JPH07252289A - Production of glycoside compound - Google Patents

Abstract

PURPOSE:To efficiently obtain a glycoside compound in high yield by using a stable thioglycoside as saccharide donor. CONSTITUTION:This glycoside compound is obtained by reaction of a thioglycoside derivative with an alcohol selected from aliphatic alcohols, aromatic alcohols, steroid alcohols, glycerol derivatives, saccharide derivatives and amino acid derivatives in the presence of iodine and a perchlorate.

Description

Detailed Description of the Invention

[0001]

SUMMARY OF THE INVENTION The present invention relates to a method for producing a novel glycoside compound. Specifically, it is characterized by reacting a thioglycoside derivative with an alcohol selected from aliphatic alcohols, aromatic alcohols, steroid alcohols, glycerol derivatives, sugar derivatives and amino acid derivatives in the presence of iodine and perchlorate. The present invention relates to a method for producing a glycoside compound.

[0002]

[Industrial application] Glycoside compounds are antibiotics,
As an anti-cancer drug and the like, attention has been focused on the use of medicines, agricultural chemicals, etc., but recently it has been revealed that they are closely related to cell adhesion and differentiation, and their development is expected as a new medicine.

[0003]

BACKGROUND OF THE INVENTION Because of the use of unstable intermediates in their synthesis, industrially superior methods are limited. The method known for a long time is to react a halogeno sugar with an alcohol, but it is difficult to industrialize due to many drawbacks such as poor stability of the starting halogeno sugar and the need for highly dehydrated reaction conditions.

[0004]

The glycosylation reaction using a thioglycoside derivative is already known as a method for solving these problems. However, the activator is expensive and difficult to handle. As a result of intensive studies in view of the above circumstances, the present inventors have arrived at a novel thioglycoside activation method, that is, the present invention.

[0005]

That is, the gist of the present invention is that thioglycoside and an alcohol selected from aliphatic alcohols, aromatic alcohols, steroid alcohols, glycerol derivatives, sugar derivatives, and amino acid derivatives, iodine and perchlorate are used. It is a method for producing a glycoside compound, which is characterized by allowing them to coexist and react.

[0006]

The present invention will be described in detail below.

First, a well-known derivative can be used for thioglycoside, which is one of the raw materials of the present invention. The cyclic structure of the sugar used may be a 5-membered ring or a 6-membered ring. Usually aldose is used, but ketose can also be used. Specifically, as these sugars, erythrose, tetraose such as threose, ribose, arabinose, pentose such as xylose, glucose, mannose, galactose, allose, hexose such as talose, or 2-deoxyglucose. , 2-deoxyribose and other sugars in which some of these sugars are deoxygenated, amino sugars such as 2-acetamido-2-deoxyglucose, and further, these sugars are ether-bonded to each other, such as lactose. Examples thereof include oligosaccharides, sialic acid and glucuronic acid. Further, these sugars have D-form and L-form, but any of them or a mixture can be used. In addition, as thioglycoside, alkyl thioglycoside such as methyl thioglycoside and ethyl thioglycoside, and aromatic thioglycoside such as phenyl thioglycoside are known, but there is no limitation by the substituent of such thioglycoside.

Needless to say, these sugars can be used with all hydroxyl groups other than the anomeric position protected, but derivatives having a free hydroxyl group protected to the minimum necessary for solubility etc. may be used.

As the protective group for the hydroxyl group, conventionally known ones can be used. Specifically, a method of protecting with an acyl group such as acetyl, trifluoroacetyl, trichloroacetyl, benzoyl, p-nitrobenzoyl group, a method of acetalizing with acetaldehyde, acetone, etc., a methyl, benzyl, triphenylmethyl group, etc. Examples thereof include a method of etherification with an alkyl group, a method of silylation with a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group and the like.

Well-known alcohols can be used as the alcohol to be reacted. As the well-known alcohol, a compound having a hydroxyl group such as an aliphatic alcohol, an aromatic alcohol, a steroid alcohol, a glycerol derivative, a sugar derivative and an amino acid derivative can be used.

As the aliphatic alcohol, methanol,
Examples thereof include ethanol, propanol, isopropanol, cetyl alcohol, butanol, ethylene glycol and propylene glycol. Of course, cycloaliphatic alcohols such as cyclohexanol, methylcyclohexanol and menthol can also be used.

As the aromatic alcohol, phenol,
Examples thereof include p-chlorophenol, o-chlorophenol, 2,4-dinitrophenol, p-cresol, o-cresol, α-naphthol, β-naphthol, catechol, resorcinol and hydroquinone.

Examples of steroid alcohols include cholesterol, cholestanol, stigmasterol, estrone, estradiol, testosterone, androsterone and the like.

Examples of glycerol derivatives include glycerin and its monoacyl and diacyl derivatives. Here, as the acyl group, acetyl, benzoyl,
Examples thereof include palmityl, stearyl, and oleyl groups, and in the diacyl form, the same or different acyl groups can be used without any problem. Some of these derivatives have stereoisomers, but it goes without saying that any of them or a mixture thereof can be used. In addition, a derivative in which some hydroxyl groups are converted into other functional groups is also included in these categories. For example, a sphingosine derivative, ceramide, etc. can be mentioned.

Well-known sugars can be used as the sugar derivative. That is, although the above-mentioned sugars can be used, they need not necessarily be cyclic, and chain sugar derivatives can also be used.
Although sugar has many hydroxyl groups, it is desirable to protect all hydroxyl groups that do not participate in the reaction by the above-mentioned method, but in consideration of reactivity etc., the use of protecting groups should be minimized to the minimum necessary. Is also possible.

Examples of amino acid derivatives include serine, threonine, hydroxyproline, hydroxylysine and tyrosine. These amino acids include D
There are body and L body, but it goes without saying that any of them or a mixture can be used. Further, amino alcohols derived from various amino acids and peptide derivatives can be used. In using these, it is natural that a derivative in which an amino group, a carboxyl group or other functional group is protected by a conventional method can be used.

Next, the activator will be described. As the activator, iodine and perchlorate are used together.

Well-known salts can be used as perchlorates. Specific examples thereof include silver perchlorate, lithium perchlorate, and trityl perchlorate. Especially, trityl perchlorate is effective.

As the solvent, a solvent other than alcohol can be used. That is, benzene, toluene, chloroform, dichloromethane, dichloroethane, carbon tetrachloride,
Examples thereof include ethyl acetate, ether, tetrahydrofuran, dimethylformamide, acetonitrile, propionitrile, nitromethane and the like.

The reaction temperature is also not particularly limited. However, it is usually in the range of -80 ° C to the boiling point of the solvent. Also,
Considering operability and the like, the range of -10 ° C to room temperature is preferable.

The equivalent relationship between the thioglycoside derivative used, the alcohol and the activator is not particularly limited. For example, it is possible to use the glycosyl donor or alcohol in excess, but it is also possible to use both in equal amounts. On the other hand, the activator usually uses 0.01 to several equivalents of perchlorate and iodine, respectively, depending on its type. Preferably perchlorate 0.1-1.5 equivalents, iodine 0.5-
It is in the range of 1.5 equivalents.

Although the reaction time varies depending on the structures of sugar and alcohol to be reacted, it is usually in the range of several minutes to several tens hours.

[0023]

INDUSTRIAL APPLICABILITY The method for producing a glycoside compound according to the present invention has the advantage of using a thioglycoside derivative having a stable glycosyl donor and using a relatively inexpensive and easy-to-use reagent as an activator. And its industrial value is great.

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the following examples as long as the gist thereof is not exceeded.

[0025]

Example 1 Methyl 2,3,4,6-tetra-O-benzyl-1-thio-D-glucopyranoside 49.9 mg (0.09 m
mol) and 3β-cholestanol 33.4 mg (0.09 mmol) in 20 ml
The mixture was placed in an eggplant-shaped flask and dissolved with 2 ml of toluene, then about 150 mg of molecular sieves 4A was added, and then 30.0 mg (0.09 mmol) of trityl perchlorate was added. 0.87 ml of 0.1 M iodine / toluene solution was added dropwise thereto by a syringe, and the mixture was stirred overnight. Stop the reaction with a 5% aqueous sodium thiosulfate solution,
Water and ethyl acetate were added and the layers were separated. It is processed by a conventional method,
When purified by silica gel thin layer chromatography,
56.3 mg of the corresponding 3β-cholestanyl glucopyranoside
(71%) was obtained.

[0026]

Example 2 When a reaction exactly the same as in Example 1 was carried out in benzene, the yield was 72%.

[0027]

Example 3 A reaction exactly the same as in Example 1 was carried out in dichloroethane, and the yield was 72%.

[0028]

Example 4 When 8.8 mg of cyclohexanol was used in place of the 3β-cholestanol of Example 1, the same procedure was carried out to find that the target cyclohexylglucopyranoside was 54.2%.
Obtained mg (99%).

[0029]

Example 5 Methyl 2,3,4-tri-O-as in Example 4
Benzyl-α-D-glucopyranoside, methyl 2,3,6-tri-
O-benzyl-α-D-glucopyranoside, 1,6-anhydro-
3,4-O-isopropylidene-β-D-galactopyranose, 1,
2: 3,4-Di-O-isopropylidene-α-D-galactopyranose was reacted using 1 equivalent each. As a result, the yields were 62%, 34%, 40%, 66%.

[0030]

Example 6 Phenyl 2,3,4,6-tetra-O-
Benzyl-1-thio-D-glucopyranoside 49.9 mg (0.0
8 mmol), 3β-cholestanol 30.7 mg (0.08 mmol) and trityl perchlorate 27.1 mg (0.08 mmol) are dissolved in dichloroethane 2 ml, and 0.1M iodine / dichloroethane solution 0.75 ml
Was added. Thereafter, when the same treatment as in Example 1 was performed, 3
42.2 mg (58%) of β-cholestanyl glucopyranoside was obtained.

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Claims (2)

[Claims] 1. A reaction between a thioglycoside derivative and an alcohol selected from aliphatic alcohols, aromatic alcohols, steroid alcohols, glycerol derivatives, sugar derivatives and amino acid derivatives in the presence of iodine and perchlorate. A method for producing a characteristic glycoside compound. 2. The production method according to claim 1, wherein trityl perchlorate is used as the perchlorate.