JP2002293792A - Method for producing nucleoside or fluorinated sugar derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a low-cost, safe and industrially excellent method for producing a nucleoside or sugar derivative in which a secondary hydroxy group is substituted with fluorine, in which the fluorination can be carried out by one process. SOLUTION: A nucleoside or sugar derivative is reacted with a perfluoroalkanesulfonyl fluoride in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an industrially useful method for producing a nucleoside or a sugar derivative in which a secondary hydroxyl group is substituted by fluorine.

[0002]

2. Description of the Related Art Conventionally, various methods have been used for replacing a hydroxyl group of a nucleoside or a sugar derivative with fluorine (for example, JA Wilkinson, Chem. Rev., 92,
505-519 (1982)). In a generally known method, two or more steps are required to replace the hydroxyl group of a nucleoside or a sugar derivative with fluorine. A method using DAST (diethylaminosulfur trifluoride) is known as a laboratory-excellent method for fluorinating in one step, but this compound is unstable and is produced in large quantities due to its toxicity and danger. It has not been done and is not an industrially useful method.

[0003]

DISCLOSURE OF THE INVENTION The present invention relates to a method for producing a nucleoside or a sugar derivative in which a secondary hydroxyl group is substituted by fluorine, which can be fluorinated in one step, is low-cost, safe, and industrially. It aims to provide a useful method.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, the secondary hydroxyl group of a nucleoside or a sugar derivative was converted to a base with a perfluoroalkanesulfonyl fluoride. By reacting in the presence, it has been found that a secondary hydroxyl group in a nucleoside or a sugar derivative is stereospecifically substituted with fluorine in one step, thereby completing the present invention. The perfluoroalkanesulfonyl fluoride is available at low cost and can be used safely, and the present invention is an industrially excellent production method.

That is, the present invention provides a nucleoside or a sugar derivative represented by the following general formula (I):

[0006]

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In the formula, A represents a hydrogen atom or a methylene group having a protected hydroxyl group, B represents a nucleobase or a derivative thereof or a protected hydroxyl group, R represents a hydroxyl-protecting group, and Y and X Represents one of a hydroxyl group and the other represents a hydrogen atom or a protected hydroxyl group. Alternatively, A and R together represent a cyclic acetal represented by the following general formula (III) (R ¹ and R ² both represent a hydrogen atom or a methyl group, or one of them represents a hydrogen atom And the other represents a methyl group or a phenyl group).

[0008]

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Alternatively, Y represents a hydroxyl group, and X and B together represent a cyclic acetal represented by the following general formula (IV) (R ³ and R ⁴ both represent a hydrogen atom or a methyl group. Or one of them represents a hydrogen atom, and the other represents a methyl group or a phenyl group). ]

[0010]

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A process for producing a nucleoside or a sugar derivative represented by the following general formula (II), characterized by reacting with a perfluoroalkanesulfonyl fluoride in the presence of a base.

[0012]

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Wherein A, B and R have the same meanings as above, and one of Y ′ and X ′ represents a fluorine atom and the other represents a hydrogen atom or a protected hydroxyl group. Further, the present invention is a fluorinated nucleoside derivative represented by the following general formula (V) produced using the nucleoside represented by the general formula (II) or the sugar derivative produced by the above production method.

[0014]

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[In the formula, B 'represents a nucleic acid base or a derivative thereof, Y "and X" each represent a fluorine atom, and the other represents a hydrogen atom or a hydroxyl group. ]

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION In the nucleoside or sugar derivative represented by the above general formula (I) used as a raw material of the present invention, when the above general formula (I) is a nucleoside derivative, B represents a purine base, pyrimidine base or the like. Or a derivative thereof. Specifically, pyrimidine bases include pyrimidine, thymine, cytosine, uracil and the like, and purine bases include purine, adenine, guanine, xanthine and hypoxanthine. Examples of B include a nucleobase derivative in which a hydrogen atom, a hydroxyl group, an amino group, or the like of the nucleobase is substituted with an appropriate substituent. Examples of the substituent include a hydrogen atom, an amino group, a hydroxyl group, a halogen group, an alkyl group having 1 to 10 carbon atoms, a vinyl group having 1 to 10 carbon atoms, a halogen group, and a nitro group.

Incidentally, these nucleobases or derivatives thereof may be protected with a protecting group generally used in nucleic acid synthesis. Examples of the protecting group include a protecting group for a hydroxyl group, for example, an acyl group such as acetyl group and benzoyl group, an alkyl group such as methoxymethyl group and allyl group, an aralkyl group such as benzyl group and triphenylmethyl group. . In the case of an amino-protecting group, examples include an acyl group such as an acetyl group and a benzoyl group, and an aralkyl group such as a benzyl group. These protecting groups include a halogen atom and a 1-carbon atom.
It may have a suitable substituent such as an alkyl group having 5 or an alkyloxy group having 1 to 5 carbon atoms.

When the general formula (I) is a sugar derivative, B represents a protected hydroxyl group. Examples of the hydroxyl-protecting group include acyl groups such as acetyl group and benzoyl group, alkyl groups such as methoxymethyl group and allyl group, and silyl groups such as aralkyl group such as benzyl group and triphenylmethyl group. These protecting groups may have a suitable substituent such as a halogen atom, an alkyl group having 1 to 5 carbon atoms, and an alkyloxy group having 1 to 5 carbon atoms.

In the general formula (I), R represents a hydroxyl-protecting group. Examples of the hydroxyl-protecting group include, as described above, acyl groups such as acetyl group and benzoyl group, alkyl groups such as methoxymethyl group and allyl group, and aralkyl groups such as benzyl group and triphenylmethyl group.
As described above, these protecting groups may have a substituent such as a halogen atom, an alkyl group having 1 to 5 carbon atoms, or an alkyloxy group having 1 to 5 carbon atoms.

In the general formula (I), A is a hydrogen atom or a methylene group having a protected hydroxyl group (that is, R′-
O-CH ₂ -) shows a. Examples of the hydroxyl-protecting group (R ') include, as described above, for example, an acyl group such as an acetyl group and a benzoyl group, an alkyl group such as a methoxymethyl group and an allyl group, an aralkyl group such as a benzyl group and a triphenylmethyl group. Is mentioned. That is, when A is a methylene group having a protected hydroxyl group, A is, for example, an acetyloxymethyl group, an aralkyloxymethyl group such as a benzoyloxymethyl group, a benzyloxymethyl group, or a trityloxymethyl group. And the like. Further, the protecting group (R ′) may have a substituent such as a halogen atom, an alkyl group having 1 to 5 carbon atoms, and an alkyloxy group having 1 to 5 carbon atoms.

In the above general formula (I), A may be a cyclic acetal represented by the following general formula (III) integrally with R.

[0022]

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In the general formula (III), R ¹ and R ² both represent a hydrogen atom or a methyl group, or one of them represents a hydrogen atom and the other represents a methyl group or a phenyl group. R ¹ and R ^{2 each} represent a halogen atom and a carbon atom of 1;
It may have a substituent such as an alkyl group having -5 or an alkyloxy group having 1 to 5 carbon atoms. The cyclic acetal represented by the general formula (III) is in a form in which 1,2-diol is protected by a protecting group, and can be deprotected by an ordinary method for protecting a hydroxyl group.

In the general formula (I), one of X and Y represents a hydroxyl group, and the other represents a hydrogen atom or a protected hydroxyl group. Examples of the hydroxyl-protecting group include acyl groups such as acetyl group and benzoyl group, alkyl groups such as methoxymethyl group and allyl group, and aralkyl groups such as benzyl group and triphenylmethyl group. Further, these protecting groups may have a substituent such as a halogen atom, an alkyl group having 1 to 5 carbon atoms, and an alkyloxy group having 1 to 5 carbon atoms.

In the above general formula (I), when Y represents a hydroxyl group, X may be a cyclic acetal represented by the following general formula (IV) together with B:

[0026]

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In the general formula (IV), R ³ and R ⁴ both represent a hydrogen atom or a methyl group, or one of them represents a hydrogen atom and the other represents a methyl group or a phenyl group. R ³ and R ^{4 each} represent a halogen atom, a carbon atom of 1;
It may have a substituent such as an alkyl group having -5 or an alkyloxy group having 1 to 5 carbon atoms. The cyclic acetal represented by the general formula (IV) is in a form in which 1,2-diol is protected by a protecting group, and can be deprotected by an ordinary method for protecting a hydroxyl group.

It should be noted here that, as described above, the general formula (I) also contains a compound represented by the following formula.

[0029]

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Wherein R, R ¹ , R ² , R ³ , R ⁴ , A,
B, X, and Y have the same meaning as described above. )

B, X and Y in the general formula (I)
May have any configuration of α or β configuration. Specifically, it is represented by any of the following general formulas (VI) to (XIII).

[0032]

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However, when Y is a hydroxyl group and X is a cyclic acetal represented by the above general formula (IV) in combination with B, the general formula (I) is replaced by the general formulas (VII), (VIII),
It has a configuration represented by (X) or (XIII).

When the general formula (I) is a nucleoside derivative, those in which A is a hydrogen atom and B has a β configuration are generally used. At this time, X and Y may have any configuration of α or β configuration. If the above is specifically shown by a general formula, the following general formulas (XIV) to (XVII)
Can be represented by

[0035]

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When the compound represented by the formula (I) is a nucleoside derivative, a method generally used for synthesizing a nucleoside derivative (for example, “Chemistry of Nucleosid”)
es and Nucleotides ", Vol. 1, LB Townsend, Ed.,
According to Plenum Press, New York (1988), 1-281), any compound can be synthesized.

When the compound represented by the general formula (I) is a sugar derivative, a method generally used in the synthesis of a sugar derivative (for example, “Preparative Carbohydrate Chemistry”, S.I.
According to Hanessian, Ed., Marcel Dekker, New York (1997)), any compound can be synthesized.

The fluorinating agent perfluoroalkanesulfonyl fluoride used in the present invention is not particularly limited, but preferred examples include those represented by the following formula (XXX).

[0039]

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In the formula, R ⁵ represents a linear or branched perfluoroalkyl group having 1 to 12 carbon atoms.

In particular, perfluoromethanesulfonyl fluoride, perfluoro-1-butanesulfonyl fluoride and perfluoro-1-octanesulfonyl fluoride can be easily obtained on an industrial scale, and are particularly useful in terms of cost. Of course, not limited to this, perfluoroalkanesulfonyl fluoride having an arbitrary number of carbon atoms can be used.

The perfluoroalkanesulfonyl fluoride is generally used in the range of 0.1 equivalent to 10 equivalents relative to the substrate. Preferably, it is used in the range of 0.5 to 5 equivalents.

The base used in the production method of the present invention is not particularly limited, and examples thereof include amines and salts thereof, metal hydroxides, metal alkoxides, ion exchange resins, carbonates, phosphates, acetates and the like. Can be Of these, amines and the like are particularly preferred. As amines, for example,
Examples thereof include hydroxylamine, ammonia or a salt thereof, primary to quaternary organic amines or a salt thereof, an ion exchange resin, and a resin of a polymerized amine. Specific examples include triethylamine, tributylamine, trioctylamine, N, N-dimethylcyclohexylamine, N, N-diethylcyclohexylamine, N-ethyldiisopropylamine, 1,8-diazabicyclo [5,4,0] undec. -7-ene, 1-ethylpiperidine, 2,2,6,6-tetramethylpiperidine,
1,1,3,3-tetramethylguanidine, 2,4,6
-Collidine, polyvinylpyridine and the like.

The base is generally used in an amount of 0.1 equivalent to 1
Used in the range of 0 equivalents. Preferably, it is used in the range of 0.5 to 5 equivalents.

The fluorination reaction with perfluoroalkanesulfonyl fluoride can be carried out in a suitable solvent, but preferably, toluene, benzotrifluoride, ethyl acetate, methylene chloride, methyl-t-butyl ether, tetrahydrofuran, acetonitrile, It is good to carry out in an organic solvent such as acetone. Reaction is usually 0 ° C
To the solvent reflux temperature. The temperature is preferably from 20 ° C. to the solvent reflux temperature.

After completion of the reaction, if necessary, the reaction mixture is neutralized with a base or perfluoroalkanesulfonic acid, and subjected to a normal extraction operation using an organic solvent which can be separated from water, such as toluene, ethyl acetate or methylene chloride. The fluorinated product represented by the general formula (II) can be extracted.

The compound represented by the general formula (II) obtained by the production method of the present invention is a compound in which the hydroxyl group in the general formula (I) is stereospecifically substituted to form a fluorine atom. Substituents other than the hydroxyl group to be substituted retain the respective positions and the configuration of α or β configuration. Specifically, it is represented by any of the following general formulas (XVIII) to (XXV).

[0048]

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However, when Y is a hydroxyl group, and X is a cyclic acetal represented by the above general formula (IV) together with B, the general formula (II) is replaced by the general formulas (XIX) and (XX) , (XXI
It has a configuration represented by I) and (XXV).

When the general formula (I) is a nucleoside derivative, as described above, those in which A is a hydrogen atom and B has a β configuration are generally used (X and Y are α or β
Any of the three-dimensional configurations may be held). In this case, the general formula (II) is converted from the following general formulas (XXVI) to (XXIX)
Is represented by

[0051]

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The hydroxyl-protecting group of the compound represented by formula (II) can be deprotected by a conventional method. For example, when the protecting group for a hydroxyl group is an acyl group such as an acetyl group or a benzoyl group, alkali treatment with sodium hydroxide or the like, or when an aralkyl group such as a benzyl group or a triphenylmethyl group is used, for example, hydrochloric acid or acetic acid. Deprotection can be performed by treating with an acid. When the nucleobase has a protecting group, it can be similarly deprotected by a usual method. In addition, a substituent of a nucleobase or a derivative thereof may be derived to another appropriate substituent, or X ′ or Y ′
Can be converted to a desired fluorine-containing nucleoside derivative, for example, by dehydroxylation of the hydroxyl group.
That is, the nucleoside or saccharide derivative represented by the general formula (II) produced by the production method of the present invention can be combined with a fluorinated nucleoside derivative represented by the following general formula (V) by a method known to those skilled in the art. I can guide you.

[0053]

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In the formula, B ′ represents a nucleobase or a derivative thereof,
One of Y "and X" represents a fluorine atom, and the other represents a hydrogen atom or a hydroxyl group. The compound represented by the general formula (V) is an important compound particularly for pharmaceutical use. For example, a compound in which B is adenine in β configuration, X ″ is a fluorine atom in β configuration, and Y ″ is a hydrogen atom, 9-
(2,3-Dideoxy-2-fluoro-β-D-threo-pentofuranosyl) adenine (FddA) is known to have potent antiviral activity against human immunodeficiency virus (HIV).

Among the compounds represented by the general formula (II), for example, A is a hydrogen atom, B is adenine having a β configuration, X ′ is a fluorine atom having a β configuration, and Y ′ is a hydrogen atom. The compound which is an atom has a hydroxyl group protecting group at the 5′-position R
Can be easily led to FddA. In addition, for example, by using the compound contained in the general formula (II), FddA
Can lead to Further, among the compounds represented by the general formula (II), for example, A is a hydrogen atom, B is uracil or thymine in β configuration, Y ′ is a fluorine atom in α configuration, and X ′ is a hydrogen atom. By deprotecting R which is a protecting group for the hydroxyl group at the 5′-position, the compound can be easily converted to 3′-fluoro-2′-deoxyuridine or 3′-fluoro- which is known to have antiviral activity. Can lead to thymidine.

When the general formula (II) is a saccharide derivative, the general formula (I
The compound of I) is, for example, a compound useful as an intermediate of a nucleoside derivative. Such a sugar derivative can be converted into a nucleoside derivative by performing a coupling reaction with a nucleobase derivative. Thereafter, similarly, deprotection of a protecting group of a hydroxyl group or a nucleic acid base, or derivation of a substituent to another suitable substituent, or dehydroxylation of a hydroxyl group of X ′ or Y ′, It can be converted to a desired fluorine-containing nucleoside derivative represented by the general formula (V). For example, VE Marquez, et.
Synthesis (1991) 1005 and VE Marquez, et.al. J.
FddA can be derived from a sugar derivative by the method described in Med. Chem. 33 (1990) 978.

[0057]

EXAMPLES Hereinafter, the present invention will be described in detail with reference to Examples, but these Examples do not limit the present invention in any way.

Example 1 6-chloro-9- [2,3-
Dideoxy-2-fluoro-5-O- (triphenylmethyl) -β-D-threo-pentofuranosyl] -9H-
Pudding

[0059]

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6-chloro-9- [3-deoxy-5-O
-(Triphenylmethyl) -β-D-erythro-pentofuranosyl] -9H-purine 2.0 grams (3.90 m
mol) was dissolved in 20 ml of toluene, and 1.07 ml (7.80 mmol) of N-ethylpiperidine was dissolved.
l) was added. This mixture is added at room temperature with perfluoro-1
2.80 ml (15.6 mmol) of butanesulfonyl fluoride was added dropwise with stirring, and the mixture was heated to 40 ° C. and stirred for 40 hours. This reaction mixture is subjected to HPLC
As a result, the target product was obtained at an area ratio of 60.4%. The desired product was isolated and purified by recrystallization.

Example 2 (Step 1) 9- [2,3-dideoxy-2-fluoro-5-O-
(Triphenylmethyl) -β-D-threo-pentofuranosyl] -9H-purine-6-amine 6-chloro-9- [2,3-dideoxy-2-fluoro-5-O- (triphenylmethyl) -Β-D-threo-
[Pentofuranosyl] -9H-purine 110 mg (0.2
14 mmol) in a 20% ammonia / methanol solution 1
Dissolved in 7.2 ml and left overnight at 60 ° C. during sealing. After cooling, the reaction mixture was concentrated, azeotroped with toluene, and the resulting crystals were filtered. Dry under reduced pressure at room temperature.
3 mg of a white solid (purity 74.4%, yield 57.7%)
I got

¹ H-NMR (300 MHz, CDCl ₃ )
δ: 8.33 (1H, s, H2), 8.06 (1H,
d, J = 3.0 Hz, H8), 7.52-7.20 (1
0H, m, 5'OTr), 6.33 (1H, dd, J =
19.9, 2.9 Hz, H1 '), 6.18 (2H, b
_{s, 6-NH 2),} 5.20 (1H, md, J = 53.
8 Hz, H2 '), 4.40 (1H, m, H4'), 3.
46 (1H, dd, J = 10.0, 6.5 Hz, H5 '
a), 3.27 (1H, dd, J = 10.0, 4.1H
z, H5'b), 2.50 (1H, dddd, J = 3)
5.5, 14.9, 9.0, 5.4 Hz, H3'a),
2.31 (1H, dddd, J = 27.5, 14.9,
4.8, 1.4 Hz, H3'b). IR (KBr, cm ^-1 ): 3151, 1649, 159
9, 1578, 1403, 1063, 703. UV (MeOH) λmax: 208 (logε 2.1
9), 259 (log ε 0.58) nm. MS (ESI) m / z: 496 (M + H) ^<+> .

Example 2 (Step 2) 9- (2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl) adenine (FddA) 9- [2,3-dideoxy-2- Fluoro-5-O-
(Triphenylmethyl) -β-D-threo-pentofuranosyl] -9H-purin-6-amine 35.3 mg
(0.0710 mmol) in 1.0 ml of acetic acid,
After stirring at room temperature for about 4 hours, the mixture was stirred at 80 ° C. for about 3 hours. 1.0 ml of acetic acid was added, the mixture was cooled to room temperature, concentrated, and the residue was purified on a preparative silica gel plate (91%).
Methylene chloride / ethanol). After extracting the fraction of the target substance with methanol, the solvent was distilled off to obtain 11.1 mg (yield 61.5%) of the target substance as a white solid in total. Product physical data were consistent with known literature values.

Example 3 6-Chloro-9- [2,3-dideoxy-2-fluoro-5-O- (triphenylmethyl) -β-D-threo-
Pentofuranosyl] -9H-purine

[0065]

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6-chloro-9- [3-deoxy-5-O
-(Triphenylmethyl) -β-D-erythro-pentofuranosyl] -9H-purine 10.0 grams (19.4
9 mmol) in 100 ml of toluene,
5.96 ml (38.99 mmol) of N, N-dimethylcyclohexylamine were added. At room temperature, 7.78 ml (38.99 mmol) of perfluoro-1-butanesulfonyl fluoride was added dropwise with stirring at room temperature, and the mixture was heated to 50 ° C. and stirred for 24 hours. The reaction mixture was added to a 10% aqueous ammonium chloride solution 2
The reaction was stopped by adding 5 ml, and the organic layer was separated. The organic layer was washed sequentially with 25 ml of a 10% aqueous ammonium chloride solution and 25 ml of water. The organic layer was analyzed by HPLC.
It was obtained at 7.6%.

Reference Example 1 6-chloro-9- [3-deoxy-5-O-acetyl-
β-D-erythro-pentofuranosyl] -9H-purine 6-chloro-9- [3-deoxy-β-D-erythro-
[Pentofuranosyl] -9H-purine was reacted with acetyl chloride in dry dimethylformamide in the presence of pyridine at room temperature. The resulting reaction mixture was treated with water and the product was extracted with methylene chloride. The oily substance obtained by concentrating the extracted organic layer was applied to a silica gel column, and ethyl acetate /
It was eluted with a normal hexane mixed solution. The eluate containing the desired compound was collected and concentrated, and the residue obtained was recrystallized twice from ethyl acetate and normal hexane to obtain the desired product.

¹ H-NMR (300 MHz, CDCl ₃ )
δ: 8.75 (1H, s, H2), 8.43 (1H,
s, H8), 6.04 (1H, d, J = 2.3 Hz, H
1 ′), 4.87 (1H, m, H2 ′), 4.81 (1
H, m, H4 '), 4.42 (1H, dd, J = 12.
4, 3.0 Hz, H5'a), 4.31 (1H, dd,
J = 12.4, 4.4 Hz, H5'b), 2.24 (2
H, m, H3 '), 2.07 (3H, s, 5'OAc).

Example 4 6-Chloro-9- [2,3-dideoxy-2-fluoro-5-O-acetyl-β-D-threo-pentofuranosyl] -9H-purine

[0070]

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6-chloro-9- [3-deoxy-5-O
-Acetyl-β-D-erythro-pentofuranosyl]-
200 mg of 9H-purine was dissolved in 4.0 ml of benzotrifluoride, and 0.196 ml of N, N-dimethylcyclohexylamine was added. To this mixture, 0.255 ml of perfluoro-1-butanesulfonyl fluoride was added dropwise with stirring at room temperature, and the mixture was stirred at 25 ° C for 24 hours, and then heated to 50 ° C and stirred for 20 hours. When the reaction mixture was analyzed by HPLC, the target compound was obtained at an area ratio of 49.3%. The desired product was isolated and purified by recrystallization from ethyl acetate and normal hexane.

¹ H-NMR (300 MHz, CDCl ₃ )
δ: 8.74 (1H, s, H2), 8.45 (1H,
d, J = 2.7 Hz, H8), 6.43 (1H, dd,
J = 18.9, 3.1 Hz, H1 '), 5.32 (1
H, ddd, J = 54.2, 9.9, 4.3 Hz, H
2 ′), 5.11 (1H, t, J = 5.8 Hz, 5′O
H), 4.26 (1H, m, H4 '), 3.75-3.
58 (2H, m, H5'ab), 2.71-2.50
(1H, m, H3'a), 2.42-2.22 (1H,
m, H3'b), 2.13 (3H, s, 5'OAc).

Example 5 9- [2,3-Dideoxy-2-fluoro-5-O-acetyl-β-D-threo-pentofuranosyl] -9H-
Purine-6-amine

[0074]

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9- [3-deoxy-5-O-acetyl-
100 mg of β-D-erythro-pentofuranosyl] -9H-purin-6-amine (5′-O-acetyl-3′-deoxyadenosine) is obtained in 3.4 of tetrahydrofuran.
Dissolve in milliliter and add 0.166 milliliter (0.68 mmol) of N, N-dimethylcyclohexylamine
Was added. To this mixture, 0.127 ml (0.68 mmol) of perfluoro-1-butanesulfonyl fluoride was added dropwise with stirring at room temperature. After stirring at 50 ° C. for 2 hours, 0.166 ml of N, N-dimethylcyclohexylamine was further added. Milliliter (0.68 mmol)
And 0.127 ml (0.68 mmol) of perfluoro-1-butanesulfonyl fluoride. The mixture was stirred at 50 ° C. for 20 hours and analyzed by HPLC. As a result, the target product was obtained at an area ratio of 7.8%.

Example 6 6-chloro-9- (5-O-trityl-3-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl) -9H-purine

[0077]

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1.0 g of 5'-O-trityl-3'-O-benzoyl-6-chloropurine riboside (1.55 m
mol) is dissolved in 10 ml of toluene, and N, N
0.47 ml (3.10 mmol) of dimethylcyclohexylamine were added. At room temperature,
Perfluoro-1-butanesulfonyl fluoride 0.
58 ml (3.10 mmol) was added dropwise with stirring, and the mixture was stirred at 50 ° C. for 24 hours. To the reaction mixture was added 10 ml of a saturated aqueous sodium hydrogen carbonate solution to terminate the reaction, and 10 ml of toluene and 20 ml of ethyl acetate were added to separate an organic layer. The organic layer was washed successively with 10 ml of a 5% aqueous citric acid solution and 10 ml of a saturated aqueous sodium hydrogen carbonate solution. When the organic layer was analyzed by HPLC, the target product was obtained in a yield of 66.2%. The desired product was isolated and purified on a silica gel column.

<Example 7 (Step 1)> 9- (5-O-
Trityl-2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine 6-chloro-9- (5-O-trityl-3-O-benzoyl-2-deoxy-2-fluoro-β-D -Arabinofuranosyl) -9H-purine (3.15 g, 4.98 m)
mol) in 100 ml of methanolic ammonia (0 ° C.
) And left in a sealed tube at 100 ° C for 2 days.
After cooling, the solvent was carefully distilled off and the residue was dissolved in 100 ml of chloroform. The insoluble matter was removed by filtration, and the solution was applied to a silica gel column (3.5 × 50 cm).
0% ethanol / dichloromethane solution (4000 ml)
Eluted. The product fractions were collected, the solvent was concentrated and the white crystals (1.87 g, 3.66 mmol, 73
%). Melting point: 210.5-212.5 ° C.

Example 7 (Step 2) 9- (5-O-trityl-3-phenoxythiocarbonyloxy-2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine 4-dimethylamino 273 mg of pyridine is dissolved in 10 ml of anhydrous acetonitrile, and 9- (5-O-trityl-2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine (419 mg, 0.82 mmol) is dissolved in this solution.
l) was suspended. Next, phenoxythiocarbonyl chloride (0.22 ml) was added with stirring, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was
and applied to a silica gel column (2.5 × 32 cm).
00 ml). Collect the product fractions,
When the solvent was distilled off, a caramel-like target product was obtained. Yield 490 mg (FW: 615.64, 0.80 mmol,
97%)

Example 7 (Step 3) 9- (5-O-trityl-2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl) adenine 9- (5-O-trityl -3-phenoxythiocarbonyloxy-2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine (386 mg, 0.63 mm)
ol) was suspended in 4 ml of dry toluene, azobisisobutyronitrile (60 mg) and tris (trimethylsilyl) silane (0.6 ml) were added, and the mixture was heated at 100 ° C. under a nitrogen stream.
For 30 minutes. After cooling, the precipitated crystals are collected by filtration,
Washed with toluene and dried. Yield 229 mg (0.46
(mmol, 73%) Melting point: 226-229 ° C.

¹ H-NMR (CDCl ₃ ) δ: 8.36
(1H, s, H2), 8.07 (1H, d, J = 2.6)
Hz, H8), 7.1-7.6 (ca 20H, T
r), 6.33 (1H, dd, J = 17, J = 3.0H)
z, H1 '), 5.70 (2H, brs, NH2),
5.22 (1H, m, J = 43.6 Hz, H2 '),
4.4 (1H, m, H4 '), 3.46 (1H, dd,
J = 8.2, J = 5.9 Hz, H5'a), 3.26
(1H, dd, J = 8.2, J = 3.2 Hz, H5 ′
b), 2.2-2.65 (2H, m, H3 ').

Example 7 (Step 4) 9- (2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl) adenine (FddA) 9- (5-O-trityl-2, 3-Dideoxy-2-fluoro-β-D-threo-pentofuranosyl) adenine (300 mg, 0.605 mmol) was added to methanol (1
8 ml), concentrated hydrochloric acid (1.2 ml) was added, and the mixture was stirred and dissolved. The mixture was stirred at room temperature for 1.5 hours, added with 4 ml of Amberlite IR400B (OAc-type), and stirred for 5 minutes. The resin is removed by filtration, and the filtrate is concentrated to about 2 ml.
40 ml of water was added, and the mixture was washed three times with 10 ml of chloroform. When the aqueous layer was concentrated, bristol crystals were obtained. Yield: 116 mg of single crystal, 19 mg of second crystal, 135 mg total yield: 135 mg (FW: 253.24, 0.533)
mmol, 88%)

[0084]

Industrial Applicability According to the present invention, in a method for producing a nucleoside or a sugar derivative in which a secondary hydroxyl group is substituted by fluorine, fluorine can be stereospecifically substituted in one step, and low cost, safe and industrial An excellent method is provided.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Kunisuke Izawa 1-1, Suzukicho, Kawasaki-ku, Kawasaki-shi, Kanagawa Prefecture Ajinomoto Co., Inc. Amino Science Research Institute (72) Inventor Etienne Decoc N.C. V. Omnichem, Koparlarn 91, B-9230 Vetteren, Bergey (72) Inventor Marc DeMilican, N.M. V. Omnichem, Koparlarn 91, B-9230 Vetteren, Bergey (72) Inventor Geert Sherkas N. V. Omnichem, Koparlarn 91, B-9230 Wetteren, Bergey (72) Inventor Josef Brepol N. V. Omnichem, Corporal 91, B-9230 Vetten, Bergey F-term (reference) 4C057 AA18 BB02 BB05 CC02 CC03 DD01 LL28

Claims (5)

[Claims] 1. A nucleoside or a sugar derivative represented by the following general formula (I): [In the formula, A represents a hydrogen atom or a methylene group having a protected hydroxyl group, B represents a nucleobase or a derivative thereof or a protected hydroxyl group, R represents a hydroxyl-protecting group,
One of Y and X represents a hydroxyl group, and the other represents a hydrogen atom or a protected hydroxyl group. Alternatively, A and R together represent a cyclic acetal represented by the following general formula (III) (R ¹ and R ² both represent a hydrogen atom or a methyl group,
Alternatively, one of them represents a hydrogen atom, and the other represents a methyl group or a phenyl group). Embedded image Alternatively, Y represents a hydroxyl group, and X and B together represent a cyclic acetal represented by the following general formula (IV) (R ³ and R ⁴ both represent a hydrogen atom or a methyl group, or One of them represents a hydrogen atom and the other represents a methyl group or a phenyl group). ] Reacting with perfluoroalkanesulfonyl fluoride in the presence of a base, characterized by the following general formula (II)
A method for producing a nucleoside or a sugar derivative represented by the formula: Embedded image [In the formula, A, B, and R have the same meanings as described above, and one of Y ′ and X ′ represents a fluorine atom, and the other represents a hydrogen atom or a protected hydroxyl group. ] 2. The method of claim 1, wherein the perfluoroalkanesulfonyl fluoride is trifluoromethanesulfonyl fluoride,
The production method according to claim 1, wherein the production method is any one of perfluoro-1-butanesulfonyl fluoride and perfluoro-1-octanesulfonyl fluoride. 3. The method according to claim 1, wherein the base is an amine. 4. A fluorinated nucleoside derivative represented by the following general formula (V) produced using the nucleoside represented by the general formula (II) or the sugar derivative produced by the production method according to claim 1. Embedded image [Wherein B ′ represents a nucleobase or a derivative thereof, Y ″ and X ″
Represents one of a fluorine atom and the other represents a hydrogen atom or a hydroxyl group. ] 5. A method for producing 9- (2,3-dideoxy-2-fluoro-β-beta) produced using the nucleoside or saccharide derivative represented by the general formula (II) produced by the production method according to claim 1. D-Threo-pentofuranosyl) adenine.