JPH0551394A - Production of beta-phenylglycoside - Google Patents

Abstract

PURPOSE:To obtain the title compound for intermediate of a substrate for measuring alpha-amylase activity in good selectivity and high yield by reacting a peracyl derivative of glucose, etc., with a (substituted)phenol compound in the presence of an acetylacetone zinc salt, etc. CONSTITUTION:A peracyl derivative (e.g. penta-O-acetyl-beta-D-glucose) of glucose or maltooligosaccharide expressed by formula I (n is integer of 0-6; R is alkanoyl or benzoyl) is reacted with a substituted or unsubstituted phenol compound (e.g. 4-nitrophenol) in the presence of an acetylacetone zinc salt or carboxylic acid zinc salt (e.g. zinc naphthenate) and ethyl acetate is added to the resultant reaction product to wash an organic layer and the organic layer is concentrated under reduced pressure and purified by a thin film chromatography to provide beta-phenylglycoside [e.g. beta-(4-nitrophenyl)tetra--O-acetyl- glycoside] expressed by formula II [R<1> is (substituted)phenyl].

Description

Detailed Description of the Invention

[0001]

The present invention relates to a compound of the general formula (I) which is useful as an intermediate for the synthesis of a substrate for an enzymatic reaction such as a reagent for measuring α-amylase activity.

[Chemical 3] (In the formula, n represents an integer of 0 to 6, R represents alkanoyl,
Represents benzoyl, and R ¹ represents substituted or unsubstituted phenyl. ) Relates to a novel method for producing β-phenylglycoside (hereinafter referred to as compound (I)).

[0002]

2. Description of the Related Art Conventionally, when the compound (I) is produced, the compound of the general formula (II)

[Chemical 4] (In the formula, each symbol has the same meaning as described above.) A peracyl derivative of glucose or maltooligosaccharide (hereinafter, referred to as compound (II)) and a phenol compound are zinc halide, titanium halide, tin halide. The Helferich method of synthesizing phenylglycoside by reacting it in the presence of a Lewis acid or paratoluenesulfonic acid is known.

[Problems to be Solved by the Invention]

However, when the above-mentioned Lewis acid or paratoluenesulfonic acid is used for the purpose of synthesizing β-phenylglycoside, many by-products are generated,
It is difficult to obtain the desired β-phenylglycoside with high selectivity and high yield. According to the study of the present inventors, when Lewis acid or paratoluenesulfonic acid is used, the configuration of the reducing terminal acyloxy group of the peracyl derivative is firstly changed from the highly reactive β-coordination to the poorly reactive α-configuration.
It was found that a side reaction of changing to a coordination occurs, and secondly, a side reaction of changing the once formed β-phenylglycoside bond to an α-phenylglycoside bond occurs. That is, since these Lewis acids have a strong property of accelerating the anomerization reaction, it cannot be said that they are necessarily the optimum catalysts for the synthesis of β-phenylglycoside. Furthermore, the use of paratoluenesulfonic acid causes a problem that sugar chains are decomposed.

[0004]

The inventors of the present invention have conducted extensive studies to obtain β-phenylglycoside represented by the compound (II) with good selectivity and high yield. By carrying out the glucosidation reaction in the presence of acetylacetone zinc salt or carboxylic acid zinc salt,
It was found that β-phenylglycoside represented by the compound (I) can be obtained with good selectivity and high yield, and the present invention has been completed. That is, the present invention provides the compound (I
The present invention relates to a process for producing a compound (I), which comprises reacting I) with a substituted or unsubstituted phenol compound in the presence of an acetylacetone zinc salt or a carboxylic acid zinc salt.

The peracyl derivative of the compound (II) used in the present invention includes penta-O-acetylglucoside, octa-O-acetylmaltoside, undeca-O-acetylmaltotrioside, tetradeca-O-acetylmaltotetraoside. , Heptadeca-O-acetylmaltopentaoside, eicosa-O-acetylmaltohexaoside,
Examples thereof include tricosa-O-acetylmaltoheptaoside, and compounds in which the acetyl group of these compounds is changed to a propionyl group, a butyryl group, a pivaloyl group, a benzoyl group or the like can also be used. The β-form (configuration of the reducing terminal acyloxy group) in these compounds is involved in the reaction of the present invention, but a mixture with the α-form can also be used.

The substituted phenol is a phenol having a halogen atom, a hydroxy group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group, an alkoxycarbonyl group, a nitro group or the like as a substituent, such as chlorophenol and dichlorophenol. Examples thereof include hydroxyphenol, alkylphenol, alkoxyphenol, hydroxybenzoic acid, nitrophenol, halogenated nitrophenol, alkylated nitrophenol, alkoxylated nitrophenol, nitrated hydroxybenzoic acid and dinitrophenol. In particular, phenols having at least one nitro group, such as 4-nitrophenol, 2-chloro-4-nitrophenol, 2,6-
Dichloro-4-nitrophenol, 2-fluoro-4-
Nitrophenol, 2,6-difluoro-4-nitrophenol, 2-bromo-4-nitrophenol, 2,6
-Dibromo-4-nitrophenol, 2-nitrophenol, 2-hydroxy-4-nitrophenol, 3-hydroxy-4-nitrophenol and the like are preferable.

The acetylacetone zinc salt of the present invention may be anhydrous or monohydrate. The carboxylic acid zinc salt may be an anhydride or a hydrate, for example, zinc acetate,
Zinc propionate, zinc octylate, zinc oleate,
Examples thereof include zinc stearate, zinc oxalate, zinc succinate, zinc maleate, zinc naphthenate, zinc salicylate, zinc benzoate, zinc phthalate, and zinc terephthalate. The charging ratio of the phenols to the peracyl derivative of the compound (II) is 1 to 10 mol times, preferably about 3 to 6 mol times. The acetylacetone zinc salt or zinc carboxylic acid salt used as a catalyst is used in an amount of about 0.5 to 20 mol% based on the peracyl derivative. Reaction temperature is 8
It can be performed at 0 to 200 ° C, preferably 100 to 130 ° C.
It is desirable to remove the lower fatty acid or benzoic acid produced along with the progress of the reaction outside the reaction system. For example, the reaction system is kept under reduced pressure, preferably about 5 to 50 mmHg, and distilled off outside the system. It is okay to react while adding an organic solvent such as benzene, toluene, xylene, chlorotoluene, heptane, and octane to the reaction system, and even if the mixture of the organic solvent and the lower fatty acid or benzoic acid is distilled out of the system by distillation. Good. The time required to complete the reaction varies depending on the type of compound, the type of zinc salt used, and the reaction temperature, but is usually about 3 to 20 hours. After completion of the reaction, the reaction product is diluted with ethyl acetate, toluene, chloroform, etc., and the organic layer is washed with dilute aqueous solution of water, hydrochloric acid, sulfuric acid, etc. to remove zinc, and then sodium hydroxide, potassium hydroxide. , Unreacted phenols are removed by washing with a dilute alkaline aqueous solution such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate. The obtained organic layer is washed with water until it becomes neutral, and the solvent is distilled off to obtain a crude product of the target. The obtained crude product is purified by a conventional method such as recrystallization or column chromatography to obtain a highly pure target product.

The target compound (I) synthesized by the method of the present invention is β- (phenyl) tetra-O.
-Acetylglucoside, β- (4-nitrophenyl) tetra-O-acetylglucoside, β- (4-chlorophenyl) tetra-O-acetylglucoside, β- (2-chloro-4-nitrophenyl) tetra-O-acetyl Glucoside, β- (4-nitrophenyl) hepta-O-acetylmaltoside, β- (2-chloro-4-nitrophenyl) hepta-O-acetylmaltoside, β- (4-nitrophenyl) deca-O- Acetyl maltotrioside, β
-(2-chloro-4-nitrophenyl) deca-O-acetylmaltotrioside, β- (4-nitrophenyl) trideca-O-acetylmaltotetraoside, β- (2-
Chloro-4-nitrophenyl) trideca-O-acetylmaltotetraoside, β- (4-nitrophenyl) hexadeca-O-acetylmaltopentaoside, β- (2-
Chloro-4-nitrophenyl) hexadeca-O-acetylmaltopentaoside, β- (4-nitrophenyl) nonadeca-O-acetylmaltohexaoside, β- (2-
Chloro-4-nitrophenyl) nonadeca-O-acetylmaltohexaoside, β- (4-nitrophenyl) heneicoser O-acetylmaltoheptaoside, β- (2-
And chloro-4-nitrophenyl) heneicosa-O-acetylmaltoheptaoside.

[0009]

The present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

Example 1: Synthesis of β- (4-nitrophenyl) tetra-O-acetylglucoside Penta-O-acetyl-β-D-glucose 3.90
g, 4-nitrophenol 6.96 g, toluene 10 ml
Then, 1.7 ml of a toluene solution of zinc naphthenate (0.5 mmol of zinc content) was placed in the flask and heated. When the temperature of the contents reached 120 ° C., the dropwise addition of toluene was started, and the toluene-acetic acid mixture distilled out was removed to the outside of the system. The reaction temperature was 120 to 125 ° C., and 50 ml of toluene was added dropwise over about 5 hours to complete the reaction. After adding ethyl acetate to the reaction product, the organic layer was washed with dilute hydrochloric acid solution, potassium carbonate aqueous solution and water in this order. The organic layer was concentrated under reduced pressure to obtain 4.50 g of light brown crude crystals. When the crude crystal was developed on thin layer chromatography (TLC), it was almost one spot, and penta-O-acetyl-D-glucose was not detected in both α and β forms. A part of the crude crystal was taken and recrystallized with a toluene-methanol mixed solvent to obtain a white target product. Melting point 176-177 [deg.] C.

Example 2: Synthesis of β- (2-chloro-4-nitrophenyl) tetra-O-acetylglucoside 117 g of penta-O-acetyl-β-D-glucose,
260 g of 2-chloro-4-nitrophenol, 300 g of toluene and acetylacetone zinc salt monohydrate 4.2
g was put in a rotary flask and mixed by heating, and the pressure was gradually reduced to distill off toluene. Then bath temperature 125-135
The reaction was performed at 20 ° C. and 20 to 5 mmHg for 10 hours. After completion of the reaction, ethyl acetate was added and filtered, and the organic layer was washed successively with aqueous potassium carbonate solution and water, and the solvent was distilled off to obtain 136.5 g of light brown crude crystals. Further recrystallization with a toluene-methanol mixed solvent gives 121.2 g of the white target product.
was gotten. Melting point 151-153 [deg.] C. Theoretical yield 80.2
%.

Example 3: Synthesis of β- (2-chloro-4-nitrophenyl) hepta-O-acetylmaltoside Octa-O-acetyl-β-D-maltose 30.0
g, 2-chloro-4-nitrophenol 30.7 g, acetylacetone zinc salt anhydrous 0.62 g and toluene 100 ml were put into a rotary flask and mixed by heating, and the pressure was gradually reduced to distill off toluene. Continued 20-5mmH
Under reduced pressure of g, the reaction was carried out at a bath temperature of 125 to 135 ° C. for 20 hours. Thereafter, the same treatment as in Example 2 was carried out to obtain light brown crude crystals 3
2.5 g was obtained. When recrystallized with a toluene-methanol mixed solvent, 29.8 g of white crystals were obtained as the desired product.
was gotten. TLC: One spot. Melting point 167-16
9 ° C. Theoretical yield 85.1%.

Example 4: Synthesis of β- (2-chloro-4-nitrophenyl) hepta-O-acetylmaltoside Octa-O-acetyl-β-D-maltose 30.0
g, 2-chloro-4-nitrophenol 30.7 g, zinc acetate anhydrous 0.81 g and toluene 100 ml were put in a flask and mixed by heating. When the internal temperature reached 130 ° C., the dropping of toluene was started and the distillate was removed to the outside of the system.
Toluene 300ml over 16 hours at 128-133 ° C
Was added dropwise to complete the reaction. Thereafter, the same treatment as in Example 2 was carried out to obtain 32.5 g of light brown crude crystals. Further, recrystallization with a toluene-methanol mixed solvent gave 28.0 g of a white crystal as a target product. TLC: One spot. Theoretical yield 80.0%.

Example 5: Synthesis of β- (4-nitrophenyl) hexadeca-O-acetylmaltopentaoside 3.00 g maltopentaose heptadecaacetate.
(However, a mixture of α and β forms, α: β = 18: 82),
4-Nitrophenol (1.35 g), a toluene solution of zinc naphthenate (0.32 ml, zinc content: 0.1 mmol) and toluene (5 ml) were placed in a flask and mixed by heating. When the internal temperature reached 125 ° C., the dropping of toluene was started and the distillate was removed to the outside of the system. At 120 to 130 ° C., 30 ml of toluene was added dropwise over 5 hours to complete the reaction. After adding ethyl acetate to the reaction product, the organic layer was washed successively with dilute hydrochloric acid solution, potassium carbonate aqueous solution and water, and the solvent was distilled off to obtain 3.02 g of a light brown solid. When developed on TLC, the main impurity was the α-form of maltopentaose heptadecaacetate. Also, the content of the target substance was 78.2% as measured by the HPLC calibration curve method. Theoretical yield from β-maltopentaose heptadecaacetate 9
3.4%. A part of the crude crystals was taken and purified by silica gel column chromatography to obtain white crystals as a target product. TLC: One spot. Softened from 130 ℃.

Example 6: Synthesis of β- (2-chloro-4-nitrophenyl) hexadeca-O-acetylmaltopentaoside 2.01 g maltopentaose heptadecaacetate,
1.13 g of 2-chloro-4-nitrophenol, 0.21 ml of a toluene solution of zinc naphthenate (zinc content 0.06
5 mmol) and 5 ml of toluene were placed in a flask and mixed by heating. When the internal temperature reached 120 ° C., the dropping of toluene was started and the distillate was removed to the outside of the system. 118-12
The reaction was completed by adding 50 ml of toluene dropwise at 5 ° C. over 5 hours. Thereafter, the same treatment as in Example 5 was carried out to obtain 2.10 g of a light brown solid. When developed on TLC, the main impurity was the α-form of maltopentaose heptadecaacetate. In addition, the content of the target substance was 77.5% as measured by the HPLC calibration curve method. Theoretical yield from β-maltopentaose heptadecaacetate 92.1
%. A part of the crude crystals was taken and purified by silica gel column chromatography to obtain white crystals as a target product. TLC: One spot. Softens from 120 ° C.

Comparative Example 1: β- (4-
Synthesis of (nitrophenyl) tetra-O-acetylglucoside Penta-O-acetyl-β-D-glucose 3.90
g, 4-nitrophenol 6.96 g, anhydrous ether 1
0 ml and 3.0 ml of anhydrous zinc chloride in ether
(Zinc chloride content 0.5 mmol) was placed in a rotary flask and mixed by heating, and the pressure was gradually reduced to a bath temperature of 125 to 135.
The reaction was performed at 20 ° C. and 20 to 5 mmHg for 5 hours. Ethyl acetate was added to the reaction product, and the organic layer was washed with water, an aqueous potassium carbonate solution and water in this order, and the solvent was distilled off to obtain a dark brown viscous oily substance. When developed on TLC, the main components are structurally unknown, α- (4-nitrophenyl) tetra-O-acetylglucoside, β- (4-nitrophenyl) tetra-O-.
A mixture of acetyl glucosides, the proportion of which is visually about 2:
It was about 6: 2.

Comparative Example 2: β- (2-
Synthesis of chloro-4-nitrophenyl) hexadeca-O-acetylmaltopentaoside 2.01 g of maltopentaose heptadecaacetate,
2-chloro-4-nitrophenol 1.13 g, acetic anhydride 10 ml and anhydrous zinc chloride acetic acid solution 0.7 ml
(Zinc chloride content 0.07 mmol) was placed in a rotary flask and mixed by heating, and the pressure was gradually reduced to a bath temperature of 125 to 13
The reaction was carried out at 5 ° C. and 20 to 5 mmHg for 5 hours. Ethyl acetate was added to the reaction product, and the organic layer was washed with water, an aqueous potassium carbonate solution and water in this order, and the bath agent was distilled off to give a brown solid of 2.04.
g was obtained. When developed on TLC, the main impurity was the α-form of maltopentaose heptadecaacetate, but when compared quantitatively, the amount was much higher than the amount originally contained in the starting material. It was found that the α form of Further, the content of the target substance was 60.3% as measured by the HPLC calibration curve method. Theoretical yield from β-maltopentaose heptadecaacetate 6
9.5%.

[0018]

EFFECTS OF THE INVENTION According to the method of the present invention, the anomerization reaction and sugar chain decomposition reaction of the raw material peracyl derivative and β-phenylglycoside are suppressed, so that the desired β-phenylglucoside can be selected with good selectivity. And can be obtained in high yield. Β obtained in Example 6 of the present invention
-(2-chloro-4-nitrophenyl) hexadeca-O
-Acetylmaltopentaoside is useful as a reagent for measuring α-amylase activity by subjecting it to a hydrolysis reaction known per se, and β-which is useful as an intermediate of the reagent.
It can lead to (2-chloro-4-nitrophenyl) -maltopentaoside.

Claims (1)

[Claims] 1. A compound represented by the general formula (II): (In the formula, n represents an integer of 0 to 6 and R represents alkanoyl or benzoyl.) A peracyl derivative of glucose or maltooligosaccharide and a substituted or unsubstituted phenol compound are acetylacetone zinc salt or zinc carboxylate. Characterized by reacting in the presence of salt,
General formula (I) (In the formula, R ¹ represents a substituted or unsubstituted phenyl, and other symbols are as defined above.) The method for producing β-phenylglycoside.