JP2007137843A - Method for producing ribofuranose compound and purine nucleoside compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially suitable method more efficiently producing a purine nucleoside compound useful as a synthetic intermediate for medicines. <P>SOLUTION: The method for producing a purine nucleoside compound comprises reacting D-xylose (II) with a compound (III) in the presence of an acid, subjecting the reaction product to acid hydrolysis to give a compound (IV), selectively protecting the OH group at the 5-position to give a compound (V), oxidizing the OH group at the 3-position to give a compound (VI), reducing the C=O at the 3-position to give a compound (VII), reacting the compound with a compound (VIII) to give a compound (IX), subjecting the compound to an acid hydrolyzed reaction to give a compound (X), acylating the compound to give a compound (I), reacting the compound with a compound (XI) in a nitrile-based solvent or an ester-based solvent in the presence of a silylating agent and a Lewis acid and deacylating the 2' position to give a compound (XII). <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a novel method for producing a ribofuranose compound and a purine nucleoside compound, and to a novel ribofuranose compound and a purine nucleoside compound.

  Formula (XVII):

A purine nucleoside compound represented by the formula (wherein DMT represents a dimethoxytrityl group) is useful as a raw material compound for antisense medicine (see Non-Patent Document 1). Although the above compound is synthesized from 2,6-diaminopurine riboside in Non-Patent Document 1, it is not an industrially suitable method such as poor reaction selectivity and requiring an enzyme reaction. Development of an efficient manufacturing method is desired.

Patent Document 1 discloses a method for producing a purine nucleoside compound from a ribofuranose compound, but does not disclose a specific method for producing a ribofuranose compound. Further, for a purine nucleoside compound, A manufacturing method like the present invention is not disclosed.
JP 2005-132767 A Nucleosides, Nucleotides & Nucleic Acids (2003), 22 (5-8), 1327-1330.

  The present invention is to provide a more efficient and industrially suitable production method for purine nucleoside compounds useful as synthetic intermediates for pharmaceuticals.

  As a result of intensive studies on an efficient production method of the above compound, the present inventors have adopted a synthetic route using a novel ribofuranose compound as an intermediate, so that there is no problem in the selectivity of the reaction, and further an enzyme reaction It was found that the desired purine nucleoside compound can be produced without requiring Furthermore, various novel purine nucleoside compounds have been found as intermediates, and the present invention has been completed. That is, the present invention is as follows.

[1] General formula (I) characterized by including the following steps (a) to (g):

(Wherein, R ³ is an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted heteroarylalkyl group, R ⁴ Represents an acyl group which may have a substituent, and the wavy line indicates that the configuration of the substituent OR ⁴ of the anomeric carbon atom is not limited at all.) (Hereinafter also referred to as compound (I)) Method for producing the represented compound:
(A) Formula (II):

(Wherein the wavy line indicates that the configuration of the substituent OH of the anomeric carbon atom is not limited at all). D-xylose represented by the general formula (III) in the presence of an acid:

(In the formula, R ¹ and R ² each independently represents a hydrogen atom or an alkyl group.) After reacting with a compound represented by the following formula (hereinafter also referred to as compound (III)), acid hydrolysis And general formula (IV):

(Wherein each symbol is as defined above), a step of obtaining a compound represented by the following (hereinafter also referred to as compound (IV));
(B) The hydroxy group at the 5-position of compound (IV) is selectively protected to give a compound represented by the general formula (V):

(Wherein P ¹ represents a benzoyl group which may have a substituent, and other symbols have the same meanings as described above) (hereinafter, also referred to as compound (V)). Process;
(C) The hydroxy group at the 3-position of compound (V) is oxidized to give a general formula (VI):

(Wherein each symbol is as defined above), a step of obtaining a compound represented by the following (hereinafter also referred to as compound (VI));
(D) The carbonyl group at the 3-position of compound (VI) is reduced to give the general formula (VII):

(Wherein each symbol is as defined above), a step of obtaining a compound represented by the following (hereinafter also referred to as compound (VII));
(E) After removing the protecting group P ¹ of the compound (VII), in the presence of a base, the general formula (VIII):

(Wherein, X ¹ represents a halogen atom, a mesyloxy group or a tosyloxy group, and R ³ has the same meaning as described above), and a compound (hereinafter also referred to as compound (VIII)) is reacted; Formula (IX):

(Wherein each symbol is as defined above), a step of obtaining a compound represented by the following (hereinafter also referred to as compound (IX));
(F) Compound (IX) is subjected to an acid hydrolysis reaction to give a general formula (X):

(Wherein R ³ has the same meaning as described above, and the wavy line indicates that the configuration of the substituent OH of the anomeric carbon atom is not limited at all) (hereinafter also referred to as compound (X)). And (g) a step of acylating the 1-position and 2-position hydroxy groups of compound (X) to obtain compound (I).

[2] A method for producing compound (X), wherein compound (IX) is subjected to an acid hydrolysis reaction.
[3] A method for producing compound (I), wherein the hydroxy groups at the 1-position and 2-position of compound (X) are acylated.

[4] Compound (I) and general formula (XI):

(Wherein Y ¹ and Y ² each independently represent a hydrogen atom, a halogen atom, an optionally substituted hydroxy group or an optionally substituted amino group). The compound represented by the formula or a salt thereof (hereinafter also referred to as compound (XI)) is reacted in the presence of a silylating agent and a Lewis acid in a nitrile solvent or an ester solvent, and then deacylated at the 2 ′ position. General formula (XII) characterized in that

(Wherein each symbol is as defined above) or a salt thereof (hereinafter also referred to as compound (XII)).

[5] The production method according to any one of the above [1] to [4], wherein R ³ is an aralkyl group having 7 to 21 carbon atoms.
[6] The production method according to any one of [1] to [4], wherein R ³ is a benzyl group.
[7] The production method according to any one of [1], [3] and [4] above, wherein R ⁴ is an acyl group having 1 to 8 carbon atoms.
[8] The production method according to any one of [1], [3] and [4] above, wherein R ⁴ is an acetyl group.
[9] The production method of the above-mentioned [4], wherein Y ¹ is a halogen atom or a hydroxy group which may have a substituent.
[10] The production method of the above-mentioned [4], wherein Y ¹ is a halogen atom.
[11] The production method of the above-mentioned [4], wherein Y ² is a halogen atom or an amino group which may have a substituent.
[12] The production method of the above-mentioned [4], wherein Y ² is an amino group.

[13] Compound (X).
[14] The compound according to [13] above, wherein R ³ is an aralkyl group having 7 to 21 carbon atoms.
[15] The compound of the above-mentioned [13], wherein R ³ is a benzyl group.

[16] General formula (XVIII):

(In the formula, Y ^{1 ′} and Y ^{2 ′} each independently represent a hydrogen atom, a halogen atom, an optionally substituted hydroxy group or an optionally substituted amino group, R ⁵ has a hydrogen atom, an acyl group that may have a substituent, an alkyl group that may have a substituent, an aralkyl group that may have a substituent, or a substituent. R ⁶ and R ⁷ each independently represent a hydrogen atom, an optionally substituted acyl group, an optionally substituted alkyl group, or a substituent. A aralkyl group optionally having a substituent or a heteroarylalkyl group optionally having a substituent) or a salt thereof (provided that 2-amino-6-chloro-9β- (2 ′ -O-acetyl-3 ', 5'-di-O-benzi ) Except for the -D- ribofuranosyl pudding.) (Hereinafter also referred to as compound (XVIII).).

[17] The compound or a salt thereof according to the above [16], wherein Y ^{1 ′} is a halogen atom or a hydroxy group which may have a substituent.
[18] The compound of the above-mentioned [16] or a salt thereof, wherein Y ^{1 ′} is a chlorine atom, a benzyloxy group or a hydroxy group.
[19] The compound or a salt thereof according to the above [16], wherein Y ^{2 ′} is a halogen atom or an amino group which may have a substituent.
[20] The compound or a salt thereof according to the above [16], wherein Y ^{2 ′} is an amino group or an isobutyrylamino group.
[21] The compound of the above-mentioned [16] or a salt thereof, wherein R ⁵ is a hydrogen atom, an acyl group having 1 to 10 carbon atoms, or an alkyl group having 1 to 5 carbon atoms which may have a substituent.
[22] The compound of the above-mentioned [16] or a salt thereof, wherein R ⁵ is a hydrogen atom, an acetyl group or a 2-methoxyethyl group.
[23] The compound or a salt thereof according to the above [16], wherein R ⁶ and R ⁷ are each independently a hydrogen atom, an aralkyl group having 7 to 21 carbon atoms, or an acyl group having 1 to 10 carbon atoms.
[24] The compound or a salt thereof according to the above [16], wherein R ⁶ and R ⁷ are each independently a hydrogen atom, a benzyl group or an acetyl group.

  The method of the present invention is an industrially useful method because a purine nucleoside compound useful as a pharmaceutical intermediate can be produced with high selectivity and high yield without requiring an enzyme reaction or the like. Moreover, the novel ribofuranose compound and novel purine nucleoside compound found by the present invention are useful as synthetic intermediates for pharmaceuticals.

The present invention will be described in detail below.
The definition of each symbol used in the present invention is as follows.

The “halogen atom” represented by X ¹ , Y ¹ , Y ² , Y ^{1 ′} or Y ^{2 ′} is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. X ¹ is preferably a chlorine atom, a bromine atom, an iodine atom or the like. Y ¹ , Y ² , Y ^{1 ′} or Y ^{2 ′} is preferably a fluorine atom, a chlorine atom, an iodine atom or the like.

The “alkyl group” represented by R ¹ or R ² is a linear or branched alkyl group having 1 to 12 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert -Butyl, pentyl, isopentyl, neopentyl, hexyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like, preferably a linear or branched alkyl group having 1 to 5 carbon atoms, for example, Methyl, ethyl, isopropyl, isobutyl and the like.

The “alkyl group” of the “alkyl group optionally having substituent (s)” represented by R ³ , R ⁵ , R ⁶ or R ⁷ has the same meaning as the “alkyl group” defined above, preferably Is a linear or branched alkyl group having 1 to 5 carbon atoms, such as methyl, ethyl, isopropyl, isobutyl and the like. The alkyl group may have a substituent at a substitutable position. Examples of the substituent include a halogen atom, a C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), hydroxy group, oxo group, amino group, nitro group, cyano group, carboxyl group, C _1-6 alkoxycarbonyl groups (eg, methoxycarbonyl, ethoxycarbonyl, etc.) and the like. The number of the substituents is not particularly limited and is preferably 0 to 3, and the substituents may be the same or different.

The “aralkyl group” of the “aralkyl group optionally having substituent (s)” represented by R ³ , R ⁵ , R ⁶ or R ⁷ is an aryl group at any position of the “alkyl group” defined above. (Preferably an aryl group having 6 to 12 carbon atoms) is an aralkyl group having 7 to 21 carbon atoms formed by substitution, such as benzyl, 1- or 2-phenylethyl, 1-, 2- or 3 -Phenylpropyl, 1- or 2-naphthylmethyl, 1- or 2- (1-naphthyl) ethyl, 1- or 2- (2-naphthyl) ethyl, benzhydryl, trityl and the like can be mentioned, preferably benzyl, trityl and the like It is. The aralkyl group may have a substituent at a substitutable position. Examples of such a substituent include a halogen atom, a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, isobutyl). Etc.), C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy etc.), hydroxy group, amino group, nitro group, cyano group, carboxyl group, C _1-6 alkoxycarbonyl group (eg, Methoxycarbonyl, ethoxycarbonyl, etc.), C _6-12 aryl groups (eg, phenyl group, naphthyl group, etc.) and the like. The number of the substituents is not particularly limited and is preferably 0 to 3, and the substituents may be the same or different.

The “heteroarylalkyl group” of the “optionally substituted heteroarylalkyl group” represented by R ³ , R ⁵ , R ⁶ or R ⁷ is any of the “alkyl groups” defined above. A heteroarylalkyl group formed by substituting a heteroaryl group at the position, for example, 2- or 3-thienylmethyl, 2- or 3-furylmethyl, 1-, 2- or 3-pyrrolylmethyl, 1-, 2-, 4- or 5-imidazolylmethyl, 2-, 4- or 5-oxazolylmethyl, 2-, 4- or 5-thiazolylmethyl, 1-, 3-, 4- or 5-pyrazolylmethyl, 3- 4-, 5-isoxazolylmethyl, 3-, 4- or 5-isothiazolylmethyl, 1,2,4-triazol-1-, 3-, 4- or 5-ylmethyl, 1,2, -Triazol-1-, 2- or 4-ylmethyl, 1H-tetrazol-1- or 5-ylmethyl, 2H-tetrazol-2- or 5-ylmethyl, 2-, 3- or 4-pyridylmethyl, 2-4 -Or 5-pyrimidinylmethyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolylmethyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl Methyl, 2-, 3-, 4-, 5-, 6- or 7-benzothienylmethyl, 1-, 2-, 4-, 5-, 6- or 7-benzimidazolylmethyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolylmethyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolylmethyl, 1- or 2- (2- or 3-thienyl) ethyl, 1- or 2- (2- or 3-phenyl) L) ethyl, 1- or 2- (1-, 2- or 3-pyrrolyl) ethyl, 1- or 2- (1-, 2-, 4- or 5-imidazolyl) ethyl, 1- or 2- (2 -, 4- or 5-oxazolyl) ethyl, 1- or 2- (2-, 4- or 5-thiazolyl) ethyl, 1- or 2- (1-, 3-, 4- or 5-pyrazolyl) ethyl, 1- or 2- (3-, 4- or 5-isoxazolyl) ethyl, 1- or 2- (3-, 4- or 5-isothiazolyl) ethyl, 1- or 2- (1,2,4-triazole- 1-, 3-, 4- or 5-yl) ethyl, 1- or 2- (1,2,3-triazol-1-, 2- or 4-yl) ethyl, 1- or 2- (1H-tetrazole) -1- or 5-yl) ethyl, 1- or 2- ( 2H-tetrazol-2- or 5-yl) ethyl, 1- or 2- (2-, 3- or 4-pyridyl) ethyl, 1- or 2- (2-, 4- or 5-pyrimidinyl) ethyl, 1 -Or 2- (1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl) ethyl, 1- or 2- (2-, 3-, 4-, 5-, 6- or 7-benzofuryl) ethyl, 1- or 2- (2-, 3-, 4-, 5-, 6- or 7-benzothienyl) ethyl, 1- or 2- (1-, 2-, 4-, 5 -, 6- or 7-benzimidazolyl) ethyl, 1- or 2- (2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl) ethyl, 1- or 2- (1- , 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl) ethyl and the like. The heteroarylalkyl group may have a substituent at a substitutable position. Examples of such a substituent include the substituents exemplified in the above-mentioned “aralkyl group optionally having substituent (s)”. The same substituents can be mentioned. The number of the substituents is not particularly limited and is preferably 0 to 3, and the substituents may be the same or different.

Examples of the “acyl group” of the “optionally substituted acyl group” represented by R ⁴ , R ⁵ , R ⁶ or R ⁷ include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl Aliphatic acyl groups such as pivaloyl, hexanoyl, isohexanoyl; aromatic acyl groups such as benzoyl, 1- or 2-naphthoyl, preferably acyl groups having 1 to 10 carbon atoms, more preferably carbon An acyl group of 1 to 8 and preferably acetyl, benzoyl and the like.
The acyl group may have a substituent at a substitutable position, and as such a substituent, the same substituent as the substituent exemplified in the above-mentioned “aralkyl group optionally having substituent” is used. Groups. The number of the substituents is not particularly limited and is preferably 0 to 3, and the substituents may be the same or different.

Examples of the substituent in the “benzoyl group optionally having substituent (s)” represented by P ¹ include the same substituents as those exemplified in the above “acyl group optionally having substituent (s)”. . The number of the substituents is not particularly limited and is preferably 0 to 3, and the substituents may be the same or different.

As the substituent in the “optionally substituted hydroxy group” and the “optionally substituted amino group” represented by Y ¹ , Y ² , Y ^{1 ′} or Y ^{2 ′} , Defined as “an optionally substituted alkyl group”, “an optionally substituted aralkyl group”, “an optionally substituted heteroarylalkyl group”, “substituted” An acyl group optionally having a group "and the like, and methyl, benzyl, acetyl, isobutyryl and the like are preferable.

  The compounds defined herein may be in the form of a salt. Examples of such salts include inorganic acid salts (eg, hydrochloride, sulfate, nitrate, phosphate, etc.); organic acid salts (eg, acetate, propionate, methanesulfonate, 4-toluene) Sulfonates, oxalates, maleates, etc.); alkali metal salts (eg, sodium salts, potassium salts, etc.); alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.); organic base salts (eg, Trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, etc.).

The R ¹ and R ^2, each independently, an alkyl group, more preferably a methyl group.
R ³ is preferably an aralkyl group which may have a substituent, more preferably an aralkyl group having 7 to 21 carbon atoms, and even more preferably a benzyl group.
R ⁴ is preferably an acyl group which may have a substituent, more preferably an acyl group having 1 to 8 carbon atoms, and still more preferably an acetyl group.
R ⁵ is preferably a hydrogen atom, an optionally substituted acyl group, or an optionally substituted alkyl group, having a hydrogen atom, an acyl group having 1 to 10 carbon atoms, or a substituent. An optionally substituted alkyl group having 1 to 5 carbon atoms is more preferred, and a hydrogen atom, an acetyl group, and a 2-methoxyethyl group are more preferred.
R ⁶ and R ⁷ are each independently preferably a hydrogen atom, an aralkyl group which may have a substituent, or an acyl group which may have a substituent, a hydrogen atom or a carbon number of 7 to 21 Are more preferable, and a hydrogen atom, a benzyl group, and an acetyl group are more preferable.

Y ¹ is preferably a halogen atom or a hydroxy group which may have a substituent, more preferably a halogen atom, and even more preferably a chlorine atom.
Y ^{1 ′} is preferably a halogen atom or an optionally substituted hydroxy group, more preferably a chlorine atom, a benzyloxy group or a hydroxy group.
Y ² is preferably a halogen atom or an amino group which may have a substituent, and more preferably an amino group.
Y ^{2 ′} is preferably a halogen atom or an optionally substituted amino group, more preferably an amino group or an isobutyrylamino group.

P ¹ is preferably a benzoyl group, a p-toluoyl group, or a p-chlorobenzoyl group.

  The reaction scheme of the present invention is shown below.

(In the formula, each symbol is as defined above.)
Below, each process is demonstrated in detail.
The compounds obtained in the following steps should be isolated (eg, neutralized, extracted, concentrated, crystallized, etc.) or purified (eg, recrystallized, column chromatography, thin layer chromatography, etc.) by conventional methods. Can do. Moreover, it can also attach | subject to a next process, without isolating or refine | purifying in particular.

Step (a)
In step (a), D-xylose is reacted with compound (III) in the presence of an acid to obtain a compound represented by the following formula (II ′) (hereinafter also referred to as compound (II ′)), The compound (IV) in which only the 1-position and 2-position hydroxy groups are protected can be produced by acid-hydrolyzing the compound and selectively deprotecting the 3-position and 5-position hydroxy groups.

(In the formula, each symbol is as defined above.)
First Step The first step is specifically carried out by mixing D-xylose, compound (III) and an acid, but the mixing order thereof is not particularly limited.

  The acid used is not particularly limited, and examples thereof include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Examples include organic acids such as trifluoromethanesulfonic acid, among which inorganic acids are preferable, and sulfuric acid and hydrochloric acid are more preferable. The usage-amount of an acid is 0.1 equivalent-10 equivalent normally with respect to D-xylose, Preferably it is 0.5 equivalent-2 equivalent.

  The usage-amount of compound (III) is 1 equivalent-100 equivalent normally with respect to D-xylose, Preferably it is 10 equivalent-50 equivalent.

  This step is preferably carried out in the presence of a dehydrating agent. Examples of the dehydrating agent include anhydrous copper sulfate (II) and anhydrous magnesium sulfate. Among them, anhydrous copper sulfate (II) is preferable. The usage-amount of a dehydrating agent is 0.1 weight times-10 weight times normally with respect to D-xylose, Preferably it is 1 weight times-5 weight times.

  In this step, when compound (III) is used in a large excess, it may also serve as a solvent, or a separate solvent may be used. Examples of the solvent include toluene, ethyl acetate and the like.

  The reaction temperature is usually in the range of 0 ° C to 100 ° C, preferably 10 ° C to 50 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

  The resulting compound (II ′) can be isolated by a conventional method such as extraction, filtration, concentration, etc. after neutralization with ammonia, ammonium hydrogen carbonate or the like.

Second Step The second step is carried out by treating compound (II ′) with an acid.

  Examples of the acid used include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as acetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid. Among these, inorganic acids are preferable, and hydrochloric acid is more preferable. What is necessary is just to add the usage-amount of an acid so that the pH of a reaction solution may be 1-2. If the pH is lower than this range, the 1-position and 2-position hydroxy groups are also easily deprotected. Conversely, if the pH is higher than this range, the 3-position and 5-position hydroxy groups cannot be deprotected.

  In this step, when a large excess of acid is used, it may serve as a solvent or a separate solvent may be used. Examples of the solvent to be used include water, a mixed solvent of water and alcohols (eg, methanol, ethanol, etc.), and the like, among which water is preferable.

  The reaction temperature is usually in the range of 0 ° C to 100 ° C, preferably 10 ° C to 50 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

Step (b)
In step (b), compound (V) can be produced by selectively protecting the hydroxy group at the 5-position of compound (IV).
In the step (b), by using a sterically relatively bulky protective group such as a benzoyl group (eg, benzoyl, toluoyl, p-chlorobenzoyl etc.) which may have a substituent, the 5-position Only the hydroxy group can be selectively protected.

  Specifically, it is carried out by mixing compound (IV), the corresponding benzoyl halide and base in a solvent, but the mixing order is not particularly limited.

  Examples of the benzoyl halide used include benzoyl chloride, p-toluoyl chloride, and p-chlorobenzoyl chloride. The amount of the benzoyl halide to be used is generally 1 equivalent to 10 equivalents, preferably 1 equivalent to 2 equivalents, relative to compound (IV).

  Examples of the base used include pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and the like, and two or more bases may be used in combination. Of these, pyridine and triethylamine are preferable. The amount of the base to be used is generally 1 equivalent to 10 equivalents, preferably 1 equivalent to 3 equivalents, relative to compound (IV).

  Any solvent may be used as long as it does not inhibit the reaction. For example, toluene, ethyl acetate and the like can be used alone or in combination. The amount of the solvent to be used is generally 1 to 100 times by weight, preferably 5 to 20 times by weight, relative to compound (IV).

  The reaction temperature is usually in the range of −10 ° C. to 100 ° C., preferably 0 ° C. to 10 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

Step (c)
In step (c), compound (VI) can be produced by oxidizing the hydroxy group at the 3-position of compound (V). Examples of the oxidation method include various known methods (for example, Pfitzner-Moffatt oxidation, swan oxidation, desmartin oxidation, etc.). Hereinafter, although Pfitzner-Moffatt oxidation is demonstrated, it is not limited to this.

  Specifically, the Pfitzner-Moffatt oxidation is carried out by mixing the compound (V), dimethyl sulfoxide, a carbodiimide condensing agent and an acid in a solvent, but the mixing order is not particularly limited.

  Any solvent may be used as long as it does not inhibit this reaction. For example, toluene, chloroform, dichloromethane or the like can be used alone or in combination. The amount of the solvent to be used is generally 1 to 10 times, preferably 5 to 20 times the compound (V).

  The amount of dimethyl sulfoxide to be used is generally 1 equivalent to 20 equivalents, preferably 2 equivalents to 10 equivalents, relative to compound (V).

  Examples of the carbodiimide condensing agent include N, N′-dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (EDC), and among them, DCC is preferable. . The amount of the carbodiimide condensing agent to be used is generally 1 equivalent to 10 equivalents, preferably 1.1 equivalent to 1.5 equivalents, relative to compound (V).

  Examples of the acid include trifluoroacetic acid and chloroacetic acid. Among them, trifluoroacetic acid is preferable. The usage-amount of an acid is 0.01 equivalent-1 equivalent normally with respect to compound (V), Preferably it is 0.05 equivalent-0.2 equivalent.

  The oxidation reaction is preferably performed in the presence of a base. Examples of the base include pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, and among them, pyridine and triethylamine are preferable. The usage-amount of a base is 0.01 equivalent-1 equivalent normally with respect to compound (V), Preferably it is 0.05 equivalent-0.5 equivalent.

  The reaction temperature is usually in the range of 0 ° C to 100 ° C, preferably 10 ° C to 50 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

Step (d)
In step (d), compound (VII) can be produced by reducing the carbonyl group at the 3-position of compound (VI). By the oxidation / reduction reaction in steps (c) and (d), the hydroxy group at the 3-position can be inverted to the α-position to obtain a ribofuranose derivative.

Step (d) is specifically carried out by mixing compound (VI) and a reducing agent in a solvent, but the order of mixing is not particularly limited.
Examples of the reducing agent include sodium borohydride and lithium borohydride, among which sodium borohydride is preferable. The amount of the reducing agent to be used is generally 0.5 equivalent to 5 equivalents, preferably 1 equivalent to 1.5 equivalents, relative to compound (VI).

  The solvent used may be any solvent as long as it does not inhibit this reaction, and examples thereof include alcohols such as methanol and ethanol, mixed solvents of alcohol and water, and the like. The amount of the solvent to be used is generally 1 to 100 times by weight, preferably 5 to 20 times by weight, relative to compound (VI).

  The reaction temperature is usually in the range of −50 ° C. to 100 ° C., preferably −10 ° C. to 20 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

Step (e)
In the step (e), the compound (IX) can be produced by removing the protecting group P ¹ from the compound (VII) and then reacting the compound (VIII) in the presence of a base.
Depending on the type of base, in step (e), compound (VII), compound (VIII) and a base can be mixed in a solvent to simultaneously remove the protecting group P ¹ . The order of mixing them is not particularly limited.

  As the compound (VIII) used, benzyl bromide, benzyl chloride and the like are preferable. The amount of compound (VIII) to be used is generally 2 to 20 equivalents, preferably 2 to 25 equivalents, relative to compound (VII).

As the base to be used, alkali metal hydrides such as sodium hydride, lithium hydride, potassium hydride and the like are preferable since the removal of the protecting group P ¹ can be simultaneously performed. . The amount of the base to be used is generally 2 equivalents to 20 equivalents, preferably 2 equivalents to 3 equivalents, relative to compound (VII).

  Any solvent may be used as long as it does not inhibit this reaction. For example, tetrahydrofuran, toluene and the like can be used alone or in combination. The amount of the solvent to be used is generally 2 to 20 times by weight, preferably 5 to 10 times by weight, relative to compound (VII).

  The reaction temperature is usually in the range of 0 ° C to 100 ° C, preferably 20 ° C to 80 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

Step (f)
In step (f), compound (IX) can be produced by acid hydrolysis of compound (IX) to deprotect the 1- and 2-position hydroxy groups. This compound (X) is a novel compound and is useful as an intermediate for antisense drugs and the like.
Step (f) is specifically carried out by mixing compound (IX) and an acid in a solvent, but the mixing order is not particularly limited.

  The acid used is not particularly limited, and examples thereof include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Examples include organic acids such as trifluoromethanesulfonic acid, among which organic acids are preferable, and trifluoroacetic acid is more preferable. The amount of the acid to be used is generally 10 equivalents to 100 equivalents, preferably 20 equivalents to 50 equivalents, relative to compound (IX).

  Examples of the solvent used include water, a mixed solvent of water and alcohols (eg, methanol, ethanol and the like), and the like, and water is preferable. The amount of the solvent to be used is generally 1 to 10 times by weight, more preferably 2 to 10 times by weight, relative to compound (IX).

  The reaction temperature is usually in the range of -10 ° C to 100 ° C, preferably -5 ° C to 50 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

  In addition, the substituent OH of the anomeric carbon atom of the obtained compound (X) can take any configuration at the α-position or β-position. Therefore, the steric configuration of the substituent OH of the anomeric carbon atom of the compound (X) is not limited at all, and any of those in which the steric configuration is α-position, β-position and a mixture thereof may be used. The ratio of the steric configuration of the substituent OH to the α-position and the β-position is any ratio from 0: 100 to 100: 0.

Step (g)
In step (g), compound (I) can be produced by acylating the 1- and 2-position hydroxy groups of compound (X). This compound (I) is useful as an intermediate for antisense drugs and the like.
The step (g) is specifically carried out by mixing the compound (X), the acylating agent and the base in a solvent, but the mixing order is not particularly limited.

The acylating agent to be used, acid anhydride corresponding to the "optionally substituted acyl group" represented by R ⁴ or an acyl halide, and the like. Among these, acetic anhydride, acetyl chloride, etc. Is preferred, and acetic anhydride is more preferred. The amount of the acylating agent to be used is generally 2 equivalents to 20 equivalents, preferably 2 equivalents to 10 equivalents, relative to compound (X).

  Examples of the base used include pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and the like, and two or more bases may be used in combination. Among these, a combination of pyridine and dimethylaminopyridine is preferable. The usage-amount of a base is 0.01 equivalent-2 equivalent normally with respect to compound (X), Preferably it is 0.1 equivalent-1 equivalent.

  Any solvent may be used as long as it does not inhibit the reaction. For example, tetrahydrofuran, toluene, ethyl acetate and the like can be used alone or in combination. The amount of the solvent to be used is generally 1 to 20 times by weight, more preferably 5 to 10 times by weight, relative to compound (X).

  The reaction temperature is usually in the range of −10 ° C. to 100 ° C., preferably 0 ° C. to 10 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

  In addition, the substituent OH of the anomeric carbon atom of the obtained compound (I) can freely adopt either steric configuration at the α-position or the β-position as in the case of the compound (X). Therefore, the steric configuration of the substituent OH of the anomeric carbon atom of the compound (X) is not limited at all, and any of those in which the steric configuration is α-position, β-position and a mixture thereof may be used. The ratio of the steric configuration of the substituent OH to the α-position and the β-position is any ratio from 0: 100 to 100: 0.

  The compound (I) which is the ribofuranose compound thus obtained is led to a purine nucleoside compound by the following step (h).

Step (h)
In the step (h), the compound (I) and the compound (XI) are reacted in a nitrile solvent or an ester solvent in the presence of a silylating agent and a Lewis acid, thereby being represented by the following formula (XII ″). Compound (XII) can be produced by obtaining a compound (hereinafter also referred to as compound (XII ″)) and then deacylating the 2 ′ position of compound (XII ″).

The first step of the first step step (h), specifically, usually, Compound (I), the compound (XI), but silylating agent and a Lewis acid is carried out by mixing in a solvent, they The order of mixing is not particularly limited. For example, compound (I), compound (XI), silylating agent, Lewis acid and solvent may be mixed together, or compound (XI), silylating agent and solvent may be mixed. Thereafter, compound (I) and Lewis acid may be added. Further, after mixing compound (I), compound (XI), silylating agent and solvent, Lewis acid may be added, or after mixing compound (XI), silylating agent, Lewis acid and solvent, compound (I) may be added. In terms of yield and stability of compound (I), it is preferable to add compound (I) and Lewis acid after mixing compound (XI), silylating agent and solvent.

  Examples of the compound (XI) include 6-fluoropurine, 6-chloropurine, 2,6-dichloropurine, 2-amino-6-chloropurine, 2-amino-6-iodopurine and the like. 2-Amino-6-chloropurine is preferred. Compound (XI) may be a commercially available one, for example, JP-A-5-170766, JP-A-6-157530, JP-A-11-60575, JP-A-2002-88082. You may use what was manufactured according to well-known methods, such as a gazette. The amount of compound (XI) to be used is generally 0.1 to 1 equivalent, preferably 0.2 to 1 equivalent, relative to compound (I).

  Examples of the silylating agent include N, O-bis (trimethylsilyl) acetamide, hexamethyldisilazane, trimethylsilyl chloride and the like, and N, O-bis (trimethylsilyl) acetamide is preferable. The amount of the silylating agent to be used is generally 0.8 equivalent to 5 equivalents relative to compound (XI).

  Examples of the Lewis acid include trimethylsilyl trifluoromethanesulfonate and trimethylsilyl iodide, and trimethylsilyl trifluoromethanesulfonate is preferable. As such Lewis acid, a commercially available product is usually used. If the amount used is too large, by-product formation of impurities increases, so that the amount used of compound (I) and compound (XI) is small. The amount is usually 0.005 to 1 equivalent, preferably 0.01 to 0.5 equivalent.

  Examples of the nitrile solvent include hydrophilic nitrile solvents such as acetonitrile and propionitrile, and examples of the ester solvent include ethyl acetate and propyl acetate. A hydrophilic nitrile solvent is preferable in that the treatment after the reaction is easy and the target compound (XII ″) can be easily taken out as crystals, and among them, acetonitrile is preferable. The amount of the solvent used is the compound (XI). On the other hand, it is usually 1 to 20 times by weight.

This reaction may be carried out under normal pressure conditions or under pressurized conditions. Moreover, in order to suppress decomposition | disassembly of a silylating agent etc., it is preferable to implement in inert gas atmosphere, such as nitrogen gas, for example.
The reaction temperature is generally 0 to 150 ° C., preferably 50 to 150 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

  After completion of the reaction, it can be isolated by a conventional method such as extraction or concentration after neutralization with an aqueous alkaline solution such as aqueous ammonia or aqueous sodium hydrogen carbonate solution, if necessary. For example, when a hydrophilic nitrile solvent such as acetonitrile is used, compound (XII ″) is precipitated as crystals by mixing water after neutralization. Can be isolated.

In the second step of the second step step (h), the compound (XII) can be produced by deacylating the 2 ′ position of the compound (XII ″). The deacylation reaction includes hydrolysis. Or alcohol decomposition etc. Specifically, it implements by processing a compound (XII ") with an acid or a base in a solvent.

Examples of the acid used include hydrochloric acid and sulfuric acid, and examples of the base include ammonia, sodium hydroxide, sodium carbonate and the like, and ammonia and sodium hydroxide are preferable.
The amount of the acid or base to be used is generally 0.1 equivalent to 10 equivalents, preferably 1 equivalent to 5 equivalents, relative to compound (I).

  Examples of the solvent used include water, alcohol (eg, methanol, ethanol, etc.) or a mixed solvent of water and alcohol, and methanol is preferable. The amount of the solvent to be used is generally 1 to 20 times by weight with respect to compound (I).

  The reaction temperature is usually in the range of 0 ° C to 100 ° C, preferably 10 ° C to 50 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

In compound (XII), compound (XII ′) in which R ³ is a benzyl group, Y ¹ is a chlorine atom, and Y ² is an amino group is represented by steps (i) to (m) shown in the following reaction scheme. ) Can lead to a compound (XVII) that is useful as a synthetic intermediate for antisense drugs.

(In the formula, Bn represents a benzyl group, and DMT represents a dimethoxytrityl group.)
Hereinafter, the steps (i) to (m) will be described in detail.

Step (i)
In step (i), compound (XIII) can be produced by benzyloxylating the 6-position chlorine atom of compound (XII ′). Specifically, the step (i) can be performed by reacting benzyl alcohol with a base to form a benzyl alkoxide, and then adding the compound (XII ′).

  The amount of benzyl alcohol to be used is generally 1 equivalent to 10 equivalents, preferably 1 equivalent to 5 equivalents, relative to compound (XII ′).

  Examples of the base used include alkali metal hydroxides such as sodium hydroxide, lithium hydroxide and potassium hydroxide; alkali metal hydrides such as sodium hydride, lithium hydride and potassium hydride; Is sodium hydroxide. The usage-amount of a base is 0.5 equivalent-2 equivalent normally with respect to benzyl alcohol, Preferably it is 0.8 equivalent-1.5 equivalent.

  The benzyl alkoxide production reaction may be performed in a solvent, or may be performed without a solvent. When a solvent is used, for example, toluene, xylene, ethyl acetate or the like is used.

  The reaction temperature for producing benzylalkoxide is usually in the range of 0 to 100 ° C, preferably 50 to 100 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

  Subsequently, compound (XII ') is added to the reaction mixture containing benzyl alkoxide, and the reaction is usually carried out in the range of 0 ° C to 100 ° C, preferably 0 ° C to 50 ° C. The reaction time is usually 1 hour to 24 hours.

Step (j)
In step (j), compound (XIV) can be produced by methoxyethylating the 2′-position hydroxy group of compound (XIII). Step (j) is specifically carried out by mixing compound (XIII), methoxyethyl halide and a base in a solvent, but the mixing order is not particularly limited.

As the methoxyethyl halide, for example, 2-bromoethyl methyl ether is preferable. The amount of methoxyethyl halide to be used is generally 1 equivalent to 10 equivalents, preferably 1 equivalent to 5 equivalents, relative to compound (XIII).
In order to activate methoxyethyl halide, an iodide such as tetrabutylammonium iodide may be added. The usage-amount of iodide is 0.01 equivalent-1 equivalent normally with respect to a methoxyethyl halide, Preferably it is 0.05 equivalent-0.2 equivalent.

  Examples of the base to be used include alkali metal hydrides such as sodium hydride, lithium hydride and potassium hydride, and sodium hydride is preferable. The amount of the base to be used is generally 1 equivalent to 10 equivalents, preferably 1 equivalent to 5 equivalents, relative to compound (XIII).

  Any solvent may be used as long as it does not inhibit the reaction. For example, tetrahydrofuran, toluene, ethyl acetate and the like can be used alone or in combination. The amount of the solvent to be used is generally 1 to 20 times by weight, more preferably 3 to 10 times by weight, relative to compound (XIII).

  In step (j), it is preferable to further use a strong base such as lithium hexamethyldisilazide or lithium diisopropylamide. The amount of the strong base to be used is generally 1 equivalent to 10 equivalents, preferably 1 equivalent to 5 equivalents, relative to compound (XIII).

  The reaction temperature is usually in the range of 0 ° C to 100 ° C, preferably 10 ° C to 50 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

Step (k)
In step (k), compound (XV) is produced by isobutyrylating the amino group at the 2-position of compound (XIV). Step (k) is specifically carried out by mixing compound (XIV), isobutyryl chloride and a base, but the mixing order thereof is not particularly limited.

  The amount of isobutyryl chloride to be used is generally 1 equivalent to 10 equivalents, preferably 1 equivalent to 2 equivalents, relative to compound (XIV).

  Examples of the base used include pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and the like, and two or more bases may be used in combination. Of these, pyridine and toluethylamine are preferable. The amount of the base to be used is generally 1 equivalent to 100 equivalents, preferably 1 equivalent to 50 equivalents, relative to compound (XIV).

  The step (k) may be performed in a solvent, but may be performed without a solvent. When a solvent is used, for example, toluene, ethyl acetate or the like is used.

  The reaction temperature is usually in the range of 0 ° C to 100 ° C, preferably 10 ° C to 50 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

Step (l)
In step (l), compound (XVI) can be produced by debenzylation of the 5 ′ position of compound (XV). At this time, the 6-position and the 3′-position are simultaneously debenzylated. As the debenzylation reaction, a hydrogenolysis reaction is preferable. Hereinafter, although hydrogenolysis reaction is demonstrated, process (l) is not limited to this.

  Specifically, the hydrogenolysis reaction is carried out by stirring the compound (XV) in a solvent in the presence of a catalyst in a hydrogen atmosphere.

  Examples of the catalyst used include palladium carbon and expanded nickel, and among them, palladium carbon is preferable. The usage-amount of a catalyst is 0.01 weight times-10 weight times normally with respect to compound (XV), More preferably, they are 0.1 weight times-1 weight times.

  As the solvent to be used, for example, alcohols such as methanol and ethanol, tetrahydrofuran, water and the like can be used alone or in combination. The amount of the solvent to be used is generally 5 to 100 times by weight, more preferably 10 to 50 times by weight, relative to compound (XV).

  The hydrogen pressure in the reaction system is not particularly limited, and may be pressurized or normal pressure, and normal pressure is more preferable.

  The reaction temperature is usually in the range of 0 ° C to 100 ° C, preferably 10 ° C to 50 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

Process (m)
In step (m), compound (XVII) can be produced by dimethyltritylation of the 5′-position hydroxy group of compound (XVI). The step (m) is specifically carried out by mixing the compound (XVI), dimethyltrityl chloride and a base, but the mixing order is not particularly limited.

  The amount of dimethyltrityl chloride to be used is generally 1 equivalent to 5 equivalents, preferably 1 equivalent to 2 equivalents, relative to compound (XVI).

  Examples of the base include pyridine, picoline, lutidine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and the like, and two or more bases may be used in combination. Of these, 2,6-lutidine and pyridine are preferable. The amount of the base to be used is generally 1 equivalent to 10 equivalents, preferably 2 equivalents to 5 equivalents, relative to compound (XVI).

  The step (m) may be performed in a solvent, but may be performed without a solvent. When a solvent is used, for example, toluene, ethyl acetate or the like is used.

  The reaction temperature is usually in the range of 0 ° C to 100 ° C, preferably 10 ° C to 50 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

  General formula (XVIII) that can be produced by the above method:

(In the formula, each symbol is as defined above.) Purine ribonucleoside compound (2-amino-6-chloro-9β- (2′-O-acetyl-3 ′, 5′-di-O) -Benzyl) -D-ribofuranosylpurine is a novel compound and is useful as a synthetic intermediate for antisense drugs.

In the compound (XVIII), ^{R 5} is a hydrogen atom, an alkyl group of 1 to 5 carbon acyl group or carbon may have a substituent group having 1 to 10 carbon atoms, ^{R 6} and ^{R 7} are each Independently, it is a hydrogen atom, an aralkyl group having 7 to 21 carbon atoms or an acyl group having 1 to 10 carbon atoms, Y ^{1 ′} is a halogen atom or a hydroxy group which may have a substituent, and A compound in which Y ^{2 ′} is a halogen atom or an amino group which may have a substituent is preferable, and among them, R ⁵ is a hydrogen atom, an acetyl group or a 2-methoxyethyl group, and R ⁶ and R ⁷ but each independently a hydrogen atom, a benzyl group or acetyl group, Y 1 ^'is a chlorine atom, a benzyloxy group or a hydroxy group, and Y ^2' is an amino group or isobutyrylamino Compounds is particularly preferred.

  Hereinafter, the present invention will be described more specifically with reference to examples. The present invention is not limited by these.

Example 1 1,2-O- (1-methylethylidene) -α-D-xylofuranose

98% sulfuric acid (10.0 g) was added to a suspension of D-xylose (30.0 g) and anhydrous copper sulfate (II) (40.0 g) in acetone (400 ml), and the mixture was stirred at room temperature for 7 hours. After confirming the completion of the reaction by TLC, the reaction mixture was filtered. The obtained filtrate was neutralized by adding 28% aqueous ammonia, and the precipitated crystals were filtered. The filtrate was concentrated and water (150 ml) was added to the residue. The solution was cooled to 0 ° C., and 35% hydrochloric acid was added to adjust the pH to 1 or less. After stirring at room temperature for 4 hours and confirming that the reaction was complete by TLC, it was neutralized with sodium bicarbonate. The obtained solution was extracted three times with toluene (100 ml), and the obtained toluene solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (36 g). Yield 95%
¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm) 1.32 (3H, s), 1.49 (3H, s), 4.07 (2H, m), 4.18 (1H, m), 4.33 (1H, d), 4.53 (1H, d), 5.98 (1H, d).
¹³ C-NMR (CDCl ₃ , 100 MHz) δ (ppm) 25.2, 25.8, 51.8, 60.1, 77.8, 84.6, 103.8, 110.7.
MS (CI, 70eV) m / z 191 (M + + H, 100), 173 (20), 133 (53).

Example 2-1 1,2-O- (1-methylethylidene) -α-D-xylofuranose 5-benzoate

Pyridine (1.56 g) is added to a toluene (30 ml) solution of 1,2-O- (1-methylethylidene) -α-D-xylofuranose (3.99 g), cooled to 0 ° C., and benzoyl chloride (2 .95 g) was added dropwise. After confirming the disappearance of the raw material by TLC, the reaction mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography to give the title compound (4.53 g). Yield 77%
¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm) 1.32 (3H, s), 1.51 (3H, s), 3.42 (1H, d), 4.20 (1H, m), 4.40 (2H, m), 4.59 (1H, d), 4.78 (1H, m), 5.97 (1H, d), 7.45 (2H, m), 7.59 (1H, m), 8.05 (2H, t).
_{^{13 C-NMR (CDCl 3,}} 100MHz) δ (ppm) 26.2, 26.8, 61.4, 74.4, 78.5, 85.0, 104.7, 111.8, 128.4, 129.2, 129.8, 133.4, 167.2.
MS (CI, 70eV) m / z 294 (M ⁺ , 100), 236 (24).

Example 2-2 1,2-O- (1-methylethylidene) -α-D-xylofuranose 5- (4′-methylbenzoate)
The same procedure as in Example 2-1 was performed except that triethylamine was used instead of pyridine, p-toluoyl chloride was used instead of benzoyl chloride, and dimethylaminopyridine was added. Obtained. Yield 73%
¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm) 1.32 (3H, s), 1.51 (3H, s), 2.42 (3H, s), 3.41 (1H, d), 4.17 (1H, m), 4.40 (2H, m), 4.59 (1H, d), 4.78 (1H, m), 5.96 (1H, d), 7.25 (2H, d), 7.94 (2H, d).
MS (CI, 70eV) m / z 309 (M ⁺ , 100), 251 (27).

Example 2-3 1,2-O- (1-methylethylidene) -α-D-xylofuranose 5- (4′-chlorobenzoate)
The title compound was obtained in the same manner as in Example 2-1, except that triethylamine was used instead of pyridine, 4-chlorobenzoyl chloride was used instead of benzoyl chloride, and dimethylaminopyridine was added. Got. Yield 48%
¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm) 1.32 (3H, s), 1.51 (3H, s), 2.42 (3H, s), 3.41 (1H, d), 4.17 (1H, m), 4.40 (2H, m), 4.59 (1H, d), 4.78 (1H, m), 5.96 (1H, d), 7.25 (2H, d), 7.94 (2H, d).

Example 3 1,2-O- (1-methylethylidene) -α-D-erythropentafurano-3-rose 5-benzoate

A toluene (30 ml) solution of 1,2-O- (1-methylethylidene) -α-D-xylofuranose 5-benzoate (3.1 g) was cooled to 0 ° C., DMSO (3 ml), pyridine (0.3 ml) ), Trifluoroacetic acid (0.1 ml) and N, N′-dicyclohexylcarbodiimide (2.9 g) were added and reacted at room temperature for 18 hours. After adding ethyl acetate (30 ml) and filtering, the filtrate was washed with water (10 ml). The organic layer was concentrated to give the title compound (2.63 g). Yield 85%
¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm) 1.36 (3H, s), 1.44 (3H, s), 4.36 (1H, d), 4.40 (1H, d), 4.61 (2H, m), 6.06 (1H, t), 7.36 (2H, m), 7.56 (1H, m), 8.06 (2H, d).
¹³ C-NMR (CDCl ₃ , 100 MHz) δ (ppm) 27.1, 27.4, 63.4, 76.1, 103.0, 114.3, 128.4, 129.2, 129.6, 133.2, 165.6, 207.4.

Example 4 1,2-O- (1-methylethylidene) -α-D-ribofuranose 5-benzoate

1,2-O- (1-methylethylidene) -α-D-erythropentafurano-3-rose 5-benzoate (5.32 g) in 90% aqueous methanol (61 ml) in sodium borohydride (0.73 g) Was gradually added and stirred at 0 ° C. for 5 hours. After the reaction was completed, 5% aqueous ammonium chloride solution (20 ml) was added to remove excess sodium borohydride. The reaction mixture was concentrated, extracted three times with acetonitrile (20 ml), and the organic layer was concentrated to give the title compound (5.0 g). Yield 94%
_{^{1 H-NMR (CDCl 3,}} 400MHz) δ (ppm) 1.39 (3H, s), 1.59 (3H, s), 3.92 (1H, dd), 4.09 (1H, d), 4.47 (1H, m), 4.61 (2H, m), 4.68 (1H, m), 4.73 (1H, d), 5.86 (1H, d), 7.44-7.56 (3H, m), 8.06 (2H, d).
¹³ C-NMR (CDCl ₃ , 100 MHz) δ (ppm) 25.6, 62.4, 71.1, 77.3, 77.5, 103.1, 111.8, 127.3, 128.7, 132.1, 165.4.
MS (CI, 70eV) m / z 295 (M ⁺ +1, 14), 237 (100), 123 (16).

Example 5 1,2-O- (1-methylethylidene) -3,5-di-O-benzyl-α-D-ribofuranose

To a solution of 60% sodium hydride (2.58 g) in THF (100 ml) was added 1,2-O- (1-methylethylidene) -α-D-ribofuranose 5-benzoate (8.00 g) and benzyl bromide ( 9.57 g) was added, and the mixture was reacted at reflux (65 ° C.) for 4 hours. The reaction solution was cooled to room temperature, methanol and water were added, and the mixture was extracted with acetonitrile. The organic layer was concentrated and purified by silica gel column chromatography to obtain the title compound (7.00 g). Yield 70%
¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm) 1.36 (3H, s), 1.59 (3H, s), 3.57 (1H, dd), 3.76 (1H, d), 3.86 (1H, m), 4.17 (1H, m), 4.48-4.58 (3H, m), 4.73 (1H, d), 5.75 (1H, d), 7.27-7.34 (10H, m).
¹³ C NMR (CDCl ₃ , 100 MHz) δ (ppm) 14.2, 22.7, 26.6, 26.8, 29.0, 31.9, 68.0, 72.2, 73.5, 78.0, 104.1, 112.8, 127.5, 127.6, 127.9, 127.9, 128.2, 128.3, 137.6 , 138.0
MS (CI, 70eV) m / z 371 (M ⁺ +1, 13), 313 (100), 205 (60), 147 (41), 133 (24).

Example 6 1,2-Di-O-acetyl-3,5-di-O-benzyl-D-ribofuranose

(A) 3,5-Di-O-benzyl-D-ribofuranose 1,2-O- (1-methylethylidene) -3,5-di-O-benzyl-α-D-ribofuranose (7.20 g) ) In 70% trifluoroacetic acid (100 g) was stirred at 0 ° C. for 1 hour and then at room temperature for 2 hours. The reaction solution was added dropwise to 38% aqueous potassium bicarbonate solution (163 g), extracted three times with ethyl acetate (100 ml), the organic layer was concentrated, and 3,5-di-O-benzyl-D-ribofuranose was concentrated. Got.
^{1 H-NMR (DMSO-d} 6, 400MHz) δ (ppm) 3.47 (1H, m), 3.55 (1H, m), 3.84 (1H, dd), 3.76 (1H, d), 3.84 (1H, m) , 4.01 (1H, m), 4.41-4.50 (4H, m), 4.62 (2H, d), 4.98 (2H, dd), 6.33 (1H, d), 7.26-7.33 (10H, m).
¹³ C-NMR (CDCl ₃ , 100 MHz) δ (ppm) 70.9, 72.1, 72.3, 73.0, 78.8, 102.0, 127.3, 127.4, 128.0, 128.0, 138.3.

(B) 1,2-di-O-acetyl-3,5-di-O-benzyl-D-ribofuranose 3,5-di-O-benzyl-D-ribofuranose obtained in (a) (63 ml) plus pyridine (9.5 ml) and dimethylaminopyridine (0.30 g). After cooling to 0 ° C., acetic anhydride (7.4 ml) was added dropwise and allowed to react for 3 hours. Dilute with ethyl acetate and wash with 1N hydrochloric acid (60 ml), 10% aqueous potassium bicarbonate (60 ml) and saturated brine (60 ml). The organic layer was concentrated and purified by silica gel column chromatography to obtain the title compound (6.92 g). Yield 86% (yield from 1,2-O- (1-methylethylidene) -3,5-di-O-benzyl-α-D-ribofuranose)
¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm) 1.92 (3H, s), 2.12 (3H, s), 3.55 (1H, dd), 3.68 (1H, dd), 4.23 (1H, m), 4.30 (1H, m), 4.44.63-4.58 (4H, m), 5.30 (1H, d), 6.12 (1H, d), 7.27-7.33 (10H, m).
¹³ C-NMR (CDCl ₃ , 100 MHz) δ (ppm) 20.8, 21.0, 69.2, 73.2, 73.6, 76.4, 81.4, 98.5, 101.5, 127.4, 127.5, 127.9, 128.2, 128.4, 137.3, 138.0, 169.1, 169.8.
MS (CI, 70eV) m / z 415 (M ⁺ +1, 1.3), 355 (100), 205 (25), 147 (54), 139 (54).

Example 7 2-Amino-6-chloro-3 ', 5'-di-O-benzylpurine riboside

  A mixture of acetonitrile (12 ml), 2-amino-6-chloropurine (1.0 g, 5.90 mmol) and N, O-bis (trimethylsilyl) acetamide (2.47 g, 12.1 mmol) was stirred at 50 ° C. for 2 hours. did. Then 1,2-di-O-acetyl-3,5-di-O-benzyl-D-ribofuranose (2.44 g, 5.90 mmol) and trimethylsilyl trifluoromethanesulfonate (0.12 g, 0.54 mmol) And reacted under reflux (85 ° C.) for 2 hours. After cooling to room temperature, water (10 ml) was added and neutralized with 28% aqueous ammonia. Extracted with ethyl acetate (10 ml) three times, and the organic layer was concentrated. 1N ammonia methanol solution (10 ml) was added to the residue and stirred for 20 hours. The reaction solution was concentrated and purified by silica gel column chromatography (ethyl acetate / heptane = 1: 1) to obtain the title compound (2.70 g) (yield 96%).

Example 8 6-O-benzyl-3 ', 5'-di-O-benzylguanosine

  A mixture of benzyl alcohol (13.5 g) and sodium hydroxide (0.50 g, 12.5 mmol) was stirred at 80 ° C. for 2 hours. Then, 2-amino-6-chloro-3 ', 5'-di-O-benzylpurine riboside (2.70 g, 5.61 mmol) was added and reacted at room temperature for 20 hours. 1% caustic water (20 g) and MTBE (methyl t-butyl ether) (20 g) were added and the layers were separated. The organic layer was concentrated and purified by silica gel column chromatography (ethyl acetate / heptane = 1: 4) to obtain the title compound (1.94 g). Yield 67%

Example 9 6-O-benzyl-2'-O- (2-methoxyethyl) -3 ', 5'-di-O-benzylguanosine

  Lithium hexamethyldisilazide in THF (10.5 g), sodium hydride (60% in oil, 0.42 g, 10.5 mmol), tetrabutylammonium iodide (0.38 g, 1.03 mmol), 6- A mixture of O-benzyl-3 ′, 5′-di-O-benzylguanosine (1.94 g, 3.51 mmol) and 2-bromoethyl methyl ether (1.46 g, 10.5 mmol) was stirred at 30 ° C. for 5 hours. did. The reaction mixture was then concentrated and purified by silica gel column chromatography (ethyl acetate / heptane = 5: 1) to obtain the title compound (1.42 g). Yield 66.3%

Example 10-1 6-O-benzyl-2-N- (2-methyl-1-oxopropyl) -3 ', 5'-di-O-benzyl-2'-O- (2-methoxyethyl) guanosine

  Pyridine (7.0 g), 6-O-benzyl-2′-O- (2-methoxyethyl) -3 ′, 5′-di-O-benzylguanosine (1.42 g, 2.32 mmol) and isobutyryl A mixture of chloride (0.30 g, 2.81 mmol) was reacted at room temperature for 11 hours. Thereafter, methanol (10 ml), water (10 ml) and ethyl acetate (10 ml) were added for liquid separation, and the organic layer was concentrated. Purification by silica gel column chromatography (ethyl acetate / heptane = 2: 1) gave the title compound (1.07 g). Yield 64%

Example 10-2 6-Chloro-2- (2-methyl-1-oxopropyl) amino-2′-O-acetyl-3 ′, 5′-di-O-benzylpurine riboside In Example 10-1 , 6-O-benzyl-2'-O- (2-methoxyethyl) -3 ', 5'-di-O-benzylguanosine instead of 2-amino-6-chloro-2'-O-acetyl-3 The title compound was obtained in the same manner as in Example 10-1, except that ', 5'-di-O-benzylpurine riboside was used. Yield 57.1%

Example 10-3 6-chloro-2- (2-methyl-1-oxopropyl) amino-2 ′, 3 ′, 5′-tri-O-acetylpurine riboside In Example 10-1, 6-O 2-benzyl-6'-chloro-2 ', 3', 5'-tri-O instead of -benzyl-2'-O- (2-methoxyethyl) -3 ', 5'-di-O-benzylguanosine -The title compound was obtained in the same manner as in Example 10-1, except that acetylpurine riboside was used. Yield 57.1%

Example 11 2'-O- (2-methoxyethyl) -2-N- (2-methyl-1-oxopropyl) guanosine

  Methanol (25 ml), 6-O-benzyl-2-N- (2-methyl-1-oxopropyl) -3 ′, 5′-di-O-benzyl-2′-O- (2-methoxyethyl) guanosine The reaction vessel containing (0.8 g, 1.17 mmol) and 10% Pd / C (50% wet, 0.80 g) was replaced with hydrogen, and the mixture was stirred at normal pressure and 40 ° C. for 22 hours. Thereafter, it was replaced with nitrogen, and Pd / C was filtered. The reaction mixture was concentrated and purified by silica gel column chromatography (ethyl acetate / heptane / methanol = 1: 3: 6) to give the title compound (0.38 g). Yield 80%

Example 12 5'-O-dimethoxytrityl-2'-O- (2-methoxyethyl) -2-N- (2-methyl-1-oxopropyl) guanosine

  2′-O- (2-methoxyethyl) -2-N- (2-methyl-1-oxopropyl) guanosine (100 mg, 0.24 mmol), 2,6-lutidine (100 mg, 0.93 mmol) and dimethoxytrityl A mixture of chloride (80 mg, 0.24 mmol) was reacted at 40 ° C. for 10 hours. The mixture was purified by silica gel column chromatography (ethyl acetate / heptane / methanol = 1: 3: 6) to give the title compound (0.14 g). Yield 83%

  ADVANTAGE OF THE INVENTION According to this invention, the more efficient and industrially suitable manufacturing method of the purine nucleoside compound useful as a synthetic intermediate of a pharmaceutical can be provided.

Claims (24)

General formula (I), characterized in that it comprises the following steps (a) to (g):

(Wherein, R ³ is an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted heteroarylalkyl group, R ⁴ Represents an acyl group which may have a substituent, and the wavy line indicates that the configuration of the substituent OR ⁴ of the anomeric carbon atom is not limited.)
(A) Formula (II):

(Wherein the wavy line indicates that the configuration of the substituent OH of the anomeric carbon atom is not limited at all). D-xylose represented by the general formula (III) in the presence of an acid:

(In the formula, R ¹ and R ² each independently represents a hydrogen atom or an alkyl group.) After reacting with the compound represented by the formula (IV):

(Wherein each symbol is as defined above), a step of obtaining a compound represented by:
(B) The hydroxy group at the 5-position of the compound represented by the general formula (IV) is selectively protected, and the general formula (V):

(Wherein P ¹ represents a benzoyl group which may have a substituent, and other symbols have the same meanings as described above) to obtain a compound represented by:
(C) The hydroxy group at the 3-position of the compound represented by the general formula (V) is oxidized to give the general formula (VI):

(Wherein each symbol is as defined above), a step of obtaining a compound represented by:
(D) A carbonyl group at the 3-position of the compound represented by the general formula (VI) is reduced to give a general formula (VII):

(Wherein each symbol is as defined above), a step of obtaining a compound represented by:
(E) After removing the protecting group P ¹ from the compound represented by the general formula (VII), the general formula (VIII):

(Wherein X ¹ represents a halogen atom, a mesyloxy group or a tosyloxy group, and R ³ has the same meaning as described above), and a compound represented by the general formula (IX):

(Wherein each symbol is as defined above), a step of obtaining a compound represented by:
(F) A compound represented by the general formula (IX) is subjected to an acid hydrolysis reaction to give a general formula (X):

(Wherein R ³ is as defined above, and the wavy line indicates that the configuration of the substituent OH of the anomeric carbon atom is not limited at all); and (g) a general formula A step of obtaining a compound represented by the general formula (I) by acylating the 1-position and 2-position hydroxy groups of the compound represented by (X). Formula (IX):

(In the formula, R ¹ and R ² each independently represent a hydrogen atom or an alkyl group, and R ³ represents an alkyl group which may have a substituent or an aralkyl which may have a substituent. A heteroarylalkyl group which may have a group or a substituent.) A compound represented by the general formula (X):

(Wherein R ³ has the same meaning as described above, and the wavy line indicates that the steric configuration of the substituent OH of the anomeric carbon atom is not limited in any way). Formula (X):

(In the formula, R ³ represents an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or a heteroarylalkyl group which may have a substituent; , The steric configuration of the substituent OH of the anomeric carbon atom is not limited at all.) The hydroxy group at the 1-position and 2-position of the compound represented by the general formula (I):

(Wherein R ³ has the same meaning as described above, R ⁴ represents an acyl group which may have a substituent, and the wavy line indicates that the configuration of the substituent OR ⁴ of the anomeric carbon atom is not limited in any way. The manufacturing method of the compound represented by this. Formula (I):

(Wherein, R ³ is an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted heteroarylalkyl group, R ⁴ Represents an acyl group which may have a substituent, and the wavy line indicates that the configuration of the substituent OR ⁴ of the anomeric carbon atom is not limited at all.) And a compound represented by the general formula (XI) :

(Wherein Y ¹ and Y ² each independently represent a hydrogen atom, a halogen atom, an optionally substituted hydroxy group or an optionally substituted amino group). A compound represented by the general formula (2), wherein the compound or a salt thereof is reacted in a nitrile solvent or an ester solvent in the presence of a silylating agent and a Lewis acid, and then deacylated at the 2′-position. XII):

(Wherein each symbol is as defined above), or a method for producing a salt thereof. The manufacturing method in any one of Claims 1-4 whose R < ³ > is a C7-C21 aralkyl group. The manufacturing method in any one of Claims 1-4 whose R < ³ > is a benzyl group. The manufacturing method in any one of Claim 1, 3 and 4 whose R < ⁴ > is a C1-C8 acyl group. The production method according to claim 1, wherein R ⁴ is an acetyl group. Y ¹ is, have a halogen atom or a substituent is also optionally hydroxy group, The method according to claim 4, wherein. The production method according to claim 4, wherein Y ¹ is a halogen atom. The production method according to claim 4, wherein Y ² is a halogen atom or an amino group which may have a substituent. Y ² is an amino group, a manufacturing method of claim 4 wherein. Formula (X):

(In the formula, R ³ represents an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or a heteroarylalkyl group which may have a substituent; And the steric configuration of the substituent OH of the anomeric carbon atom is not limited at all.) The compound according to claim 13, wherein R ³ is an aralkyl group having 7 to 21 carbon atoms. R ³ is a benzyl group, according to claim 13 A compound according. Formula (XVIII):

(In the formula, Y ^{1 ′} and Y ^{2 ′} each independently represent a hydrogen atom, a halogen atom, an optionally substituted hydroxy group or an optionally substituted amino group, R ⁵ has a hydrogen atom, an acyl group that may have a substituent, an alkyl group that may have a substituent, an aralkyl group that may have a substituent, or a substituent. R ⁶ and R ⁷ each independently represent a hydrogen atom, an optionally substituted acyl group, an optionally substituted alkyl group, or a substituent. A aralkyl group optionally having a substituent or a heteroarylalkyl group optionally having a substituent) or a salt thereof (provided that 2-amino-6-chloro-9β- (2 ′ -O-acetyl-3 ', 5'-di-O-benzi ) Except for the -D- ribofuranosyl pudding.). The compound or a salt thereof according to claim 16, wherein Y ^{1 '} is a halogen atom or a hydroxy group which may have a substituent. The compound or a salt thereof according to claim 16, wherein Y ^{1 '} is a chlorine atom, a benzyloxy group or a hydroxy group. The compound or its salt of Claim 16 whose Y2 ^' is a halogen atom or the amino group which may have a substituent. The compound or a salt thereof according to claim 16, wherein Y ^{2 '} is an amino group or an isobutyrylamino group. R ⁵ is a hydrogen atom, an alkyl group having an acyl group or substituent 1 to 5 carbon atoms which may have a 1 to 10 carbon atoms, or a salt thereof according to claim 16, wherein. The compound or a salt thereof according to claim 16, wherein R ⁵ is a hydrogen atom, an acetyl group or a 2-methoxyethyl group. The compound or salt thereof according to claim 16, wherein R ⁶ and R ⁷ are each independently a hydrogen atom, an aralkyl group having 7 to 21 carbon atoms, or an acyl group having 1 to 10 carbon atoms. The compound or a salt thereof according to claim 16, wherein R ⁶ and R ⁷ are each independently a hydrogen atom, a benzyl group or an acetyl group.