JP2002284792A - Method for producing 1-phosphorylated sugar derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing highly versatile 1-phosphorylated sugar derivatives. SOLUTION: The 1-phosphorylated sugar derivative expressed by general formula (2) or its salt is produced by the phosphorolysis of a 1-halogenated sugar derivative of general formula (1) (W is O or S; Z is O, S or a (substituted) C; and (n) is 0 or 1) while removing water in the phosphoric acid and the reaction solvent by azeotropic dehydration. A concrete example of the production method is the use of a compound of formula (3) as the compound of formula (1) to produce a 1-phosphorylated sugar derivative of formula (4) or its salt as the compound of formula (2).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing a 1-phosphorylated saccharide derivative. 1-Phosphorylated saccharide derivatives widely exist in the living world, serve as reaction substrates for various enzymes, and serve as raw materials for producing useful substances such as pharmaceuticals and nutritional foods. In addition, non-natural 1-phosphorylated saccharide derivatives are expected to be used as raw materials for producing antiviral agents and enzyme inhibitors.

[0002]

2. Description of the Related Art As a method for producing a 1-phosphorylated saccharide derivative, 1) a method of condensing a 1-brominated saccharide with a silver phosphate salt (J.
Biol. Chem. , Vol. 121, P465 (1
937); Am. Chem. Soc. , Vol. 7
8, P811 (1956); Am. Chem. So
c. , Vol. 79, P5057 (1957)), 2) A method of condensing a 1-halogenated sugar with a triethylamine salt of dibenzylphosphoric acid (J. Am. Chem. So
c. , Vol. 77, P3423 (1955); A
m. Chem. Soc. , Vol. 80, P1994
(1958); Am. Chem. Soc. , Vo
l. 106, P7851 (1984); Org. C
hem. , Vol. 59, P690 (1994)), 3) A method of heat-condensing 1-acetylated sugar with orthophosphoric acid (J. Org. Chem., Vol. 27, P1107).
(1962), Carbohydrate Res. ,
Vol. 3, P117 (1966), Carbohyd
rate Res. , Vol. 3, P463 (196
7), Can. J. Biochem. , Vol. 50,
P574 (1972)), 4) A method of imidating and activating the 1-position and then condensing with dibenzyl phosphate (Carbohydrate R)
es. , Vol. 61, P181 (1978), Tet
rahedron Lett. , Vol. 23, P40
5 (1982)), 5) A method of activating the 1-position as thallium or lithium alcoholate, followed by treatment with dibenzyl phosphate chloride (Carbohydrate Res., Vol. 9)
4, P165 (1981), Chem. Lett. , V
ol. 23, P405 (1982)), 6) A method for producing a 1-phosphorylated saccharide derivative by performing a phosphorolytic reaction of a nucleoside by the action of a nucleoside phosphorylase (J. Biol. Chem., Vo).
l. 184, P437, 1950) and the like.

However, each of these methods has problems in the following points.

[0004] The problems common to the chemical production methods 1) to 5) are that the anomeric selectivity of α-form / β-form changes due to the effect of the functional group adjacent to the 1-position, and the desired isomer cannot be obtained. The point is that it is difficult to consider a general synthesis method for obtaining with good selectivity. In order to realize selectivity and high yield, the presence of a 2-position acetoxy group or a 2-position acetamino group is indispensable, and in addition, the 2-position deoxy sugar may be unstable. The range is small. Therefore, for the synthesis of 1-phosphorylated form of deoxypyranose at position 2, since it is difficult to control the anomeric selectivity, purification by column chromatography is required, and only a low yield is obtained [Chem. Zvesti, Vol. 28
(1), P115 (1974), Izv. Akad. N
aux SSSR, Ser. Khim. , Vol. 8,
P1843 (1975)].

[0005] Accordingly, the 1-phosphorylated form of deoxyfuranose at the 2-position, which is more unstable than the 1-phosphorylated form of deoxypyranose at the 2-position and whose selectivity is difficult to control, has not been produced chemically. Not reported.

Regarding 6), it is difficult to supply nucleosides other than ribonucleosides such as inosine which are very limited, and it is necessary to produce only 1-phosphorylated saccharide derivatives such as ribose-1-phosphate. Can not. Furthermore, the cost of the raw material nucleoside itself is not satisfactory because of its high cost.

We have also found that a 1-phosphorylated saccharide derivative is produced by reacting a 1-halogenated saccharide derivative with phosphoric acid. However, since phosphoric acid usually contains water, the water causes decomposition of the 1-halogenated saccharide derivative, so that the desired 1-phosphorylated saccharide derivative cannot be obtained.

As described above, an industrial method for producing a 1-phosphorylated saccharide derivative has not been established.

[0009]

An object of the present invention is to be influenced by differences in sugar skeleton such as furanose and pyranose, presence or absence of a substituent such as deoxy sugar, and types of sugar such as natural type and non-natural type. It is an object of the present invention to provide a method for producing a 1-phosphorylated saccharide derivative which is not widely used.

[0010]

Means for Solving the Problems The present inventors have conducted intensive studies in order to achieve the above object, and have found a method for producing a 1-phosphorylated saccharide derivative by a phosphorolysis reaction of a 1-halogenated saccharide derivative. In the above, by subjecting the water contained in the phosphoric acid and the solvent to be used to azeotropic dehydration, the decomposition of the raw material 1-halogenated sugar derivative can be suppressed, and the desired 1-phosphorylated sugar derivative can be obtained in high yield. I found a thing.

Further, it has been found that the yield can be further improved by performing the azeotropic dehydration at a temperature of 100 ° C. or lower, and the present invention has been completed.

That is, the present invention provides: [1] General formula (1)
[Formula 5]

[0013]

Embedded image Wherein R ¹ and R ² are each independently a hydrogen atom,
Represents a methyl group, a protected hydroxymethyl group or a protected carboxyl group, R ³ represents an acyl group or a sulfonyl group, R ⁴ represents a hydroxyl-protecting group, X represents a halogen atom, an alkoxy group or an alkylthio group. W represents an oxygen atom or a sulfur atom, Y represents a halogen atom, Z represents an oxygen atom, a sulfur atom or an optionally substituted carbon atom, m represents an integer of 1 to 3, and n represents 0 Or 1; p and q each represent an integer of 0 to 4; r represents 0 or 1; (However, p, q,
r and n are p + when Z is an oxygen atom or a sulfur atom.
r ≦ n + 1, q ≦ 2 × (n + 1) −2 × (p + r)
When Z is a carbon atom, p + r ≦ n + 2, q ≦ 2 × (n +
2) Satisfies −2 × (p + r). )] Is phosphorolyzed to give a 1-halogenated sugar derivative represented by the general formula (2)

[0014]

Embedded image (Wherein, R ¹ , R ² , R ³ , R ⁴ , X, W, Z, n, p,
q and r have the same meanings as in the general formula (1). 1)
In the step of producing a phosphorylated sugar derivative and a salt thereof,
A method for producing a 1-phosphorylated sugar derivative represented by the general formula (2), wherein the reaction is carried out by azeotropically dehydrating the phosphoric acid to be used and water in the solvent; The azeotropic dehydration of the contained water is performed at a temperature of 100 ° C. or lower, and the production method according to [1], and [3] a method of azeotropic dehydration at 100 ° C. or lower, has a boiling point of 100 ° C. or higher. When the solvent is used, the boiling point is adjusted to 100 ° C. or less under reduced pressure and azeotropic dehydration is carried out. [4] The phosphoric acid and solvent used in [4] Dehydration so that the amount of water contained in the 1-halogenated sugar derivative represented by the general formula (1) becomes 20 mol% or less, the production method according to [1] to [3], [5] A 1-halogenated sugar derivative represented by the general formula (1) is a compound represented by the formula (3):

[0015]

Embedded image Wherein the 1-phosphorylated saccharide derivative represented by the general formula (2) is a compound represented by the formula (4):

[0016]

Embedded image Is a 1-phosphorylated saccharide derivative and a salt thereof,
The production method according to [1] to [4].

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.

The halogenated saccharide used in the present invention is preferably a 6-deoxy saccharide such as fucose, rhamnose, digitoxose, oleandrose, quinobose, allose, altrose, glucose, mannose, gulose, idose, galactose, Hexoses such as talose, ribose, arabinose, xylose, pentoses such as lyxose, erythrose, tetroses such as threose, glucosamine,
D-series or L-series such as amino sugars such as daunosamine, uronic acids such as glucuronic acid and galacturonic acid, ketoses such as psicose, fructose, sorbose, tagatose and pentulose, and deoxy sugars such as 2-deoxyribose. Residues derived from natural monosaccharides, pyranose-type or furanose-type non-natural saccharides, and sugar residue derivatives in which the hydroxyl group and / or amino group of the sugar group are protected or acylated, or the hydroxyl group thereof Is a saccharide having a halogenated saccharide residue substituted with a halogen atom such as fluorine. In the present invention, the most preferred compound is a deoxy saccharide represented by the formula (3) wherein the hydroxyl group is a halogen such as fluorine. Halogenated saccharides substituted with atoms can be mentioned. The present invention is not limited to.

[0019]

Embedded image In the present invention, the 1-phosphorylated saccharide derivative refers to a saccharide derivative in which the hydroxyl group at the 1-position is phosphorylated among residues derived from a natural monosaccharide or a non-natural saccharide.

The protecting group for protecting the protected hydroxymethyl group represented by R ¹ or R ² and the hydroxyl group represented by R ⁴ is defined by chemical methods such as hydrogenolysis, hydrolysis and photolysis. Refers to protecting groups that are removed. Examples of such a group include a formyl group, an acyl group, a silyl group, an alkyl group, an aralkyl group, and a carbonyl group. Among them, a formyl group, an aliphatic acyl group, an aromatic acyl group, a silyl group, and an alkoxy group are preferable. Examples thereof include an alkyl group, a halogenated alkyl group, an aralkyl group, an alkoxycarbonyl group, and an aralkyloxycarbonyl group.

Examples of the aliphatic acyl group include an alkylcarbonyl group and a halogen-substituted lower alkylcarbonyl group.

Specific examples of the above alkylcarbonyl group include acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonylcarbonyl, decylcarbonyl, Methylnonylcarbonyl group, 8-methylnonylcarbonyl group, 3-ethyloctylcarbonyl group, 3,7-dimethyloctylcarbonyl group, undecylcarbonyl group, dodecylcarbonyl group, tridecylcarbonyl group, tetradecylcarbonyl group, pentadecylcarbonyl Group, hexadecylcarbonyl group, 1-methylpentadecylcarbonyl group, 14-methylpentadecylcarbonyl group, 13,13-dimethyltetradecylcarbonyl group, heptadecylcarbonyl group, 15-methylhexa Sill carbonyl group, and the like can be exemplified octadecyl group.

Specific examples of the halogen-substituted lower alkylcarbonyl group include a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, and a trifluoroacetyl group.

Examples of the aromatic acyl group include an arylcarbonyl group, a halogen-substituted arylcarbonyl group, a lower alkylarylcarbonyl group, a lower alkoxyarylcarbonyl group, a nitroarylcarbonyl group, a lower alkoxycarbonylarylcarbonyl group, and an arylarylcarbonyl group. Can be mentioned.

Specific examples of the above arylcarbonyl group include a benzoyl group, an α-naphthoyl group and a β-naphthoyl group.

As specific examples of the halogen-substituted arylcarbonyl group, 2-fluorobenzoyl group, 3
-Fluorobenzoyl group, 4-fluorobenzoyl group,
2-chlorobenzoyl group, 3-chlorobenzoyl group, 4
-Chlorobenzoyl group, 2-bromobenzoyl group, 3-
Bromobenzoyl group, 4-bromobenzoyl group, 2,4
-Dichlorobenzoyl group, 2,6-dichlorobenzoyl group, 3,4-dichlorobenzoyl group, 3,5-dichlorobenzoyl group, and the like.

Specific examples of lower alkylarylcarbonyl groups include 2-toluyl group, 3-toluyl group,
-Toluyl group, 2,4,6-trimethylbenzoyl group and the like.

Further, specific examples of the lower alkoxyarylcarbonyl group include a 2-anisoyl group, a 3-anisoyl group and a 4-anisoyl group.

Specific examples of the nitroarylcarbonyl group include a 2-nitrobenzoyl group, a 3-nitrobenzoyl group, a 4-nitrobenzoyl group, and a 3,5-dinitrobenzoyl group.

Further, specific examples of the lower alkoxycarbonylarylcarbonyl group include a 2- (methoxycarbonyl) benzoyl group, and specific examples of the arylcarbonyl group include a 4-phenylbenzoyl group.

Examples of the silyl group include a lower alkylsilyl group and a lower alkylsilyl group substituted with an aryl group.

Specific examples of the lower alkylsilyl group include a trimethylsilyl group, a triethylsilyl group, an isopropyldimethylsilyl group, a tert-butyldimethylsilyl group, a methyldiisopropylsilyl group, and a triisopropylsilyl group.

Specific examples of the lower alkylsilyl group substituted with an aryl group include a diphenylmethylsilyl group, a diphenylisopropylsilyl group, and a phenyldiisopropylsilyl group.

Examples of the aralkyl group include an aralkyl group substituted with a lower alkyl group, an aralkyl group substituted with a lower alkoxy group, an aralkyl group substituted with a nitro group,
Examples thereof include an aralkyl group substituted with a halogen and an aralkyl group substituted with a cyano group.

Specific examples of these groups include 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 2-methoxybenzyl, and 3-methoxybenzyl. Benzyl group, 4-methoxybenzyl group, 2-nitrobenzyl group, 3-nitrobenzyl group, 4-nitrobenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2
-Bromobenzyl group, 3-bromobenzyl group, 4-bromobenzyl group, 2-cyanobenzyl group, 3-cyanobenzyl group, 4-cyanobenzyl group and the like.

The aralkyloxycarbonyl group includes
Aralkyloxycarbonyl groups substituted with lower alkyl groups, aralkyloxycarbonyl groups substituted with lower alkoxy groups, aralkyloxycarbonyl groups substituted with nitro groups, aralkyloxycarbonyl groups substituted with halogens, substituted with cyano groups An aralkyloxycarbonyl group and the like can be mentioned.

Specific examples thereof include a 2-methylbenzyloxycarbonyl group, a 3-methylbenzyloxycarbonyl group, a 4-methylbenzyloxycarbonyl group,
2,4,6-trimethylbenzyloxycarbonyl group,
2-methoxybenzyloxycarbonyl group, 3-methoxybenzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 2-nitrobenzyloxycarbonyl group, 3-nitrobenzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group
Nitrobenzyloxycarbonyl group, 2-chlorobenzyloxycarbonyl group, 3-chlorobenzyloxycarbonyl group, 4-chlorobenzyloxycarbonyl group, 2
-Bromobenzyloxycarbonyl group, 3-bromobenzyloxycarbonyl group, 4-bromobenzyloxycarbonyl group, 2-cyanobenzyloxycarbonyl group,
Examples thereof include a 3-cyanobenzyloxycarbonyl group and a 4-cyanobenzyloxycarbonyl group.

Examples of the alkoxycarbonyl group include a lower alkoxycarbonyl group, a halogen-substituted alkoxycarbonyl compound, and an alkoxycarbonyl group substituted with an alkylsilyl group.

Specific examples of lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, sec.
-Butoxycarbonyl group, tert-butoxycarbonyl group and the like.

A specific example of a halogen-substituted alkoxycarbonyl group is a 2,2,2-trichloroethoxycarbonyl group, and a specific example of an alkoxycarbonyl group substituted with a lower alkylsilyl group is a 2-trimethylsilylethoxycarbonyl group. Can be exemplified.

Examples of the alkyl group for protecting the hydroxymethyl group represented by R ¹ or R ² and the hydroxyl group represented by R ⁴ include a methoxymethyl group, an ethoxymethyl group, a 2-methoxyethyl group and a 2-methoxyethoxymethyl Such as an alkoxyalkyl group such as a group, a halogenated alkyl group such as a 2,2,2-trichloroethyl group, a benzyl group, an α-naphthylmethyl group, a β-naphthylmethyl group, a diphenylmethyl group, and a triphenylmethyl group. And lower alkyl groups substituted with an aryl group.

Of these, preferred are an aliphatic acyl group, an aromatic acyl group and an aralkyl group, and more preferred are a 4-toluyl group, a 4-chlorobenzoyl group and a benzyl group.

The protecting group in the protected carboxyl group represented by R ¹ and R ² refers to a protecting group removed by a chemical method such as hydrogenolysis, hydrolysis, and photolysis. As such a group, a lower alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group, Examples thereof include silylated lower alkyl groups such as a (trimethylsilyl) ethyl group and a 2- (triethylsilyl) ethyl group, and the above-mentioned aralkyl groups and alkoxyalkyl groups. More preferably, they are a methyl group, a tert-butyl group, or a benzyl group.

The halogen atom represented by X is a fluorine atom,
Indicate chlorine, bromine or iodine.

Examples of the alkoxy group and alkylthio group represented by X include the above-mentioned lower alkyl group, aralkyl group, alkoxy group having an alkoxyalkyl group, and alkylthio group. More preferably,
A methoxy group, a methoxyethoxy group, and a methylthio group.

The optionally substituted carbon atom represented by Z represents a carbon atom in which one or two substituents represented by the general formula are substituted, and when not substituted, it is substituted by a hydrogen atom. Refers to a carbon atom.

R ³ represents an acyl group or a sulfonyl group. Examples of the acyl group include the above-mentioned aliphatic acyl group, aromatic acyl group, alkoxycarbonyl group, and aralkyloxycarbonyl group. And a lower alkanesulfonyl group such as a methanesulfonyl group and a trifluoromethanesulfonyl group, and an arylsulfonyl group such as a benzenesulfonyl group and a p-toluenesulfonyl group. Preferably, they are an aliphatic acyl group, an aromatic acyl group, and a lower alkanesulfonyl group, and specifically, an acetyl group, a trifluoroacetyl group, a benzoyl group, and a methanesulfonyl group.

The saccharide residue having the general formula (1) or (2) is preferably a residue derived from a natural monosaccharide, a residue derived from an unnatural saccharide, a saccharide residue derivative, or a halogenated saccharide residue. Examples include, but are not limited to, groups.

The most preferred 1-phosphorylated saccharide derivative in the present invention is a salt of a deoxy saccharide represented by the formula (4), but is not limited thereto.

[0050]

Embedded image The salt of the present invention represented by the general formula (2) refers to a salt formed by a phosphate group in the molecule of the compound. In particular,
Salts of alkali metals such as sodium, potassium and lithium, salts of alkaline earth metals such as magnesium, calcium and barium, salts of metals such as aluminum and iron, ammonium salts, primary, secondary and tertiary And the like.

In the above, primary amines include alkylamines such as methylamine, ethylamine, propylamine, isopropylamine, butylamine, hexylamine, octylamine, cycloalkylamines such as cyclohexylamine, and benzylamine. Such can be mentioned.

Examples of the secondary amine include dialkylamines such as diethylamine, diisopropylamine, dibutylamine, dihexylamine and dioctylamine, dicycloalkylamines such as dicyclohexylamine, piperidine, morpholine and N-methyl. A cyclic amine such as piperazine can be exemplified.

As the tertiary amine, trimethylamine,
Triethylamine, tripropylamine, N-ethyldiisopropylamine, tributylamine, trihexylamine, trioctylamine, N-ethyldicyclohexylamine, N-methylpiperidine, N-methylmorpholine, N, N, N ', N'- Tertiary alkylamines such as tetramethylethylenediamine, aniline, N,
N-dimethylaniline, N, N-diethylaniline,
Anilines such as N, N-dibutylaniline, N, N-dioctylaniline, salts of pyridines such as pyridine, 2,6-dimethylpyridine, 2,4,6-lutidine, nicotinamide, glycine, alanine; Amino acids such as proline, lysine, arginine, glutamine, cinchonidine, 1- (1-naphthyl) ethylamine, 1-
Examples include optically active amines such as phenylethylamine, and all include monovalent or divalent salts.

Further, the compound represented by the general formula (2) or (4) of the present invention absorbs water when left in the air, and may become adsorbed water or form a hydrate. However, such salts are also included in the present invention.

The 1-phosphorylated saccharide derivative in the present invention is obtained by the reaction formula (A)

[0056]

Embedded image Can be manufactured. (Where R ¹ ,
R ² , R ³ , R ⁴ , X, W, Z, n, p, q and r are
As defined in the above formula (1), Y represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. )

The phosphoric acid is preferably one having a low water content such as orthophosphoric acid, but is not particularly limited. For example, phosphoric acid and water obtained by hydrolyzing pyrophosphoric acid and polyphosphoric acid are used. Industrially used phosphoric acid containing 25% or recovered phosphoric acid may be used.

The solvent used for azeotropic dehydration is not particularly limited as long as it has an azeotropic composition with water, and can be used as it is as a reaction solvent for the 1-phosphosaccharide derivative.
For example, benzene, toluene, xylene, mesitylene,
Aromatic hydrocarbons such as chlorotoluene and dichlorotoluene; ketones such as methyl isopropyl ketone, methyl isobutyl ketone and methyl ethyl ketone; halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane; and fats such as hexane, heptane, nonane and decane Group hydrocarbons, ethyl formate, ethyl acetate, propyl acetate, n-butyl acetate, esters such as diethyl ester, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethers such as diglyme, and the like. Or a mixed solvent of one or three selected from them, preferably an aromatic hydrocarbon such as toluene or benzene, or a ketone such as methyl isobutyl ketone or methyl ethyl ketone. Door can be.

The amount of the solvent used in the azeotropic dehydration is not particularly limited as long as it does not affect the dehydration, but is preferably 0.5 to 20 times by weight, more preferably 5 to 15 times, the weight of phosphoric acid.
Weight times. After dehydration, this amount may be used as a reaction solvent.

The azeotropic dehydration temperature is not particularly limited, and is preferably carried out at the boiling point of the solvent. However, at a high temperature, the reaction yield is reduced due to the influence of the decomposition product of phosphoric acid. In addition, the boiling point is 1
For solvents exceeding 00 ° C., azeotropic dehydration is performed under reduced pressure, and the temperature is reduced to 0 ° C. to 100 ° C., preferably 30 to 80 ° C.
Temperature can be adjusted to ° C.

The degree of reduced pressure used for lowering the azeotropic dehydration temperature is arbitrarily determined depending on the boiling point of the solvent and the temperature at which dehydration is performed, but is preferably from 0.1 kPa to atmospheric pressure.

The azeotropic dehydration time is determined by the amount of water contained, but is preferably from 2 hours to 48 hours.

The reaction temperature between the dehydrated phosphoric acid and the 1-halogenated sugar derivative is not particularly limited, and is preferably in the range of -80 ° C to 60 ° C, more preferably -10 ° C to 25 ° C.

The reaction time varies depending on the types of starting materials, reagents and solvents, and the reaction temperature, but is preferably from 1 minute to 48 hours, more preferably from 10 minutes to 15 hours.

Since the 1-halogenated sugar derivative represented by the general formula (1) is decomposed in an equimolar amount to the water content, the water content must be reduced as much as possible. The amount of water in the phosphoric acid solution after dehydration is preferably 20 mol% or less, more preferably 10 mol% or less, based on the 1-halogenated sugar derivative used.

The ratio of the 1-halogenated sugar derivative to phosphoric acid in this reaction is not particularly limited, and is preferably 1-halogenated sugar derivative: phosphoric acid = 1: 1 to 1:10, more preferably 1: 1. : 1.5 to 1: 5.

The base used in the reaction is prepared by selectively crystallizing either the α- or β-form of the resulting 1-phosphorylated sugar derivative monomer to tilt the equilibrium of the anomeric mixture, and to form the α- or β-form of the 1-phosphorylated derivative monomer. Used to selectively manufacture one of the bodies. Usually, an optimum base can be selected in combination with a solvent used in the reaction, but preferably, the above-mentioned inorganic bases, tertiary alkylamines, anilines, pyridines, amino acids, optically active amines Can be mentioned.

The ratio of the 1-halogenated sugar derivative to the base in this reaction is not particularly limited, and the reaction is preferably carried out in the range of 1-halogenated sugar derivative: base = 1: 0.5 to 1: 5. be able to. At that time, the pH in the reaction system is desirably on the acidic side, preferably 1 to 7, more preferably 1 to 4.

The reaction is preferably performed in the presence of a solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction, and the solvent used in the azeotropic dehydration operation may be used as it is, or the solvent may be replaced. As a method for replacing the solvent, it can be usually achieved by concentrating a solvent used for azeotropic dehydration under reduced pressure and replacing the solvent with a reaction solvent. When the solvent is replaced, a sufficiently dehydrated solvent is used so that the amount of water in the reaction mass after the solvent replacement does not exceed 20 mol% based on the 1-halogenated sugar derivative used.

As the solvent used as the reaction solvent,
For example, aliphatic hydrocarbons such as hexane and heptane, aromatic hydrocarbons such as benzene, toluene, xylene and anisole, halogenated compounds such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene. Hydrocarbons, ethyl formate, ethyl acetate, propyl acetate, n-butyl acetate, esters such as diethyl carbonate, diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane, diglyme, nitriles such as acetonitrile, propionitrile, isobutyronitrile, formamide, N, N
Amides such as -dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, N, N-dimethyl-2-imidazolidinone, acetone, 2-butanone, methyl isopropyl ketone And ketones such as methyl isobutyl ketone or a mixed solvent of one to three selected from them, preferably ketones such as methyl isobutyl ketone and methyl ethyl ketone or nitriles such as acetonitrile. .

The amount of the solvent used in the reaction is not particularly limited as long as it does not affect the reaction, but is preferably 0.5 to 20 times, more preferably 5 to 15 times the weight of phosphoric acid.

Further, the produced 1-phosphorylated saccharide derivative is subjected to salt exchange reaction, purified, and taken out as a phosphate having a base different from the base used in the reaction system.

The base used here includes the above-mentioned inorganic bases, primary alkylamines, secondary alkylamines, tertiary alkylamines, anilines, pyridines, and the like.
Amino acids and optically active amines can be mentioned, and the salts formed include monovalent or divalent salts.

The 1-phosphorylated saccharide derivative thus produced is isolated by applying a conventional method such as concentration, crystallization, dissolution, column chromatography, adsorption / desorption treatment with an ion exchange resin or activated carbon. Can be.

[0075]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

Analytical Method (1) Analysis of Water in Dehydrated Solvent About 0.2 g of dehydrated solvent was injected into a Karl-Fischer moisture meter and analyzed. (2) Analysis of 1-phosphorylated sugar derivative

[0077]

[Table 1] Example 1 3,5-O-bis (4-chlorobenzoyl) -2-deo
Xy-α-D-ribose-1-phosphate (5) A mixture of 15.4 g of 89% phosphoric acid (Mitsui Chemicals, containing 11% water) and 154.8 g of methyl isobutyl ketone in a reactor equipped with a Dean-Stark trap. , The boiling point of the solvent (116
° C) and azeotropically dehydrated. At this time, the water content in the azeotropic dewatered mass was 880 ppm. Further, 86 g of methyl isobutyl ketone is added to the reaction mass, and 85 g of the solvent is distilled off. At this time, the water content in the mass after the azeotropic dehydration is 270 ppm.
(5 mol% based on 1-halogenated sugar). Tri-n-butylamine 8.6 was added to the phosphoric acid solution thus obtained.
g was added and cooled to 5 ° C. while stirring. In addition, 3,5
—O-bis (4-chlorobenzoyl) -2-deoxy-
23.6 g of α-D-ribosyl chloride (85% purity) was added and stirred for 5 hours. When the amount of the title compound (5) formed in the obtained suspension solution was examined, 16.5 g (yield 72.2%) was obtained.
Met.

Example 2 3,5-O-bis (4-chlorobenzoyl) -2-deo
Xy-α-D-ribose-1-phosphate (5) A mixture of 15.4 g of 89% phosphoric acid (Mitsui Chemicals, containing 11% water) and 157.6 g of methyl isobutyl ketone in a reactor equipped with a Dean-Stark trap. Under reduced pressure, the degree of reduced pressure was adjusted so that the reflux temperature was 80 ° C., and azeotropic dehydration was performed. At this time, the water content in the mass after the azeotropic dehydration was 640 ppm. Further, 85.2 g of methyl isobutyl ketone was added to the reaction mass, and 87 g of the solvent was distilled off. At this time, the amount of water in the azeotropic dehydrated mass was 190 ppm (4 to 1-halogenated sugar derivative).
Mol%). 8.6 g of tri-n-butylamine was added to the phosphoric acid solution thus obtained, and the mixture was cooled to 5 ° C. with stirring. Further, 23.6 g of 3,5-O-bis (4-chlorobenzoyl) -2-deoxy-α-D-ribosyl chloride (purity: 85%) was added, and the mixture was stirred for 5 hours. When the amount of the title compound (5) produced in the obtained suspension solution was examined, it was 18.3 g (82.6% yield).

Example 3 3,5-O-bis (4-chlorobenzoyl) -2-deo
Xy-α-D-ribose-1-phosphate (5) A mixture of 15.4 g of 89% phosphoric acid (Mitsui Chemicals, containing 11% water) and 157.6 g of methyl isobutyl ketone in a reactor equipped with a Dean-Stark trap. Under reduced pressure, the degree of reduced pressure was adjusted so that the reflux temperature was 60 ° C., and azeotropic dehydration was performed. At this time, the water content in the mass after the azeotropic dehydration was 530 ppm. Further, 79.2 g of methyl isobutyl ketone is added to the reaction mass, and 81 g of the solvent is distilled off. At this time, the water content in the azeotropic dehydrated mass was 330 ppm (7 mol% based on 1-halogenated sugar). 8.6 g of tri-n-butylamine was added to the phosphoric acid solution thus obtained, and the mixture was cooled to 5 ° C. with stirring. Further, 23.6 g of 3,5-O-bis (4-chlorobenzoyl) -2-deoxy-α-D-ribosyl chloride (purity: 85%) was added, and the mixture was stirred for 5 hours. When the production amount of the title compound (5) in the obtained suspension solution was examined,
The amount was 19.6 g (yield: 85.4%).

Example 4 3,5-O-bis (4-chlorobenzoyl) -2-deo
Xy-α-D-ribose-1-phosphate (5) A mixture of 15.4 g of 89% phosphoric acid (Mitsui Chemicals, containing 11% water) and 157.6 g of methyl isobutyl ketone in a reactor equipped with a Dean-Stark trap. Under reduced pressure, the degree of reduced pressure was adjusted so that the reflux temperature was 40 ° C., and azeotropic dehydration was performed. At this time, the water content in the mass after azeotropic dehydration was 420 ppm. Further, 76.8 g of methyl isobutyl ketone is added to the reaction mass, and 78.6 g of the solvent is distilled off. At this time, the amount of water in the azeotropic dehydrated mass was 160 ppm (7 mol% based on 1-halogenated sugar). 8.6 g of tri-n-butylamine was added to the phosphoric acid solution thus obtained, and the mixture was cooled to 5 ° C. with stirring. Further, 23.6 g of 3,5-O-bis (4-chlorobenzoyl) -2-deoxy-α-D-ribosyl chloride (purity: 85%) was added, and the mixture was stirred for 5 hours. When the production amount of the title compound (5) in the obtained suspension solution was examined,
The amount was 19.5 g (yield: 85.1%).

Comparative Example 1 3,5-O-bis (4-chlorobenzoyl) -2-deo
Xy-α-D-ribose-1-phosphate (5) 98% phosphoric acid (Aldrich product, containing 2% water) 13.68
g and methyl ethyl ketone 161 g in a mixture of tri-n-
9.06 g of butylamine was added, and the mixture was cooled to 5 ° C. while stirring. When the water in the solution was measured, 1500 pp
m (33 mol% based on 1-halogenated sugar). Further, 3,5-O-bis (4-chlorobenzoyl) -2
-Deoxy-α-D-ribosyl chloride (purity 85
%) And stirred for 5 hours. 3,5-O-bis (4-chlorobenzoyl) -2 in the resulting suspension
The amount of -deoxy-α-D-ribose-1-phosphate (5) produced was 9.1 g (40% yield).

Comparative Example 2 3,5-O-bis (4-chlorobenzoyl) -2-deo
Xy-α-D-ribose-1-phosphate (5) 89% phosphoric acid (Mitsui Chemicals, containing 11% water) 15.3
To a mixture of 7 g and 161 g of methyl ethyl ketone
9.06 g of -butylamine was added, and the mixture was cooled to 5 ° C with stirring. When the water in the solution was measured,
pm (140 mol% based on 1-halogenated sugar). Further, 23.5 g of 3,5-O-bis (4-chlorobenzoyl) -2-deoxy-α-D-ribosyl chloride (purity: 85%) was added, and the mixture was stirred for 5 hours. When the amount of the title compound (11) produced in the obtained suspension solution was examined, it was 2.0 g (8.8% yield).

Reference Example 1 The solution of 3,5-O-bis (4-chlorobenzoyl) -2-deoxy-α-D-ribose-1-phosphate (5) obtained in Example 3 in methyl isobutyl ketone was used. Neutralize and dissolve with 30.0 g of tri-n-butylamine, and wash twice with 100 g of water. To the obtained organic layer, 11.6 g of cyclohexylamine was added at room temperature, and after 1 hour, the precipitated crystals were collected by filtration and dried under reduced pressure to give 26.4 g of the dicyclohexylamine salt of the title compound (5) (yield: 3,3). 5-O-bis (4-
(Chlorobenzoyl) -2-deoxy-α-D-ribosyl chloride (82%). ¹ H NMR (DMSO-d ₆ , 270 MHz) d 8.00 (d, J = 8.6 Hz, 2
H), 7.96 (d, J = 8.6 Hz, 2 H), 7.58 (d, J = 8.6 H
z, 2 H), 7.58 (d, J = 8.6 Hz, 2 H), 5.82 (dd, J =
5.3, 5.3 Hz, 1 H), 5.36 (d, J = 8.6 Hz, 1 H), 4.6-
4.3 (m, 3 H), 4.7-3.5 (br, 6 H), 2.7-2.6 (m, 2 H),
2.55-2.4 (m, 1 H), 2.25 (d, J = 4.2 Hz, 1 H), 1.8
5-1.75 (m, 4 H), 1.7-1.6 (m, 4 H), 1.55-1.45 (m, 2
H), 1.25-0.9 (m, 10 H), MS (APCI) m / z 590 (M + C6H
14N)

Reference Example 2 Synthesis of 2-deoxy-α-D-ribose-1-phosphate (6) 25 g of the dicyclohexylamine salt of the compound (5) obtained in Example 7 was added to 296 g of methanol and 28% ammonia water 6
After suspending in 8 g of the mixed solution and stirring at room temperature for 28 hours, the precipitated crystals were collected by filtration, dried at room temperature under reduced pressure, and 7.2 g of the ammonium salt of the title compound (6) (80.0% yield).
Was obtained as a colorless powder. ¹ H NMR (D ₂ O, 270 MHz) d 5.56 (s, 1 H), 4.03 (m, 2
H), 3.52 (dd, J = 3.3,12.2 Hz, 1 H), 3.41 (dd, J =
5.3, 12.2 Hz, 1 H), 2.17 (m, 1 H), 1.87 (d, J =
13.9 Hz, 1 H), MS (APCI) m / z 213 (MH)

[0085]

INDUSTRIAL APPLICABILITY The present invention is expected to be widely used as an industrial process for producing 1-phosphorylated sugar derivatives with high yield and high versatility.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Kiyoteru Nagahara 30 Asamuta-cho, Omuta-shi, Fukuoka Mitsui Chemicals Co., Ltd. F-term (reference) 4C057 BB02 CC02 DD02 HH04 4H050 AA02 AC40 BA51 BB16 BB71 BC10 BC31 BC34 BC35 BE04

Claims (5)

[Claims] 1. A compound of the general formula (1) Wherein R ¹ and R ² are each independently a hydrogen atom,
Represents a methyl group, a protected hydroxymethyl group or a protected carboxyl group, R ³ represents an acyl group or a sulfonyl group, R ⁴ represents a hydroxyl-protecting group, X represents a halogen atom, an alkoxy group or an alkylthio group. W represents an oxygen atom or a sulfur atom, Y represents a halogen atom, Z represents an oxygen atom, a sulfur atom or an optionally substituted carbon atom, m represents an integer of 1 to 3, and n represents 0 Or 1; p and q each represent an integer of 0 to 4; r represents 0 or 1; (However, p, q,
r and n are p + when Z is an oxygen atom or a sulfur atom.
r ≦ n + 1, q ≦ 2 × (n + 1) −2 × (p + r)
When Z is a carbon atom, p + r ≦ n + 2, q ≦ 2 × (n +
2) Satisfies −2 × (p + r). )] Is phosphorolyzed to give a 1-halogenated sugar derivative represented by the following general formula (2): (Wherein, R ¹ , R ² , R ³ , R ⁴ , X, W, Z, n, p,
q and r have the same meanings as in the general formula (1). 1)
In the step of producing a phosphorylated sugar derivative and a salt thereof,
A method for producing a 1-phosphorylated sugar derivative represented by the general formula (2), wherein the reaction is carried out by azeotropically dehydrating phosphoric acid to be used and water in a solvent. 2. The method according to claim 1, wherein the azeotropic dehydration of the water contained in the phosphoric acid and the solvent is carried out at a temperature of 100 ° C. or lower. 3. A method of performing azeotropic dehydration at 100 ° C. or lower, wherein a solvent having a boiling point of 100 ° C. or higher is used under reduced pressure.
The method according to claim 1 or 2, wherein the azeotropic dehydration is performed by adjusting the boiling point to 100 ° C or lower. 4. An azeotropic dehydration method wherein the amount of water contained in the phosphoric acid and the solvent used is 20 mol% or less with respect to the 1-halogenated sugar derivative represented by the general formula (1). 4. The method according to claim 1, wherein: 5. A 1-halogenated sugar derivative represented by the general formula (1) is a compound represented by the formula (3): A compound represented by the general formula (2):
The phosphorylated saccharide derivative has the formula (4) The method according to any one of claims 1 to 4, which is a 1-phosphorylated saccharide derivative or a salt thereof represented by the formula: