JPH05140202A - Cyclic oligosaccharide and its production and intermediate thereof - Google Patents

Abstract

PURPOSE:To provide a new cyclic oligosaccharide having a specified molecular structure and obtained by imparting a new function to cyclodextrin. CONSTITUTION:A cyclic oligosaccharide of formula I (wherein Rs which are independent of each other are hydrogen or alkyl; and (n) is an integer of 0-4) or formula II (wherein Rs which are independent of each other are hydrogen or alkyl; and (n) is an integer of 0-4). This oligosaccharide is obtained by converting a maltooligosaccharide thioglycoside of formula III (wherein Rs which are independent of each other are hydrogen or alkyl; R' is alkyl or aryl; and (n) is an integer of 0-4), as a starting material, into a 1,2-unsaturated derivative and cyclizing this derivative by intramolecular glycosylation by using iodine cations as an accelerator.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a cyclic oligosaccharide, a method for producing the same, and a synthetic intermediate useful for producing the cyclic oligosaccharide.

[0002]

2. Description of the Related Art Cyclodextrin (hereinafter referred to as CD)
Is a cyclic oligosaccharide having an inclusion function and is used in the fields of cosmetics, foods, pharmaceutical preparations, and the like. In particular,
Since being used for the formulation of prostaglandin, it has been widely used at home and abroad as an inclusion complex or an additive, mainly for orally administered formulations.

In recent years, direct chemical conversion of CD has been attempted in order to introduce a new function into the CD.

[0004]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
Is a multifunctional cyclic molecule, so its application was limited. Therefore, an object of the present invention is to provide a novel cyclic oligosaccharide having a new function introduced into CD.

Another object of the present invention is to provide a method for producing the cyclic oligosaccharide and a synthetic intermediate useful for producing the cyclic oligosaccharide.

[0006]

DISCLOSURE OF THE INVENTION The present inventors
It has succeeded in preparing a maltooligosaccharide derivative having a degree of polymerization of 6 to 8 by treating a CD derivative in which all or part of the hydroxyl groups of the class are protected with acetic anhydride or an acetic anhydride derivative in the presence of an acid. (See JP-A-2-235898).

Using the thus obtained chain oligosaccharide as a starting material, a novel cyclic oligosaccharide which cannot be produced by direct chemical modification of CD was successfully produced, and the present invention was completed. That is, the present invention provides a cyclic oligosaccharide represented by the following formulas (I) and (II), a method for producing the same, and the following formula (I
The present invention provides a cyclic oligosaccharide synthetic intermediate represented by V) and (V).

[0008]

[Chemical 8]

(In the formula, each R independently represents a hydrogen atom or an alkyl group, and n represents an integer of 0 to 4)

[0010]

[Chemical 9]

(In the formula, each R independently represents a hydrogen atom or an alkyl group, and n represents an integer of 0 to 4)

[0012]

[Chemical 10]

(In the formula, each R independently represents a hydrogen atom or an alkyl group, and n represents an integer of 0 to 4)

[0014]

[Chemical 11]

(Wherein each R independently represents a hydrogen atom or an alkyl group, and n represents an integer of 0 to 4) In the above formulas (I), (II), (IV), and (V) R
Are each independently a hydrogen atom or an alkyl group, and the alkyl group has 1 to 1 carbon atoms such as a methyl group and an ethyl group.
There may be mentioned 10 linear or branched alkyl groups. Further, this alkyl group may have a substituent such as a phenyl group and a vinyl group. Of these, a methyl group and a benzyl group are preferable.

In the above formulas (I), (II), (IV) and (V), n represents an integer of 0 to 4, of which 1 to
3 is preferable. The cyclic oligosaccharide represented by the above formula (I) or (II) is a malto-oligosaccharide thioglycoside represented by the following formula (III) as a starting material, and is converted into a 1,2-unsaturated derivative, followed by iodine cation. Is used as a promoter to carry out an intramolecular glycosylation reaction to cyclize the compound.

[0017]

[Chemical 12]

In the formula (III), R and n are as described above, and R'represents an alkyl group or an aryl group. The alkyl group has 1 to 10 carbon atoms such as methyl group and ethyl group.
The straight chain or branched alkyl group can be mentioned. Further, the alkyl group may have a substituent such as a phenyl group. Examples of the aryl group include phenyl group, nitrophenyl group, halogenated phenyl group and the like. Of these, a methyl group, an ethyl group and a phenyl group are preferable.

The maltooligosaccharide thioglycoside represented by the formula (III) is represented by N. Sakairi, LX. Wang, and H. Kuzuhara, J. Ch.
It can be produced by the method described in em.Soc., Chem. Commun., 289 (1991). The maltooligosaccharide thioglycoside represented by the formula (III) produced as described above is 1 to 10 ° C. under an inert gas atmosphere at −100 ° C. to 0 ° C.
It is converted to a 1,2-unsaturated derivative represented by the formula (V) by reacting naphthalene with an alkali metal such as lithium or sodium for 24 hours. The above reaction is carried out in an ether solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane.

An iodinated maltooligosaccharide derivative represented by the formula (IV) is produced by cyclizing the above 1,2-unsaturated derivative by an intramolecular glycosylation reaction using iodine cation as a promoter. .. Examples of the ion source of iodine cations include iodonium dicoridine perchlorate and N-iodosuccinimide.
The reaction is carried out at -50 ° C to 50 ° C for 1 to 4 hours in an aprotic solvent such as dichloromethane, chloroform or acetonitrile, preferably dichloromethane.

Further, the iodomalto-oligosaccharide derivative represented by the formula (IV) is deiodinated as described below and converted into the cyclic oligosaccharide represented by the formula (I). That is, using a tin hydride compound such as triphenyltin hydride and tributyltin hydride in a non-polar solvent such as benzene, toluene and xylene at room temperature to 1
The reaction is carried out at 00 ° C for 1 to 10 hours.

The iodomalto-oligosaccharide derivative represented by the formula (IV) is converted into the cyclic oligosaccharide represented by the formula (II) as follows. That is, potassium t- in a solvent such as tetrahydrofuran that dissolves the raw material and the reagent.
A base such as butoxide, sodium methoxide, and 1,8-diazabicyclo [5.4.0] undec-7-ene is used and reacted at -50 ° C to 100 ° C for 1 to 10 hours.

Hereinafter, typical reaction examples for producing the cyclic oligosaccharide of the present invention are shown in the schemes, but the present invention is not limited to the following reaction schemes. In the scheme, R,
R'and n are as defined above. One compound in the scheme is, for example, N. Sakairi, LX.Wang, and H.
It can be obtained by the method described in Kuzuhara, J. Chem. Soc., Chem. Commun., 289 (1991).

[0024]

[Chemical 13]

[0025]

[Chemical 14]

[0026]

[Chemical 15]

In the above reaction scheme, reagents and reaction conditions which can be preferably used are described below. 1. 1 → 2 solvent: diethyl ether, tetrahydrofuran, 1,4
-Ethyl solvent such as dioxane Temperature: -100 to 0 ° C Time: 1 to 24 hours Reagent: Naphthalene and alkali metal such as lithium and sodium 2. 2 → 3 solvent: aprotic solvent such as dichloromethane, chloroform, acetonitrile temperature: −50 to 50 ° C. time: 1 to 4 hours reagent: iodonium dicoridine perchlorate, iodocation equivalent such as N-iodosuccinimide 3. 3 → 4 Solvent: non-polar solvent such as benzene, toluene, xylene Temperature: room temperature to 100 ° C. Time: 1 to 10 hours Reagent: triphenyltin hydride, tributyltin hydride and other tin hydride compounds 4. 3 → 5 Solvent: There is no particular limitation as long as it dissolves the raw material such as tetrahydrofuran and the reagent Temperature: -50 to 100 ° C Time: 1 to 10 hours Reagent: Potassium t-butoxide, sodium methoxide, 1,8-diazabicyclo [5.4.0] Undecay
Furthermore, the substituents R of the compounds 4 and 5 can be substituted by a conventional method, for example, in Green's literature (TWGreen "Protective Groups i
n Organic Synthesis "John Wiley and Sons (1991) pp.9-
It can be converted into hydrogen by the method described in 86).

[0028]

EXAMPLE A preferred embodiment of the present invention will be described below with reference to an example.
Aspects will be described in detail. The scope of the invention is
It is not limited. The compounds in the examples1a
Is N.Sakairi, L-X.Wang, and H.Kuzuhara, J.Chem.Soc.,
According to the method described in Chem. Commun., 289 (1991), α-cycline
Rodextrin was synthesized as a starting material.

In the examples, Bn represents a benzyl group and Ph represents a phenyl group. [Example 1]

[0030]

[Chemical 16]

1,5-anhydro-3,6-di-O-be
And 4--4-O- (2¹, 2², 2 ³, 2^Four, 2^Five, 3
¹, 3², 3³, 3^Four, 3^Five, 6¹, 6², 6³，
6^Four, 6 ^Five-Pentadeca-O-benzyl-α-maltope
Ntaosyl) -2-deoxy-arabino-hex-2-
Enitol (compound2a) Production of phenyl 2¹, 2², 2³, 2^Four, 2^Five, 2⁶, 3¹，
Three², 3³, 3^Four, 3 ^Five, 3⁶, 6¹, 6², 6³, 6
^Four, 6^Five, 6⁶-Octadeca-O-benzyl-1-thio
-Β-maltohexaside (compound1a2.33 g, 0.
86 mmol) was dissolved in tetrahydrofuran (20 ml),
It cooled at -80 degreeC under argon atmosphere. Lithiate with this solution
Um (69 mg), naphthalene (1.28 g), and tet
Dark green solution prepared from lahydrofuran (8 ml) is green
The solution was added dropwise until it disappeared. Add a small amount of acetic acid
After stopping the reaction, warm the reaction mixture to room temperature and
Extracted with rum. The extract was saturated with sodium hydrogen carbonate.
The extract was washed with saturated saline solution and dried over anhydrous potassium carbonate.
The syrup obtained by distilling off the solvent under reduced pressure was washed with silica gel.
Rum chromatography (toluene-ethyl acetate 24:
1-19: 1) purified compound2a(1.54 g, yield
72%).

[0032] ^{_{[α] D 22 + 71 °}} (c 0.39, chloroform) IR: νmax ^{(film) 1640,3500cm -1 1 H-NMR:} δ 2.54 (s, 1H, OH), 5.38 (d, 1H, J 3.
7Hz, H-1), 5.60 (d, 1H, J 4.0Hz, H-1), 5.62 (d, 1H,
J 4.0Hz, H-1), 5.64 (d, 1H, J 3.9Hz, H-1), 5.68
(d, 1H, J 3.7Hz, H-1), 6.50 (d, 1H, J 6.1Hz, H-
1 ¹ ).

Elemental analysis: measured value; C, 73.62; H, 6.4
9. _{C 155 H 162 O 29 · 2H} 2 O Calculated: C, 73.73; H,
6.62. [Example 2]

[0034]

[Chemical 17]

Cyclo {→ 4) -O-3,6-di-O-benzyl-2-deoxy-2-iodo-α-D-mannopyranosyl)-[(1 → 4) -O- (2,3,3 6-tri-
O-benzyl-α-D-glucopyranosyl)]-(1
-} (Compound 3a ) Preparation of Compound 2a (0.205 g, 0.082 mmol) and Molecular Sieves 4A (1.2
g) was suspended in dichloromethane (10 ml) under an argon atmosphere and cooled to 0 ° C. A dichloromethane solution (0.2 ml) of iodonium dilolidine perchlorate (70 mg, 0.15 mmol) was added dropwise to this mixture, and stirring was continued at 0 ° C. for 3.5 hours. The reaction mixture was filtered, washed with dichloromethane, and then washed successively with aqueous sodium thiosulfate solution, 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained syrup was separated by silica gel column chromatography (toluene-ethyl acetate 35: 1) to obtain compound 3a (0.106 mg, yield 48%).

[0036] ^{_{[α] D 21 + 41 °}} (c 0.10, ^{chloroform) 1 H-NMR: δ (} C 6 D 6); 3.28-3.31 (m, 1H, H-2 1),
3.43 (dd, 1H, J 2.9, 8.3Hz, H-2), 3.50 (dd, 1H, J
3.2, 7.9Hz, H-2), 3.52 (dd, 1H, J 3.2, 7.9Hz, H-2)
, 3.55 (dd, 1H, J 2.9, 7.9Hz, H-2), 3.57 (dd, 1H,
J 2.9, 8.3Hz, H-2), 4.97 (d, 1H, J 3.2Hz, H-1),
5.17 (d, 1H, J 2.9Hz, H-1), 5.20 (d, 1H, J 2.9Hz, H
-1), 5.27 (d, 1H, J 2.9Hz, H-1), 5.40 (d, 1H, J 3.
2Hz, H-1), 5.58 (s, 1H, H-1 ¹ ).

Elemental analysis: measured value; C, 71.08; H, 6.23
I, 5.06. Calculated as C ₁₅₅ H ₁₆₁ O ₂₉ I: C, 71.20
; H, 6.21; I, 4.85. [Example 3]

[0038]

[Chemical 18]

Cyclo {→ 4) -O- (3,6-di-O-
Benzyl-2-deoxy-α-D-arabinohexopyranosyl) -pentakis [(1 → 4) -O- (2,3,6)
-Tri-O-benzyl-α-D-glucopyranosyl)]
Preparation of- (1-} (Compound 4a ) Compound 3a (0.25g) and azobisisobutyronitrile (30mg) were dissolved in toluene (10ml) and the reaction vessel was purged with argon. Triphenyltin hydride (0.1 ml) was added with heating and stirring, and the mixture was stirred at the same temperature for 5 minutes, chloroform (10 ml) was added to the reaction solution, and after cooling to room temperature, the solvent was distilled off under reduced pressure. Purification by compounding thin layer chromatography (benzene-ethyl acetate 97: 3) gave compound 4a (16
0 mg, yield 68%) was obtained.

[Α] _D ²² + 61 ° (c 0.12, chloroform) ¹ H-NMR: δ (C ₆ D ₆ ); 1.71 (ddd, 1H, J 2.8, 8.
2, 11.2Hz, H-2 ¹ ax), 2.19 (dt, 1H, J 3.0, 11.2H
z, H-2 ¹ eq). Elemental analysis: measured value; C, 72.89; H, 6.69. C ₁₅₅ H ₁₆₂ O
₂₉ · 4H ₂ O Calculated: C, 72.98; H, 6.43 .

Solubility in water (25 ° C.): 17 g / dL [Example 4]

[0042]

[Chemical 19]

Preparation of 2-deoxy-cyclomaltohexaose (Compound 6a ) Compound 4a (120 mg) was added to 2-methoxyethanol (9).
ml), water (1 ml) and 10% palladium carbon (50 mg) were added, and the mixture was shaken under a hydrogen atmosphere at atmospheric pressure for 12 hours, further water (4 ml) was added and shaken for 12 hours. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to Sephadex G-25 column chromatography (developing solvent:
White powdery compound 6a (40 mg, yield 87)
%) Was obtained.

[Α]_D ^{twenty four}+ 143 ° (c 0.21, water)¹ H-NMR: δ (D₂O); 1.65 (dt, 1H, J 2.1, 11.6
Hz, H-2¹ax), 2.26 (ddd, 1H, J 1.5, 4.5, 11.6H
z, H-2¹eq), 3.43 (t, 1H, J 9.5Hz, H-4¹), 3.51 (bt,
5H, J 8.6 Hz, H-4², Four³, Four^Four, Four^Five, Four⁶), 3.57 (bt, 5H,
J 9.8 Hz, H-2², 2³, 2^Four, 2^Five, 2⁶), 3.65-3.75 (m, 18H,
 3 × H-5, 6a, 6b), 3.89 (bt, 5H, J 9.5Hz, H-3², 3³,
3^Four, 3^Five, 3⁶), 4.10 (m, 1H, H-3¹), 5.00 (bs, 5H, H-
1², 1³, 1 ^Four, 1^Five, 1⁶), 5.06 (bs, 1H, H-1¹).

Elemental analysis: measured value; C, 42.89; H, 6.2
6. _{C 36 H 60 O 29 · 3H} 2 O Calculated: C, 42.77; H,
6.58. [Example 5]

[0046]

[Chemical 20]

Cyclo {→ 4) -O- (3,6-di-O-
Benzyl-2-deoxy-α-D-erythrohexo-2
-Enopyranosyl) -pentakis [(1 → 4) -O-
Preparation of (2,3,6-tri-O-benzyl-α-D-glucopyranosyl)]-(1-} (Compound 5a ) Compound 3a (100 mg) was added to tetrahydrofuran (2 ml).
, Potassium t-butoxide (30 mg) was added, and the mixture was stirred at room temperature for 2 hours. It was diluted with dichloromethane, washed with an aqueous solution of ammonium chloride and water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained syrup was subjected to silica gel column chromatography (toluene-
Compound 5a (83 mg, purified with ethyl acetate 96: 4)
Yield 87%) was obtained.

[Α]_D ^{twenty four}+ 77 ° (c 0.24, chloro
Holm)¹ H-NMR: δ (C₆D₆); 4.76 (d, 1H, J 11.8Hz,CH
₂Ph), 4.81 (d, 1H, J4.1Hz. H-2), 4.87 (d, 1H, J 11.
0Hz,CH ₂Ph), 4.99 (m, 2H, H-1,CH ₂Ph), 5.10 (m, 2H,
 H-1,CH ₂Ph), 5.15 (d, 1H, J 2.5Hz, H-1), 5.24 (m,
 2H, H-1,CH ₂Ph), 5.37 (d, 1H, J 11.2Hz,CH ₂Ph),
5.50 (d, 1H, J 11.2Hz, CH₂Ph), 5.57 (d, 1H, J 3.0Hz,
 H-1), 5.67 (d, 1H, J 3.9Hz, H-1¹).

Elemental analysis: measured value; C, 74.64; H, 6.2
Five. Calculated for C ₁₅₅ H ₁₆₀ O ₂₉ : C, 74.86; H, 6.49.

[0050]

INDUSTRIAL APPLICABILITY The cyclic oligosaccharide of the present invention has an inclusion function and is excellent in solubility in water, alcohol and the like, and thus is expected to be used as a solubilizer for injections. Further, the cyclic oligosaccharide of the present invention affects the surface structure of a biological membrane, improves absorption into mucous membranes, and improves percutaneous absorption, so that the nose, oral cavity, rectum, ocular lung, etc. It is expected to be used for formulation of a mucosal site administration agent.

Claims (5)

[Claims] 1. A cyclic oligosaccharide represented by the following formula (I): [Chemical 1] (In the formula, each R independently represents a hydrogen atom or an alkyl group, and n represents an integer of 0 to 4) 2. A cyclic oligosaccharide represented by the following formula (II). [Chemical 2] (In the formula, each R independently represents a hydrogen atom or an alkyl group, and n represents an integer of 0 to 4) 3. A maltooligosaccharide thioglycoside represented by the following formula (III) is used as a starting material, which is converted to a 1,2-unsaturated derivative and then subjected to an intramolecular glycosylation reaction using an iodine cation as a promoter to cyclize. A method for producing a cyclic oligosaccharide represented by the following formula (I) or the following formula (II): [Chemical 3] (In the formula, each R independently represents a hydrogen atom or an alkyl group, R'represents an alkyl group or an aryl group, and n is 0 to
Indicates an integer of 4) (In the formula, each R independently represents a hydrogen atom or an alkyl group, and n represents an integer of 0 to 4) (In the formula, each R independently represents a hydrogen atom or an alkyl group, and n represents an integer of 0 to 4) 4. A synthetic intermediate of a cyclic oligosaccharide represented by the following formula (IV). [Chemical 6] (In the formula, each R independently represents a hydrogen atom or an alkyl group, and n represents an integer of 0 to 4) 5. A synthetic intermediate of a cyclic oligosaccharide represented by the following formula (V): [Chemical 7] (In the formula, each R independently represents a hydrogen atom or an alkyl group, and n represents an integer of 0 to 4)