WO2002051852A1

WO2002051852A1 - Process for producing nonnatural saccharide derivative

Info

Publication number: WO2002051852A1
Application number: PCT/JP2001/011561
Authority: WO
Inventors: Hideki Umetani; Tomoyuki Ando; Junya Fujiwara
Original assignee: Mitsui Chemicals, Inc.
Priority date: 2000-12-27
Filing date: 2001-12-27
Publication date: 2002-07-04

Abstract

A process in which a nonnatural halogenated saccharide derivative obtained anomer-selectively is subjected to phosphorylation under such conditions that epimerization is inhibited to thereby obtain the desired anomer of a 1-phosphorylated saccharide derivative. This technique is useful for the anomer-selective production of a nonnatural 1-phosphorylated saccharide derivative useful as a starting material for an antiviral agent, enzyme inhibitor, etc.

Description

Specification

Manufacturing method of unnatural sugar derivatives

The present invention relates to a method useful for producing a non-naturally occurring mono-monophosphorylated sugar derivative in a anomeric selective manner, a compound used therefor, and a method for producing the same.

Background technology

Unnatural mono-phosphorylated saccharide derivatives are expected to be used as raw materials for the production of antiviral agents and enzyme inhibitors. In recent years, nucleosides having an unnatural sugar structure have attracted attention as antiviral drugs. For example, compounds having a thioxolan structure have been reported in EP 3 82526, Drug soft furniture 2000, 25 (8), 855-857, In WO 0009494 and the like, compounds having a dioxolane structure are known from JP-A-8-501086, Drug soft Future 2000, 25 (5), 454-461, WO 0039143 and the like.

1 As a method for producing a monophosphorylated sugar derivative,

1) Method of condensing 1-brominated sugar with silver phosphate (J. Biol. Chem., Vo. 121, P465 (1937), J. Am. Chem. Soc) , Vol. 78, P 811 (1956), J. Am. Chem. Soc., Vol. 79, P 5057 (1957)),

2) 1 Condensation of monohalogenated sugar with triethylamine salt of dibenzyl phosphate (J. Am. Chem. Soc., Vol. 77, P 3423 (1955), J.

Am. Chem. Soc., Vol. 80, P 1994 (1958), J. Am. Chem. Soc., Vol. 106, P 7851 (1984), J. Org. Chem. , Vol. 59, P 690 (1994)),

3) Heat condensing monoacetylated sugar with orthophosphoric acid (J. Org. Chem., Vol. 27, P 1107 (1962), Carbohyd rate Res., Vo l. 3, P 117 (1966), Car bohyd rate Res., Vo 1.3, P 463 (1967), Can. J. Bio chem., Vo l. 50, P 574 (1972)) ,

4) A method of condensing with dibenzyl phosphate after activating the 1-position by imidation (Carbohyd rate Res., Vol. 61, P 181 (1978) Tet ahedron on Lett., Vol. 23, P 405 (1982)),

5) Activation of 1-position as thallium or lithium alcoholate followed by treatment with dibenzyl phosphate (Carbohyd rate Res., Vo1.94, P165 (1981), Chem. Lett., Vo) l. 23, P405 (198 2))

6) A method for producing 1-monophosphorylated sugar derivatives by phosphorylation of nucleosides by the action of nucleoside phosphorylase (J. Biol. Chem., Vo 1.184, Ρ437, 1950), etc. Are known.

However, each of these methods has the following problems.

The common problem with the chemical production methods 1) to 5) is that the anomeric selectivity of α-form Ζ 3 is affected by the functional group adjacent to the 1-position, and the desired isomer has good selectivity. The point is that it is difficult to consider a general synthesis method to obtain a good result. In order to achieve selectivity and high yield, the presence of 2-acetoxy group or 2-acetamino group is indispensable, and in addition, 2-position deoxy sugar may be unstable. The range is small. Therefore, it is difficult to control the anomeric selectivity in the synthesis of 1-phosphorylated form of 2-hydroxypyroxypyranose, so column chromatography purification is required, and only low yields are obtained [Chem Zve sti, Vol. 28 (1), P115 (1974), Izv. Akad. Nauk SSSR, Ser. Khim., Vol. 8, P1843 (1975)].

Therefore, the mono-phosphorylated form of 2-position deoxyfuranoses, which is more unstable and difficult to control the selectivity than the mono-phosphorylated form of 2-position deoxypyranose, has been produced by chemical production. Has not been reported. Regarding 6), it is difficult to supply nucleosides other than very limited liponucleosides such as inosine, and only limited 1-phosphorylated sugar derivatives such as report-1-phosphate can be produced. In addition, the cost of the raw material nucleosides themselves is not satisfactory because of their high cost.

As described above, an industrial production method for a 1-phosphorylated saccharide derivative, particularly, a non-natural type 1-monophosphorylated saccharide derivative such as a compound having a thioxolan structure and a dioxolane structure has not been established yet. 'Furthermore, even when a single anomer of a non-natural type 1 monochlorinated saccharide is obtained, it is expected that epimerization will occur as a side reaction during the phosphorylation reaction. Therefore, in the production of anomeric-selective mono-phosphorylated saccharides, control of epimerization during phosphorylation was also an issue.

On the other hand, for a method for synthesizing a non-natural octalogenated saccharide derivative which can be used for the production of a non-natural mono-phosphorylated derivative, see Japanese Patent Application Laid-Open No. 2000-501714, etc. A method for synthesizing xymethyl-4-hydroxy-1,3-dioxolane is disclosed. However, in this synthetic method, the product is given as a mixture of the top anomas. As described above, the non-natural halogenated sugar derivative requires a stereoselective synthesis method, which may be an intermediate for the production of a non-natural nucleoside. Yes not yet known. Disclosure of the invention

An object of the present invention is to provide a method for selectively producing a non-naturally occurring mono-phosphorylated sugar derivative by an anomer. Another object of the present invention is to provide a non-natural 1-phosphorylated saccharide derivative useful as a raw material for producing an antiviral agent or an enzyme inhibitor. Another object of the present invention is to provide a method for producing a non-natural octogenated saccharide derivative useful for anomeric selective production of a non-natural 1-phosphorylated saccharide derivative, and a non-natural halogenated saccharide obtained by the method. An object of the present invention is to provide a derivative and a sugar derivative useful for producing the non-natural halogenated sugar derivative.

The present inventors have made intensive studies to achieve the above object and can suppress epimerization. It has been found that a desired 1-phosphorylated saccharide derivative can be obtained with high anomeric selectivity from a halogenated sugar such as a single anomeric chlorinated sugar by using a means such as performing a phosphorylation reaction under conditions.

Furthermore, a method for anomeric selective production of the octogenated saccharide derivative as a raw material for producing the above monophosphorylated saccharide derivative was established, whereby the anomeric selection of the above monophosphorylated saccharide derivative was established. It has been found that the sex can be further improved. The present invention has been made based on these findings.

That is, the present invention includes the following embodiments.

[1] A method for producing an α-form or a) -form 3 of a non-natural type 1 monophosphorylated saccharide derivative, wherein the formula (1)

, 0 (1)

(Wherein, W is a hydroxyl-protecting group, X and 酸素 are each independently an oxygen atom or an ゥ atom, and Ζ is a halogen atom). Phosphorylating the saccharide derivative, the formula (2)

(Wherein, W, X and Y are as defined above.)

The anomeric configuration of the halogenated sugar derivative represented by the formula (1) is inverted by the phosphorylation, and one of the desired a-form or / 3 form of the monophosphorylated sugar derivative represented by the formula (2) is obtained. Selectively get A method for producing a non-natural type 1-monophosphorylated saccharide derivative, characterized in that: Formula (1) represents either the Q! Or / 3 isomer of the octogenated saccharide derivative. In this production method, the mono-phosphorylated saccharide is converted from the α-form of the halogenated saccharide derivative. Either one of the following two cases is obtained: a case where 8 derivatives of the derivative are obtained, a case where a single monophosphorylated sugar derivative is obtained from 0 of the halogenated sugar derivative.

[2] The unnatural halogenated sugar derivative which is one of the anomers represented by the formula (1) is

Equation (4)

(In the formula, X and 独立 each independently represent an oxygen atom or a sulfur atom, R represents a hydrogen atom, an alkyl group, an alkenyl group, or an acyl group, and W represents a hydroxyl-protecting group.) Obtaining an anomeric mixture of a non-natural halogenated sugar derivative in which the -OR group in the formula (4) is substituted with a halogen atom using a halogenating agent for the sugar derivative, and the α-form or the isomer contained in the mixture. Selectively crystallization of one to incline the equilibrium between the anomeric mixture and selectively obtain either the α-form or the / 3-form of the halogenated sugar derivative represented by the formula (1);

The method according to the above item [1], which is obtained by a method having the following.

[3] The above item [1] or [2], wherein the three-dimensional structure of the unnatural octalogenated sugar derivative is a β-D form, and the three-dimensional structure of the unnatural 1-lyin oxidized sugar derivative is an α-D form. The method described in.

[4] The method according to any one of the above items [1] to [3], wherein X is an oxygen atom.

[5] The method according to the above item [4], wherein Υ is an oxygen atom. [6] The method according to any one of the above items [1:] to [4], wherein Z is a chlorine atom.

[7] The method according to any one of the above items [1] to [5], wherein W is an unsubstituted or substituted aromatic acyl group.

[8] The method according to the above item [7], wherein W is 412 trobenzoyl group.

[9] A non-naturally occurring mono-phosphorylated saccharide derivative represented by the following formula (2a): a

ο

ρ ο ..

O ΗH-one a)

Ya ο (2

(In the above formula (2a), X a and Y a both represent an oxygen atom, and Wa represents a 412 trobenzoyl group.)

[10] A method for producing an unnatural monophosphorylated sugar derivative,

Equation (2)

(Wherein, W represents a hydroxyl-protecting group, and X and Y each independently represent an oxygen atom or a zeolite atom). And equation (3)

(Wherein, X and Y have the same meanings as described above.) A non-natural type mono-phosphorylated sugar derivative represented by the formula:

[11] The method according to the above item [10], wherein X is an oxygen atom.

[12] The method according to the above item [11], wherein Υ is an oxygen atom.

[13] The method according to any one of the above items [10] to [12], wherein W is an unsubstituted or substituted aromatic acyl group.

[14] The method according to the above item [13], wherein W is a 412 trobenzoyl group.

[15] A method for selectively producing one of a non-natural halogenated sugar derivative in a spider body or a zero body,

Equation (4)

(Wherein, X and それぞれ each independently represent an oxygen atom or a sulfur atom, R represents a hydrogen atom, an alkyl group, an alkenyl group, or an acyl group, and W represents a hydroxyl-protecting group.) Obtaining an anomeric mixture of a non-natural halogenated sugar derivative in which one OR group in the formula (4) is substituted with a halogen atom by using a halogenating agent for the sugar derivative. By selectively crystallizing one of the bodies, Tilting the equilibrium between the monomer mixture, the following equation (1)

(Wherein, X, Y and W are the same as above, and Z represents a halogen atom.) A step of selectively obtaining one of three or three halogenated sugar derivatives represented by the following formula: A method for selectively producing one of the unnatural or halogenated sugar derivative.

[16] The method according to the above item [15], wherein X and Y are both oxygen atoms.

[17] The method according to the above item [15] or [16], wherein Z is a chlorine atom.

[18] The above item [15] or [1], wherein W is an unsubstituted or substituted aromatic acyl group.

6].

[19] The method according to the above item [15] or [16], wherein W is 412 trobenzoyl group.

[20] A non-natural halogenated sugar derivative represented by the formula (1a):

(In the formula, X and Y each independently represent an oxygen atom or an io atom, Z represents a halogen atom, and Wa represents a nitrobenzoyl group.)

[21] The compound according to the above item [21], wherein X and Y are both oxygen atoms, W is a 4-nitrobenzoyl group, and Z is a chlorine atom.

[22] Equation (4)

(In the formula, X and Y each independently represent an oxygen atom or a sulfur atom, R represents a hydrogen atom, an alkyl group, an alkenyl group, or an acyl group, and W represents a substituted aromatic acyl group.) A non-natural type sugar derivative represented by the formula:

[23] The compound according to the above item [22], wherein W is a nitrobenzoyl group.

[24] The compound according to the above item [23], wherein X and Υ are oxygen atoms, W is a 4-nitrobenzoyl group, and R is an acetyl group.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

In the present invention, 1 mono-phosphorylated sugar derivative refers to a sugar derivative in which the 1-hydroxyl group is phosphorylated among the residues of unnatural sugars, and unless otherwise specified, monomer 1, dimer 1 Trimers may also be included or a mixture of them may be used, and the ratio is not particularly limited.

The “protecting group” of the hydroxyl group represented by W in the above formula (1) or the like refers to a protecting group that is removed by a chemical method such as hydrogenolysis, hydrolysis, or photolysis. Examples of such a group include an acyl group, a silyl group, an alkyl group, an aralkyl group, and a carbonyl group. Of these, an aliphatic acyl group, an aromatic acyl group, an alkoxyalkyl group, a halogenated alkyl group, and an aralkyl group are preferred. And an alkoxycarbonyl group and an aralkyl carbonyl group.

Examples of the aliphatic acryl group that can function as the above-mentioned protective group include an alkyl group or a halogen-substituted lower alkylcarbonyl group. Specific examples of the above alkylcarbonyl group include acetyl group, propionyl group, butyryl group, isoptyryl group, pentanoyl group, pivaloyl group, valeryl group, isovaleryl group, octanoyl group, nonylcarbonyl group, decylcarbonyl group, and 3-methylethyl group. Lunonyl carbonyl, 8-methyl nonyl carbonyl, 3-ethyl octyl carbonyl, 3,7-dimethyl octyl carbonyl, pendecyl carbonyl, dodecyl carbonyl, tridecyl carbonyl, tetradecyl Carponyl group, pen decyl carbonyl group, hexadecyl carbonyl group, 1-methyl pent decyl carbonyl group, 14-methyl pent decyl carbonyl group, 13, 13-dimethyl tetradecyl carbonyl group, heptadecyl carbonyl group, 15 —Methylhexadeci Cal Poniru group, and the like can be exemplified O Kuta de Circa Lupo 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 capable of functioning as the protective group include an arylcarbonyl group, a halogen-substituted arylaryl group, a lower alkylated arylaryl group, and a lower alkoxyarylcarbonyl group as a substituted aromatic acyl group. And a nitrated arylcarbonyl group, a lower alkoxylated arylcarbonyl group, and an arylphenylcarbonyl group.

Specific examples of the above arylcarbonyl group include a benzoyl group, a mononaphthoyl group, and a 3-naphthoyl group.

Specific examples of the above-mentioned halogen-substituted arylcarbonyl group include 2-fluorobenzoyl group, 3-fluorobenzoyl group, 4-fluorobenzoyl group, and 2-chlorobenzoyl group. , 3-cyclobenzoyl group, 4-monobenzoyl group, 2-bromobenzoyl group, 3-bromobenzoyl group, 4-bromobenzoyl group, 2,4-dichlorobenzoyl group, 2,6-dichlorobenzoyl group, 3 , 4-dicro-benzoyl group and 3,5-dichloro-benzoyl group.

Specific examples of the lower alkylated arylcarbonyl group include 2-toluene. Examples thereof include a methyl group, a 3-toluoyl group, a 4-toluoyl group, and a 2,4,6-trimethylbenzoyl group.

Further, specific examples of the lower alkoxyarylcarbonyl group include a 2-anisyl group, a 3-anisyl group, a 4-anisyl group, and the like. Specific examples of the above-mentioned arylnitrocarbonyl group include 2-nitrobenzoyl group, 3-nitrobenzoyl group, 4-nitrobenzoyl group, and 3,5-dinitrobenzoyl group. .

Further, as a specific example of the above-mentioned lower alkoxylated arylcarbonyl group, a 2- (methoxycarbonyl) benzoyl group can be exemplified.

Specific examples of the arylated carbonyl group include a 4-phenylbenzoyl group.

Examples of the silyl group that can function as the protective 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 t-tert-butyldimethylsilyl group, a methyldiisopropylpropylsilyl group, and a triisopropylsilyl group.

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

Examples of the aralkyl group capable of functioning as the above protective 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, an aralkyl group substituted with a halogen, and a cyano group. And an aralkyl group substituted with a group.

Specific examples of these groups include 2-methylbenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 2,4,6-trimethylbenzyl group, 2-methoxybenzyl group, and 3-methoxybenzyl group. , 4-methoxybenzyl group, 2-nitrobenzene Benzene, 3-nitrobenzyl, 4-nitrobenzyl, 2-chlorobenzyl, 3-cyclobenzyl, 4-cyclobenzyl, 2-bromobenzyl, 3-bromo Examples include a benzyl group, a 4-bromobenzyl group, a 2-cyanobenzyl group, a 3-cyanobenzyl group, and a 4-cyanobenzyl group.

Examples of the aralkyloxycarbonyl group capable of functioning as the above protecting group include an aralkyloxycarbonyl group substituted with a lower alkyl group and an aralkyloxycarbonyl group substituted with a lower alkoxy group. And aralkyloxycarbonyl substituted with a nitro group, aralkyloxycarbonyl substituted with a halogen, and aralkyloxycarbonyl substituted with a cyano.

Specific examples thereof include a 2-methylbenzyloxycarbonyl group, a 3-methylbenzyloxycarbonyl group, a 4-methylpentyloxycarbonyl group, a 2,4,6-trimethylbenzyloxycarbonyl group, and a 2-methoxybenzyloxycarbonyl group. Benzyloxycarbonyl group, 3-methoxybenzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 2-nitrobenzyloxycarbonyl group, 3-nitrobenzyloxycarbonyl group, 3-nitrobenzyloxycarbonyl group, 4 12 trobenzyloxycarbonyl group, 2-cyclobenzyloxycarbonyl group, 3-cyclobenzyloxycarbonyl group, 4-cyclobenzyloxycarbonyl group, 2-bromobenzyloxycarbonyl group , 3-bromobenzyloxycarponyl group, 4-bromobenzyloxycarponyl group, 2-cyanobenzyloxycarbonyl Examples thereof include a luponyl group, a 3-cyanobenzyloxycarbonyl group, and a 4-cyanobenzyloxycarbonyl group. '

Examples of the alkoxycarbonyl group that can function as the above-mentioned protective group include a lower alkoxycarbonyl group, a halogen-substituted alkoxycarbonyl compound, and an alkoxyl group substituted with an alkylsilyl group.

Specific examples of the lower alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, a sec-butoxycarbonyl group, and a tert-butoxycarbonyl group. A halogen-substituted alkoxy group capable of functioning as the above protecting group Specific examples of the alkoxycarbonyl group in which a 2,2,2-trichloroethoxycarbonyl group is substituted with a lower alkylsilyl group include a 2-trimethylsilylethoxycarbonyl group and the like.

Examples of the alkyl group that can function as the protective group include an unsubstituted alkyl group; an alkoxyalkyl group such as a methoxymethyl group, an ethoxymethyl group, a 2-methoxyethyl group, and a 2-methoxyethoxymethyl group; —Halogenated alkyl groups such as tricycloethyl group; lower alkyl groups substituted with aryl groups such as benzyl group, α-naphthylmethyl group, 6-naphthylmethyl group, diphenylmethyl group and triphenylmethyl group Is mentioned.

Of these, an aromatic acyl group is preferable, and a 4-nitrobenzoyl group is more preferable.

As the alkyl group and the alkyl group used in the above-described various groups, a lower alkyl group is preferred, and a lower alkyl group in a lower alkyl group or a lower alkoxy group is preferably a linear alkyl group having 1 to 6 carbon atoms. A branched or branched alkyl group is preferred. R in one OR in the formula (4) is an alkyl group, an acyl group, or an alkenyl group in which —OR can be substituted with a halogen atom by a halogenating agent. As the alkyl group and the acyl group, various specific groups exemplified as the alkyl group and the acyl group that can be used as the protective group described above can be used. As the alkenyl group, a lower alkenyl group, preferably having 2 to 6 carbon atoms. Alkenyl groups can be used. A more preferred R is an acetyl group.

The halogen atom represented by Z represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. More preferably, it is a chlorine atom.

The 1-phosphorylated saccharide derivative in the present invention usually forms a salt.

The salt in this case refers to a salt formed by a phosphate group in the molecule of the compound. Salts include alkali metal salts such as sodium, potassium, and lithium; alkaline earth metal salts such as magnesium, calcium, and barium; metal salts such as aluminum and iron; ammonium salts; , Secondary or tertiary alkylamine salts I can do it.

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

Examples of the secondary amine include dialkylamines such as getylamine, diisopropylamine, dibutylamine, dihexylamine, and dioctylamine, and cyclic amines such as dicine and N-methylpiperazine.

Tertiary amines include trimethylamine, triethylamine, tripropylamine, N-ethyldiisopropylamine, triptylamine, trihexylamine, trioctylamine, N-ethyldicyclohexylamine, N-methylpiperidine, N-methylmorpholine. Tertiary alkylamines such as phosphorus, N, N, N ', N'-tetramethylethylenediamine, aniline, N, N-dimethylaniline, N, N-diethylaniline, N, N-dibutylaniline Anilines such as N, N-dioctylaniline, salts of pyridines such as pyridine, 2,6-dimethylpyridine, 2,4,6-lutidine, nicotinamide, glycine, alanine, proline, lysine Amino acids, such as arginine, glutamine, cinchonidine, 1_ (1 naphthyl) ethylamine And optically active amines such as 1-phenylethylamine, all of which include monovalent or divalent salts.

The phosphorylation reaction process in the present invention is represented by the following reaction formula (I)

Reaction formula (I)

0H

w, ₀ to 丫 z Phosphate ：:.

Base Υ ^0Η

(1) Dehydrating agent ( ₂ )

(In the above reaction formula, W, X, Y and Z have the same meanings as in the above formula (1)). Phosphoric acid that can be used in this reaction is preferably one having a small amount of water, such as orthophosphoric acid, but is not particularly limited.

The base that can be used in this reaction is not particularly limited as long as it does not inhibit the reaction and functions as a deoxidizing agent. Preferably, the inorganic base is an alkali metal, an alkaline earth metal carbonate, or water. Examples of organic bases such as oxides include tertiary alkylamines, anilines, pyridines, and optically active amines.

The dehydrating agent that can be used in this reaction is preferably used when water mixed in from a solvent or an additive adversely affects the reaction. The dehydrating agent is not particularly limited as long as it has a water-adsorbing property or a reactivity with water, but preferably includes molecular sieves or phosphorus pentoxide.

This phosphorylation reaction is usually performed in the presence of a solvent. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include aliphatic hydrocarbons such as hexane and heptane, benzene, toluene, and xylene. Aromatic hydrocarbons such as ren, anisol, methylene chloride, chloroform, carbon tetrachloride, halogenated hydrocarbons such as dichloroethane, cyclobenzene, dichlorobenzene, ethyl formate, ethyl acetate, acetic acid Esters such as propyl, n-butyl acetate, and getyl carbonate, ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme, acetonitrile, propionitrile, isoptyronitrile Nitriles such as formamide, N, N-di Amides such as methylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, N, N-dimethyl-12-imidazolidinone, acetone, 2-butenonone, methyliso Examples thereof include ketones such as propyl ketone and methylisobutyl ketone, or a mixed solvent of two or three selected from them.

The reaction temperature is not particularly limited, and is usually in the range of −80 ° C. to 60 °, preferably −10 ° C. to 25 ° C.

The reaction time varies depending on the starting materials, the types of reagents and solvents, and the reaction temperature. It is usually achieved in 1 minute to 24 hours, preferably in 10 minutes to 2 hours.

In this reaction, the ratio of the halogenated saccharide derivative represented by the formula (1) to the phosphoric acid can be carried out as long as the phosphoric acid is at least 1 equivalent to the compound (1). In order to enhance the selectivity of (α-form or ^ -form), the compound of the formula (1): phosphoric acid = 1: 1 to 1:15 is preferable.

The ratio of phosphoric acid to salt clogging is an important factor in suppressing the epimeri- lation reaction. When an excess amount of phosphoric acid such as phosphoric acid: base = 3: 1 is reacted, the epimeri- lation reaction proceeds. Therefore, by reacting with phosphoric acid using an equimolar or more base, the epimerization reaction is suppressed, and the selectivity of the desired anomer (α-form or jS-form) of the monophosphorylated saccharide derivative can be suppressed. That is, the content of the desired anomer in the resulting anomer mixture can be significantly improved.

Further, the desired anomer of the 1-phosphorylated saccharide derivative can be purified by performing a salt exchange reaction and extracted as a phosphate of a base different from the base used in the reaction system.

Examples of the base used herein include the aforementioned inorganic bases, primary alkylamines, secondary alkylamines, tertiary alkylamines, anilines, pyridines, amino acids, and optically active amines. The salts include monovalent and divalent salts.

Further, the elimination reaction of the protecting group is represented by the reaction formula (I I)

Reaction formula (I ί)

To produce 1-monophosphorylated saccharide derivative (3).

When the above-mentioned aliphatic acyl group, aromatic acyl group, or alkoxycarbonyl group is used as the hydroxyl-protecting group represented by W, for example, it may be removed by treating with a base in a water-soluble solvent. Can be. Preferably, the base is sodium carbonate Alkali metal carbonates such as potassium carbonate, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, ammonia water, ammonium hydroxides such as tetra-n-butylammonium hydroxide The reaction can be performed using the above-mentioned inorganic bases, primary alkylamines, secondary alkylamines, tertiary alkylamines, and the like.

The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction, but preferably, alcohols such as water, methanol, ethanol, n-propanol and isopropanol, and the above-mentioned alcohols are used. Ethers can be used. The reaction temperature and the reaction time vary depending on the starting material and the base used, etc., and are not particularly limited.

When the above-mentioned aralkyl group or aralkyloxycarbonyl group is used as the 7K acid group-protecting group, it can be removed by catalytic reduction using a metal catalyst, for example.

As the catalyst, preferably, palladium carbon, Raney nickel, platinum oxide, platinum black, rhodium aluminum monoxide, triphenylphosphine-rhodium chloride, barium palladium monosulfate and the like can be used. The pressure is not particularly limited, but the solvent generally used is not particularly limited as long as it is one used in a usual hydrolysis reaction. Preferably, the solvent is water, methanol, ethanol, η-propanol, or isopropanol. Alcohols such as ethyl and the aforementioned ethers and esters can be used. The reaction temperature and reaction time vary depending on the starting material, the base used, and the like, and are not particularly limited. Usually, the reaction is carried out at 110 ° C. to 100 ° C. for 1 hour to 5 days. When the above-mentioned silyl group is used as the hydroxyl-protecting group, the silyl group can be removed by using a compound such as tetrafluoro-n-butylammonium which generates a fluorine anion.

The reaction solvent is not particularly limited as long as it does not inhibit the reaction, and the above-mentioned ethers can be used. The reaction temperature and reaction time are not particularly limited, but are usually from 10 to 50 T, and are completed in 10 minutes to 10 hours. When removing any of the protecting groups, the phosphate group in the molecule of the product is obtained as a salt of a base present in the reaction system, but may be changed to a salt of another base if desired. You can also take it out. Examples of the base used at this time include the above-mentioned inorganic bases, primary alkylamines, secondary alkylamines, tertiary alkylamines, anilines, pyridines, amino acids, optical activity Amines can be mentioned, and the salts formed include monovalent and divalent salts.

On the other hand, the halogenated saccharide derivative as a raw material for producing the monophosphorylated saccharide derivative represented by the formula (1) can be produced by halogenating the saccharide derivative represented by the above formula (4). it can. Examples of the sugar derivative used in the halogenation step include a raw material consisting of either one of the anomers (that is, a raw material consisting of only the body or a raw material consisting of only the / 3 body), and a anomeric mixture (that is, the α body and] 3). Body mixture). At that time, a mixture of α- and) 3 isomers is obtained as a halogenated sugar derivative, so that one of the ο; or; 6 isomers contained in the mixture is selectively crystallized to form a mixture between the anomeric mixture. By tilting the equilibrium, it is possible to selectively obtain a desired anomaly.

The halogenating agent to be used may be one usually used for halogenating natural and unnatural sugars, and is not particularly limited. Specifically, it is a hydrogen halide such as hydrogen chloride and hydrogen bromide, and an acid halogen compound such as oxalyl bromide, oxalyl chloride, acetyl chloride, acetyl bromide, propionyl chloride, and phosgene; and trimethylsilane chloride. And halogenated trialkylsilanes such as trimethylsilane iodide; phosphorus halides such as trichlorosilane and oxychloride; and inorganic halides such as thionyl chloride, sulfuryl chloride, and titanium tetrachloride. Is mentioned. As the form to be used, the above-mentioned halogenating agent may be used as it is, or it may be in the form of a Vilsmeier type 1 reagent obtained by reacting an acid halide compound with dimethylformamide. Methanol, ethanol, water or the like may be reacted with the agent to generate hydrogen halide in the reaction system and used. The equivalent used is not limited as long as it is 1 equivalent or more, but 3 equivalents or more and 15 equivalents from the viewpoint of reaction rate and economics. The following is desirable.

The solvent used is not limited as long as it is an aprotic solvent. Specifically, saturated hydrocarbon solvents such as hexane and heptane / cyclohexane, 1,2-dichloroethane, halogen solvents such as methylene chloride and chloroform, dimethyl ether / diisopropyl ether, t Examples include ether solvents such as monobutyl methyl ether. Further, two or more aprotic solvents may be mixed.

The reaction temperature is not lower than 170 ° C. and not higher than the boiling point of the solvent, preferably not lower than 110 ° C. and not higher than 50 ° C.

In the case where the halogenated non-natural type sugar does not crystallize, as described in the comparative example described later, the mixture of the spleen and the) 3 body (the ratio of the spleen and the body as in the comparative example 1) Gives 1: 1 power, 2: 1), and stereoselective synthesis is difficult. Therefore, by focusing on the difference in physical properties existing between the anomeric isomers of the halogenated sugar derivative represented by the formula (1) and utilizing the difference, that is, from the anomeric mixture, one of the α-form or the / 3-form is obtained. By selectively crystallizing the compound, the equilibrium between the anomer and the mixture is inclined, and it is possible to selectively produce either the <1> body or the / 3 body.

According to this anomeric-selective production method, it is possible to adopt a method of isolating the target halogenated sugar derivative by a simple operation only by filtration, so that an operation such as concentration under reduced pressure is not required. Thus, it is possible to provide a production method suitable for an industrial production method.

(Example)

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

Comparative Example 1

Synthesis of 2 R-benzoyloxymethyl-4 S-cloth — 1,3-dioxolan 2 R-benzoyloxymethyl-4 (R, S) -acetoxy 1,3-dioxolane (trans Z cis = 3/2) 5 ml of getyl ether was added to 26.6 m, and 2 ml of a 4N hydrochloric acid-dioxane solution was added dropwise. The mixture was stirred at room temperature for 16 hours, and the reaction solution remained homogeneous. After that, it was concentrated under reduced pressure and analyzed by iH NMR. The mixture of isomers had an s / cis = 2/1.

Example 1

Synthesis of 2R— (4-12 trobenzoyloxymethyl) 1-4S—chloro-1,3-dioxolane

(1-1) 2- (4,12-Trobenzonyloxymethyl) —4 (R, S) —Acetoxy 1,3-Dioxolane Synthesis

2 R_benzyloxymethyl-4 (R, S) -acetoxy-1,3-dioxolane (trans / cis = 2 / l) 21.2 g of methanol in 350 ml solution, 10% water-containing Pd carbon powder 2. lg was added and reacted under a stream of hydrogen. After completion of the reaction, the Pd carbon powder was removed, and then the mixture was concentrated under reduced pressure. Further, azeotropic dehydration was performed by adding toluene. The obtained compound was 2R-hydroxymethyl-4-1 (R, S) -acetoxy-1,3-dioxolane, which was used for the next reaction without further purification.

To 2R-hydroxymethyl-4 (R, S) -acetoxy-1,3-dioxolane described above, 20.4 ml of pyridine and 300 ml of THF were added, and the mixture was cooled on ice. To this was added dropwise a solution of 18.7 g of 412 trobenzozoyl chloride in 10 mL of THF. After completion of the dropwise addition, the temperature was raised to the ambient temperature, and the reaction was carried out for 5 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After concentration under reduced pressure, purify by column chromatography to obtain 2R- (4-dinitrobenzoyloxymethyl) 1-4 (R, S) -α 23.6 g (trans / cis = 3/2) of sethoxy-1,3-dioxolan were obtained. (Yield 90%)

Ή NMR (CDC1 _3, TMS: isomer mixture) 2.04ppm (3H, s: minor ), 2.12 (3H, s: major), 4.0-4.3 (2H, m), 4.49 (2H, m: major), 4.52 (2H, dd, J = 1.7, 3.9Hz: minor), 5.48 (1H, m: minor), 5.56 (1H, m,: major), 6.40 (lH, m,: minor), 6.46 (lH, m: major), 8.2'8.3 (4H, m)

AMCI-MS m / z 252 [M-OAc] +

Synthesis of (1 -2) 2 R— (4-12 trobenzoyloxymethyl) — 4 S—chloro-1,3-dioxolan

2 To 16.4 g of R- (4,2-neck benzoyloxymethyl) -4 (R, S) -acetoxy-1,3-dioxolane, add 70 g of saturated isopropyl ether solution of hydrochloric acid under ice-cooling. Was dropped. After completion of the dropwise addition, the mixture was allowed to react at ambient temperature for 5 hours. The precipitate was collected by filtration and washed with 30 ml of isopropyl ether. Drying under reduced pressure gave 12.7 g of the title compound as a white solid. (Yield 84%)

_{Ή NMR (CDC1 3, TMS)} 4.25ppm (lH, dd, J = 3.7, 9.8Hz), 4.49 (1H, m), 4.64 (2H, dd, J = 1.2, 3.7Hz), 5.5l (lH, t , J = 3.7Hz), 6.27 (1H, d, J = 3.7Hz), 8.3 (4H, m) Melting point 98.1-99. (TC

[a _D ] ²⁹ -56.72 ° (c 1.01, CH ₂ C1 ₂ )

Example 2

Synthesis of 2S- (4,12-trobenzoyloxymethyl) -14R-chloro-1,3-dioxolan

(2-1) 2 S- (4-12 trobenzoyloxymethyl) —4 (R, S) 1,3-dioxolane

2S-benzyloxymethyl-4 (R, S) -acetoxy 1,3-dioxolane (trans sZc is = 2/1) 4.7 g was reacted in the same manner as in Example 1 (1-1). , 2 S— (4_nitrobenzoyloxymethyl) —4 (R, S) acetoxy 1,3 dioxolane 4.4 g (trans / cis = 3/2) were obtained. (Yield 77%)

NMR (CDC1 _3, TMS: isomer mixture) 2.04ppm (3H, s: minor ), 2.12 (3H, s: major), 4.0-4.3 (2H, m), 4.49 (2H, m: major), 4.52 ( 2H, dd, J = 1.5, 3.9Hz: minor), 5.48 (1H, m: minor), 5.56 (lH, m,: major), 6.40 (lH, m,: minor), 6.46 (lH, m: major) ), 8.2 "8.3 (4H, m)

AMCI-MS m / z 252 DVE "OAc] ⁺

(2-2) Synthesis of 2 S- (4-12 trobenzoyloxymethyl) 1 4R-chloro- 1,3 dioxolane

2 S- (41-2 benzoyloxymethyl) -1 4 (R, S) -acetoxy-1,3-dioxolane 2. Og was reacted in the same manner as (1-2) in Example 1. This gave 0.92 g (trans sZc is 1Z10) of the title compound as a white solid. (Yield 52%)

_{Ή NMR (CDC1 3, TMS)} 4.25ppm (lH, dd, J = 3.7, 9.8Hz: major), 4.32 (lH, dd, J = 1.7,9.2Hz: minor), 4.42 (lH, dd, J = 4.1,9.5Hz: minor),

4.49 (lH, d, J = 9.8Hz: major), 4.54 (2H, d, J = 3.7Hz: minor), 4.64 (2H, dd, J = 1.2, 3.4Hz: major), 5.5l (lH, t , J = 3.7Hz: major), 5.69 (lH, t, J = 3.7Hz: minor), 6.27 (1H, d, J = 3.7Hz: major), 6.34 (lH, d, J = 3.6Hz: minor) , 8.3 (4H, m)

[a _D ] ²⁹ + 52.48 ° (cl.05, CH ₂ C1 ₂ )

Example 3

[2 R- (4-12 trobenzoyloxymethyl) 1 4 S—black mouth—1,3-dioxolane and 2 S— (4—nitrobenzobenzoyloxymethyl) 1 4R— Of chloro-1,3-dioxolane]

+ +

In Example 1, (1-1) 2R- (412-trobenzoyloxymethyl) -4 (R, S) -acetoxy-1,3-dioxolane (2.0 g) and Example (2 — 1) 2 S— (4—Nitrobenzoyloxymethyl) -1- (R, S) -acetoxy—1,3-dioxolane 2.0 g was combined with saturated hydrochloric acid—isopropyl ether 17.0 g of the solution was added dropwise under ice cooling. The mixture was returned to room temperature and stirred for 5 hours, and the precipitate was collected by filtration and washed with a small amount of isopropyl ether. After drying under reduced pressure, 1.3 g (trans / cis = 1/10) of the target product as a white solid was obtained. (Yield 35%)

_{NMR (CDC1 3, TMS) 4.25ppm} (lH, dd, J = 3.7, 9.8Hz: major), 4.32 (lH, dd, J = 1.7,9.2Hz: minor), 4.42 (lH, dd, J = 4.1, 9.5Hz: minor), 4.49 (lH, d, J = 9.8Hz: major), 4.54 (2H, d, J = 3.7Hz: minor), 4.64 (2H, dd, J = 1.2, 3.4Hz: major), 5.5l (lH, t, J = 3.7Hz: major), 5.69 (lH, t, J = 3.7Hz: minor), 6.27 (1H, d, J = 3.7Hz: major), 6.34 (lH, d, J = 3.6Hz: minor), 8.3 (4H, m)

Example 4

Synthesis of 2R- (4,2-trobenzoyloxymethyl) -4S-chloro-1,3-dioxolan

2R- (4-12 trobenzoyloxymethyl) 1-4 (R, S) acetate 1,3-dioxolane (trans / cis = 3/1) 20.100 g of diisopropyl ether In addition, the mixture was ice-cooled, and hydrogen chloride gas was blown until the gas became saturated. After further reacting at room temperature for 3 hours, the precipitate was collected by filtration and washed with 40 ml of isopropyl ether. Drying under reduced pressure gave 14.4 g of the title compound as a white solid. (Yield 78%)

Example 5

2 Synthesis of R- (4-12 trobenzoyloxymethyl) -14S-chloro-1,3-dioxolane

2 R— (4_Nitrobenzoyloxymethyl) -4 (R, S) -acetoxy 1,3-dioxolane (trans / cis ^ l / 2) 1.0 g, oxalyl chloride 561 ^ 1 To 3 ml of cyclohexane to which methanol was added, 1301 of methanol was added. After reacting at room temperature for 6 hours, the mixture was cooled on ice. This was returned to room temperature, isopropyl ether lm 1 was added, and the mixture was stirred overnight. The precipitate was collected by filtration and washed with isopropyl ether. Drying under reduced pressure gave 0.60 g of the title compound as a white solid. (Yield 67%) Example 6

2 Synthesis of R-hydroxymethyl-1,3-dioxolane-14-monophosphate (7) Reaction formula (III) Reaction formula (III)

To a solution of 1.70 g (17.4 mmo 1) of orthophosphoric acid and 4.14 m 1 (17.4 mmo 1) of tri-n-butylamine in acetonitrile (15 m 1) was added 1.00 g of Molecular Beam 4A. Was. Under ice-cooling, add 2 R- (4-nitrobenzoyloxymethyl) -14S-chloro-1,3-dioxolane (5) 0.5 g (1.74 mmo 1) and react for 40 minutes did. HPLC analysis of the reaction solution revealed that the anomeric ratio of compound (6) was αΖ3 = 94Ζ6. [HP LC conditions: column YMC-AM312, moving bed lOmM phosphate buffer (pH3), flow rate lml / min, detection UV (254 nm)]

The reaction solution was partitioned between water and form, and the form layer was concentrated under reduced pressure. To the concentrate, acetone and cyclohexylamine (2.39 ml, 20.9 mmol) were added, and the precipitated cyclohexylamine salt of the target product (6) was collected by filtration.

Next, a saturated ammonia methanol solution was added to the compound (6), and the mixture was reacted at 60 for 5 hours. The precipitate was collected by filtration to obtain an ammonium salt of compound (7) as a white solid. Yield 200 mg

Yield 49% [Yield from (5)]

_{lH NMR (D 2 0) δ} ppm: 3. 52 (2H, dd, J = 2. 20Hz), 3. 7 3 (1H, dd, J = 1. 95, 8. 72Hz), 3. 98 (1 H, m), 5.14 (1H, m), 5.71 (1H, m;).

3 characteristic signal was observed even at ¹ P NMR (D ₂ 〇). Melting point 166.1-168.3 ° C (decomposition)

Comparative Example 2

Synthesis of 2R- (4-nitrobenzoyloxymethyl) -1,3-dioxolane-14 (R, S) monophosphate (6,8) (Epimerification conditions)

Reaction formula (IV)

To a solution of 153 mg (1.56 mmo 1) of orthophosphoric acid and 130 ml of tree n-butylamine (0.55 mmo 1) in acetonitrile (1 m 1) was added 0.15 g of Molecular Particles 4A and then ice-cooled. Bottom, 2R- (4-nitrobenzoyloxymethyl) -14S-chloro-1,3-dioxolane (5) 15 Omg (0.52mmo 1) was added and reacted for 23 hours. The reaction solution was analyzed by HPLC (under the same conditions as in Example 6). As a result, the anomeric ratio of compound (6) / (8) was aZi3 = 65/35.

Synthesis of the di (cyclohexylamine) salt of 2R— (412-trobenzoyloxymethyl) 1-1,3-dioxolane-4-phosphate (6)

Orthophosphoric acid 51.1 g (52 lmmo 1), tree n-pentylamine 150

To a solution of lml (52 lmmo1) in MIBK (300 ml) was added 30. Og of molecular bus 4A. Under ice cooling, 2 R— (4-nitrobenzoyloxymethyl

) 14S-chloro-1,3-dioxolane (5) 30.0 g (104mm o 1) was added and reacted for 1.5 hours. After the reaction is completed, the organic layer is washed with deionized water (450 ml). Washed 4 times. The obtained organic layer was cooled with ice, and 59.7 ml of cyclohexylamine was added dropwise. The precipitate was collected by filtration and dried under reduced pressure.

Yield 48.0 g (/ β = 95X5)

Purity converted yield 80%

ΐΉ NMR (D ₂ 0) dp pm: 1.0—1.2 (10H, m), 1.49 (2H, m), 1.64 (4H, m), 1.83 (4H, m) , 2.99 (2H, m), 3.83 (1H, m), 4.02 (lH, m), 4.41 (2H, d, 1 = 2.20), 5.50 (1H, m) ), 5.78 (1H, m), 8.11 (2H, m), 8.21 (2H, m).

Characteristic signals were also observed in si P NMR (D ₂₀ ).

Example 8 Synthesis of 2R- (4-nitrobenzoyloxymethyl) 1-1,3-dioxolan-4-monophosphate (6)

To a solution of 273 mg (2.78 mmol) of orthophosphoric acid and tree n-hexylamine 9451 (2.78 mmol) in MIBK (lm 1) was added 4 mg of molecular weight 4A10 Omg. Under ice-cooling, add 2R- (4-12 trobenzoyloxymethyl) -4S-chloro-1,3-dioxolane (5) 10 Omg (0.348mmo 1) and add 1.5 Reacted for hours. Observation of the reaction mixture by HP LC revealed that the title compound had been formed in an amount of 78% (αβ = 88/12).

Example 9 Synthesis of 2R- (4-nitrobenzoyloxymethyl) -1,1,3-dioxolan-4monophosphate (6)

The reaction was carried out in the same manner as in Example 8 except that orthophosphoric acid was changed to 17 lmg (1.74 mmol) and tree n-hexylamine was changed to 591 / zl (1.74 mmol). Observation of the reaction mixture by HP LC showed that the title compound had been produced at 84% (α /) 3 = 92/8).

Example 10 Synthesis of 2R- (412-trobenzoyloxymethyl) 1-1,3-dioxolane-4-monophosphate (6)

102 mg (1.04 mmol) of orthophosphoric acid from Example 8 The reaction was carried out in the same manner, except that rumine was changed to 354 1 (1.04 mmo 1). Observation of the reaction mixture by HP LC revealed that the title compound had been produced in an amount of 78% (/ β = 93/7).

Example 1 1

Synthesis of 2R- (4,2-trobenzoyloxymethyl) -1,3-dioxolan-14-phosphoric acid (6)

The reaction was carried out in the same manner as in Example 8 except that the amount of orthophosphoric acid was changed to 102 mg (1.04 mmol) and the amount of tree n-hexylamine was changed to 4731 (1.39 mm01). Observation of the reaction mixture by HP LC showed that the title compound was 81% (α / β = 91/9) ^.

Example 12

Synthesis of 2R- (412-Trobenzoyloxymethyl) — 1,3-dioxolan-14-phosphoric acid (6)

Orthophosphoric acid 102mg (l. 04mmol), tri-n-octylamine 45

6 To a solution of UL 1 (1.04 mmo 1) in MIBK (lm 1) was added 4 A 10 Omg of molecular bus. Under ice-cooling, add 2 R— (412-trobenzoyloxymethyl) -48-chloro_1,3-dioxolane (5) 10 Omg (0.348 mmo 1) and react for 1.5 hours did. When the reaction mixture was observed by HP LC, the title compound was

79%

It turned out that it generated.

Example 13

2 Synthesis of R-hydroxymethyl-1,3-dioxolane-14-phosphate (7) 2R- (412-Trobenzoyloxymethyl) 1-1,3-dioxolane-14-phosphate (7) 6) Di (cyclohexylamine) salt (aZi3 ^ 95Z5) (45.Og) was suspended in 7M ammonia methanol solution (45Oml) and heated to 50 ° C. The mixture was reacted at the same temperature for 4 hours, cooled on ice, and filtered. The filtered product was washed with 20 ml of isopropyl ether and dried under reduced pressure to obtain the title compound.

17.0 g Purity converted yield 93%

Example 14

2 Synthesis of the di (cyclohexylamine) salt of S- (412-benzobenzoyloxymethyl) -11,3-dioxolane-14-phosphoric acid (10)

Reaction formula (V)

To a solution of 1.19 g (12.2 mmol) of orthophosphoric acid and n-50 ml (12.2 mmol) of a tree in a solution of MIBK (7 ml) was added 0.7 g of molecular bus 4A. Under ice-cooling, 698 mg (104 mmo 1) of 2S- (4-nitrobenzoyloxymethyl) -14R-chloro-1,3-dioxolane (9) was added, and the mixture was reacted for 1.5 hours. After the reaction was completed, the organic layer was washed five times with deionized water (11 ml). The obtained organic layer was cooled with ice, and 1.39 ml of cyclohexylamine was added dropwise. The precipitate was collected by filtration and dried under reduced pressure to give the title compound.

Yield 968mg (aZiS 96Z4)

Purity converted yield 68%

! H NMR (D ₂ 〇) d ppm: 1.0—1.2 (10H, m), 1.46 (2H, m), 1.61 (4H, m), 1.80 (4H, m) ), 2.95 (2H, m), 3.80 (1H, m), 3.98 (1H, m), 4.38 (2H, d, 3 = 2.68), 5.46 (1H, m) m), 5.75 (1H, m), 8.05 (2H, m), 8.1.6 (2H, m). Characteristic signals were also observed in si P NMR (D ₂₀ ).

Example 15

Synthesis of 2 S-hydroxymethyl-1,3-dioxolane-4-phosphate (11) Reaction formula (VI)

Reaction formula (VI)

(2 S- (4-Nitrobenzoyloxymethyl) -1,3-dioxolane-14-monophosphate (10) di (cyclohexylamine) salt (a / i3 96/4) 0.81 g Was suspended in 8 ml of a 7 M ammonia-methanol solution, and the temperature was raised to 50 ° C. The mixture was reacted at the same temperature for 4 hours, cooled with ice, and collected by filtration. Drying under reduced pressure gave the title compound.

Yield 0.32 g

96% yield in terms of purity

iH NMR (D ₂ 〇) δ p pm: 3.52 (2H, d, J = l. 22 Hz), 3.72 (1H, m), 3.96 (1H, m), 5.13 ( 1H, m), 5.69 (1H, m).

A characteristic signal was also observed in 3i P NMR (D ₂ 〇).

Industrial applicability

ADVANTAGE OF THE INVENTION According to this invention, the anomeric selective production method of a non-natural type | mold 1-monophosphorylated saccharide derivative, the raw material compound useful for use in the said method, and its production method can be provided.

Claims

The scope of the claims

1. A method for producing a non-natural type 1-monophosphorylated saccharide derivative or a ^ -form, comprising the formula (1)

, 0 (1)

(Wherein W is a protecting group for a hydroxyl group, X and Y each independently represent an oxygen atom or an ゥ atom, and Z represents a halogen atom.) A non-natural halogen which is one of the anomers represented by Phosphorylating the saccharide derivative, the formula (2)

(2)

(Wherein IX and Y have the same meanings as described above.)

The desired α-form or / 3-form of the monophosphorylated saccharide derivative represented by the formula (2) is obtained by inverting the steric configuration at the anomeric position of the octogenated saccharide derivative represented by the formula (1) by the phosphorylation. Selectively obtain one of

A method for producing a non-natural 1-phosphorylated saccharide derivative, characterized in that:

2. The unnatural halogenated saccharide derivative which is one of the anomers represented by the formula (1) is

Equation (4)

(Wherein, X and Y each independently represent an oxygen atom or a sulfur atom, R represents a hydrogen atom, an alkyl group, an alkenyl group, or an acyl group, and W represents a hydroxyl-protecting group.) Obtaining an anomeric mixture of unnatural halogenated saccharide derivatives in which one OR group in the formula (4) is substituted with a halogen atom by using a halogenating agent for the saccharide derivative; Selectively crystallization of one of the three isomers to incline the equilibrium between the anomeric mixtures, and selectively obtaining one of the body or the body of the halogenated sugar derivative represented by the formula (1);

The method according to claim 1, which is obtained by a method having the following.

3. The method according to claim 1, wherein the three-dimensional structure of the unnatural halogenated sugar derivative is a / 3-D form, and the three-dimensional structure of the non-naturally occurring monophosphorylated sugar derivative is an α-D form.

The method according to any one of claims 1 to 3, wherein X is an oxygen atom.

5. The method according to claim 4, wherein Υ is an oxygen atom.

6. The method according to any one of claims 1 to 4, wherein Ζ is a chlorine atom.

7. The method according to any one of claims 1 to 6, wherein W is an unsubstituted or substituted aromatic acyl group.

The method according to claim 2, wherein 8-W is a 4-nitrobenzene group.

9. An unnatural 1-phosphorylated saccharide derivative represented by the following formula (2a):

10. A method for producing a non-natural type 1 monophosphorylated saccharide derivative,

Equation (2)

(Wherein, W represents a hydroxyl-protecting group, and X and Y each independently represent an oxygen atom or a thiol atom.) And equation (3)

(Wherein, X and で have the same meanings as described above).

11. The method according to claim 10, wherein X is an oxygen atom.

12. The method according to claim 11, wherein Υ is an oxygen atom.

13. Any of claims 10 to 12, wherein W is an unsubstituted or substituted aromatic acyl group. The method according to claim 1.

14. The method according to claim 13, wherein W is a 4-12 trobenzoyl group.

15. A method for selectively producing one of a; or) 3 unnatural halogenated sugar derivatives,

Equation (4)

(Wherein, X and Y each independently represent an oxygen atom or a sulfur atom, R represents a hydrogen atom, an alkyl group, an alkenyl group, or an acyl group, and W represents a hydroxyl-protecting group.) Obtaining an anomeric mixture of a non-natural halogenated sugar derivative in which the _OR group in the formula (4) is substituted with a halogen atom using a halogenating agent for the sugar derivative, and the α-form or (3) By selectively crystallizing one of the bodies, the equilibrium between the anomeric mixtures is tilted, and the following formula (1):

(Wherein, X, Y and W are the same as above, and Z represents a halogen atom.) A step of selectively obtaining one of a hemibody or an i3 body of a halogenated sugar derivative represented by the following formula: A method for selectively producing the α-form or the 0-form of a non-natural halogenated sugar derivative which is a feature.

16. The method according to claim 15, wherein both X and ともに are oxygen atoms.

17. The method according to claim 15, wherein Ζ is a chlorine atom.

18. The method according to claim 15 or 16, wherein W is an unsubstituted or substituted aromatic acyl group.

19. The method according to claim 15 or 16, wherein W is a 41-2 tonopen benzoyl group. 20. A non-natural halogenated sugar derivative represented by the formula (1a):

21. The compound according to claim 20, wherein X and Y are both oxygen atoms, W is a 412 trobenzoyl group, and Z is a chlorine atom.

2 2. Equation (4)

23. The compound according to claim 22, wherein W is a two-mouth benzoyl group.

24. The compound according to claim 23, wherein X and Y are oxygen atoms, W is 412 trobenzoyl group, and R is acetyl group.