WO2000078775A1 - Novel 3'-4' bridged nucleosides and oligonucleotide analogues - Google Patents

Abstract

Compounds represented by general formula (1) and salts thereof: wherein R?1 and R2¿ are each independently hydrogen, a hydroxyl-protecting group, a phosphate group or -P(R3)R4 [wherein R?3 and R4¿ are each independently hydroxyl, amino, C¿1?-C4 alkoxy, or the like]; A is C1-C4 alkylene; and B is a purin-9-yl or 2-oxo-1,2-dihydropyrimidin-1-yl group which may have a substituent selected from among optionally protected hydroxyl, C1-C4 alkoxy, optionally protected mercapto, C1-C4 alkylthio, C1-C4 alkoxy, optionally protected amino, and so on.

Description

 Description New 3'-4'-bridged nucleoside and oligonucleotide analogues [Technical field]

 The present invention relates to a 2-5 A (ie, 2 ′, 5′-oligoadenylic acid) analog known as a biological substance having antiviral activity, a stable and excellent antisense or antigene drug, or Novel 3'-4'-bridged oligonucleotide analogs and excellent 3'-4'-bridges, which are excellent intermediates for detection of specific genes (probes) or primers for initiating amplification It relates to nucleoside analogs.

 [Background technology]

 2-5 A (Pharmacol. Ther. Vo 1.78, No. 2, pp. 55-113, 1998), which is known as a substance having antiviral activity, is composed of two adenosines, 2 'and 5 'Is an oligonucleotide consisting of three or more nucleotide units, in which a hydroxyl group of' is linked by a phosphodiester group and a triphosphate is bonded to the 5 'end.

 2-5A is a substance that converts inactive RNase L (RNase L) into active RNase L in host cells. Activated RNase L blocks viral growth in cells by degrading the viral mRNA.

 Therefore, 2-5A can be expected as a virus growth inhibitor, that is, an antiviral drug.

 However, since 2-5A itself is easily decomposed to AMP and ATP by 2 ', 5'-phosphodiesterase, the more stable 2-5A analog having the same activity is It can be expected as a better virus growth inhibitor.

 Oligonucleotides that have excellent antisense or antigene activity and are strong and stable in vivo are expected to be useful medicines, and form stable complementary strands with DNA or mRNA. Oligonucleotide analogs having high activity are useful as detection agents for specific genes or primers for initiating amplification.

On the other hand, natural oligonucleotides are known to be rapidly degraded by various nucleases present in blood and cells. In addition, natural oligonucleotides In some cases, the sensitivity is limited by the affinity with the complementary base sequence, and it may not have sufficient sensitivity as a drug for detecting a specific gene or a primer for initiating amplification.

 In order to overcome these disadvantages, various non-natural oligonucleotide analogs have been produced, and attempts have been made to develop them as pharmaceuticals or detection agents for specific genes. That is, for example, those in which an oxygen atom bonded to a phosphorus atom in a phosphodiester bond of an oligonucleotide is substituted with a sulfur atom, those in which the oxygen atom is substituted with a methyl group, those in which the oxygen atom is substituted with a boron atom, Known are those in which the sugar moiety or base moiety of the nucleotide is chemically modified. For example, ISIS has developed and is marketing a titanium-type oligonucleotide, ISIS2922 (Vitrane), as a therapeutic agent for human cytomegalovirus retinitis in the United States.

 However, the strength of the antisense or antigene activity of the above-mentioned unnatural oligonucleotide analog, that is, the ability to form a stable complementary strand with DNA or mRNA, the stability to various nucleases, Considering the occurrence of side effects due to non-specific binding to various proteins in the body, it has even better in vivo stability, has few side effects, and has a high ability to form phase capture. Non-naturally occurring oligonucleotides have been desired. Further, in synthesizing such a non-natural type oligonucleotide, a nucleoside analog that can be easily synthesized can be used by using a DNA synthesizer or a synthetic method similar to that of the natural type such as a PCR method.

 Further, a compound having a chemical structure related to the compound of the present invention, that is, a compound having an oxetane structure is described in Japanese Patent Application Laid-Open No. 10-195988.

(In Kishiki, Upsilon ¹ and Upsilon ² is a hydrogen atom or a protecting group of a hydroxyl group, beta is a purine or pyrimidyl down nucleobase or s緣体.)

However, oligonucleotides using the above compounds have low resistance to nuclease enzymes in vivo and lack stability in vivo, and thus have insufficient antiviral and antisense activities. There was a problem. [Disclosure of the Invention]

 The present inventors have enthusiastically studied for many years a non-natural oligonucleotide analog having antiviral activity, excellent antisense or antigene activity, stable in vivo, and exhibiting few side effects. Done. As a result, 3'-4 'cross-linked oligonucleotide analogues and nucleoside analogues having an intramolecular ether bond become stable and excellent antiviral drugs, antisense or antigene drugs, specific gene detection drugs (probes) or amplifications. The present invention was found to be useful as a primer for starting and an intermediate for producing the same, and the present invention was completed.

 The novel 3′-4 ′ bridged nucleoside analogs of the present invention are

 General formula (1)

(1)

[Wherein, R ¹ and R ² are the same or different and are each a hydrogen atom, a protecting group for a hydroxyl group for nucleic acid synthesis, a phosphate group, a phosphate group protected by a protecting group for nucleic acid synthesis, or one P (R ³ ) R ^{4 wherein} R ³ and R ⁴ are the same or different and each is a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an amino group, or a carbon atom; Represents an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, a cyanoalkoxy group having 1 to 5 carbon atoms or an amino group substituted with an alkyl group having 1 to 4 carbon atoms] Show,

A represents an alkylene group having 1 to 4 carbon atoms,

 B represents a purine 9-yl group, a 2-oxo-1,2-dihydroxypyrimidine 11-Tl group, or a substituted purine 9-yl group or a substituted 2-oxo-1-yl group having a substituent selected from the following α group. It represents a 1,2-dihydropyrimidine-11-yl group. And a salt thereof, wherein the 3′-4 ′ bridged oligonucleotide analogue of the present invention is

General formula (2)

 (2)

 [Wherein, A represents an alkylene group having 1 to 4 carbon atoms;

B represents a purine 9-yl group, a 2-oxo-1,2-dihydropyrimidine-11-yl group or a substituted purine 9-yl group or a substituted 2-oxo-1,2-substituted group having a substituent selected from the following α group. 2-Dihydropyrimidine-1-yl group. ] And one or more pharmacologically acceptable salts thereof. However, when two or more of the above structures are included, Β is the same or different between the structures.

 Group)

 Hydroxyl group,

 A hydroxyl group protected by a protecting group for nucleic acid synthesis,

 An alkoxy group having 1 to 4 carbon atoms, a mercapto group protected with a protecting group for nucleic acid synthesis,

 An alkylthio group having 1 to 4 carbon atoms,

 Amino group,

 An amino group protected with a protecting group for nucleic acid synthesis,

 An amino group substituted with an alkyl group having 1 to 4 carbon atoms,

 An alkyl group having 1 to 4 carbon atoms, and

 Halogen atom.

 In the above general formula (1) or (2), examples of the “alkylene group having 1 to 4 carbon atoms” in Α include methylene, ethylene, trimethylene, and tetramethylene groups. It is a methylene group.

In the above general formula (1) or (2), 1 ^ and 1 ^ ² of "hydroxyl protecting group for nucleic acid synthesis"; and The protecting group of the `` hydroxyl group protected by a protecting group for nucleic acid synthesis '' in the group R ^3, R ⁴ or ct is not particularly limited as long as it can stably protect the hydroxyl group during nucleic acid synthesis. Specifically, protecting groups that are stable under acidic or neutral conditions and that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis and photolysis. Such protecting groups include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, vivaloyl, valerinole, isovalerinole, octanoyl, nonanoyl, decanol, 3-methylnonanoyl, 8-methylnonanol, 3-methylnonanol, 3-methylnonanol, and 3-methylnonanol. , 3,7—Dimethyloctanoyl, Pendecanoyl, Dodecanoyl, Tridecanoyl, Tetradecanoyl, Pentadecanoyl, to Xadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13, 13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, Alkylcarbonyl groups such as nonadecanoyl, eicosanoyl and henicosanoyl, carboxylated alkylcarbonyl groups such as succinoyl, glutaroyl, adipoxyl, halogeno lower alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl. , lower alkoxy lower alkylcarbonyl group such as main Tokishiasechiru, (E) - 2-methyltransferase - "aliphatic Ashiru group" such as an unsaturated alkylcarbonyl group such as 2-Butenoiru; methyl, Echiru, _n Propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butynole, n-pentinole, isopentinole, 2-methinolebutinole, neopentinole, 1-ethylenolepropinole, n-hexinole, isohexinole, 4-methinolepentyl, 3-Methynolepentinole, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl "Lower alkyl groups" such as 3-dimethylbutyl and 2-ethylbutyl;

Ethenyl, 1-propenil, 2-propeninole, 1-methinole 1-propeninole, 1-methinole 1-propeninole, 2-methinole 1-propininole, 2-methinole 1 2- Propenyl, 2-ethyl-2-propenyl, 1-butyr, 2-butul, 1-methyl-2-butul, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2 —Butenyl, 3-butyr, 1 —Methyl-3-butenyl, 2-Methyl-3-butur, 1-Ethyl-3-Butinole, 1-Pentinole, 2-Pentinole, 1-Methinole 2—penthenore, 2—methinole 2 —Pentenyl, 3-pentenyl, 1—methyl-3-pentenole, 2-methyl-1-pentenole, 4-penteninole, 1—methinole 4-pentenole, 2-methinole 4-pentenole, 1 "Lower alkenyl groups" such as —hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexeninole;

Benzoyl, a-naphthoyl, arylcanolebonyl groups such as naphthyl, 2-bromobenzoyl, halogenoarylcarbonyl groups such as 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, 4-toluoyl Lower alkylated arylcarbonyl groups such as lower alkylated arylcarbonyl groups such as 4-anisyl, carboxylation such as 2-carboxybenzoyl, 3-carboxybenzoyl and 4-carboxybenzoyl. Aryloxycarbonyl groups, nitrated arylcarbonyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl; lower-alkoxy forces such as 2- (methoxycarbonyl) benzoyl, rubonylated arylcarbonyl groups, 4- Arylated aryls such as phenylbenzoyl "aromatics" such as carbonyl Ashiru group ";

Like tetrahydridopyran-2 ^ ^, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahidropyran-4-yl, tetrahydrodrothiopyran-2-yl, 4- methoxytetrahydrodopiroran-4-yl A "tetrahydrofuranyl or tetrahydrothiopyranyl group"; a "tetrahydrofuranyl or tetrahydrothiofuranyl group" such as tetrahydrofuran-2-yl or tetrahydrofurofuran-2-yl;

 Tri-methylsilyl group, triethynolesilyl group, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-1-butylsilyl, tri-lower alkylsilyl group such as triisopropylsilyl, diphenyl A "silyl group" such as a tri-lower alkylsilyl group substituted with one or two aryl groups, such as dimethylsilyl, diphenylbutylsilanol, diphenylisopropylsilyl, phenylinoisoisopropylsilyl; "Lower alkoxymethyl groups" such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl;

“Lower alkoxylated lower alkoxymethyl group” such as 2-methoxyethoxymethyl; “No2” such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl Logeno lower alkoxymethyl ";

 "Lower alkoxylated tyl groups" such as 1-ethoxyxyl, 1- (isopropoxy) ethyl;

 "Halogenated tyl groups", such as 2,2,2-trichloromethylethyl;

A "methyl group substituted with one to three aryl groups", such as benzyl, α-naphthylmethyl, 3-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl;

 4-Methylbenzyl, 2,4,6-trimethyolbenzinole, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 4,4'-dimethoxytriphenylinole Substituted aryl groups with lower alkyl, lower alkoxy, halogen, cyano groups such as methinole, 2-nitrobenzene, 4-nitrobenzene, 4-chlorobenzene, 4-bromobenzyl, 4-cyanobenzyl A methyl group substituted with one to three substituted aryl groups ";

"Lower alkoxycarbonyl" such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl;

 "Halogen atom, lower alkoxy group or nitro group, such as 4-chloro phenol, 2-cyclo phenol, 4-methoxy phenol, 4-nitro phenol, 2,4-dinitrophenyl Aryl group substituted with

 A "lower alkoxycarbonyl group substituted by a halogen or tri-lower alkylsilyl group" such as 2,2,2-trichloromouth ethoxycarbonyl, 2-trimethylsilylethoxycanolevonyl;

"Alkenyloxycarbonyl" such as vinyloxycarbonyl, aryloxycarbonyl;

1 or 2 such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl "An aralkyloxycarbonyl group in which the aryl ring may be substituted with a lower alkoxy or nitro group".

1 ^ and 11 ² of the "protecting group for a hydroxyl group of the nucleic acid synthesis" is preferably "aliphatic Ashiru group" , "Aromatic acyl group", "methyl group substituted with 1 to 3 aryl groups", "1 to 3 aryl groups substituted with an aryl ring with lower alkyl, lower alkoxy, halogen, cyano group" A methyl group or a silyl group substituted with a phenyl group, and more preferably an acetyl group, a benzoyl group, a benzyl group, a p-methoxybenzoyl group, a dimethoxytrityl group, a monomethoxytrityl group or a tert- group. Butyldiphenylsilyl group,

In the protecting group of the “hydroxyl group protected by a protecting group for nucleic acid synthesis” of R ³ and R ⁴ or _α group, preferably, a “methyl group substituted by 1 to 3 aryl groups”, a “halogen atom” An aryl group substituted with a lower alkoxy group or a nitro group, a lower alkyl group or a lower alkenyl group, more preferably a benzyl group or a 2-chlorophenyl group. , A 4-chloro phenyl group or a 2-propenyl group.

In the above general formula (1),! The protecting group of “phosphate group protected by protecting group for nucleic acid synthesis” in ^ and 1 ^ ² is not particularly limited as long as it can stably protect the phosphate group during nucleic acid synthesis. But specifically, a protecting group that is stable under acidic or neutral conditions and can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis and photolysis. Examples of the group include methyl, ethyl, η-propyl, isopropyl, η-butyl, isobutyl, s-butynole, tert-butynole, n-pentynole, isopentinole, 2-methylinobutynole, neopentyl, 1-ethylpropyl, and n- Xyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-diethyl "Lower alkyl groups" such as methylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl

"Cyanated lower alkyl groups" such as 2-cyanoethyl, 2-cyano-1,1,1-dimethylethyl;

 "Ethyl groups substituted by silyl groups", such as 2-methinoresifeninolesilinoleethyl, 2-trimethylsilinoleleethyl, and 2-triphenylenolesilylethyl;

"Halogenated lower alkyls such as 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 2,2,2-trifluorophenol, 2,2,2-trichloroethyl-1,1-dimethylethyl" Group ”; 1-propeninole, 2-propeninole, 1-methinole, 1-methinole, 1-methinole, 1-propinyl, 2-methinole, 1-propininole, 2-methinolene, 2-propeninole Ninole, 2-ethyl-2-propeninole, 1-buteninole, 2-buteninole, 1-methyl-2-buteninole, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butul, 1-methyl-3-butul, 2-methyl-1-butenyl, 1-ethyl-3-nor-butene, 1-penthenore, 2-penthenore, 1-methinole 2- Penteninore, 2-Methinole, 2-pentinole, 3-pentenyl, 1-Methinole 3-penteninole, 2-Methinole, 3-penten'inole, 4-penteninole, 1-Methinole, 4-penteninole, 2-pentinole, 2-methinole 1 4—Pente 2 "Lower alkenyl groups" such as nore, 1-hexeninole, 2-hexeninole, 3-hexeninole, 4-hexeninole, 5-hexeninole;

"Cycloalkyl groups" such as cyclopropynole, cyclobutynole, cyclopentynole, cyclohexynole, cycloheptinole, norenobornyl, adamantyl;

"Cyanated lower alkenyl groups" such as 2-cyanobutenyl;

Benzinole, α-naphthylmethyl, 0-naphthylmethyl, indenylmethyl, phenanthrenylmethyl, anthracenylmethyl, diphenylmethyl, triphenylmethyl, 1-phenetinole, 2-phenetinole, 1-naphthinolethynole, 2-naphthinole Ethynole, 1-phenylphenol, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4 —Phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylenopentenole, 4-phenylenopentenole, 5-phenylene Two pentinoles, 1—Naphtinolenc , 2-naphthylpentyl, 3-naphthylpentinole, 4-naphthylopentyl, 5-naphthylpentinole, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexynole, 4-phenylhexenole, 4-phenylhexenole, 5 -Feninole hexinole, 6-Feninole hexinole, 1-naphthinole hexinole, 2-naphthinole hexinole, 3-naphthinole hexinole, 4-naphthinole hexinole, 5-naphthylhexyl, 6-naphthylhexyl "Aralkyl groups" such as;

4 crochet veninole, 2— (4—trophoeninole) echinore, 0—nitroveninole, 4—nito vengoinole, 2, 4—gini troveninole, 4 Nitrobenginore A toro group, an aralkyl group having an aryl ring substituted with a halogen atom ";

"Aryl groups" such as phenyl, indenyl, naphthyl, phenanthrenyl, anthracenyl;

 2-Methinorefnenole, 2, 6—Dimethinolephenynole, 2-Black diphthine, 4-Black diphthine, 2,4-Dichlorophenynole, 2,5-Dichloroethnole, 2— Examples of "aryl groups substituted by lower alkyl groups, nitrogen atoms, and nitro groups" such as bromophenylene, 412 trophenyl, and 4-chloro-2-nitrophenyl,

Preferably, a "lower alkyl group", a "lower alkyl group substituted with a cyano group", an "aralkyl group", a "nitro group, an aralkyl group having an aryl group substituted with a halogen atom" or a "lower alkyl group" An aryl group substituted with a halogen atom or a nitro group ", and more preferably, a 2-cyanoethyl group, a 2,2,2-trichloroethyl group, a benzyl group, a 2-chlorophenyl group or a 4-chloroethyl group. It is a black phenyl group.

In the above general formula (1) or (2), the “C 1 to C ⁴ alkoxy group” of R ³ and R ⁴ or α group includes, for example, methoxy, ethoxy, η-propoxy, isopropoxy, η —Butoxy, isobutoxy, s-butoxy or tert-butoxy, and a methoxy or ethoxy group is preferred.

In the above general formula (1) or (2), as the protecting group for R ^{: i} and R ⁴ or the “mercapto group protected with a protecting group for nucleic acid synthesis”, a mercapto group is stably used during nucleic acid synthesis. There is no particular limitation as long as it can be protected, but specifically, it is stable under acidic or neutral conditions, and is cleaved by a chemical method such as hydrogenation, caro water, electrolysis and photolysis. And a protecting group capable of forming a disulfide such as, for example, those mentioned above as the protecting group for a hydroxyl group, and a "group forming a disulfide" such as an alkylthio group such as methylthio, ethylthio, tert-butylthio, and an arylthio group such as benzylthio. It is preferably an "aliphatic acyl group" or an "aromatic acyl group", and more preferably a benzoinole group.

In the above general formula (1) or (2), examples of the “C 1 -C 4 alkylthio group” of R ³ and R ⁴ or α group include, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio , S-butylthio and tert-butylthio, preferably a methylthio or ethylthio group. In the above general formula (1) or (2), as the protecting group of “amino group protected by a protecting group for nucleic acid synthesis” of R ′ ³ and R ⁴ or _α group, an amino group that is stably synthesized during nucleic acid synthesis. There is no particular limitation as long as it can protect the group.Specifically, it is stable under acidic or neutral conditions, and can be prepared by chemical methods such as hydrogenation, hydrolysis, electrolysis and photolysis. A cleavable protecting group, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloynole, valeryl, isovaleryl, octanoinole, nonanoyl, decanoyl, 3-methinolenonyl, 8-methyl-notylanoyl Noyl, 3,7-dimethyloctanol, nddecanol, dodecanol, tridecanol, tetradecanol, pentadecanol, Hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadenicol, octadecanoyl, 1-methylheptadecayl Alkylcarbonyl groups such as noyl, nonadecanoyl, eicosanoyl and henicosanoyl, carboxylated alkylcarbonyl groups such as succinoyl, glutaroyl, and adiboyl; lower halogeno such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl. An "aliphatic acyl group J" such as an alkylcarbonyl group, a lower alkoxy lower alkylcarbonyl group such as methoxyacetyl, an unsaturated alkylcarbonyl group such as (-)-2-methyl-2-butenoyl;

Benzoyl, α-naphthoyl, —arylcarbonyl such as naphthoinole, halogenoarylcarbonyl such as 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, and 4-toluoyl Lower alkylated aryl carbonyl group, lower alkoxylated aryl carbonyl group such as 4-anisyl, carboxylated aryl such as 2-carboxybenzyl, 3-carboxybenzoyl, 4-carboxybenzoyl, etc. Groups, such as 4-nitrobenzoyl and 2-nitrobenzoyl, a lower carbonyl group such as 2- (methoxycarbonyl) benzoyl; a lower alkoxy group such as 2- (methoxycarbonyl) benzoyl; Benzoyl and other arylated carbonyl groups Family Ashiru group ";

"Lower alkoxycarbonyl" such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl; A "lower alkoxycarbonyl group substituted with a halogen or a tri-lower alkylsilyl group" such as 2,2,2-trichloromouth ethoxycarbonyl and 2-trimethylsilylethoxycarbonyl;

 "Alkenyloxycarbonyl" such as buroxycarbonyl, aryloxycarbonyl;

 1 such as benzyloxycarbonyl, 4-methoxypentinoleoxycarbonyl, 3,4-dimethoxy'benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl Or two `` aralkyloxycarbonyl groups which may be substituted with an aryl group by a lower alkoxy or a two-terminal group '', preferably an `` aliphatic acyl group '' or It is an "aromatic acyl group", more preferably a benzoyl group.

In the above general formula (1) or (2), examples of the “amino group substituted with an alkyl group having 1 to 4 carbon atoms” of R ³ and R ⁴ or α group include, for example, methylamino, ethylamino, propylamino, Isopropylamino, butylamino, isobutylamino, s-butylamino, tert-butylamino, dimethylamino, getylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di (s-butyl) amino, di (tert-butylamino) Examples of the amino group include amino, preferably a methylamino, ethylamino, dimethylamino, getylamino or diisopropylamino group.

In the above general formula (1), the “C1 to C5 alkoxy group” for R ³ and R ⁴ is a group in which the above “C1 to C4 alkoxy group” is substituted by a cyano group. Examples of such a group include, for example, cyanomethoxy, 2-cyanoethoxy, 3-cyanopropoxy, 4-cyanobutoxy, 3-cyano 2-methylpropoxy, or 1-cyanomethyl-11,1-dimethylmethoxy. And is preferably a 2-cyanoethoxy group.

 In the general formula (1) or (2), the “alkyl group having 1 to 4 carbon atoms” in the α group includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, tert— And butyl, preferably a methyl or ethyl group.

In the above general formula (1) or (2), the “halogen atom” of the α group includes, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or It is a chlorine atom.

 In the above general formula (1) or (2), in the “purine-9-yl group” and the “substituted purine-9-yl group” of B, a preferable group is 6-aminopurine-9-yl. (Ie, adenyl), 6-aminopurine-9-yl, 2,6-diaminopurine-1-yl, 2-amino-6-chloropurine-9 in which the amino group is protected by a protecting group for nucleic acid synthesis. 2-Amino-6-chloropurine, which is protected by a protecting group for nucleic acid synthesis, where 2-amino-6-fluorinated purine is substituted with 9-yl-6, fluorinated purine. 2-amino-6-fluoro mouth purine protected by a protecting group—9-yl, 2-amino-6-bromopurine—9-1-yl, 2-amino-1 whose amino group is protected by a protecting group for nucleic acid synthesis 6-Bromopurine 9-1 ^ T, 2-amino-1 6-Hydroxypurine-9-yl (ie Guani 2-amino-6-hydroxypurine-9-yl in which the amino group is protected with a protecting group for nucleic acid synthesis, 2-amino-6- in which the amino group and hydroxyl group are protected with a protecting group for nucleic acid synthesis. Hydroxypurine 9-yl, 6-amino-1 2-methoxypurine 9-yl, 6-amino-2-chloro-purine 9-yl, 6-amino-1 2-fluoropurine 9-yl , 2,6-dimethoxypurine-9-yl, 2,6-dichloropurin-9-yl or 6-mercaptopurine-19-yl, more preferably 6-benzoylamino It is a purine-9-yl, adenyl, 2-isobutyrylamino-16-hydroxypurine-19-yl or guaninyl group.

In the above general formula (1) or (2), “2-oxo-1,2-dihydropyrimidine-11-yl group” and “substituted 2-oxo-1,2-dihydropyrimidine-11-B” of B In general, preferred groups are 2-oxo-14-amino-1,2-dihydropyrimidine-11-yl (ie, cytosine), an amino group protected with a protecting group for nucleic acid synthesis. —Oxo-1-4-amino-1,2-dihydropyrimidine-11-yl, 2-oxo-14-amino-5-fluoro-1,2-dihydropyrimidin-1-yl and the amino group are protecting groups for nucleic acid synthesis. Protected 2-oxo-1-amino-5-fluoro-1,2-dihydropyrimidin-1-yl, 4-amino-2-oxo-1-5-chloro-1,2-dihydropyrimidine-1-yl, 2- 4-oxo- 1,2-dihydropyrimidine 1-yl, 2-oxo Sodium 4-mercapto-1,2-dihydroxypyrimidine-1-yl, 2-oxo-4-hydroxy-1--1,2-dihydropyrimidine-11-yl (ie peracinyl), 2-oxo-1-4 —Hydroxy-5—methylpyrimidine-1 1-yl (that is, thymii Or 4-amino-1-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl (that is, 5-methylcytosinyl) group, and more preferably 2-oxo-1 4- Benzoylamine 1,2-dihydropyrimidin-1-yl, cytosinyl, thyminyl, peracinyl, 2-oxo-14-benzoylamino-5-methyl-1,2-dihydropyrimidin-1-1-yl or 5- It is a methylcytosinyl group.

 “Nucleoside analog” refers to a non-naturally-occurring “nucleoside” in which a purine or pyrimidine base is bound to a sugar.

 “Oligonucleotide analog” refers to a non-natural type derivative of “oligonucleotide” in which the same or different “nucleosides” are bonded by 2 to 50 phosphodiester bonds, and as such analogs Is preferably a sugar derivative having a modified sugar moiety; a phosphoric acid diester; a thioate derivative in which a binding moiety is titanated; an ester in which a terminal phosphoric acid moiety is esterified; Amidated amides can be mentioned, and more preferably, a sugar derivative in which the sugar moiety is modified and a cholate derivative in which the phosphodiester binding moiety is titrated. I can do it.

 "Salt" means that the compound (1) of the present invention can be converted into a salt.

The salt is referred to as such a salt, and such a salt is preferably an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, or an anolemminium salt. Metal salts such as iron salts, zinc salts, copper salts, nickel salts, and cobalt salts; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, phenyldaricin alkyl ester salts, Ethylenediamine salt, N-methyldalcamine salt, guanidine salt, getylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dipenzinoleethylenediamine salt, black mouth pro-in salt, pro-in salt , Jetanolamine, N-benzyl-phenethylamine, Piperazine Amines such as organic salts such as tetramethylammonium salt and tris (hydroxymethyl) amino methane salt; halogen atoms such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide Inorganic acid salts such as hydride, nitrate, perchlorate, sulfate and phosphate; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; benzenesulfone Acid salts, aryl sulfo such as p-toluene sulfonate Organic acid salts such as phosphate, acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate; and glycine, lysine, arginine, and ornithi And amino acid salts such as glutamate, aspartate and the like.

 “Pharmacologically acceptable salt” refers to the salt of the oligonucleotide analogue of the present invention because it can be converted into a salt. Such a salt is preferably a sodium salt, potassium hydroxide or the like. Metal salts such as alkali metal salts such as lithium salts, lithium salts, alkaline earth metal salts such as calcium salts and magnesium salts, anorenium salts, iron salts, zinc salts, copper salts, nickel salts, and cobalt salts; Inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, monoleforin salts, dalcosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methyldalcamine salts, guanidine salts, getylamine salts, triethylamine salts, dicycloamine Hexylamine salt,, N 'dibenzylethylenediamine salt, black mouth procaine salt, Amine salts such as organic salts such as potassium salt, diethanolamine salt, N-benzyleneethylamine salt, perazine salt, tetramethylammonium salt, and tris (hydroxymethyl) amino methane salt; Inorganic acid salts such as hydrohalides, such as hydrochloride, hydrochloride, hydrobromide, and hydroiodide, nitrates, perchlorates, sulfates, and phosphates; methane sulfonate Lower alkane sulfonates such as trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate, aryl sulfonate such as p-toluene sulfonate, acetate, malate, Organic acid salts such as fumarate, succinate, citrate, tartrate, oxalate, maleate; and glycine, lysine, arginine, ordinine, Amino acid salts such as glutamate and aspartate can be mentioned. Among the compounds (1) of the present invention and salts thereof, preferred compounds include

(1) R ¹ is a hydrogen atom, an aliphatic acyl group, an aromatic acyl group, a methyl group substituted with one to three aryl groups, a lower alkyl, a lower alkoxy, a halogen or a cyano group, and an aryl ring. Is a methyl group or a silyl group substituted with 1 to 3 aryl groups, and a salt thereof,

(2) R ¹ is a hydrogen atom, an acetyl group, a benzoyl group, a benzyl group, a p-methoxybenzyl group, a dimethoxytrityl group, a monomethoxytrityl group or a terbutyldiphenylsilyl A compound that is a group and a salt thereof,

(3) R ² force; hydrogen atom, aliphatic acyl group, aromatic acyl group, methyl group substituted with 1 to 3 aryl groups, lower alkyl, lower alkoxy, halogen or cyano group. Compounds that are a methyl group, a silyl group, a phosphoramidite group, a phosphonyl group, a phosphate group, or a phosphate group protected with a protecting group for nucleic acid synthesis substituted with one to three aryl groups having a ring. And its salts,

(4) R ² is a hydrogen atom, an acetyl group, a benzoyl group, a benzyl group, a p-methoxybenzyl group, a tert-butyldiphenylsilyl group, a -P (0C: H ₄ CN) (NCH (CH ₃ ) ₂ ), -P (0CH ₃ ) (NCH (CH ₃ ) ₂ ), a phosphonyl group, or a 2-chloro or 4-chlorophenyl phosphate group and a salt thereof,

 (5) a compound wherein A is a methylene group and a salt thereof,

(6) B is 6-aminopurine-9-yl (that is, adenyl), 6-aminopurine-9-yl in which the amino group is protected by a protecting group for nucleic acid synthesis, 2,6-diaminopurine-9-yl, 2-amino-6-chloro-purine 9-yl, 2-amino-6-chloro-purine 9-yl, 2-amino-6-fluoro-purine 9 in which the amino group is protected by a protecting group for nucleic acid synthesis — 2-amino-6-fluoropurine 9-yl, 2-amino-6-bromopurine-9-yl, and amino group protected with a nucleic acid synthesis protecting group. 2-amino-16-bromopurine-9-yl, 2-amino-16-hydroxypurine-19-yl (ie, guaninyl), 2-amino in which the amino group is protected by a nucleic acid synthesis protecting group. 6—Hydroxypurine—9-yl, Ami 2-amino-6-hydroxypurine-9-yl, 6-amino-12-methoxypurine-9-1-yl, 6-amino-2-chloropurine whose base and hydroxyl groups are protected by protecting groups for nucleic acid synthesis 9-yl, 6-amino-2-fluoropurine 9 f, 2,6-dimethoxypurine 19-yl, 2,6-dichloropurine 91-yl, 6-mercaptopurine 9-yl, 2-oxo-4-amino-1,2-dihydropyrimidine-11-inole (ie, cytosinyl), 2-oxo-4-amino-1,2- in which the amino group is protected by a protecting group for nucleic acid synthesis Dihydropyrimidin-1-yl, 2-oxo-4-amino-1-5-fluoro 1,2-dihydroxypyrimidin-1-yl, 2-oxo-4 with the amino group protected by a protecting group for nucleic acid synthesis Amino-5-fluoro-1,2-dihydropyrimidine-1-1-yl, 4 Ami 1,2-dihydroxypyrimidine 1-yl, 2-oxo-4-methoxy 1,2-dihydroxypyrimidine 1-yl, 2-oxo-1 4-mercapto-1,2-dihydroxypyrimidine-11-yl, 2-oxo-4-hydroxy-1--1,2-dihydroxypyrimidine-11-yl (that is, peracynil), 2-oxo-1-4- Hydroxy 5-methylpyrimidine — 1-yl (ie, thymnil), 4-amino-15-methyl-12-oxo-1,2, -dihydro-mouth pyrimidine — 1-yl (ie, 5-methylcytosinyl) A compound wherein the group or amino group is a 4-amino-5-methyl-2-oxo-11,2-dihydroxypyrimidine-11-yl group protected with a protecting group for nucleic acid synthesis, and a salt thereof;

 (7) B-force; 6-benzoylaminopurine 9-yl, adenyl, 2-isobutyrylamino-6-hydroxypurine-19-yl, guaninyl, 2-oxo14-benzoylamino-1,1 Compounds which are 2-dihydropyrimidin-1-yl, cytosinyl, 2-oxo-5-methyl-14-benzoylamino-1,2-dihydropyrimidine-11-yl, 5-methylcytosinyl, peracinyl or thyminyl group and The salt can be given.

In addition, the above (1) to (2), (3) to (4) or (6) to (7) show more preferable compounds as the number increases, and in the general formula (1), ¹ is arbitrarily selected from (1) to (2), R ² is arbitrarily selected from (3) to (4), A is arbitrarily selected from (5), and B is (6) to ( Compounds and salts thereof, which are arbitrarily selected from 7) and arbitrarily combined with each other, are also suitable. Particularly preferable combinations are (2)-(3)-(5)-(6 ), (2)-(3)-(5)-(7), (2)-(4)-(5)-(6) and (2)-(4)-(5)-(7) And more preferably a compound selected from the following group and a salt thereof.

(Compound group)

 3'-0, 4'-C-ethylene guanosine,

3 '-0, 4' -C -ethylene adenosine,

 5'-O-Dimethoxytritinole-3'-〇, 4'-C-ethylene-6-Ν-benzoyladenosine, 5'-0-Dimethoxytrityl-3'-0, 4'-C-ethylene-2 -Ν-isobutyrylguanosine

3'-0,4'-C-ethylene-2-Ν-isobutyrylguanosine,

3'-0, 4'-C-ethylene-6-Ν-benzoyladenosine, 5 '-O-Dimethoxytrityl-3' -0, 4 '-C-ethylene-6-N-benzoyladenosine -2

'-O- (2-cyanoethyl N, N-diisopropyl) phosphoramidite

 5'-0-Dimethoxytriter-3 '-0, 4'-C-ethylene-2-N-isobutyrylguanosine-

2'-0-(2-Cyanoethyl N, N-diisopropyl) phosphoramidite

3 '-0, 4'-C-ethylene pyridine,

 3'-0,4'-C-ethylene-5-methinoredridine,

 3'-0, 4'-C-ethylene cytidine,

 3'-0, 4'-C-ethylene-5-methylcytidine,

 2 ', 5'-di-0-benzyl-3'-0,4'-C-ethyleneperidine,

5'-〇-dimethoxytritinol-3'-0,4'-C-ethyleneperidine,

 5'-0-Dimethoxytrityl-3'-0,4'-C-ethylene-5-methylperidine,

5'-0-Dimethoxytrityl-3'-0, 4'-C-ethylene-4-N-benzoylcytidine, 5'-O-Dimethoxytrityl-3'-0,4'-C-ethylene-4 -N-benzoinole-5-methylcytidine,

3'-0,4'-C-ethylene-4-N-benzoylcytidine,

 3'-0, 4'-C-ethylene-4-N-benzoinole-5-methylcytidine,

 5'-O-dimethoxytrityl-3'-O, 4'-C-ethylene-peridine-2'-O- (2-cyanoethyl N, N-diisopropyl) phosphoramidite,

 5'-0-Dimethoxytrityl-3'-O, 4'-C-ethylene-5-methylperidine-2'-O- (2-cyanoethyl N, N-diisopropyl) phosphoramidite,

 5'-0-Dimethoxytrityl-3'-0,4'-C-ethylene-4-N-benzoylcytidine-2'-O- (2-cyanoethyl N, N-diisopropyl) phosphoramidite and

5'-0-Dimethoxytrityl-3'-0,4'-C-ethylene-4-N-benzoyl-1-5-methylcytidine-2'-〇- (2-cyanoethyl N, N-diisopropyl) phosphoramidite. Among the oligonucleotide analogs containing one or more of the structures represented by the general formula (2) of the present invention and the pharmaceutically acceptable salts thereof, preferred are:

(8) A is a methylene group oligonucleotide analog and a pharmaceutically acceptable salt thereof (9) B is 6-aminopurine 9-yl (that is, adenyl), 6-aminopurine 19-yl, and 2,6-diaminopurine 9-yl in which the amino group is protected by a protecting group for nucleic acid synthesis. 2-amino-6-chloro-purine 9-1yl, 2-amino-6-chloro-purine 9-1yl, 2-amino-6-fluoropurine in which the amino group is protected by a protecting group for nucleic acid synthesis 9-yl and amino groups protected with protecting groups for nucleic acid synthesis 2-amino-6-fluoropurine-1-inole, 2-amino-6-bromopurine 9-yl and amino groups protect nucleic acid synthesis 2-amino-6-bromopurine 91-yl, 2-amino-6-hydroxypurine 91-yl (ie, guaninyl), 2-amino-6-protected with a protecting group for nucleic acid synthesis. —Hydroxypurine 91-yl, 2-amino-6-hydroxypurine-1-yl, 6-amino-2-methoxypurine-9-yl, 6-amino-2-chloropurine-9-yl, 6-amino- and hydroxyl-protected —Amino 2—Phnoleurine Purine 9-yl, 2, 6—Dimethoxypurine 19-yl, 2, 6—Dichloropurine 19-yl, 6—Mercaptopurine 9-yl, 2-oxo-14-amino-1,2-dihydropyrimidin-11-yl (ie, cytosinyl), 2-amino-14-amino-1,2-dihi in which the amino group is protected by a protecting group for nucleic acid synthesis Dropyrimidine-1 1-yl, 2-oxo-4- 4-amino-1 5-fluoro-1,2-dihydropyrimidin-1 1-yl, 2-amino-1 4-amino in which the amino group is protected by a protecting group for nucleic acid synthesis Amino 5-fluoro-1,2-dihydropyrimidin-1-yl, 4-amino 2-oxo-5-black 1,2-dihydroxypyrimidine-1-yl, 2-oxo-4-methoxy1,2-dihydropyrimidine 1-1,2-oxo-1 4-mercapto-1,2-dihydropyrimidin-1-yl, 2-oxo-1-4-hydroxy-1,2,2-dihydropyrimidin-1-yl (that is, シ lasinyl), 2-oxo-1-4-hi Doxy-5-methylpyrimidine-1-yl (that is, thyminyl), 4-amino-5-methyl-2-oxo-1,2-dihydroxypyrimidine-11-inole (that is, 5-methylcytosinyl) or amino group is used for nucleic acid synthesis. Oligonucleotides which are 4-amino-15-methyl-2-oxo-1,2-dihydropyrimidine-11-yl groups protected with the protecting group of the above, and pharmacologically acceptable salts thereof,

(10) B-force 6—Benzoylaminopurine 9-1yl, adenyl, 2-isobutylinolenoamino-1-6-hydroxypurine 9-1yl, guaninyl, 2-oxo1-4-benzoylamino1 , 2-Dihydropyrimidin-1-yl, cytosinyl, 2-oxo-1-5-methyl-4- Oligonucleotide analogs which are benzoylamino-1,2-dihydropyrimidin-1-yl, 5-methylcytosinyl, peracinyl or thyminyl group, and pharmacologically acceptable salts thereof can be listed.

 Further, the above (9) to (10) show more preferred oligonucleotide analogs as the number increases, and in the general formula (2), A is arbitrarily selected from (8), and B is Oligonucleotides obtained by arbitrarily selecting from (9) to (10) and arbitrarily combining them, and pharmacologically acceptable salts thereof are also suitable. Particularly preferred combinations are ( 8)-(9) and (8)-(10).

 Specific compounds included in the compound of the above formula (1) of the present invention are shown in Tables 1 and 2. However, the compound of the present invention is not limited to these.

 In Tables 1 and 2, Me represents a methyl group, Bn represents a benzyl group, and Bz represents

, A benzoyl group, PMB indicates a p-methoxybenzyl group, Tr indicates a trimethylmethyl group, MMTr indicates a 4-methoxytriphenylmethylinole (monomethoxytrityl) group, and DMTr Represents a 4,4′-dimethoxytriphenylmethyl (dimethoxytrityl) group, Mt r represents a 4,4 ′, 4 ′ ″-trimethoxytriphenylmethyl (trimethoxytrityl) group, and TMS represents TBDMS indicates a tert-butyldimethylsilyl group, TBDPS indicates a tert-butyldiphenylsilyl group, and TIPS indicates a triisopropylsilyl group.

[Table 1] Example

Compound No.AR ¹ R ⁶

1-1 CH ₂ HHHH

1-2 CH ₂ HHH NH ₂

1-3 CH ₂ HHH OH

1-4 CH ₂ HH OH H

1-5 CH ₂ HH OH NH _:

1-6 CH ₂ HH OH OH

1-7 CH ₂ HH NH ₂ H

1-8 CH ₂ HH NH ₂ NH ₂

1-9 CH ₂ HH NH ₂ CI

1-10 CH ₂ HH NH ₂ F

1-11 CH ₂ HHH ₂ Br

1-12 CH ₂ HH NH ₂ OH

1-13 CH ₂ HH OMe H

1-14 CH ₂ HH OMe OMe

1-15 CH ₂ HH OMe NH ₂

1-16 CH ₂ HH CI H

1-17 C¾ H H Br H

1-18 C¾ H H F H

1-19 CH ₂ HH CI CI

1-20 CH ₂ HH SH H

1-21 CH ₂ Bn H NHBz H

1-22 CH ₂ Bn H OH NHC0CH (CH ₃ ) ₂

1-23 CH ₂ Bn Ac NHBz H

1-24 CH ₂ Bn Ac OH NHCOCH (CH ₃ ) ₂

1-25 C¾ PMB H NHBz H

1-26 PBH OH NHCOCH (CH ₃ ) ₂ 1-27 CH ₂ PMB Ac NHBz H

1-28 CH ₃ PMB Ac OH NHCOCH (CH ₃ ),

1-29 CH ₂ Tr H NHBz H

1-30 CH ₂ MMTr H NHBz H

1-31 CH ₂ DMTr H NHBz H

1-32 CH ₂ Ac Ac NHBz H

1-33 CH ₂ Tr H OH NHCOCH (CH ₃ ) ₂

1-34 CH ₂ MMTr H OH NHCOCH (CH _:) ) ₂

1-35 CH ₂ DMTr H OH HCOCH (CH ₃ ) ₂

1-36 CH ₂ Ac Ac OH NHCOCH (CH ₃ ) ₂

1-37 CH ₂ TBDPS Ac NHBz H

1-38 CH ₂ TBDMS H NHBz H

1-39 CH ₂ TBDPS H NHBz H

1-40 c¾ TIPS H NHBz H

1-41 c¾ TBDPS Ac OH NHCOCH (CH ₃ ) ₂

1-42 CH ₂ TBDMS H OH NHC0CH (CH ₃ ) ₂

1-43 CH ₂ TBDPS H OH NHCOCH (CH ₃ ) ₂

1-44 CH ₂ TIPS H OH NHCOCH (CH ₃ ) ₂

1-45 (C¾) ₂ HHHH

1-46 (CH ₂ ) ₂ HHH NH ₂

1-47 (CH ₂ ) ₂ HHH OH

1-48 (C¾) ₂ HH OH H

1-49 (C¾) ₂ HH OH NH ₂

1-50 (CH ₂ ) ₂ HH OH OH

1-51 (C¾) ₂ HH NH ₂ H

1-52 (CH ₂ ) ₂ HHH ₂ NH ₂

1-53 (C¾) ₂ HH NH ₂ CI

1-54 (C) ₂ HH NH ₂ F 1-55 (CH ₂ ) ₂ HH NH ₂ Br

1-56 (CH ₂ ) ₂ HH NH _; OH

1-57 (CH ₂ ) ₂ HH OMe H

1-58 (CH ₂ ) ₂ HH OMe OMe

1-59 (CH ₂ ) ₂ HH OMe H ₂

1-60 (CH ₂ ) ₂ HH CI H

1-61 (CH ₂ ) ₂ HH Br H

1-62 (CH ₂ ) ₂ HHFH

1-63 (CH ₂ ) ₂ HH CI CI

1-64 (CH ₂ ) ₂ HH SH H

1-65 (CH ₂ ) ₂ Bn H NHBz H

1-66 (CH ₂ ) ₂ Bn H OH NHCOCH (CH ₃ ) ₂

1-67 (C) ₂ Bn Ac NHBz H

1-68 (CH ₂ ) ₂ Bn Ac OH NHC0CH (CH ₃ ) ₂

1-69 (C¾) ₂ PMB H NHBz H

1-70 (C¾) ₂ PMB H OH NHCOCH (CH ₃ ) ₂

1-71 (CH ₂ ) ₂ PMB Ac NHBz H

1-72 (CH ₂ ) ₂ PMB Ac OH NHCOCH (CH ₃ ) ₂

1-73 (C) ₂ Tr H NHBz H

1-74 (CH ₂ ) ₂ MMTr H NHBz H

1-75 (CH ₂ ) ₂ DMTr H NHBz H

1-76 (C) ₂ Ac Ac NHBz H

1-77 (CH ₂ ) ₂ Tr H OH NHCOCH (CH ₃ ) ₂

1-78 (C¾) ₂ MMTr H OH NHCOCH (CH ₃ ) ₂

1-79 (C¾) ₂ DMTr H OH NHCOCH (CH ₃ ) ₂

1-80 (C¾) ₂ Ac Ac OH NHC0CH (CH ₃ ) ₂

1-81 (C¾) ₂ TBDPS Ac NHBz H

1-82 (C¾) ₂ TBDMS H NHBz H 1-83 (CH ₂ ) ₂ TBDPS H NHBz H

1-84 (CH ₂ ) ₂ TIPS H NHBz H

1-85 (CH ₂ ) ₂ TBDPS Ac OH HCOCH (CH ₃ ) ₂

1-86 (CH ₂ ) ₂ TBDMS H OH NHC0CH (CH ₃ ) ₂

1-87 (CH ₂ ) ₂ TBDPS H OH NHC0CH (CH ₃ ) ₂

1-88 (CH ₂ ) ₂ TIPS H OH NHCOCH (CH ₃ ) ₂

1-89 (CH ₂ ) ₃ HHHH

1-90 (CH ₂ ) ₃ HHH NH ₂

1-91 (CH ₂ ) ₃ HHH OH

1-92 (CH ₂ ) ₃ HH OH H

1-93 (CH ₂ ) ₃ HH OH NH ₂

1-94 (CH ₂ ) ₃ HH OH OH

1-95 (CH ₂ ) ₃ HH NH ₂ H

1-96 (CH ₂ ) ₃ HH NH ₂ NH ₂

1-97 (CH ₂ ) ₃ HH NH ₂ CI

1-98 (CH ₂ ) ₃ HH NH ₂ F

1-99 (CH ₂ ) ₃ HH NH ₂ Br

1-100 (CH ₂ ) ₃ HHH ₂ OH

1-101 (CH ₂ ) ₃ HH OMe H

1-102 (CH ₂ ) ₃ HH OMe OMe

1-103 (c) ₃ HH OMe NH ₂

1-104 (c) ₃ HH CI H

1-105 (C) ₃ HH Br H

1-106 (CH ₂ ) ₃ HHFH

1-107 (CH ₂ ) ₃ HH CI CI

1-108 (CH ₂ ) ₃ HH SH H

1-109 (C¾) ₃ Bn H NHBz H

1-110 (C) ₃ Bn H OH NHC0CH (CH ₃ ) ₂ 1-111 (CH ₂ ) ₃ Bn Ac image z H

1-112 (CH ₂ ) ₃ Bn Ac OH NHCOCH (CH ₃ ) ₂

1-113 (CH ₂ ) ₃ PMB H NHBz H

1-114 (CH ₂ ) ₃ PMB H OH NHCOCH (CH) ₂

1-115 (CH ₂ ) ₃ PMB Ac NHBz H

1-116 (CH ₂ ) ₃ PMB Ac OH NHCOCH (CH ₃ ) ₂

1-117 (CH ₂ ) ₃ Tr H NHBz H

1-118 (CH ₂ ) ₃ MMTr H NHBz H

1-119 (CH ₂ ) ₃ DMTr H NHBz H

1-120 (CH ₂ ) ₃ Ac Ac NHBz H

1-121 (C¾) ₃ Tr H OH NHC0CH (CH ₃ ) ₂

1-122 (CH ₂ ) ₃ MMTr H OH NHCOCH (CH ₃ ) ₂

1-123 (C) ₃ DMTr H OH NHCOCH (CH ₃ ) ₂

1-124 (CH ₂ ) ₃ Ac Ac OH NHC0CH (C¾) ₂

1-125 (C) _3- ring PS Ac NHBz H

1-126 (C¾) ₃ TBDMS H NHBz H

1-127 (C) ₃ TBDPS H NHBz H

1-128 (C) ₃ TIPS H NHBz H

1-129 (C¾) ₃ TBDPS Ac OH NHC0CH (CH ₃ ) ₂

1-130 (CH ₂ ) ₃ TBDMS H OH NHC0CH (CH ₃ ) ₂

1-131 (C) ₃ TBDPS H OH HCOCH (CH ₃ ) ₂

1-132 (C) ₃ TIPS H OH NHCOCH (CH ₃ ),

1-133 (C¾) ₄ HHHH

1-134 (C¾) ₄ HHH NH ₂

1-135 (c¾) ₄ HHH OH

1-136 (CH ₂ ) ₄ HH OH H

1-137 (C¾) ₄ HH OH NH ₂

1-138 (C¾) ₄ HH OH OH 1-139 (CH ₂ ) ₄ HHH ₂ H

1-140 (CH ₂ ) ₄ HHH ₂ NH,

1-141 (C¾) ₄ HH NH ₂ CI

1-142 (CH ₂ ) ₄ HH NH ₂ F

1-143 (CH ₂ ) ₄ HHH ₂ Br

1-144 (CH ₂ ) ₄ HH NH ₂ OH

1-145 (C¾) ₄ HH OMe H

1-146 (CH ₂ ) ₄ HH OMe OMe

1-147 (CH ₂ ) ₄ HH OMe NH ₂

1-148 (CH ₂ ) ₄ HH CI H

1-149 (CH ₂ ) ₄ HH Br H

1-150 (CH ₂ ) ₄ HHFH

1-151 (C¾) ₄ HH CI CI

1-152 (CH ₂ ) ₄ HH SH H

1-153 (C¾) ₄ Bn H NHBz H

1-154 (C) ₄ Bn H OH NHC0CH (CH ₃ )

1-155 (CH ₂ ) ₄ Bn Ac NHBz H

1-156 (CH ₂ ) ₄ Bn Ac OH NHCOCH (CH ₃ )

1-157 (CH ₂ ) ₄ PMB H NHBz H

1-158 (C¾) ₄ PMB H OH NHC0CH (CH ₃ )

1-159 (C¾) ₄ PMB Ac NHBz H

1-160 (C¾) ₄ PMB Ac OH NHC0CH (CH ₃ )

1-161 (CH ₂ ) ₄ Tr H NHBz H

1-162 (C¾) ₄ MMTr H NHBz H

1-163 (CH ₂ ) ₄ DMTr H NHBz H

1-164 (CH ₂ ) ₄ Ac Ac NHBz H

1-165 (CH ₂ ) ₄ Tr H OH NHC0CH (CH ₃ )

1-166 (C¾) ₄ MMTr H OH NHC0CH (CH ₃ ) 1-167 (CH ₂ ) ₄ DMTr H OH NHCOCH (CH ₃ ) ₂

1-168 (CH ₂ ) ₄ Ac Ac OH NHCOCH (CH ₃ ) ₂

1-169 (CH ₂ ) ₄ TBDPS Ac NHBz H

1-170 (CH ₂ ) ₄ TBDMS H NHBz H

1-171 (CH ₂ ) ₄ TBDPS H NHBz H

1-172 (CH ₂ ) ₄ TIPS H NHBz H

1-173 (C¾) ₄ TBDPS Ac OH NHCOCH (CH ₃ ) ₂

1-174 (CH ₂ ) ₄ TBDMS H OH NHCOCH (CH ₃ ) ₂

1-175 (CH ₂ ) ₄ TBDPS H OH NHCOCH (CH ₃ ) ₂

1-176 (CH ₂ ) ₄ TIPS H OH NHCOCH (CH ₃ ) ₂

1-177 CH ₂ HH OH NHCOCH (CH ₃ ) ₂

1-178 CH ₂ HH NHBz H

1-179 (C¾) ₂ HH OH NHCOCH (CH ₃ ) ₂

1-180 (C¾) ₂ HH NHBz H

1-181 (C¾) ₃ HH OH NHCOCH (CH ₃ ) ₂

1-182 (CH ₂ ) ₃ HH NHBz H

1-183 (CH ₂ ) ₄ HH OH NHCOCH (C¾) ₂

1-184 (C¾) ₄ HH NHBz H

1-185 CH ₂ DMTr P (N (iPr) ₂ ) (0C ₂ H ₄ CN) OH NHCOCH (CH ₃ ) ₂

1-186 C¾ DMTr P (N (iPr) ₂ ) (0C ₂ ¾CN) NHBz H

1-187 (C¾) ₂ DMTr P (N (iPr) ₂ ) (0C ₂ ¾CN) OH NHCOCH (CH ₃ ) ₂

1-188 (C¾) ₂ DMTr P (N (iPr) ₂ ) (0C ₂ ¾CN) NHBz H

1-189 (C) ₃ DMTr P (N (iPr) ₂ ) (0C ₂ H ₄ CN) OH NHCOCH (CH ₃ ) ₂

1-190 (C) ₃ DMTr P (N (iPr) ₂ ) (0C ₂ H ₄ CN) NHBz H

1-191 (C¾) ₄ DMTr P (N (iPr) ₂ ) (OC ^ CN) OH NHCOCH (CH ₃ ) ₂

1-192 (C¾) ₄ DMTr P (N (iPr) ₂ ) (0C ₂ ¾CN) NHBz H

1-193 C¾ DMTr P (N (iPr) ₂ ) (OCH ₃ ) OH NHCOCH (CH ₃ ) ₂

1-194 CH, DMTr P (N (iPr) ₂ ) (0CH ₃ ) NHBz H 1-195 (CH ₂ ) ₂ DMTr P (N (iPr) ₃ ) (0CH) OH NHC0CH (CH ₃ ) ₂ 1-196 (CH ₂ ) ₂ DMTr P (N (iPr) ₂ ) (0CH ₃ ) NHBz H 1-197 (CH ₂ ) ₃ DMTr P (N (iPr)) (0CH _{: i} ) OH NHC0CH (CH ₃ ) 1-198 (CH ₂ ) ₃ DMTr P (N (iPr) ₂ ) (0CH ₃ ) NHBz H 1-199 (CH ₂ ) ₄ DMTr P (N (iPr) ₂ ) (OCH ₃ ) OH NHC0CH (CH ₃ ) ₂ 1-200 (CH ₂ ) ₄ DMTr P (N (iPr) ₂ ) (0CH ₃ ) NHBz H

1-201 CH ₂ DMTr P (0) (OH) H OH NHC0CH (CH ₃ ) _; 1-202 CH ₂ DMTr P (0) (OH) H NHBz H 1-203 (CH ₂ ) ₂ DMTr P (0) (OH) H OH NHC0CH (CH ₃ ) ₂ 1-204 (CH ₂ ) ₂ DMTr P (0) (OH) H NHBz H

1-205 (CH ₂ ) ₃ DMTr P (0) (OH) H OH NHC0CH (CH ₃ ) ₂ 1-206 (CH ₂ ), DMTr P (0) (OH) H NHBz H

1-207 (CH ₂ ), DMTr P (0) (0H) H OH NHC0CH (CH ₃ ) ₂ 1-208 (CH ₂ ) ₄ DMTr P (0) (0H) H NHBz H

1-209 CH ₂ H Ac NHBz H

(1 ")

 [Table 2] Example

Compound

Number AR ² 2-1 CH ₂ HH OH H

2-2 CH ₂ HH OH CH ₃

2-3 CH ₂ HH NH ₂ H

2-4 CH ₂ HH NH ₂ CH ₃

2-5 CH ₂ HH NH ₂ F

2-6 CH ₂ HH CI H

2-7 CH ₂ HH OMe H

2-8 CH ₂ HH SH H

2-9 CH ₂ Bn H OH H

2-10 CH ₂ Bn Ac OH H

2-11 CH ₂ PMB H OH H

2-12 CH ₂ PMB Ac OH H

2-13 CH ₂ Tr H OH H

2-14 CH ₂ MMTr H OH H

2-15 C DMTr H OH H

2-16 CH ₂ Ac Ac OH H

2-17 CH ₂ TBDPS Ac OH H

2-18 CH ₂ TBDMS H OH H

2-19 CH ₂ TBDPS H OH H

2-20 C¾ TIPS H OH H

2-21 C¾ Bn H OH CH ₃

2-22 CH ₂ Bn Ac OH CH ₃

2-23 C¾ PMB Ac OH CH ₃

2-24 CH ₂ PMB PMB OH CH ₃

2-25 C Tr H OH CH ₃

2-26 CH ₂ MMTr H OH CH ₃

2-27 CH ₂ DMTr H OH CH ₃

2-28 CH, Ac Ac OH 2-29 CH ₂ TBDPS Ac OH CH ₃

2-30 CH ₂ TBDMS H OH CH ₃

2-31 CH ₂ TBDPS H OH CH ₃

2-32 C¾ TIPS H OH CH ₃

2-33 CH ₂ Bn H NHBz H

2-34 CH ₂ Bn Ac NHBz H

2-35 CH ₂ PMB H NHBz H

2-36 CH ₂ PMB Ac NHBz H

2-37 CH ₂ Tr H NHBz H

2-38 CH ₂ MMTr H NHBz H

2-39 CH ₂ DMTr H NHBz H

2-40 CH ₂ Ac Ac NHBz H

2-41 C¾ TBDPS Ac NHBz H

2-42 c¾ TBDMS H NHBz H

2-43 CH ₂ TBDPS H NHBz H

2-44 CH ₂ TIPS H NHBz H

2-45 C¾ Bn H NHBz CH ₃

2-46 CH ₂ Bn Ac NHBz CH ₃

2-47 c¾ PMB H NHBz CH ₃

2-48 c¾ PMB Ac NHBz CH ₃

2-49 CH ₂ Tr H NHBz CH ₃

2-50 CH ₂ MMTr H NHBz CH ₃

2-51 CH ₂ DMTr H NHBz CH ₃

2-52 CH ₂ Ac Ac NHBz CH ₃

2-53 CH ₂ TBDPS Ac NHBz CH ₃

2-54 CH ₂ TBDMS H NHBz CH ₃

2-55 C¾ TBDPS H NHBz CH ₃

2-56 CH ₂ TIPS H NHBz CH ₃ 2-57 (CH ₂ ) ₂ HH OH H

2-58 (CH ₂ ) ₂ HH OH CH ₃

2-59 (CH ₂ ) ₂ HH NH ₂ H

2-60 (CH ₂ ) ₂ HH NH ₂ CH ₃

2-61 (CH ₂ ) ₂ HH NH ₂ F

2-62 (CH ₂ ) ₂ HH CI H

2-63 (CH ₂ ) ₂ HH OMe H

2-64 (CH ₂ ) ₂ HH SH H

2-65 (CH ₂ ) ₂ Bn H OH H

2-66 (CH ₂ ) ₂ Bn Ac OH H

2-67 (CH ₂ ) ₂ PMB H OH H

2-68 (CH ₂ ) ₂ PMB Ac OH H

2-69 (CH ₂ ) ₂ Tr H OH H

2-70 (CH ₂ ) ₂ MMTr H OH H

2-71 (CH ₂ ) ₂ DMTr H OH H

2-72 (CH ₂ ) ₂ Ac Ac OH H

2-73 (C¾) ₂ TBDPS Ac OH H

2-74 (CH ₂ ) ₂ TBDMS H OH H

2-75 (CH ₂ ) ₂ TBDPS H OH H

2-76 (CH ₂ ) ₂ TIPS H OH H

2-77 (CH ₂ ) ₂ Bn H OH CH ₃

2-78 (CH ₂ ) ₂ Bn Ac OH CH ₃

2-79 (CH ₂ ) ₂ PMB H OH CH ₃

2-80 (CH ₂ ) ₂ PMB Ac OH CH ₃

2-81 (CH ₂ ) ₂ Tr H OH CH ₃

2-82 (CH ₂ ) ₂ MMTr H OH CH ₃

2-83 (CH ₂ ) ₂ DMTr H OH CH ₃

2-84 (CH ₂ ) ₂ Ac Ac OH CH ₃ 2-85 (CH ₂ ) ₂ TBDPS Ac OH CH ₃

2-86 (CH ₂ ) ₂ TBDMS H OH CH ₃

2-87 (CH ₂ ) ₂ TBDPS H OH CH ₃

2-88 (CH ₂ ) ₂ TIPS H OH CH ₃

2-89 (CH ₂ ) ₂ Bn H NHBz H

2-90 (CH ₂ ) ₂ Bn Ac NHBz H

2-91 (CH ₂ ) ₂ PMB H NHBz H

2-92 (CH ₂ ) ₂ PMB Ac NHBz H

2-93 (CH ₂ ) _: Tr H NHBz H

2-94 (CH ₂ ) ₂ O Tr H NHBz H

2-95 (CH ₂ ) ₂ DMTr H NHBz H

2-96 (CH ₂ ) ₂ Ac Ac NHBz H

2-97 (CH ₂ ) ₂ TBDPS Ac NHBz H

2-98 (CH ₂ ) ₂ TBDMS H NHBz H

2-99 (CH ₂ ) ₂ TBDPS H NHBz H

2-100 (CH ₂ ) ₂ TIPS H NHBz H

2-101 (CH ₂ ) ₂ Bn H NHBz CH ₃

2-102 (CH ₂ ) ₂ Bn Bn NHBz CH ₃

2-103 (CH ₂ ) ₂ PMB Ac NHBz CH ₃

2-104 (CH ₂ ) ₂ PMB Ac NHBz CH ₃

2-105 (CH ₂ ) ₂ Tr H NHBz CH ₃

2-106 (CH ₂ ) ₂ Cafe Tr H NHBz CH ₃

2-107 (CH ₂ ) ₂ DMTr H NHBz C¾

2-108 (CH ₂ ) ₂ Ac Ac NHBz CH ₃

2-109 (CH ₂ ) ₂ TBDPS Ac NHBz CH ₃

2-110 (CH ₂ ) ₂ TBDMS H NHBz CH ₃

2-111 (CH ₂ ) ₂ TBDPS H NHBz c¾

2-112 (CH ₂ ) ₂ TIPS H NHBz CH ₃ -113 (CH ₂ ) ₃ HH OH H

2-114 (CH ₂ ) 3 HH OH CH ₃

2-115 (CH ₂ ) ₃ HH NH ₂ H

2-116 (CH ₂ ) ₃ HH NH ₂ CH ₃

2-117 (CH ₂ ) ₃ HH NH ₂ F

2-118 (CH ₂ ) ₃ HH CI H

2-119 (CH ₂ ) ₃ HH OMe H

2-120 (CH ₂ ) ₃ HH SH H

2-121 (C¾) ₃ Bn H OH H

2-122 (CH ₂ ) ₃ Bn Ac OH H

2-123 (CH ₂ ) ₃ PMB H OH H

2-124 (C¾) ₃ PMB Ac OH H

2-125 (CH ₂ ) ₃ Tr H OH H

2-126 (CH ₂ ) ₃ MMTr H OH H

2-127 (CH ₂ ) ₃ DMTr H OH H

2-128 (C¾) ₃ Ac Ac OH H

2-129 (CH ₂ ) ₃ TBDPS Ac OH H

2-130 (CH ₂ ) ₃ TBDMS H OH H

2-131 (CH ₂ ) ₃ TBDPS H OH H

2-132 (CH ₂ ) ₃ TIPS H OH H

2-133 (CH ₂ ) ₃ Bn H OH CH ₃

2-134 (CH ₂ ) ₃ Bn Ac OH CH ₃

2-135 (CH ₂ ) ₃ PMB Ac OH C¾

2-136 (CH ₂ ) ₃ PMB PMB OH c¾

2-137 (CH ₂ ) ₃ Tr H OH CH ₃

2-138 (CH ₂ ) ₃ MMTr H OH CH ₃

2-139 (CH ₂ ) ₃ DMTr H OH CH ₃

2-140 (CH ₂ ) ₃ Ac Ac OH CH ₃ -141 (CH ₂ ) ₃ TBDPS Ac OH CH ₃

2-142 (CH ₂ ) TBDMS H OH CH ₃

2-143 (CH ₂ ) ₃ TBDPS H OH CH ₃

2-144 (CH ₂ ) ₃ TIPS H OH CH ₃

2-145 (CH ₂ ) ₃ Bn H NHBz H

2-146 (CH ₂ ) ₃ Bn Ac NHBz H

2-147 (CH ₂ ) ₃ PMB H NHBz H

2-148 (CH ₂ ) ₃ PMB Ac NHBz H

2-149 (CH ₂ ) ₃ Tr H NHBz H

2-150 (CH ₂ ) ₃ MMTr H NHBz H

2-151 (CH ₂ ) ₃ DMTr H NHBz H

2-152 (CH ₂ ) ₃ Ac Ac NHBz H

2-153 (CH ₂ ) ₃ TBDPS Ac NHBz H

2-154 (CH ₂ ) ₃ TBDMS H NHBz H

2-155 (CH ₂ ) ₃ TBDPS H NHBz H

2-156 (CH ₂ ) ₃ TIPS H NHBz H

2-157 (CH ₂ ) ₃ Bn H NHBz CH ₃

2-158 (CH ₂ ) ₃ Bn Ac NHBz CH ₃

2-159 (CH ₂ ) ₃ PMB H NHBz C

2-160 (CH ₂ ) ₃ PMB Ac NHBz CH ₃

2-161 (CH ₂ ) ₃ Tr H NHBz CH ₃

2-162 (CH ₂ ) ₃ MMTr H NHBz C

2-163 (CH ₂ ) ₃ DMTr H NHBz CH ₃

2-164 (CH ₂ ) ₃ Ac Ac NHBz CH ₃

2-165 (CH ₂ ) ₃ TBDPS Ac NHBz CH ₃

2-166 (CH ₂ ) ₃ TBDMS H NHBz CH ₃

2-167 (CH ₂ ) ₃ TBDPS H NHBz CH ₃

2-168 (CH ₂ ) ₃ TIPS H NHBz O 00/78775

 -35-

2-169 (CH ₂ ) ₄ HH OH H

2-170 (CH ₂ ) ₄ HH OH CH ₃

2-171 (CH ₂ ) ₄ HH NH ₂ H

2-172 (CH ₂ ) ₄ HH NH ₂ CH ₃

2-173 (CH ₂ ) ₄ HH NH ₂ F

2-174 (CH ₂ ) ₄ HH CI H

2-175 (CH ₂ ) ₄ HH OMe H

2-176 (CH ₂ ) ₄ HH SH H

2-177 (CH ₂ ) ₄ Bn H OH H

2-178 (CH ₂ ) ₄ Bn Ac OH H

2-179 (C¾) ₄ PMB H OH H

2-180 (CH ₂ ) ₄ PMB Ac OH H

2-181 (CH ₂ ) ₄ Tr H OH H

2-182 (CH ₂ ) ₄ O Tr H OH H

2-183 (CH ₂ ) ₄ DMTr H OH H

2-184 (CH ₂ ) ₄ Ac Ac OH H

2-185 (CH ₂ ) ₄ TBDPS Ac OH H

2-186 (CH ₂ ) ₄ TBDMS H OH H

2-187 (CH ₂ ) ₄ TBDPS H OH H

2-188 (CH ₂ ) ₄ TIPS H OH H

2-189 (CH ₂ ) ₄ Bn H OH CH ₃

2-190 (CH ₂ ) ₄ Bn Ac OH CH ₃

2-191 (CH ₂ ) ₄ PMB H OH CH ₃

2-192 (CH ₂ ) ₄ PMB Ac OH CH ₃

2-193 (CH ₂ ) ₄ Tr H OH CH ₃

2-194 (CH ₂ ) ₄ Awake Tr H OH CH ₃

2-195 (CH ₂ ) ₄ DMTr H OH CH ₃

2-196 (CH ₂ ) ₄ Ac Ac OH CH ₃ 2-197 (CH ₂ ) ₄ TBDPS Ac OH CH ₃

2-198 (CH ₂ ) ₄ TBDMS H OH CH ₃

2-199 (CH ₂ ) ₄ TBDPS H OH CH ₃

2-200 (CH ₂ ) ₄ TIPS H OH CH ₃

2-201 (CH ₂ ) ₄ Bn H Image z H

2-202 (CH ₂ ) ₄ Bn Ac HBz H

2-203 (CH ₂ ) ₄ PMB H NHBz H

2-204 (CH ₂ ) ₄ PMB Ac NHBz H

2-205 (CH ₂ ) ₄ Tr H NHBz H

2-206 (CH ₂ ) ₄ MMTr H NHBz H

2-207 (CH ₂ ) ₄ DMTr H NHBz H

2-208 (CH ₂ ) ₄ Ac Ac NHBz H

2-209 (CH ₂ ) ₄ TBDPS Ac NHBz H

2-210 (CH ₂ ) ₄ TBDMS H NHBz H

2-211 (CH ₂ ) ₄ TBDPS H NHBz H

2-212 (CH ₂ ) ₄ TIPS H NHBz H

2-213 (CH ₂ ) ₄ Bn H NHBz CH ₃

2-214 (CH ₂ ) ₄ Bn Ac NHBz CH ₃

2-215 (CH ₂ ) ₄ PMB H NHBz CH ₃

2-216 (CH ₂ ) ₄ PMB Ac NHBz CH ₃

2-217 (CH ₂ ) ₄ Tr H NHBz c

2-218 (CH ₂ ) ₄ MMTr H NHBz CH ₃

2-219 (CH ₂ ) ₄ DMTr H NHBz CH ₃

2-220 (CH ₂ ) ₄ Ac Ac NHBz CH ₃

2-221 (CH ₂ ) ₄ TBDPS Ac NHBz C

2-222 (CH ₂ ) ₄ TBDMS H NHBz CH ₃

2-223 (CH ₂ ) ₄ TBDPS H NHBz CH _;

2-224 (CH ₂ ) ₄ TIPS H NHBz CH _; Old t

((DNipMTr po

 o

 3 3 O O o o o o

a: a: a: c 3 3 OOQ a: a: o re m

2-253 (CH ₂ ) ₂ DMTr P (N (iPr) ₂ ) (OCH ₃ ) OH H

2-254 (CH ₂ ) ₂ DMTr P (N (iPr) ₂ ) (OCH ₃ ) OH CH ₃

2-255 (CH ₂ ) ₂ DMTr P (N (iPr) ₂ ) (0C¾) NHBz H

2-256 (CH ₂ ) ₂ DMTr P (N (iPr) ₂ ) (OCH ₃ ) NHBz CH ₃

2-257 (CH ₂ ) ₃ DMTr P (N (iPr) ₂ ) (OCH3) OH H

2-258 (CH ₂ ) ₃ DMTr P (N (iPr) ₂ ) (OCH3) OH CH ₃

2-259 (C¾) ₃ DMTr P (N (iPr) ₂ ) (OCH3) NHBz H

2-260 (C) ₃ DMTr P ((iPr) ₂ ) (OCH3) NHBz CH ₃

2-261 (CH ₂ ) ₄ DMTr P (N (iPr) ₂ ) (OCH3) OH H

2-262 (CH ₂ ) ₄ DMTr P (N (iPr) ₂ ) (OCH3) OH CH ₃

2-263 (CH ₂ ) ₄ DMTr P (N (iPr) ₂ ) (OCH3) NHBz H

2-264 (CH ₂ ) ₄ DMTr P (N (iPr) ₂ ) (OCH ₃ ) NHBz CH _{3 In the} above Tables 1 and 2, suitable compounds are (1-5), (1-7), (1-7 23), (1-24), (1-3 1), (1 32), (1 35), (1 36), (1 37), (1 39), (1 41 ), (1-43), (1-49), (1-51), (1-67), (1-68), (1-75), (1-76), (1-79) , (1-80), (1-81), (1-83), (1-85), (1-87), (1-93), (1-95), (1

 (1-1 1 2) (1-1 5) 1-.6) (1 1 9)

-120) (1-1 23) 24)-1 25) (1 27) (1-1 29) (1-13 1) (1-1 37)-139) (1 55) (1-1 56) (1-163) (1-1 64)-1 67) (1 68) (1-169) (1-1 7 1) (1-1 73)-1 75) (1-1 77), (1 -1 78) (1-185) (1-1 86)-1 93) (1-1 94), (1-201) (1 -202), (2-1), (2-2), ( 2-3), (2-4), (2-10), (2-1-5), (2-1-6), (2-17-1), (2-19-1), (2-22) ,

(2—27), (2—28), (2—29), (2—3 1), (2—34), (2—39), (2—40), (2—4 1), (2—43), (2—46), (2—5 1), (2— 52 (2-53), (2--55 (2-57 (2-58) (2-59 (

 One

 2 1 60 (2-66) (2 — 7 1 (2--72 (2 ― (3) (2-75) (2-78), (2-83) (2-84) (2-85) — 87 (2-9 (Δ− 95 (2− 96 (2-97) O

 , (― Q no (2-102), (r

0 1

 Δ 丄 U / 1, Δ 丄 1, Δ—— 丄 L * y, — 1

 丄 丄 丄 (2— 1 1 3 (丄 丄 4 Δ—— 丄 丄 iD J (— 丄 丄 b, (2-122 (2— 127), (丄 ίί o1 ri Q,

 Δ—— 丄 ό 丄, (2-134 (2-139), (Otsu 4 U ^ 丄 4 丄 J (2-143), (2-146, 2-15-1), ( ― 丄; \ ― 丄 t> cS J (2-155) (2-158 (2-163), (0 ― 丄 b4 Δ 丄) 0 J (2-167) (2-1 69 ヽ (2-170), (― 丄 丄 J (2-172) (2-178) (2-183 ゝ (2-184), (-185) (2-187) (2-190), (2-195 (2-196), (

Δ1 197) (2-199) (2-202) (2-20 7 (2-208), (room 209), (2-2 1 1) (2-2 14) (2-2 1 9 (2—220), (5 o Δ 22 1) (2-223) (2-225), (2-226 (2—233), (

 234) (2-235) or (2-236), and more preferably,

 3 '-0, 4,-C-Ethylenegfucin (1-5)

3, -O, 4 ^J -C-ethylenecin (1-7)

 5, -O-Dimethoxytrityl-3'-O, 4'-C-ethylene-6-N- -F

0 (1-3 1)

 5,-0-Dimethoxytrityl-3'-O, 4'-C-ethylene-2-N -'- f ^ 1)

(1 — 35)

 3, 0, 4, -C-ethylene-2-N-isobutyryl (1-177),

 3 '-0, 4, -C-ethylene-6 -N 1 1 1 78

5 5'-O-Dimethoxytrityl-3'-0,4'-C-ethylene-2isobutyrylguanosine-2'-0- (2-cyanoethyl N, N-diisopropyl) phosphoramidite (1-185) ,

5 '-0-Dimethoxytrityl-3' -0, 4 '-C-ethylene-6-N-benzoyladenosine-2 '-O- (2-cyanoethyl N, N-diisopropyl) phosphoramidite (1-186),

 3 '-0, 4'-C-ethyleneperidine (2-1),

 3'-0, 4'-C-ethylene 5-methylperidine (2-2),

 3'-0, 4'-C-ethylene cytidine (2-3),

 3'-0, 4'-C-ethylene-5-methylcytidine (2-4),

 2 ', 5'-di-0-benzinole-3'-0,4'-C-ethyleneperidine (2-10),

 5 'dimethoxytrityl-3'-O, 4'-C-ethyleneperidine (2-15),

 5'-O-dimethoxytritinol-3'-0,4'-C-ethylene-5-methylperidine (2-27)

5'-O-dimethoxytrityl-3'-0,4'-C-ethylene-4-N-benzoylcytidine (2

— 39),

 5'-O-Dimethoxytritinole-3'-〇, 4'-C-ethylene-4- 4-benzoyl-5-methynolecitidine (2-51),

 3'-0, 4'-C-ethylene-4- 4-benzoylcytidine (2-225),

3'-0, 4'-C-ethylene-4- 4-benzoyl-5-methylcytidine (2-226),

5'- 0-Dimethoxytrityl-3 '-0, 4'-C-ethylene-peridine -2'-Ο- (2-cyanoethyl Ν, Ν-diisopropyl) phosphoramidite (2-233),

5'-0-Dimethoxytrityl-3'-0,4'-C-ethylene-5-methylperidine-2'-Ο- (2-cyanoethylΝ, Ν-diisopropyl) phosphoramidite (2-234),

5'-0-Dimethoxytrityl-3'-0,4'-C-ethylene-4- 4--benzoinolecitidine-2'-Ο- (2-cyanoethylΝ, Ν-diisopropyl) phosphoramidite (2-235 ), Or

 5'- 0-Dimethoxytrityl-3'-Ο, 4 'Ethylene-4-Ν-benzoyl-1-5-methylcytidine-2'-0- (2-cyanoethylΝ, Ν-diisopropyl) phosphoramidite (2

-236).

 [Best Mode for Carrying Out the Invention]

Compound (1) of the present invention can be produced by the following method or method. Α έ

(6) (1a)

 (1b) (1C) (1d)

B method

(3) (7) (8)

(9) (10)

 (") (1e) (1c)

In the methods A and X, X and Y represent the same or different protecting groups, Z represents an acyl group, and A Represents the same meaning as described above, and B ¹ represents a purine-9-yl group, a 2-oxo-1,2-dihydroxypyrimidine-11-yl group or a substituent having a substituent selected from the aforementioned α group. purin 9 Iru group or 2-Okiso one 1, 2-dihydrazide Doropiri spermidine shows an 1-I group, those substituted with Amino groups are removed, beta ^2, the purine one 9 Iru group, 2- Okiso (I) 1,2-dihydroxypyrimidine- (1) a substituted purine having a monoyl group or a substituent selected from the aforementioned α group; (9) a monoyl group or 2-oxo-1,2-dihydroxypyrimidine. R ¹¹ represents a group that forms a leaving group together with an oxygen atom, excluding those substituted with an amino group protected with a protecting group for nucleic acid synthesis, except for those substituted with an amino group.

 The "protecting group" in the definition of X and Υ includes, for example, formyl, acetyl, propioninole, butylinole, isobutylinole, pentanoinole, vivaloyole, nok relinole, isovalerinole, octanoyl, nonanoyl, decanoyl, 3-methyl-nanol Nonanoinole, 3-Ethylocanol, 3,7-Dimethyloctanoyl, Pendecanoyl, Dodecanoyl, Tridecanoyl, Tetradecanol, Pentadecanoyl, Hexadecanoyl, 1-Methylpentadecanoyl, 14-Methyl Pentadecanoyl, 13, 13-Dimethyltetradecanoyl, Heptadecanoyl, 15-Methylhexadecanoyl, Octadecanoyl, 1 —Methylheptadecanoyl, Nonadecanoyl, Eicosanoyl and Henicosanoyl Alkylcarbonyl groups, carboxylated alkylcarbonyl groups such as succinoyl, glutaroirene, and adiboyl; halogeno lower alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl; lower alkoxy lower groups such as methoxyacetyl An “aliphatic acyl group” such as an alkylcarbonyl group or an unsaturated alkylcarbonyl group such as (Ε) -2-methyl-2-butenoyl;

Benzyl, α-naphthoyl, arylcarbonyl groups such as / 3-naphthoyl, 2-bromobenzoyl, halogenoarylcarbonyl groups such as 4-cyclobenzoyl, 2,4,6-trimethylbenzoyl, 4-toluoyl Such as lower alkyl ^ (aryl carbonyl group, lower alkoxylated aryl carbonyl group such as 4-anisyl, carboxylated group such as 2-carboxybenzoyl, 3-carboxybenzoyl, 4-carboxybenzoyl, etc. Nylated arylcarbonyl groups such as reelcarbonyl group, 4-nitrobenzoyl and 2-nitrobenzoylole; lower alkoxy groups such as 2- (methoxycarbonyl) benzoyl An "acyl-type" protecting group such as an "aromatic acyl group" such as a carboxylated arylcarbonyl group or an arylated arylcarbonyl group such as 4-phenylbenzoyl;

Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butynole, n-pentynole, isopentinole, 2-methylinobutynole, neopentynole, 1-ethynolepropyl, n-hexyl, isohexyl Xyl, 4-Methynolepentyl, 3-Methynolepentinole, 2-Methylpentyl, 1-Methylpentyl, 3,3-Dimethylbutyl, 2,2-Dimethinolebutyl, 1,1-Dimethylbutyl, 1,2-Dimethylbutyl "Lower alkyl groups" such as, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl;

1-propeninole, 2-propidinole, 1-methodinole 2-propidinole, 1-methodinole—1d-peptinole, 2-methinolex 1-propidinyl, 2-methinolend 2-pro Peninole, 2-ethynole 2-propenyl, 1-butenyl, 2-buteninole, 1-methinole-1-buteninole, 1-methyl-1-butenyl, 3-methylinone 2-butenyl, 1-ethynole 1-buteninole , 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methynol-1-pentenyl, 2-methinolay 2 — Pentenore, 3—Pentinole, 1—Methinole 3—Pentinole, 2—Methinole 3 _Pentenore, 4—Pentenore, 1-Methinole 1, 4-Pentenore, 2-Metinole 1—Pente Norre, 1 one to Kiseninore, 2 - to Kiseninore, to 3-Kiseninore, Kiseninore to 4, good UNA "lower alkenyl group" of Kiseninore to 5;

Arylcarbonyl groups such as benzoyl, α-naphthoyl and j3-naphthoyl; halogenoarylcarbonyl groups such as 2-bromobenzoyl and 4-cyclobenzoyl; 2, 4,

Lower alkylated arylcarbonyl such as 6-trimethylbenzoyl, 4-toluoyl, lower alkoxylated arylcarbonyl such as 4-anisyl, 2-carboxybenzoyl, 3-carboxybenzoyl, 4- Carboxylated arylcarbonyl groups such as carboxybenzoyl, nitrated arylcarbonyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl; lower alkoxyl groups such as 2- (methoxycarbonyl) benzoyl An "aromatic acyl group" such as an arylcarbonyl group such as a arylcarbonyl group or a 4-phenylbenzoyl group;

Tetrahydridopyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxy "Tetrahydrodrobilanyl or tetrahydrodrothiopyranyl groups" such as Trahidropyran-4-yl, Tetrahidrothiopyran-2-yl and 4-methoxytetrahydrodrothiopyran-4-yl; — {Tetrahydrofuranyl or tetrahydrothiofuranyl group such as yl ”;

 Tri-lower alkylsilyl groups such as trimethinoresilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-butylsilyl, triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl "Silyl groups", such as tri-lower alkylsilyl groups substituted with one or two aryl groups, such as yl, diphenylisopropylylsilyl, phenyldiisopropylsilyl; methoxymethyl, 1,1-dimethyl- "Lower alkoxymethyl groups" such as 1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl;

 "Lower alkoxylated lower alkoxymethyl group" such as 2-methoxyethoxymethyl; "Nologeno lower alkoxymethyl" such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl ;

 "Lower alkoxylated tyl groups" such as 1-ethoxyxyl, 1- (isopropoxy) ethyl;

 A "halogenated tyl group", such as 2,2,2-triclomethylethyl;

1 to 3 aryls such as benzinole, α-naphthinolemethinole, / 3-naphthinolemethinole, dipheninolemethinole, trifeninolemethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl A methyl group substituted with a group ";

 4-Methinolebenzyl, 2,4,6-trimethyolebenzinole, 3,4,5-Trimethynolebenzil, 4-Methoxybenzyl, 4-Methoxyphenyldiphenylmethyl, 4,4'-Dimethoxy “Lower alkyl, lower alkoxy, halogen, cyano groups such as pheninolemethinole, 2-nitrobenzene, 4-nitrobenzene, 4-chlorobenzene, 4-bromobenzyl, 4-cyanobenzyl A methyl group substituted with one to three aryl groups having a substituted aryl ring ";

Methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbo A "lower alkoxycarbonyl group" such as nil;

 Halogen, lower alkoxy or nitro groups such as 4-chloro, 2-chloro, 4-methoxy, 4-nitro, 2,4-dinitrophenyl Aryl group substituted with

A "lower alkoxycarbonyl group substituted with a halogen or a tri-lower alkylsilyl group" such as 2,2,2-trichloromouth ethoxycarbonyl and 2-trimethylsilylethoxycarbonyl;

"Alkenyloxycarbonyl" groups such as vinyloxycarbonyl and aryloxycarbonyl;

1 such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxy pendinoleoxycarbonyl, 2-dimethoxybenzoyloxycarbonyl, 4-nitrobenzoyloxycarbonyl And 2 "aralkyloxycarbonyl groups in which the aryl ring may be substituted with a lower alkoxy or a two-terminal group".

Examples of the “group forming a leaving group” of R ⁹ include a lower alkylsulfonyl group such as methanesulfonyl and ethanesulfonyl, a halogen-substituted lower alkylsulfonyl group such as trifluoromethanesulfonyl, and p-toluenesulfonyl. Examples of such an arylsulfonyl group include a methanesulfonyl group and a p-toluenesulfonyl group.

Examples of the “acyl group” in the definition of Z include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, nok relinole, isonok relinole, octanoyl, nonanoyl, decanoyl, 3-methylnonyl. Methyl nonanoinole, 3-ethyloctanol, 3,7-dimethyloctanol, nddecanol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, 1-methylpentadecanol, 14-methylpentanoyl Alkyls such as decanoyl, 13, 13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methyl heptadecanoyl, nonadecanoyl, eicosanoyl and henikosanoyl Carbonyl group, Sukushinoiru, glutaroyl, Karubokishii spoon § Honoré Kino Leka Honoré Boni Honoré groups such as Ajiboiru, chloroacetyl, dichloroacetyl acetyl Roh trichloroacetic acetylide Honoré, tri "Aliphatic acyl groups" such as halogeno lower alkylcarbonyl groups such as fluoroacetyl, lower alkoxy lower alkylcarbonyl groups such as methoxyacetyl, and unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl;

 Benzoyl, α-naphthoyl, arylcarbonyl groups such as i3-naphthoyl, 2-bromobenzoyl, halogenoarylcarbonyl groups such as 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, and 4-toluoyl Lower alkylated arylcarbonyl groups, such as lower alkylated arylcarbonyl groups, 4-anisole, and carboxylarylcarbonyl groups such as 2-carboxybenzoyl, 3-carboxybenzoyl, and 4-carboxybenzoyl. Groups such as 4-nitrobenzoyl and 2-nitrobenzoyl arylcarbonyl groups; lower alkoxycarbonylylarylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl, 4-phenyl "Aromas" such as arylated arylcarbonyl groups such as benzoyl Ashiru group "and the like.

 Hereinafter, each step of the A to B methods will be described in detail.

 (A-1 process)

 In this step, a compound (4) is produced by reacting a leaving group-introducing reagent with a compound (3) produced by a method C to E described below in an inert solvent in the presence of a base catalyst. It is.

Solvents used include, for example, aliphatic hydrocarbons such as hexane, heptane, lignoin, petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, chloroform Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, dichlorobenzene, dichlorobenzene: esters such as ethyl ethyl formate, ethyl ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl ether Ethers such as toluene, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether; ketones such as acetone, methylethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; and nitrethane and nitrobenzene. Nitro compounds such as acetonitrile and isobutyronitrile; nitrinoles; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone; Amides such as N-methylpyrrolidinone and hexamethylphosphorotriamide; sulfoxides such as sulfolane; ability to raise pyridines; Suitably, it is pyridine.

 The base catalyst used is preferably a base such as triethylamine, pyridine or dimethylaminopyridine.

 Examples of the leaving group-introducing reagent used include alkylsulfonyl halides such as methanesulfonyl chloride and ethanesulfonyl bromide; and arylsulfonyl halides such as p-toluenesulfonyl chloride. Preferred are methanesulfonyl chloride and p-toluenesulfonyl chloride.

 The reaction temperature varies depending on the starting compound, solvent, leaving group-introducing reagent and base catalyst used, but is usually 0 to 50 ° C, preferably 10 to 4 CTC.

 The reaction time varies depending on the starting compound used, the solvent, the leaving group-introducing reagent, the base catalyst, and the reaction temperature, but is usually 10 minutes to 24 hours, preferably 1 to 10 hours. It is. After completion of the reaction, the target compound (4) of this reaction is, for example, neutralizing the reaction solution, concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and containing the target compound. The organic layer is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 (A—2 steps)

 This step is a step of reacting the compound (4) produced in the step A-1 with an acid anhydride in a solvent in the presence of an acid catalyst to produce a compound (5).

 Examples of the solvent used include ethers such as getyl ether, dioxane, and tetrahydrofuran; nitrinoles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide; Amides such as N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide; organic acids such as acetic acid; Is preferably acetic acid.

 Examples of the acid catalyst to be used include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, and preferred is sulfuric acid (particularly, concentrated sulfuric acid).

Examples of the acid anhydride to be used include anhydrides of lower aliphatic carboxylic acids such as acetic anhydride and propionic anhydride, and acetic anhydride is preferred. The reaction temperature varies depending on the starting compound, solvent, acid catalyst and acid anhydride used, but is usually 0 ° C to 50 ° C, preferably 10 to 4 (TC).

 The reaction time varies depending on the starting compound used, the solvent, the acid catalyst, the acid anhydride and the reaction temperature; it is usually from 10 minutes to 12 hours, preferably from 30 minutes to 3 hours. .

 After completion of the reaction, the target compound (5) of this reaction is obtained, for example, by concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and separating the organic layer containing the target compound. After drying over anhydrous magnesium sulfate or the like, the solvent is distilled off.

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography or the like.

 (A—3 steps)

 In this step, the compound (5) produced in step A-2 in an inert solvent in the presence of an acid catalyst can be added to the literature (H. Vorbueggen, K. Krolikiewicz and B, Bennua, Chem. Ber., 114, This is a step of producing a compound (6) by reacting a trimethylsilylated form corresponding to a desired purine or pyrimidine optionally having a substituent, prepared according to 1234-1255 (1981)).

 Solvents used include aromatic hydrocarbons such as benzene, toluene and xylene; halogens such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, cyclobenzene, and dichlorobenzene. Hydrocarbons; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone Amides such as xamethyl phosphorotriamide; carbon sulfide and the like, but preferably 1,2-dichloroethane.

The acid catalyst used, for _{example, A1C1 3, SnCl 4, TiCl} 4, ZnCl 2, BF 3, can be mentioned a Lewis acid catalyst such as Torifuruorome Tan acid trimethylsilyl, preferably, triflumizole Ruo b methane Trimethylsilyl sulfonate.

 The reaction temperature varies depending on the starting compound, solvent and acid catalyst used, but is usually from 0 ° C to 100 ° C, preferably from 50 ° C to 80 ° C.

The reaction time varies depending on the starting compound used, the solvent, the acid catalyst, and the reaction temperature, but is usually 1 hour to 24 hours, and preferably 1 hour to 8 hours. After completion of the reaction, the target compound (6) of this reaction is obtained, for example, by concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and separating the organic layer containing the target compound. It is obtained by drying with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 (A—4 processes)

This step, A- 3 compound produced in step performs cyclization reaction with 3 '0H group and OR ⁹ groups are deprotected simultaneously with the removal of the protecting group Y of (6), compounds of the present invention (la) This is the process of manufacturing.

 The method of deprotection varies depending on the type of protecting group, but is not particularly limited as long as it does not cause other side reactions. For example, "Protective Groups in Organic Synthesis (Theodora W. Greene, 1981, A Wiley-Interscience Publication).

 In particular, when the protecting group for the hydroxyl group is an aralkyl group or an aralkyloxycarbonyl group, it is usually contacted with a reducing agent in a solvent (preferably, at room temperature under a catalyst at room temperature). Reduction) A method of removing or using an oxidizing agent is preferred. The solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in the reaction. Examples of the solvent include alcohols such as methanol, ethanol and isopropanol, and alcohols such as getyl ether, tetrahydrofuran and dioxane. Ethers, aromatic hydrocarbons such as toluene, benzene, and xylene; aliphatic hydrocarbons such as hexane and cyclohexane; esters such as ethyl acetate and propyl acetate; fatty acids such as acetic acid Or a mixed solvent of these organic solvents and water is preferred.

 The catalyst to be used is not particularly limited as long as it is usually used for a catalytic reduction reaction, but is preferably palladium carbon, palladium hydroxide, Raney nickel, platinum oxide, white gold black, and rhodium. Aluminum monoxide, triphenylphosphine-rhodium chloride, and palladium monosulfate are used.

 The pressure is not particularly limited, but it is usually 1 to 10 atm.

The reaction temperature and reaction time vary depending on the starting material, solvent, type of catalyst, etc. From 100 to 100 ° C. for 5 minutes to 24 hours.

 In particular, when the protecting group for the hydroxyl group is a p-methoxybenzyl group, the method of removing by oxidation in a solvent is generally preferred.

 The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction, but is preferably a water-containing organic solvent.

 Suitable examples of such organic solvents include ketones such as acetone, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, nitriles such as acetonitrile, geethylether, and tetrahydrofuran. And ethers such as dioxane, amides such as dimethylformamide, dimethylacetamide and hexamethylphosphorotramide, and sulfoxides such as dimethylsulfoxide.

 The oxidizing agent to be used is not particularly limited as long as it is a compound used for the oxidation, but is preferably, for example, potassium persulfate, sodium persulfate, ammonium cellium nitrate (CAN), 2, 3 -Dichloro mouth-5,6-dicyano-p-benzoquinone (DDQ) is used.

 The reaction temperature and reaction time vary depending on the type of the starting material, the solvent and the catalyst, etc., but are usually from 0 to 150 ° C. for from 10 minutes to 24 hours.

 After completion of the reaction, the target compound (la) of this reaction is obtained, for example, by concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and separating the organic layer containing the target compound. After drying over anhydrous magnesium sulfate or the like, the solvent is distilled off.

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 (A-5 process)

 In this step, the protective group X of the compound (la) obtained in step A-4 is removed in an inert solvent to produce a compound (lb).

 The method of deprotection varies depending on the type of protecting group, but is not particularly limited as long as it does not cause other side reactions. For example, "Protective Groups in Organic Synthesis" (by Theodora W. Greene, Peter GM Wuts) , 1999, published by A Wiley-Interscience Publication).

In particular, when the protecting group is (1) an “aliphatic acyl group or an aromatic acyl group”, (2) “1 to 3 A methyl group substituted with one to three aryl groups, wherein the aryl group is substituted with a lower alkyl, lower alkoxy, halogen, or cyano group; or, (3) a silyl group In this case, the following method can be used.

 (1) In the case of an aliphatic acyl group or an aromatic acyl group, the reaction is usually carried out by reacting a base in an inert solvent.

 The solvent to be used is not particularly limited as long as it is easily mixed with water, does not inhibit the reaction, and dissolves the starting material to a certain extent or more. For example, hydrated or anhydrous dimethylformamide, dimethylacetate Amides such as amides; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane or carbon tetrachloride; ethers such as tetrahydrofuran, getylether and dioxane. , Preferably ethers

More preferably, it is tetrahydrofuran.

 Examples of the base used include alkali metal hydroxides such as lithium hydroxide, potassium hydroxide and sodium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium methoxide and sodium ethoxide. Alkali metal alkoxides; ammonia water, and ammonia solutions such as ammonia / methanol solutions. The reaction temperature is between 0 ° C. and 60 ° C., preferably between 20 ° and 40 ° C.

 The reaction time is 10 minutes to 24 hours, preferably 1 to 3 hours.

 After completion of the reaction, the target compound (1b) of this reaction is obtained, for example, by concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and separating the organic layer containing the target compound. It is obtained by drying over anhydrous magnesium sulfate or the like, and then distilling off the solvent.

 The obtained compound can be further purified, if necessary, by a conventional method, for example, recrystallization or silica gel column chromatography.

 (2) The protecting group is substituted with `` methyl group substituted with 1 to 3 aryl groups '' or `` 1 to 3 aryl groups substituted with aryl groups with lower alkyl, lower alkoxy, halogen, and cyano groups. In the case of “a methyl group”, the reaction is performed using a reducing agent in an inert solvent.

Examples of the solvent used include alcohols such as methanol, ethanol and isopropanol; ethers such as getyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene, benzene and xylene; Hexane, like cyclohexane Preferred are aliphatic hydrocarbons; esters such as ethyl acetate and propyl acetate; organic acids such as dicarboxylic acid; or mixed solvents of these organic solvents and water.

 The reducing agent to be used is not particularly limited as long as it is usually used in a catalytic reduction reaction, but is preferably palladium carbon, Raney nickel, platinum oxide, platinum black, rhodium aluminum monoxide, Triphenylphosphine rhodium monochloride and palladium-barium sulfate are used.

 The pressure is not particularly limited, but it is usually 1 to 10 atm.

 The reaction temperature is from 0 ° C. to 60 ° C., preferably from 20 ° C. to 40 ° C.

 The reaction time is 10 minutes to 24 hours, preferably 1 to 3 hours.

 After completion of the reaction, the target compound (1b) of the reaction is, for example, by removing the reducing agent from the reaction mixture.

A water-immiscible organic solvent such as ethyl acetate is added, and after washing with water, an organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 In the case of "a methyl group substituted with three aryl groups", that is, in the case of a trityl group, the reaction can be performed using an acid.

 In this case, the solvent used is an aromatic hydrocarbon such as benzene, toluene, or xylene; such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, or dichlorobenzene. Halogenated hydrocarbons; alcohols such as methanol, ethanol, isopropanol and tert-butanol; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethyl Amides such as acetoamide, N-methyl-12-pyrrolidone, N-methylpyrrolidinone, and hexamethylphosphorotriamide; and organic acids such as acetic acid. Acids (especially acetic acid) or alcohols (especially tert-butanol).

 The acid used is preferably acetic acid or trifluoroacetic acid.

 The reaction temperature is from 0 ° C to 60 ° C, and preferably from 20 ° C to 40 ° C.

The reaction time is 10 minutes to 24 hours, preferably 1 to 3 hours. After completion of the reaction, the target compound (1b) of this reaction is obtained by, for example, neutralizing the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and separating the organic layer containing the target compound. Then, after drying over anhydrous magnesium sulfate, the solvent is distilled off.

If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 (3) When the protecting group is a "silyl group", a compound that produces a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydropyridine monopyridine, potassium fluoride, etc. Or an organic acid such as sulfuric acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or an inorganic acid such as hydrochloric acid.

 In addition, when removing with a fluorine anion, the reaction may be accelerated by adding an organic acid such as formic acid, acetic acid or propionic acid.

 The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. Preferably, it is dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol. Ethers such as dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; water; organic acids such as acetic acid; and mixed solvents thereof.

 The reaction temperature is from 0 ° C to 100 ° C, preferably from 20 ° C to 70 ° C.

 The reaction time is 5 minutes to 48 hours, preferably 1 to 24 hours.

 After completion of the reaction, the target compound (1b) of this reaction is obtained, for example, by concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and separating the organic layer containing the target compound. After drying over anhydrous magnesium sulfate, the solvent is distilled off.

The obtained compound can be further purified, if necessary, by a conventional method, for example, recrystallization or silica gel gel chromatography.

 (Step A-6)

In this step, a step of removing the protecting group Z present in the compound (lb) obtained in step A-5 in an inert solvent in the presence of a base catalyst to produce the compound (1c) of the present invention It is.

Solvents used include water; pyridines; acetonitrile, isopyronitrile and the like. Nitriles such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, and amides such as hexamethylphosphorotriamide Or a mixed solvent thereof, preferably a mixed solvent of water and pyridine.

 Examples of the base catalyst to be used include alkali metal hydroxides such as sodium hydroxide and hydroxylated hydroxide; alkali metal carbonates such as sodium carbonate and carbonated carbon; sodium methoxide; sodium methoxide And alkali metal alkoxides; ammonia water, etc .; and preferably alkali metal hydroxides (particularly sodium hydroxide).

 The reaction temperature varies depending on the starting compound, solvent and acid catalyst used, but is usually from OT to 50 ° C, preferably from 10 ° C to 30 ° C. C.

 The reaction time varies depending on the used starting compound, solvent, acid catalyst and reaction temperature, but is usually 1 minute to 5 hours, preferably 1 minute to 30 minutes.

 After completion of the reaction, the target compound (1a) of this reaction is obtained, for example, by concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and separating the organic layer containing the target compound. After drying over anhydrous magnesium sulfate, the solvent is distilled off.

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

Further, when the functional group on B ¹ is deprotected in the usual way as required (e.g., "Prote ctive Groups in Organic Synthesis " (Theodora W. Greene, Peter GM Wuts al, 1999, A The functional group is protected again according to the method described in Wiley-Interscience Publication).

 (A—7 steps)

In this step, the compound (I d) of the present invention is reacted with a deprotection reagent in an inert solvent to remove the protecting group present in B ¹ of the compound (lc) obtained in step A-6. This is the manufacturing process. The method of deprotection varies depending on the type of the protecting group.

* JJ, Protective Groups in Organic Synthesis (Theodora W. Greene, 1981, A Wiley-Interscience Publication), The power to do.

 In particular, when the protecting group is an aliphatic acyl group or an aromatic acyl group, it can be carried out by the following method.

 That is, when the protecting group is an aliphatic acyl group or an aromatic acyl group, the reaction is usually carried out by reacting a base in an inert solvent.

 The solvent used is not particularly limited as long as it is easily miscible with water, does not inhibit the reaction, and dissolves the starting material to a certain extent or more, for example, water-containing or anhydrous alcohols such as methanol and ethanol. Amides such as dimethylformamide and dimethylacetamide; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane or carbon tetrachloride; tetrahydrofuran, getyl ether And ethers such as dioxane, preferably alcohols, and more preferably methanol.

 Examples of the base used include alkali metal hydroxides such as lithium hydroxide, potassium hydroxide and sodium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium methoxide and sodium ethoxide. Alkali metal alkoxides; and ammonia, and preferably ammonia.

 The reaction temperature is from 0 ° C to 50 ° C, preferably from 10 ° C to 40 ° C.

 The reaction time is from 10 minutes to 24 hours, preferably from 10 to 15 hours. After completion of the reaction, for example, the reaction mixture is concentrated, an immiscible organic solvent such as water and ethyl acetate is added, and after washing with water, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate, and the like. Obtained by distillation.

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 In addition, (A-5 step) and (A-6 step), (A-5 step) to (A-7 step), or (A-6 step) and (A-7) step, if desired, The target compound (lb), (lc) or (Id) can be obtained from (la) or (lb) in a one-step reaction.

 (B-1 process)

In this step, the compound (3), which can be produced by the methods C to E described below, is prepared in an inert solvent. In this step, the protecting group Y is removed by reacting with a deprotecting reagent to produce a compound (7).

 The method of deprotection varies depending on the type of the protecting group, but is not particularly limited as long as it does not cause other side reactions; for example, "Protective Groups in Organic Synthesis (Theodora W. Greene, 1981, published by A Wiley-Interscience Publication).

 In particular, when the protecting group for the hydroxyl group is an aralkyl group or an aralkyloxycarbonyl group, it is usually contacted with a reducing agent in a solvent (preferably at room temperature under a catalyst; (Catalytic reduction) A method of removing or using an oxidizing agent is preferable. The solvent used in the removal by catalytic reduction is not particularly limited as long as it does not take part in the reaction. Examples of alcohols such as methanol, ethanol, and isopropanol, dimethyl ether, tetrahydrofuran and dioxane Such as ethers, aromatic hydrocarbons such as toluene, benzene, xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, and fatty acids such as acetic acid Or a mixed solvent of these organic solvents and water is preferred.

 The catalyst to be used is not particularly limited as long as it is usually used in a catalytic reduction reaction, but is preferably palladium carbon, palladium hydroxide, Raney nickel, platinum oxide, white gold black, and rhodium. -Aluminum oxide, triphenylphosphine-rhodium chloride, palladium monosulfate barium is used.

 The pressure is not particularly limited, but it is usually 1 to 10 atm.

 The reaction temperature and reaction time vary depending on the starting material, solvent, type of catalyst and the like, but are usually 0 to 10 Ot: for 5 minutes to 24 hours.

 In particular, when the protecting group for the hydroxyl group is a p-methoxybenzyl group, the method of removing by oxidation in a solvent is generally preferred.

 The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction, but is preferably a water-containing organic solvent.

Suitable examples of such an organic solvent include ketones such as acetone, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, nitriles such as acetonitrile, getyl ether, tetrahydrofuran, Ethers such as dioxane, Examples include amides such as tilformamide, dimethylacetamide, hexamethylphosphorotriamide, and sulfoxides such as dimethylsulfoxide.

 The oxidizing agent to be used is not particularly limited as long as it is a compound used for the oxidation. Preferably, the oxidizing agent is persulfuric acid lime, sodium persulfate, ammonia cell silicate (CAN), 2, 3 -Dichloro-5,6-dicyano-p-benzoquinone (DDQ) is used.

 The reaction temperature and reaction time vary depending on the type of the starting material, the solvent and the catalyst, etc., but are usually from 0 to 150 ° C. for from 10 minutes to 24 hours.

 (B— 2 processes)

This step is a step of producing a cyclized compound (8) by reacting the leaving group-introducing reagent with the compound (7) produced in the step B-1 in an inert solvent.

 Examples of the solvent to be used include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, and chloride. Halogenated hydrocarbons such as mouth form, carbon tetrachloride, dichloroethane, cyclobenzene, and cyclobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; Ethers such as disopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethinoleether; ketones such as acetone, methylethyl ketone, methyl isobutynoletone, isophorone, cyclohexanone; nitrethane, nitrobenzene Nitro compounds such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-1- Amides such as pyrrolidone, N-methylpyrrolidinone, and hexamethylphosphorotriamide; sulfoxides such as sulfolane; pyridines are preferred, and pyridine is preferred.

 The base catalyst used is preferably a base such as triethylamine, pyridine or dimethylaminoviridine.

Examples of the leaving group-introducing reagent to be used include alkylsulfonyl halides such as methanesulfonyl chloride and ethanesulfonylonyl chloride: arylsulfonyl halides such as p-toluenesnolephonyl chloride. Preferably, methanesulfonate These are Luck mouth and p-toluenesulfoyluc mouth.

 The reaction temperature varies depending on the starting compound used, the solvent, the leaving group-introducing reagent, and the base catalyst, but is usually from 0 ° C to 50 ° C, and preferably from 10 ° C to 40 ° C. .

 The reaction time varies depending on the starting compound used, the solvent, the leaving group-introducing reagent, the base catalyst and the reaction temperature, but is usually from 10 minutes to 24 hours, preferably from 1 to 10 hours. It is. After completion of the reaction, the target compound (8) of this reaction is, for example, neutralizing the reaction solution, concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and containing the target compound. The organic layer is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 (B— 3 steps)

This step is a step of reacting the compound (8) produced in the step B-2 with an acid anhydride in a solvent in the presence of an acid catalyst to produce a compound (9).

 This step is performed according to (A-2 step).

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 (B— 4 processes)

This step is a step of removing the protecting group X of the compound (9) produced in the step B-3 in an inert solvent to produce the compound (10).

 This step is performed according to (Step A-5).

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization or silica gel column chromatography.

 (B— 5 steps)

In this step, the compound (10) produced in the step B-4 is reacted with an acid anhydride, an acid chloride or a carboxylic acid in an inert solvent in the presence or absence of a base catalyst to give the compound ( This is the process for manufacturing 11).

As the solvent used, preferably, aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, and cyclobenzene are used. Halogenated hydrocarbons such as benzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and dimethoxetane Ethers such as diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; two-mouth compounds such as nitroethane and nitropenbenzene; acetonitrile Ditolyls, such as isobutyronitrile; amides, such as formamide, dimethylformamide (DMF), dimethylacetamide, hexamethylphosphorotriamide; and dimethylsulfoxide, sulfolane. Aliphatic tertiary amines such as trimethylamine, triethylamine and N-methylmorpholine; aromatic amines such as pyridine and picoline; more preferably, halogenated hydrocarbons (particularly methylene chloride); De), aromatic amines (especially pyridines).

 The base used in the present method includes, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; and alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, and lithium hydrogen carbonate. Alkali metal hydrides such as lithium hydrogen hydride, sodium hydride, hydrogen hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, lithium hydroxide; lithium methoxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide; triethylamine, tributinoleamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine , N, N-dimethylaniline, N, N-jet Luaniline, 1,5-diazabicyclo [4.3.0] nona-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] —7—Organic amines such as pendene (DBU), preferably organic amines (particularly preferably triethylamine).

 Examples of the carboxylic acid to be used include lower aliphatic carboxylic acids such as hydroxy acid and propionic acid, and acetic acid is preferred.

Particularly when a carboxylic acid is used, a dehydration-condensation reagent can be used. (a) Phosphoric esters such as getyl phosphoryl cyanide, diphenyl phosphoryl azide, dimethyl cyanophosphate;

 (b) carbodimids such as 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide; the carbodimids And a combination of the following bases; N- such as the above-mentioned carbodiimides and N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboxyimide A combination of hydroxys;

 (c) Combination of disulfides such as 2,2'-dipyridyl disulfide and 2,2'-dibenzothiazolinole disulfide with phosphines such as triphenylphosphine and tributylphosphine;

 (d) N, N'-disuccinimidyl carbonate, di-2-pyridyl carbonate-, S, S'-bis (1-fueneru 1H-te torazo-1ru 5-yl) Like dithiocarbonate Carbonates:

 (e) N, N'-phosphinic chlorides such as bis (2-oxo-l3-oxazolidinyl) phosphinic chloride;

 (f) N, N'-disuccinimidyloxalate, N, N 'diphthalimidoxalate, N, N'-bis (5-norbornene-1,2,3-dicarboximidinole) oxalate, 1,1'-bis (Benzotriazolyl) oxalate, 1,1'-bis (6-benzobenzotriazolyl) oxalate, 1,1'-bis (6-trifluoromethylbenzotriazolyl) oxalate Class;

 (g) a combination of the above phosphines and azodicarboxylate ester or azodicarboxyamide such as 1,1 ′-(azodicarbonyl) dipiperidine;

(h) N-Ethyl-5-phenylisoxazolidinum 3'-Sulfonate-like N-lower alkyl-5-arylisoxazolidinum-3'-Sulfonates (i) diheteroaryl diselenides such as di-2-pyridyl diselenide; (j) p-arylsulfonyl triazolides such as p-nitrobenzene sulphonyl triazolide;

 (k) 2-halo-1-lower alkylpyridinium halides, such as 2-chloro-1-methylpyridinyl amide;

 (1) imidazoles such as 1,1'-oxalyldiimidazole and N, N'-carbonyldiimidazole;

 (m) 3 —Ethyl-2 —chloro-benzothiazolium fluoroborate, such as 3—lower alkyl—2 —halogen-benzothiazolium fluoroborate; (n) 3 —methyl-benzothiazole-2 —cellon Una 3-lower alkyl-benzothiazolu-2-elones;

 (o) Phosphates such as pheninoresin chlorinated phosphates, polyphosphate esters, and the like;

 (p) halogenosulfonylyl cyanates, such as black-mouthed sulfonyl acids;

 (q) Trimethylsilinorechloride, triethylsilinorechloride, and other genocylanes;

 (r) Lower alkenyl sulfonyl halides, such as methanesulfonyl chloride; (s) N, N, N ', Ν' —, Ν, Ν ', such as tetramethyl chlorinated formamide chloride , N′-tetra lower alkylhalogenoformamide media chlorides, and preferably, carbodiimides, and phosphines and azodicarboxylates or azodicarboxyamides are preferred. It is a combination of

 Examples of the acid anhydride to be used include anhydrides of lower aliphatic carboxylic acids such as acetic anhydride and propionic anhydride, and acetic anhydride is preferred.

 Examples of the acid chloride to be used include lower aliphatic carboxylic acid chlorides such as acetyl chloride and propionic acid chloride, and acetyl chloride is preferred.

The reaction temperature depends on the starting compound used, solvent, catalyst, carboxylic acid, carboxylic acid chloride It is usually from 0 ° C. to 150 ° C., and preferably from 20 ° C. to 100 ° C. The reaction time varies depending on the starting compound, solvent, catalyst, carboxylic acid, carboxylic acid chloride, acid anhydride and reaction temperature used, but is usually from 10 minutes to 12 hours, preferably from 30 minutes. 3 hours.

 After completion of the reaction, the target compound (11) of this reaction is obtained, for example, by concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and separating the organic layer containing the target compound. After drying over anhydrous magnesium sulfate or the like, the solvent is distilled off.

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 (B— 6 processes)

 In this step, compound (11) produced in step B-5 in an inert solvent in the presence of an acid catalyst was added to the literature (H. Vorbrggen, K, Krol ikiewicz and B, Bennua, Chem. Ber., 114 , 1234-1255 (1981)) to produce a compound (le) by reacting a trimethylsilylated compound corresponding to a purine or pyrimidine which may have a desired substituent.

 This step is performed according to (Step A-3).

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 (B-7 process)

This step is a step of producing a compound (lc) of the present invention by reacting a deprotection reagent in an inert solvent to remove Z of the compound (1e) obtained in step B-6. .

 This step is performed according to (Step A-6).

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography or the like.

Further, when the functional group on B ¹ is deprotected in the usual way as required (e.g., "Prote ctive Groups in Organic Synthesis " (Theodora W. Greene, Peter GM Wuts al, 1999, A The functional group is protected again according to the method described in “Wyley-Interscience Publication”).

Intermediate (3) described above can be produced by the following C to E methods.

(3b)

In the C to E methods, X and Y have the same meanings as described above, and R ¹ . Is a leaving group connected with an oxygen atom And E represents an ethylene, trimethylene or tetramethylene group, and W represents a single bond, a methylene or ethylene group.

^Examples of the group forming the leaving group for R ^1Q include the same groups as those described above for R ⁹ , preferably a trifluoromethanesulfonyl group.

R ¹² and R ¹³ are the same and represent a hydrogen atom or together represent an oxygen atom.

R ¹¹ has a carbon number of 1 to 4 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and tert-butyl when R ¹² and R ¹³ together represent an oxygen atom; And preferably a methyl group, and when R ¹² and R ¹³ are the same and are hydrogen atoms, an aralkyl group such as a benzyl group; an alkoxyalkyl group such as a methoxymethyl group A benzyloxymethyl group such as a benzyloxymethyl group or an aralkyloxymethyl group such as a benzyloxymethyl group; an alkoxyalkoxyalkyl group such as a methoxyethoxymethyl group; t-butyldimethylsilyl, diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropyl It is possible to increase the silyl groups such as Rushiriru.

 Compound (12), which is a starting compound used in Method C or Method D, can be produced by the following method.

That is, using commercially available 1,2,5,6-diisopropylidene D-glucose as a starting material, a known method (RD Youssefyeh, JPH Verheyden, JG Moffat t. J. Org. Chem., 44, 1301-1309) According to (1979)), a compound in which the “X” portion of the compound (12) corresponds to a hydrogen atom can be produced, and then produced according to a known method (JP-A-10-304889). In addition, commercially available 1,2,5,6-diisopropylidene D-glucose is used as a starting material, and a known method (Mersmaeker, Alain De, Leberton, Jacques, Jouanno, Chant al, Fritsh, Valerie, Wolf, Romain M , Wedenborn, Sebastian, Syn. Lett., 11, 1287-1290) (1997)) to synthesize 1,2-diisopropylidene D-arofuranois, and using this, a known method is used. (Wood, William W., Watson, Graham M., J. Chem. Soc. Chem. Commun., 21, 1599-1600 (1986))

Then, the aldehyde group is subjected to a reduction reaction according to a conventional method (for example, a method described in Hudlicky "Reductions in Organic Chemistry", Ellis Horwood (1984), etc.). Can also be obtained.

 Hereinafter, each of the steps C to E will be described in detail.

 ()

 (C-one process)

 This step is a step of reacting the compound (12) produced by the above method with a leaving group-introducing reagent in an inert solvent in the presence of a base catalyst to produce a compound (13).

 This step is performed in the same manner as in (A-1).

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 (C-1 two steps)

 This step is a step of reacting the compound (13) produced in Step C-11 with an cyanating reagent in an inert solvent to produce the compound (14).

 Solvents used include, for example, amides such as dimethylformamide and dimethylacetamide; halogenated carbons such as methylene chloride, chloroform, 1,2-dichloroethane or tetrachloroanilide. Hydrogens; ethers such as tetrahydrofuran, getyl ether, and dioxane; acetonitrile; dimethyl sulfoxide; and the like, preferably amides (dimethylformamide).

 Examples of the cyanation reagent to be used include KCN, NaCN, and trimethylsilane cyanide, and NaCN is preferred.

 The reaction temperature varies depending on the starting compound, solvent and cyanating reagent used, but is usually from 0 ° C to 100 ° C, and from 30 ° C to 7 (TC).

 The reaction time varies depending on the used starting compound, solvent, cyanating reagent and reaction temperature, but is usually 30 minutes to 12 hours, and preferably 1 to 3 hours.

After completion of the reaction, the target compound (14) of this reaction is obtained, for example, by concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and separating the organic layer containing the target compound. It is obtained by drying with anhydrous magnesium sulfate or the like, and then distilling off the solvent. If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 (C-1 three steps)

 This step is a step of producing a compound (15) by reacting the compound (14) produced in the C-12 step with a reducing agent in an inert solvent.

 Solvents used include, for example, halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane or carbon tetrachloride; hexane, heptane, rig mouth oil, petroleum ether, and the like. Aliphatic hydrocarbons; Aromatic hydrocarbons such as benzene, toluene and xylene; Aethenoles such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycol dimethyl ether

Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; and the like, preferably halogenated hydrocarbons (particularly, methylene chloride). is there.

 Examples of the reducing agent to be used include diisobutylaluminum hydrogen, triethoxyaluminum hydrogen and the like, and preferred is diisobutylaluminum hydride.

 The reaction temperature varies depending on the starting compound, solvent and reducing agent used, but is from 110 ° C. to 150 °, preferably from −90 ° C. to 170 °.

 The reaction time varies depending on the used starting compound, solvent, reducing agent and reaction temperature, but is usually 30 minutes to 12 hours, and preferably 1 to 5 hours.

 After completion of the reaction, the target compound (15) of this reaction is obtained, for example, by concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and separating the organic layer containing the target compound. After drying over anhydrous magnesium sulfate or the like, the solvent is distilled off.

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 (C—4 processes)

This step is a step in which a compound (15) produced in step C-13 is reacted with a reducing agent in an inert solvent to produce compound (3a) which is one of the starting compounds for method A. is there. Examples of the solvent used include methanol, ethanol, n-propanol, isopropanol, _n- butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, and cyclohexane. Alcohols such as xanol and methinolysate sorb; power capable of raising acetic acid and the like; preferably alcohols (particularly, ethanol).

 Examples of the reducing agent used include: alkali metal borohydrides such as sodium borohydride and lithium borohydride; aluminum hydride compounds such as lithium aluminum hydride and lithium tritoxide aluminum; borane And the like, but preferably sodium borohydride.

 The reaction temperature varies depending on the used starting compound, solvent and reducing agent, but is usually from 0 C to 50 C, preferably from 10 C to 40 C.

 The reaction time varies depending on the used starting compound, solvent, reducing agent and reaction temperature, but is usually from 10 minutes to 12 hours, preferably from 30 minutes to 5 hours.

 After completion of the reaction, the target compound (3a) of this reaction is obtained by, for example, decomposing a reducing agent, concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and isolating the target compound. It is obtained by separating the organic layer containing, drying with anhydrous magnesium sulfate etc., and distilling off the solvent. If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 (Method D)

 (D-1 process)

 This step is a step of reacting the compound (12) produced by the above-mentioned method with an oxidizing agent in an inert solvent to produce the compound (16).

Examples of the solvent used include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, and chloroform Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, dichlorobenzene, and dichlorobenzene; esters such as ethyl ethyl formate, ethyl ethyl acetate, propyl acetate, butyl dicarboxylate, and getyl carbonate; getyl ether, diisopropyl ether ―Tenore, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethy Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone, and preferred are halogenated hydrocarbons (particularly methylene chloride). C).

 The oxidizing agents used include Swern oxidation reagents, Dess-Martin oxidation reagents, pyridine hydrochloride and chromium trioxide complex (pyridinium chromate chromate and pyridinium dichromate). Such a chromium trioxide complex and the like can be mentioned, and a preferable reagent is a reagent for swan oxidation (that is, dimethylsulfoxydoxalyl chloride).

 The reaction temperature varies depending on the starting compound, solvent, and oxidizing agent used, but is usually from −100 ° C. to −50 ° C., preferably from −100 ° C. to −70 ° C. is there.

 The reaction time varies depending on the used starting compound, solvent, oxidizing agent and reaction temperature, but is usually 30 minutes to 12 hours, and preferably 1 to 5 hours.

 After completion of the reaction, the target compound (16) of the present reaction is, for example, decomposing the oxidizing agent, concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and containing the target compound. The organic layer is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 (D—two processes)

 This step is a step of producing a compound (17) by reacting the compound (16) produced in the step D-1 with an increasing carbon reagent in an inert solvent.

Examples of the solvent used include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, and chloroform Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, dichlorobenzene, dichlorobenzene; esters such as ethyl ethyl formate, ethyl ethyl acetate, propyl acetate, butyl acetate, dimethyl acetate; getyl ether, diisopropyl ether Ethers such as phenol, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether; ketones such as acetone, methylethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; , Suitable Are halogenated hydrocarbons, especially methylene chloride.

The reagents used, Uitsutihi (Witt ig) reagent, e one Na one 'Emmons (Horner - Emm ons) reagent, Pita one Son (Peterson) _{reagent, TiCl 4 - CH 2 C1 2} -Zn system reaction agent, Examples of the reagent include a Tebbe reagent and the like, and preferred are a Peitig reagent, a Homon's reagent, and a Tebe reagent.

 The reaction temperature varies depending on the starting compound, solvent and carbon-enriching reagent used, but is usually from 120 ° C to 20 ° C, preferably from 0 ° C.

 The reaction time varies depending on the used starting compound, solvent, carbon-enriching reagent and reaction temperature, but is 30 minutes to 12 hours, preferably 1 to 5 hours.

 After completion of the reaction, the target compound (17) for this reaction is obtained, for example, by concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and separating the organic layer containing the target compound. After drying over anhydrous magnesium sulfate or the like, the solvent is distilled off.

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography or the like.

 (D—3 steps)

 In this step, a compound (3a) is produced by selectively introducing a hydroxyl group into the terminal carbon of the olefin of compound (17) produced in step D-2 in an inert solvent.

Solvents used include, for example, aliphatic hydrocarbons such as hexane, heptane, lignoin, petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, chloroform , Tetrasalt ^ ^ carbon, halogenated hydrocarbons such as dichloroethane, dichlorobenzene, dichlorobenzene; esters such as ethyl ethyl formate, ethyl acetate, propyl acetate, butyl nitrate, and getyl carbonate; getyl ether, Ethers such as disopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether; ketones such as acetone, methylethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone. Preferably, the force Tenore acids (particularly, as tetrahydrofuran) is. Examples of the reaction reagent to be used include borane, disiamylborane, sexylborane, 9-BBN (9-borabicyclo [3.3.1] nonane) and the like, preferably 9-BBN. The reaction temperature varies depending on the starting compound, solvent and reagent used, but is 0 C to 50 ^: 'C, preferably 10 to 40' ^: 'C.

 The reaction time varies depending on the used starting compound, solvent, reagent and reaction temperature, but is usually 6 to 48 hours, preferably 12 to 24 hours.

 After completion of the reaction, the target compound (3a) of this reaction is obtained by, for example, concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and separating the organic layer containing the target compound. After drying over anhydrous magnesium sulfate, the solvent is distilled off.

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 (Method E)

 (E—one process)

 This step is a step of producing a compound (18) by reacting the compound (16) produced in the step D-1 with an increasing carbon reagent in an inert solvent.

 Solvents used include, for example, aliphatic hydrocarbons such as hexane, heptane, lignoin, petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, chloroform Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, dichlorobenzene, dichlorobenzene; esters such as ethyl ethyl formate, ethyl ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl ether Ethers such as phenol, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycol dimethyl ether; and ketones such as acetone, methylethyl ketone, methyl isobutyl ketone, isophorone, and cyclohexanone. Is Ethers (particularly as tetrahydrofuran) and more preferably the force can be given such a halogenated hydrocarbon (particularly, Mechirenkurori de).

Examples of the carbon-enriching reagent used include Wittig reagents such as methyl triphenylphosphoranilideneacetate, ethoxycarbonylmethinole (triphenyl) phosphonium bromide, and methoxymethyltriphenylphosphonium chloride; Horner-Emmons reagents such as ethyl ester, 3-ethylethyl phosphonopropionate, and diphenylphosphonoacetic acid ethyl ester. The reaction temperature varies depending on the starting compounds, solvents and reagents used, but is usually 120 ^: 'C to 40, preferably 0 to 2O'C.

 The reaction time varies depending on the used starting compound, solvent, reagent and reaction temperature, but is 30 minutes to 12 hours, preferably 1 to 5 hours.

 After completion of the reaction, the target compound (18) of this reaction is obtained, for example, by concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and separating the organic layer containing the target compound. After drying over anhydrous magnesium sulfate or the like, the solvent is distilled off.

 The obtained compound can be further purified, if necessary, by a conventional method, for example, recrystallization or silica gel column chromatography.

 (E—2 processes)

 In this step, compound (18) produced in step E-1 is reacted with a reducing agent in an inert solvent to produce compound (19).

This step can be performed according to (2) of step A-5. However, when R ¹¹ is a benzyl group which may have a substituent and R ¹² and R ¹³ are hydrogen atoms, the compound (3b) must be directly produced by this step. Can be.

 (E—3 steps)

 In this step, compound (19) produced in step E-2 is reacted with a reducing agent in an inert solvent to produce compound (3b), which is one of the starting compounds of method A or method B This is the step of performing

(a) when R ¹² and R ¹³ together form an oxygen atom

Solvents used include, for example, methanol, ethanol, _n -propanol, isopropanol, _n -butanol, isobutanol, _t- butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellulose Alcohols such as Solve; acetic acid and the like can be mentioned, and alcohols (particularly, ethanol) are preferable.

Examples of the reducing agent to be used include an alkali metal borohydride such as lithium borohydride; an aluminum hydride compound such as lithium aluminum hydride and lithium triethoxide aluminum; and borane. Preferably, it is borane or lithium aluminum hydride. The reaction temperature varies depending on the used starting compound, solvent and reducing agent, but is usually 0 C to 50 C, preferably 10 to 4 (TC).

 The reaction time varies depending on the used starting compound, solvent, reducing agent and reaction temperature, but is usually from 10 minutes to 12 hours, preferably from 30 minutes to 5 hours.

 After completion of the reaction, the target compound (3b) of this reaction is obtained by, for example, decomposing a reducing agent, concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and isolating the target compound. It is obtained by separating the organic layer containing, drying with anhydrous magnesium sulfate or the like, and distilling off the solvent.

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

(b) When R ¹² and R ¹³ are hydrogen and R ¹¹ is other than a benzyl group

When R ¹¹ is a silyl group, it can be carried out according to the method (3) in Step A-5. R ¹¹ is an aralkyl group such as a phenethyl group; an alkoxyalkyl group such as a methoxymethyl group; an aralkyloxymethyl group such as a benzyloxymethyl group or a benzyloxymethyl group; In the case of an alkoxyalkoxyalkyl group such as a methoxyethoxymethyl group, an acid catalyst is used. Examples of the acid catalyst used in this case include organic acids such as p-toluenesulfonic acid, trifluoroacetic acid, and dichloroacetic acid. BF _3, A1C1 can increase the Lewis acid, such as _3.

 Examples of the solvent used include aromatic hydrocarbons such as benzene, toluene, and xylene; halogens such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, cyclobenzene, and dichlorobenzene. Hydrocarbons; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-12-pyrrolidone, N-methyl Amides such as pyrrolidinone and hexamethyl phosphorotriamide; and carbon sulfide. The reaction temperature varies depending on the starting compound, solvent and acid catalyst used, but is usually from 0 ° C to 50 ° C, preferably from 10 ° C to 40 ° C.

 The reaction time varies depending on the used starting compound, solvent, acid catalyst and reaction temperature, but is usually from 10 minutes to 12 hours, preferably from 30 minutes to 5 hours.

After completion of the reaction, the target compound (3b) of the present reaction is, for example, neutralizing the reaction mixture, and adding water and acetate. It is obtained by adding an immiscible organic solvent such as chill, washing with water, separating the organic layer containing the target compound, drying with anhydrous magnesium sulfate, and distilling off the solvent.

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 Using the compound (1) of the present invention, an oligonucleotide containing a modified nucleoside or a titanate derivative thereof can be produced by the method F described below.

Oligonucleotide

(twenty one)

In the method F, A represents the same meaning as described above, R ¹³ represents a hydroxyl-protecting group (particularly, a trityl group optionally substituted with a methoxy group), R ¹⁴ represents a phosphonyl group, A group formed by reacting a monosubstituted mono (alkoxy) phosphine or a disubstituted monoalkoxyphosphine described below.

 (F method)

 (F—one process)

 This step is a step of producing a compound (20) by reacting a compound (1c) produced by the method A with a protecting reagent in an inert solvent.

The solvent used is preferably an aromatic hydrocarbon such as benzene, toluene, or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, or chlorobenzene. Halogenated hydrocarbons such as benzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl nitrate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl butyl ether, tetrahydrofuran, dioxane, and dimethoxetane Ethers such as diethylene diol glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane, nitro benzene; acetonitrile; Nitrils such as disobutyronitrile; amides such as formamide, dimethylformamide (DMF), dimethylacetamide, and hexamethylphosphorotriamide; dimethylsulfoxide and sulfolane Aliphatic tertiary amines such as trimethylamine, triethylamine and N-methylmorpholine; aromatic amines such as pyridine and picoline; more preferably, halogenated hydrocarbons (particularly methylene chloride). De), aromatic amines (especially pyridines).

The protecting reagent to be used is not particularly limited as long as it can selectively protect only the 5'-position and can be removed under acidic and neutral conditions, but is preferably trityl chloride or monomethoxide. It is a trimethyl methyl halide such as citrityl chloride or dimethoxytrityl chloride, or a trimethyl alcohol such as dimethoxytrityl-0-triflate.

When a triarylmethyl halide is used as the protecting reagent, a base is generally used. In this case, the base used is a heterocyclic amine such as pyridine, dimethylaminopyridine, pyrrolidinopyridine, or trimethylamine. And tertiary amines such as triethylamine, preferably pyridine, dimethylaminopyridine and pyrrolidinopyridine.

 When a liquid base is used as the solvent, the base itself acts as a deoxidizing agent, so there is no need to add a new base.

The reaction temperature is usually 0 to 150 ° C, preferably 20 to 100 ° C, depending on the starting materials, reagents, solvents and the like used. The reaction time varies depending on the starting material, solvent, reaction temperature and the like to be used, but is usually 1 to 100 hours, preferably 2 to 24 hours. After completion of the reaction, the target compound (20) for this reaction is obtained, for example, by concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, and separating the organic layer containing the target compound. After drying over anhydrous magnesium sulfate or the like, the solvent is distilled off.

 If necessary, the obtained compound can be further purified by a conventional method, for example, recrystallization, silica gel column chromatography, or the like.

 (F—2 processes)

 In this step, the compound (20) produced in the step F-1 is reacted with a monosubstituted monocyclic (alkoxy) phosphine or a disubstituted alkoxyphosphine usually used for amidation in an inert solvent. This is a step of producing the compound (21).

 The solvent to be used is not particularly limited as long as it does not affect the reaction, but is preferably an ether such as tetrahydrofuran, geethylether, or dioxane; Halogenated hydrocarbons such as mouth form, carbon tetrachloride, dichloroethane, cyclobenzene, and dichlorobenzene.

 Examples of the mono-substituted monochloro (alkoxy) phosphines used include, for example, chloro (morpholino) methoxy phosphine, chloro (monorephorino) cyanoethoxyphosphine, chloro (dimethylamino) methoxy phosphine, Phosphines such as dimethylamino) cyanoethoxy phosphine, black mouth (diisopropylamino) methoxyphosphine, and black mouth (diisopropylamino) cyanoethoxyphosphine are preferred. (Monoreholino) cyanoethoxyphosphine, black mouth (diisopropylamino) methoxyphosphine, black mouth (diisopropylamino) cyanoethoxyphosphine.

 When mono-substituted mono- (alkoxy) phosphines are used, a deoxidizing agent is used. In this case, the deoxidizing agent used is a complex ring amine such as pyridine or dimethylaminopyridine. Aliphatic amines such as trimethylamine, triethylamine and diisopropylamine are preferred, and aliphatic amines (particularly diisopropylamine) are preferred.

Examples of the di-substituted monoalkoxyphosphines used include bis (diisopropylamino) cyanoethoxyphosphine, bis (getylamino) methanesulfonylethoxy Phosphines such as phosphine and bis (diisopropylamino) (2,2,2-trichloroethoxy) phosphine and bis (diisopropylamino) (4-chlorophenylmethoxy) phosphine; Is bis (diisopropylamino) cyanoethoxyphosphine.

 When disubstituted-alkoxyphosphines are used, an acid is used, and in that case, the acid used is preferably tetrazole, acetic acid or p-toluenesulfonic acid. Although the reaction temperature is not particularly limited, it is generally 0 to 80 ° C., and preferably room temperature. The reaction time varies depending on the starting materials, reagents, temperature and the like to be used, but is usually 5 minutes to 30 hours, preferably 30 minutes to 10 hours when the reaction is carried out at room temperature.

 After completion of the reaction, the target compound (21) of this reaction is obtained by, for example, appropriately neutralizing the reaction mixture, and removing any insoluble matter by filtration, followed by filtration with water and ethyl acetate. An immiscible organic solvent as described above is added, washed with water, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

 Alternatively, in this step, the compound (20) produced by F-1 in an inert solvent (preferably, a halogenated hydrocarbon such as methylene chloride) is added to the tris- (1,2,4-triazolyl) ) This is a process in which after the reaction of the phosphate, water is added and the mixture is H-phosphonated to produce compound (21).

 Although the reaction temperature is not particularly limited, it is generally −20 to 100. C, and preferably 10 to 40 ° C.

 The reaction time varies depending on the starting materials, reagents, temperature, etc. used, but is usually 5 minutes to 30 hours, preferably 30 minutes when reacted at room temperature.

After completion of the reaction, the target compound (21) of the present reaction is, for example, appropriately neutralizing the reaction mixture, and, if insolubles are present, removing by filtration and then mixing with water and ethyl acetate. It is obtained by adding an organic solvent, washing with water, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. (F-3 process)

 In this step, at least one compound (21) produced by F-2 and a commercially available phosphoramidite reagent necessary for producing an oligonucleotide analog having a desired nucleotide sequence are used. This is a step of producing the target oligonucleotide derivative on an automatic DNA synthesizer by a usual method.

 Oligonucleotide analogs having a desired nucleotide sequence can be obtained from a DNA synthesizer, for example, a phosphoramidite model 392 of Parkin Elma Inc. using a model 392 or the like (Nucleic Acids Research, 12, 4539 (1984)). It can be synthesized according to the method.

 In addition, if desired, when forming a chain, it reacts with trivalent phosphoric acid such as tetraethylthiuram disulfide (TETD, Applied Biosystems) and Beaucage reagent (Millipore) in addition to sulfur. Using a reagent that forms a salt, a carbonate derivative can be obtained according to the method described in the literature (Tetarhedron Letters, 32, 3005 (1991), J. Am. Chem. Soc., 112, 1253 (1990)). Can be done.

 The obtained crude oligonucleotide analog can be purified using an Oligopack (reverse phase chromatography column) and the purity of the purified product can be confirmed by HPLC analysis. The obtained oligonucleotide analog chain The length is usually from 2 to 50, preferably from 10 to 30, nucleoside units.

 The complementary strand-forming ability and nuclease enzyme resistance of the obtained oligonucleotide analogues can be examined according to the following method.

 (Test method 1)

 The obtained various oligonucleotide analogues and natural DNA having a complementary sequence are subjected to annealing treatment with an oligonucleotide consisting of RNA, and the melting temperature (Tm value) is measured. The ability of the oligonucleotide analogues of the present invention to form hybrids to DNA and RNA is examined.

The sample solution containing the same amount of the sodium phosphate buffer oligonucleotide analog and the natural complementary oligonucleotide is immersed in boiling water and slowly cooled to room temperature over time (annealing). In the cell chamber of a spectrophotometer (for example, Shimadzu UV-2100PC), Gradually increase the temperature from 20 ° C to 90 ° C and measure the UV absorption at 260 nm.

 (Test method 2) Measurement of nuclease enzyme resistance

The oligonucleotide is heated in a buffer with the addition of nuclease. Examples of nucleases include snake venom phosphodiesterase, endonuclease Pl, and endonuclease SI. The buffer is not particularly limited as long as it is a buffer suitable for the enzyme. For snake venom phosphodiesterase, Tris-HCl buffer, for endonuclease P1, sodium acetate buffer, etc. are used. If necessary, metal ions are added to the buffer. The metal I-one, M g ^{2 +} For snake venom phosphodiesterase, for Endonukurea Ichize Z n ² +, or the like is used. The reaction temperature is preferably from 0 to 100 ° C, more preferably from 30 to 50 ° C.

 After a certain time, stop the reaction by adding ethylenediaminetetraacetic acid (EDTA) and heating at 100 ° C for 2 minutes.

 To quantify the remaining amount of oligonucleotide, a method of labeling the oligonucleotide with a radioisotope or the like and quantifying the cleavage reaction product with a image analyzer or the like, and reverse-phase high performance liquid chromatography of the cleavage reaction product ( HPLC) or a method in which the cleavage reaction product is stained with a dye (such as ethidium bromide) and quantified by image processing using a computer.

Examples of the dosage form of the oligonucleotide analog containing one or more of the structures represented by the general formula (2) of the present invention include, for example, oral administration by tablets, capsules, granules, powders, syrups, or the like. parenteral administration by ai or suppository, etc., and these preparations include excipients (eg, sugar derivatives such as lactose, sucrose, dextrose, mannitol, sorbitol; corn starch, potato starch, _α- starch, Starch derivatives such as dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; organic shaping agents such as pullulan: and light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium meta-aluminum silicate Such as calcium hydrogen phosphate; calcium carbonate Carbonates such as um;. The inorganic excipients such as sulfuric acid salts, such as calcium sulfate can ani gel), lubricants (e.g., stearic acid, calcium stearate, stearyl Metal salts of stearic acid such as magnesium alginate; talc; colloidal silica; waxes such as veegum and gay; boric acid; adipic acid; sulfates such as sodium sulfate; dalicol; fumaric acid; sodium benzoate; Leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and the above starch derivatives. ), Binders (for example, hydroxypropynolecellulose, hydroxypropylmethinoresenolose, polyvinylinolepyrrolidone, macrogol, and compounds similar to the above-mentioned excipients). Disintegrants (eg, cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxy group methylcellulose, carboxymethylcellulose calcium, and internally crosslinked carboxymethylcellulose sodium; carboxymethylstarch, carboxymethylstyrene sodium) And chemically modified starch and cellulose such as cross-linked polyvinylpyrrolidone.), Stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; chlorobutanol and chlorobutanol). Alcohols such as jyl alcohol and phenol alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydrocholic acid; and sorbic acid.) It is manufactured by a well-known method using additives such as an agent (for example, a commonly used sweetener, an acidifier, a flavor, etc.) and a diluent.

The amount used depends on the symptoms, age, administration method, etc. For example, in the case of oral administration, the lower limit is 0.01 mg / kg body weight (preferably 0.1 mg / kg body weight) and the upper limit per dose. 1000 mg / kg body weight (preferably 100 _mg / kg body weight). In the case of intravenous administration, the lower limit is 0.001 mg / kg body weight (preferably 0.01 mg / kg body weight) per dose. ), as an upper limit, 100 m _g / kg body weight (preferably, Shi desirable to administer according 10 mg / k _g body weight) the symptoms per day to several times les.

Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, and Test Examples.

 [Example]

 (Example 1)

2'-0-Acetyl-5'-0-t-butinoresiphenylsilyl-3'-04'-C-ethylene-5-methynoleperidine (Exemplified Compound No. 2-29) 2'-0-Acetyl-3'-O-benzyl-4'-p-toluenesulfonyloxy etynole obtained in Reference Example 6 5'-0-t-butynolefifeninole resinole 5- Dissolve methinoredridine (120 mg, 0.145 ol) in methanol (10 ml), add 10% of 20% palladium hydroxide-carbon, and add the resulting reaction solution under a hydrogen atmosphere. The mixture was stirred at normal pressure for 2 days. After filtering the catalyst and evaporating the solvent of the filtrate under reduced pressure, the obtained residue was purified by silica gel chromatography (dichloromethane: methanol = 40: 1) to obtain a colorless amorphous substance (7 Omg, 0.1%). 24 ol, yield 85%).

Ή- thigh _{(400MHz, CDC1 3): 1.14} (9H, s), 1.43 (3H, s), 1.9K1H, dt, 8.0 and 13Hz), 2. 08 (1H, ddd, 4.8, 6.3 and 13Hz), 2 .16 (3H, s), 3.72 (1H, d, 11Hz), 3.97 (1H, dt, 4.8 and 8Hz), 4.11 (1H, m), 4.13 (1H, d, 11Hz), 4.64 (1H, d, 5.0Hz), 5.28 (1H, dd, 5.0 and 8.4Hz), 6.33 (1H, d, 8.4Hz), 7.4-7.7 (10H, m), 8.01 (1H, s).

FABMS (mNBA): 549 [M + H] ⁺

 (Example 2)

 5'-O-tbutyldiphenylsilyl-3'-0-_4'-C-ethylene-5-methinoredridine (Ex. Compound No. 2-31)

 Dissolve 1 O mg of potassium carbonate in a small amount of water, add 10 ml of methanol, and further add 2'-0-acetyl-5'-0_t-butyldiphenylsilyl-3'-0,4 obtained in Example 1. '-C-Ethylene-5-methylperidine (70 mg, 0.124 mmol) was dissolved and left for 3 hours. After the completion of the reaction, water and ethyl acetate were added, the layers were separated, and the organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a colorless solid (43 mg, 0.1 Ommol, yield 81%).

 -Thigh (400MHz, CDCI3): 1.11 (9H, s), 1.47 (3H, d, 1.5Hz), 1.95 (1H, dt, 8.4 and 13-3Hz), 2.10 (1H, ddd, 4.4, 6.3 and 13.3Hz) ), 2.93 (1H, d, 10Hz), 3.71 (1H, d, 11Hz), 4.06 (2H, m), 4.08 (1H, d, 11Hz), 4.28 (1H, m), 4.44 (1H, d, 5.2 Hz), 6.01 (1H, d, 7.9Hz), 7.4-7.7 (10H, m), 8.23 (1H, s).

FABMS (mNBA): 523 [M + H] *

 (Example 3)

3'- 0, 4'-C-ethylene-5-methylperidine (Example Compound No. 2-2) Under a stream of nitrogen, 5′-0-tbutyldiphenylsilyl-3′-0,4′-C-ethylene-5-methylperidine (19 mg, 0.0363 mmol) obtained in Example 2 was added to anhydrous tetrahydrofuran (19 mg). 2m1), and thereto was added a 1.0 M tetrabutylammonium fluoride tetrahydrofuran solution (0.05 ml, 0.05 mmol), and the mixture was stirred at room temperature for 90 minutes. After completion of the reaction, 0.5 ml of methanol was added, the solvent was distilled off, and the obtained residue was purified by silica gel chromatography (dichloromethane: methanol = 12: 1) to give a colorless solid (7 mg, 0.5%). 024 6 olol, yield 68%).

_{Ή-NMR (400MHz, CD 3} 0D): 1.89 (3H, s), 2.03 (2H, t, 6.9Hz), 3.69 (1H, d, 12Hz), 3.85 (1H, d, 12Hz), 4.02 (2H, t, 6.9Hz), 4.26 (1H, d, 4.9Hz), 4.31 (1H, dd, 4.9 and 7.9Hz), 5.97 (1H, d, 7.9Hz), 7.88 (1H, s).

FABMS (m BA): 285 [M + H] ⁺

 (Example 4)

 2'-O-Acetyl-5'-O-t-butyldiphenylsilyl-3'-0,4'-C-ethylene-6-N-benzoyladenosine (Exemplary Compound No. 1-37)

 Reference Example 2'-0-Acetyl-3'-O-benzyl-4'-p-toluenesulfonyloxyethyl-5'-0-t-butyldiphenylsilyl-6-N-benzo obtained in Ί Silyl adenosine (68 mg, 0.0723 mraol) was dissolved in methanol (10 ml), and 20 mg of 20% palladium hydroxide-carbon was added. The resulting reaction solution was stirred under a hydrogen atmosphere at 50 atm for 2 days. . The catalyst was filtered off, the solvent in the filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (dichloromethane: methanol = 16: 1) to give a colorless amorphous substance (11 mg, 0 mg). 0.162 ol, yield 21%).

_{Ή-NMR (400MHz, CDC1 3} ): 1.12 (9H, s), 2.09 (3H, s), 2.16 (2H, m), 3.78 (1H, d, 11Hz), 4.05 (1H, dt, 5.0, 8.7Hz ), 4.15 (1H, d, 11Hz), 4.17 (1H, m), 4.73 (1H, d, 4.8Hz), 5.82 (1H, dd, 4.8 and 8.0Hz), 6.36 (1H, 8.0Hz), 7.35- 7.70 (13H, m), 8.02 (2H, d, 7.4 Hz), 8.22 (1H, s), 8.72 (1H, s), 9.03 (1H, s).

FABMS (raNBA): 678 [M + H] ⁺

 (Example 5)

2'-O-acetyl-3'-0.4'-C-ethylene-6-N-benzoyladenosine (Exemplary Compound No. 1-20 9)

 2′-O-Acetyl-5′-0-t-butyldiphenylsilyl-3′-0,4′-C-ethylene-6-N-benzoyladenosine obtained in Example 4 (11 mg, 0.0162 mmol) was dissolved in anhydrous tetrahydrofuran (2 ml), and 1.0 M tetrabutylammonium fluoride tetrahydrofuran solution (0.03 ml, 0.03 mmol) was added thereto. Stirred at room temperature for 90 minutes. 2 ml of methanol was added, the solvent was distilled off, and the obtained residue was purified by silica gel chromatography (dichloromethane: methanol = 12: 1) to give a colorless solid (7 mg, 0.0159 mlolol). , Yield 98%).

_{Ή-NMR (400MHz, CDC1 3} ): 2.09 (3H, s), 2.10 (1H, m), 2.22 (1H, ddd, 4.7, 6.5 and 13H z), 3.74 (1H, t, 11Hz), 4.10-4.20 (3H, m), 4.83 (1H, d, 4.6Hz), 5.85 (1H, dd, 4.6 an d 8.1Hz), 6.07 (1H, d, 8.1Hz), 6.36 (1, d, 11Hz), 7.56 ( 2H, t, 7.5Hz), 7.65 (1H, t, 7.5Hz), 8.05 (2H, 7.5Hz), 8.82 (1H, s), 9.04 (1H, s).

FABMS (mNBA): 440 [M + H] *

 (Example 6)

3'-0, 4'-C-ethylene adenosine (Exemplary Compound No. 1-7)

 2′-0-Acetyl-3′-0,4′-C-ethylene-6-N-benzoyladenosine (7 mg; 0.0159 mmol) obtained in Example 5 was added to a saturated ammonia methanol solution (7 mg; 0.0159 mmol). 5ml) and left to stand. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (dichloromethane: methanol = 7: 1) to obtain a white powder (about 5 mg, quantitative yield).

_{Ή-NMR (400MHz, CD 3} 0D): 2.12 (2H, t, 5, 8Hz), 3.75 (1H, d, 12Hz), 3.94 (1H, d, 12H z), 4.04 (2H, m), 4.39 ( 1H, d, 4.4Hz), 4.78 (1H, dd, 4.4 and 8.0Hz), 6.03 (1H, d, 8.0Hz), 8.44 (1H, s), 8.58 (1H, s).

FABMS (mNBA): 294 [M + H] ⁺

 (Example 7)

 2 ', 5'-O-diacetoxy-3'-0, 4'-C-ethylene-6-N-benzoyladenosine (Exemplary Compound No. 1-132)

2,3-Diacetoxy-6a-acetoxime obtained in Reference Example 16 at room temperature under a nitrogen stream Cyl-hexahydrofuro [3,2-d] furan (1.88 g, 6.22 mmol) was dissolved in anhydrous 1,2-dichloroethane (100 ml), and the solution was added to the above-mentioned reference (H. Vorbueggen). , K. Kroli kiewicz and B, Bennua, Chem. Ber., 114 1234-1255 (1981)). Trimethylsilylated benzoyl adenine (4.60 g, about 12 mmol) was added. Further, trimethylsilinole trifluoromethanesulfonate (1.0 ml, 5.5 ol) was added dropwise thereto, and the mixture was heated under reflux for 8 hours.

 After completion of the reaction, a saturated aqueous solution of sodium hydrogen carbonate (about 1 O Otnl) was added to the reaction solution, and the mixture was filtered using celite. Dichloromethane (about 100 ml) was added to the filtrate, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate. (About 100 ml) and then with a saturated saline solution (about 100 ml), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel chromatography (dichloromethane: methanol = 100: 8), and the target compound (2.52 g, 5.23 mmol, yield: colorless amorphous) was obtained. 84%).

- Anonymous _{(400MHz, CDC1 3): 2.09} (3H, s), 2.18 (3H, s), 2.19 (1H, m), 2, 30 (1H, ddd, 4 .1 6.2 and 13Hz), 4.15 (2H, m), 4.43 (1H, d, 12Hz), 4.48 (1H, d, 12Hz), 4.70 (1H, d, 4.9Hz), 5.81 (1H, dd, 4.9 and 7.9Hz), 6.33 (1H, d, 7.9Hz) Hz), 7.52-7.64 (3H, tn), 8.0 3 (2H, m), 8.23 (1H, s), 8.81 (1H, s), 8.95 (1H, brs).

FABMS (mNBA): 482 [M + H] ⁴ .

 (Example 8)

 3 -0 4'- C -ethylene-6-N-benzoyladenosine (Exemplified Compound No. 1-178) 2 ', 5'-O-diacetoxy obtained in Example 7-3'-0.4 -C-ethylene-6-N-benzoyldenosine (1.39 g, 2.89 ol) was dissolved in 15 ml of pyridine, 6 ml of a 1 N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 20 minutes. After completion of the reaction, the reaction solution was neutralized with 0.1 N aqueous acetic acid, and the solvent was distilled off. The obtained residue was purified as it was using silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain the target compound as a colorless amorphous (889 mg 2.24 imnol, yield 77%).

Ή—Awake (400MHz, MeOD): 2.14 (2H, m), 3.31 (2H ₍ m), 3.76 (1H, d, 12Hz), 3.99 (1H, d, 12Hz), 4.12 (2H, m), 4.42 ( 1H, 4.7Hz), 4.92 (1H, dd, 4.7 and 8.0Hz), 6.09 (1H, d, 8.0Hz), 7.54-7.68 (3H, m), 8.08 (2H, d, 7.2Hz), 8.63 ( 1H, s), 8.70 (1H, s). FABMS (mNBA): 398 [M + H] ⁺ .

 (Example 9)

 5'-0-Dimethoxytrityl-3'-0,4'-C-ethylene-6-Ν-benzoyladenosine (Exemplified Compound No. 1-3 1)

 3′-〇, 4′-C-ethylene-6-Ν-benzoyladenosine (1.89 g, 4.76 mmol) obtained in Example 8 was azeotropically dehydrated with anhydrous pyridine, and then dried under a nitrogen stream. The residue was dissolved in anhydrous pyridine (20 ml). To this was added 4,4′-dimethoxytrityltrifluoromethanesulfonic acid (2.7 g, 6.0 mmol), and the mixture was heated at 100 ° (:, 5 hours).

After a small amount of methanol (about 3 ml) was added to the reaction solution, the solvent was concentrated under reduced pressure, water (about 50 ml) was added, and the mixture was extracted with chloroform (about 100 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (about 50 ml × 2) and saturated saline (about 50 ml), and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (dichloromethane: methanol). = 100: 10), a colorless amorphous target product (900 mg, 1.28 mmol, yield 27%) was obtained.

_{Ή-NMR (400MHz, CDC1 3} ): 2.08 (1H, dt, 8.8 and 13Hz), 2.19 (1H, dt, 5.0 and 13Hz), 3.30 (1H, d, 10Hz), 3.59 (1H, d, 10Hz), 3.76 (3H, s), 3.77 (3H, s), 4.08 (2H, m), 4.25 (1H, brs), 4.50 (1H, d, 5.0Hz), 5.02 (1H, brd, 5.0Hz), 6.06 (1H, d, 7.2Hz), 6.79 (4H, d, 8.7Hz), 7.2-7.6 (12H, m), 8.03 (2H, d, 7.4Hz), 8.25 (1H, s), 8.77 (1H, s), 9.19 (1H, s).

 FABMS (mNBA): 700 [M + H] +

 (Example 10)

 5'-O-Dimethoxytrityl-3'-O, 4'-C-ethylene-6-N-benzoyladenosine-2'-0- (2-cyanoethyl N, N-diisopropyl phosphoramidite) ( Exemplified compound number 1-186)

5′-0-Dimethoxytrityl-3′-0,4′-C-ethylene-6-N-benzoyladenosine (82 mg, 1.17 ol) obtained in Example 9 was treated with anhydrous pyridine. After azeotropic dehydration, it was dissolved in anhydrous dichloromethane (2 Oml) under a nitrogen stream, and N, N-diisopropylaminetetrazole salt (340 mg, 2.Ommol), N, N, N ', N'-tetra Add isopropyl-1-cyanoethyl phosphoramidite (6 35 μl, 2.Ommol) and stir at 45 ° C for 5 hours . The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate (1 Oml) and saturated saline (1 Oml), and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (dichloromethane: ethyl acetate). = 4: 1) to give the target compound as a colorless liquid (835 mg, 0.927 mol, yield 80%).

1 H-NMR (400MHz, CDC1 3): 0.7-1.2 (12H, m), 1.26 (1H, m), 2.16 (1H, m), 2.38 (2H, m), 3.5-3.7 (6H, m), 3.78 (3H, s), 3.79 (3H, s), 3.8-4.2 (3H, m), 4.5 (1H, d, 4.7 Hz), 6.2 (1H, d, 7.9 Hz), 6.82 (4H, m ), 7.2-7.6 (12H, m), 8.02 (2H, m), 8.18 (1H, s), 8.68 (1H, s), 9.03 (1H, brs).

 (Example 11)

 (Synthesis of Oligonucleotide Analogs)

 Using a nucleic acid synthesizer (ABI model 392 DNA / RNA synthesizer manufactured by PE Biosystems), the reaction was performed on a 1. μπιol scale. The concentration of the solvent, reagent and phosphoramidite in each synthesis cycle was the same as in the case of natural oligonucleotide synthesis, and the solvent, reagent and phosphoramidite of the natural nucleoside were all manufactured by PE Biosystems. 3'-hydroxyl group 5'-O- DMTr bound to PG support Deprotection of thymidine (1.0 / imol) DMTr group by trichloroacetic acid, and the 5'-hydroxyl group is used for natural nucleotide synthesis. The condensation reaction was repeated using the amidite of Example 1 and the compound of Example 10 to synthesize a modified oligonucleotide analog having each sequence. The synthesis cycle is as follows.

Synthesis cycle

1) detritylation trichloroacetic acid / dichloromethane; 85sec

 2) coupling phosphoramidite (25eq), tetrazole / acetonitrile; 25sec or lOmin

3) capping 1-Methylimidazonole / tetrahydrofuran, acetic anhydride / pyridine / tetrahydrofuran; 15 sec

 4) oxidation iodine / water / pyridine / tetrahydrofuran; 15sec

In the above, when performing the reaction using the compound of Example 10 in cycle 2), the reaction was performed for 10 minutes, and when using another phosphoramidite, the reaction was performed for 25 seconds.

After synthesizing the oligonucleotide having the target sequence and proceeding until 1) of the synthesis cycle to deprotect the 5'-DMTr group, the oligomer is cleaved from the support by concentrated ammonia water treatment according to a conventional method. At the same time, the protecting group on the phosphorus atom was removed, and the protecting group on the nucleobase was removed.

 The obtained natural oligonucleotides and modified oligonucleotide analogs were purified by reversed-phase HPLC to obtain the desired oligonucleotides.

 According to this synthesis method, the following sequence:

 5'-ttttttttttnt- 3 '(SEQ ID NO: 1 in the sequence listing)

An oligonucleotide analog (hereinafter, referred to as “oligonucleotide (1)”) having a sequence represented by the following formula, wherein the sugar moiety of adenosine having base number 11 is 3′-0, 4′-C-ethylene adenosine: Obtained. (0.55μιηο1 (55% yield))

Purification of the resulting modified oligonucleotide analog was performed by reversed-phase HPLC (HPLC: LC-VP manufactured by Shimadzu Corporation; column: GL Science Inertsil Prep-0DS (20 X 250 mm); 0.1 M aqueous triethylamine acetate solution (TEAA), pH 7; 10 → 60% CH ₃ CN / 30 min, linear gradient; 40 ° C .; 10 ml / min; 254 nm), and the fraction eluted at 29.6 minutes was collected. This compound was eluted at 16.58 minutes when analyzed by HPLC (Wako Pure Chemicals Wakosil DNA (4.6 × 150 mm), 0.1 M TEAA, pH 7, 10 → 50% C¾CN / 20 min, linear gradient, 60 ° C, lml / min) . (Umax = 263nm)

 (Reference example 1)

 3-O-benzyl-4-forminole-5-〇-t-butyldiphenylsilinole-1,2-O-isopopenpyridene-a-D-erythropentofuranose

Oxalyl chloride (3.53 ml, 40.5 mol) was added to anhydrous dichloromethane (150 ml) cooled to 178 ° C under a nitrogen stream, and dimethyl sulfoxide dissolved in anhydrous dichloromethane (75 ml) was added thereto. (4.62 ml, 64.8 mmol) was added dropwise. After stirring for 20 minutes, 3-O-benzyl-4-C-hydroxymethyl-5-0-t-butyldiphenylsilinole-1,2-0-isopropylidene dissolved in anhydrous dichloromethane (75 ml) was added to the reaction solution. -α-D-Eris mouth pentofuranose (which can be produced according to the method described in JP-A-10-304889) (7.40 g, 13.5 Ommol) was added dropwise, and the mixture was further stirred for 30 minutes. Further, triethylamine (16.7 ml, 12 Ommol) was added, and the temperature was slowly returned to room temperature. Water (about 200 ml) was added to the reaction solution, and the mixture was separated. The organic layer was washed with water and then with a saturated saline solution, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane: acetic acid). Chill = 5: 1) to give a colorless oil (6.82 g, 12.49 mmol, 93% yield). (Reference example 2)

 3-0_-Benzyl-4-vinyl-5-O-t-butyldiphenyl_silyl-1,2-0-isopropylidene-H-D-erythropentofuranose.

 Under a stream of nitrogen, the 3-0-benzyl-4-formyl-5-0-t-butyldiphenylsilyl-1,2-O-isopropylidene-α-D-erythral bentfuranois obtained in Reference Example 1 (6 .82 g, 12.49 ol) was dissolved in anhydrous tetrahydrofuran (200 ml) and cooled to 0 ° C. Thereto was added a 0.5 M solution of Tobe's reagent in toluene (28 tnl, 14.0 mmol), and the mixture was stirred at 0 C for 1 hour.

After the reaction was completed, getyl ether (200 ml) was added, and then a 0.1 N aqueous sodium hydroxide solution (30 m) was slowly added. The obtained precipitate was filtered using celite, and the collected matter was washed with getyl ether, separated, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was roughly purified by alumina (basic) chromatography (ethyl acetate), and the obtained crude product was further purified by silica gel chromatography (hexane: Ethyl acetate = 7: 1) to give a colorless oily substance (1.68 g, 3.09πυηο1 ₍ yield 25%)).

_{Ή-NMR (400MHz, CDC1 3} ): 0.97 (9H, s), 1.32 (3H, s), 1.54 (1H, s), 3.49 (1H, d, 11Hz), 3.53 (1H, d, 11Hz), 4.45 (1H ₍ d, 4.9Hz), 4.64 (1H, t, 3.8Hz), 4.65 (1H, d, 12Hz), 4.82 (1H, d, 12Hz), 5.18 (1H, dd, 1.9 and 11Hz), 5.44 ( 1H, dd, 1.9 and 18Hz), 5.80 (1H, d, 3.8Hz), 6.16 (1H, dd, 11 and 18Hz), 7.2-7.7 (15H, m).

FABMS (mNBA): 545 [M + H] ⁺

 (Reference example 3)

 3-O-benzyl-4-hydroxyethyl-5-O-t-butyldiphenylsilyl-1,2-0-isopropylidene-a-D-erythropentofuranois

Under a stream of nitrogen, 3-0-benzyl-4-butyl-5-〇-t-butyldiphenylsilyl-1,2-0-isopropylidene-α-D-erythrate ventfurano obtained in Reference Example 2 was obtained. Dissolve (1.68 g, 3.09 mmol) in anhydrous tetrahydrofuran (50 ml), and add 0.5M 9-BBN (9-borabicyclo [3.3.1] nonane) / tetrahydrofuran Drofuran solution (10 ml, 5 mmol) Was added dropwise, followed by stirring at room temperature.

 Water was added until no bubbles appeared in the reaction solution, and then a 3N aqueous solution of sodium hydroxide (5 ml) was added. Further, 30% aqueous hydrogen peroxide (10 ml) was slowly added so that the temperature of the reaction solution became 3 ° C. to 50 ° C., followed by stirring for 30 minutes.

 After completion of the reaction, a saturated saline solution and ethyl acetate were added to the reaction mixture, and the mixture was separated. The organic layer was washed with a neutral phosphate buffer and then with a saturated saline solution, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1) to obtain a colorless oil (1154 mg, 2.05 sleep 01, yield 66%). Was.

Ή-NMR (400MHz, CDC1,): 0.99 (9H, s), 1.36 (3H, s), 1.68 (3H, s), 1.70 (1H, ddd, 3.3, 6.2 and 20Hz), 2.45 (1H, ddd, 4.0, 8.6 and 20Hz), 3.42 (1H, d, 11Hz), 3.68 (2H, m), 3.74 (1H, d, 11Hz), 4.29 (1H, d, 5.2Hz), 4.56 (1H, d, 12Hz) , 4.69 (1H, dd, 4.0 an d 5.2Hz), 4.81 (1H, d, 12Hz), 5.80 (1H, d, 4.0), 7.3-7.7 (15H, m).

FAB S (mNBA): 563 [M + H] *

 (Reference example 4)

3-〇-benzyl-4- (p-toluenesulfonyloxethyl) -5-O-t-butyldiphenylsilyl-1,2-O-isopropylidene-a-D-erythropentofuranos_

 Under a nitrogen stream, 3-0-benzyl-4-hydroxystyl-5-O-t-butyldiphenylsilyl-1,2-O-isopropylidene-a-D-elis-pentpentfuranois obtained in Reference Example 3 (980 mg, 1.74 mmol) was previously azeotropically dehydrated with toluene, dissolved in anhydrous dichloromethane (30 ml), and cooled to 0 ° C. To this, triethylamine (1.25 ml, 90 mol), dimethylaminopyridine (2 Omg, 0.17 mmol), and salt-p-toluenesulfonyl (572 mg, 3 nimol) were added, and the mixture was stirred at room temperature.

 After completion of the reaction, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction solution, and the mixture was separated. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 9: 1, then 7: 1) to give a colorless oil (953 mg, 1.33). , 76%).

賺-news (400MHz, CDC1: 0.95 (9H, s), 1.30 (3H, s), 1.46 (3H, s), 1.89 (1H, ddd, 6.9 , 9 and ΙδΗζ), 2.38 (3H, s), 2.52 (1H, ddd, 5.4, 9 and 15Hz), 3.35 (1H, d, 11Hz), 3.58 (1H, d, 11Hz), 4.14 (1H, dt, 6.9 and 9Hz), 4.19 (1H, d, 5.2Hz), 4.27 (1H, dt, 5.4 and 9Hz), 4.49 (1H, d, 12Hz), 4.61 (1H, dd, 4.0 and 5.2), 4.74 (1H, d, 12Hz), 5.7 KlH, d, 4.0Hz), 7.2-7.7 (19H, m).

FABMS (mBA): 717 [M + H] '

 (Reference example 5)

 Di-O-acetyl-3-O-benzinole-4- (p-toluenesulfonyloxityl) -5-0-t-ludiphenylsilyl-a-D-erythropentofuranois

 3-0-benzyl-4- (Ρ-toluenesulfonyloxicetyl) -5-O-t-butyldiphenylsilinole-1,2-O-isopropylidene-a-D-erythropent obtained in Reference Example 4 933 mg (1.3 Ommol) of furanose was dissolved in 1 Oml of acetic acid, and 1.13 ml (12 ol) of acetic anhydride and 0.01 ml of concentrated sulfuric acid were added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was poured into ice-cold water (5 Oml) and further stirred for 30 minutes. Saturated saline and ethyl acetate were added, and the organic layer was washed with a neutral phosphate buffer, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was purified by silica gel chromatography (hexane: dimethyl acetate = 3: 1) to give 61 mg of a colorless oil (0.803 mmol, yield 62%, α: β = 1:14) was obtained.

_{Ή-NMR (400MHz, CDC1 3} ) (/ 3 body): 11.06 (9H, s) , 1.79 (3H, s), 2.06 (3H, s), 2.15 (1H, m), 2.33 (1H, ddd, 5 , 10 and 15Hz), 2.43 (3H, s), 3.52 (1H, d, 10Hz), 3.55 (1H, d, 10Hz), 4.22 (1H, dt, 6.0 and 10Hz), 4.27 (1H, d, 5.1) Hz), 4.34 (1H, dt, 5.3 and 10Hz), 4.51 (1H, d, 11Hz), 4.57 (1H, d, 11Hz), 5.33 (1H, d, 5.1Hz), 6.08 (1H, s), 7.1 -7.7 (19H, m).

 FABMS (mNBA): 761 [M + H] ^

 (Reference example 6)

2'-O-Acetyl-3'-O-benzyl-4'-D-toluenesulfonyloxixyl-5'-0-t-butyldiphenylsilinole-1-5-methinoredridine

1,2-Di-0-acetyl-3-0-benzyl-4- (p-toluenesulfonyloxicetyl) -5-ot-butyldiphenylsilyl-α-D-eryth-opened ventfurano obtained in Reference Example 5 One (26 8 mg 0.352 mmol) was dissolved in anhydrous 12-dichloroethane (10 ml). There, trimethylsilylated thymine (I 90 mg, about 0.7 ol) prepared according to JS. Own literature (H. Vorbrueggen, K. Krolikiewicz and B, Bennua, Chera. Ber., 114, 1234-1255 (1981)). ) Was added and the mixture was cooled to 0: 'C, trimethylsilinole trifluoromethanesulfonate (0.13m10.7mmol) was added, and the mixture was stirred at 50C for 3 hours. The reaction solution was returned to room temperature, and a saturated aqueous solution of sodium hydrogen carbonate (about 10 ml) was added.

After completion of the reaction, methylene chloride (about 20 ml) was added to the reaction mixture, the mixture was stirred, and the precipitated white insoluble matter was filtered using celite. The organic layer was separated from the obtained filtrate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was purified by silica gel chromatography (hexane: ethyl ester = 1.5: 1, then 1: 1), and 24 1 mg of a colorless amorphous substance (0.29 lmmol) to give a 83% yield) - thigh _{(400MHz, CDC1 3): 1.08} (9H, s), 1.57 (3H, s), 2.07 (3H, s), 2.39 (3H, s), 3.55 (1H d , 11Hz), 3.79 (1H, d, 11Hz), 4.12 (2H, m), 4.36 (1H, d, 6Hz), 4.39 (1H, d 11Hz), 4.55 (1H, d, 11Hz), 5.38 (1H , t, 6Hz), 6.01 (1H, d 6Hz), 7.2-7.6 (19H, m), 7.96 (1H s).

 FABMS (mNBA) 827 [M + H] '

 (Reference example 7)

 2'-O-Acetyl-3'-O-benzyl-4'-1-n-toluenesulfonyloxexetyl-5'-0-t-butyl diph: ^ lucyl-6-N-benzoyladenosine

12-di-O-acetyl-3-0-benzyl-4- (p-toluenesulfonyloxicetyl) obtained in Reference Example 5-5-〇-t-butyldiphenylsilyl-a-D-erythrole Bentfuranose (340 mg 0.447 mmol) was dissolved in anhydrous 1,2-dichloroethane (10 ml). Then, trimethylsilylated benzoyl adenine (307 mg, about 0.8 ol) prepared according to the aforementioned reference (H. Vorbrueggen, K. Krolikiewicz and B, Bennua, Chem. Ber., 114, 1234-1255 (1981)) was used. In addition, the mixture was cooled to 0 ° C, 0.15 ml of trimethylsilyl trifluoromethanesulfonate (0.8 ol) was further added, and the mixture was heated under reflux for 2 hours. The reaction solution was returned to room temperature, and a saturated aqueous sodium hydrogen carbonate solution (about 10 ml) was added. After completion of the reaction, the reaction mixture Methylene chloride (about 2 Oml) was added to the mixture, and the mixture was stirred, and the precipitated insoluble matter was filtered using celite. The organic layer was separated from the obtained filtrate, and the organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was purified by silica gel chromatography (dichloromethane: methanol = 50: 1) to obtain a colorless amorphous substance (155 mg, 0.165 mmol, yield 34%).

_{Ή-NMR (400MHz, CDC1 3} ): 1.0K9H, s), 2.04 (3H, s), 2.15 (1H, m), 2.38 (3H, s), 2.40 (1H, m), 3.53 (1H, d, 11Hz), 3.82 (1H, d, 11Hz), 4.21 (1H, m), 4.25 (1H, m), 4.53 (1H, d, llHz), 4.58 (1H, d, 11Hz), 4.70 (1H, d, 5.8Hz), 5.97 (1H, t, 5.4Hz), 6.10 (1H, d, 5.0Hz), 7.2-8.0 (24H, m), 8.04 (1H, s), 8.58 (1H, s), 8.95 (1H , s).

FABMS (mNBA): 940 [M + H] '

 (Reference Example 8)

 3-0-p-Methoxybenzyl-4-hydroxymethyl 1,2-0-isopropylidene- _a- D-erythr

6- (4-Methoxy-benzyloxy) 1,2,2-dimethyltetrahydrofuro [2,3—d] —1,3-dioxo-mono-5-carbaldehyde (6- (4-methoxv—benzyloxy) ) — 2,2-dime thyl-tetrahydro-furo [2,3-d] [1, 3] dioxole-5-carbaldehyde) (3450 mg, 1 1 1 1 9) 1) (Woodson, William W .; Watson, 21, 1986, 1599-1600) was dissolved in a mixed solution of 5 Oml of water / 5 Oml of tetrahydrofuran and cooled to 0 ° C. This is in formaldehyde _{(37% in H 2 0)} 6. 5ml and 1 N aqueous sodium solution 3 OML hydroxide and the mixture was stirred over晚at room temperature. After completion of the reaction, dichloromethane (about 300 ml) was added to the reaction solution, and the mixture was separated. The organic layer was washed with 0.1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate (about 200 ml) and a saturated saline solution (about 200 ml), and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 3) to give the target compound as a colorless solid (3510 mg, 10.32 benzyl, yield 92%). %). _{Ή- MR (400MHz, CDC1 3)} : 1.34 (3H, s), 1.64 (3H, s), 1.84 (1H, dd, 3.7 and 9.5Hz), 2 .38 (1H, t, 7.0Hz), 3.55 ( 1H, dd, 9.5 and 12Hz), 3.77 (1H, dd, 3.7 and 12Hz), 3.82 (3H, s), 3.90 (2H, m), 4.20 (1H, d, 5.1Hz), 4.50 (llHz), 4.63 (1H, dd, 3.7 and 5.1Hz), 4.74 (1H, d, 11Hz), 5.76 (1H, 3.7Hz), 6.90 (2H, m), 7.30 (2H, m).

FABMS (mNBA): 34l [M ^ H] \

 (Reference Example 9)

3-O-p-Methoxyxindil-4-hydroxyhydroxy-5-0-benzyl-1,2-O-isopropylidene-a-D-erythral pentofuranose

Under a stream of nitrogen, 3-〇-ρ-methoxybenzyl-4-hydroxyhydroxy-1,2-〇-isopropylidene-α-D-erythral ventfuranose (3000 mg, 8.82 ol) was added to anhydrous dimethylform. The amide was dissolved in 45 ml and cooled to 0 ° C. Sodium hydride (60% in mineral oil) 3 Add 50mg, stir at 0 C for 20 minutes, then slowly add benzyl bromide (1.05ml, 8.82mmol) dropwise, then stir at room temperature overnight did. After completion of the reaction, the reaction solution was poured into ice water, and extracted with ethyl acetate (about 100 ml × 3). The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (about 200 ml) and a saturated saline solution (about 200 ml), and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 2.5: 1) to give the target compound as a colorless oil (2.12 g, 4.9 3 yield, 56% yield).

'H-NMR (400MHz, CDC1 3): 1.34 (3H, s), 1.63 (3H, s), 3.52 (1H, d, 11Hz), 3.59 (1H, d, 11Hz), 3.80 (3H, s), 3.82 (1H, d, 12Hz), 3.89 (1H, d, 12Hz), 4.25 (1H, d, 5.1Hz), 4.44 (1H, d, 12Hz), 4.45 (1H, d, 12Hz), 4.54 ( 1H, d, 12Hz), 4.61 (1H, dd, 3.7 and 5.1 Hz), 4.71 (1H, d, 12Hz), 5.77 (1H, d, 3.7Hz), 6.85-6.89 (2H, m), 7.23-7.36 (7H, m). FABMS (mNBA): 431 [M + H] *.

 (Reference example 10)

3-O-Methoxybenzyl-4-formyl-5-O-benzyl-1,2-O-isopropylidene-a-D- Ellis Lopent Furanois

 Using 3-〇-p-methoxybenzyl-4-hydroxymethyl-5-5-benzyl-1,2-O-isopropylidene-α-D-erythral ventfuranose (2.07 g, 4.81 mmol), A colorless oily target compound (1.73 g, 4.06 ol, yield 85%) was obtained in the same manner as in Reference Example 1.

'H-NMR (400MHz, CDC1 3): 1.34 (3H, s), 1.60 (3H, s), 3.60 (IH, d, 11Hz), 3.65 (IH, d, 11Hz), 3.80 (3H, s), 4.34 (1H, d, 4.4Hz), 4.46 (IH, d, 12Hz), 4, 50- 4.58 (3H, m), 4.64 (IH, d, 12Hz), 5.82 (IH, d, 3.3Hz), 6.85 -6.88 (2H, m), 7.22-7.35 (7H, m), 9.90 (IH, s).

 FABMS (mNBA): 429 [M + H] *.

 (Reference Example 11)

3 -Ο-β-Methoxybenzyl-4-vinyl-5-Ο-benzyl-1,2-，-isopropylidene-a-D-erythropentofuranois

85 mg of sodium hydride (60% in mineral oil) was suspended in 2 ml of anhydrous dimethylforsulfoxide and stirred at 80 ° C for 45 minutes. After the temperature was returned to room temperature, 3 ml of a solution of methyltriphenylphosphonium bromide (757 mg, 2.12 countries ol) in anhydrous dimethylforsulfoxide was added dropwise, and the mixture was stirred at room temperature for 10 minutes. Furthermore, 3-0-P-methoxybenzyl-4-formyl-5-0-benzyl-1,2-O-isopropylidene-α-D-erythropentofuranoic acid (758 mg, 1.77 mmol) was dissolved. 3 ml of an anhydrous dimethylforsulfoxide solution was added dropwise, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into ice water, extracted with ethyl acetate (about 50 ml × 3), and the organic layer was washed with water (about 10 Oml) and saturated saline (about 100 ml), and then dried over anhydrous magnesium sulfate. . The solvent was concentrated under reduced pressure, and the obtained residue was purified using silica gel chromatography (hexane: ethyl acetate = 5: 1) to give the target compound as a colorless oil (455m g, 1.07 mmol, yield 60%).

_{Ή-NMR (400MHz, CDC1 3} ): 1.28 (3H, s), 1.52 (3H, s), 3.28 (1H, d, 11Hz), 3.33 (1H, d, llHz), 3.79 (3H, s), 4.23 (1H, d, 5.1Hz), 4.40 (1H, d, 12Hz), 4.50-4.55 (3H, m), 4.69 (1H, d, 12Hz), 5.24 (1H, dd, 2.0 and 12Hz), 5.51 (1H, dd, 2.0 and 17Hz), 5.75 (1H, d, 3.7Hz), 6.18 (1H, dd, 12 and 17Hz), 6.84-6.88 (2H, m), 7.21-7.35 (7H, m). FABMS (mNBA): 449 [M + Na] ^T , 365 [M + K] ⁺ .

 (Reference Example 1 2)

 3-O- -Methoxybenzyl-4 hydroxystyl-5-0-benzyl-1,2-0-isopropylidene

3-Ο-ρ-Methoxybenzyl-4-vinyl-5-Ο-benzyl-1,2-Ο-isopropylidene-a-D-erythral ventfuranose (485 mg, 1.14 mmol) In the same manner as in Reference Example 3, the target compound (32 mg, 0.727 mol, yield 64%) was obtained as a colorless oil.

'H-NMR (400MHz, CDC1 3): 1.33 (3H, s), 1.66 (3H, s), 1.77 (1H, 3, 7, 6.6 and 15Hz), 2.48 (1H, dq, 4.4, and 15Hz), 3.28 (1H, d, 11Hz), 3.53 (1H, d, 11Hz), 3.74 (1H, m), 3.80 (3H, s), 3.83 (1H, m), 4.11 (1H, d, 5.1Hz), 4.43 (1H, d, 12Hz), 4.48 (1H, d, 12Hz), 4.52 (1H, d, 12Hz), 4.62 (1H, dd, 3.7 and 5.1Hz), 4.69 (1H, d, 12Hz), 5.76 ( 1H, d, 3.7Hz), 6.86 (2H, m), 7.22-7.36 (7H, m).

FABMS (mNBA): 445 [M + H] ⁺ .

 (Reference Example 13)

4-Hydroxityl-5-O-benzyl-1, 2-O-isopropylidene-α-D-erythropentofuranos

3-Ο-ρ-methoxybenzyl-4-hydroxystyl-5-5-benzyl-1,2-0-isopropylidene -α-D-Eris vent bentfuranois (13.5 g, 30.36 mmol) was dissolved in 20 Oml of 10% aqueous dichloromethane solution, and 2,3-dichloro-5,6-disocyano-1 was added thereto. , 4 - Ben Zokinon (9 5%) (8. 7 g, 3 6. 43 discussions ₀ 1), and the mixture was stirred for 4 hours at room temperature. After completion of the reaction, the reaction solution was extracted with dichloromethane (about 300 ml), and the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (about 300 ml) and a saturated saline solution (about 300 ml), and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified using silica gel chromatography (hexane: ethyl acetate = 1: 2) to give the target compound as a colorless oil (7.9 g, 24.38 mmol, yield). Rate of 80%).

_{Ή-NMR (400MHz, CDC1 3} ): 1.38 (3H, s), 1.62 (3H, s), 1 · 86 (1Η, dq, 3.7 and 15Hz), 2.19 (1H, ddd, 4.4, 8.0 and 15Hz), 3.46 (1H, d, 10Hz), 3.50 (1H, d, 10Hz), 3.74 (1H, dq, 3.7 and 12Hz), 3.85 (1H, dq, 3.7, 12Hz), 4.25 (1H, d, 6.6Hz), 4.51 (1H, d, 12Hz), 4.57 (1H, d, 12Hz), 4.72 (1H, dd, 4.4 and 6.6Hz), 5.88 (1H, d, 4.4Hz), 7.2-7.4 (5H, m).

FABMS (mNBA): 325 [M + H] ⁺ .

 (Reference example 14)

 6 a-benzyloxymethyl-1,2,2-dimethylhexahi drawflow [2 ', 3': 4,

5] Flo [2,3—d] —1,3-dioxole.

 4-Hydroxitytyl-5-0-benzinole-1,2-O-isopropylidene-a-D-erythopentopenturanose (7.9 g, 24.38 mmol) was dissolved in 200 ml of anhydrous pyridine, and p-toluene sulfone was dissolved. Acid chloride (5.72 g, 3 Ommol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, pyridine was distilled off, a saturated aqueous solution of sodium hydrogen carbonate (about 10 Oml) was added, and ethyl acetate was added.

(About 200 mix 2). The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (about 100 ml) and a saturated saline solution (about 100 ml), and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified using silica gel chromatography (hexane: ethyl acetate = 2: 1) to give the desired product as a white solid (6.93 g, 22.64 mmol, yield Rate 93%) Obtained.

_{Ή-NMR (400MHz, CDC1 3} ): 1.37 (3H, s), 1.63 (3H, s), 1.82 (IH, ddd, 8.0, 10 and 13 Hz), 2.1K1H, ddd, 3.0, 6.5 and 13Hz), 3.41 (IH, d, 10Hz), 3.70 (IH, d, 10Hz), 4.0 4 (1H, dt, 2.2 and 8.1Hz), 4.20 (IH, ddd, 6.3, 8.0 and lOHz), 4.49 (IH, d, 5.9Hz), 4.52 (IH, d, 12Hz), 4.60 (IH, d, 12Hz), 4.62 (IH, dd, 3.7 and 5.9Hz), 5.92 (IH, d, 3.7Hz), 7.2-7.4 (5H , m).

FABMS (mNBA): 307 [M + H] \

 (Reference example 15)

2,3-Diacetoxy-6a-benzyloxymethyl-1-hexafluoro [3,2-d] furan

6a-benzyloxymethyl-2,2-dimethylhexahydrofuro obtained in Reference Example 14 [2 ', 3': 4,5] furo [2,3-d] -l, 3-dioxo Using the same compound (6.8 g, 22.22 mrnol) in the same manner as in Reference Example 5, the target compound as a colorless oil (7.03 g, 20.1 mmol, 90% yield) (α: ; 3 = about 3: 4) was obtained.

_{'H- MR (400MHz, CDC1 3} ): (α Body) 2.03 (1H, dt, 9.0 and 13Hz), 2.12 (IH, m), 2.12 (3H, s), 2.15 (3H, s), 3.50 (IH , d, 10 Hz, 3.67 (IH, d, 10 Hz), 4.01 (IH, dt, 3.2 and 8.3 Hz), 4.25 (IH, ddd, 6.4, 8.4 and 9.6 Hz), 4.51 (IH, d, 5.3 Hz) ), 4.52 (IH, d, 12Hz), 4.62 (IH, d, 12Hz), 5.12 (IH, t, 5.3Hz), 6.46 (1H, d, 5.3Hz), 7.2-7.4 (5H, m). β-form) 2.01 (3H, s), 2.06 (IH, ddd, 8.0, 10 and 13Hz), 2.13 (IH, dq, 2.8 and 13Hz), 2.14 (3H, s), 3.61 (1H, d, 10Hz) , 3.65 (IH, d, 10Hz), 3.92 (1H, ddd, 5.9, 8.5 and lOHz), 4.0K1H, dt, 2.7 and 8.5Hz), 4.58 (IH, d, 12Hz), 4.60 (IH, d, 5.7 Hz), 4.62 (IH, d, 12Hz), 5.17 (IH, dd, 3.2 and 5.7Hz), 6.24 (IH, d, 3.2Hz), 7.2-7.4 (5H, m).

FABMS (mNBA): 349 [MH] ⁺ .

 (Reference Example 16)

2,3-Diacetoxy 6a-Acetoxymethyl-hexahydrofuro [3,2-d] furan

The compound (6.93 g 19.8 mmol) obtained in Reference Example 15 was dissolved in 10 Oml of ethyl acetate, palladium on activated carbon (150 mg) was added, and the mixture was added at room temperature under normal pressure hydrogen. Stir for 1 hour. After the completion of the reaction, palladium-activated carbon was filtered, and the solvent was distilled off. The residue was dissolved in anhydrous pyridine (8 Oml), acetic anhydride (10 ml) was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off, a saturated aqueous solution of sodium hydrogencarbonate (about 100 ml) was added, and the mixture was extracted with ethyl acetate (about 100 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (about 100 ml) and a saturated saline solution (about 100 ml), and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified using silica gel chromatography (hexane: ethyl acetate = 1 15: 1) to give the target compound as a white solid ( _α: | 3 = about 1: 1). ) (4.13 g 13.67 mmol, yield 69%).

'H-NMR (400MHz, CDC1 3): α Body) 2.08 (1H m), 2.11 (3H, s), 2.13 (3H, s), 2.16 (3H, s 2.21 (1H, dq, 2.9 and 13Hz), 4.05 (1H, dt, 2.9 and 8.0Hz), 4.10 (1H, d, 12Hz), 4.29 (1H, ddd, 6.6, 8.0 and lOHz), 4.36 (1H, d, 12Hz), 4.49 (1H, d , 5.1Hz), 5.09 (1H, t, 5.1Hz), 6, 45 (1H d, 5.1Hz). (3) 2.01 (1H, ddd, 8.0, 10 and 13Hz), 2.10 (3H, s) , 2.12 (3H, s), 2.15 (3H, s), 2.19 (1H, ddd, 2.2, 5.9 and 13Hz), 3.90 (1H, ddd, 5.9, 8.8 and 10Hz), 4.04 (1H, dt , 2.2 and 8.0), 4.25 (1H, d, 12Hz), 4.35 (1H, d 12Hz), 4.60 (1H, d, 5.8Hz), 5.15 (1H, dd, 2.9 and 5.8Hz), 6.27 (1H, d , 2.9Hz).

FABMS (mNBA) 303 [M + H] ⁺

 (Test Example 1)

 (Measurement of nuclease enzyme resistance)

Buffer solution containing various oligonucleotides (80 μg) 2250 u 1 (50 mM Tris (pH 8.0) and 10 mM Mg 2) (this 3'-exonuclease ≥ ^ phosphodiesterase from Crotalus durissus (Bo ehringer Mannheim)) 0.3 μ g was added, and the mixture was kept at 37 C to carry out a reaction. After a certain period of time, a part of the mixture was removed and heated at 90 ° C for 2 minutes to inactivate the enzyme and stop the reaction. The remaining amount of the oligonucleotide in the mixture at each time is quantified by reversed-phase high-performance liquid column chromatography, and the change over time in the amount of oligonucleotide in the presence of nuclease is measured. did.

Oligonucleotides used in the test

 1. Oligonucleotide (1) obtained in Example 11.

 2. Sequence adjusted according to JP-A-10-1995098:

 5'-ttttttttttnt- 3 '(SEQ ID NO: 1 in Sequence Listing)

Wherein n is 3'-0,4'-C-methylene adenosine (hereinafter referred to as "oligonucleotide (2)")

 3. Array:

 5'-ttttttttttnt- 3 '(SEQ ID NO: 1 in Sequence Listing)

Wherein n is riboadenosine, and the 2′-hydroxyl group of n and the 5′-hydroxyl group of n-thymidine 3 ′ are linked with 2 ′, 5 ′ phosphoric diester (Hereinafter referred to as “oligonucleotide (3)”.)

 4. Array:

 5'-ttttttttttnt- 3 '(SEQ ID NO: 1 in Sequence Listing)

Wherein n is 2′-deoxyadenosine (hereinafter referred to as “oligonucleotide (4)”).

(Result)

 Time (minutes)

 Oligonucleotides (1)

 : Nutrition:. ::: oligonucleotide (2)

 Oligonucleotides (3)

 Oligonucleotide (4) The oligonucleotide analogue of the present invention showed remarkable nuclease resistance as compared with the natural type. Furthermore, it showed remarkable nuclease resistance even when compared with known non-natural oligonucleotide analogs.

 [Possibility of industrial use]

 The novel 3′-4 ′ bridged oligonucleotides and nucleosides of the present invention can be used as stable and excellent antiviral drugs, antisense or antigene drugs, specific gene detection drugs (probes), or amplification starters. Useful as primers and intermediates for producing the same.

Claims

The scope of the claims

1. General formula (1)

(1)

[Wherein, R ¹ and R ² are the same or different and are each a hydrogen atom, a protecting group for a hydroxyl group for nucleic acid synthesis, a phosphate group, a phosphate group protected with a protecting group for nucleic acid synthesis, or —P (R ³ ) R ^{4 wherein} R ³ and R ⁴ are the same or different and each is a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an amino group, or a carbon atom; Represents an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, a cyanoalkoxy group having 1 to 5 carbon atoms or an amino group substituted with an alkyl group having 1 to 4 carbon atoms] Show,

A represents an alkylene group having 1 to 4 carbon atoms,

B is a substituted purine 9-yl group, a 2-oxo-1,2-dihydropyrimidine 11-yl group or a substituted purine 9-yl group or a substituted 2-oxo group having a substituent selected from the following α group. It represents a 1,2-dihydropyrimidine-11-yl group. ] The compound represented by these, and its salt.

 (ct group)

 Hydroxyl group,

 A hydroxyl group protected by a protecting group for nucleic acid synthesis,

 An alkoxy group having 1 to 4 carbon atoms,

 Mercapto group,

 A mercapto group protected with a protecting group for nucleic acid synthesis,

 An alkylthio group having 1 to 4 carbon atoms,

 Amino group,

 An amino group protected with a protecting group for nucleic acid synthesis,

 An amino group substituted with an alkyl group having 1 to 4 carbon atoms,

 An alkyl group having 1 to 4 carbon atoms, and

Halogen atom.

2. R ¹ is a hydrogen atom, an aliphatic acyl group, an aromatic acyl group, a methyl group substituted with 1 to 3 aryl groups, a lower alkyl, a lower alkoxy, a halogen or cyano group, and the aryl ring is substituted. The compound according to claim 1, which is a methyl group or a silyl group substituted with 1 to 3 aryl groups, and a salt thereof.

3. The method according to claim ¹ , wherein R ¹ is a hydrogen atom, an acetyl group, a benzoyl group, a benzyl group, a p-methoxybenzyl group, a dimethoxytrityl group, a monomethoxytrityl group, or a tert-butyldiphenylsilyl group. Compounds and salts thereof.

4. R ² force 1 aryl group substituted with hydrogen atom, aliphatic acyl group, aromatic acyl group, methyl group substituted with 1 to 3 aryl groups, lower alkyl, lower alkoxy, halogen or cyano group 4.A methyl group, a silyl group, a phosphoramidite group, a phosphonyl group, a phosphate group, or a phosphate group protected with a protecting group for nucleic acid synthesis, which is substituted with 3 to 3 aryl groups. Or the compound according to item 1 or a salt thereof.

5. R ² force hydrogen atom, acetyl group, benzoyl group, benzyl group, p-methoxybenzyl group, tert-butyldiphenylsilyl group, -P (0C ₂ CN) (NCH (CH ₃ ) ₂ ), -P (0CH ₃ ) (NCH (C) ₂ ), a phosphonyl group, or a 2-chloro phenyl or 4-chloro phenyl phosphate group, and the compound according to any one of claims 1 to 3, and a compound thereof. salt.

 6. The compound according to any one of claims 1 to 5, wherein A is a methylene group, and a salt thereof.

7. B is 6-aminopurine-9-yl (that is, adenyl), 6-aminopurine-1-yl, 2,6-diaminopurine-9-yl, 2_ in which the amino group is protected with a protecting group for nucleic acid synthesis. Amino-6-chloro-purine 9-yl, 2-amino-6-chloro-purine 9-yl, in which the amino group is protected by a protecting group for nucleic acid synthesis, 2-amino-6-fluoro-purine 9-yl, 2-amino-6-fluoropurine-1-yl, 2-amino-6-fluoropurine-9-yl in which the amino group is protected by a nucleic acid synthesis-protecting group, 2-amino-6-bromopurine-19-yl, in which the amino group is protected by a nucleic acid synthesis-protecting group —Amino-6-bromopurine-9Tyl, 2-amino-6-hydroxypurine-19-yl (ie, guaninyl), 2-amino-6-hydroxypurine- _9- yl with the amino group protected by a protecting group for nucleic acid synthesis And amino groups 2-amino-6-hydroxypurine-1-yl, 6-amino-2-methoxypurine-9-inole, 6-amino-2-chloropurine-9-inole whose hydroxyl group is protected by a protecting group for nucleic acid synthesis , 6—Amino 1 2—Fluoroplin 1 9 2,6—Dimethoxypurine 9-1,2,6-Dichloropurine 9-1,6—Mercaptopurine 9-1,2—oxo-1-4-amino-1,2—Jihi Dropyrimidine (ie, cytosinyl), a 2-oxo-one in which the amino group is protected with a protecting group for nucleic acid synthesis.

4-amino-1,2-dihydroxypyrimidine-11-yl, 2-oxo-4-amino-5-fluoro-1,2-dihydroxypyrimidine-11-yl, and the amino group is a protecting group for nucleic acid synthesis. Protected 2-oxo-4-amino-1 5-fluoro-1,2-dihydroxypyrimidine 1-11, 4-amino-1

2-oxo-5-chloro-1,2-dihydroxypyrimidine-1-yl, 2-oxo-4-methoxy-1,2-dihydroxypyrimidine-1 T-l, 2-oxo-14-mercapto 1,2-dihydropyrimidine-1T, 2-oxo-14-hydroxy-1,2-dihydropyrimidine-1-inole (i.e., peracidil), 2-oxo-1-hydroxy-1-5 —Methylpyrimidine-1-yl (ie, thyminyl), 4-amino-5-methyl-2-oxo-11,2-dihydroxypyrimidine—-1-yl (ie, 5-methylcytosinyl) or amino group The compound according to any one of claims 1 to 6, which is a 4-amino-5-methyl-12-oxo-1,1,2-dihydropyrimidine-11-yl group protected by a synthetic protective group. Its salt.

 8. B-force; 6-benzoylaminopurine-1 9-yl, adenyl, 2-isobutyrylamino-1 6-hydroxypurine-19-yl, guaninyl, 2-oxo4, 1-benzoylamino-1,2- A dihydropyrimidin-1-yl, cytosinyl, 2-oxo-5-methyl-14-benzoylamino-1,2-dihydroxypyrimidine-11-yl, 5-methylcytosinyl, peracinyl or thyminyl group. 7. The compound according to any one of claims 1 to 6, and a salt thereof.

 9. Compounds and salts thereof selected from the following group;

 3'-0, 4'-C-ethylene guanosine,

3'-0, 4'-C-ethylene adenosine,

 5'-O-Dimethoxytrityl-3'-0,4, -C-ethylene-6 --- benzoinoleadenosine, 5'-0-Dimethoxytrityl-3'-0,4'-C-ethylene-2 -Ν-isobutyrylguanosine

3'-0, 4'-C-ethylene-2- 2-Ν-isobutyrinoleguanosine,

3'-0,4'-C-ethylene-6-Ν-benzoyladenosine,

5'-0-Dimethoxytrityl-3'-0,4'-C-ethylene-6- 6-benzoinoleadenosine-2 '-Ο-(2-cyanoethyl Ν, Ν-diisopropyl) phosphoramidite

 5'-Ο-Dimethoxytrityl-3 '-0, 4' Ethylene-2- 2-isobutyrylguanosine

2'-Ο- (2-cyanoethyl Ν, Ν-diisopropyl) phosphoramidite

 3'-0, 4'-C-ethylene pyridine,

 3'-〇, 4'-C-ethylene-5-methylperidine,

 3 '-0, 4'-C-ethylene cytidine,

 3'-0, 4'-C-ethylene-5-methylcytidine,

 2 ', 5'-di-Ο-benzyl-3'-0,4'-C-ethyleneperidine,

 5 '-0-Dimethoxytritinol-3' -0, 4'-C-ethyleneperidine,

 5'-0-Dimethoxytrityl-3'-〇, 4'-C-ethylene-5-methylperidine,

 5'-0-Dimethoxytritinol-3'-0,4'-C-ethylene-4- 4-Ν-benzoylcytidine,

5'-0-Dimethoxytritinole-3'-0,4'-C-Ethylene-4 --- benzoinole-5-methinolecitidine,

 3'-0, 4'-C-ethylene-4- 4-benzoylcytidine,

 3'-0,4'-C-ethylene-4- 4-benzoyl-5-methylcytidine,

 5'-0-Dimethoxytrityl-3'-Ο, 4'-C-ethylene-peridine-2 '--- (2-cyanoethyl Ν, Ν-diisopropyl) phosphoramidite,

 5'-0-Dimethoxytrityl-3'-0,4'-C-ethylene-5-methylperidine-2'-Ο- (2-cyanoethylΝ, Ν-diisopropyl) phosphoramidite,

 5'-Ο-Dimethoxytritinole-3'-0,4'-C-ethylene-4- 4--benzoylcytidine-2'-Ο- (2-cyanoethylΝ, Ν-diisopropyl) phosphoramidite and 5'- 0-Dimethoxytrityl-3'-0,4'-C-ethylene-4 --- benzoyl-5-methylcytidine-2'-0- (2-cyanoethylΝ, Ν-diisopropyl) phosphoramidite.

1 0. The following general formula (2)

(2)

 [Wherein, A represents an alkylene group having 1 to 4 carbon atoms;

B is a purine 9-yl group, a 2-oxo-1,2-dihydroxypyrimidine 11-yl group or a substituted purine 9-yl group or a substituted 2-substituted group having a substituent selected from the following α group. —Oxo-1,2—dihydropyrimidine-1-yl. ] Oligonucleotide analogs containing one or more of the structures represented by the following formulas, and pharmacologically acceptable salts thereof. However, when two or more of the above structures are contained, Β is the same or different between the structures.

 Group)

 Hydroxyl group,

 A hydroxyl group protected by a protecting group for nucleic acid synthesis,

 An alkoxy group having 1 to 4 carbon atoms,

 Mercapto group,

 A mercapto group protected with a protecting group for nucleic acid synthesis,

 An alkylthio group having 1 to 4 carbon atoms,

 Amino group,

 An amino group protected with a protecting group for nucleic acid synthesis,

 An amino group substituted with an alkyl group having 1 to 4 carbon atoms,

 An alkyl group having 1 to 4 carbon atoms, and

 Halogen atom.

 11. The oligonucleotide analogue according to claim 10, wherein Α is a methylene group, and a pharmacologically acceptable salt thereof.

12. B is B, 6-aminopurine 9-yl (that is, adenyl), 6-aminopurine 9-yl, 2,6-diaminopurine in which the amino group is protected by a protecting group for nucleic acid synthesis. 9-yl, 2-amino-6-chloro-purine 9-yl, 2-amino-6-chloro-purine 9-yl, 2-amino-6-, whose amino group is protected by a protecting group for nucleic acid synthesis 2-Amino-6-fluoropurine 9-yl, 2-amino-6-bromopurine 19-yl, whose amino group is protected with a protecting group for nucleic acid synthesis, and the amino group is a nucleic acid 2-amino-6-bromopurine 9-yl, 2-amino-6-hydroxypurine-9-yl (ie, guaninyl), protected by a synthetic protecting group, is a protecting group for nucleic acid synthesis. 2-aminopurine-19-yl, 2-amino-2-hydroxypurine-19-yl, amino- and hydroxyl-protected with protecting groups for nucleic acid synthesis —Methoxy pudding —9—Innole, 6—Amino 2 —Cloth pudding 9 —Yl, 6-amino-2-fluorinpurine 9-yl, 2,6-dimethoxypurine 19-yl, 2,6-dichloropurine 19-yl, 6-mercaptopurine 91-yl 2-oxo-14-amino-1,2-dihydropyrimidine-1-yl (ie, cytosinyl), 2-oxo-14-amino-1,2-dihydropyrimidine-1 in which the amino group is protected by a protecting group for nucleic acid synthesis 1-yl, 2-oxo-1-amino-5-fluoro-1,2-dihydropyrimidine-1-yl, 2-amino-4-amino with the amino group protected by a protecting group for nucleic acid synthesis 5-fluoro-1,2-dihydropyrimidine-1-yl, 4-amino-1,2-oxo-5-chloro-1,2-dihydroxypyrimidine-1-yl, 2-oxo-4-methoxy-1,1, 2-Dihydropyrimidine-1-yl, 2-oxo-1-4-mercap 1,2-dihydroxypyrimidine-1-yl, 2-oxo-4-hydroxy-1,2-dihydropyrimidine—1-yl (that is, peracidil), 2-oxo-4-hydroxy-1 The 5-methylpyrimidin-1-yl (ie, thyminyl), 4-amino-1-5-methyl-12-oxo-1,2-dihydropyrimidin-1-yl (ie, 5-methylcytosinyl) or amino group is a nucleic acid 12. The compound according to any one of claims 10 to 11, which is a 4-amino-15-methyl-12-oxo-11,2-dihydropyrimidin-11-yl group protected by a synthetic protecting group. And a pharmacologically acceptable salt thereof.

13 B power; 6-benzoylaminopurine 9-yl, adenyl, 2-isobutyrylamine 6-hydroxypurine 9-yl, guaninyl, 2-oxo-1-4-benzoylamino 1,2- Dihydropyrimidine-1 1-yl, cytosine, 2-oxo-5-methinole _4-benzylamino 1,2-dihydroxypyrimidine-1 1-yl, 5-methylcytosinyl, peracyn 12. The oligonucleotide according to claim 10, which is a thiol or thyminyl group, and a pharmacologically acceptable salt thereof.