JP3101002B2 - Method for producing α-D-glucopyranoside derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an α- (substituted phenyl)
The present invention relates to an improvement in a method for producing a D-glucopyranoside derivative.

[0002]

2. Description of the Related Art It is well known that various monosaccharides or polysaccharides and oligosaccharides which are condensates thereof play an important role in living organisms. Attempts have been made to artificially produce saccharide derivatives. For this reason, for example, it is urgently necessary to establish a glycosylation reaction in which the position of a glycosidic bond forming condensation can be freely selected and the reaction step is simple.

Various methods have been proposed for the glycosylation reaction. For example, a method is known in which a sugar is acylated and then reacted with a nucleus-substituted phenol in the presence of a Lewis acid (JP-A-62-289595).

[0004] Also, INDIAN J. CHEM., VOL9, APRIL P315 ~
317 (1971) discloses a method using stannic chloride as a catalyst for glycosylation of phenols. Furthermore, a method is known in which a glycoside is produced by using a heteropolyacid as a catalyst and performing o-glucosidation, s-glucosidation, acetalization, etherification, esterification, ether exchange and transesterification of saccharides. (JP 63
-84637).

[0005]

However, even if these conventionally known methods are applied to the production of α- (substituted phenyl) -D-glucopyranoside derivatives as the object of the present invention, they cannot be used as precursors. Low yield of certain acetylated compounds,
Neither of them is complicated enough to take out (separate), etc., and they are not sufficient for an industrial production method.

[0006] The object of the present invention is to provide α-
It is an object of the present invention to provide a method for selectively producing glucoside in high yield and industrially advantageous.

[0007]

According to the present invention, glucose pentaacetate and a substituted phenol are reacted in a halogenated hydrocarbon solvent in the presence of stannic chloride at a temperature of 40 to 70 ° C.
Reacting with tetraacetyl-α-
This is a method for producing a (substituted phenyl) -D-glucopyranoside derivative.

The present invention also relates to a method of reacting glucose pentaacetate with a substituted phenol in a halogenated hydrocarbon solvent at a temperature of 40 to 70 ° C. in the presence of stannic chloride to obtain tetraacetyl-α- (substituted This is a method for producing an α- (substituted phenyl) -D-glucopyranoside derivative, which comprises obtaining (phenyl) -D-glucopyranoside and then deacetylating it.

A feature of the method of the present invention is that α- and / or β
Is to selectively produce a target α- (substituted phenyl) -D-glucopyranoside derivative at a high yield by performing a predetermined chemical reaction using glucose pentaacetate as a starting material. The method of the present invention is easy to take out (separate) the target substance, and is particularly excellent as an industrial production method.

The substituted phenols used in the method of the present invention include, specifically, 2-chloro-4-nitrophenol, 4-nitrophenol, 2-chlorophenol,
Examples thereof include 4-methylphenol. Particularly, when 2-chloro-4-nitrophenol or 4-nitrophenol is used, it is a method of high industrial value as a method for selectively producing α-form D-glucopyranoside.

Examples of the halogenated hydrocarbon solvent used in the method of the present invention include halogenated aliphatic hydrocarbons such as carbon tetrachloride, dichloromethane, dichloroethane, chloroform, trichloroethane, trichloroethylene and perchloroethylene; And aromatic halogenated hydrocarbons such as-, m-, p-chlorobenzene, and trichloroben. Particularly preferred are halogenated aliphatic hydrocarbons, which can be used alone or in the form of a mixture.

The reaction temperature between glucose pentaacetate and a substituted phenol in the method of the present invention is usually from room temperature to room temperature.
The temperature is 100 ° C, preferably 40 to 70 ° C, more preferably 40 to 60 ° C. The reaction time is usually 1 to 10
Hours, preferably 2 to 5 hours.

The reaction molar ratio of glucose pentaacetate, which is a starting material, to a substituted phenol such as 2-chloro-4-nitrophenol or 4-nitrophenol is such that 1 mol of glucose pentaacetate has 1 to 1 mole of the substituted phenol. 2 moles.

The removal of the reaction product is usually carried out by a known method, and is easily carried out, for example, by the following method. The reaction product is diluted by adding it to an organic solvent such as benzene or toluene, poured into ice water, separated, washed with water, washed with alkali, dried over anhydrous sodium sulfate, filtered with activated carbon. Next, the organic solvent is distilled off, and the mixture is dissolved by adding an alcohol or the like, and then cooled to precipitate crystals, which is filtered, washed with methanol, and dried.

The tetraacetyl-α- (substituted phenyl) -D-glucopyranoside obtained by the above method is
The following deacetylation reaction can be performed by the above-mentioned method or isolated without isolation.

For this deacetylation reaction, a generally known deacetylation method is applied. For example, tetraacetyl-α
-(2-Chloro-4-nitrophenyl) -D-glucopyranoside is easily dissolved or suspended in an alcohol such as methanol or ethanol, added with an alkali (for example, sodium methoxide solution), and stirred to easily carry out. Will be The deacetylation reaction can be monitored by TLC.

If necessary, the reaction solution is neutralized with an ion-exchange resin, and the methanol is concentrated by a rotary evaporator or the like to crystallize and precipitate. This crystallization is performed using a suitable organic solvent (for example, isopropyl alcohol).

[0018]

According to the method of the present invention, the desired α-
(2-Chloro-4-nitrophenyl) -D-glucopyranoside or α- (4-nitrophenyl) -D-glucopyranoside can be selectively produced at a high yield and industrially advantageously.

[0019]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples.

EXAMPLE 1 117 g (0.3 mol) of glucose pentaacetate, 2-
80 ml of dichloromethane was added to 69 g (0.4 mol) of chloro-4-nitrophenol, and the mixture was stirred.
(0.42 mol) was added dropwise over 1 hour. After dropping,
The temperature was gradually increased, and the mixture was refluxed (55 ° C to 59 ° C) for 3 hours.
Add 500 ml of benzene to dilute, cool, pour into ice water, separate, wash with water, wash several times with dilute aqueous sodium carbonate solution, wash with water, dry with anhydrous sodium sulfate, add activated carbon After filtration, the solvent was evaporated under reduced pressure.

After adding isopropyl alcohol to the remaining candy-like substance and dissolving it by heating, it is allowed to stand and cooled to separate into two layers. After removing the upper layer isopropyl alcohol solution, methanol was added to the lower layer candy, and after heating and dissolving, the mixture was allowed to cool, and after curing, the precipitated crystals were filtered, washed with cold methanol, dried, and tetraacetyl-α- (2-chloroform). 37.8 g of -4-nitro-phenyl) -D-glucopyranoside was obtained. After evaporating the filtrate under reduced pressure, the filtrate was purified with isopropyl alcohol and the methanol solution was cooled to obtain the desired product. Yield: 25%; melting point: 125.5-126 ° C .;

[0022]

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Next, the obtained tetraacetyl-α- (2
-Chloro-4-nitro-phenyl) -D-glucopyranoside (10.0 g) was dissolved in 500 ml of dehydrated methanol, and 0.2 ml of 0.5N sodium methoxide was added with stirring and reacted for 5 hours to perform deacetylation. Was. α- (2-
5.6 g of (chloro-4-nitro-phenyl) -D-glucopyranoside were obtained. It was confirmed that this substance had α-coordination by reacting α-glucosidase and β-glucosidase.

Melting point: 143 to 145 ° C. Infrared absorption spectrum cm ⁻¹ ; 3330 (OH), 1590, 1510, 1350 350 (PhNO ₂ C), 750, 710, 690 (Ph) 270 MHz Nuclear magnetic resonance spectrum ( (In methanol); δ 3.32 to 4.16 (m, 6H, H-2 to 6) 5.81 (d, 1H, J _1,2 = 3.0Hz, H-1) 7.42, 8.19, 8.30 (m, 3H, Ph) Every time ;

[0025]

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EXAMPLE 2 To 117 g (0.3 mol) of glucose pentaacetate and 75 g (0.43 mol) of 2-chloro-4-nitrophenol were added 75 ml of chloroform, and 120 g of stannic chloride (0.
(46 mol) was kept at 15-20 ° and added dropwise. After that, the temperature was gradually raised, and after one hour, the temperature was raised to 50 ° C., and the temperature was kept at 50 to 55 ° C. for 4 hours.
It was kept at 6060 ° C. for 0.5 hour. Then, 500 ml of toluene was added for dilution, and the mixture was poured into ice and saline, and separated.The organic layer was washed with saline, washed several times with a 3% aqueous sodium carbonate solution, washed with saline, and then washed with magnesium sulfate. After drying, the solvent was removed under reduced pressure, and post-treatment was performed in the same manner as in Example 1 to obtain 25.5 g of tetraacetyl-α- (2-chloro-4-nitrophenyl) -D-glucopyranoside.

Next, tetraacetyl-α- (2-chloro-4-nitro-phenyl) -D-glucopyranoside 10
g was dissolved in dehydrated methanol and deacetylated using sodium methoxide in the same manner as in Example 1 to obtain α- (2-chloro-
5.9 g of 4-nitrophenyl) -D-glucopyranoside was obtained.

EXAMPLE 3 117 g (0.3 mol) of glucose pentaacetate, 4-
Dichloromethane is added to 46 g (0.33 mol) of nitrophenol.
0 ml was added and stirred, and stannic chloride 81 g (0.34 mol) was added dropwise over 1 hour. After the completion of the dropwise addition, the temperature was gradually raised, and the mixture was refluxed (55 ° C to 59 ° C) for 3 hours. Benzene 500
Then, the mixture was cooled and poured into ice water.
After washing with water, the mixture was washed several times with a dilute aqueous sodium carbonate solution, further washed with water, dried over anhydrous sodium sulfate, filtered with activated carbon, and the solvent was evaporated under reduced pressure. Methanol is added to the remaining candy-like substance, which is then dissolved and cooled. The precipitated crystals are filtered, washed with cold methanol, and dried.
69 g of (nitro-phenyl) -D-glucopyranoside were obtained. Yield: 49%; melting point: 110-114 ° C .;

[0029]

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Next, the obtained tetraacetyl-α- (4
-Nitro-phenyl) -D-glucopyranoside 10.0 g
Was dissolved in 10 ml of benzene and 10 ml of methanol, 0.2 ml of 0.5N sodium methoxide was added with stirring, deacetylated, recrystallized from water to obtain α- (4-
4.5 g of (nitro-phenyl) -D-glucopyranoside were obtained (yield 70%). The fact that this substance is in the α-coordinate means that α-
It was confirmed by reacting glucosidase and β-glucosidase.

Melting point: 215 to 217 ° C. infrared absorption spectrum cm ⁻¹ ; 3480, 3320 (OH), 1590, 1500 1350 (PhNO ₂ ), 750, 710, 690 (Ph) 270 MHz nuclear magnetic resonance spectrum (deuterated methanol) Medium); δ 3.48 to 3.93 (m, 6H, H-2 to 6) 5.65 (d, 1H, J _1,2 3.66 Hz, H-1) 7.28, 8.22 (m, 4H, Ph) Optical rotation;

[0032]

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──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Akio Taki 1087-226 Oba, Mishima City, Shizuoka Prefecture (72) Inventor Koichi Ogawa 3-2-3, Arihito, Shizuoka City, Shizuoka Prefecture Aki Ki (56) Reference Chem. Pharm. Bull. , Vol. 24, No. 3 (1976) p. 394 -399 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07H 1/00 B01J 27/135 C07H 15/203 CA (STN) CAOLD (STN) CAPLUS (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. A method comprising reacting glucose pentaacetate with a substituted phenol in a halogenated hydrocarbon solvent at a temperature of 40 to 70 ° C. in the presence of stannic chloride. A method for producing a phenyl) -D-glucopyranoside derivative. 2. The tetraacetyl-α- according to claim 1, wherein the halogenated hydrocarbon is selected from carbon tetrachloride, dichloromethane, dichloroethane, chloroform, trichloroethane, trichloroethylene and perchloroethylene.
A method for producing a (substituted phenyl) -D-glucopyranoside derivative. 3. The method according to claim 1, wherein the substituted phenol is 2-chloro-4-.
3. The tetraacetyl- according to claim 1, which is nitrophenol or 4-nitrophenol.
A method for producing an α- (substituted phenyl) -D-glucopyranoside derivative. 4. A reaction between glucose pentaacetate and a substituted phenol in a halogenated hydrocarbon solvent at a temperature of 40 to 70 ° C. in the presence of stannic chloride to obtain tetraacetyl-α- (substituted phenyl) -D. -To obtain glucopyranosides,
A method for producing an α- (substituted phenyl) -D-glucopyranoside derivative, which is followed by deacetylation. 5. The α- (substituted phenyl)-according to claim 4 , wherein the halogenated hydrocarbon is selected from carbon tetrachloride, dichloromethane, dichloroethane, chloroform, trichloroethane, trichloroethylene and perchloroethylene.
A method for producing a D-glucopyranoside derivative. 6. The method according to claim 6, wherein the substituted phenol is 2-chloro-4-.
Method for producing a nitrophenol or 4-nitro phenol according to claim 4 or claim 5 alpha-(substituted phenyl)-D-glucopyranoside derivatives.