JPH10130293A - Production of glycoside sialate with alpha bond - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for simply producing, in high yield, the subject compound useful as an intermediate or the like for synthesis of medicines by bringing a specific sialic acid derivative in an inert solvent into contact with a hydrogen chloride gas, and then by reacting the effluent solution with an alcohol in the presence of a Lewis acid. SOLUTION: This method brings a sialic acid derivative shown by formula I [(R<1> is a 2-7C acyl; and R<2> is a 1-6C alkyl or phenylalkyl (where, 1-3C in the case of alkyl)], e.g. 5-acetamide-2,4,7,8,9-pent-O-acetyl-3,5-dideoxy-β-D-glycero- D-galacto-2-nonulopyranosonic benzyl ester and the like, in an inert solvent, e.g. toluene or the like, into contact with a hydrogen chloride gas, and then reacts the effluent containing the 2-chlorosialic acid derivative produced, shown by formula II, with an alcohol, e.g. methanol or the like, in the presence of a Lewis acid, to simply produce a glycoside sialate with α-bond as the objective compound, shown by formula III (R<3> is the same as R<2> ), in high yield.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a sialic acid glycoside having an α bond. Specifically, the sialic acid derivative is chlorinated under specific conditions, and then the resulting reaction mixture is reacted with an alcohol in the presence of a Lewis acid to obtain a sialic acid glycoside having an α bond in high yield and stereoselection. The present invention relates to a method for manufacturing a semiconductor device. Sialic acid glycosides having an α-bond are useful as synthetic intermediates for pharmaceuticals.

[0002]

2. Description of the Related Art Sialic acid is known to be widely present as a constituent unit of glycoproteins and glycolipids in various tissues of living organisms, and attracts attention because it is related to nerve functions, cancer, differentiation, hormone receptors and the like. I am collecting. Therefore, synthetic studies of various derivatives have been actively conducted from the viewpoint of application as pharmaceuticals. Among these derivatives, compounds in which R ² is a benzyl group in sialic acid glycoside (3) having an α bond can selectively deprotect a benzyl ester, and its usefulness as a synthetic intermediate for pharmaceuticals has been reported. (JP-A-7-228592).

Conventionally, various techniques have been tried for glycosidation of sialic acid in the organic synthesis of sialic acid derivatives, but sialic acid is a 3-deoxy sugar, and the anomeric position is quaternary carbon. For some reason, it is difficult to obtain sialic acid with α-bond in good yield because α-bond is more thermodynamically unstable than β-bond (Haruo Ogura, Chemistry and Application of Glycoconjugates) , CMC, 1989,
p80-104; Kaoru Okamoto, Toshio Goto, Synthetic Organic Chemistry, 4
7, vol. 4, p. 349-362).

As a method for producing a sialic acid glycoside using a sialic acid derivative of the formula (2), there have been conventionally used a method using a heavy metal salt such as a silver salt or a mercury salt, or a method using stannous chloride without using a heavy metal salt. , A method using a Lewis acid such as stannous bromide (WO 91/13079; Chem. Phar)
m. Bull. 40 (9), 2300 (1992). )
It has been known.

[0005]

However, the conventional methods involve the use of expensive silver salts or harmful heavy metal salts such as mercury salts, and the problems of the stability of the compound of the formula (2). Mass production is difficult. Further, the method using a Lewis acid is not satisfactory in both yield and stereoselectivity.

It is an object of the present invention to provide a method for producing sialic acid glycosides which can be mass-produced industrially and satisfy both the yield and the α selectivity.

[0007]

Means for Solving the Problems The present inventors have conducted various studies in order to solve the above problems, and as a result, chlorinating a sialic acid derivative under specific conditions. It has been found that by reacting a reaction mixture containing an oxidized derivative with an alcohol in the presence of a Lewis acid, a desired sialic acid glycoside having an α bond can be obtained in a high yield and stereoselectively. It was completed.

That is, in the present invention, a sialic acid derivative represented by the following general formula (1) is contacted with hydrogen chloride gas in an inert solvent (step (a)). A reaction mixture containing a 2-chlorosialic acid derivative represented by 2) is reacted with an alcohol in the presence of a Lewis acid (step (b)) to form an α bond represented by the following general formula (3). A method for producing a sialic acid glycoside having

[0009]

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[In the formula, R ¹ represents an acyl group having 2 to 7 carbon atoms, and R ² represents an alkyl group or a phenylalkyl group having 1 to 6 carbon atoms (provided that the alkyl group has 1 to 3 carbon atoms. )]

[0011]

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(Wherein R ¹ and R ² are as defined in formula (1))

[0013]

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Wherein R ¹ and R ² are as defined in formula (1), and R ³ is an alkyl group having 1 to 6 carbon atoms or a phenylalkyl group (provided that the alkyl group has 1
To 3). Hereinafter, the present invention will be described in detail.

[0015]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is carried out according to the following scheme.

[0016]

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Wherein R ¹ and R ² are as defined in formula (1), and R ³ is as defined in formula (3). Chlorination with hydrogen gas (step (a)) gives compound (2), which is reacted without isolation, with the reaction mixture containing it, in the presence of a Lewis acid with alcohol (4) (step (a)). (B))
Thereby, the compound (3) is synthesized.

Step (a) The sialic acid derivative as a starting material is a compound represented by the formula (1). In the formula (1), the acyl group having 2 to 7 carbon atoms as defined in R ^1, for example, acetyl group, propionyl group and the like, carbon atoms defined in R ² 1
Examples of the alkyl group of (6) to (6) include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a butyl group and the like, and a phenylalkyl group (where the alkyl group has 1 to 3 carbon atoms) Examples include a benzyl group and a phenylethyl group.

The starting material represented by the formula (1) can be prepared by a known method (for example, Chem. Ber. 99 , 611 (196)
6); Chem. Pharm. Bull. 35 (9),
3609 (1987)) or a method analogous thereto. Specific examples of preferred compounds as the starting material represented by the formula (1) are shown in Table 1 below.

[0020]

[Table 1]

As the inert solvent, for example, toluene,
Aromatic hydrocarbons such as xylene and benzene, hexane,
Aliphatic hydrocarbons such as heptane, methylene chloride, 1,2
-Halogenated hydrocarbons such as dichloroethane and chloroform, and esters such as methyl acetate, ethyl acetate and isopropyl acetate. Among these, aromatic hydrocarbons such as toluene, xylene and benzene are preferred, and toluene is particularly preferred. These are used alone or as a mixture with another inert solvent. The purity of the solvent is sufficient for industrial use, but the water content is preferably as small as possible. The amount used is usually in the range of 1 to 100 times by weight, preferably 2 to 30 times by weight of the raw material.

As the hydrogen chloride gas, one having an industrial purity is sufficient, but the water content is preferably as small as possible. The amount of use is usually 1 mol or more, preferably 2 mol or more per 1 mol of the raw material. Usually, hydrogen chloride gas is used in an amount such that the saturated concentration is maintained in the solvent, the shape and size of the reaction vessel. It is convenient to appropriately adjust and blow in accordance with the size of the air.

The reaction may be a batch reaction or a flow reaction. The reaction is usually carried out at a temperature in the range of -30 ° C to 50 ° C, preferably -10 ° C to room temperature, and the reaction time is not particularly limited in the case of a batch reaction, but is usually 1 to
10 hours, preferably 1 to 3 hours. In addition, it is preferable to perform the reaction operation and the reaction under anhydrous conditions because the yield is improved.

After the completion of the chlorination reaction, an inert gas such as nitrogen is blown in under reduced pressure or normal pressure to drive off excess hydrogen chloride gas, whereby the yield of the reaction (glycosylation) in step (b) is improved. It is preferred. Also, sodium acetate,
An inorganic solid base such as potassium acetate, sodium carbonate and potassium carbonate is usually used in an amount of 0.5 to 50 equivalents, preferably 0.5 to 50 equivalents.
Even if 20 equivalents are added and stirred to neutralize excess hydrogen chloride gas, it is preferable because the yield is improved. In addition, an inert gas such as nitrogen is blown under reduced pressure or normal pressure to expel excess hydrogen chloride gas, and subsequently, an inorganic solid base such as sodium acetate, potassium acetate, sodium carbonate, and potassium carbonate is usually used in an amount of 0.5 to 50%. It is preferable to add an equivalent, preferably 10 to 20 equivalents and stir to neutralize the remaining hydrogen chloride gas since the yield is further improved. When a neutralization reaction with an inorganic solid base such as sodium acetate, potassium acetate, sodium carbonate, and potassium carbonate is performed, excess inorganic solid base and salts such as sodium chloride generated by the neutralization are removed by filtration or decantation. May or may not be removed.

Step (b) In the glycosylation reaction, the reaction mixture containing the compound (2) obtained in step (a) is used without isolation. Examples of the alcohol (4) include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, benzyl alcohol, phenylethyl alcohol and the like, and these can be easily obtained as commercial products. Although the purity of alcohol is sufficient for industrial use, it is preferable that the water content is as small as possible. In addition, the amount of use is generally 1 to 100 equivalents, preferably 1 to 20 equivalents, relative to compound (1). When adding the Lewis acid and the alcohol (4), they may be added separately or may be added after being mixed in advance. In the case where the Lewis acid and the alcohol are mixed in advance and added, it is preferable to add them as a solution of esters such as methyl acetate and ethyl acetate, since they are well dispersed in the reaction system.

Examples of the Lewis acid include stannous chloride, stannous bromide, tin trifluoromethanesulfonate, zinc chloride, zinc bromide, and zinc trifluoromethanesulfonate. These Lewis acid salts are generally used in 0.1 to 10 equivalents, preferably 0.1 to 5 equivalents, relative to compound (1).

The reaction may be a batch reaction or a flow reaction. The reaction temperature is usually −30 ° C. to 50 ° C., preferably −10 ° C. to 10 ° C., and the reaction time is not particularly limited in the case of a batch reaction, but is usually 0.5 to 0.5 ° C.
It is 10 hours, preferably about 0.5 to 5 hours. At this time, it is preferable to perform the reaction operation and the reaction under anhydrous conditions, because the yield is improved. The glycosyl compound thus obtained can be purified by silica gel column chromatography, recrystallization and the like according to a conventional method. Specific examples of the product represented by the formula (3) are shown in Table 2 below.

[0028]

[Table 2]

[0029]

[Table 3]

[0030]

Hereinafter, the present invention will be described in more detail with reference to examples. However, this example is merely for explanation, and the present invention is limited to this example unless it exceeds the gist thereof. Not something.

Example 1 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-O-methyl-α-D-
Glycero-D-galact-2-nonulopyranosonic acid
Preparation of benzyl ester (compound of formula (3) in which R ¹ is an acetyl group, R ² is a benzyl group, and R ³ is a methyl group) (Compound No. 31 in Table 2)

5-acetamido-2,4,7,8,9-
Penta-O-acetyl-3,5-dideoxy-β-D-
Glycero-D-galact-2-nonulopyranosonic acid
10.0 g (16.4 mmol) of benzyl ester were suspended in 100 ml of toluene, and hydrogen chloride gas was suspended in 120 to 1 g.
Blow at a rate of 50 ml / min for 1.5 hours, then
Left for 2 hours. Next, nitrogen gas was blown at a rate of 250 ml / min for 2 hours, and then sodium acetate 1.3 under ice cooling.
5 g (16.4 mmol) was added, and the mixture was stirred for 30 minutes. Here, 11.1 g (49.2 mmol) of zinc bromide
Was dissolved in 9.98 ml (246 mmol) of methanol and 10 ml of methyl acetate, and the mixture was stirred under ice cooling for 1.5 hours. 50 ml of water was added thereto, and the mixture was stirred and separated.
The aqueous layer was further extracted with 50 ml of toluene. The organic layers were combined, washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 9.62 g of an oil containing the title compound. This oil was analyzed using high performance liquid chromatography [Analysis conditions Column: inertsi
1 ODS-II (15 cm), solvent: methanol-water (60:40), flow rate: 1 ml / min, detection wavelength: 210
nm], the title compound contained 81.3%, the β-isomer of the title compound was 4.2%, and the ratio of α to β was 95: 5.

IR (KBr, cm ^-1 ) 3290, 1750, 1660. ¹ H-NMR [CDCl ₃ , ppm] (only peaks corresponding to the title compound are shown) 1.87, 2.02, 2.04, 2.13, 2.15
(15H, SX5, Ac), 2.62 (1H, dd, J
= 4.6 Hz, 12.7 Hz, H-3 eq), 3.26
_{(3H, OCH 3), 4.31} (1H, dd, J = 2.
6Hz, 12.4Hz, H-9), 4.83 (1H,
m, H-4), 5.23 (2H, s, C H 2 C
_{6 H 5), 7.30~7.40 (5H} , m, C
₆ H _5).

[0034]

According to the method of the present invention, sialic acid glycosides having an α-bond can be easily produced in high yield.

Claims (7)

[Claims] 1. A sialic acid derivative represented by the following general formula (1) is contacted with hydrogen chloride gas in an inert solvent (step (a)), and then the resulting sialic acid derivative is represented by the following general formula (2). A reaction mixture containing a 2-chlorosialic acid derivative to be reacted with an alcohol in the presence of a Lewis acid (step (b)), wherein the sialic acid glycoside having an α-bond represented by the following general formula (3): Manufacturing method. Embedded image [In the formula, R ¹ represents an acyl group having 2 to 7 carbon atoms, R ²
Represents an alkyl group having 1 to 6 carbon atoms or a phenylalkyl group (provided that the alkyl group has 1 to 3 carbon atoms). (Wherein R ¹ and R ² are as defined in formula (1)) [Wherein, R ¹ and R ² are as defined in the formula (1), and R ³ is an alkyl group having 1 to 6 carbon atoms or a phenylalkyl group (provided that the alkyl group has 1 to 3 carbon atoms. Is)
Represents] 2. The method according to claim 1, wherein after the reaction is completed in step (a), excess hydrogen chloride gas is removed. 3. The method according to claim 1, wherein after the reaction is completed in step (a), an excess of hydrogen chloride gas is removed by introducing an inert gas. 4. The method according to claim 1, wherein after completion of the reaction in step (a), excess hydrogen chloride gas is neutralized and removed with an inorganic solid base. 5. The method according to claim 1, wherein after the reaction in step (a) is completed, excess hydrogen chloride gas is removed by introducing an inert gas, and further neutralized with an inorganic solid base. 6. Lewis acids as stannous chloride, stannous bromide, tin trifluoromethanesulfonate, zinc chloride,
The method according to any one of claims 1 to 5, wherein at least one selected from zinc bromide and zinc trifluoromethanesulfonate is used. 7. The method according to claim 1, wherein methanol is used as the alcohol.