- Yl) phenyloxy] propyl} -β-cyclodextrin (18.1 mg) was obtained in 9% yield as an oil. Furthermore, heptakis (2,3-di-O-benzyl) -6 ^B , 6 ^C , 6 ^E , 6 ^F , 6 ^G -penta-O-benzyl-6 ^A , 6 ^D -bis-O- {3- [ 4- (2,3,4,6-Tetra-O-benzyl-β-D-galactopyranose-1-yl-1,4-dioxa-hexane-6-yl) phenyloxy] propyl} -β-cyclodextrin (16.1 mg / 0.0037 mmol) is placed in a bifurcated eggplant flask, further palladium hydroxide (26.3 mg / 0.17 mmol) is added, dissolved in N, N-dimethylformamide (8.0 mL), and stirred at room temperature with a hydrogen generator. Hydrogenation with was carried out for 24 hours. The reaction was traced by TLC, and further solvent was added as necessary. Palladium hydroxide was removed by pleat filtration, further filtered through a membrane filter, and lyophilized. Next, it was purified by gel filtration (LH-20) and freeze-dried. As a result, 6 ^A , 6 ^D -bis-O- {3- [4- (β-D-galactopyranose-1-yl-1, 4-Dioxa-hexane-6-yl) phenyloxy] propyl} -β-cyclodextrin [3] (5.9 mg) was obtained as white crystals in a yield of 83%.
MALDI-TOF MS; Found: m / z [M + Na] ⁺ 1926.3: Calcd for [M + Na] ⁺ 1925.7.

[Example 3]
(Step 1) Spacer synthesis
1-Hydroxy-3-oxa-5- (4-allyloxyphenyl) pentane (623.6 mg / 2.81 mmol) is dissolved in N, N-dimethylformamide (10.0 mL) and sodium hydride (325.0 mg / 13.54 mmol) Was added at 0 ° C. and stirred for 1 hour. Thereafter, 2-chloroethyltetrahydropyran-2-yl ether (561.9 mg / 3.41 mmol) was dissolved in N, N-dimethylformamide (1.0 mL) and added. After 19 hours, the organic layer was extracted with dichloromethane and brine and dried over anhydrous sodium sulfate. Purification was performed by flash column chromatography (developing solvent ratio hexane: ethyl acetate = 5: 1), and 2- [9- (4-allyloxy) phenyl-4,7-dioxa-nonyloxy] -tetrahydropyran (84.7 mg) was obtained. Yield 9%, obtained with oil.
Then 2- [9- (4-allyloxy) phenyl-4,7-dioxa-nonyloxy] -tetrahydropyran (59.0 mg / 0.17 mmol) was dissolved in tetrahydrofuran (4.0 mL), and 1N hydrochloric acid (1.0 mL) was dissolved. The mixture was further stirred for 1.5 hours. The organic layer was extracted with ethyl acetate and aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. Purified by thin layer chromatography (developing solvent ratio chloroform: methanol = 20: 1), 1-hydroxy-3,6-dioxa-8- (4-allyloxyphenyl) octane (41.3 mg) yield 93% Obtained with oil.

¹ H NMR (150 MHz, CDCl ₃ ): δ 35.30 (C-6), 61.84 (C-1 or 2 or 3 or 4 or 5), 68.85 (C-7), 70.33 (C-1 or 2 or 3 or 4 or 5), 70.42 (C-1 or 2 or 3 or 4 or 5), 72.47 (C-1 or 2 or 3 or 4 or 5), 72.56 (C-1 or 2 or 3 or 4 or 5) , 114.67 (Ph), 117.54 (C-9), 129.80 (Ph), 130.96 (Ph), 133.42 (C-8), 157.13 (Ph).

(Step 2) Synthesis of glycoside Pentaacetyl-β-D-galactose (463.5 mg / 1.18 mmol) and 1-hydroxy-3,6-dioxa-8- (4-allyloxyphenyl) octane (379.4 mg / 1.42 mmol) ) Was dissolved in propiononitrile (6.0 mL), boron trifluoride diethyl ether complex (298.0 μL / 2.37 mmol) was added at 0 ° C. under an argon gas atmosphere, and the mixture was stirred for 14 hours. The reaction was stopped with an aqueous sodium hydrogen carbonate solution (5.0 mL), and then the organic layer was extracted with ethyl acetate and an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. Purification was performed by flash column chromatography (developing solvent ratio hexane: ethyl acetate: allyl alcohol = 12: 1: 1), and 2,3,4,6-tetra-O-acetyl-1-O- [3,6- Dioxa-8- (4-allyloxyphenyl) octyl] -β-D-galactopyranoside (458.4 mg) was obtained in an oil yield of 65%.
Next, 2,3,4,6-tetra-O-acetyl-1-O- [3,6-dioxa-8- (4-allyloxyphenyl) octyl] -β-D-galactopyranoside (106.8 mg / 0.18 mmol) was dissolved in methanol (5.0 mL), sodium methoxide (0.2 mL) was added, and the mixture was stirred for 2 hours. Methanol was removed under reduced pressure, then dissolved in N, N-dimethylformamide (8.0 mL), sodium hydride (73.1 mg / 3.05 mmol) was added at 0 ° C., and the mixture was stirred for 30 min. Then benzyl bromide (102.2 μL / 0.86 mmol) was added. After 24 hours at room temperature, the organic layer was extracted with ethyl acetate and brine and dried over anhydrous sodium sulfate. Purification was performed by thin layer chromatography (developing solvent ratio hexane: ethyl acetate = 2: 1), and 2,3,4,6-tetra-O-benzyl-1-O- [3,6-dioxa-8- ( 4-Allyloxyphenyl) octyl] -β-D-galactopyranoside (115.82 mg) was obtained in 82% yield as an oil.
In addition, 2,3,4,6-tetra-O-benzyl-1-O- [3,6-dioxa-8- (4-allyloxyphenyl) octyl] -β-D-galactopyranoside (89.4 mg /0.11 mmol) was dissolved in tetrahydrofuran (2.0 mL), and 9-borabicyclo- [3.3.1] -nonane 0.5 M tetrahydrofuran solution (1.6 mL / 0.67 mmol) was added and stirred for 5 hours in an argon gas atmosphere at 0 ° C. Then, 30% hydrogen peroxide (128.5 μL / 1.13 mmol) and 0.5 M aqueous sodium hydroxide solution (600 μL / 0.33 mmol) were added at room temperature and stirred for 18 hours. The organic layer was washed with ethyl acetate and brine. Extracted and dried over anhydrous sodium sulfate.
Purified by thin layer chromatography (developing solvent ratio hexane: ethyl acetate = 1: 1), 2,3,4,6-tetra-O-benzyl-1-O- {3,5-dioxa-7- [ 4- (3-Hydroxypropyloxy) phenyl] heptyl} -β-D-galactopyranoside (75.3 mg) was obtained as an oil in 82% yield.
Subsequently, 2,3,4,6-tetra-O-benzyl-1-O- {3,5-dioxa-7- [4- (3-hydroxypropyloxy) phenyl] heptyl} -β-D-galacto Pyranoside (59.9 mg / 0.074 mmol), triphenylphosphine (104.1 mg / 0.40 mmol), and iodine (93.3 mg / 0.37 mmol) were dissolved in N, N-dimethylformamide (4.0 mL). Thereafter, the organic layer was extracted with ethyl acetate and brine and dried over anhydrous sodium sulfate. Purified by thin layer chromatography (developing solvent ratio hexane: ethyl acetate = 1: 1), 2,3,4,6-tetra-O-benzyl-1-O- {3,5-dioxa-7- [ 4- (3-iodoxypropyloxy) phenyl] heptyl} -β-D-galactopyranoside (46.3 mg) was obtained in 68% yield as an oil.
¹ H NMR (150 MHz, CDCl ₃ ): δ 2.59 (C-10 ').

(Step 3) Synthesis of cyclodextrin derivative [4]
2,3,4,6-Tetra-O-benzyl-1-O- {3,5-dioxa-7- [4- (3-iodoxypropyloxy) phenyl] heptyl} -β-D-galactopyr Noside (11.2 mg / 0.012 mmol) and heptakis- (2,3-di-O-benzyl) -6 ^B , 6 ^C , 6 ^E , 6 ^F , 6 ^G -penta-O-benzyl-β-cyclodextrin (9.1 mg / 0.032 mmol) is added to an eggplant flask, N, N-dimethylformamide (2.5 mL) is added, and potassium hydroxide (22.1 mg / 0.39 mmol) and tetra-n-butyl-ammonium iodide ( 0.3 mg / 0.00081 mmol) was added, a calcium chloride tube was attached, and the mixture was stirred at room temperature for 2 days. The organic layer was extracted with ethyl acetate and brine and dried over anhydrous sodium sulfate. Purified by thin layer chromatography (developing solvent ratio hexane: ethyl acetate = 3: 2), heptakis (2,3-di-O-benzyl) -6 ^B , 6 ^C , 6 ^E , 6 ^F , 6 ^G- Penta-O-benzyl-6 ^A or 6 ^D -mono-O- {3- [4- (2,3,4,6-tetra-O-benzyl-β-D-galactopyranose-1-yl-1, 4,7-Trioxa-nonan-9-yl) phenyloxy] propyl} -β-cyclodextrin (8.4 mg) was obtained in 72% yield as an oil.
Next, heptakis (2,3-di-O-benzyl) -6 ^B , 6 ^C , 6 ^E , 6 ^F , 6 ^G -penta-O-benzyl-6 ^A or 6 ^D -mono-O- {3- [4- (2,3,4,6-Tetra-O-benzyl-β-D-galactopyranose-1-yl-1,4,7-trioxa-nonane-9-yl) phenyloxy] propyl} -β -Cyclodextrin (8.4 mg / 0.0023 mmol) is placed in a bifurcated eggplant flask, further palladium hydroxide (16.2 mg / 0.10 mmol) is added and dissolved in N, N-dimethylformamide (6.0 mL), and stirred at room temperature. Hydrogenation with a hydrogen generator was performed for 2 days. The reaction was traced by TLC, and further solvent was added as necessary. Palladium hydroxide was removed by pleat filtration, further filtered through a membrane filter, and lyophilized. Next, it was purified by gel filtration (LH-20) and freeze-dried. As a result, 6-mono-O- {3- [4- (β-D-galactopyranose-1-yl-1,4,7- Trioxa-nonan-9-yl) phenyloxy] propyl} -β-cyclodextrin [4] (2.9 mg) was obtained in 81% yield as white crystals.
MALDI-TOF MS; Found: m / z [M + Na] ⁺ 1587.0: Calcd for [M + Na] ⁺ 1585.6

  It is useful as a drug carrier for targeted drug delivery systems.

Claims (6)

A sugar-branched cyclodextrin derivative represented by the following formula [1].

N is an integer from 1 to 5, m is an integer from 1 to 5, R is glucose, mannose, galactose, N-acetyl-glucosamine, glucosamine, fucose, N-acetylneuraminic acid bonded by a glycosidic bond, or Disaccharides or trisaccharides composed of glucose, mannose, galactose, N-acetyl-glucosamine, glucosamine, fucose and N-acetylneuraminic acid. ) A sugar-branched cyclodextrin derivative represented by the following formula [2].

A sugar-branched cyclodextrin derivative represented by the following formula [3].

A sugar-branched cyclodextrin derivative represented by the following formula [4].

  The sugar-branched cyclo of any one of claims 1 to 4, wherein 2- (4-hydroxyphenyl) ethyl alcohol and 2-chloroethanol are used as a raw material as a spacer for binding a cyclodextrin and a sugar molecule. A method for producing dextrin derivatives. Heptakis- (2,3-di-O-benzyl) -6 ^B , 6 ^C , 6 ^E , 6 ^F , 6 ^G -penta-O-benzyl-β-cyclodextrin is used as a raw material 5. A method for producing a sugar-branched cyclodextrin derivative according to any one of 1 to 4.