JPH0696583B2 - Aldose epilation method - Google Patents

Description

TECHNICAL FIELD The present invention relates to an aldose epimerization method and a method for producing an epimer using the same.

[Conventional technology]

In recent years, there has been growing interest in carbohydrates as a substance essential to the living body or in terms of use as a drug or a research reagent such as an antibiotic and an anti-cancer agent.

However, among these sugars, sugars that are highly necessary as raw materials are often rare in nature and are often difficult to obtain.

Therefore, there has been a long-felt need for a method of synthesizing useful rare sugars from naturally occurring sugars.

In response to this, in the old days, so-called epimerization, which converts aldose into a part of C-2 epimer via 1.2-enediol in a weak alkaline aqueous solution,
The reaction was known. However, this method has a problem that the epilation rate is low and ketose is also produced as a by-product.

Therefore, as a method for improving this, a method using molybdate has been proposed (Augew.chem.83 [23] 967).
(1971): Czechoslovak Patent No. 149051, etc.). This method is certainly carried out as a more advanced method without the byproduct of ketose, but it still has some problems to be improved.

[Problems to be solved by the invention]

That is, the method using molybdate has a high reaction temperature, a reaction time is too long, and the essential epimerization rate is not sufficient. Because there is a problem.

Therefore, in order to improve this, molybdic acid is fixed to an ion exchange resin or an ion exchange fiber (JP-A-51-14).
1807, JP-A-55-76894) A method of using a boric acid compound in combination (JP-A-60-81196, etc.) has been proposed, but unfortunately, a fundamental solution to the above problems. It can't be.

[Means for solving problems]

The present inventor, in view of such circumstances, the reaction conditions are mild, and as a result of earnest research on an epilation method having a high epilation rate and a high recovery rate, by using a nickel salt and a specific diamine,
The inventors have found that the object can be achieved and arrived at the present invention.

That is, the present invention is an aldose epimerization method characterized in that an aldose is heated and reacted in the presence of a complex formed from a nickel salt and N, N, N ', N'-tetramethylethylenediamine and / or both.

Further, in the presence of a complex formed from a nickel salt and N, N, N ', N'-tetramethylethylenediamine and / or both, aldose is heated and reacted to form an epi and then treated with a weakly acidic aqueous solution. And a method for producing an epimer of the aldose.

The present invention will be described in detail below.

The sugar used as the raw material for epilation in the present invention is aldose,
Aldohexose and aldopentose are particularly preferred. Among these, examples of aldohexose include D-glucose (abbreviated as D-Glc, and abbreviated hereinafter), D-mannose (D-Man) D-allose (D, All), D-altrose (D-Alt). , D-galactose (D-Gal), D
-Talose (D-Tal), D-Gulose (D-Gul), D
-Idose (D-Ido) can be mentioned.

Similarly, examples of aldopentoses include D-xylose (D-Xyl), D-lyxose (D-Lyx), D-arabitose (D-Ara), and D-ribose (D-Rib).

These aldoses are epimerized into the respective epimers by the method of the present invention. For example, D-Glc is D-Man and D-Ar
a becomes D-Rib.

The nickel salt used in the present invention forms a complex with a specific diamine which will be described later, and serves as a catalyst for epilation. Further, in the present invention, the metal salt and the diamine, which are the raw materials of the complex, may be added and the aldose may be added directly thereto (the present inventor named the latter method one pot method).

The nickel salt of the present invention is preferably a halide, particularly preferably nickel chloride, nickel bromide or nickel iodide.

On the other hand, the selection of the diamine is particularly important, and N, N, N ', N'-tetramethylethylenediamine (hereinafter abbreviated as tetmen) is used in the present invention.

The inventors' studies have revealed that the length of the methylene chain of this diamine plays an important role in its action and function.

In the one pot method, the amount ratio of Ni and diamine can be appropriately selected according to other conditions, but is usually preferably 1: 1 or more. In particular, when the ratio is 1: 2 to 1:10, there is an advantage that the epilation rate from D-Glc to D-Man is increased.

The above complex or Ni salt and diamine dissolve them,
It is preferable that the aldose is also used by dissolving it in a solvent that also dissolves. This solvent is water or lower alcohol, DM
F, DMSO and the like are used, but lower alcohols such as methanol and ethanol are particularly excellent.

The reaction temperature is set in the range of 30 to 100 ° C.

The reaction pressure is not particularly limited and may be normal pressure.

The reaction time is one of the features of the method of the present invention, but it may be 3 minutes to 30 minutes, which is extremely short as compared with the conventional method. Usually 5-10 minutes is sufficient.

In addition, although better results can be obtained by stirring during the reaction, this is not essential.

As described above, in the method of the present invention, the above metal salt and diamine are added to a solvent such as methanol, aldose is added, and the mixture is heated for 5 to 10 minutes with stirring to carry out the epilation reaction.

In order to take out the epimer after the epilation reaction, it is treated with a weakly acidic aqueous solution and then separated.

The treatment may be carried out under weak acidity (usually around pH 6.5) by adding water to the reaction solution as necessary and adding acids such as dilute hydrochloric acid and dilute sulfuric acid.

The reaction is preferably performed at room temperature or higher for about 10 minutes or more with stirring.

Although various known methods can be used for the separation operation, using a cation exchange resin and an anion exchange resin,
A method of removing the metal ion, complex ion, Cl ⁻ ion and the like and then taking out the desired epimer by concentration or the like is simple and preferable.

〔Example〕

 The present invention will be described below with reference to examples.

In addition, sugar analysis is performed by high performance liquid chromatography (hereinafter
HPLC), but specifically, a post-cam detection method using 2-cyanoacetamide as a color reagent (for details, see
S.Honda et al. Anal. Chem. 52.1079 (1982)) using a fluorescence detector.

Example 1 NiCl ₂ and N, N, N, N′-tetramethylethylenediamine were added to anhydrous n-butanol in a molar ratio of 1: 1 and heated to give a complex [NiCl ₂ (tetmun )] (G
melin.Ni [C], 181) 0.492 g (2 mmol) and D-Glc
0.360 g (2 mmol) was dissolved in 30 ml of methanol. This was reacted for 5 minutes while refluxing at 64 ° C. under normal pressure.

Immediately after the reaction, cool, add 30 ml of water, and add PH6 with diluted sulfuric acid.
The mixture was adjusted to 5 and stirred at room temperature for 30 minutes.

The reaction solution was deionized using a cation exchange resin Dowex 50W-X-2 and an anion exchange resin Dowex MSA-1.

The sugar in the obtained liquid was analyzed by HPLC, and as a result, 35% of the D-Glc added initially was epimeric, and the epimer DM
converted to an. No sugars other than D-Glc and D-Man were detected. The recovery rate (yield) of sugar to raw sugar is
It showed a high rate of 96%.

From these results, it can be seen that the present invention is an excellent method with high epilation rate, high selectivity and high recovery rate.

Examples 2 to 6 The procedure of Example 1 was repeated, except that the aldose was changed as shown in Table 1. The results are shown in Table 1. Similar to Example 1, good results are obtained.

Examples 7 and 8 The halogen of the complex was changed to Br or I, the aldosource was changed to D,
The same procedure as in Example 1 was carried out except that Xyl was used. The results are shown in Table 2.

Example 9 NiCl ₂ .6H ₂ O 0.475 g (2 mmol) and tetmen 0.465 g (4 mmol)
After dissolving and in 30 ml of methanol, 0.360 g of D-Glc (2 mm
ol) was added, and the mixture was heated under reflux at 64% under normal pressure for 5 minutes.

When treated with a weakly acidic aqueous solution, deionized and analyzed by HLPC in the same manner as in Example 1, the yield (recovery rate) of recovered aldose was 98% based on D-Glc as a raw material. The aldose production ratio is D-Glc: D-Man = 44: 56.
Met. Therefore, D-Glc conversion rate (epitification rate) 55
% Was high.

This method is the one pot method referred to by the present inventor.

Example 10 The procedure of Example 9 was repeated except that 0.360 g (2 mmol) of D-Man was used instead of D-Glc.

The result shows that the recovery rate of aldose for the raw material D-Man is 94%.
And the production ratio of aldose is D-Glc: D-Man = 44: 56.
(Epitification rate was 41%).

Example 11 Instead of methanol, the solvent was (a) ethanol (b) DM.
The same procedure as in Example 9 was repeated except that F was used instead.

The results are (a) for ethanol: aldose yield (recovery rate) 89%, epimer production ratio D-Glc: D-Man = 56: 44, and (b) for DMF: aldose yield (recovery rate). 88
%, The epimer production ratio was D-Glc: D-Man = 97: 3.

Examples 12 to 19 As shown in Table 3, the procedure of Example 9 was repeated except that the reaction temperature and the amounts of NiCl ₂ .6H ₂ O and tetmen, that is, the ratios of Ni and tetmen were changed.

The results are shown in Table 3.

Example 20 NiCl ₂ .6H ₂ O 0.475 g (2 mmol) and tetmen 0.465 g (4 mmo
l) was dissolved in 30 ml of methanol and then D-Glc 0.36
After dissolving 0 g (2 mmol), the mixture was reacted at 60 ° C. for 5 minutes.

Next, 30 ml of water was added to the reaction solution, and the pH was adjusted to 6.5 with diluted hydrochloric acid. This was treated at room temperature for 30 minutes with stirring.

From this reaction solution, using cation exchange resin Dowex 50WX-2 and anion exchange resin Dowex MSA-1, metal ions, Cl ⁻
Etc. were removed.

As a result of HPLC analysis of sugars in the liquid obtained by the above operation, the epimer formation ratio was D-Glc: D-Man = 48: 52, and sugars other than D-Man and the raw material D-Glc were found. Was not detected.

The sugar yield (recovery rate) with respect to the raw material D-Glc was 83%.

〔The invention's effect〕

The present invention has realized an epitaxy method that can be carried out under extremely mild conditions as compared with conventional methods such as the molybdic acid method, has a high epilation rate, and has no side reaction. Therefore, the utilization of the present invention makes it possible to convert rare sugars, which have been in high demand in recent years, from sugars that are abundant in nature, and it is expected that the utilization of sugars will further increase.

Claims (10)

[Claims] 1. An aldose epimerization method comprising reacting an aldose by heating in the presence of a complex formed from a nickel salt and N, N, N ', N'-tetramethylethylenediamine and / or both. 2. The method for epidifying aldose according to claim 1, wherein the nickel salt is selected from nickel chloride, nickel bromide and nickel iodide. 3. The aldose is aldpentose or aldhexose, and claim 1.
Aldose epitaxy method as described in the item. 4. The method for epidifying aldose according to claim 1, wherein the reaction is carried out in the presence of a lower alcohol solvent. 5. The method for epidifying aldose according to claim 1, wherein the heating reaction is carried out at 30 to 100 ° C. 6. An aldose is heated and reacted in the presence of a complex formed from a nickel salt and N, N, N ', N'-tetramethylethylenediamine and / or both, and then treated with a weakly acidic aqueous solution. A method for producing an epimer of the aldose, comprising: 7. The method for producing an epimer according to claim 6, wherein the nickel salt is selected from nickel chloride, nickel bromide and nickel iodide. 8. The method according to claim 6, wherein the aldose is aldpentose or aldhexose.
A method for producing the epimer according to the item. 9. The method for producing an epimer according to claim 6, wherein the reaction is carried out in the presence of a lower alcohol solvent. 10. The method for producing an epimer according to claim 6, wherein the heating reaction is carried out at 30 to 100 ° C.