JP3030064B2 - Novel method for producing sialic acid derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to 2-α-sialic acid, which is useful as a raw material and an intermediate for various pharmaceuticals including gangliosides and analogs thereof, biochemical reagents and the like. The present invention relates to a method for selectively producing -O-glycoside compounds.

BACKGROUND OF THE INVENTION As is well known, naturally occurring sialic acid derivatives that play an important role in biological systems such as glycoproteins and glycolipids present in cell membranes are known as cytidine monophosphate-N-acetylneuine. Except for laminic acid, all sialic acids are linked to sugar chains and the like by α-O-glycoside bonds. Therefore, it is extremely important to easily and selectively produce an α-O-glycoside compound of sialic acid in synthesizing a sialoglycoconjugate.

Recently, several new attempts have been made toward the synthesis of α-glycoside compounds of N-acetylneuraminic acid, all of which have been described in terms of yield, position and stereoselectivity, and mass production. There is still a lot of room for improvement.

The inventors have previously used methyl α-2-thioglycoside of sialic acid as a glycosyl donor, and in a polar solvent such as acetonitrile in the presence of a Lewis acid such as dimethyl (methylthio) sulfonium triflate. The present inventors have developed a method for glycosylation of sialic acid having excellent regio- and stereoselectivity by reacting with a receptor having an appropriate protecting group at low temperature, and thereby synthesizing various gangliosides and their analogs ( JP-A-2-49794,
JP-A-2-49795, Carbohydr.Res., 200 , 269-285
(1990), J. Carbohydr. Chem., 9 , 181-199 (1990).
etc). However, methyl α-2-thioglycoside of sialic acid, which is an important glycosyl donor used in this method, must be synthesized from N-acylneuraminic acid through six steps, and the operation is complicated. Good for scale production, but not always suitable for mass production.

Therefore, for example, a 2-α-O-glycoside compound of sialic acid, which is extremely useful as a raw material and an intermediate for various pharmaceuticals including gangliosides and analogs thereof, biochemical reagents, etc., can be easily and selectively collected. There is currently a long-awaited need for a production method that can be manufactured efficiently and in large quantities.

[Object of the Invention] The present invention has been made in view of the above-mentioned circumstances, and for examining the relationship between the physiological activity of a natural sialic acid derivative such as a glycoprotein or a glycolipid and its chemical structure, For example, 2-alpha-O-glycoside compounds of sialic acid, which are extremely useful as raw materials and intermediates for various pharmaceuticals including gangliosides and analogs thereof, biochemical reagents, etc., can be easily, selectively, and in good yield. Another object of the present invention is to provide a method for mass production.

[Constitution of the Invention] The present invention relates to a compound represented by the general formula [I]: (Wherein R and R ′ each independently represent an acyl group;
R ¹ represents a lower alkyl group. ) Is reacted with an (alkylthio) trialkylsilane in the presence of a trialkylsilyl ester of perfluoroalkanesulfonic acid to give a general formula [II] (Wherein, R ² represents a lower alkyl group, and R and R ¹ are the same as described above). An anomeric mixture of an alkylthiosialic acid derivative represented by the formula: Sialic acid 2 which is reacted with a compound having an alcoholic hydroxyl group at room temperature or lower in the presence of triflate, trimethylsilyl triflate or dimethyl (methylthio) sulfonium triflate (hereinafter abbreviated as DMTST). It is an invention of a method for producing a -α-O-glycoside compound.

Further, the present invention provides a compound represented by the general formula [II]: (Wherein R, R ¹ and R ² are the same as described above) in an anomeric mixture of an alkylthiosialic acid derivative in a polar solvent having no hydroxyl group in the presence of methyltriflate, trimethylsilyltriflate or DMTST. It is an invention of a method for producing a 2-α-O-glycoside compound of sialic acid, which comprises reacting a compound having an alcoholic hydroxyl group at room temperature or lower.

Examples of R in the general formulas [I] and [II] and R 'in the general formula [I] include acyl groups such as an acetyl group, a propionyl group and a butanoyl group. Examples of R ^{1 in} [II] and R ² in general formula [II] include lower alkyl groups such as methyl group, ethyl group, propyl group and butyl group.

The method for producing a 2-α-O-glycoside compound of sialic acid according to the present invention is generally carried out as follows.

That is, first, sialic acid is converted into a lower alcohol such as methanol in accordance with the method described in Carbohydr. Res., 110 , 11-18 (1982), for example, Amberlite IR-120 (trade name of Organo, H ⁺ After treating with a cation exchange resin such as a cation-exchange resin to form an ester, and then acylating the ester, an anomeric mixture of sialic acid derivatives represented by the general formula [I] (hereinafter abbreviated as compound [I]). ) Can be obtained almost quantitatively.

The anomeric ratio (α: β) of this compound was confirmed to be 3: 8 from the intensity ratio of the ester groups in the NMR spectrum.

Next, the compound [I] thus obtained is mixed with a trialkylsilyl perfluoroalkanesulfonate in a solvent (preferably sufficiently dried) such as 1,2-dichloroethane, carbon tetrachloride, or acetonitrile. For example, in the presence of trifluoromethanesulfonic acid trimethylsilyl ester (hereinafter, sometimes abbreviated as TMS-triflate), a heat reaction with (alkylthio) trialkylsilane such as (methylthio) trimethylsilane is carried out to obtain the general formula [II]. An anomeric mixture (α: β = 1: 1, hereinafter abbreviated as compound [II]) of an alkylthiosialic acid derivative represented by is obtained in high yield.

The trialkylsilyl perfluoroalkanesulfonate used in the present invention includes, in addition to TMS-triflate, for example, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, pentafluoroethanesulfonic acid Trimethylsilyl ester, heptafluoropropanesulfonic acid trimethylsilyl ester,
Examples include pentafluoroethanesulfonic acid triethylsilyl ester, trifluoromethanesulfonic acid dimethyl t-butylsilyl ester, pentafluoroethanesulfonic acid dimethyl t-butylsilyl ester, and heptafluoropropanesulfonic acid dimethyl t-butylsilyl ester. As the (alkylthio) trialkylsilane, in addition to (methylthio) trimethylsilane,
For example, (methylthio) triethylsilane, (ethylthio) trimethylsilane, (ethylthio) triethylsilane, (methylthio) tributylsilane and the like can be mentioned.
The reaction temperature of this reaction varies slightly depending on the solvent used, but is usually 40 to 100 ° C, preferably 50 to 60 ° C,
The reaction time varies slightly depending on the solvent used and the reaction temperature, but is usually about 1 to 10 hours.

Surprisingly, this exchange reaction from an acyloxy group to an alkylthio group according to the present invention shows no side reaction even in large-scale production. On the other hand, in this reaction,
When a BF ₃ -ether complex is used instead of TMS-triflate or the like, almost no desired product is obtained.

The anomeric mixture of the alkylthiosialic acid derivative (compound [II]) thus obtained is used as a glycosidation sugar donor, and is used as a polar solvent having no hydroxyl group such as acetonitrile, propionitrile, butyronitrile, nitromethane, etc. In the presence of a Lewis acid such as methyl triflate (methyl trifluoromethanesulfonate), trimethylsilyl triflate (trimethylsilyl trifluoromethanesulfonate) or DMTST, a low temperature, for example, room temperature or lower, preferably Reaction with a compound having an alcoholic hydroxyl group at -5 ° C or lower, more preferably -10 ° C or lower, for 0.5 to several tens of hours (the reaction time varies depending on the type of receptor and other reaction conditions). If the target α-
O-glycosides are selectively obtained. The amount of the compound [II] which is a sugar donor is about twice equivalent to the compound having an alcoholic hydroxyl group which is an acceptor, and a Lewis acid such as DMTST is used for the compound [II] which is a sugar donor. Usually, about three equivalents are used, but the present invention is not particularly limited thereto. DMTST is a publicly known document J. Chem. Soc., Perki
n According to the method described in Trans. II, 1569 (1982), it is prepared from dimethyl disulfide and methyl trifluoromethanesulfonate before use and used. After the reaction, post-treatment may be performed according to a conventional method such as, for example, filtering off insolubles and concentrating the filtrate. Purification by column chromatography or the like may be optionally performed. According to this method, no β-glycoside compound is produced as a by-product. Examples of the compound having an alcoholic hydroxyl group used in the present invention include, but are not limited to, compounds represented by the following general formulas [III], [IV], [V], or [VI]. The compound may be any compound as long as it has a primary or secondary hydroxyl group.

[Wherein, R ³ represents —OH, —NH ₂ , —OR ⁰ or —NHR ⁰ (where R ⁰ represents an acyl group), R ⁴ represents a hydroxyl-protecting group, and R ⁵ and R ^{5 One of 6} represents a hydroxyl group and the other represents a hydrogen atom. TAS represents a trialkylsilyl group. ] The compound shown by these.

(Wherein, R ⁷ represents an acyl group, and R ³ , R ⁵ , R ⁶ and TAS are the same as those described above).

(In the formula, R ⁸ represents an acyl group, R ⁹ and R ¹⁰ each represent a hydroxyl group and the other represents a hydrogen atom, and TAS is the same as described above.)

An aliphatic alcohol represented by R ¹¹ OH [VI] (wherein, R ¹¹ represents an alkyl group).

R ^{3 in the} general formulas [III] and [IV] includes, for example, —OH, —NH ₂ , —OR ⁰ or —NHR ⁰ , and R ⁰ includes, for example, an acetyl group, a propionyl group, a butanoyl group And benzoyl groups. Examples of R ⁴ in the general formula [III] include hydroxyl-protecting groups commonly used in this field, such as acetyl, propionyl, butanoyl, benzoyl, and benzyl. Further, one of R ⁵ and R ⁶ in the general formula [III] represents a hydroxyl group, and the other represents a hydrogen atom. Examples of R ⁷ in the general formula [IV] include acyl groups such as an acetyl group, a propionyl group, a butanoyl group, and a benzoyl group. TAS in the general formulas [III], [IV] and [V] represents, for example, a trialkylsilyl group such as a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group and a dimethyl t-butylsilyl group. Examples of R ⁸ in the general formula [V] include acyl groups such as an acetyl group, a propionyl group, a butanoyl group, and a benzonoyl group, and R ⁹ and R ¹⁰ in the general formula [V] are either one of them. Represents a hydroxyl group, and the other represents a hydrogen atom. Examples of R ¹¹ in the general formula [VI] include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group,
Examples include an alkyl group such as a heptyl group, an octyl group, a nonyl group, a decyl group, a dodecyl group, a pentadecyl group, a hexadecyl group, and an octadecyl group. The alkyl group may be linear or branched, but may be any of the general formula [VI] A branched alkyl group such that the alcohol represented by is a tertiary alcohol is excluded. The compound having an alcoholic hydroxyl group represented by the above general formula [III], [IV] or [V] is described in, for example, JP-A-2-49794 and J. Carbohydr, Chem. 8 , 265-28.
3 (1989) and the like disclose the synthesis method, and a method appropriately synthesized according to the method may be used.

According to the method of the present invention, 2-α-O-glycoside of sialic acid is obtained in an extremely high yield, and formation of 2-β-O-glycoside is hardly recognized. Further, according to the method of the present invention, the hydroxyl group of the receptor may be primary or secondary.

JP-A-2-49794 and J. Carbohydr. Chem, 8 , 265
It has been known that α-O-glycosides can be obtained in high yield from α-alkylthiosialic acid derivatives as described in US Pat. : Β = 1: 1), it was surprising that similarly, only α-O-glycoside can be obtained selectively and in high yield.

Examples and Reference Examples are shown below, but the present invention is not limited by these Examples and Reference Examples.

[Example] Reference Example 1. 1- [2- (trimethylsilyl) ethyl]
Synthesis of -2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside 10.08 g of 1,2,3,4,6-penta-O-acetyl-D-galactopyranoside 100 ml of fully dehydrated dichloromethane
After adding 50 g of a 30% acetic acid solution of hydrogen bromide at 0 ° C., the mixture was reacted at room temperature with stirring for 1.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a syrup-like substance, which was dissolved in 50 ml of dichloromethane, added with 4 to 10 g of molecular sieve, and reacted with stirring for 5 hours (reaction liquid-1). on the other hand,
14 g of Ag ₂ CO ₃ , 5.4 g of AgClO ₄ , 7.32 ml of trimethylsilylethanol and _{4 to 10} g of molecular sieves were suspended in 50 ml of sufficiently dehydrated dichloromethane, and reacted with stirring for 5 hours (reaction liquid-2). Then, the reaction solution-1 and the reaction solution-
The two were mixed and reacted overnight with stirring. After the reaction,
The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the resulting syrup was subjected to column chromatography [filler: Wakogel C-200 (trade name of Wako Pure Chemical Industries, Ltd.); eluent: CH purification by ₂ Cl _2], to obtain a syrup 8.4g of 1- [2- (trimethylsilyl) ethyl] -2,3,4,6-tetra -O- acetyl-beta-D-galactopyranoside.
Yield 72.5%. [Α] _D = -9.49 ゜ (C = 1.01, CHCl ₃ ).

Reference Example 2. 1- [2- (trimethylsilyl) ethyl]
Synthesis of -β-D-galactopyranoside 1- [2- (trimethylsilyl) obtained in Reference Example 1
Ethyl] -2,3,4,6-tetra-O-acetyl-β-D-
Methanol 3 fully dehydrated 8.06 g of galactopyranoside
0 ml, add a catalytic amount of sodium methylate and add
Stirred for hours. After completion of the reaction, Amberlite IR-120
The reaction solution was neutralized with an (organo company, trade name, H ⁺ type), and the filtrate obtained by filtration was concentrated under reduced pressure to give 1- [2- (trimethylsilyl) ethyl] -β-D-galactopyranoside. Was quantitatively obtained.

[Α] _D = −22.06 ° (C = 1.012, CH ₃ OH).

Reference Example 3. 2- (Trimethylsilyl) ethyl 3-O-
Benzoyl-β-D-galactopyranoside (general formula [II
I], R ³ = —OH, R ⁴ = benzoyl group, R ⁵ = —OH, R ⁶ =
H, TAS = trimethylsilyl group compound. Hereinafter, the compound [I
II a]. 1- [2- (trimethylsilyl) ethyl] -β-D-
Dissolve 1.5 g of galactopyranoside in 15 ml of pyridine and add -50
Cooled to ° C. A solution of 905 mg of benzoyl chloride dissolved in 15 ml of dichloromethane and cooled to -50 ° C was added dropwise over 12 minutes. After stirring for 3 hours, methanol was added and concentrated. Chloromethane was added to the residue for extraction, the dichloromethane layer was washed with water, dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting syrup was subjected to column chromatography [filler: Wakogel C-200 (product of Wako Pure Chemical Industries, Ltd.). Name), Eluate:
Purification by CH ₂ Cl ₂ / CH ₃ OH = 40/1] gave 1.38 g of the desired compound [IIIa]. Yield 67%.

[Α] _D = + 30.50 ° (C = 1.20, CHCl ₃ ).

 IR and NMR data were consistent with those of the standard.

Reference Example 4. 2- (Trimethylsilyl) ethyl 3-O-
Benzoyl-β-D-galactopyranoside (general formula [II
I], R ³ = —OH, R ⁴ = benzyl group, R ⁵ = —OH, R ⁶ = H,
TAS = trimethylsilyl group compound. Hereinafter, the compound [III
b]. 1- [2- (trimethylsilyl) ethyl] -β-D-
4.56 g of galactopyranoside was suspended in 100 ml of benzene,
After adding 6.10 g of (nC ₄ H ₉ ) ₂ SnO and stirring at 80 ° C. for 5 hours, 2.64 g of (n-C ₄ H ₉ ) ₄ HBr and 28.8 m of benzyl bromide were added thereto.
l was added thereto, and the mixture was further stirred and reacted for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, n-hexane was added to the residue, excess benzyl bromide was removed by a gradient method, and the selected syrup was subjected to column chromatography [filler: Wakogel C-200 (Wako Pure Chemical Industries, Ltd.) And the eluent: CH ₂ Cl ₂ / CH ₃ OH = 125/1] to obtain 4.63 g of the compound [IIIb]. Yield 76.6%.

[Α] _D = + 5.6 ° (C = 0.50, CH ₂ Cl ₂ ).

 IR and NMR data were consistent with those of the standard.

Reference Example 5. 2- (Trimethylsilyl) ethyl 6-O-
Benzoyl-β-D-galactopyranoside (general formula [I
V] At ^{a, R 3 = -OH, R 5} = -OH, R 6 = H, R 7 = benzoyl, the compound of TAS = trimethylsilyl group. Hereinafter, it is abbreviated as compound [IVa]. (1) Synthesis of 2- (trimethylsilyl) ethyl 6-O-benzoyl-3-O-benzyl-β-D-galactopyranoside (hereinafter abbreviated as compound [IVb]) Compound [III b] 4.2 g was dissolved in a mixed solvent of 12 ml of pyridine and 48 ml of dichloromethane, cooled to -50 ° C, a solution of 2.18 g of benzoyl chloride dissolved in 25 ml of dichloromethane was added dropwise, and the mixture was stirred and reacted for 1 hour. After completion of the reaction, methanol was added and the mixture was further stirred for 30 minutes, and then concentrated under reduced pressure. Dichloromethane was added to the residue for extraction, and the dichloromethane layer was washed with water, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure.
The obtained syrup is subjected to column chromatography [filler:
Wakogel C-200 (trade name of Wako Pure Chemical Industries, Ltd.),
Eluate: CH ₂ Cl ₂ / CH ₃ OH = 150/1] to give compound [IV b]
3.79 g was obtained. Yield 70.5%.

[Α] _D = -1.55 ° (C = 0.900, CHCl ₃ ).

 IR and NMR data were consistent with those of the standard.

(2) Synthesis of Compound [IVa] Dissolve 3.50 g of Compound [IVb] in 150 ml of methanol, and add
6% of palladium-carbon and 2.5 ml of formic acid were added and reacted at 60 ° C. for 1 hour with stirring. After the reaction, the reaction solution was filtered to remove insolubles, and the filtrate was concentrated under reduced pressure. The resulting syrup was subjected to column chromatography [filler: Wakogel C-200 (trade name of Wako Pure Chemical Industries, Ltd.), Eluent: CH ₂ Cl ₂ / CH ₃ OH = 40 /
1] to give 1.90 g of compound [IVa]. Yield 67%.

[Α] _D = -3.693.6 (C = 0.92, CHCl ₃ ).

 IR and NMR data were consistent with the standard.

Reference Example 6. 2- (Trimethylsilyl) ethyl O- (6
-O-benzoyl-β-D-galactopyranosyl)-
(1 → 4) 2,6-di-O-benzoyl-β-D-glucopyranoside (in the general formula [V], R ⁸ = benzoyl group, R
^{9 = -OH, R 10 = H} , the compounds of the TAS = trimethylsilyl group. Hereinafter, it is abbreviated as compound [Va]. (1) 2- (Trimethylsilyl) ethyl O- (3-O-
Benzyl-β-D-galactopyranosyl)-(1 → 4)
Synthesis of -β-D-glucopyranoside (hereinafter abbreviated as compound [Vb]) 2- (trimethylsilyl) ethyl β-D-lactoside
The 6.59g was dissolved in methanol 100 ml, in which (n-C ₄ H ₉₎
4.92 g of ₂ SnO was added, and the mixture was stirred and reacted under reflux for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure and dried sufficiently,
200 ml of benzene was added to dissolve this, and (n-C ₄ H ₉ ) ₄ NB
r4.80 g and benzyl bromide 14.2 ml were added, and the mixture was heated to reflux 3
The reaction was stirred for a period of time. After completion of the reaction, the reaction solution was concentrated under reduced pressure, n-hexane was added to the residue, and excess benzyl bromide was removed by a gradient method. Eluent: ethyl acetate / n-hexane =
4/1] to give 5.96 g of compound [Vb]. Yield 75.2
%. mp 164-167 ° C.

[Α] _D = -0.14 ゜ (C = 1.48, CH ₂ Cl ₂ ).

 IR and NMR data were consistent with those of the standard.

(2) 2- (trimethylsilyl) ethyl O- (6-O-
Benzoyl-3-O-benzyl-β-D-galactopyranosyl)-(1 → 4) -2,6-di-O-benzoyl-β
Synthesis of D-glucopyranoside (hereinafter abbreviated as compound [Vc]) 3.96 g of compound [Vb] was added to 24 ml of pyridine and dichloromethane.
After dissolving in 60 ml of a mixed solvent and cooling to −50 ° C., a solution of 3.6 ml of benzoyl chloride dissolved in 45 ml of dichloromethane was added dropwise thereto, and the mixture was stirred and reacted for 30 minutes. After completion of the reaction, excess benzoyl chloride was decomposed by adding methanol, and then the reaction solution was concentrated under reduced pressure. Dichloromethane was added to the residue for extraction, and the dichloromethane layer was washed with hydrochloric acid and water, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The obtained syrup was subjected to column chromatography [filler: Wakogel C-200 (trade name of Wako Pure Chemical Industries, Ltd.), eluent: CH]
₂ Cl ₂ / CH ₃ OH = 200/1] to give 4.20 g of compound [V c]. Yield 67%.

[Α] _D = + 14.01 ° (C = 0.856, CHCl ₃ ).

 IR and NMR data were consistent with those of the standard.

(3) Synthesis of Compound [Va] 3.36 g of Compound [Vc] was dissolved in 100 ml of methanol, and
% Palladium on carbon 2.4 g and formic acid 2.4 ml
The reaction was stirred for a period of time. After completion of the reaction, the reaction solution was filtered to remove insolubles, and the filtrate was concentrated under reduced pressure. The resulting syrup was subjected to column chromatography [filler: Wakogel C-200].
(Trade name of Wako Pure Chemical Industries, Ltd.), Eluent: CH ₂ Cl ₂ / CH ₃ O
H = 50/1] to give 2.11 g of compound [Va]. Yield 70
%.

[Α] _D = + 11.0311 (C = 0.58, CHCl ₃ ).

 IR and NMR data were consistent with those of the standard.

Example 1. Methyl (methyl 5-acetamido-4,7,8,
9-tetra-O-acetyl-3,5-dideoxy-2-thio-D-glycero-D-galact-2-nonulopyranoside) onate (In the general formula [II], R = acetyl group, R
¹ = Methyl group, R ² = Methyl group compound. Hereinafter, the compound [II
a]. According to the method described in the known literature [Carbohydr. Res., 110 , 11-18 (1982)], methyl esterification of carboxylic acid at the 2-position of N-acetyl-tetra-O-acetylneuraminic acid is carried out. Acetylation of the hydroxyl group at the 2-position to give methyl 5-acetamido-2,4,7,8,9-penta-O-acetyl-3,5-
Dideoxy-D-glycero-D-galact-2-nonulopyrazonate (hereinafter abbreviated as compound [Ia]) was obtained almost quantitatively. Then, 40 g of this compound [Ia] (61
mmol) was dissolved in 600 ml of dry 1,2-dichloroethane, and 27 g of (methylthio) trimethylsilane was added to this solution with stirring.
25 mmol), 13.5 g (61 mmol) of TMS-triflate and 4-10 g of molecular sieves were added, and the mixture was stirred and reacted at 50 ° C. for 6 hours. After confirming the completion of the reaction by thin-layer chromatography, stirring and cooling, 500m of 1M sodium carbonate aqueous solution
l was added and the oil layer was separated. The oil layer is washed with water and anhydrous Na ₂ SO ₄
, And concentrated to obtain a syrup. This was subjected to silica gel column chromatography [filler: Wakogel C
−200 (trade name of Wako Pure Chemical Industries, Ltd.), eluent: CH ₂ Cl ₂ →
CH ₂ Cl ₂ / CH ₃ OH = 200/1 → CH ₂ Cl ₂ / CH ₃ OH = 50/1]
The eluate of H ₂ Cl ₂ / CH ₃ OH = 50/1 was concentrated to give compound [IIa] 3
7.7 g were obtained as amorphous crystals. 96% yield. The anomeric ratio (α: β) of this compound was confirmed to be 1: 1 from the intensity ratio of the methyl ester group in the NMR spectrum.

Example 2. 2- (Trimethylsilyl) ethyl O- (methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galact-2- Nonuropyranosylonate)-(2 → 3) -6
Synthesis of —O-benzoyl-β-D-galactopyranoside (hereinafter abbreviated as compound [VIIa]) 2.7 g (5.2 mmol) of compound [IIa] obtained in Example 1 in 20 ml of dry acetonitrile ) And 1.0 g (2.6 mmol) of the compound [IVa] obtained in Reference Example 5, 3 g of molecular sieves 3Å (hereinafter abbreviated as MS-3A) were added thereto, and the mixture was stirred at room temperature for 5 hours. Afterwards, the mixture was cooled to -40 ° C. Under cooling and stirring, a mixture of DMTST (3 equivalents used for compound [IIa]) and MS-3A (DMTST was added to 61.7%) was added.
% By weight. ) 6.53 g, and the mixture was stirred and reacted at -15 ° C for 17 hours. After the reaction, 1 ml of methanol was added to the reaction solution, and then triethylamine was added to neutralize the reaction solution. The precipitate was collected by filtration, washed with dichloromethane, and the filtrate and the washing were combined and concentrated. The residue was dissolved in dichloromethane, which was washed successively with a 1 M aqueous sodium carbonate solution and water, and dried over anhydrous Na ₂ SO ₄
, And concentrated to obtain a syrup. The syrup was subjected to silica gel column chromatography [filler: Wakogel C-200 (trade name of Wako Pure Chemical Industries, Ltd.), eluent: ethyl acetate / n-hexane = 1/1] to give compound [V
IIa] 1.16 g were obtained as amorphous crystals.

(Bz: benzoyl group, TMS: trimethylsilyl group) Yield 52%. [Α] _D = -6.0 ° (C = 2.0, CHCl ₃ ).

 IR and NMR data were consistent with those of the standard.

In this example, no β-glycoside of sialic acid was obtained at all.

Example 3. 2- (Trimethylsilyl) ethyl O- (methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galact-2- Nonuropyranosylonate)-(2 → 6) -3-
O-benzoyl-β-D-galactopyranoside (hereinafter, referred to as O-benzoyl-β-D-galactopyranoside)
Abbreviated as compound [VIIIa]. In 15 ml of dry acetonitrile, 2.7 g (5.2 mmol) of the compound [IIa] obtained in Example 1 and 1.0 g (2.6 mmol) of the compound [IIIa] obtained in Reference Example 3 were dissolved. MS-3A
After adding 3 g and stirring at room temperature for 6 hours, the mixture was cooled to -40 ° C. DMTST (compound [II
a) and a mixture of MS-3A (DMTST was 61.7 equivalents).
% By weight. ) 6.53 g, and the mixture was stirred and reacted at -15 ° C for 17 hours. Thereafter, post-processing is performed in the same manner as in Example 2,
Purified by column chromatography and ethyl acetate / n
1.56 g of the compound [VIIIa] was obtained as amorphous crystals from an eluent of -hexane = 1/1.

(Bz: benzoyl group, TMS: trimethylsilyl group) Yield 70%. [Α] _D = -6.4 ゜ (C = 0.4, CHCl ₃ ).

 IR and NMR data were consistent with those of the standard.

In this example, no β-glycoside of sialic acid was obtained at all.

Example 4. 2- (Trimethylsilyl) ethyl O- (methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galact-2- Nonulopyranosylonate)-(2 → 3) -O
-(6-O-benzoyl-β-D-galactopyranosyl)-(1 → 4) -2,6-di-O-benzoyl-β-D
Synthesis of Glucopyranoside (hereinafter abbreviated as Compound [IXa]) In Example 3, 1.9 g of the compound [Va] obtained in Reference Example 6 was used instead of 1.0 g of the compound [IIIa]. Otherwise, the reaction and post-treatment were carried out in exactly the same manner as in Example 3, and the mixture was purified by column chromatography to give ethyl acetate / n-
From the eluent of hexane = 4/1, 1.47 g of the compound [IXa] was obtained as amorphous crystals.

(Bz: benzoyl group, TMS: trimethylsilyl group) Yield 48%. [Α] _D = + 10.8 ° (C = 1.74, CHCl ₃ ).

 IR and NMR data were consistent with the standard.

In this example, no β-glycoside of sialic acid was obtained at all.

[Effects of the Invention] The present invention provides a method for easily selecting a 2-α-O-glycoside compound of sialic acid, which is useful as a raw material and an intermediate for various drugs such as gangliosides and analogs thereof, biochemical reagents, and the like. In particular, it has a remarkable effect in that it is the first to provide a method for obtaining a large amount with good yield,
It is a great invention that contributes to the industry.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-2-49794 (JP, A) JP-A-63-41494 (JP, A) CARBOHYDRATE CH EMISTRY, Vol. 9, No. 4 (1990) p. 393-414J. CARBOHYDRATE CH EMISTRY, Vol. 7, No. 2 (1988) p. 501-506 (58) Field surveyed (Int. Cl. ⁷ , DB name) C07H 15/00-15/26 C07H 23/00 CAPLUS (STN) REGISTRY (STN)

Claims (10)

(57) [Claims] 1. A compound of the general formula [I] (Wherein R and R ′ each independently represent an acyl group;
R ¹ represents a lower alkyl group. ) Is reacted with an (alkylthio) trialkylsilane in the presence of a trialkylsilyl ester of perfluoroalkanesulfonic acid to give a general formula [II] (Wherein, R ² represents a lower alkyl group, and R and R ¹ are the same as described above). An anomeric mixture of an alkylthiosialic acid derivative represented by the formula: Production of 2-α-O-glycoside compound of sialic acid, characterized by reacting with a compound having an alcoholic hydroxyl group at temperatures other than room temperature in the presence of triflate, trimethylsilyl triflate or dimethyl (methylthio) sulfonium triflate. Method. 2. A compound having an alcoholic hydroxyl group represented by the general formula [III]: [Wherein, R ³ represents —OH, —NH ₂ , —OR ⁰ or —NHR ⁰ (where R ⁰ represents an acyl group), R ⁴ represents a hydroxyl-protecting group, and R ⁵ and R ^{5 One of 6} represents a hydroxyl group and the other represents a hydrogen atom. TAS represents a trialkylsilyl group. The method according to claim 1, which is a compound represented by the formula: 3. A compound having an alcoholic hydroxyl group,
General formula [IV] (Wherein R ⁷ represents an acyl group, and R ³ , R ⁵ , R ⁶ and TAS are the same as those described above). 4. A compound having an alcoholic hydroxyl group,
General formula [V] (Wherein, R ⁸ represents an acyl group, R ⁹ and R ¹⁰ each represent a hydroxyl group and the other represents a hydrogen atom, and TAS is the same as defined above). The manufacturing method as described. 5. The compound according to claim 1, wherein the compound having an alcoholic hydroxyl group is an aliphatic alcohol represented by the general formula [VI] R ¹¹ OH [VI] (wherein R ¹¹ represents an alkyl group). Manufacturing method. 6. A compound of the general formula [II] (Wherein R, R ¹ and R ² are the same as defined above) in an anomeric mixture of an alkylthiosialic acid derivative in a polar solvent having no hydroxyl group, in a methyltriflate, trimethylsilyltriflate or dimethyl (methylthio) sulfonium A method for producing a 2-α-O-glycoside compound of sialic acid, comprising reacting a compound having an alcoholic hydroxyl group at room temperature or lower in the presence of triflate. 7. A compound having an alcoholic hydroxyl group,
General formula [III] (Wherein R ³ , R ⁴ , R ⁵ , R ⁶ and TAS are the same as described above). 8. A compound having an alcoholic hydroxyl group represented by the general formula [IV]: (Wherein R ³ , R ⁵ , R ⁶ , R ⁷ and TAS are the same as described above). 9. A compound having an alcoholic hydroxyl group,
General formula [V] (Wherein R ⁸ , R ⁹ , R ¹⁰ and TAS are the same as described above). 10. The compound according to claim 6, wherein the compound having an alcoholic hydroxyl group is an aliphatic alcohol represented by the general formula [VI] R ¹¹ OH [VI] (wherein R ¹¹ is the same as defined above). Manufacturing method.