JPH0615043B2 - Acid catalyst for saccharide modification - Google Patents

Description

TECHNICAL FIELD The present invention relates to a saccharide-modifying acid catalyst.

Conventional technology and its problems Various monosaccharides or their condensates, polysaccharides and oligosaccharides, are well known to play important roles in information transmission in the living body, and their mechanism of action is well known. It has been desired to artificially produce various kinds of sugar derivatives in order to clarify the above.

Therefore, there is an urgent need to establish a glycosylation reaction in which the position of glycoside bond forming a condensation can be freely selected and the reaction process is simple. Various methods have been conventionally proposed for the glycosylation reaction. For example O-
Glucosidation Koenigs-
According to the Knorr method, a glycoside is produced by reacting an acetohalogenated sugar obtained by acylating and halogenating the sugar with an alcohol in the presence of an acid scavenger. According to the Helferich method, a glycoside is produced by acylating a sugar and then reacting it with an alcohol in the presence of a catalyst such as ZnCl ₂ or P-toluenesulfonic acid. However, in the König-Knorr method, the reaction is multi-step, the acetohalogenated sugar is unstable and easily decomposed, and Ag ₂ O, HgO, Hg (CN) ₂ , and CdCO are used as acid scavengers.
There are drawbacks such as the need to use equimolar amounts of heavy metals such as _{3 and the} like, and in the Helferreich method, decomposition of the sugar moiety occurs (sugar chains are cleaved when two or more sugars are used as a raw material), coloring etc. There are drawbacks, and the yields of the target products are all very low. S as a method of modifying many sugars
-Glycosidation, acetalization, etherification other than the above, esterification, ether exchange, transesterification, etc. have been proposed to synthesize sugar derivatives. However, the disadvantage that the sugar moiety is decomposed when two or more sugars are used for S-glycosidation, and the sugar chain is cleaved when two or more sugars are used for etherification, ether exchange, and transesterification other than the above. However, the esterification has drawbacks such that by-products resulting from cleavage of the sugar ring or sugar chain are produced, and none of these methods is satisfactory because the yield of the desired product is low.

As described above, the production of sugar derivatives is more difficult than the production of other organic compounds. It is also due to the physicochemical property that the solubility of sugar or sugar derivative in organic solvents is low,
It is caused by the catalyst used for production, 1) sugar chain is cleaved, 2) sugar ring is decomposed, 3) it is very difficult to specify the position of the substituent, and in order to specify it, multistep reaction is required. The main causes are chemical properties such as 4) difficulty in stereospecific reaction, 5) many side reactions, and easy browning reaction peculiar to sugar reaction.

Means for Solving Problems As a result of intensive studies conducted by the present inventors in view of the problems of the prior art, a specific heteropoly acid that has not been used as a catalyst in the production of sugar derivatives up to the present. By using 1), it is possible to solve the problems of the conventional glycosylation reaction, 2) to obtain the target sugar derivative with high selectivity and high yield, and 3) to simplify the reaction. Found and completed the present invention.

That is, the present invention has the general formula H _n XM ₁₂ O ₄₀ · mH ₂ O (1) [wherein, X represents P, As, Si or Ge. M is Mo
Or W. n represents 2 or 3 (however, when X is P or As, n = 3, and when X is Si or Ge, n =
4). m shows the integer of 0-30. ] And the formula _{H 6 Y 2 M 18 O 62} · mH 2 O (2) wherein, Y represents P or As, M and m are as defined above. ] The present invention relates to an acid catalyst for saccharide modification, which comprises at least one selected from the heteropoly acids represented by

As the heteropoly acid used for modifying the saccharide in the present invention, a known heteropoly acid represented by the above general formula (1) or (2) can be used. Specific examples of the heteropoly acid include phosphotungstic acid (in the above general formula,
X or Y = P, M = W), phosphomolybdic acid (X or Y = P, M = Mo in the above general formula), silicotungstic acid (X = Si, M = in the above general formula)
W) silicomolybdic acid (in the above general formula, X = S
i, M = Mo), arsenic tungstic acid (X or Y = As, M = W in the above general formula), arsenic molybdic acid (X or Y = As, M = M in the above general formula)
o), germanotungstic acid (in the above general formula,
X = Ge, M = W), germano-molybdic acid (X = Ge, M = Mo in the above general formula), and the like.

Of the above-exemplified heteropolyacids, those having a Keggin structure are particularly preferable in view of stability as a catalyst, and examples thereof include 12-tungstophosphoric acid and 12-tungstophosphoric acid.
-Molybdophosphoric acid, 12-tungstosilicic acid, 12-molybdosilicic acid, etc. can be mentioned.

These heteropolyacids can be used alone or in admixture of two or more, and can be used as an insoluble catalyst by supporting them on silica gel, alumina or the like. Furthermore, these heteropolyacids can be used in combination with conventionally used catalysts.

In the present invention, various saccharides can be used as the saccharides to be modified with the heteropoly acid as a catalyst. Representative examples of monosaccharides include hexasaccharides such as glucose, mannose, galactose, glucosamine, mannosamine, lactosamine sugar, and pentasaccharides such as arabinose, xylose, and ribose. Representative examples of oligosaccharides include sucrose, lactose, trehalose, maltose, cellobiose, isomaltose, gentiobiose, laminaribiose, chitobiose, xylobiose, mannobiose, sophorose, maltotriose, maltotetraose, starch, cellulose and the like. Hydrolyzate etc. can be mentioned. Further, typical examples of the polysaccharides include chitin, chitosan, starch, cellulose and the like. Further, derivatives of the above-mentioned monosaccharides, oligosaccharides and polysaccharides such as sugar esters and glycosides can be mentioned. Heteropoly acid is easily reduced by a saccharide having a reducing terminal, and if the heteropoly acid is used as it is for modification of the reducing saccharide, its catalytic ability is lost. However, the inventor
As a result of further research, it was found that by introducing a protecting group into the reducing terminal of the saccharide in advance, the heteropoly acid exerts excellent catalytic ability even for modification of the reducing saccharide. The introduction of the protecting group can be carried out by a conventionally known appropriate method (for example, a method of acetylating glucose with acetic anhydride and sodium acetate, a method of boiling glucose in methanol containing hydrochloric acid gas, etc.). It is carried out by introducing a protecting group such as an acyl group or an alkyl group at the terminal.

In the present invention, the saccharide modification includes a reaction for converting a sugar substituent to synthesize a sugar derivative, for example, a substitution reaction, an oxidation reaction,
It includes elimination reaction and the like. Specifically, O-glycosidation, S-glycosidation, acetalization, etherification reaction such as etherification other than the above, esterification reaction, ether exchange, exchange reaction such as transesterification, N-glycosidation reaction, oxidation Reactions, elimination reactions and the like are included.

O-glycosidation includes, for example, a saccharide acylated by a conventionally known method and a general formula R ₁ —OH [wherein R ₁ represents a group —C _x H _2x-y O _z (in the formula, x, Both y and z are integers, and x ≧ 3, y
≧ −1 and z ≧ 0. ). ] It is performed by reacting an alcohol represented by the following formula or a saccharide having one or more unprotected OH groups in the presence of a heteropolyacid. By this reaction, a glycoside in which the 1-position hydroxyl group of the sugar ring is substituted with R ₁ O can be obtained. Specific examples of the alcohols include saturated alcohols such as n-butanol and eicosanol, unsaturated alcohols such as allyl alcohol and oleyl alcohol, secondary alcohols such as 2-octanol, sterols such as cholesterol, and benzyl alcohol. Examples thereof include alcohols having an aromatic ring, such as phenol, and saccharides.

S-glycosidation is, for example, a mercaptan represented by a saccharide acylated by a conventionally known method and a general formula R ₂ -SH (wherein R ₂ represents an alkyl group, a phenyl group, or an aryl group). And are reacted in the presence of a heteropoly acid. By this reaction, a glycoside in which the 1-position hydroxyl group of the sugar ring is substituted with R ₂ S can be obtained. Specific examples of the mercaptans include methyl mercaptan, ethyl mercaptan, propyl mercaptan, isopropyl mercaptan, n-butyl mercaptan, allyl mercaptan, lauryl mercaptan, benzyl mercaptan and phenyl mercaptan. The acetalization is carried out, for example, by reacting an unprotected hydroxyl group of sugar with an aldehyde or a ketone in the presence of a heteropolyacid. A cyclic ether can be obtained by this reaction. Specific examples of the aldehydes include:
Formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, valeraldehyde, pivalinaldehyde, capronaldehyde, heptaldehyde, caprylaldehyde, caprinaldehyde, laurinaldehyde, myristinaldehyde, palmitinaldehyde, stearaldehyde, benzaldehyde, salicylaldehyde, cinnamaldehyde, naphthaldehyde Aldehydes and the like can be mentioned. Specific examples of the ketones include acetone, methyl ethyl ketone, methyl propyl ketone, isopropyl methyl ketone, butyl methyl ketone, diethyl ketone, diisopropyl ketone, methyl vinyl ketone, mesityl oxide, acetophenone, propiophenone, butyrophenone, benzophenone, diketone. Examples thereof include benzyl ketone.

For etherification other than the above, for example, a hydroxyl group other than a hemiacetal of a saccharide is reacted with an alcohol represented by the general formula R ₁ —OH (wherein R ₁ is the same as above) in the presence of a heteropolyacid. It is carried out by This reaction gives an ether.

The esterification can be carried out, for example, by using a hydroxyl group of a sugar and a general formula R ₃ -C.
It is carried out by reacting with a carboxylic acid represented by OOH (wherein R ₃ represents an alkyl group or an aryl group) in the presence of a heteropoly acid. This reaction produces an ester bond. Specific examples of the carboxylic acids include formic acid, acetic acid, propionic acid, isobutyric acid, valeric acid, pivalic acid, lauric acid, myristic acid, palmitic acid, stearic acid, benzoic acid, toluic acid, hydroatropic acid, atropic acid, silicic acid. Examples thereof include cinnamic acid.

For the transesterification, for example, a sugar ester represented by the general formula R ₃ —COO-G (wherein R ₃ is the same as above, G represents a sugar skeleton) and a general formula R ₄ —COOH (wherein R ₃ is the same). ₄ represents an alkyl group or an aryl group) and is reacted in the presence of a heteropolyacid. By this reaction, the sugar ester R
₃ COO- is replaced with R ₄ COO-. As the carboxylic acids, the same carboxylic acids as those represented by the above formula R ₃ COOH can be used.

The ether exchange can be carried out, for example, by the general formula R ₃ —O—G (wherein
R ₃ and G are the same as above. ) And the alcohols represented by the general formula R ₁ —OH (wherein R ₁ is the same as above) in the presence of a heteropolyacid. By this reaction, R ₃ —O— of glycosides is replaced with R ₁ —O—.

The oxidation reaction is carried out, for example, by oxidizing the hemiacetal saccharide in the presence of a heteropolyacid. By this reaction, a carboxyl group is generated in the hemiacetal part of the saccharide.

Heteropoly acid exerts a remarkable catalytic effect in any of the above reactions, whereby an alkyl glycoside, an aromatic glycoside, an oligosaccharide, a sugar ester, a sugar derivative such as a partially oxidized sugar can be easily and highly yielded. Can be manufactured.

In order to carry out O-glycosidation in the present invention, a type acylated by a conventionally known method and an alcohol represented by the general formula R ₁ —OH (wherein R ₁ is the same as above) are used without a solvent. Or melted in a suitable solvent and added with about 0.1 to 5.0% by weight of heteropolyacid,
The reaction may be performed at about 180 ° C. for about 1 to 24 hours.
The reaction pressure can be appropriately selected within the range of atmospheric pressure to reduced pressure of 1 mmHg, and the anomeric ratio of the obtained sugar derivative can be arbitrarily selected by changing the pressure or the kind of the heteropolyacid. Examples of the suitable solvent include hexane, heptane, octane, saturated hydrocarbons such as ISOPER (trade name, manufactured by Esso Petroleum Co., Ltd.), aromatic hydrocarbons such as toluene, xylene, mesitylene, ethylbenzene and laurylbenzene, Examples include ketones such as acetone, diethyl ketone, and methyl isobutyl ketone, esters such as ethyl acetate, butyl acetate, ethyl butyrate, and ethers such as diethyl ether, isopropyl ether, ethylene glycol dibutyl ether, and diethylene glycol dibutyl ether. . When a lower alcohol is used, it is preferable that 1) the above reaction is carried out at a low temperature, 2) the amount of catalyst is increased, or 3) the lower alcohol is introduced into another derivative before the reaction.

In the present invention, the same reaction conditions as above (amount of heteropolyacid used, solvent used, reaction temperature, reaction time and reaction pressure) are also applied when reactions other than the above O-glycosidation are carried out.
Can be adopted.

The sugar derivative thus produced is isolated and purified from the reaction mixture by a conventionally known purification means.

EFFECT OF THE INVENTION The catalyst of the present invention has the following excellent effects.

(1) When the catalyst of the present invention is used for O-glycosidation, an alkyl glucoside having about 1 to 20 carbon atoms can be produced, decomposition of the sugar moiety is extremely small, control of the anomer ratio is easy, and coloring (browning reaction) occurs. Almost none. Since the catalyst of the present invention does not cleave sugar rings and sugar chains, two or more sugars can be used when S-glycosidation, etherification other than the above, ether exchange, and transesterification are performed. When the catalyst of the present invention is used for acetalization, the amount of the catalyst can be about 1/50 of the amount of the conventional catalyst used.

(2) Since the stereospecific reaction is easy and side reactions do not occur, the target sugar derivative can be obtained with high selectivity and high yield.

(3) Since the position of the substituent is easily specified, the reaction process can be simplified.

EXAMPLES The present invention will be further clarified by giving Examples and Comparative Examples below.

Example 1 (Synthesis of Alkyl Glucoside) 39 g (0.1 mol) of pentaacetyl glucose, 20 ml (0.12 mol) of octyl alcohol and toluene 7
0.4 g of phosphomolybdic acid was added to 0 ml, and the mixture was heated to 85 ° C. with stirring and reacted for 4 hours. The reaction solution was diluted with ethyl acetate, washed with water, and the organic layer was concentrated to obtain 62 g of brown oil. This was subjected to silica gel column chromatography, and eluted with toluene-ethyl acetate (4: 1) for purification to obtain 32 g (yield about 70%) of tetraacetyloctyl glucoside, which was a target substance.

Comparative Example 1 Pentaacetyl glucose 39 g (0.1 mol), octyl alcohol 20 ml (0.12 mol) and toluene 7
0.4 g of p-toluenesulfonic acid was added to 0 ml, and the mixture was heated to 85 ° C. with stirring and reacted for 4 hours. The reaction solution was cooled, diluted with ethyl acetate, washed with water, and the organic layer was concentrated to obtain 62 g of a brown oil. This oil contains 7 g of tetraacetyloctyl glycoside
(Yield 11%) was contained, but most of them were compounds in which the raw sugar was browned, and even if purified in the same manner as in Example 1, 5 g of tetraacetyloctylglycoside, which was the target product, Only a rate of 7.9 g) was obtained.

Example 2 (Synthesis of alkyl glucoside) 32 g (0.1 mol) of tetraacetyl xylose, 20 ml (0.12 mol) of octyl alcohol and toluene 7
0.3 g of phosphomolybdic acid was added to 0 ml, and the mixture was heated to 85 ° C. with stirring and reacted for 3 hours. Thereafter, in the same manner as in Example 1, 32 g (yield: 82%) of the target product, triacetyloctyl xyloside, was obtained as a pale yellow oily substance.

Comparative Example 2 p-toluenesulfonic acid was replaced with phosphomolybdic acid.
When the reaction was carried out in the same manner as in Example 2 except that 3 g was used, about 30 mol% of the raw sugar was converted to triacetyloctylxyloside, but a large amount of unreacted sugar and sugar decomposition products were produced. It remained, and it was difficult to isolate the target triacetyloctyl xyloside.

Example 3 (Synthesis of Aromatic Alkyl Glucoside) To 39.0 g (0.10 mol) of pentaacetyl glucose, 11.3 g (0.12 mol) of phenol and 0.5 g of phosphomolybdic acid were added, and this mixture was mixed at 40 mmHg. The reaction was performed at 90 ° C. under reduced pressure for 3 hours. 100 ml of toluene was added to the reaction solution, and then 0 ° C.
After being washed twice with 0.5 M aqueous sodium hydroxide solution,
The organic layer was evaporated to dryness to obtain 41 g of a pale yellow solid. This solid was recrystallized from ethanol to give the desired product phenyl-2,3,4,6-tetra-o-acetyl-β-D.
-35.2 g (yield 83%) of glucopyranoside was obtained.
The melting point, specific optical rotation, IR, and NMR of the compound were in good agreement with the values obtained by the conventional method (Helferaich method) of Comparative Example 3 below.

Comparative Example 3 P-toluenesulfonic acid 3.9 was added to phenol 292 g.
g and β-pentaacetyl-D-glucose 300 g
Was added, and the mixture was heated in an oil bath with vigorous stirring for 1.5 hours to cause reaction. The crude product was recrystallized from ethanol by extraction with about 400 ml of benzene, and the target product, phenyl-2,3,3.
A solid containing 39 g of 4,6-tetra-o-acetyl-β-D-glucopyranoside (yield 42%) was obtained, but it was markedly colored. In order to obtain a crystal having a color tone similar to that of Example 3, a decoloring operation and a recrystallization operation with activated carbon were necessary, and the yield after performing these operations was 33 g (yield 36%). Met.

Melting point: 124 to 125 ° C., ▲ [α] ²¹ _D ▼ = -22 ° (Cl, CHCl ₃ ) Example 4 (Synthesis of aromatic alkyl glucoside) Pentaacetyl glucose 39.0 g (0.10 mol), phenol. 11.3 g (0.12 mol) and 0.5 g of silicotungstic acid were added, and the mixture was heated at 90 ° C. under a reduced pressure of 40 mmHg.
Was reacted for 3 hours. 100 ml of toluene was added to the reaction solution, which was then washed twice with a 0.5 M aqueous sodium hydroxide solution at 0 ° C., and the organic layer was evaporated to dryness to give a yellow oily substance 4
5 g was obtained. Add ethanol to this oily substance,
At room temperature for 24 hours, the precipitated crystals are collected, and the desired product phenyl-2,3,4,6-tetra-o-acetyl-
30.6 g (yield 72%) of α-D-glucopyranoside was obtained.

From the above Examples 3 and 4, it is understood that the anomeric ratio of the obtained sugar derivative changes depending on the kind of the heteropolyacid used.

Comparative Example 4 To 46 g of phenol, 12.5 g of zinc chloride and 50 g of β-pentaacetyl-D-glucose were added, and heated at 125 to 130 ° C. for 45 minutes under vigorous stirring. The resulting dark-colored acetic acid odor melt was dissolved in 300 ml of benzene, washed several times with sodium hydroxide and water, dried over calcium chloride, filtered over activated charcoal and evaporated to dryness. The obtained residue was recrystallized twice with anhydrous alcohol to obtain the desired product phenyl-2,3,4,6-tetra-o-acetyl-α-D-.
13.3 g (yield 25%) of glucopyranoside was obtained. Melting point: 114 to 115 ° C. Example 5 (exchange of aglycone) Tetraacetylmethyl glucoside 35 g (0.1 mol), octyl alcohol 20 ml (0.12)
Mol) and toluene 50 ml, phosphomolybdic acid 0.4
g was added, and the mixture was heated to 85 ° C. with stirring under reduced pressure of about 50 mmHg and reacted for 4 hours. The reaction solution was diluted with ethyl acetate, washed with water, and the organic layer was concentrated. The obtained residue was subjected to silica gel column chromatography and eluted with toluene-ethyl acetate for purification to obtain 30 g (yield 65%) of a target product, tetraacetyloctylglucoside, as a pale yellow oily substance.

Comparative Example 5 In place of phosphomolybdic acid, p-toluenesulfonic acid 0.
18 g of a brown oily matter containing 16.2 g (yield 36%) of tetraacetyloctylglycoside was obtained in the same manner as in Example 5 except that 4 g was used. This oily substance was decolorized by treatment with activated carbon to obtain 15.5 g (yield 34%) of tetraacetyloctylglycoside having a color tone similar to that of Example 5.

Example 6 34 g of octaacetyl maltose, 30 ml of lauryl alcohol and 70 ml of toluene, and 0.35 of phosphomolybdic acid.
g was added and reacted at 90 ° C. for 4 hours while stirring.
The reaction solution was diluted with ethyl acetate, washed with water, and the organic layer was concentrated. The obtained residue was purified by silica gel cam chromatography to obtain 25 g (yield 62%) of heptaacetyllauryl maltoside in the form of a pale yellow oil. Fractions other than the target product were mainly octaacetylmaltose as a raw material, and did not contain an acetylated product of lauryl glucoside which was a decomposition product.

Comparative Example 6 Instead of phosphomolybdic acid, p-toluenesulfonic acid 0.
2.1 g of oily heptaacetyllauryl maltoside (yield 5.0%) was obtained in the same manner as in Example 6 except that 34 g was used. A brown oily substance containing 5.0 g of an acetylated product of lauryl glucoside from the other fractions.
2 g was obtained.

From Example 6 and Comparative Example 6, it can be seen that the heteropoly acid does not cleave the sugar chain.

Example 7 (Synthesis of thioglycoside) 39 g (0.1 mol) of pentaacetyl glucose, 40 g (0.2 mol) of laralyl mercaptan and toluene 5
0.4 g of phosphotungstic acid was added to 0 ml, and the mixture was reacted at 80 ° C. for 3 hours in a nitrogen atmosphere. The reaction solution was treated in the same manner as in Example 5 to obtain 47 g of tetraacetyllaurylthioglucoside (yield 88%).

Comparative Example 7 39 g (0.1 mol) of pentaacetylglycose, 40 (0.2 mol) of lauryl mercaptan and 50 ml of toluene saturated with hydrogen chloride gas were added to a nitrogen atmosphere at 80 ° C.
And reacted for 3 hours. The reaction mixture was treated in the same manner as in Example 5 to give tetraacetyllaurylthioglucoside 25.
1 g (yield 47%) was obtained.

Example 8 400 g of propylene glycol and 137 g of sucrose (0.
4 mol), methyl stearate 121.5 g (0.4 mol) and sucrose monostearate (20 g) at 130 ° C.
After heating for 1 hour, lower the temperature to 100 ℃ and 70mm
About 10% of propylene glycol was distilled off under reduced pressure of Hg.

To this, add 4.0 g of silicotungstic acid, and add 50 mm.
After reacting under reduced pressure of Hg, further reduce the pressure to 1 mmHg and
The reaction was carried out at 40 ° C for 30 minutes. The obtained pale yellow syrupy substance was dissolved in methanol and passed through an anion exchange resin column. The resulting solution was purified by silica gel column chromatography to give 142 g of sucrose monostearate.
(Yield 51%) was obtained.

Example 9 (oxidation reaction) 180 g (1 mol) of glucose was dissolved in 120 ml of water,
To this solution was added 2.0 g of silicomolybdic acid. This was heated to 60 ° C. and, while maintaining this temperature, it was stirred for 5 hours while blowing air. When 300 ml of ethanol was added to the reaction solution and the precipitated oily substance was purified, it contained 175 g of gluconic acid (yield 89%).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display area C07H 15/203

Claims (3)

[Claims] 1. A general formula H _n XM ₁₂ O ₄₀ .mH ₂ O [wherein X represents P, As, Si or Ge]. M is Mo
Or W. n represents 2 or 3 (however, when X is P or As, n = 3, and when X is Si or Ge, n =
4). m shows the integer of 0-30. ] And the formula _{H 6 Y 2 M 18 O 62} · mH in 2 O [wherein, Y represents P or As, M and m are as defined above. ] An acid catalyst for saccharide modification, which comprises at least one selected from the heteropolyacids represented by 2. The heteropoly acid is phosphotungstic acid, phosphomolybdic acid, silicotungstic acid, silicomolybdic acid, arsenic tungstic acid, arsenic molybdic acid, germanotungstic acid or germanomolybdic acid. The acid catalyst according to 1. 3. A saccharide-modified etherification reaction selected from O-glycosidation, S-glycosidation, acetalization, and etherification other than the above, esterification reaction, exchange reaction selected from ether exchange and transesterification. Alternatively, the acid catalyst according to claim 1, which is an oxidation reaction.