JPH0717994A - Synthesis of deoxyribonucleoside derivative - Google Patents

Abstract

PURPOSE:To obtain the derivative into which a desired nucleophilic group is introduced in the saccharide moiety simply under mild conditions by allowing a nucleophilic reagent to react with an anhydronucleoside of a specific structure in the presence of an acid catalyst. CONSTITUTION:In the presence of an acid catalyst, preferably Lewis acid, for example, boron trifluoride, a nucleophilic reagent, preferably a halide, for example, lithium halide, is allowed to react with an anhydro cyclonucleoside in which the hydroxy group in the saccharide moiety other than those participating the formation of said anhydro ring is protected with a group, preferably 1,1,3,3- tetraisopropyldisiloxane-1,3-diyl group, preferably a pyrimidine cyclonucleoside, to provide the derivative, for example, (2'R)-3',5'-0-(1,1,3,3-tetra- isopropyldisiloxane-1,3'-diyl)-2'-bromo-2'-deoxyuridine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for synthesizing a nucleoside derivative utilizing a ring-opening reaction of an anhydronucleoside compound with a nucleophile in the presence of an acid catalyst as an activating agent.

[0002]

2. Description of the Related Art Conventionally, for example, as a method for introducing a halogen atom such as Br at the 2'position of pyrimidine deoxyribonucleoside, 3 ', 5'-diamine shown in the following formula (Formula 1) has been used.
- O - benzoyl - 2'-bromo - 2'-deoxyuridine as seen in synthesis, pyrimidine - O ^2, by the action 2'anhydronucleoside the acyl halide, or hydrogen halide, nucleoside Is generally known (Honjo, M .;
Marumoto, R. Chem. Pharm. Bull ., 1974, 22 , 128-
134 / Russell, AF; Prystasz, M .; Hamamura, E.
K. Verheyden, JPH; Moffatt, JG J. Or g. Ch
em. , 1974, 39 , 2182-2186 / Hamamura, EK; Prys
tasz, M .; Verheyden, JPH; Moffatt, JG; Yam
aguchi, K. ； Uchida, N .; Sato, K .; Nomura, A .; Shira
tori, O .; Takase, S .; Katagiri, K .; J. Med. Chem.
, 1976, 19 , 663-667 ／ Rechman, U .; Chiu, CK; Ol
lenberg, DHH; Watanabe, KA; Fox, JJ S
ynthesis ., 1976, 533-534 ./ Kondo, K .; Adachi,
T .; Inoue, I. J. Org. Chem. , 1976, 41 , 2 995-299
9.).

[0003]

[Chemical 1]

[0004] For example, the reaction of uridine and various acyl halides, O ^2, 2'-anhydro - beta-D-arabinofuranosyl but furanosyl uracil is obtained, the reaction proceeds further 2'halogeno - 2 A'-deoxyuridine derivative is obtained. This is because the above uridine is 2 ', 3'in the middle.
-It becomes a cyclo compound via an acyloxonium ion, and an anhydro bond of the cyclo compound is cleaved by an attack at the 2'-position of a coexisting halide ion to give a 2'-halogeno-2'-deoxyuridine derivative. Yes (Chemical formula 2).

[0005]

[Chemical 2]

As examples of such an acyl halide, 2-acetoxyisobutyryl chloride, 2-acetoxybenzoic acid chloride, propionyl bromide and the like are known,
Silicon tetrachloride is also used as another halogenating agent. On the other hand, the anhydro form of uridine gives a 2'-halogeno derivative by hydrogen halide treatment (Codington,
JF; Doerr, IL; Fox, JJJ Org. Chem., 196
4, 29 , 558-564; J. Org. Chem., 1964, 29 , 564-569./
Cushley, RJ; Codington, JF; Fox, JJCan J.
Chem., 1968, 46 , 1131-1140./ Holy, A .; Cech, D.
Collect. Czech. Chem. Commun. , 1974, 39 , 3157-31
67.). However, depending on the above-mentioned conventional method, the 2'-bromo compound in which the 3 ', 5'-position hydroxyl group is free, or the 2'-bromo group in which the 3', 5'-position hydroxyl group is protected by an acyl group is used.
Other than a bromo derivative, a hydroxyl group having a 3 ', 5'position other than an acyl group, such as 1,1,3,3-tetraisopropyldisiloxane-1,3-diyl (TPD
2'-Br-2 protected by a silicon-containing protecting group such as S) group
It is difficult to obtain'-deoxyuridine. For example, 3', 5'- O - TPDS- O 2, 2'- anhydro - To obtain the beta-D-arabinofuranosyl-bromo derivative furanosyl uracil as a starting material, in the conventional method, the reaction fairly strong acidic conditions Although it needs to be used as a condition,
Under such strong acidic conditions, 3 ', 5'of the above raw material
- there is a possibility that O -TPDS group is removed.

On the other hand, after the conventional bromination reaction,
Although it is conceivable to use a synthetic route in which the above TPDS group is introduced into the 3 ', 5'- O -position, in general, deacylation of an acyl-protected compound requires basic conditions. When a bromo group is present at the 1-position, nucleophilic attack of an anion is likely to occur on the carbon to which the bromo group binds under the basic conditions. Therefore, such synthetic routes are difficult to use. Furthermore, 2'-Br-2'-deoxy form (2'-bromo form in which 3 ', 5' hydroxyl groups are free)
Although it is possible to directly introduce the TPDS group into, the Br group at the 2'position may react under the condition of introducing TPDS when such a method is used.

[0008]

The object of the present invention is to provide a deoxyribonucleoside derivative in which one of the hydroxyl groups constituting the sugar moiety is substituted with a nucleophile and the other hydroxyl group of the sugar moiety is protected with a protecting group. It is intended to provide a method for synthesizing a deoxyribonucleoside derivative which can be easily obtained under mild conditions.

[0009]

Means for Solving the Problems As a result of earnest research by the present inventor, the anhydrocyclonucleoside compound in which a sugar moiety hydroxyl group other than the hydroxyl group involved in the formation of anhydro ring is protected by a protecting group is detected in the presence of an acid catalyst. Then, it was found that it exhibits a good reactivity with a nucleophile.

The method for synthesizing the deoxyribonucleoside derivative of the present invention is based on the above findings. More specifically, a sugar moiety hydroxyl group other than the hydroxyl group having an anhydro ring and participating in the formation of the anhydro ring is a protecting group. It is characterized in that the protected anhydrocyclonucleoside compound is reacted with a nucleophile in the presence of an acid catalyst.

The present invention will be described in detail below.

(Cyclonucleoside Compound) In the present invention, an anhydrocyclonucleoside compound having an anhydro ring and a sugar moiety hydroxyl group other than the hydroxyl group involved in the formation of the anhydro ring is protected by a protecting group is used as a raw material ( Or as a substrate). The cyclonucleoside compound used in the present invention is preferably a pyrimidine cyclonucleoside compound.

The position of the anhydro ring is O ² , ^{2 '} .
-, O ^2, 3'-, or O ^2, may be either 5 'of. In the present invention, the position of the hydroxyl group of the sugar moiety involved in the formation of the anhydro ring (for example, the raw material is O ² , ^{2 ′)} .
In the case of the anhydropyrimidine cyclonucleoside compound, a functional group (for example, a halogen atom) based on a nucleophile is introduced at the 2'position of pentose).

(Protecting Group) In the cyclonucleoside compound as a raw material in the present invention, a sugar moiety hydroxyl group other than the hydroxyl group involved in the formation of the anhydro ring (for example, the raw material is O
^In the case of the 2,2'-anhydropyrimidine cyclonucleoside compound, the hydroxyl groups at the 3'and 5'positions of the pentose are protected with a protecting group. In the present invention, since an acid catalyst is used, it is preferable that the protective group is a group that is difficult to react with the acid catalyst (Lewis acid etc.). From this point, the protecting group is preferably a group other than an acyl group (a carbonyl group is likely to act on an acid catalyst).

[0015] (O ^2, the protecting group of the 2'-anhydro form) More specifically for example, the raw material is O ^2, when a 2'-anhydro body, as a protecting group for the 3'and 5'-position of the hydroxyl group It is preferable to use a silicon-containing protective group capable of collectively protecting these (that is, a protective group containing at least one silicon). In the present invention, at least one lower alkyl group (having 1 carbon atom) is used as the silicon-containing protective group.
It is preferable to use a protective group having a silicon atom to which an alkyl group of 4 to 4) is bonded. As such a protecting group, for example, the following protecting groups are preferably used.

[0016] _{-Si (i- C 3 H 7)} 2 -O-Si
_{(I- C 3 H 7) 2} - (1,1,3,3- tetraisopropyldisiloxane -
1,3-diyl (TPDS) group; divalent protecting _{group) -Si (t- C 4 H 9} ) 2 - ( di-tert-butyl silane diyl (DTBS) group;
(Divalent Protecting Group) Among the above protecting groups, the TPDS group is 3 of the sugar moiety.
It is preferably used because it can be introduced selectively into the hydroxyl groups at the 1'-position and the 5'-position in a high yield. On the contrary,
When a benzoyl group, which is one of the acyl groups, is used as a protecting group for the hydroxyl groups at the 3'-position and 5'-position of ribose,
Since its selectivity is relatively low (a benzoyl group is also introduced into the 2'-position hydroxyl group), it is necessary to purify the target material by column chromatography or the like.

On the other hand, when protecting the hydroxyl groups at the 3'and 5'positions with respective protecting groups, the protecting group for the hydroxyl groups at the 5'position is a trityl group or its derivative, a monovalent silicon-containing protecting group, or benzyl. group _{(C 6 H 5 CH 2 -} ) is preferably used. More specifically, for example, as the above-mentioned trityl group or a derivative thereof, the following protecting groups are preferably used.

(CH ₃ OC ₆ H ₄ ) ₂ (C ₆ H ₅ ) C- (dimethoxytrityl (DMTr) group) (CH ₃ OC ₆ H ₄ ) (C ₆ H ₅ ) ₂ C- (monomethoxytrityl ( the MMTr) _{group) (C 6 H 5) 3} C- ( trityl (Tr) group) the monovalent silicon-containing protecting group, the following protecting groups as shown in preferably used.

T-C ₄ H ₉ Si (CH ₃ ) _2- (tert-butyldimethylsilyl (TBDMS)
_{Group) t- C 4 H 9 Si (} C 6 H 5) 2 - ( tert-butyldiphenylsilyl (TBDPS)
Group) On the other hand, as the protecting group for the 3′-position hydroxyl group, the above TB
It is preferable to use a DMS group, a tetrahydropyranyl (THP) group, a benzyl group, or the like.

[0020] (O ^2, the protecting group of the 3'-anhydro form) More specifically for example, when the raw material is O ^2, 3'-anhydro body, as the protective group for the 5'-position of a hydroxyl group, a trityl group It is preferable to use a derivative thereof, a monovalent silicon-containing protecting group, a benzyl group or the like. More specifically, for example, the above DMTr group, MMTr group, Tr group, TBD
It is preferable to use MS group, TBDPS group, benzyl group and the like.

On the other hand, as a protective group for the 2'-position hydroxyl group,
It is preferable to use the above TBDMS group, benzyl group and / or THP group.

[0022] (O ^2, 5'-protecting group of the anhydro body) material is O ^2, when 5'-anhydro body, the protecting group of the 2'and 3'-position of the hydroxyl group can be protected by collectively Groups, more specifically, for example, the following protecting groups are preferably used.

[0023] _{-C (CH 3) 2 - (} 2', 3'-O- isopropylidene _{group) -CH (C 6 H 5)} - (2', 3'-O- benzylidene group) Meanwhile, 2'and When the 3′-position hydroxyl group is protected with each protecting group, the protecting group for each hydroxyl group is 1
It is preferable to use a valent silicon-containing protecting group or a benzyl group. More specifically, for example, the above TBDMS group,
A protecting group such as a benzyl group or a THP group is preferably used.

(Acid catalyst) In the present invention, a Lewis acid (electron pair acceptor) is preferably used as the acid catalyst. As such a Lewis acid, more specifically, for example, B
Boron halide (B ₃ such as F ₃ (boron trifluoride))
X ₃ ), aluminum halide (AlX ₃ ), titanium halide (TiX ₄ ), zinc chloride (ZnCl ₂ ), iron chloride (FeCl ₃ ), tin chloride (SnCl ₄ ), etc. are preferably used. The acid catalyst used in the present invention, if necessary,
It may be used as an adduct or a complex with an electron pair donor. For example, the above boron trifluoride may be used as a boron trifluoride diethyl ether complex (BF ₃ · OEt ₂ ).

In the present invention, the acid catalyst is preferably used in an amount of 0.2 to 2 mol (further 1.1 to 1.5 mol) per 1 mol of the above raw material (or substrate).

[0026] In (nucleophile) the present invention, the halide as a nucleophile, azido (-N ₃₎ compounds, alkoxide ^(- OR), cyanide (NaCN, KC
N), alkyl lithium (RLi), Grineer reagent (RMgX), disulfide (RSSR), dialkyl selenide (RSeSeR), etc. are preferably used. When a halide is used as the nucleophile, the halogen is preferably bromine (Br) from the viewpoint of reactivity of the product (deoxyribonucleoside derivative).

The nucleophile may have a cation component. As such a cation component, an alkali metal is preferably used, but Li (lithium) is preferably used among the alkali metals from the viewpoint of solubility in a solvent. It is possible to use an ammonium ion (for example, a tetraalkylammonium ion having a lower alkyl group having 1 to 4 carbon atoms) instead of the above alkali metal ion, but it is difficult to remove the quaternary ammonium salt in the post-treatment of the reaction. In consideration of the above, the cation component is preferably an alkali metal.

The nucleophile is preferably used in an amount of 1 to 5 mol (further 1.1 to 2 mol) per 1 mol of the raw material.

(Solvent) In the present invention, a solvent may be used if necessary. As such a solvent, an organic or inorganic compound (or a mixture thereof) which is substantially inert to the nucleophilic reaction of the present invention and which is liquid at the reaction temperature of the reaction is used without particular limitation. You can From the viewpoint of the solubility of the raw material and the nucleophile, for example, dioxane, diglyme, HMPA (hexamethylphosphorus triamide) and the like are preferably used.

(Reaction temperature) The temperature of the nucleophilic reaction of the present invention is not particularly limited, but may be heated if necessary in consideration of the reaction rate and the like. When heating, the temperature is room temperature to 1
It is preferably about 20 ° C.

(Synthesis of 2'-bromo-2'-deoxyuridine) 3 ', 5'- O , which is one embodiment of the synthetic method of the present invention, is described below.
-The synthesis of TPDS-2'-bromo-2'-deoxyuridine will be described.

The following routes (1) to (3) are conceivable as synthetic routes to 3 ', 5'- O -TPDS-2'-bromo-2'-deoxyuridine.

(1) Uridine is acylated and brominated by a conventional method using an acyl halide to give 3 ', 5'.
- O - acyl - 2'-bromo derivative was prepared, 3'and 5'-position of the hydroxyl group was free by deacylation the bromo derivative, the path to be protected by the TPDS group considered. However, in general, the above deacylation requires fairly strong basic conditions. Therefore, when a bromo group is present at the 2′-position, nucleophilic attack of anion on the carbon to which the bromo group binds under basic conditions may occur. It is not preferable because it easily occurs.

(2) A method in which uridine is converted into TPDS and then treated with hydrogen bromide by a conventional method can be considered. However, this method requires a reaction under a fairly strong acidic condition, and therefore, when brominating a derivative which is a TPDS group in which the protecting groups at the 3 ′ and 5 ′ positions may be removed under acidic conditions. Is difficult to apply.

(3) O ² , 2'-anhydro-β-D-
Starting from arabinofuranosyluracil, 3 ',
A method of introducing a TPDS group at the 5'position and then performing a bromination reaction.

From the viewpoint of simplicity, the above (1)-
Of the three methods (3), it is preferable to use the method (3). In the method (3), for example, it can be obtained by reacting O ² , 2′-β-D-arabinofuranosyluracil with TPDSCl ₂ in pyridine as a substrate 3
′, 5′- O − (1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) -O ² , 2′-β-D
It is preferred to use arabinofuranosyluracil.

According to the knowledge of the present inventor, in the above aspect (3) of the present invention, a Lewis acid (BF ₃ .OE in the aspect shown in Chemical formula 3) is added to the O ⁴ atom of the substrate structure.
t ₂ ) is coordinated to increase the δ + property at the 2′-position of the sugar moiety,
Since nucleophilic attack of the nucleophile (bromide ion in this embodiment) is likely to occur there, it is presumed that bond cleavage due to nucleophilic attack of the anhydro ring is promoted (Chemical Formula 3).

[0038]

[Chemical 3]

According to the experiments of the [0039] present invention, the substrate serving as the 3'of the bromination reaction, 5'- O -TPDS- O ^2, 2'- anhydro - a beta-D-arabinofuranosyl-uracil, serving Lewis acid Boron trifluoride diethyl ether complex (BF
₃ · OEt ₂ ) (1.1 eq) in 1,4-dioxane at 80 ° C., lithium bromine (LiB) as a nucleophile.
r) (1.1 eq.) was reacted to give the desired (2 ′ R ) -3 ′, 5′- O —TPDS-2′-bromo-
2'-Deoxyuridine was obtained in a yield of 76% (Chemical Formula 4).

[0040]

[Chemical 4]

On the other hand, the same experiment as above was repeated except that the boron trifluoride diethyl ether complex (BF ₃ .OEt ₂ ) was not added, and 100% of the raw material was recovered under the same reaction conditions. These experimental results support the reaction mechanism shown in (Chemical Formula 3) above.

[0042] described above (2'R) -3', 5'- O -
Similar to the method for synthesizing (1,1,3,3-tetraisopropyl-1,3-diyl) -2'-bromo-2'-deoxyuridine, 3 ', 5'- O- TPDS-2'-bromo Thymidine synthesis is possible.

That is, according to the experiments conducted by the present inventor, 3 ', 5'- O- TPDS-O, which is a substrate for this bromination reaction, was used.
^2, _{2'-thymine, BF 3 · Et 2 O (} 1.1 equiv)
In the presence of 1,4-dioxane at 80 ° C. with LiBr (1.
When 1 equivalent) is applied, the target (2 ' R ) -3 is obtained.
', 5'- O -TPDS-2'-bromothymidine is 78
It was obtained in a yield of 5% (Chemical Formula 5).

[0044]

[Chemical 5]

(Product) The above-mentioned synthesis method of the present invention is 2
Not only ′ -halogeno-2′-deoxyuridine derivatives and 2′-halogenothymidine derivatives but also 3′-halogeno-
Synthesis of 3'-deoxyuridine derivatives and 3'-halogeno-3'-deoxythymidine derivatives, or 5'-halogeno-
It can also be applied to the synthesis of 5'-deoxyuridine derivatives and 5'-halogeno-5'-deoxythymidine derivatives. When deoxyuridine is used as the starting material, 3'-halogeno-
2 ', 3'-dideoxyuridine derivative, 5'-halogeno
-Applicable to the synthesis of 2 ', 5'-dideoxyuridine derivatives, etc., and using ribosylthymine as a starting material, 3'-halogeno-3'-deoxyribosylthymine derivatives, 5'-halogeno-5'-deoxyribosylthymine derivatives It can be applied to the synthesis of etc. Furthermore, by using an azide compound (for example, LiN ₃ ) as the nucleophile, AZT
(Anti-human immunodeficiency virus (HIV) drug) It can also be applied to the synthesis of 3'-azido-3'-deoxythymidine and the like.

Hereinafter, the present invention will be described more specifically based on examples.

[0047]

EXAMPLES Example 1 (2 ' R ) -3', 5'- O- (1, 1, 3, 3-tetraisopropyldisiloxane-1,3-diyl) -2'-bromo-2'- synthesis of deoxyuridine 3 ', 5'- O - (1 , 1, 3, 3- tetraisopropyldisiloxane -1, 3-diyl) -O ^2, 2'-anhydro - beta-D-arabinofuranosyl-uracil (468.7 mg, 1.0 mmo
l) was added to lithium bromide (95.5 mg, 1.1 mmo)
suspended in 1,4-dioxane (20 mL) with 1),
Boron trifluoride diethyl ether complex (0.135m
L, 1.1 mmol) was added and the mixture was stirred at 80 ° C. for 6 hours. The reaction solution was concentrated under reduced pressure, water (40 mL) was added,
Extract with chloroform (50 mL x 3), water (40 m
L), and the organic layer was concentrated under reduced pressure. This concentrate was purified by silica gel column chromatography (mobile phase: chloroform) to give the desired product (2 ' R ) -3', 5'-.
O- (1, 1, 3, 3-tetraisopropyldisiloxane-1,3
-Diyl) -2'-bromo-2'-deoxyuridine 419.
1 mg (yield 76%) was obtained.

¹ H-NMR (CDCl ₃ , 10 ppm): δ0.78-1.3 (28
H, m, CH (CH ₃ ) ₂ × 4), 4.01 (1H, dd, J _{5 '} , _4' 2.31Hz,
J _{5 ', 5'} 13.66Hz, H-5 '), 4.18-4.29 (3H, m, H-3', H-
4 ', H-5'), 4.37 (1H, dd, J _{2 ', 1'} 0Hz, J _{2 ', 3'} 4.71Hz,
H-2 '), 5.67 (1H, dd, J _5,6 8.18Hz, ⁴ J _{5, N3H} 1.89H
z, H-5), 6.11 (1H, d, J _{1 ', 2'} 0Hz, H-1 '), 7.88 (1H,
d, J _6,5 8.18Hz, H-6), 8.30 (1H, bs, N ³ H) Elemental analysis value C ₂₁ H ₃₇ O ₆ N ₂ BrSi ₂ C H N Calcd 45.89 6.79 5.10 Found 45. 88 6. 61 5. 09 example 2 (2 'R) -3' , 5'- O - (1, 1, 3, 3- tetraisopropyldisiloxane -1, 3-diyl) -2 ' - synthesis of bromo thymidine 3 ', 5'- O -TPDS-O 2, 2'- anhydro - beta-D-arabinofuranosyl thymine (482.7mg, 1.0mmol)
Was suspended in 1,4-dioxane (20 mL) with lithium bromide (95.5 mg, 1.1 mmol), and boron trifluoride diethyl ether complex (0.135 mL, 1.1) was suspended.
mmol) was added and the mixture was stirred at 80 ° C. for 6 hours. The reaction solution is concentrated under reduced pressure, water (40 mL) is added, extracted with chloroform (50 mL × 3), washed with water (40 mL), and the organic layer is concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (chloroform),
(2 'R) -3', 5'- O - (1, 1, 3, 3- tetraisopropyldisiloxane -1, 3-diyl) -2'-bromo-thymidine 43
9.2 mg (yield 78%) was obtained.

¹ H-NMR (CDCl ₃ , 10 ppm): δ 0.8-1.25 (28
H, m, CH (CH ₃ ) ₂ × 4), 1.92 (3H, d, ⁴ J _5CH3 , 61.19H
z, 5-CH ₃ ), 4.01 (1H, dd, J _{5 ', 4'} 2.68Hz, J _{5 ', 5'} 1
3.58Hz, H-5 '), 4.14-4.33 (3H, m, H-3', H-4 ', H-5'),
4.39 (1H, dd, J _{2 ', 1'} 0Hz, J _{2'3 '} 5.36Hz, H-2'), 6.09
(1H, d, J _{1 ', 2'} 0Hz, H-1 '), 7.56 (1H, s, H-6), 8.21
(1H, s, N ³ H) Elemental analysis value C ₂₂ H ₃₉ O ₆ N ₂ BrSi ₂ C H N Calcd 46.88 6.97 4.97 Found 46.83 6.82 4.86 Comparative Example 1 (three) method) 3 not using boron fluoride-diethyl ether complex ', 5'- O - (1, 1, 3, 3- tetraisopropyldisiloxane -1, 3-diyl) -O ^2, 2'-anhydro - beta- D-
Arabinofuranosyluracil (468.7 mg, 1.0
mmol) to lithium bromide (95.5 mg, 1.1 mm
Ol) and suspended in dioxane (20 mL) at 80 ° C.
And stirred for 6 hours. The reaction solution was concentrated under reduced pressure, and water (40
mL) and extracted with chloroform (50 mL × 3),
It was washed with water (40 mL), and the organic layer was concentrated under reduced pressure. When this concentrate was purified by silica gel column chromatography (chloroform), 100% of raw materials were recovered.

[0050]

As described above, according to the present invention, an anhydrocyclonucleoside compound having an anhydro ring and a sugar moiety hydroxyl group other than the hydroxyl group involved in the formation of the anhydro ring is protected with a protecting group, Provided is a method for synthesizing a deoxyribonucleoside derivative, which comprises reacting a nucleophile in the presence of an acid catalyst.

In the present invention, the anhydro ring is easily opened by the reaction with a nucleophile in the presence of an acid catalyst, and the nucleophile is introduced into the sugar moiety of the anhydrocyclonucleoside compound. A deoxyribonucleoside derivative having a desired nucleophile introduced therein can be obtained under simple and mild conditions.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Ryoji Ishido 1432-1 Horinouchi, Hachioji, Tokyo Tokyo Pharmaceutical University

Claims (7)

[Claims] 1. An anhydrocyclonucleoside compound having an anhydro ring and having a sugar moiety hydroxyl group other than the hydroxyl group involved in the formation of the anhydro ring protected with a protecting group,
A method for synthesizing a deoxyribonucleoside derivative, which comprises reacting a nucleophile in the presence of an acid catalyst. 2. The method for synthesizing a deoxyribonucleoside derivative according to claim 1, wherein the anhydrocyclonucleoside compound is a pyrimidine cyclonucleoside compound. 3. The protective group is 1,1,3,3-tetraisopropyldisiloxane-1,3-diyl (TPD
The method for synthesizing a deoxyribonucleoside derivative according to claim 1, which is a group S). 4. The method for synthesizing a deoxyribonucleoside derivative according to claim 1, wherein the acid catalyst is an Lewis acid acid catalyst. 5. The method for synthesizing a deoxyribonucleoside derivative according to claim 4, wherein the acid catalyst is an acid catalyst composed of boron trifluoride. 6. The method for synthesizing a deoxyribonucleoside derivative according to claim 1, wherein the nucleophile is a halide. 7. The method for synthesizing a deoxyribonucleoside derivative according to claim 6, wherein the nucleophile is a halide of lithium.