JPS62149696A - 2'-deoxy-5-fluorouridine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (one of R<1> and R<2> is phenyl-lower alkyl, naphthyl-lower alkyl, etc., which may have a substituent group such as lower alkyl, halogen, etc., on the phenyl ring and the other is H or acyl; R<3> is H, acyl or tetrahydrophenyl). EXAMPLE:5'-O-benzyl-2'-deoxy-5-fluorouridine. USE:An antitumor agent having excellent carcinostatic activity and low toxicity. PREPARATION:A compound of formula II (at least one of R<4> and R<5> is H and the other is H, acyl, etc.) is made to react with the compound of formula RX (R is phenyl-lower alkenyl, naphthyl-lower alkyl, etc.; X is halogen) in the presence of a dehydrohalogenation agent such as NaOH in a solvent such as THF and the reaction product is optionally subjected to deprotection or deacylation reaction. The amount of the compound of formula RX is preferably 1-5mol per 1mol of the compound of formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel 2'-deoxy-5-fluorouridine derivatives.

Conventional technology The derivative of the present invention is a new compound that has not been described in any literature.

Problems to be Solved by the Invention The present inventors have conducted intensive studies to improve the antitumor activity and reduce the toxicity of 2'-deoxy-5-fluorouridine. Successfully synthesized a new compound in which the 3' or 5' position of fluorouridine was substituted with a phenyl lower alkoxy group, a phenyl lower alkenyloxy group, or a naphthyl lower alkoxy group with or without a specific substituent, and It has been found that this compound exhibits an excellent anticancer effect that meets the above objectives and is extremely useful as an antitumor agent.

The present invention is based on the general formula [wherein R' and R2 are substituted on a phenyl ring selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, and a di(lower alkyl)amine group] A phenyl lower alkyl group which may have a phenyl lower alkyl group or a phenyl lower alkyl group having a lower alkylenedioxy group or a phenyl group as a substituent, a phenyl lower alkenyl group or a naphthyl lower alkyl group, and the other one represents a hydrogen atom or an acyl group . R
3 represents a hydrogen atom, an acyl group, or a tetrahydrofuranyl group.

In this specification, the terms "lower alkyl" and "lower alkoxy", whether used as such or included in various functional groups, refer to methyl, ethyl, propyl, respectively. , isopropyl, butyl, t-butyl, pentyl, hexyl and other linear or branched alkyl groups having 1 to 6 carbon atoms, and methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, hexyloxy groups Straight chain or branched CI such as
An example is a Cs alkoxy group.

In addition, in this specification, the word "halogen", whether used as it is or included in various functional groups, includes fluorine, chlorine, bromine, iodine, etc. shall be taken as a thing. Furthermore, in this specification, the term "lower alkylene dioxy" refers to methylene dioxy, ethylene dioxy, trimethylene dioxy, whether used as such or included in various functional groups. Examples include CI C4 alkylenedioxy groups such as dioxy and tetramethylenedioxy groups. Furthermore, in this specification, the term "lower alkenyl", whether used as such or included in various functional groups, refers to vinyl, 1-propenyl, allyl, isopropenyl, Examples include C2C6 alkenyl groups such as 1-butenyl, 3-butenyl, 1-pentenyl, 4-pentenyl, 1-hexenyl, 3-hexenyl, and 5-hexenyl.

The lower alkyl group as a substituent of the substituted phenyl lower alkyl group includes, for example, a straight chain or branched chain having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, and hexyl group. an alkyl group,
Examples of lower alkoxy groups include those having 1 to 1 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, and hexyloxy groups.
Examples of the linear or branched alkoxy group of 6 and the halogen atom include fluorine, chlorine, bromine, and iodine atoms, respectively. Examples of the lower alkoxycarbonyl group include linear or branched alkoxycarbonyl groups having 2 to 7 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonylcarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl. Examples of the di(lower alkyl)amino group include N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, N,N-dibutylamino, N,N-diethylamino, N,N-diethylamino, N-methyl, N-ethylamino, N-methyl, N-propylamino, N-methyl, N-butylamino, N-methyl, N-pentylamino, N-methyl, N
Examples include dialkylamino groups having the same or different alkyl groups having 1 to 6 carbon atoms, such as -hexylamino, N-ethyl, and N-propylamine groups.

Examples of phenyl lower alkyl groups that may have each of the above substituents or carboxyl groups on the phenyl ring include phenyl groups that may have 1 to 3 of the above substituents, and alkylene groups having 1 to 6 carbon atoms, such as methylene, Ethylene, trimethylene, 1-methylethylene, tetramethylene, 2
Examples include phenylalkyl groups bonded to -methyltrimethylene, pentamethylene, hexamethylene groups, etc.

A specific example is shown below.

benzyl, 2-methylbenzyl, 3-methylbenzyl,
4-Methylbenzyl, 2-ethylbenzyl, 3-ethylbenzyl, 4-ethylbenzyl, 2-propylbenzyl, 3-propylbenzyl, 4-propylbenzyl, 2-
Butylbenzyl, 3-butylbenzyl, 4-butylbenzyl, 2-t-butylbenzyl, 3-t-butylbenzyl, 4-t-butylbenzyl, 2-pentylbenzyl,
3-pentylbenzyl, 4-pentylbenzyl, 2-hexylbenzyl, 3-hexylbenzyl, 4-hexylbenzyl, 2,3-dimethylbenzyl, 2,4-dimethylbenzyl, 2,5-dimethylbenzyl, 2,6 -dimethylbenzyl, 3,4-dimethylbenzyl, 3,5-dimethylbenzyl, 2.3.4-trimethylbenzyl, 2
, 4.5-trimethylbenzyl, 2,3.5-trimethylbenzyl, 2,4,6-trimethylbenzyl, 3゜4
．． 5-trimethylbenzyl, 2,3-diethylbenzyl, 2,4-diethylbenzyl, 2,5-diethylbenzyl, 2,6-diethylbenzyl, 2.4,6-triethylbenzyl, 2,4-dipropylbenzyl, 3,4.5
-Triethylbenzyl, 3-methyl-keyethylbenzyl, 1-phenylethyl, 2-phenylethyl, 2-phenyl-1-methylethyl, 1-(2-methylphenyl)ethyl, 2-(2-methylphenyl)ethyl , 2-(
3-Methylphenyl)ethyl, 2-(4-methylphenyl)ethyl, 1-(2,4-dimethylphenyl)ethyl, 2-(2,4-dimethylphenyl)ethyl, 1-(
2,4,6-dotmethylphenyl)ethyl, 2-(2
, 4,6-drimethylphenyl)ethyl, 3-phenylpropyl, 3-(4-methylphenyl)propyl, 4-
Phenyl.

Butyl, 4-(2-methylphenyl)butyl, 5-phenylpentyl, 5-(3-methylphenyl)pentyl,
6-phenylhexyl, 6-(4-methylphenyl)
Hexyl, 2-methoxybenzyl, 3-methoxypenzyl, 4-methoxybenzyl, 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl, 3-methoxy-4-ethoxybenzyl, 2,
6-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3.5-dimethoxybenzyl, 2.3.4-trimethoxybenzyl, 2,4.5-trimethoxybenzyl, 2
, 3.5-trimethoxybenzyl, 2゜4.6-1-dimethoxybenzyl, 3.4.5-trimethoxybenzyl, 2-ethoxybenzyl, 4-propoxypencyl, 3
-butoxybenzyl, 2-t-butoxybenzyl, 3-
Pentyloxybenzyl, 4-hexyloxybenzyl, 2,3-jethoxypencyl, 1-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)
Ethyl, 3-(4-methoxyphenyl)propyl, 4-
(2-methoxyphenyl)butyl, 5-(4-methoxyphenyl)pentyl, 6-(4-methoxyphenyl)hexyl, 6-(3,4゜5-tripentyloxyphenyl)hexyl, 2-fluorobenzyl, 3 -fluorobenzyl, 4-fluorobenzyl, 2,3-difluorobenzyl, 2,4-difluorobenzyl, 2,5-difluorobenzyl, 2-fluoro-3-chlorobenzyl,
2-fluoro-3-bromobenzyl, 2゜6-difluorobenzyl, 2.3.4-trifluorobenzyl, 2,
4.5-trifluorobenzyl, 2.3.5-trifluorobenzyl, 2.4゜rotrifluorobenzyl, 3
, 4.5-trifluorobenzyl, 1-(2-fluorophenyl)ethyl, 2-(2-fluorophenyl)ethyl, 3-(3-fluorophenyl)propyl, 4-(2-fluorophenyl)ethyl
-fluorophenyl)butyl, 5-(2-fluorophenyl)pentyl, 6-(3-fluorophenyl)hexyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2,3-dibromobenzyl, 2- Bromo-3-fluorobenzyl, 2-fluoro-4-bromobenzyl, 2゜4-dibromobenzyl, 2,5-dibromobenzyl, 2,6-dibromobenzyl, 2.3.4-tribromobenzyl, 2,4 .5-tribromobenzyl,
2,3.5-tribromobenzyl, 2,4゜6-tribromobenzyl, 3,4.5-tribromobenzyl, 1-
(2-bromophenyl)ethyl, 2-(2-bromophenyl)ethyl, 3-(2-bromophenyl)propyl, 4-(3-bromophenyl)butyl, 5-(2-bromophenyl)pentyl, 6- (4-Bromophenyl)hexyl, 2-chloropencyl, 3-chlorobenzyl, 4
-chlorobenzyl, 2,3-dichlorobenzyl, 2゜4
-dichlorobenzyl, 2,5-dichlorobenzyl, 2,
6-dichlorobenzyl, 2-bromo-4-chlorobenzyl, 2-fluoro-4-chlorobenzyl, 2,3.4-
Trichlorobenzyl, 2゜4.5-trichlorobenzyl, 2,3.5-trichlorobenzyl, 2,4.6-trichlorobenzyl, 3,4.5-trichlorobenzyl, 1
-(4-talolophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 3-(2-chlorophenyl)propyl, 4-(4-chlorophenyl)butyl, 5-(3-chlorophenyl)pentyl, 6-(4-chlorophenyl) )
Hexyl, 2-(3,4-dichlorophenyl)ethyl, 2-iodobenzyl, 3-iodobenzyl, 4-iodopencyl, 3,4-shortbenzyl, 3,4.5-
Triiodobenzyl, 2-(3-iodophenyl)ethyl, 6-(2-iodophenyl)hexyl, 2-carboxybenzyl, 3-carboxybenzyl, 4-carboxybenzyl, 2,3-dicarboxybenzyl, 2,4
-dicarboxybenzyl, 2,5-dicarboxybenzyl, 3,4-dicarboxybenzyl, 3,5-dicarboxybenzyl, 2.3.4-tricarboxybenzyl, 2,4.6-tricarboxybenzyl, 3,4.5-
tricarboxybenzyl, 1-(4-carboxyphenyl(4-carboxyphenyl)ethyl), 2-(2.

6-dicarboxyphenyl)ethyl, 3-(3-carboxyphenyl)propyl, 5-(2,4.

6-Doricarpoxyphenyl)pentyl, 6-(4-carboxyphenyl)hexyl, 6- (3.

5-Dicarboxyphenyl>hexyl group, 4-methoxycarbonylbenzyl, 3-methoxycarbonylbenzyl, 2-methoxycarbonylbenzyl, 4-ethoxycarbonylbenzylcarbonylbenzylundyl, 4-propoxycarbonylbenzyl, 4-butoxycarbonylbenzyl, 4 -pentyloxycarbonylbenzyl, 4-hexyloxycarbonylbenzyl,
3,4-dimethoxycarbonylbenzyl, 2,4-dimethoxycarbonylbenzyl 2,3,4-trimethoxycarbonylbenzyl, 3,4
．． 5-trimethoxycarbonylbenzyl 2-(4-methoxycarbonylphenyl)ethyl, 6-(4-methoxycarbonylphenyl)hexyl, 2-(N,N-dimethylamino)benzyl, 3-(N,N-dimethylamino)
Benzyl, 4-(N,N-dimethylamino)benzyl,
4-(N-methyl, N-ethylamino)benzyl, 2,
4-di(N,N-dimethylamino)benzyl, 2.

4,6-tri(N,N-dimethylamino)benzyl group, etc.

In the above general formula (1), the lower alkylene dioxy group or phenyl lower alkyl group having a phenyl group as a substituent defined by R1 and R2 is, for example, 2,
3-methylenedioxybenzyl, 3,4-methylenedioxybenzyl, 2.

3-ethylenedioxypencyl, 3,4-ethylenedioxybenzyl, 3,4-trimethylenedioxybenzyl, 3,4-tetramethylenedioxybenzyl, 1-(3
．． 4-methylenedioxyphenyl)ethyl, 2-(3.
4-methylenedioxyphenyl)ethyl, 3-(3.4
-methylenedioxyphenyl)propyl, 4-(3.4
-methylenedioxyphenyl)butyl, 5- (3.4
-methylenedioxyphenyl)pentyl, 6-(3.

4-methylenedioxyphenyl)hexyl, 3-(3.
4-trimethylenedioxyphenyl)propyl, 2-phenylbenzyl, 3-phenylbenzyl, 4-phenylbenzyl, 2-(3-phenylphenyl)ethyl, 1-
(4-Phenylphenyl)ethyl, 2-(4-phenylphenyl)ethyl, 3-(4-phenylphenyl)propyl, 4-(4-phenylphenyl)butyl, 5-(
A phenyl group bonded to an alkylene dioxy group having 1 to 4 carbon atoms such as 4-phenylphenyl)pentyl or 6-(4-phenylphenyl)hexyl group or a phenyl group to an alkylene group having 1 to 6 carbon atoms. Examples include phenylalkyl groups.

In addition, the phenyl lower alkenyl group represented by R1 and R2 includes 2-phenylvinyl, 3-phenyl-1-
Propenyl, 3-phenyl-2-propenyl, 4-phenyl-1-butenyl, 4-phenyl-2-butenyl, 4
-Phenyl-C such as phenyl-3-butenyl, 5-phenyl-4-pentenyl, 6-phenyl-5-hexenyl, etc.
An example is a 2-C6 alkenyl group.

In addition, the naphthyl lower alkyl group represented by R1 and R2 includes α-naphthylmethyl, β-naphthylmethyl,
2-(α-naphthyl>ethyl, 3-(β-naphthyl)propyl, 4-(α-naphthyl)butyl, 5-(β-naphthyl)pentyl, 6-(α-naphthyl)hexyl, 3-
Examples include naphthyl lower alkyl groups in which the alkyl moiety has 1 to 6 carbon atoms, such as (α-naphthyl)-2-methylpropyl and 1-(α-naphthyl)ethyl groups.

Furthermore, as disclosed herein, in particular R1, R2 and R
The acyl group represented by 3 includes a wide variety of groups, including the following.

(i) halogen atom, hydroxyl group, lower alkoxy group,
An alkanoyl group having 1 to 20 carbon atoms and having or not having as a substituent a group selected from the group consisting of an aryloxy group, a substituted or unsubstituted aryl group, a phenyl lower alkoxycarbonyl group, and a lower alkyl carbamoyl group.

(11) As a substituent on the aryl ring, a halogen atom, a lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a nitro group, a cyano group,
Contains 1 to 3 substituents selected from the group consisting of a phenyl lower alkoxycarbonyl group, a hydroxyl group, a guanidyl group, a phenyl lower alkoxy group, an amino group, and an amine group substituted with a lower alkyl group, or a lower alkylene dioxy group Sometimes an arylcarbonyl group.

(iii> A 5- or 6-membered unsaturated heterocyclic carbonyl group having a nitrogen atom, sulfur atom, or oxygen atom as a heteroatom.

(iv) carbonate residues such as aryloxycarbonyl groups, chain or cyclic alkoxycarbonyl groups;

(V) Substituted or unsubstituted cycloalkylcarbonyl group.

(vi) lower alkenyl (or lower alkynyl) carbonyl group.

(vii) Lower alkenyl (or lower alkynyl)
Oxycarbonyl group.

(viii) Formula (wherein RX is a substituent such as a hydroxyl group, an oxo group, a halogen atom, an amino group, a carboxyl group, a cyan group, a nitro group, a carbamoyl group, a lower alkylcarbamoyl group, a carboxylower alkylcarbamoyl group, a lower alkoxycarbonyl lower Alkylcarbamoyl group, which may have 1 to 3 halogen atoms, lower alkoxy groups, or lower alkyl groups as substituents on the phenyl ring), lower alkyl group, lower alkenyl group, lower alkoxycarbonyl group, tetrahydrofuran Nyl group, tetrahydropyranyl group, lower alkoxy lower alkyl group,
A pyridyl group which may have 1 to 4 g of a group selected from a lower alkylthio-lower alkyl group, a phenyl lower alkoxy lower alkyl group, a phthalidyl group, and an acyloxy group in which the acyl moiety is the acyl group of R1, R2, and R3 described above. , Y represents an arylene group] pyridyloxy, arylene, and arylene groups. Specific examples of groups that conform to each group of the second class are as shown below.

(1) Has or does not have a group selected from the group consisting of a halogen atom, a hydroxyl group, a lower alkoxy group, an aryloxy group, a substituted or unsubstituted aryl group, a phenyl lower alkoxycarbonyl group, and a lower alkyl carbamoyl group as a substituent. Alkanoyl group having 1 to 20 carbon atoms.

formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl,
Unsubstituted alkanoyl groups having 1 to 20 carbon atoms such as octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, eicosanoyl; monochloroacetyl; Monobromoacetyl, dichloroacetyl, trichloroacetyl, 3-chloropropionyl,
Alkanoyl group having 2 to 6 carbon atoms substituted with 1 to 3 halogen atoms such as 4-talobutyryl, 5-chloropentanoyl, 6-chlorohexanoyl group; hydroxyacetyl, 3-bitroxypropionyl, 5-hydroxypentanoyl , 4-hydroxybutanoyl, 6-hydroxyhexanoyl, and other hydroxyl-substituted alkanoyl groups having 2 to 6 carbon atoms; methoxyacetyl, ethoxyacetyl, 3-propoxyprobionyl, 6-hexyloxyhexanoyl, 3-methoxy Alkanoyl groups having 2 to 6 carbon atoms substituted with alkoxy having 1 to 6 carbon atoms such as propionyl groups: phenoxyacetyl, 2-phenoxypropionyl, 3-phenoxypropionyl, 4-phenoxybutyryl, 5-phenoxypentanoyl, 6-phenol Ninoxyhexanoyl,
α-C2-C6 alkanoyl group substituted with phenoxy or naphthyloxy such as naphthyloxyacetyl group; α-
Phenylacetyl, 2-phenylpropionyl, 3-phenylpropionyl, 4-phenylbutyryl, 5-phenylpentanoyl, 6-phenylhexanoyl, α-(
2-talolophenyl>acetyl, α-(4-methylphenyl)acetyl, α-<3.4゜5-trimethoxyphenyl)acetyl, α-(3,4-dimethoxyphenyl)
Acetyl, 6-(4-carboxyphenyl 4-(4-ethoxycarbonylphenyl)pentanoyl, α-(4-nitrophenyl)acetyl, α-(4-cyanophenyl)acetyl, α-naphthylacetyl, β-naphthylacetyl group A group selected from the group consisting of halogen atom, lower alkyl group, lower alkoxy group, carboxyl group, lower alkoxycarbonyl group, nitro group and cyan group as a substituent on the aryl ring (phenyl ring, naphthyl ring, etc.) such as C2-C6 alkanoyl group with or without 1-3 aryl substitutions; α-benzyloxycarbonylacetylpionyl, 3-benzyloxycarbonylpropionyl, 4-benzyloxycarbonylbutyryl, 5-benzyloxy Carbonylpentanoylpropionyl, 3-(β-phenethyloxycarbonyl)propionyl, 5-(benzyloxycarbonyl)hexanoyl, 7-(benzyl-oxycarbonyl)heptanoyl, 8-(α-phenethyloxycarbonyl)octanoyl, 9-( β-phenethyloxycarbonyl)
Nonanoyl, 10-(benzyloxycarbonyldecanoyl), 11-(β-phenethyloxycarbonyl)tridecanoyl, 15-(benzyloxycarbonyl)pentadecanoyl, 17-(benzyloxycarbonyl)heptadecanoyl, 20-(benzyloxycarbonyl)
Alkanoyl group having 1 to 20 carbon atoms having a phenyl-02C7 lower alkoxycarbonyl group such as eicosanoyl: methylcarbamoylacetyl, ethylcarbamoylacetyl, propylcarbamoylacetyl, butylcarbamoylacetyl, t-butylcarbamoylacetyl, pentylcarbamoylacetyl, hexylcarbamoyl Acetyl, methylcarbamoylpropionylthylcarbamoylbutyryl, propylcarbamoylpentanoyl, ethylcarbamoylhexanoyl, ethylcarbamoylheptanoyl, methylcarbamoyloctanoylnonylcarbamoylpentadecanoyl, methylcarbamoylheptadecanoyleicosanoyl ~ 6 lower alkylcarbamoyl having a group with 1 or more carbon atoms
Examples include 20 alkanoyl groups.

(11) As a substituent on the aryl ring, a halogen atom, a lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a nitro group, a cyan group,
Contains 1 to 3 substituents selected from the group consisting of a phenyl lower alkoxycarbonyl group, a hydroxyl group, a guanidyl group, a phenyl lower alkoxy group, an amino group, and an amine group substituted with a lower alkyl group, or a lower alkylene dioxy group An inevitable arylcarbonyl group.

Benzoyl, α-naphthylcarbonyl, β-naphthylcarbonyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methylbenzoyl, 2.4-dimethylbenzoyl, 3,4.5-trimethylbenzoyl, 4-ethylbenzoyl, 2- Methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2,4-dimethoxybenzoyl, 3,4.5-trimethoxybenzoyl, 4
-Ethoxybenzoyl, 2-methoxy-4-ethoxybenzoyl, 2-propoxybenzoyl, 3-propoxybenzoyl, 4-propoxybenzoyl, 2,4-dipropoxybenzoyl, 3,4.5-tripropoxybenzoyl, 2-carboxybenzoyl , 3-carboxybenzoyl, 4-carboxybenzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2,3-dichlorobenzoyl, 2,4.6-i-dichlorobenzoyl, 2-bromobenzoyl, 4 -Fluorobenzoyl, 2-methoxycarbonylbenzoylmethoxycarbonylbenzoyl, 2-ethoxycarbonylbenzoyl, 3-ethoxycarbonylbenzoyl 3-propoxycarbonylbenzoyl, 4-propoxycarbonylbenzoyl, 2-isopropoxycarbonylbenzoyl, 3-isopropoxycarbonylbenzoyl, 4-Impropoxycarbonylbenzoyl, 2-butoxycarbonylbenzoyl, 3-butoxycarbonylbenzoyl, 4-butoxycarbonylbenzoyl, 2-t
-Butoxycarbonylbenzoyl, 3-t-butoxycarbonylbenzoyl, 4-butoxycarbonylbenzoyloxycarbonylbenzoyl, 3-pentyloxycarbonylbenzoyl, 4-pentyloxycarbonylbenzoyl, 2-hexyloxycarbonylbenzoyl, 3
-hexyloxycarbonylbenzoyl, 4-hexyloxycarbonylbenzoyl, 3,5-dimethoxycarbonylbenzoyl, 3,4.5-trimethoxycarbonylbenzoyl, β-methyl-α-naphthylcarbonyl,
α-methoxy-β-naphthylcarbonyl, β-chloro-
α-Naphthylcarbonyl, 2-cyanobenzoyl, 4-
Cyanobenzoyl, 2-nitrobenzoyl, 4-nitrobenzoyl, 2-benzyloxycarbonylbenzoyl, 4-benzyloxycarbonylbenzoyl, 3-(
α-phenethyloxycarbonyl)benzoyl, 4-(
β-phenethyloxycarbonyl)benzoyl, 4-(
3-phenylpropoxylcarbonyl>benzoyl, 4
-(6-]Dylhexyloxycarbonyl)benzoyl, 2-hydroxybenzoyl, 3-hydroxybenzoyl, 2,3-dihydroxybenzoyl, 3,4-dihydroxybenzoyl, 3,4.5-trihydroxybenzoyl, 4-hydroxy Benzoyl, 2-guanidylbenzoyl, 3-guanidylbenzoyl, 4-guanidylbenzoyl, 2-(benzyloxy)benzoyl, 3-
(benzyloxy)benzoyl, 4-(benzyloxy)benzoyl, 2-(α-phenethyloxy)benzoyl, 3-(α-phenethyloxy)benzoyl, 4-(
α-phenethyloxy)benzoyl, 2-(β-phenethyloxy)benzoyl, 3-(β-phenethyloxy)benzoyl, 4-(β-phenethyloxy)benzoyl, 4-(3-phenylpropoxy)benzoyl, 4-
(4-phenylbutoxy)benziyl, 4-(5-phenylpentyloxy)benzoyl, 4-(6-phenylhexyloxy)benzoyl, 2-aminobenzoyl,
3-7 minobenzoyl, 4-aminobenzoyl, 2-methylaminobenzoyl, 3-methylaminobenzoyl,
4-Methylaminobenzoyl, 2-ethylaminobenzoyl, 3-propylaminobenzoyl, 4-butylaminobenzoyl, 3-pentylaminobenzoyl, 4-hexylaminobenzoyl, 2-(N,N-dimethylamino)benzoyl, 3 - (N,N-dimethylamino)
Benzoyl, 4-(N,N-dimethylamino)benzoyl, 3-(N-methyl-N-ethylamino)benzoyl, 4-(N,N-diethylamino)benzoyl,
3-(N,N-dipropylamino)benzoyl, 4-
(N,N-dibutylamino)benzoyl, 4-(N
, N-diethylamino)benzoyl, 4- (N,N-
Diethylamino>benzoyl, 3-benzyloxycarbonyl-6-(β-phenethyloxycarbonyl-naphthylcarbonylcarbonyl-2-naphthylcarbonyl, 5-(α-phenethyloxycarbonyl)-2-naphthylcarbonyl, 2
-Hydroxy-1-naphthylcarbonyl, 3-hydroxy-1-naphthylcarbonyllunyl, 6-hydroxy-1-naphthylcarbonyl, 7-
Hydroxy-1-naphthylcarbonyl, 8-hydroxy-1-naphthylcarbonyl, 1-hydroxy-2-naphthylcarbonyl, 4-hydroxy-2-naphthylcarbonyl, 5-bitroxy-2-naphthylcarbonyl, 7-
Hydroxy-2-naphthylcarbonyl, 2-guanidyl-1-naphthylcarbonyl, 3-guanidyl-1-naphthylcarbonyl, 5-guanidyl-1-naphthylcarbonyl, 6-guanidyl-1-naphthylcarbonyl, 8-
Guanidyl-1-naphthylcarbonyl, 1-guanidyl-2-naphthylcarbonyl, 4-guanidyl-2-naphthylcarbonyl, 6-guanidyl-2-naphthylcarbonyl, 8-guanidyl-2-naphthylcarbonyl, 2-
Amino-1-naphthylcarbonyl, 3-amino-1-naphthylcarbonyl, 4-amino-1-naphthylcarbonyl, 6-amino-1-naphthylcarbonyl 2-naphthylcarbonyl, 5-amino-1-naphthylcarbonyl, 7-amino -2-naphthylcarbonyl, 8-
Amino-2-naphthylcarbonyl, 3-(N.N-dimethylamino)-2-naphthylcarbonyl, 4-(N
-Methyl-N-ethylamine〉-1-naphthylcarbonyl, 6- (N,N-dimethylamino〉-1-naphthylcarbonyl, 7- (N-methyl-N-ethylamino)
-2-naphthylcarbonyl, 8- (N-methyl-N-
ethylamino)-1-naphthylcarbonyl, 3,4-methylenedioxybenzoyl, 3,4-ethylenedioxybenzoyl, 2.

Substituents such as 3-methylenedioxybenzoyl group include lower alkyl group, lower alkoxy group, halogen atom, carboxyl group, nitro group, cyano group, lower alkoxycarbonyl group, phenyl lower alkoxycarbonyl group, hydroxyl group, guanidyl group, phenyl group. 1 to 3 groups selected from the group consisting of lower alkoxy groups, amino groups, and amine groups substituted with lower alkyl groups, or phenylcarbonyl or naphthylcarbonyl with or without lower alkylenedioxy groups; An example is an arylcarbonyl group.

(iii) A 5- or 6-membered unsaturated heterocyclic carbonyl group having a nitrogen atom, sulfur atom or oxygen atom as a heteroatom.

2-chenylcarbonyl, 3-chenylcarbonyl, 2
-furanylcarbonyl, 3-furanylcarbonyl, 4-
Thiazolylcarbonyl, 2-quinolylcarbonyl, 2-
Pyrazinylcarbonyl, 2-pyridylcarbonyl, 3-
Examples include chenylcarbonyl groups such as pyridylcarbonyl and 4-pyridylcarbonyl groups, furanylcarbonyl, thiazolylcarbonyl, quinolylcarbonyl, pyridinylcarbonyl, and pyridylcarbonyl groups.

(iv) carbonate residues such as aryloxycarbonyl groups, chain or cyclic alkoxycarbonyl groups;

Phenoxycafflebonyl, α-naphthyloxycarbonyl 2-methylphenoxycarbonyl, 3-methylphenoxycarbonyl, 4-methylphenoxycarbonylnylbonyl, 4-ethylphenoxycarbonyl, 2-methoxyphenoxycarbonylxphenoxycarbonyl, 4-methoxyphenoxycarbonyl , 2,4-dimethoxyphenoxycarliponyl, 3,4.5-trimethoxyphenoxycarbonyl, 4
-Ethoxyphenoxycarbonyl, 2-propoxyphenoxycarbonyl, 3-propoxyphenoxycarbonyl, 4-propoxyphenoxycarbonyl, 2,4-dipropoxyphenoxycarbonyl, 3,4.

5-tripropoxyphenoxycarbonyl, 2-chlorophenoxycarbonyl, 3-chlorophenoxycarbonyl, 4-talolophenoxycarbonyl, 2,3-dichlorophenoxycarbonyl, 2,4.6-dichlorophenoxycarbonyl, 2 -bromophenoxycarbonyl,
4-Fluorophenoxycarbonyl, β-methyl-α-
Halogen atoms, lower alkoxy groups, and lower alkyl as substituents on aryl rings (phenyl rings, naphthyl rings, etc.) such as naphthyloxycarbonyl, α-zume 1 to xy β naphthyloxycarbonyl β-chloro-α-naphthyloxycarbonyl groups, etc. Aryloxycarbonyl group with or without 1 to 3 groups; methoxycarbonyl,
Chains in which the alkyl moiety has 1 to 8 carbon atoms, such as ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, butoxycarbonyl, pentyloxycarbonylluloptyloxysulfonyl, cyclopentyloxycarbonylluuroctyloxylcarbonyl group Or a cyclic alkoxycarbonyl group can be exemplified.

(V) Substituted or unsubstituted cycloalkylcarbonyl group.

cyclopropylcarbonyl, cyclobutylcarbonyl,
A halogen atom, hydroxyl group, lower alkoxy group or lower alkyl group is used as a substituent on the cycloalkyl ring such as cyclopentylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl, 2-chlorocyclohexylcarbonyl, 3-hydroxycyclopentylcarbonylcarbonyl group. Examples include cycloalkylcarbonyl groups in which the cycloalkyl ring has 3 to 8 carbon atoms.

(vi) lower alkenyl (or lower alkynyl) carbonylvinylcarbonyl, allylcarbonyl, 2-butenylcarbonyl, 3-butenylcarbonyl, 1-methylallylcarbonyl, 2-pentenylcarbonyl, 3-hexenylcarbonyl, ethynylcarbonyl, Examples include carbonyl groups having an alkenyl group or an alkynyl group having 2 to 6 carbon atoms, such as propynylcarbonyl, 2-butynylcarbonyl, 1-methyl-3-pentynylcarbonyl, and 4-hexynylcarbonyl.

(vii) Lower alkenyl (or lower alkynyl)
Oxycarbonyl group.

vinyloxycarbonyl, allyloxycarbonyl, 2
-butenyloxycarbonyl, 3-butenyloxycarbonyl, 2-hexenyloxycarbonyl, 1-methylallyloxycarbonyl, 2-pentenyloxycarbonyl, 3-hexenyloxycarbonyl, ethynyloxycarbonyl, propynyloxycarbonyl, 2- Examples include carbonyl groups having a fulkenyloxy group or an alkynyloxy group having 2 to 6 carbon atoms, such as butynyloxycarbonyl, 1-methyl-3-pentynyloxycarbonyl, and 4-hexynyloxycarbonyl.

(Viii) A pyridyloxyalponylarylene group represented by the formula (Y).

Examples of the substituent in the substituted pyridyl group represented by RX include the following. Examples of the lower alkylcarbamoyl group include N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-butylcarbamoyl, Nt-butylcarbamoyl, N-pentylcarbamoyl, N-hexylcarbamoyl, N,N- Dimethylcarbamoyl N,N-dipropylcarbamoyl, N-isopropyl-
N-methylcarbamoyl, N-ethyl-N-methylcarbamoyl, N-methyl-N-pentylcarbamoyl lunthylcarbamoyl, N,N-diethylcarbamoyl,
N-ethyl-N-hexylcarbamoyl, N-ethyl-
N-hexylcarbamoyl N-hexyl-N-pentylcarbamoyl, N.

Examples include alkylcarbamoyl groups having 1 to 2 alkyl groups having 1 to 6 carbon atoms such as N-diethylcarbamoyl group.

Examples of phenylcarbamoyl groups that may have 1 to 3 halogen atoms, lower alkyl groups, and lower alkoxy groups as substituents on the phenyl ring include N-(2-chlorophenyl)carbamoyl, N-(3.5- Dichlorophenyl N-(3-methoxyphenyl)carbamoyl, N-(4
-propoxyphenyl)carbamoyl, N-(2-methylphenyl)carbamoyl, N-(4-ethylphenyl)carbamoyl, N-(3-isopropylphenyl)carbamoyl, N-(4-hexylphenyl)carbamoyl, N-phenyl One or two phenyl groups are substituted with a halogen atom, an alkoxy group having 1 to 6 carbon atoms, and 1 to 3 alkyl groups having 1 to 6 carbon atoms as substituents on the phenyl ring such as a carbamoylmoyl group. Examples include carbamoyl groups.

Examples of lower alkenyl groups include alkenyl groups having 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, and 2-hexenyl.

Examples of the lower alkoxycarbonyl group include carbonyl groups having an alkoxy group having 1 to 6 carbon atoms, such as a methoxycarbonylcarbonyltoxycarbonyluroxycar group.

Examples of the tetrahydrofuranyl group include 2-tetrahydrofuranyl and 3-tetrahydrofuranyl.

Examples of the lower alkoxy lower alkyl group include methoxymethyl, 3-methoxypropyl, 4-ethoxybutyl, 6-
Propoxyhexyl, 5-isopropoxypentyl, 1
, 1-dimethyl-2-butoxyethyl, 2-methyl-3
-t-butoxypropyl, 2-pentyloxyethyl,
Examples include alkoxyalkyl groups in which the alkoxy moiety and the alkyl moiety each have 1 to 6 carbon atoms, such as a 2-hexyloxyethyl group.

Examples of the phenyl lower alkoxy lower alkyl group include benzyloxymethyl, 2-benzyloxyethyl, 5-(2-phenylpentyloxy)pentyl, in addition to the above-exemplified lower alkoxy lower alkyl group having a phenyl group.
6-benzyloxyhexyl, 4-hexyloxyhexyl, phenylmethoxymethyl, 2-phenylethoxymethyl, 2-(phenylmethoxy)ethyl, 2-(phenylmethoxy)propyl, 4-(phenylbutoxy)butyl, 5-( Phenylmethoxy)pentyl, 6-(phenylbutoxy)hexyl, 2-(2-)ethylethoxy)ethyl, 2-(4-phenylbutoxy)ethyl, 4-
Examples of phenylalkoxyalkyl groups having a phenyl group as a substituent, such as (4-phenylbutoxy)butyl and 6-phenylmethoxyhexyl groups, and in which the alkoxy moiety and the alkyl moiety each have 1 to 6 carbon atoms can.

Examples of the lower alkoxycarbonyl lower alkylcarbamoyl group include methoxycarbonylmethylcarbamoyl, ethoxycarbonylmethylcarbamoylisoproboxycarbonylmethylcarbamoyl, butoxycarbonylmethylcarbamoyl, t-butoxycarbonylmethylcarbamoyl, pentyloxycarbonylmethylcarbamoyl, and hexyl. Oxycarbonylmethylcarbamoyl, 2-methoxycarbonylethylcarbamoylcyclocarbonyl-1-methylethylcarbamoyl, 4-methoxycarbonylbutylcarbamoyl, 2-methoxycarbonyl-rubamoylrbamoylrubamoyl, 4-ethoxycarbonylbutylcarbamoyl, 6- propoxycarbonylhexylcarbamoyl,
5-impropoxycarbonylpentylcarbamoyl,
1,1-dimethyl-2-butoxycarbonylethylcarbamoyl = 3-t-butoxycarbonylpropylcarbamoylmoyl, and the alkyl moiety is an example of a carbamoyl group substituted with one alkoxycarbonylalkyl group having 1 to 6 carbon atoms. can.

As the carboxy lower alkylcarbamoyl group, N-
(Carboxymethyl)carbamoyl-(2-carboxyethyl)carbamoyl, N-(3-carboxypropyl)carbamoyl, N-(2-methyl-2-carboxyethyl)-rubamoyl, N-(4-carboxybutyl)
Examples include carbamoyl)carbamoyl, N-(2,2-dimethyl-2-carboxyethyl)carbamoylcarboxypentyl)carbamoyl, and N-(6-carboxyhexyloxy-C+Cs alkylcarbamoyl).

Examples of the tetrahydropyranyl group include 2-te[·rahydropyranyl, 3-tetrahydropyranyl, and 4-tetrahydrofuranyl.

Lower alkylthio lower alkyl groups include methylthiomethyl, ethylthiomethyl, propylthiomethyl, butylthiomethyl, t-butylthiomethyl, pentylthiomethyl, hexylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, methylthiopentyl, methylthio Examples include C+ Cs alkylthio-C+ Cs alkyl groups such as hexyl, ethylthioethyl, ethylthiobutyl, and propylthiohexyl groups.

As for the acyloxy group, the acyl moiety is the above-mentioned R1, R2
and an acyloxy group represented by R3, but preferably the acyl moiety is one of the above (i) to (vii).
) can be exemplified by the acyloxy group which is the acyl group described in .

Among these substituents of the pyridine ring, hydroxyl group, halogen atom, amine group, carboxyl group, cyano group, nitro group, oxo group, lower alkyl group, lower alkenyl group, lower alkoxycarbonyl group, carbamoyl group and acyloxy group are preferably One to four substituents are substituted at any of the 2nd, 3rd, 4th, 5th, and 6th positions of the pyridine ring. Among the substituents on the pyridine ring, a halogen atom, a lower alkoxy group, and a lower alkyl group are used as substituents on the carbamoyl group, lower alkylcarbamoyl group, and phenyl ring.
A phenylcarbamoyl group, a tetrahydrofuranyl group, a phthalidyl group, a lower alkoxy lower alkyl group, a lower alkoxy lower alkyl group having a phenyl group, and a lower alkoxycarbonyl lower alkyl carbamoyl group, which may have ~3, are preferably at the 1-position of the pyridine ring. join to.

Preferred examples of the group represented by formula (Y) include
is (wherein, R81 is a hydroxy group or an acyloxy group,
Rx2 and Rx4 are each a hydrogen atom, a halogen atom, an amine group, a carboxyl group, a carbamoyl group, a cyano group,
a nitro group, a lower alkyl group, a lower alkenyl group or a lower alkoxycarbonyl group, ×3 R and Rx5 each represent a hydrogen atom, a hydroxy group or an acyloxy group, and at least one of Rx1, Rx3 and Rx5 is a free bitroxyl group When necessary, the keto-enol tautomer atom at the 1-position of the pyridine ring is a lower alkyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a lower alkoxy lower alkyl group, a phthalidyl group, a carbamoyl group, a lower alkoxycarbonyl group. Lower alkylcarbamoyl group, phenyl lower alkoxy lower alkyl group, phenylcarbamoyl group having 1 to 3 substituents selected from halogen atom, lower alkoxy group and lower alkyl group on the phenyl ring, lower alkylcarbamoyl group, carboxyl It may be substituted with a substituent selected from the group consisting of a lower alkylcarbamoyl group, a lower alkylthio lower alkyl group, and a lower alkenyl group. However, at least one of Rx1, Rx3 and Rx5 represents a hydroxy group, and these R81, Rx3 or Rx
It is assumed that the hydrogen atom of one hydroxy group shown in 5 is a group. ].

More preferable groups represented by formula (Y) include formula (Y-a) in which Rx4 is a halogen atom, an amino group, a carboxyl group, a carbamoyl group, a cyan group, a nitro group, a lower alkyl group, a lower alkenyl group, or a lower alkoxy It indicates a carbonyl group.

The most preferred group of formula (Y) is, in formula (Ya),
Rx4 represents a halogen atom or a cyano group.

Specific examples of the pyridyl group represented by RX, which may have the various substituents described above, include the following groups.

2-pyridyl, 3-pyridyl, 4-pyridyl, 2-hydroxy-3-pyridyl, 2-hydroxy-4-pyridyl, 2-hydroxy-5-pyridyl, 2-hydroxy-6
-pyridyl, 2-hydroxy-5-chloro-3-pyridyl, 2-hydroxy-5-chloro-4-pyridyl, 4-
Hydroxy-5-chloro-2-pyridyl, 2-hydroxy-5-chloro-6-pyridyl, 2-hydroxy-5-
Fluoro-4-pyridyl, 4-hydroxy-5-fluoro-2-pyridyl, 2-hydroxy-5-fluoro-6
-pyridyl, 2-hydroxy-5-bromo-4-pyridyl, 4-hydroxy-5-bromo-2-pyridyl, 2-
Hydroxy-5-bromo-6-pyridyl, 2-hydroxy-5-iodo-4-pyridyl, 4-hydroxy-5-
Iodo-2-pyridyl, 2-hydroxy-5-iodo-
6-pyridyl, 2-hydroxy-3-bromo-4-pyridyl, 4-hydroxy-3-bromo-2-pyridyl, 2
-hydroxy-3-chloro-4-pyridyl, 4-hydroxy-3-chloro-2-pyridyl, 2-hydroxy-3
-chloro-6-pyridyl, 2-hydroxy-4-chloro-6-pyridyl, 1-(2-tetrahydrofuranyl)-
1,2-dihydro-2-oxo-3-pyridyl, 1-(
2-tetrahydrofuranyl)-1,2-dihydro-2-
Oxo-4-pyridyl, 1-(2-tetrahydrofuranyl)-1,2-dihydro-2-oxo-5-pyridyl,
1-(2-tetrahydrofuranyl)-1,2-dihydro-2-oxo-6-pyridyl, 1-(3-tetrahydrofuranyl)-1,2-dihydro-2-oxo-4-pyridyl, 1-(2 -tetrahydrofuranyl)-1,2-dihydro-2-oxo-5-chloro-4-pyridyl, 1-
(2-tetrahydrofuranyl), -1,2-dihydro-
2-oxo-5-chloro-6-pyridyl, 1-(2-tetrahydrofuranyl)-1,2-dihydro-2-oxo-5-fluoro-4-pyridyl, 1-(2-tetrahydrofuranyl)-1, 2-dihydro-2-oxo-5-bromo-4-pyridyl, 1-(2-tetrahydrofuranyl)-1,2-dihydro-2-oxo-5-iodo-4-
Pyridyl, 1-(3-tetrahydrofuranyl)-1,2
-dihydro-2-oxo-5-chloro-4-pyridyl,
1-(2-tetrahydrofuranyl)-1,2-dihydro-2-oxo-3-chloro-4-pyridyl, 1-ethoxymethyl-1,2-dihydro-2-oxo-3-pyridyl, 1-ethoxymethyl -1゜2-dihydro-2-oxo-4-pyridyl, 1-■ Toxymethyl-1,2-dihydro-2-oxo-5-pyridyl, 1-ethoxymethyl-1,2-dihydro-2-suquin-6 -viridyl, 1-
Methoxymethyl-1,2-dihydro-2-oxo-4-
Pyridyl, 1-(2-methoxyethyl)-1゜2-dihydro-2-oxo-4-pyridyl, 1-ethoxymethyl-1,2-dihydro-2-oxo-5-chloro-3-pyridyl, 1- Ethoxymethyl-1,2-dihydro-2-
Oxo-5-chloro-4-pyridyl, 1-ethoxymethyl-1,2-dihydro-2-oxo-5-chloro-6-
Pyridyl, 1-ethoxymethyl-1,2-dihydro-2
-oxo-5-fluoro-4-pyridyl, 1-ethoxymethyl-1,2-dihydro-2-oxo-5-bromo-
4-pyridyl, 1-ethoxymethyl-1,2-dihydro-2-oxo-5-iodo-4-pyridyl, 1-methoxymethyl-1,2-dihydro-2-oxo-5-chloro-4-pyridyl, 1-(2-methoxyethyl)-1,2
-dihydro-2-oxo-5-chloro-4-pyridyl,
1-(2-ethoxymethyl)-1,2-dihydro-2-
Oxo-3-chloro-4-pyridyl, 2-acetyloxy-5-chloro-4-pyridyl, 2-acetyloxy-
5-fluoro-4-pyridyl, 2-acetyloxy-5
-bromo-4-pyridyl, 2-acetyloxy-5-iodo-4-pyridyl, 2-acetyloxy-5-methyl-4-pyridyl, 2-acetyloxy-5-cyano-4
-pyridyl, 2-acetyloxy-5-nitro-4-pyridyl, 2-7cetyloxy-5-carboxy-4-pyridyl, 2-propanoyloxy-5-chloro-4-pyridyl, 2-butanoyloxy-5 -chloro-4-pyridyl, 2-imbutanoyloxy-5-chloro-4-pyridyl, 2-pentanoyloxy-5-chloro-4-pyridyl, 2-hexanoyloxy-5-chloro-4-pyridyl, 3-acetyloxy-5-chloro-4-pyridyl, 2-acetyloxy-3-chloro-4-pyridyl,
4-acetyloxy-5-chloro-2-pyridyl, 4-niacetyloxy-5-fluoro-2-pyridyl, 4-7
Cetyloxy-5-bromo-2-pyridyl, 4-acetyloxy-5-iodo-2-pyridyl, 4-acetyloxy-5-methyl-2-pyridyl, 4-acetyloxy-5-cyano-2-pyridyl, 4 -acetyloxy-5
-nitro-2-pyridyl, 4-acetyloxy-5-carboxy-2-pyridyl, 6-acetyloxy-5-chloro-2-pyridyl, 4-propanoyloxy-5-chloro-2-pyridyl, 4-butyridyl Noyloxy-5-chloro-2-pyridyl, 4-isobutanoyloxy-5-chloro-2-pyridyl, 4-pentanoyloxy-5-chloro-2-pyridyl, 4-hexanoyloxy-5-chloro- 2-pyridyl, 4-acetyloxy-3-chloro-2-pyridyl, 3-acetyloxy-5-chloro-2
-pyridyl, 2-acetyloxy-4-pyridyl, 2-
Propanoyloxy-4-pyridyl, 2-hexanoyloxy-4-pyridyl, 4-acetyloxy-2-pyridyl, 4-propanoyloxy-2-pyridyl, 4-hexanoyloxy-2-pyridyl, 2-methoxy Carbonyloxy-5-chloro-4-pyridyl, 2-methoxycarbonyloxy-6-chloro-4-pyridyl, 2-ethoxycarbonyloxy-3-chloro-4-pyridyl,
2-Ethoxycarbonyloxy-5-chloro-4-pyridyl, 2-ethoxycarbonyloxy-4-pyridyl, 2-ethoxycarbonyloxy-5-bromo-4-pyridyl, 2-ethoxycarbonyloxy-
6-chloro-4-pyridyl, 2-ethoxycarbonyloxy-dyl, 2-ethoxycarbonyloxy-5-chloro-6
-pyridyl, 2-propoxycarbonyloxy-5-chloro-4-pyridyl, 2-hexyloxycarbonyloxy-5-chloro-4-pyridyl, 2-benzoyloxy-4-pyridyl, 3-benzoyloxy-4-pyridyl , 4-benzoyloxy-2-pyridyl, 3-benzoyloxy-2-pyridyl, 2-(2-methylbenzoyl)oxy-4-pyridyl, 2-(3-methylbenzoyl)oxy-4-pyridyl, 2-( 4-Methylbenzoyl)oxy-4-pyridyl, 2-(4-ethylbenzoyl)oxy-4-pyridyl, 2-(2-chlorobenzoyl)oxy-4-pyridyl, 2-(3-chlorobenzoyl)oxy-4 -pyridyl, 2-(4-chlorobenzoyl)oxy-4-pyridyl, 2-(4-fluorobenzoyl)oxy-4-pyridyl, 2-(4-t-butylbenzoyl>oxy-4-pyridyl, 2-( 4-Hexylbenzoyl)oxy-4-pyridyl, 4-(2-methylbenzoyl)oxy-2-pyridyl, 4-(4-ethylbenzoyl)oxy-2-pyridyl, 4-(3-chlorobenzoyl)oxy- 2-pyridyl, 4-(4-fluorobenzoyl)oxy-2-pyridyl, 4-(4
-t-butylbenzoyl)oxy-2-pyridyl, 2-
Benzoyloxy-5-chloro-4-pyridyl, 2-benzoyloxy-5-fluoro-4-pyridyl, 2-benzoyloxy-5-bromo-4-pyridyl, 2-benzoyloxy-5-iodo-4-pyridyl, 2-benzoyloxy-5-methyl-4-pyridyl, 2-benzoyloxy-5-cyano-4-pyridyl, 2-benzoyloxy-5-ditro-4-pyridyl, 2-benzoyloxy-5-cyano-4-pyridyl -pyridyl, 3-benzoyloxy-5-chloro-4-pyridyl, 2-benzoyloxy-3-chloro-4-pyridyl, 2-(2-methylbenzoyl)oxy-5-chloro-4-pyridyl, 2-(
3-Methylbenzoyl)oxy-5-chloro-4-pyridyl, 2-(4-methylbenzoyl)oxy-5-chloro-4-pyridyl, 2-(3,4,5-trimethylbenzoyl)oxy-5-chloro -4-pyridyl, 2-(
4-ethylbenzoyl)oxy-5-chloro-4-pyridyl, 2-(4-t-butylbenzoyl)oxy-5-
Fluoro-4-pyridyl, 2-(4-hexylbenzoyl)oxy-5-bromo-4-pyridyl, 2-(2-chlorobenzoyl)oxy-5-chloro-4-pyridyl,
2-(3-chlorobenzoyl)oxy-5-chloro-4
-pyridyl, 2-(4-chlorobenzoyl)oxy-
5-chloro-4-pyridyl, 2-(4-fluorobenzoyl)oxy-5-chloro-4-pyridyl, 2-(2
,4-dichlorobenzoyl)oxy-5-chloro-4-
Pyridyl, 2-(3,4,5-trichlorobenzoyl)oxy-5-chloro-4-pyridyl, 2-(2-methoxybenzoyl)oxy-5-chloro-4-pyridyl,
2-(3-methoxybenzoyl)oxy-5-chloro-
4-pyridyl, 2-(4-methoxybenzoyl)oxy-5-chloro-4-pyridyl, 2-(3,4,5-
trimethoxybenzoyl)oxy-5-chloro-4-pyridyl, 4-benzoyloxy-5-chloro-2-pyridyl, 4-benzoyloxy-5-fluoro-2-pyridyl, 4-benzoyloxy-5-bromo-2 -pyridyl, 4-benzoyloxy-5-iodo-2-pyridyl, 4-benzoyloxy-5-methyl-2-pyridyl,
4-benzoyloxy-5-cyano-2-pyridyl, 4
-benzoyloxy-5-nitro-2-pyridyl, 4-
Benzoyloxy-5-carboxy-2-pyridyl, 3
-benzoyloxy-5-chloro-2-pyridyl, 6-
Penzoyloxy-5-chloro-2-pyridyl, 4-(
4-methylbenzoyl)oxy-5-chloro-2-pyridyl, 4-(2,4-dimethylbenzoyl)oxy-5
-chloro-2-pyridyl, 4-(3,4,5-trimethylbenzoyl)oxy-5-chloro-2-pyridyl, 4
-(2-chlorobenzoyl)oxy-5-chloro-2-
Pyridyl, 4-(2,4-dichlorobenzoyl)oxy-5-chloro-2-pyridyl, 4-(4-methoxybenzoyl)oxy-5-chloro-2-pyridyl, 1-phthalidyl-1,2-dihydro- 2-oxo-3-pyridyl, 1-phthalidyl-1,2-dihydro-2-oxo-4
-pyridyl, 1-phthalidyl-1,2-dihydro-2-
Oxo-5-pyridyl, 1-phthalidyl-1,2-dihydro-2-oxo-6-pyridyl, 1-carpomethoxymethylcarbamoyl-3-pyridyl, 1-carbomethoxymethylcarbamoyl-1,2-dihydro-2- Oxo-4-pyridyl, 1-
Carbomethoxymethylcarbamoyl-1-carbomethoxymethylcarbamoyl-dihydro-2-oxo-6-
Pyridyl, 1-carboethoxymethylcarbamoyl-dro-2-oxo-4-pyridyl, 2-hydroxy-5
-Methyl-3-pyridyl, 2-hydroxy-5-methyl-4-pyridyl, 2-hydroxy-5-methyl-6-pyridyl, 2-hydroxy-5-ethyl-4-pyridyl,
2-hydroxy-3-methyl-4-pyridyl, 2-hydroxy-3-cyano-4-pyridyl, 2-hydroxy-
3-cyano-5-pyridyl, 2-hydroxy-3-cyano-6-pyridyl, 2-hydroxy-5-cyano-6-
Pyridyl, 2-hydroxy-3-nitro-4-pyridyl, 2-hydroxy-3-nitro-5-pyridyl, 2-hydroxy-5-nitro-6-pyridyl, 2-hydroxy-6-nitro-4-pyridyl, 2-hydroxy-5-carboxy-3-pyridyl, 2-hydroxy-5-carboxy-4-pyridyl, 2-hydroxy-5-carboxy-6-pyridyl, 2-hydroxy-3-carboxy-4
-pyridyl, 2-hydroxy-5-ethoxycarbonyl-3-pyridyl, 2-hydroxy-5-ethoxycarbonyl-4-pyridyl, 2-hydroxy-5-ethoxycarbonyl-6-pyridyl, 2-hydroxy-3-ethoxycarbonyl -pyridyl, 2-hydroxy-3,5-dichloro-4-pyridyl, 2-hydroxy-3,5-dichloro-6-pyridyl, 2-hydroxy-3,5-dibromo-4-pyridyl, 2-hydroxy-3 , 5-dibromo-6-pyridyl, 2-hydroxy-3-amino-4-pyridyl, 2-hydroxy-3-amino-5-pyridyl,
2-Hydroxy-3-amino-6-pyridyl, 2-hydroxy-3-carbamoyl-4-pyridyl, 2-hydroxy-3-carbamoyl-5-pyridyl, 2-hydroxy-3-carbamoyl-6-pyridyldroxy- 6-pyridyl, 2,6-cyhydroxy-4-
Pyridyl, 1,2-dihydro-2-oxo-4-pyridyl, 1,6-dihydro-6-oxo-2-pyridyl, 1
-(benzyloxymethyl)-5-chloro-1,2-dihydro-2-oxo-4-pyridyl, 1-(benzyloxymethyl)-5-fluoro-1,2-dihydro-2-
Oxo-6-pyridyl, 1-(β-phenethyloxymethyl)-5-bromo-1,2-dihydro-2-oxo-
4-pyridyl, 1-(2-benzyloxyethyl)-5
-Chloro-1,2-dihydro-2-oxo-4-pyridyl, 5-chloro-4- (p-(N.N-dimethylamino)benzoyloxy)-2-pyridyl, 5-bromo-
4-(1)-(N.

N-dimethylamino)benzoyloxy)-2-pyridyl, 5-chloro-4- (p- (N,N-dimethylamino)benzoyloxy)-3-pyridyl, 5-chloro-4- (p- (N- Methyl-N-ethylamino)benzoyloxy)-2-pyridyl, 5-fluoro-4-
(o-(N,N-dimethylamino)benzoyloxy)-2-pyridyl, 5-fluoro-4-hexanoyloxy-2-pyridyl, 5-bromo-4-hexanoyloxy-2-pyridyl, 5-iodo -4-hexanoyloxy-2-pyridyl, 5-fluoro-4-octadecanoyloxy-2-pyridyl, 5-chloro-4-octadecanoyloxy-2-pyridyl, 5-bromo-4-octadecanoyl Oxy-2-pyridyl, 5-iodo-4
-octadecanoyloxy-2-pyridyl, 5-fluoro-4-(2-furoyloxy)-2-pyridyl, 5-
chloro-4-(2-furoyloxy)-2-pyridyl,
5-bromo4-(2-furoyloxy)-2-pyridyl, 5-iodo-4-(2-furoyloxy)-2-pyridyl, 5-chloro-4-(3-furoyloxy)-2
-pyridyl, 5-bromo-4-(3-furoyloxy)
-2-pyridyl, 5-fluoro-4-(2-thenoyloxy)-2-pyridyl, 5-chloro-4-(2-thenoyloxy)-2-pyridyl, 5-bromo-4-(2-thenoyloxy)-2 -pyridyl, 5-iodo-4-(2
-Thenoyloxy)-2-pyridyl, 5-chloro-4-
(3-Thenoyloxy)-2-pyridyl, 5-iodo-
4-(3-Thenoyloxy)-2-pyridyl, 4-(1
-naphthoyloxy)-2-pyridyl, 4-(2-naphthoyloxy)-2-pyridyl, 5-(1-naphthoyloxy)-2-pyridyl, 5-(2-naphthoyloxy)-2- Pyridyl, 6-(2-naphthoyloxy)-
2-pyridyl, 3-cyano-6-(2-thenoyloxy)-2-pyridyl, 3-cyano-6-(3-thenoyloxy)-2-pyridyl, 4-cyano-6-(2-thenoyloxy)-2- Pyridyl, 6-penzoyloxy-3
-cyano-2-pyridyl, 6-(2-chlorobenzoyloxy)-3-cyano-2-pyridyl, 6-(4-fluorobenzoyloxy)-3-cyano-2-pyridyl,
6-(2,4-dichlorobenzoyloxy)-3-cyano-2-pyridyl, 6-(2-methylbenzoyloxy)-3-cyano-2-pyridyl, 6-(3-methylbenzoyloxy)-3- Cyano-2-pyridyl, 6-(4
-methylbenzoyloxy)-3-cyano-2-pyridyl, 6-(2,3゜4-trimethoxybenzoyloxy)-3-cyano-2-pyridyl, 6-(2-furoyloxy)-3-cyano-2 -pyridyl, 6-penzoyloxy-3-chloro-2-pyridyl, 6-(3,4゜5
-trimethoxybenzoyloxy〉-3-cyano-2-
Pyridyl, 6-(4-fluorobenzoyloxy)-3
-chloro-2-pyridyl group, etc.

In addition, the arylene group represented by pyridyloxycarbonylarylenecarbonyl represented by the above formula (Y) is an aromatic hydrocarbon or has 1 to 2 same or different petro atoms selected from nitrogen atoms and oxygen atoms in the ring. A divalent group formed by removing hydrogen atoms bonded to different carbon atoms one by one from a 5- or 6-membered aromatic multiple ring. Examples of the arylene group include 1,2-phenylene, 1,3-phenylene, 1,4-
Phenylene groups such as phenylene, 1,2-naphthylene,
1.

3-naphthylene, 1,4-naphthylene, 1,5-naphthylene, 1,6-naphthylene, 1,7-naphthylene, 1,
Naphthylene groups such as 8-naphthylene, 2,3-pyridinediyl, 2,4-pyridinediyl, 2,5-pyridinediyl, 2,6-pyridinediyl, 3,4-pyridinediyl, 3,5-pyridinediyl, etc. pyridinediyl group,
2,3-pyrazindiyl, 2,6-pyrazindiyl, 2
, 5-pyrazindiyl and other pyrazindiyl groups, 2,3-
Furandiyl groups such as furandiyl, 3,4-furandiyl, 2,5-furandiyl, 4-pyridone-1-methyl-2,3-diyl, 4-pyridone-1-methyl-2,
Examples include 4-pyridone-1-lower alkyl-diyl groups such as 5-diyl and 4-pyridone-1-methyl-2,6-diyl.

The compound of the present invention having a group represented by formula (Y) has keto-enol tautomers, and the present invention naturally includes these isomers.

The compound of the present invention represented by the above general formula (1) can be produced by the method shown in the following reaction scheme ad.

<Reaction scheme a> [In the formula, R3 is the same as above. At least one of R4 and R5 is a hydrogen atom, and the other is a hydrogen atom, an acyl group, or a protective group. R is a lower alkyl group on the phenyl ring,
A phenyl lower alkyl group which may have a substituent selected from a lower alkoxy group, a halogen atom, a carboxyl group, a lower alkoxycarbonyl group and a di(lower alkyl)amine group, or a lower alkylene dioxy group or a phenyl group as a substituent. It represents a phenyl lower alkyl group, a phenyl lower alkenyl group, or a naphthyl lower alkyl group. One of Rla and R2a is a hydrogen atom or an acyl group, and the other is the same group as R above. X represents a halogen atom. ] The protecting group represented by R4 or R5 above includes the following groups.

(A> General formula % formula % () [In the formula, Ar represents an aryl group] A triaryl-substituted methyl group represented by the following.The group includes a halogen atom, a nitro group, a lower alkyl group, or a lower alkoxy group as a substituent. Examples include methyl groups substituted with three aryl groups such as phenyl groups.

(B) A cyclic ether residue represented by the general formula [wherein R' is a lower alkyl group and n represents 2 or 3]. Examples of such groups include 2
Examples include -tetrahydrofuranyl group and 2-detrahydropyranyl group.

(C) Lower alkoxymethyl group. Examples of such groups include methoxymethyl, ethoxymethyl, and he:1:siloxymethyl groups.

(D) Tri-lower alkylsilyl group. Examples of such groups include trimethylsilyl and t-butyldimethylsilyl groups.

This reaction is carried out by reacting the compound of general formula (2) (referred to as compound (2) hereinafter) with phenyl lower argyl halide, phenyl lower alkenyl halide, or naphthyl lower alkyl halide (RX>). Compound (2
) to obtain compound (3) by substituting the hydrogen atom of the hydroxyl group at the 3' or 5' position with the desired R group, and then performing a deprotecting group reaction or deacylation reaction as necessary. It is.

In the above, the reaction for introducing the R group is carried out under the reaction conditions of a normal dehydrohalogenation reaction. As the dehydrohalogenation agent, any of various basic compounds commonly used in this type of reaction can be used. As a specific example,
Sodium hydroxide, potassium hydroxide, sodium carbonate,
Examples include potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, alkali metals such as sodium and potassium, and alkali metal hydrides such as sodium hydride and potassium hydride.

The above reaction can be carried out without a solvent or in the presence of a solvent. As solvent, any common inert solvent can be used, for example water, tetrahydrofuran (THF
Ethers such as dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene, ketones such as acetone and methyl ethyl ketone, and nitriles such as acetonitrile and propionitrile are advantageously used.

The ratio of compound (2) and phenyl lower alkyl halide, phenyl lower alkenyl halide, or naphthyl lower alkyl halide (RX) is not particularly limited and may be appropriately selected from a wide range, but usually the latter is at least equal to the former. It is preferable to use about a molar amount, preferably an equimolar amount to 5 times the molar amount.

The reaction temperature is not particularly limited and is appropriately selected from a wide range, but it is generally selected from the range of 0 to 100°C, preferably room temperature to 80°C, and usually about 30 minutes to 64 hours, preferably 1 The reaction is completed in about 5 hours.

The compound obtained by the above reaction is
When a protecting group is present at the '-position, the desired compound (3) can be obtained by subsequently performing an elimination reaction of the protecting group. This deprotecting group reaction can be carried out using suitable catalysts commonly used in ordinary acid hydrolysis reactions, such as inorganic acids such as hydrochloric acid, sulfuric acid, and perchloric acid, lower alkanoic acids such as formic acid, acetic acid, and propionic acid, benzoic acid, and methane. It is usually carried out in a solvent using an appropriate amount of an organic acid such as an organic sulfonic acid such as sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid and the like. Examples of solvents include common inert solvents, such as water, lower alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, THF, and dioxane, benzene, toluene, and xylene. , aromatic hydrocarbons such as chlorobenzene, lower alkanoic acids such as acetic acid and propionic acid, and mixed solvents thereof can be used. The reaction temperature is not particularly limited and may be appropriately selected from a wide range, but it may be generally from 0 to 100°C, preferably from room temperature to about 80°C, and the reaction is completed in about 3 minutes to 20 hours. The acid used is usually in a catalytic amount to an excess amount, preferably in an excess amount.

Furthermore, in the compound (3) obtained in the above reaction scheme a, a compound having an acyl group at at least one of the 3-position, 3'-position and 5'-position can be hydrolyzed to remove any of the acyl groups. One or all of them can be converted into hydrogen atoms. This hydrolysis reaction is carried out under conventional acid or alkaline hydrolysis conditions. As the catalyst used in this case, any catalyst used in ordinary acid or alkaline hydrolysis reactions can be used. Typical examples include basic compounds such as sodium hydroxide, potassium hydroxide, and barium hydroxide, and inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid. The use of the second-class catalyst is not particularly limited and may be appropriately selected from a wide range. This reaction generally proceeds advantageously in a solvent, and a wide range of common inert solvents can be used as the solvent. For example, water, lower alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, and mixed solutions of these.
l1 etc. can be advantageously used. The reaction temperature is not particularly limited and may be appropriately selected from a wide range, but is usually O~
The reaction is preferably carried out at about 100°C, preferably from room temperature to about 80°C. This reaction is completed in about 30 minutes to 10 hours.

<Reaction scheme b> (In the formula, one of R1' and R2/ represents the above R group, and the other represents a hydrogen atom, an acyl group, or a FJL4 group.

R3a represents an acyl group. R1 and R2 are the same as above.

) This reaction is a reaction (acylation reaction) for introducing an acyl group into the 3-position of the pyrimidine skeleton, and can be carried out according to a conventional method such as an acid halide method.

According to the acid halide method, the target compound (5) is obtained by reacting the compound (4) with an acyl halide (R3aX> in the presence of an acid-reducing agent in a suitable solvent. As the deoxidizing agent, for example, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, pyridine, triethylamine, etc. can be used. As the solvent, for example, benzene, dichloroform, methylene chloride, carbon tetrachloride, dioxane, tetrahydrofuran, etc. can be used. .

The amount of acyl halide to be used is at least equimolar, preferably equimolar to about 3 mol, relative to compound (4). The reaction temperature is usually about -30 to 100'C1, preferably room temperature to about 80'C, and the reaction is completed in about 20 minutes to 20 degrees Celsius.

In the above reaction, compound (4) is at the 3' or 5' position.
When a free hydroxyl group is present at the '-position, these sites are also acylated at the same time as the 3-position. Therefore, in the above-mentioned acylation of the secondary compound, it is preferable to protect the 3'- or 5'-position hydroxyl group in advance, and then remove the protecting group after the acylation. The reaction for introducing this protecting group will be described later. Further, the elimination reaction of the protecting group can be carried out in the same manner as the method explained in the section of the reaction scheme a.

<Reaction scheme C> (In the formula, one of R1b and R2b represents a hydrogen atom and the other represents the above-mentioned R group. One of R1 and R2 represents an acyl group and the other represents the above-mentioned 1-dog group. R3 is the same as above. ) According to this reaction, compound (7) is obtained by acylating the free hydroxyl group at the 3' or 5' position of compound (6). For this acylation reaction, the usual acylation reaction method,
For example, acid halide method, acid anhydride method, mixed acid anhydride method, N
, N-dicyclohexylcarbodiimide method CDCC method>
Any of these methods can be applied, and the acid anhydride method and the acid halide method are particularly advantageously applied.

The acid anhydride method is carried out by heating compound (6) together with an acid anhydride in a suitable solvent.

As the acid anhydride, the anhydride of the acid corresponding to the acyl group to be introduced at the 3' or 5' position is used. Specific examples include acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride, and the like.

These acid anhydrides are preferably used in at least an equimolar amount, preferably about 1 to 3 times the molar amount of compound (6). As a solvent, various inert solvents such as pyridine,
Halogenated hydrocarbons such as chloroform and dichloromethane, ethers such as dioxane and THF, aromatic hydrocarbons such as benzene and toluene, dimethylformamide (D
MF>, dimethyl sulfoxide (DMSO>), acetonitrile, etc. can be used.The reaction temperature is usually -30'C.
The temperature is about 100° C., preferably about 80° C., and the reaction is completed in about 20 minutes to 20 hours. Further, the above reaction is advantageously carried out in the presence of a basic compound. Examples of the basic compound include organic bases such as tertiary amines such as pyridine, triethylamine, and N,N-dimethylaniline, and inorganic basic compounds such as sodium bicarbonate, potassium carbonate, and sodium acetate.

In the acid halide method, compound (6) is added with acyl halide (R3
aX) in a suitable solvent in the presence of a deoxidizing agent. The method can be carried out analogously to that shown in the reaction scheme above.

In the above Reaction Schemes and Reaction Schemes C, when the amount of the reagent, i.e., acid anhydride or acid halide used is at least twice the molar amount relative to the raw material, the 3' or 5' position (0-
acyl form) and the 3-position (N-acyl form) can be obtained at the same time, but this
The -acyl form can be easily separated from the 0-acyl form or the N-acyl form.

[In the formula, R1 and R2 are the same as above. A is a tri-lower alkylsilyl group and B is a lower alkanoyl group.

For example, C+Ce represents an alkanoyl group. Also R1"
and R2'', one of which is the R group and the other is the A group or acyl group.] According to the above, compound (8) is reacted with bis-N, 〇-trilower alkylsilylacetamide (trialkylsilylation). reaction) to obtain compound (9), which was then reacted with 2-
Compound (10) can be obtained by reacting lower alkanoyloxytetrahydrofuran (tetrahydrofuranylation reaction).

The trialkylsilylation reaction is preferably carried out in a suitable inert solvent, such as ethers such as dioxane and THF, aromatic hydrocarbons such as benzene and toluene, and solvents such as DMF, DMSO, and acetonitrile, with a concentration of about 0 to 100'C1. The step is carried out at a temperature of room temperature to 50° C. for 30 minutes to 6 hours. In the above, bis-N,O-trilower alkylsilylacetamide is preferably used in an amount that is at least equivalent, preferably 1 to 2 times equivalent, per functional group to be reacted.

The subsequent tetrahydrofuranylation reaction is carried out in the same solvent as above, from about 0 to 100°C, preferably from room temperature to 50°C.
The reaction is carried out at a temperature of 30 minutes to 6 hours at a temperature of 1.5°C.The amount of 2-lower alkanoyloxytetrahydrofuran to be used is at least equimolar to the raw material, preferably 1 to 2 times the molar amount.

This reaction also uses stannic chloride (SnCQt) in the reaction system.
>, aluminum chloride, zinc chloride, or other Lewis acid is present in an amount of about 0.1 mole or more based on the raw material. In addition, in the tetrahydrofuranylation reaction, when using a compound in which R1'' or R2'' is a tri-lower alkylsilyl group, the target compound (1Q ) is obtained. This elimination reaction is carried out in the same manner as the deprotecting group reaction described in the section of reaction scheme a.

The compound of the present invention is thus obtained. The resulting compound can be easily isolated and purified by conventional separation means such as reprecipitation, recrystallization, silica gel chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, etc.

The starting material compounds used in the reaction schemes a to d can be obtained, for example, by the methods shown in the following reaction schemes e to g.

<Reaction scheme e> OHQH (11) (12> [R6 represents an acyl group and R7 represents a protecting group] The acylation reaction of compound (11) is the acylation reaction of compound (6) shown in the above reaction scheme C. It is carried out in the same manner as the reaction.More preferably,
In the acylation reaction, the acid anhydride corresponding to the acyl group to be introduced into the 5' position is added to the compound (11) in a ratio of about 1 to 1.5
The reaction is carried out using twice the molar amount in an inert solvent similar to the acid anhydride method shown in Reaction Scheme C, at a temperature of about -30°C to 80°C, and taking about 1 to 6 hours.

Compound (12) acylated at the 5' position by the above reaction
is obtained as the main component, and a compound acylated at the 3' position is also obtained as a subcomponent.

Compound (12) obtained above is then
The hydroxyl group is subjected to a protection reaction. This protection reaction introduces the protecting group explained in the section of reaction scheme a into the 3' position of compound (12), and the reagent for introducing the protecting group is a compound represented by the general formula (A>). A triaryl-substituted methyl halide which provides a protecting group represented by the general formula (B), an unsaturated compound represented by the following general formula [wherein R' and n are the same as those in the general formula (B)] Cyclic ethers, lower alkoxymethyl halides and l-lower alkyl:1-nylsilyl halides are used.

The protecting group introduction reaction utilizing a halide is carried out in the same manner as the dehydrohalogenation reaction shown in the reaction scheme a. However, the ratio of reagent ■ to compound (12) is 1 to 2.
18 mol, preferably 1.5 times L to 1, and the reaction temperature is preferably 130'C to 80'C.

The protecting group introduction reaction using the unsaturated cyclic ether represented by the above general formula (B') is carried out in the presence of an acid catalyst, for example, in an aprotic inert solvent such as THF, dioxane, acetonitrile or the like.

As the acid catalyst, hydrohalic acids such as hydrogen bromide and hydrogen chloride, and Lewis acids such as aluminum chloride, boron fluoride, and zinc chloride can be used. The reaction is carried out using a reagent in an amount of 1 to 1.5 times the molar amount of compound (12) at -30'C to 60'C for about 2 to 5 hours.

The elimination reaction of the 5'-position acyl group of compound (13) thus obtained is carried out under alkaline hydrolysis conditions. The conditions are based on the above reaction scheme a using a basic compound as a catalyst.
The hydrolysis reaction is similar to that explained in the section.

<Reaction process formula f> (In the formula, R7 is the same as above) According to the above, a compound (15) in which a deeply protecting group is introduced at the 5' position by directly performing a protecting group introduction reaction on the compound (11) or 14. This protecting group introduction reaction is carried out under the same conditions as shown in reaction scheme e.

By the reactions shown in the above reaction schemes e and f, 1q of compounds each having an acyl group or protecting group introduced at either the 3'-position or the 5'-position can be obtained.

<Reaction process formula Ω> 0 0A (1
8) t −+ n X [in the formula A
is the same as above] The trialkylsilylation reaction of compound (16) is carried out using the compound shown in reaction scheme d ( It is carried out in the same manner as the trialkylsilylation reaction in 8).

The tetrahydrofuranylation reaction at the 3-position of the resulting compound (17) and the subsequent elimination reaction of the tri-lower alkylyl groups at the 3'- and 5'-positions of the compound (18) are each carried out by each reaction shown in reaction scheme d. It is done in the same way. Thus, a compound having a tetrahydrofuranyl group at the 3-position (
19) is obtained. By subjecting the compound (19) to the reactions shown in the above reaction schemes e and f, it has a tetrahydrofuranyl group at the 3-position and an acyl group or a protective group at either the 3'-position or the 5'-position. The introduced raw material compound can be obtained.

The raw material compounds obtained by the reactions shown in the above formulas can be used as raw material compounds as they are, or can be used as raw material compounds after being separated from the reaction system according to a conventional method.

Further, in the above-mentioned acylation reaction, when the acyl group of formula (Y) described above is introduced as the acyl group, the acyl halide that is the raw material can be produced, for example, by the method shown in the following reaction scheme.

<Reaction scheme h> RX -OH+ XC0-Y-COX (20>
(21> In formula C, Rx, Y, and X are the same as described above) The above reaction can be carried out by the same method as the acid halide method in Reaction Scheme C above.

Furthermore, the compound of the present invention can also be produced by the methods shown in the following reaction schemes i to n.

<Reaction scheme i> In formula C, R', R2, X and Yt;

Reaction Scheme j> [In the formula, R, R1b, [and 2b, R3, X and Y are the same as above] The above reaction can be carried out in the same manner as in Reaction Scheme i.

<Reaction scheme k> [In each formula, R', R2, R3, X, Y, R and RX are the same as above. R8 represents a hydrogen atom or a tri(lower alkyl)silyl group] The above reaction is performed by acting the compound (26) on any of the acid halides (23>, (24) and (25) obtained by reaction schemes i and j). When a compound (26) in which R8 represents a hydrogen atom is used, it can be carried out in the same manner as the method shown in Reaction Scheme C above.

In addition, when using a compound in which R8 represents a tri(lower alkyl)silyl group among compounds (26), a solvent that does not adversely affect the reaction is preferably used, preferably a halogenated hydrocarbon such as dichloromethane or chloroform, or benzene. , aromatic hydrocarbons such as toluene, and aprotic solvents such as dioxane, acetonitrile, acetone, and tetrahydrofuran in a dry state, particularly preferably in an anhydrous state. Compound (26) is an acid halide (23
), (24) or (25) is usually used in at least an equimolar amount, preferably 1 to 3 times the molar amount. The process is completed in about 6 hours, preferably about 2 hours. In addition, in this reaction, when R8 is a hydrogen atom, triethylamine, trimethylamine, dimethylaniline,
It is preferable to use a base such as pyridine, and when R8 is a tri(lower alkyl)silyl group, it is preferable to use a Lewis acid such as stannic chloride, zinc chloride, aluminum chloride or the like.

The compounds (26) used in this reaction are generally known, but include some new compounds, and such compounds can be easily synthesized by the following method.

That is, a compound in which the 1-position of the pyridine ring is substituted with a 2-tetrahydrofuranyl group is obtained by adding hexamethyldisilazane to a corresponding known pyridine derivative in which the 1-position is a hydrogen atom.
After flowing for about 20 hours, remove excess hexamethyldisilazane, dissolve the residue in a halogenated hydrocarbon such as dichloromethane or chloroform, or an aprotic solvent such as dioxane or acetonitrile, and dissolve 2-acetoxytetrahydrofuran. A Lewis acid such as stannic chloride, zinc chloride, aluminum chloride, etc. is added to the pyridine derivative as the starting material, at least in an equimolar amount to about twice the molar amount, and the mixture is O~100'
It can be obtained by keeping the temperature at about C, preferably around room temperature, for about 1 to 10 hours. In addition, in the above reaction, aroyl halide, lower alkanoyl halide, aroyloxycarbonyl halide, lower alkoxycarbonyl halide, 2-halogenophthalide, allyl halide, phenyl lower alkoxy lower alkyl halide, or lower alkoxy lower alkyl halide is used in place of 2-acetoxytetrahydrofuran. By using a compound in which an aroyloxy group, a lower alkanoyloxy group, an aroyloxycarbonyloxy group, or a lower alkoxycarbonyloxy group is substituted at the 2-position and/or 4-position of the pyridine ring, respectively, and a phthalidyl group at the 1-position of the pyridine ring, A compound substituted with an allyl group, a phenyl lower alkoxy lower alkyl group, or a lower alkoxy lower alkyl group is obtained. Furthermore, compounds in which an N-(lower alkoxycarbonyl lower alkyl) aminocarbonyl group is substituted at the 1st position of the pyridine ring include dioxane, dichloromethane, chloroform,
In a solvent such as acetonitrile, acetone, or pyridine,
At least an equimolar amount of lower alkoxycarbonyl lower alkyl isocyanate is added to the corresponding pyridine derivative having a hydrogen atom at the 1st position, and 1
It can be obtained by reacting for about 0 minutes to 1 hour, preferably about 30 minutes.

<Reaction Scheme-Q> [In each formula, R1, R2, R3, R8, X, Y and R are the same as above. R9 represents a lower alkyl group] This reaction is a reaction in which compound (30) is reacted on any of the acid halides (23), (24), and (25) obtained by reaction schemes 1 and j. , carried out under the same reaction conditions as in the reaction scheme.

<Reaction Scheme-m> (In each formula, R1, R2, R, X, and Y are the same as above) The above reaction can be carried out in the same manner as in the above-mentioned Reaction Scheme i.

The compound (1) of the present invention has an excellent anticancer effect, is low in toxicity, has few side effects such as weight loss, and is extremely useful as an antitumor agent for cancer treatment in humans and animals. .

Further, according to the research conducted by the present inventors, it has been confirmed that the anticancer effect of the compound (1) of the present invention is further enhanced by combining it with a pyridine derivative represented by the following general formula (X). Ta.

[In the formula, one of Y1 and Y3 represents a hydrogen atom and the other represents a hydroxyl group. Y2 represents a water M atom, a halogen atom, a lower alkyl group, a cyano group, or a 21.0 group, and 1 g of water at the 2.4 and/or 6 positions may be acylated. ) The above compound (X> is known or can be prepared by a known method (T
riv, Chem, Rec, 73.704 (
1954)). 2゜4 and/
Alternatively, acylation at the 6-position can be carried out in the same manner as in Reaction Scheme 2 or C.

The compound of the present invention is usually used in the form of a common pharmaceutical preparation. The formulation contains commonly used fillers, extenders, binders,
It is prepared using diluents or excipients such as wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, tablets, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections ( (solutions, suspensions, etc.), ointments, etc. When forming into a tablet, carriers such as milk, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin,
Excipients such as crystalline cellulose and silicic acid, water, ethanol,
Proper tool, simple syrup, glucose solution, starch solution,
Gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binder such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate,
Disintegrants such as calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as white sugar, stearin, cocoa butter, hydrogenated oil, quaternary ammonium base, lauryl Absorption enhancers such as sodium sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, polyethylene glycol, etc. Agents, etc. can be used. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as dragee-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, or multilayered tablets. When forming into a rough shape, excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc, powdered gum arabic, powdered tragacanth, etc. are used as carriers.
Binders such as gelatin and ethanol, and disintegrants such as laminaran and agar can be used. When molding into a suppository, carriers such as polyethylene glycol,
Cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc. can be used. Capsules are prepared by mixing the compound of the present invention with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules, etc. according to conventional methods. When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and when molded into these forms, diluents such as water, ethyl alcohol, macrogol, etc. , propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like can be used. In this case, sufficient amounts of salt, glucose, or glycerin may be included in the pharmaceutical formulation to adjust the isotonicity of the solution, and conventional solubilizing agents, buffers, soothing agents, etc. may also be added. It's okay. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary. paste,
When forming creams and gels, diluents such as white petrolatum, paraffin, glycerin,
Cellulose derivatives, polyethylene glycol, silicon, bentonite, etc. can be used.

The amount of the compound of the present invention to be contained in the pharmaceutical formulation of the present invention is not particularly limited and may be appropriately selected within a wide range, but it is usually 1 to 70% by weight in the pharmaceutical formulation.

The administration method of the above pharmaceutical preparation is not particularly limited, and is determined depending on the various preparation forms, age, sex, and other conditions of the patient, such as the severity of the patient. For example, tablets, emulsions, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, intramuscularly or intramuscularly alone.
Administered subcutaneously or intraperitoneally. Suppositories are administered rectally.

The dosage of the above pharmaceutical preparation is appropriately selected depending on the method of use, age, sex and other conditions of the patient, degree of disease, etc., but usually the active ingredient, the mold of the compound of the present invention, is 1 kg of body weight per day.
The dosage is preferably about 0.5 to 20 mc+ per day, and the preparation can be administered in 1 to 4 divided doses per day.

Examples Reference examples, working examples, pharmacological test examples, and formulation examples are listed below.

Regarding NMR data in Reference Examples and Examples, "C"
, rHJ or rNJ indicates the position in the compound. For example, rcs HJ indicates a hydrogen atom bonded to the carbon atom at position 6.

Similarly, for example, rc3', ', s' HJ is 3
Indicates a hydrogen atom bonded to a carbon atom at the ', 4', or 5' position. Further, for example, "Hl" indicates a hydrogen atom bonded to the carbon atom at the 1st position, and further, for example, "N3 HJ is 5
- Indicates a hydrogen atom bonded to the nitrogen atom at the 3-position of the fluorouracil ring.

Reference Example 1 Production of 2'-deoxy-5'-0-trityl-5-fluorouridine 9.0 OCI of trityl chloride was added to a pyridine solution of 5.0 OCI of 2'-deoxy-5-fluorouridine under stirring at room temperature.
added. After 15 hours, the solvent was distilled off, and the residue was dissolved in ethyl acetate and washed three times with saturated brine. The ethyl acetate layer was dried over sodium sulfate, concentrated, and the residue was eluted with chloroform using a silica gel column with 2% methanol-chloroform to give 2'-deoxy-5'-0-trityl-5.
- 6.80 CJ (69%) of fluorouridine was obtained.

Reference Example 2 Production of 2'-deoxy-5-fluoro-3-(2-tetrahydrofuranyl)uridine A suspension of 5.0 OCI of 2'-deoxy-5-fluorouridine in dry dichloromethane was added with N under stirring at room temperature. , 16.5 g of O-bis(trimethylsilyl)acetamide were added. After 4 hours, 2-
Acetoxytetrahydrofuran 4. A solution of OOC+ and 1.17 mf2 of stannic chloride in 10 mQ of dry dichloromethane was added, and the mixture was further stirred for 1.5 hours. Next, triethylamine 8.011112 was added to neutralize the mixture, and the mixture was washed with water. The dichloromethane layer was concentrated, the residue was dissolved in methanol 100 times, 3 tablespoons of vinegar was added thereto, and the mixture was left at 40'C for 3 hours. The solvent was distilled off, and the residue was purified using a silica gel column.
Elution with 4% methanol-chloroform in chloroform gave an oily 2'-deoxy-5-fluoro-3-(2-tetrahydrofuranyl)uridine (5.25 CI) (81,
7%).

'HNMR (CDCQ3) δ: 8.06 ('IH, d, J=6Hz, Cs H)6
．． 23 (1H, bt, J=6H2,C+'-H)
4.45-3.75 (8H, m, C3'4'5'-H 2.29-2.16 (6H, m.

Preparation of 5-chloro-4-hydroxy-1-(2-tetrahydrofuranyl)-2(1H)-pyridone 5-chloro-4-hydroxy-2(1H)-pyridone 1
．． Hexamethyldisilazane was added to OOg, and the mixture was refluxed for 6 hours. Excess hexamethyldisilazane was then distilled off and the oily residue was dissolved in 50 ml of dichloromethane.

Here, 2-acetoxytetrahydrofuran 1. OOg and 0.1 g of stannic chloride were added and stirred overnight at room temperature. After neutralization with triethylamine), the medium was distilled off, methanol was added to the residue, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off again, and the residue was eluted with 2% methanol-chloroform using a silica gel column to obtain the target compound (1.07 Cl (73,5
%) was obtained.

Melting point 170-173°C +H-'NMR (DMSO-ds) δ: 11.6 (
1H, bs, 0H) 7.59 (1H, S, C6H> 5.76 (IH15, C3H> 4, 39-3.73 (2H, m, (γ) Reference Example 4 5-chloro-1-ethoxymethyl -4-hydroxy-2
Production of (1H)-pyridone In Reference Example 3, chloromethyl ethyl ether was used instead of 2-acetoxytetrahydrofuran, and 5-chloro-1-ethoxymethyl-4-hydroxy-2(1H)-
Pyridone was obtained with a yield of 39%.

Melting point 217-219℃ 'HNMR (DMSOds) δ: 11.63 (IH, bs, 0H) 7.87 (1H, S, Cs H) 5.75 (1H, s, C3-H) 5.16 (2H ,s,N-CH2-0-)3.49
(2H, Q, J=7Hz, -OCC20CH3) 1.09 (3H,t, J=7Hz, -0CH2Cdan3) Reference Example 5 Production Reference Example 3 of 2-benzoyloxy-5-chloro-4-hydroxypyridine Using benzoyl chloride instead of 2-acetoxytetrahydrofuran, the target compound was obtained in a yield of 5.
Obtained at 1%.

Melting point Softened at 184°C 'HNMR (DMSO-ds) δ: 8.27 (1H,S,CsH) 6.91 (1H,S,03H) Reference example 6 4-hydroxy-1-(3-phthalidyl )-2(1H)
-Production of pyridone 10 mQ of hexamethyldisilazane was added to 1.000 ml of 4-human xyl 2(1H)-pyridone, and the mixture was rapidly flowed for 6 hours. The reaction solution was then concentrated under reduced pressure, and the residue was dissolved in 20 mQ of acetonitrile. To this, 3-bromophthalide 2.2
90 was added and stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes. Next, the reaction solution was concentrated under reduced pressure, and the residue was applied to a silica gel column using 1% methanol-chloroform as an eluent.
2c+ (30%) was obtained.

Melting point 239-241°C 'HNMR (DMSO-d6) δ: 6.99 (1H, d, J=8H2, Cs H)5.
88 (IH, dd, J3, s -2H2, Js,
s = 8 Hz, Cs -H) 5.65 (IH, d, J = 2 Hz, Ca H) Reference Example 7 Production of 1-carbomethoxymethylcarbamoyl--hydroxy-2(1H)-pyridone 4-1 Nitroxy-2 (
1H)-Pyridone 2, 2.49C of carbomethoxymethyl isocyanate in a suspension of OOq in 60ml of dioxane
] and stirred at 90'C for 30 minutes. The solvent was distilled off, ether was added to the residue, and the resulting precipitate was collected.
2.20 g (54%) of the target compound was obtained.

Melting point 1 24-1 26°C 'H NMR (DMSO-ds) δ: 1 1, 5
2 (1H, bs, OH) 10, 82 (1H, t, J=6Hz.

-CON Dan CH2 > 8, 20 (IH, d, J=8Hz, Cs H) 6,
1 7 (1H, dd, Js, e = sHz, J3
, s = 2Hz, Cs H) 5, 74 (IH, d, J = 2Hz, Ca H) 4,
1 5 (2HS d, J=6Hz.

-CONHCtan2-) 3,68 (3H,s,-COOCdan3) Reference Example 8 Production of 1-benzyloxymethyl-5-chloro-4-hydroxy-2(IH)-pyridone In Reference Example 3, 2- Using benzyloxymethyl chloride in place of acetoxytetrahydrofuran and acetonitrile in place of dichloromethane as the solvent, the target compound was obtained in a yield of 57%.

Melting point 165-167°C 'H-NMR (DMSO-d6) δ: 1 1, 65
(1H, bsloH> 7,92 (1H,S,CaH) 7,31(5H,s, phenyl-H) 5,77 (1H,S,CaH) Reference Example 9 2,4-bis(trimethylsilyloxy )-Production of 5-chloropyridine 5-chloro-4-hydroxy-2<IH)-pyridone 9
．． 60 was added with 50 mi2 of hexamethyldisilazane, and the mixture was stirred overnight at 140°C in an oil bath. One insoluble matter was removed, and the furnace liquid was distilled under reduced pressure to obtain 14.4 g (75%) of the target compound with a boiling point of 120°C/7 mmH (l).

Reference Example 10 2-acetoxy-5-chloro-4-hydroxy-2(I
Preparation of H)-pyridone2,4-bis(trimethylsilyloxy)-5-chloropyridine5. OOCI dry dichloromethane 250mQ
In the solution, add 2.0 9 mQ of acetyl bromide and sulfur chloride.
0.10 mQ of tin was added and stirred at room temperature for 3.5 hours. After neutralization with triethylamine, the solvent was distilled off, and the residue was eluted with 40% ethyl acetate-benzene using a silica gel column to obtain target compound 2.07Q (64%).

Melting point 270-272°C 'HNMR (DMSO-d 6 ) δ: 11.90 (
1f-1, bs, OH>8.20. (IH, S, Cs
H) 6.69 (1H,S,C3-H) 2.27 (3H,s, COCH3) Example 1 5'-〇-benzy-21-deoxy-5-fluorouridine (R1=R3=H, R2=Cs Hs CH2)
Production of 5'-〇-acetyl-2'-deoxy-5-fluoro-
A 1N aqueous sodium hydroxide solution was added to a methanol 301TIG solution of 1.0OCI of 3'-0-trityluridine, and the mixture was stirred at room temperature for 4 hours. After neutralization by adding acetic acid, it was concentrated, and the residue was washed with petroleum ether and dried. This was dissolved in a mixture of 20 ml of benzene and 20 Inf2 of dioxane, and 0.27+nQ of benzyl bromide and 0.15 g of potassium hydroxide fine powder were added thereto and refluxed overnight. The solvent was distilled off, the residue was dissolved in 50ml of 80% acetic acid, and the mixture was heated at 80'C.
I left it for 4 hours. The solvent was distilled off, the residue was eluted with chloroform-2% methanol-chloroform using a silica gel column, and the fraction corresponding to 5'-〇-benzyl-2'-deoxy-5-fluorouridine was collected, concentrated, and dissolved in ethanol. The target compound was recrystallized from 0.
33CI (52%) was obtained.

Melting point 129-130°C Elemental analysis value: Ct s H+ y Calculated value (%) as FN205 2G 57.14: H5,09; N8.3
3 Actual value (%): C57,14; H5,35: N8.34'H-NMR (DMSO-d6) δ: 11.76 (
1H, bs, disappeared by addition of -NH-1D20) 7.95 (1H, d, J = 7H2, C6H) 7.34
(5H,s, phenyl-H)6.15 (1H,t,
J=7HzS Ct' -H)5.33 (1H,
bs, 3'-〇H, disappeared by addition of D20) 4.34-4.16 (1H, m, C3'-H)4.
00 3.89 (1H1m, Ct'H) 3.6
9-3.63 (2H,m,Cs'-H)2.14
(2H, t, J=6H2,C1)' -H) Example 2 3'-〇-benzy-2'-deoxy-5-fluorouridine (R2=R3-H, R' = Cs Hs CH2
) Production of benzene 501T12 and dioxane 50m (2'-deoxy-5-fluoro-5'-0-trityluridine 1.0OCI, benzyl bromide 0.30- and potassium hydroxide 0.23C)] The mixture was refluxed for 25 hours. Insoluble materials were removed, and the Tsukiyo was concentrated. The residue was dissolved in 5 mQk of 80% acetic acid and allowed to stand at 80°C for 2 hours. The solvent was distilled off, the residue was eluted with chloroform-2% methanol-chloroform using a silica gel column, and the fraction corresponding to 3'-〇-benzy-21-deoxy-5-fluorouridine was collected, concentrated, and purified from ethanol. Recrystallize to obtain the target compound 0.14Cl (2
0%) was obtained.

Melting point 138-139°C Elemental analysis value: Ct s H+ v Calculated value (%) as FN205: C57,14:H5,09:N8.33 Actual value (%): C57,16; H5,30:N8.13' H-NMR (DMSOds) δ: 11.82 (disappeared by addition of IH, bs, -NH-1D20), 8.21 (IH, d, J=7Hz, C6H) 7.3
5 (5H,s, phenyl-H)6.16 (1H,t
, J=6Hz, Cs'-H)5.22 (1H,
bs, 5'-OH, disappeared by addition of D20) 4.24-4.19 MHSm, C3'-H>4.0
9 4.06 (1H, m, C4'H)3.65-
3.53 (2H,m,Cs'H)2.51-2
．． 16 (2H,m,C2'-H)Example 3 2'-deoxy-5-fluoro-3'-〇-(3,4
-methylenedioxybenzyl)uridine (R2=R3=
H, R' = 3.4-methylenedioxybenzyl group] The reaction was carried out in the same manner as in Example 2 except that dioxane used as the reaction solvent was replaced with acetonitrile, and the target compound was obtained in a yield of 23%.

Melting point 186-188°C Elemental analysis value: Cs 7 H+ y FN20y ・0.
Calculated value (%) as 5H20: C52,44: H4,66; N7.19 Actual value (%): C52,60; H4,62: N7.03 'H-NMR (CDC93) δ: 11.80 (1 'H, d, J=5Hz, -NH-1D
20 addition), 8.18 (IH, d, J-7Hz, C6H) 6.90
-6.85 (3H,m, phenyl-H)6.1'1
(1H, t, J=6Hz, Cs'H>5.99
(2H,s, OCH20>!5.17 (1H,t,
J=5Hz, disappeared by adding 5'-0H1D20) 4.18-4.00 (2H, m.

C3', C4'H>3.64"-3,61 (2H,m, Cs'-H>
2.30-2.20 (2H, m, C2'-H>Examples 4 and 5 3'-〇-benzy-2'-deoxy-5-fluorouridine (R2=R3=H, R' -Cs Hs CH2
) and 5'-〇-benzy-2'-deoxy-5-fluorouridine (R' = R3 = H, R2 = C6H5CH
11.4 C of potassium hydroxide was dissolved in a mixture of 350 ml of water produced in 2) and 100 ml of dioxane, and 2'-
Deoxy-5-fluorouridine 10. Oq and benzyl bromide3. Added OmQ. 5% every 24 hours after this
100 μl of an aqueous potassium hydroxide solution and 3.0 μl of benzyl bromide were added three times, and the mixture was continued to be stirred roughly overnight. After washing the reaction solution twice with 200 mQ of ether, the aqueous layer was washed with 6N-HCQ.
and concentrated to about 200 mQ. Do this again for 6N
-Adjust the pH to about 3-4 with HCQ and add 100ml of ethyl acetate.
Extracted twice with f2. Separate the ethyl acetate layer and anhydrous IM
After drying with sodium chloride, it was concentrated. The oily residue was eluted with chloroform-2% methanol-chloroform using a silica gel column, and the fraction corresponding to 3'-〇-benzy-2'-deoxy-5-fluorouridine was collected, concentrated, and recrystallized from ethanol to obtain the desired product. Compound 3.
570 (26.1%) was obtained.

Melting point 138-139°C Elemental analysis value: Cs s H+ 7 Calculated value (%) as FN205: C57,14:H5,09;N8.33 Actual value (%>:c 57.12+H5,28:N8.
24 The 5'-O-benzyl-21-deoxy-
Collect the fraction corresponding to 5-fluorouridine,
Concentrate and recrystallize from ethanol to obtain 0.4 of the target compound.
0 g (2.9%) was obtained.

Melting point 129-130'C Elemental analysis value: C+ 6 H+ 7 Calculated value (%) as FN205: C57,14; H5,09; N8.33 Actual value (%): C57,29; H5,30: N8.26 Examples 6 to 17 The following compounds were obtained in the same manner as in Examples 4 and 5.

Example 6 3'-0-(2-fluoropencyl)-2'-deoxy-5-fluorouridine [R2=R3=H, R'=
2-fluorobenzyl group] Yield 34% Melting point 121-123°C 'HNMR (DMSO-da) δ: 11.82 (1HSbs, -NH-1 Disappeared by addition of D20) 8.21 (1H, d, J = 7H2 , Cs H) 7.6
7-7.19 (4H,m, phenyl-H)6.15
(IH, t, J-6H2, C+ 'H) 5.26
(1H, bs, 5' OH, disappeared by addition of D20) 4.28-4.05 (2H, m.

C3', C4' H) 3.77-3.67 (2H, m, Cs' -H)2
．． 41 2.18 (2H,m,C2'-H>Example 7 5'-0-(2-fluorobenzyl)-2'-deoxy-5-fluorouridine (R1=R3=H, R2=2
-fluorobenzyl group) Yield 5.2% Melting point - (oil) 'H-NMR (DMSO-ds) δ: 11.7 (1
H, bs, disappeared by addition of -NH-1D20) 7.92 (IH, d, J=7H2SCs H>7.
52-7.07 (4H,m, phenyl-H)6.20
(IH, t, J=6Hz, C+'-H>4.44
-3.97 (2HSm, C3', C4'H> 3.84-3.57 (2H, m, C5' H)2.
21-2.08 (2H,m,C2'-H>Example 8 3'-0-(3-fluorobenzyl)-2'-deoxy-5-fluorouridine (R2-R3=H,R"=
3-fluorobenzyl group] Yield 27% Melting point 113~] 15°C 'H' NMR (DMSO-ds) δ: 11.81
(Disappeared by adding 1H, bs, -NH-1D20) 8.21 (IH, d, J=7t71Z, CG H)7.
46-7.01 (4H,m, phenyl-H)6.17
(1H, t, J=6H2,C+'-H)5.22
(1H, bt, J=5Hz, 5' -0H14,31
-4,06 (2H, m.

C3', 4' H) 3.74-3.59 (2H, m, Cs' H)2
．． 38 2.03 (2H, m, C2' -H) Example 9 5'-〇-(3-fluorobenzyl)-2'-deoxy-5-fluorouridine [R1=R3=H, R2=3-
Fluorobenzyl group] Yield 5.9% Melting point - (oil) 'HNMR (CDC93) δ: 10.4 (1H, bs, -NH-1 Disappeared by addition of D20) 7.92 (1H, d, J = 7Hz , Cs H)7.
41-6.77 (4H, m, phenyl-H) 6.28
(1H, bs, C+ 'H) 4.63-3.51
(6H,m, 2.49-1.93 (2H,m,C2'-H>Example 10 3'-0-(2-bromobenzyl)-2'-deoxy-5-fluorouridine [R2=R3 =H, R' =2
-Bromobenzyl group] Yield 33% Melting point 122-124°C 'HNMR (DMSO-ds) δ: 11.81 (IH, bs, disappeared by addition of -NH-1D20), 8.20 (1H, d, J =7H2,C6H)7.67
-7.32 (4H,m, phenyl-H)6.15 (
1H,t,J=6H2,C+'-H)5.21 (
1H, t, J=5Hz, 5'-0H14,25-4,
05 (2H, m, C3', -' H) 3.70-3.52 (2H, m, Cs' -H)2
．． 40 1.94 (2H, m, C2' H) Example 11 5'-〇-(2-bromobenzyl)-2'-deoxy-5-fluorouridine [R1=R3=H, R2=2-
Bromobenmol] Yield 5% Melting point - (oil) 1HNMR (DMSO-ds) δ: 11.78 (disappeared by addition of IH, bs, -NH-1D20), 7.91 (IH, d, J = 7HzSCs - H)7.
69-7.32 (4H, m, phenyl-H) 6.15
(IH, t1J=6H2, C+ '-H>5.35
(1H, t, J=7Hz.

5'-〇H, disappeared by addition of D20) 4.31-3.
42 (4H, m.

C3'14'+5' H) 2.20 2.09 (2H, m, C2' H) Example 12 3'-0-(3-bromobenzyl)-2'-deoxy-5-fluorouridine [R2= R3=H, R'=3
-Bromobenzyl group] Yield 19% Melting point 166-168°C' HN M R (DM SO-d 6) δ: 11
．． 80 (IH, bs, disappeared by addition of -NH-1D20), 8.18 ("IH, d, J = 7H2, C6H) 7.6
9-7.31 (4H,m, phenyl-H)6.15
(1H,t,J=6H2,C+'H)5.19
(1H, t, J=5Hz, 4.23-4.03 (2H, m, C3',, L'H> 3.71 3.57 (2H, m, Cs' - H>2
．． 34-2.21 (2H, m, C2' H) Example 13 5'-0-(3-bromobenzyl)-2'-deoxy-5-fluorouridine [R1=R3=H, R2=3-
Bromobenzyl group] Yield 3% Melting point - (oil) 'HNMR (DMSO-ds) δ: 11.9'O (disappeared by addition of IH, bs, -NH-1D20), 8, ○O (1H, d , J=7Hz, Cs-H)7.6
7-7.34 (4H,m, phenyl-H)6.12
(1H, t, J=6Hz, C+' -H)5.46
(1H, bs, 3' OH, disappeared by addition of D20) 4.30-3.90 (2H, m.

C3',4'H) 3.74-3.68 (2H,m,C5'-H)2.
13 (2H, t, J=6H2,C2'H) Example 1
4 3'-0-(4-bromobenzyl)-2'-deoxy-5-fluorouridine (R2=R3=H, R'=4
-Bromobenzyl group] Yield 12% Melting point 214-217°C 'H-NMR (DMSO-d6) δ: 11.80 (
1H, bs, disappeared by addition of -NH-1D20), 8.18 (1H, d, J = 7H2, C6H) 7.55
and 7.30 (2H, d, J = 8Hz, phenyl-
H) 6.11 (1H, t, J=6Hz, C+ 'H
)5.19 (1H, t, J=5Hz, 5'-〇H,D
Disappeared by adding 20) 4.23-4.02 (2H, m, C3', L' H) 3.73-3.60 (2H, m, Cs' H)2
,'36-2.07 (2H,m,C2'-H) Example 15 3'-0-(4-t-butylbenzyl)-2'-deoxy-5-fluorouridine (R2=R3=H, R'
=4-t-butylbenzyl group] Yield 17% Melting point - (powder) 'H-NMR (DMSO-d6) δ: 11.80 (
1H, bs, disappeared by addition of -NH-1D20), 8.18 (1H, d, J = 7H2, C6H) 7.48
and 7.30 (2H, d, J = 8H2゜phenyl-H
) 6.12 (1H, t, J=6Hz, C+ '-H>
5.18 (1H, t, J=5Hz, 5'-○H1D2
disappeared by addition of 0> 4.30-4.04 (2H, m, C3', A' H) 3.76-3.60 (2H, m, Cs' -H) 2.
24-2.08 (2H,m,C2'H)1.2
7 (9H, s, CH3x3> Example 16 5'-0-(4-t-butylbenzyl)-2'-deoxy-5-fluorouridine (R' = R3 = H, R2
= 4-t-butylbenzyl group] Yield 2% Melting point - (oil) 'HNMR (DMSO-d6) δ: 11.80 (disappeared by addition of 1H, bs, -NH-1D20), 7.94 (1H , d, J=7H2,C6-H)7.3
4 and 7.16 (2H, d, J = 8Hz, phenyl-
H) 6.14 (1H, t, J=6Hz, C+'H)
5.3.1 (1H, bs, 3'-OH, disappeared by addition of D20) 4.28-3.94 (2H, m, C3', 4' -H) 3.74 3.64 (2H, m , Cs' H)2
．． 13 (2H, t, J=6H2, C2'H) 1.2
7 (9H,s, CH3x3) Example 17 3'-0-(4-phenylbenzyl)-2'-deoxy-5-fluorouridine [R2-R3=H, R'=
4-phenylbenzyl group] Yield 12% Melting point 207-209°C 'HNMR (DMSO-ds > 5: 11.90
(1H, bs, disappeared by addition of -NH-1D20), 8.19 (1H, d, J=7Hz, Cs H)7.
69-7.39 (9H, m, phenyl-H) 6.15
('lH, t, J=6Hz, C+'H)5.25
(1H,t, J=5Hz, 5'-0H1D20 addition> 4.29-4.07 (2H,m, C3',4'H>3.83-3.63(2H,m,Cs' -H)2
．． 26 2.06 (2H, m, C2'H) Examples 18 and 19 3'-0-(4-chlorobenzyl)-2'-deoxy-5-fluorouridine (R2=R3=H, R' = 4
-chlorobenzyl group] and 5'-〇-'(4-chlorobenzyl)-2'-deoxy-5-fluorouridine [R
1=R3=HSR2=4-chlorobenzyl group] 4.0 CI of potassium hydroxide was dissolved in a mixture of 150 mQ of water and 40 mQ of dioxane, and 2.000 CI of 2'-deoxy-5-fluorouridine was dissolved under stirring at room temperature. and 5.50 g of 4-chlorobenzyl chloride were added. After 2 days, post-treatment was carried out in the same manner as in Examples 4 and 5, and the column was eluted with chloroform-2% methanol-chloroform using a silica gel column.
The fractions corresponding to '-0-(4-chlorobenzyl)-2'-deoxy-5-fluorouridine were collected and concentrated to yield 0.50c+ (17%) of the target compound.

Melting point 196-198°C'H-NMR (DMSO-ds) δ: 11.81 (
IH, bs, disappeared by addition of -NH-1D20), 8.20 (IH, d, J-7H2, CG H)7.
38 (4H,s, phenyl-H)6.14 (1H,
t, J=7H2,C+'-H>5.21 (IH,
bt, J=5Hz, 5'-〇H1D20 added) 4.23 4.14 (1H,m, C3'H>4
．． 10-4.03 (1H,m,C4'-H)3.7
1 3.58 (2H, m, Cs' H) 2.41
2.02 (2H, m, C2' H) elemental analysis value: C+ s H+ s CQ Calculated value (%) as FN20s: C51,83: H4,35: N7.56 Actual value (%): C51,82: H4,60; N7.41 Then eluted 5'-0-(4-chlorobenzyl)-
The fractions corresponding to 2'-deoxy-5-fluorouridine were collected and concentrated to obtain 0.12C of the target substance in powder form.
1 (4.0%).

'H-NMR(DMSO-d6)δ:
11.79 (1H, bs, disappeared by addition of -NH-1D20), 7.91 ('IH, d, J=7H2, C6-H)7.
38 (4H,s, phenyl-H)6.13 (1H,
t, J=6Hz, C+'-H)5.33 (1H,
bs, 3' -〇H, disappeared by addition of D20) 4.38 4.21 (IH, m, C3' -H) 4.
04-3.82 (IH, m, C4'-H) 3.78
3.74 (2H,m,Cs'H)2.25
1.98 (2H, m, C2'H) elemental analysis value: C
+6th s CQ Calculated value as FN20s (%)
:C51,83:H4,35N7.56 Actual value (%):C51,73:H4,80:N7.97 Examples 20 to 22 1q of each of the following compounds was prepared in the same manner as in Examples 18 and 1.

Example 20 3'-〇-(2,4-dichloro[1benzyl)-2'-
Deoxy-5-fluorouridine (R2=) or "=H
, R' = 2.4-dichlorobenzyl group] Yield 14% Melting point 88-90°C' H-N M R (DM S Od 6 ) δ: 1
1y82 (1H, bs, disappeared by addition of -NH-1D20), 8.20 (1H, dSJ=7H2, Cs H)7.
60-7.37 (3H,m, phenyl-H)6.14
(1H, t, J=6Hz, C+' -H)5.21
(1H, tSJ=5Hz, 5'-〇disappeared by addition of H1D20) 4.28-4.03 (2H, m, C3', 4'-H> 3.69-3.60 (2H, m, C5' -H)2.
37-2.19 (2H, m, C2'H) Example 2
1 5'-0-(2,4-dichlorobenzyl)-2'-deoxy-5-fluorouridine(R' = R3 = H, R
2 = 2.4-dichlorobenzyl group] Yield 3.3% Melting point 109-111°C 'H-NMR (DMSO-ds) δ: 11.77 (
1H, bs, disappeared by addition of -NH-1D20), 7.89 (1H, d, J=7Hz, Cs H)7.
60-7.36 (3HSm, phenyl-H) 6.14
(1H, t, J=6Hz, C+' -H)5.33
(1H', bs, 3' OH, disappeared by addition of D20) 4.36-3.83 (2H, m, C3', 4'H> 3.74-3.60 (2H, m, Cs "H> 2.14
(2H, t, J=6H2,C2'H) Example 2
2 3'-0-(4-methoxybenzyl)-2'-deoxy-5-fluorouridine [R2=R3=H, R'=
4-Methoxybenzyl group] Yield 8.1% Melting point 164-166°C ” HNMR (DMSO-ds) δ: 1
1.81 (1H, bs, disappeared by addition of -NH-1D20), 8.19 (IH, d, J=7H2, Cs -H)7.
27 and 6.91 (each 2H, d, J = 8Hz, phenyl-H> 6.12 (1H, t, J = 6Hz, C+'H) 5
．． 19 (1H, bt, J=5Hz, 5'-OH.

disappeared by addition of D20) 4.19-4.02 (2H,m, C3', 4'-H) 3.70 3.50 (2H,m, Cs'-H)
2.31-2.13 <2H,m,C2'-H) Example 23 2'-deoxy-5-fluoro-3'-(2-methylbenzyl)uridine (R" = R3=H, R' = 2-Methylbenzyl group] To a mixture of 331 Tl12 of water and 16 mQ of acetonitrile, add 1.14 CI of potassium hydroxide.
2'-deoxy-5-fluorouridine 1.000 and 2-methylbenzyl bromide 1.000 and 2-methylbenzyl bromide 1.000 and 2-methylbenzyl bromide
．． 50C] was added. Thereafter, post-treatment was carried out in the same manner as in Examples 4 and 5 to obtain 0.29 CI (20%) of the target compound.

Melting point: 114-116°C'HNMR (DMSO-ds) δ: 11.79 (disappeared by addition of IH, bS, -NH-1D20), 8.19 (1H, d, J=7H2, CB -H)7.
30-7.17 (4H,m, phenyl-H)6.11
(1H, t, J=6Hz, C+'-H>5.
19 (IH, t, J=5Hz, 5'-0H1D20
Disappears upon addition) 4.22-4.02 (2H, m, C3', C4' H) 3.66 3.62 (2H, m, Cs' H)2
．． 29-2.21 (5H, m, C2' -H and CH3
) Elemental analysis value: C+ v H+ 9 Calculated value (%) as FN20s: C58,28; H5,46N7.99 Actual value (%): C58,12; H5,64; N8.01 Examples 24 and 25 Examples The following compounds were obtained in the same manner as in Example 23.

Example 24 3'-〇-(3-methylbenzyl)-2'-deoxy-
5-Fluorouridine [R2=R3=H, R'=3-
Methylbenzyl group] Yield 23% Melting point 129-131°C 'H-NMR (DMSO-ds) δ: 11.80 (
IH, bs, disappeared by addition of -NH-1D20), 8.19 (1H, d, J=7H2, Cs H)7.
15 (4H,S, phenyl-H)6.12 (1H,
t, J=6Hz, C+'-H)5.18 (1H,
t, J=5Hz, disappeared by addition of 5'-0H1D20) 4.21-4.02 (2H, m.

C3', C, L' H) 3.66-3.61 (2H, m, Cs' -H)2
．． 31-2.22 (5H, m, 02' H and CH
3) Example 25 3'-0-(4-methylbenzyl)-2'-deoxy-5-fluorouridine [R2=R3=H, R'=4
-Methylbenzyl group) Yield 21% Melting point 178-180'C'H-NMR (DMSO-ds) δ: 11.81 (
1H, bs, disappeared by addition of -NH-1D20), 8.18 (1H, d, J=7Hz, C6H) 7.30
-7.13 (4H,m, phenyl-H)6.12(1
H, ↑, J=6Hz, C+ ' -H)5.17 (1
H, t, J = 5 Hz, 5'-0H1 Disappeared by addition of D20) 4.20-4.01 (2H, m, C3', C-' H) 3.65-3.60 (2H, m, Cs' H)2
．． 29-2.12 (5H, m, C2'-H and CH3
) Example 26 3'-〇-benzy-2'-deoxy-5-fluoro-
5'-〇-nicotinoyluridine (R' = Cs H5
CH2, R3=H, R2=3-pyridinecarbonyl group]
To a solution of 0.20C of 3'-〇-benzy-2'-deoxy-5-fluorouridine in 10ml of pyridine was added 0.2'IQ of nicotinoyl chloride hydrochloride, and the mixture was left at 80'C for 3 hours. After distilling off the solvent, the residue was diluted with 30ml of ethyl acetate.
It was dissolved in Q and washed twice with 20 mg of water. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated, and the oily residue was purified using a silica gel column and eluted with chloroform to obtain the target compound 0.18C] (69%).

Melting point 130~]32°C 'HNMR (CDC93) δ: 11.14 (disappeared by addition of IH, bs, -NH-1D20), 8.24 (1H, d, J=8Hz, C3'#4' l 5 '-H> 2.75 2.04 (2H, m, C2' H) Elemental analysis value: C22H2o Calculated value as FN306 (%)
:c 59.86; H4,57N9.52 Actual value (%): C60,0'l;H4,56; N9.5
8 Examples 27 to 38 The following compounds were obtained in the same manner as in Example 26.

Example 27 3'-〇-benzyl-5'-〇-benzoyl-2'-deoxy-5-fluorouridine (R' = Cs Hs
CH2, R2=Cs Hs CO.

R3=H) Yield 75% Melting point 125-127°C 'HNMR (DMSOds) δ: 11.94 (disappeared by addition of 1H, bs, -NH-1D20), C3., 4., s' H) 2. 40-2.27 (2H,m,C2'-H)Example 28 3'-〇-benzyl-5'-〇-phenoxycarbonyl-uridine (R'=Ce HS CH2, R2=C
6 HS 0CO, R3=H) Yield 38% Melting point - (oil) 'H NMR (DMSO-ds) δ: 1 2, 0
0 (IH, bs, -NH-, disappeared by addition of 020), 7, 95 (IH, d, J = 7Hz, Cs H) 7,
55-7.16 (IOH, m, phenyl-H)6,1
7 (1H,t,J=6Hz,C+'-H>4,
56-4.21 (6H1m,eCdan.-,C3'+
4' + 5' H) 2,39-2.28 (2H,m,C2'-H) Example 29 3'-〇-benzyl-5'-〇-n-hexanoyl-
2'-deoxy-5-fluorouridine (R' -Os
Hs CH2, R” = CH3 (CH2>4 Co,
R3=H) Yield 51% Melting point - (oil) 'H-NMR (DMs○-ds) δ; 11.94 (
1H, bs, disappeared by addition of -NH-1D20), 7.90 (1H, d, J-7HzSCs H)7.
33 (5H,!3, phenyl-H)6.19 MH,
t, J-6H2,C+'H)4.29-4.1
2 (4H, m, C3' + 4' l s'H> 2.38 2.23 (4H, m, C2' Hl-C
H3CO-) 1.61-1.15 (6H, m, CH3(CH2>30H2CO) 0.84 (3H, t, J=6Hz, CH3CH2) Example 30 3'-〇-hensyl-5'-〇- benzyl carbonyl
2'-deoxy-5-fluorouridine (R" = Cs
Hs CH2, R2=C6H5CH2Go, R3=H
] Yield 42% Melting point = (oil) 'HNMR (CDC93) δ: 10.06 (1H, bs, disappeared by addition of -NH-1D20), 7.42-7.23 (11H, m, phenyl-HlC
s H) 6,'15 (1H,t, J=6Hz, C+'-H
)4,. 33-4.11 (3H, m.

C3', 5' H) 3.96 3.83 (1H, m, Ct' H) 2.4
7-2.27.1.65-1.49 (2H, m, C2'
-H) Example 31 3'-〇-benzyl-5'-〇-ethoxycarbonyl-
2'-deoxy-5-fluorouridine (R' = Cs
Hs CH2, R2=CH3CH20CO1R3=H
) Yield 37% Melting point = (oil) 'H-NMR (CDCQ3) δ: 10.18 (IH, bs, -N) (disappeared by addition of -1D20), 7.68 <1H, d, J = 6Hz , CF, -1-
1>7.32 (5H,s, phenyl-H)6.31
(1HXt, J=6Hz, C+'H)4.37-
4.10 (6H, m.

C3', 4' l s' H%○Cdan2 CH3)
2.67-2.42.2.23-1.92 (2H, ml
C2'H) 1.30 (3H,t, J=7Hz, 0CH2CH3) Example 32 3'-〇-benzyl-5'-0-(3-methylbenzoyl)-2'-deoxy-5-fluorouridine (R
'=Cs H5CH2, R2=3-methylbenzoyl, R3=H) Yield 67% Melting point 33°C 'HNMR (CDCQ3) δ: 9.61 (1H, bs, -Nl-t- 1020 attachment 11
disappeared from G2), 6.25 (1H, t, J=6Hz, C+'
H) 4.55-4.35 (5H, m, C3', 5'-Hl 4.28-4.18 (IH, m, C, t' -H
) 2.73-2.47.2.16-1.87 (2H, m
. Benzoyl, R3=H) Yield 78% Melting point = (oil) 'HNMR (CDC93) δ: 9.27 (disappeared by addition of 1H, bs, -NH-1D20), 6.91 (2H, d, J= 9Hz.

Cs' H) 4.45-4.39 (IH, m, C3' H)4.
29 4.15 (IH, mS Ca' H)
3.97 (2H, t, J=7Hz, -CH20-
) 2.74-2.52.2.16-1.64 (4H, m
, CH3CH2CH2-0-1C2'H) 1.04 (3H,t, J=7H2゜Cdan3CH2> Example 34 3'-0-benzyl-5'-〇-phenoxymethylcarbonyl-ruolouridine (R' = Cs H5 CH2, R2
= Phenoxymethylcarbolenyl H] Yield 90% Melting point - (oil) 'H-NMR (CDC93) δ: 1 0, 03 (1 H, b's, -NH-, D2
disappeared by addition of 0), 7, 58 (IH, d, J = 6 Hz, C6 H)
7, 35-6.77 (10H, m, phenyl-H)6
, 22 (IH, t, J=6Hz, C+' -H)
4, 42-4.23 (5H, m.

3,97 3.84 (IH, m, C4',
H) 2, 49-2.23, 1.96-1.65 (1H,
m, C2 ”H> Example 35 3'-〇-benzyl-5'-〇-α naphthylcarbonyl-louridine (R' = Cs Hs CH2, R2 = α
-naphthylcarbonyl, R3=H) Yield 48% Melting point 158-160°C 'H-NMR (CDC93) δ: 9, 20 (1H, bs, -NH-, disappeared by addition of D20), 6.25 ( 1H,t,J=6H2,CI'H)
4.68 4.56 (4H,m,Cs'-R14
,45-4,38(1H,m,C3'-H)4.32
-4.18 (1H,m,C4'-H)2.70-2
．． 43.2.17-1.86 (2H, m, C2'H
) Example 36 3'-0-(4-chlorobenzoyl)-5'-〇-benzy-2'-deoxy-5-fluorouridine (R'
=4-chlorobenzoyl, R2=C6H5CH2, R3
=H] Yield 57% Melting point 215-217°C 'H-NMR (DMSO-C16') δ: 11.8
3 (disappeared by addition of 1H, bs, -NH-1D20)
, 8,○6-7.97 (3H,m,Cc R17,61
(2H, d, J=8Hz, 6.27 (IH, t, J=6Hz, CI'-H>
5.54 5.47 (1H,m,C3'-H)4.
42-4.32 (IH, m, C4'-H>3.80
-3.71 (2H,m,Cs'-H>2.52
2.38 (2H,m,C2'H) Example 37 3'-〇-benzy-5'-〇-(3,4゜5-trimethoxybenzoyl)-2'-deoxy-5-fluorouridine [R1= C5R5CH2, R2=3.4.5-trimethoxybenzoyl, R3=H) Yield 63% 'H-NMR (DMSO-ds) δ: 11.87 (
IH,s, disappeared by adding -NH-1D20) 6.17 (1H,t, J=7Hz, CI'H>
4.61-4.35 (6H, m, 3.82.3.77 (total 9H1 each S, 2.54 2.
39 (2H,m,C2'-H)Example 38 3'-0-(4-chlorobenzyl)-5'-0-acetyl-2'-deoxy-5-fluorouridine (R'
=4-chlorobenzyl, R2=CH3CO1R3=H) Yield 90% 'HNMR (CDC93) δ near, 67 (IH, d, J=6t-1z, Ca
H)7,. 28 (5H,s, phenyl-H)6,'2
2 (IH, t, J=6H2, CI'H)4.
50 (2H, s, < fi sea C dan 2-) 4, 40-4
．． 11 (4H, m.

C3' r c' + s' H) 2,7'l-2,46,2,28-1,93(5H,m
, C2'H, CH3Go>Example 39 3'-〇-benzy-2'-deoxy-5-fluoro-
Production of 3-phenoxycarbonyluridine R3 = phenoxycarbonyl] 3'-〇-benzy-2'-deoxy-5-fluorouridine 0.50 CI dioxane 2
Trimethylchlorosilane 0.38111Q in 01N solution
and triethylamine 1.0411f2 were added thereto, stirred at air temperature for 2 hours, and then left at 60°C for 30 minutes. Next, 0.40 g of phenoxycarbonyl chloride and 1.0 g of triethylamine were added. OOmQ was added and the mixture was left in a colander at 60'C for 3 hours. The solvent was distilled off, the residue was dissolved in 50 mQ of ethyl acetate, washed with saturated brine, and the ethyl acetate layer was separated.

This was concentrated and the residue was dissolved in 30 mQ of methanol.

Vinegar 110 here. Added 51T12 and concentrated overnight. The residue was eluted with chloroform to 2% methanol-chloroform using a silica gel column to obtain 0.580 (86%) of the target compound.

Melting point 110-112°C 'H-NMR (CDC93) δ: 8, 16 (1H, d, J = 7Hz, Cs H), 7,
34-7.22 (10H.m, phenyl-H)6,2
7 (1H,t,J=6Hz,C+'-H)4,2
6-4.1 7 (2H, m.

C3',4'H) 3,95 3.60 (2H,m,Cs'H
)2,63-1.98 (2H,m,C2'H
) Elemental analysis value: Calculated value (%) as C2 3 R2 + FN2 07 C 60.53:H 4.64:R
6.14 Actual value (%) C 60.60; H 4.72: R6
．． 08 Example 40 The following compounds were obtained in the same manner as in Example 3.

3'-〇-benzy-2'-deoxy-3-(4-propoxybenzoyl)-5-fluorouridine (R' =
Cs R5 CH2, R2 = H, R3 = 4-propoxybenzoyl] Yield 65% Melting point - (glassy powder) "H NMR (CDC (i3) δ: 8, 19 (1
H, d, J = 7Hz, Cs H) 7, 85 (2H,
d, J=9Hz, 6, 25 (1H, ↑, J=6Hz, C+ 'H)
4, 20-3.55 (6H, m, C3' + 4' + 5' Hl-CH
2 CR20-) 2,57 1.58 (4H,m,C2'H
, CH3Cdan2CH20->0,99 (3H,t,J=7Hz.

Cdan3CH2> Example 41 3'-〇-benzy-2'-deoxy-3-benzoyl-5-fluorouridine [R1-Cs R5 CH2
, R'' = H, R3 = Cs Hs Co) A solution of 0.50 C of 3'-〇-benzyl-2'-deoxy-5-fluorouridine] in dioxane, 0.75 mQ of trimethylchlorosilane, and 2.
OOmi2 was added and the mixture was stirred at 1 liter for 2 hours, and then left at 60'C for 30 minutes. Then benzoyl bromide 0.42C]
and triethylamine 1.0 Om2, and further 60'
It was left at C for 1 hour. The solvent was distilled off, and the residue was dissolved in 50 rnQ of ethyl acetate and washed with saturated brine. The ethyl acetate layer was separated and concentrated, and the residue was dissolved in 30 mQ of methanol, to which 0.5+r+i2 acetic acid was added and left overnight at air temperature.

After evaporating the solvent, the residue was eluted with chloroform-2% methanol-chloroform using a silica gel column to obtain 0.35 Cl (54%) of the target compound in powder form.

Melting point - (glassy powder) 'HNMR (CDC93) δ: 8.19 (1H, d, J = 7Hz, Cs H), 6
．． 24 (IHSt, J=6Hz, C+'-H>4
．． 24-4.12 (2H, m.

C3', 4'1'') 3.92 3.56 (2H, m, Cs' H)
2.60 1.96 (2H, m, C2' H) Example 42 5'-〇-acetyl-3'-0-benzyl-3-benzoyl-2'-deoxy-5-fluorouridine (R'
=Cs R5CH2, R2-CH3Co, R3=C5H
s Co) (D'A construction 5'-〇-acetyl-3'-〇-
Benzyl-2'-deoxy-5-fluorouridine 0.
0 benzoyl chloride in 20q dioxane 10ml 12 solution
．． 29C] and 0.73 mQ of triethylamine and left at 80'C for 2 hours. After distilling off the solvent, the residue was dissolved in 50 m2 of ethyl acetate and washed with water. After drying the ethyl acetate layer over anhydrous sodium sulfate and concentrating, the residue was applied to a silica gel column and eluted with chloroform to obtain the target compound as an oil (0.20C] (78%).

"HNMR (CDC93) δ near, 95-7.27 (11H, m, phenyl-HlC
s H), 6.20 (IH, t, J=6Hz, C+'H
>4.23-4.08 (4H, m, C3'・4'・s' H) 2.60-2.05 (5H, m, C2' -H1C
OCH3> Elemental analysis value: Calculated value as C2s R23FN207 (
%) C62,24; H4,80; R5,81 Actual value (%) C62,34: H5,06: R5,77 Examples 43 to 53 The following compounds were obtained in the same manner as in Example 42.

Example 43 3'-〇-benzyl-5'-〇-acetyl-2'-deoxy-3-(4-propoxybenzoyl)-5-fluorouridine [R1=C5R5CH2, R2=CH3Co
, R3 = 4-propoxybenzoyl] Yield 38% Melting point - (oil) 'HNMR (CDCIQ3) δ: 6.20 (1H, t, J = 6Hz, C+ '-H>
4.23-4.08 (4H, m, C3', 4', 5' H) 3.96 (2H, t, J=6Hz, -OCC20CH2CH3) 2.70-1.68 (7H, m, C2 '-H.

COCH3, -〇CH2Cdan20H3) 1.01 (
3H, t, J=7Hz, -O(CH2>2 CH3) Example 44 3'-〇-benzyl-5'-〇-acetyl-2'-deoxy-3-(4-chlorobenzoyl)-5-fluorouridine [R1=C5R5CH2, R2=CH3Co, R3=4-chlorobenzoyl] Yield 73% Melting point = (oil) 'HNMR (CDCQ3) δ near, 78 (1H, d, J=6Hz, CaH)7.
44 (2H, d, J=9t-1z, 6.20 (IH
,t,J=6H2,C+'H)4.51 (
2H, d, J=1Hz, 4.28-4.08 (4H
, m.

C3'ra' + s' H)2
．． 70-2.43.2.25-2.03 (5H, m, C
2' H, COCH3) Example 45 3'-〇-benzyl-5'-〇-acetyl-2'-deoxy-3-(2-methylbenzoyl)-5-fluorouridine [R1= C5Hs CH2, R2=CH3Co, R3=2-methylbenzoyl] Yield 44% Melting point - (oil) 'H-NMR (CD093) δ near, 62-7.32 (IOH, m, Cs H.

Phenyl-H) 6.19 (1H, t, J=7Hz, CI'-H)4
．． 25-4.07 (4HSm.

C3' p t' + s' H) 2.67-2.00 (8H, m, C2'-H.

Example 46 3'-〇-benzyl-5'-〇-acetyl-2'-deoxy-3-(3-methylbenzoyl)-5-fluorouridine (R1- Cs R5CH2, R2=CH3Co, R3=3-methylbenzoyl ] Yield 68% Melting point - (oil) 'H-NMR (CDC123) δ near, 81-7.65 (3H, m, Cs H.

4.25-4.08 (4H, m, C3', a' + s' -H) 2.67 2
．． 00 (8H, m, C2'H.

Example 47 3'-〇-benzyl-5'-acetyl-2'-deoxy-3-(4-methylbenzoyl)-5-fluorouridine [R1-C5Hs CH2, R2=CH3Co, R3=4-methylbenzoyl] Yield 84% Melting point - (oil) 'HNMR (CDCQ3) δ near, 79 (2H, d, J=8Hz.

7.78 (IH, d, J=7Hz, Ce H)7.
22 (2H, d, J=8Hz, 6.20 (1H, t, J=6H2, C+ '-H>
4.24-4.08 (4H, m.

C3' * a' + s' H) 2, 60 2.05 (8H, rrL, C2' H
1 Example 48 3'-〇-benzyl-5'-〇-acetyl-2'-deoxy-3-(4-methoxybenzoyl)-5-fluorouridine [R1=C6HS CH2, R2=CH3Co
, R3 = 4-methoxybenzoyl] Yield 70% Melting point - (powder) 'H-NMR (CDC93) δ near, 85 (2H, d, J = 8 Hz, 6.91 (2H, d, J = 8 Hz, 6.21 (IH, t, J=6Hz, C+'H)
4.25-4.09 (4H, m, C3'・4'・s' H) 3.80 (3H, s, C3O-) 2.49-2.07 (5H, m, C2' - H1CO
CH3) Example 49 3'-〇-benzyl-5'-〇-benzoyl-2'-
Deoxy-3-benzoyl-5-fluorouridine (R
'=Cs Hs CH2, R2=R3=C6Hs C
o) Yield 94% Melting point - (oil) 'H-NMR (CDC93) δ: 8.03-7.32 (16H, m, phenyl-Hlo
s H) 6.20 (IH, t, J=6H2, C+' -H)
4.48-4.16 (6H, m, 2.70-2.42.2.25-1.95 (2H, m,
C2'-H) Example 50 3'-〇-benzyl-5'-〇-phenoxycarbonyl-2'-deoxy-3-fe/-t''dicarbonyl-5
-Fluorouridine (R'=Cs HS CH2, R2
=R3=phenoxycarbonyl] Yield 48% Melting point - (oil) 'H-NMR (DMSO-ds) δ: 8.21 (1
H, d, J=7Hz1Cs H)7.57-7.16
(15H,m, phenyl-H)6.20 (1H,t
, J=7Hz, C+'H>4.59-4.28
(6H, m.

2.54 2.38 (2H,m,C2'H)Example 51 3'-〇-benzyl-5'-〇-α-naphthylcarbonyl-phthylcarbonyl- (R'=Cs HS CH2, R2=C3= α-Naphthylcarbonyl yield 29% Melting point - (oil) 8, 11-7.19 (13HSm, 6, 20 (1H, t, J = 7Hz, C+ 'H)
4, 71-4.10 (6H.m, 2, 64-2.36, 2.15-1.85 (2H,m,
C2'-H> Example 52 3'-〇-benzyl-5'-〇- (3-methylbenzoyl)-2'-deoxy-3-(3-methylbenzoyl)-5-fluorouridine (R' = Cs Hs
CH2, R2=C3=3-methylbenzoyl] Yield 18% Melting point - (oil) 'H-NMR (CDCQ3) δ near, 81-7.62 (5H, m.

7, 43-7.24 (9H, m, 6, 23 (IH, t, J-6Hz, C+ ' -H)
4, 60-4.20 (6H, m, 2, 78-2.50, 2.24-1.93 (2H, m,
C2'-H) 2, 3, 2.37 (S, 3 days each, Example 53 3'-〇-benzyl-5'-〇-acetyl-2'-deoxy-3-hexanoyl-5-fluorouridine ( R”
=Cs R5 CH2, R2=CH3CO, R3=hexanoyl] Yield 48% Melting point - (oil) 'H NMR (CDCQ3) δ near, 66 (I
H, d, J = 6Hz, Cs H) 7, 32 (5H;
s, phenyl-day) 6, 20 (1H, t, J=6H
z, C+ 'H)4, 54 (2H, s, <
IH Cdan 2-) 4, 38-4.07 (4H, m, C3'*', s' H) 2, 82 (2H, t, J=9Hz, -CH2Co) 2, 59-2. 44, 2.22-2.02 (5H.

m. C2'-H and CH3Co)1,92-1
．． 67 (2H, m.

CH2 0H2 Co->1, 56-1.22 (4H, m, CH3 Gdan2Cdan2 CH2 CH2 Co->0,
90 (3H, t, J = 5Hz, CH3 CH2) Example 54 3'-〇-benzyl-5'-〇-acetyl-2'-deoxy-5-fluorouridine (R' = Cs R5 C
H2, R2=CH3Co.

Preparation of R3=H) 3.33 mf2 of acetic anhydride was added to a pyridine 30 mQ solution of 3'-〇-benzyl-2'-deoxy-5-fluorouridine 3.95C] and left overnight at 40'G. The solvent was distilled off, the residue was dissolved in 30 mQ of ethyl acetate, and 1 mQ of water was dissolved.
The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated, and eluted with chloroform using a silica gel column to give the target compound 3.62 to 7 (81,
5%).

Melting point 87-88 °C 'HNMR (DMSOds) δ: 11.86 (1H, d, J = 4Hz, -NH-1D2
7.93 (1H, d, J=7Hz, Cs H)7.
35 (5HXS, phenyl-H)6.15 (IH,
tSJ=6H2,C+'-H)4.32-4.20
(4H, m, C3'ra' + s'H> 2.39-2.28 (2H, t, J=6Hz, C2'
-H) 2.04 (3H, S, COCH3) Elemental analysis value: C+ e H+ 9 Calculated value as FN206 (%) C, 57,14; H5,06N7.40 Actual value (%) C56,99: H5, 22N7.37 Example 55 3'-〇-acetyl-5'-〇-benzyl-2'-deoxy-5-fluorouridine (R' = CH3Co, R
2=C5Hs CH2, R3=H) In the same manner as in Example 54, 5'-〇-benzyru 2'
-Deoxy-5-fluorouridine was reacted with 1.0 OCI to obtain the target compound at 1.0 OCI (88.9%
) was obtained.

Melting point 1141'I 6°C'H-NMR (DMSO-d6) δ: 11.85 (
IH, bs, disappeared by addition of -NH-1D20) 7.95 (IH, d, J=7Hz, Cs H)7.
34 (5H,S, phenyl-H)6.17(1H,t
1J=6H2,C+'H)5.25 5.23 (
1H,m,C3'-H)4.32 4.20 (1
H, m, C, t'H>, 3.84 3.73
(2HSm, Cs' H) 2.37 2.25
(2H,m,C2'-H)2.06 (3H,S,C
OCH3) Elemental analysis value: Calculated value as CteH19FN206 (%
) C57,14: H5,06N7.40 Actual value (%) C56,91; H5,32N7.25 Example 56 3'-〇-benzyl-5'-〇-chloroacetyl-2'
-deoxy-5-fluorouridine (R' = Ca H
s Production of CH2, R2=CH2CQ Co, R3=H) Pyridine 1Qm of 3'-〇-benzyl-2'-deoxy-5-fluorouridine 0.20C .

The post-treatment was carried out in the same manner as in Example 54, and the target compound was reduced to 0.11
Cl (45%) was obtained as an oil.

'H-NMR (CDC93) δ: 10.22 (1H, bs, disappeared by addition of -NH-1D20) 7.60 (1H, d, J-6Hz, Cs H)7.
32 (5H,s, phenyl-H)6.23 (IH,
t, J=6Hz, C+'H)4.53 (2H,
d, J = 3Hz.

4.45-4.08 (6H, m, CG', 4', 5'-H, COCH2Go
>2.69-2.06 (2H, m, C2'-H> Elemental analysis value: C+ a H+ a CQ Calculated value (%) as FN206 0 52.37; H4,39N6.79 Actual value (%) C52 ,43:H4,63N6.80 Example 57 3'-〇-benzy-2'-deoxy-3-(2-tetrahydrofuranyl)-5-fluorouridine (R' =
Cs H5CH2, R2=H, R3-2-tetrahydrofuranyl] Using 0.40 CI of 3'-〇-benzyl-2'-deoxy-5-fluorouridine, the reaction was carried out in the same manner as in Reference Example 2 to obtain an oily target product. Compound 0.370 (77%) was obtained.

'H-NMR (CDCQ3) δ: 8.01 (1H, d, J-6Hz, Cs-H)7.
30 (5H,S, phenyl-H)4.51 (2HS
s, C→Cdan 2-) 4.39-3.50 (7H, m.

C3' * t' + s' HN C6'
0H12,60-1,86(6H,m,C2'
H.

Elemental analysis value: 020 Calculated value as H23FN206 (
%) C59,11; H5,7ON6.89 Actual measurement 1 shift (%) 0 59.02: H6,11N6.78 Example 58 5'-〇-acetyl-3'-〇-benzyl-2'-deoxy-5- Fluoro-3-(3-(2-hydroxy-4
Preparation of 5'-〇-acetyl-3'-〇-benzyl-2'-deoxy-5-fluorouridine (3.009 g) of inphthaloyl chloride in 112 ml of dry dioxane (100 II).
40 g of triethylamine and 8.5 g of triethylamine were added, and the mixture was refluxed for 2 hours. Here 4-hydroxy-2(IH)-pyridone 1.
A suspension of 100 In12 of dry dioxane containing 77 CI and 9.60 times of triethylamine was added and the mixture was refluxed for 2 hours.

Insoluble matter was removed, the liquid was concentrated, and the residue was dissolved in ethyl acetate.
00 Peng and washed twice with 30 ml of saturated saline. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated.
The residue was eluted with chloroform-2% methanol-chloroform using a silica gel column, and the fractions corresponding to the target compound were collected and concentrated to dryness to give a powder of the target compound (1.48 g).
C1 (30%) was obtained.

'HNMR (CD093) δ: 8.62-7.31 (11HSm, phenyl-Hlo
B-day and 06 H of the pyridine ring) 6.50 (1HScJSJ=2Hz, C of the pyridine ring
3-H) 6.31 (1H, (jd, Js, e = 7H2゜J 31 s ” = 2 Hzs Cs − of pyridine ring
H) 6, 23 (it-1, partially overlapped with Cs -H of pyridine ring, C+' -H > 4.30-4.13 (4H, m.

C3Z4Z5'H), 2.53-2.06 (5H,m, C2'H and CO
Cdan3) Example 59 5'-〇-acetyl-3'-〇-benzyl-3゛-(3
-(Production of 5-chloro-4-hydroxy-2-pyridyloxycarbonyl-2'-deoxy-5-fluorouridine5'-〇-acetyl-3'-〇-benzyl-2'-deoxy-5-fluorouridine1. Isophthaloyl chloride o, aog in a solution of 00Q in 50ml of dry dioxane
and 2.95 mQ of triethylamine were added and refluxed for 2 hours. Insoluble materials were removed, the residue was concentrated, the residue was dissolved in 50 ml of dry dichloromethane, 1.35 CI of 2,4-bis(trimethylsilyloxy)-5-chloropyridine was added, and the mixture was stirred at room temperature overnight. After evaporating the solvent, the residue was dissolved in 50 mQ of ethyl acetate and washed three times with 30 mQ of saturated hydrogen carbonate water and three times with 30 mQ of saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated, and the residue was eluted with chloroform-1% methanol-chloroform using a silica gel column. Fractions corresponding to the target compound were collected and concentrated to dryness to obtain a powder of the target compound. 0.30c+ (17
%) was obtained.

'HNMR (CDCQ3) δ: 8.61-7.31 (11H, m, phenyl-HlC
s-H and C6H of the pyridine ring) 6.82 (1H,s, 03H of the pyridine ring)6.
19 (IH,L J=6H2,C+'H
>4.29-3.95 (4H, m, C3', ', s' H) 2.74-2.10 (5H, m, C2' -H and CO
CH3> Example 60 5'-〇-acetyl-3''-0-benzyl-2'-deoxy-3-[3-(1,2-dihydro-2-oxo-1
-(2-tetrahydrofuranyl)-4-pyridyloxycarbonyl]benzoyl]-5-fluorouridine In Example 58, 4-hydroxy-1-(2-tetrahydrofuranyl) was substituted for 4-hydroxy-2(1H)-pyridone. Using IH)-2(IH)-pyridone, the reaction and post-treatment were carried out in the same manner to obtain a powder of the target compound in a yield of 41%.

'HNMR (CD093) δ: Cs H) 7.53 (1)-1, d, J = 8 Hz, C5-H of pyridine ring) 6.40 (1)-1, d, J = 2 Hz, C5-H of pyridine ring 03 H) 6.27 6.12 (3H, m, C+' H.

(Cs H of γ and pyridine ring) 4.27-3.92 (6H, m.

C3Z4', 5' H Tonia) 2.50 1.98 (9HSm, C2' H.

Example 61 5'-〇-acetyl-3'-〇-benzyl-3-[3-
(5-chloro-1,2-dihydro-2-oxo-1-(
Preparation of 2-tetrahydrofuranyl)-4-pyridyloxycarbonyl]benzoyl]-2'-deoxy-5-fluorouridine In Example 58, 3-chloro-4-hydroxy was used instead of 4-hydroxy-2(1H)-pyridone. Using -1-(2-tetrahydrofuranyl)-2(1H)-pyridone, the reaction and post-treatment were carried out in the same manner to obtain a powder of the target compound in a yield of 72%.

'H-NMR (CDC93) δ: 8.93-7.58 (6HSm1Cs H, pyridine 6.58 (1H,s, 03H of pyridine ring)6.
20-6.08 (2H,m,C+'-H and 4.3
6-3.97 (6H, m, Q COCH3 and rγ) Example 62 5'-O-acetyl-3'-〇-benzyl-2'-deoxy-5-fluoro-3-(3-(1,2-dihydro −
Preparation of 1-ethoxymethyl-2-oxo-4-pyridyloxycarbonylbenzoyl]uridine In Example 58, 1-ethoxymethyl-4-hydroxy-2(1H) was used instead of 4-hydroxy-2(1H)-pyridone.
)-pyridone, the reaction and post-treatment were carried out in the same manner to obtain a powder of the target compound in a yield of 32%.

'H NMR (CDCQ3) δ: 8, 70-7.
31 (1 1H, m, phenyl-HlCs H and Cs H of pyridine ring) 6, 47 (1H, bs, C3 -H of pyridine ring) 6, 20-6.10 (2H, m
, C+ '-H and C5 H of the pyridine ring) 5, 36 (2H,s,N-CH20C2 Hs)4
, 52-4.00 (6H, m, 3,63 (2H, Q, J=7Hz, OCH2 CH3) 2,80 1.90 (5H, m,, C2' H
and COCH3) 1,22 (3H,t,J=7Hz.

OCH2 CH3 ) Example 63 5'-〇-acetyl-3'-〇-benzyl-3- (3
- (4-hydroxy-2(IH)- Using 5-chloro-1-ethoxymethyl-4-hydroxy-2(IH)-pyridone in place of pyridone, the reaction and post-treatment were carried out in the same manner to obtain a powder of the target compound in a yield of 20%.

'H NMR (CDCQ3) δ:.

8, 66 7.68 (5H, m, 06 H and 6,
64 (1H, S, 03H of pyridine ring) 6, 21
(IH, t, J=6Hz, C+ ' -H)5, 31
(2H,s,N-CH20C2H5)4,28
-4.06 (4H, m.

C3'. 4', 5' H) 3, 63 (2H, (1, J=7Hz, -O CH2
CH3) 2,58 2.02 (5H, m, C2'H and COCH3) 1,22 (3H, tS J-7Hz.

-OCH3 CH3) Example 64 5'-〇-acetyl-3- (3- (2-benzoyloxy-5-chloro-4-pyridyloxycarbonylbenzyl-2'-deoxy-5-fluorouridine) In Example 58, 4 Using 2-benzoyloxy-5-chloro-4-hydroxypyridine instead of -hydroxy-2(1H)-pyridone, the reaction and post-treatment were carried out in the same manner to obtain a powder of the target compound in a yield of 27%. Ta.

'HNMR (CDC93) δ: 6.20 (IH, t, J=6Hz, C+ 'H
)4.27-4.04 (4H, m.

C3'+4'l5'H)2.7
0 2.07 (5H, m, C2'H and COCH3
) Example 65 5'-〇-acetyl-3'-〇-benzyl-2'-deoxy-3-(3-(1,2-dihydro-1-carbomethoxymethylcarbamoyl-nyl)benzoylcou-5-fluorouridine) In Production Example 58, 4-hydroxy-1-carbomethoxymethylcarbamoyl-2(1H)-pyridone was used instead of 4-hydroxy-2(IH)-pyridone, and the same reaction and post-treatment were performed to obtain a powder of the target compound. Obtained with a yield of 5.7%.

'H-NMR (CDC93) δ: 10, 86 (1H, t, J = 6Hz, -CONHCH
2) 6,62 (1H, d, J=2Hz, 03 of pyridine ring
H > 6, 44-6.14 (2H, m, C+ 'H and Cs H of pyridine ring) 4, 30-4.00 (6H, m.

C3'#4'#5' H and one NHCH2 COOCH3) 3,78 (3H,s, -coocdan3)2,76
1.92 (5H, m, C2'H and COCH3
) Example 66 5'-〇-acetyl-3'-〇-benzyl-3- [4
-(5-chloro-1,2-dihydro-2-oxo-1-
Preparation of (2-tetrahydrofuranyl)-4-pyridyloxycarbonyl]benzoyl]-2'-deoxy-5-fluorouridine In Example 58, terephthaloyl chloride was used instead of isophthaloyl chloride. 5-Chloro-4-hydroxy-1-(2-tetrahydrofuranyl)-2(1)-pyridone was used in place of 5-chloro-4-hydroxy-1-(2-tetrahydrofuranyl)-2(1)-pyridone, and the reaction and post-treatment were carried out in the same manner to yield a powder of the target compound. Obtained at 38%.

'H-NMR (DMSO-da) δ: 8, 50-8
．． 20 (5H,m,Ce-H and 6,66 (1H,
S, pyridine ring 03 H) 6, 20-6.10 (
2H,m,C+'-H and r) 4,55-3.70 (8H,m.

C3',4',5'-H, 2,60-1.80 (9H,m,C2'-H, Example 67 3-benzoyl-3'-〇-benzyl-5'-O-(3
-(5-Chloro-4-hydroxy-2-pyridyloxycarbonyl)benzoyl)-2'-deoxy-5-fluorouridine Production Example 59 5'-〇-acetyl-3'-0-benzyl-21-deoxy -5-In place of fluorouridine 3-
Benzoyl-3'-0-benzyl-2'-deoxy-
The reaction and post-treatment were carried out in the same manner using 5-fluorouridine to obtain a powder of the target compound in a yield of 15%.

'H-NMR (CDC93) δ: Cs of pyridine ring) (> 6.21 (1H, i, J-7H2, C+' H)2
．． 60 2.13 (2H,m,C2'H)Example 68 3-benzoyl-3'-〇-benzyl-5'-O-[3
-(5-chloro-1,2-dihydro-2-oxo-1-
Preparation of (2-tetrahydrofuranyl)-4-pyridyloxycarbonyl]penzoylco-2'-deoxy-5-fluorouridine In Example 58, 5'-〇-acetyl-3'-0-benzyl-2'-deoxy-5- 3- instead of fluorouridine
Benzoyl-3'-〇-benzyl-2'-deoxy-5
- using fluorouridine and 4-1 nitroxy-2
Using 5-chloro-4-hydroxy-1-(2-tetrahydrofuranyl)-2(1H)-pyridone in place of (IH)-pyridone, the reaction and post-treatment were carried out in the same manner to obtain a powder of the target compound in a yield of 46. Obtained in %.

1H-NMR (CDCQ3) δ: Cs H of pyridine ring) 6.57 (IH,s, C3H of pyridine ring>6.21
-6.06 (2H, m, CI' H jump) 4.53-4.02 (6H, m, 2.55-1.96 (6f-1, m, C2' H and Example 69 5'- 〇-acetyl-3'-〇-benzyl-2'-deoxy-3-(3-(1,2-dihydro-2-oxo-1
Production of -phthalidyl-4-pyridyloxycarbonyl)benzoyldi-5-fluorouridine In Example 58, 4-hydroxy-1-phthalidyl-2(1H)-pyridone was used instead of 4-hydroxy-2(1H)-pyridone, The reaction and post-treatment were performed in the same manner to obtain the target compound in a yield of 19%.

'HNMR (CD093) δ: 8.60 7.57 (IOH, m, Cs H.

6.90 (IH, d, J = 8H71 Cs of pyridine ring
H) 6.60 (1H, d, J = 2Hz, 03 of the pyridine ring
H) 6.28-6.04 (2H, m, C+ ' -H and Cs H of pyridine ring) 4.28-4.06 (4H, m1 C3'p4'15' -H) 2.60-2 .01 (5H,m,C2'-H and CO
CH3) Example 70 5'-〇-acetyl-3'-〇-benzyl-3-(3-
Preparation of 4-hydroxy-2(carbomethoxybenzoyl)-2'-deoxy-5-fluorouridine In Example 58, 4-hydroxy-2(
Using methanol in place of 1H)-pyridone, the reaction and post-treatment were carried out in the same manner to obtain a powder of the target compound in a yield of 69%.

'HNMR (CD093) δ: 8.54 7.47 (5H, m, Cs H and 6.2
0 (1H,t,J=6H2,C+'H)4.4
8-4.13 (4H, m, C3' + t' + 5' H) 3.89 (3H, s, -coocCOCH350-1
,93(5H,m,C2'-H and COCH3) Example 71 5'-〇-acetyl-3'-〇-benzyl-3-(3-
(1-benzyloxymethyl-5-chloro-1,2-dihydro-2-oxo-4-pyridyloxycarbonyl)
Preparation of benzoyl-2'-deoxy-5-fluorouridine In Example 58, 4-hydroxy-2(IH)-pyridone was replaced with 1-benzyloxymethyl-5-chloro-4-hydroxy-2(1H)-pyridone. The reaction and post-treatment were carried out in the same manner as above to obtain a powder of the target compound in a yield of 34%.

'H-NMR (CDCQ3) δ: 8.65-7.58 (6H,m, Cs C16,6
4 (1H,s, C3H of pyridine ring)6.22 (1H
, t, J=7Hz, C+ ' -H)5.42 (2H
Ss, -NCC200) 4.30-4.03 (4H
,m.

C3' l 4' m s' H) 2.77
1.97 (5H, m, C2' H and COCH3) Example 72 5'-〇-acetyl-3- (3-(2-acetoxy-
Production of 5-chloro-4-pyridyloxycarbonyl)benzoyl)-3'-0-benzyl-2'-deoxy-5-fluorouridine 5'-〇-acetyl-3'-〇-benzyl-2'-deoxy-5 - A solution of 2.00 q of fluorouridine in 100 rrcl of dry dioxane and 1.6 q of isophthaloyl chloride.
Add 0C1 and triethylamine 1.47rllf2 3
Refluxed for 0 minutes. Then roughly triethylamine 4.4
0 times and refluxed for 50 minutes. Remove the generated salt, 2
The solution was concentrated under reduced pressure. Dilute the residue with 100 mQ of acetonitrile.
Here triethylamine 3.66+nQ and 2
-acetoxy-5-chloro-4-hydroxypyridine 1
．． 19CI was added and stirred at room temperature for 1.5 hours.

The solvent was removed, the residue was eluted with chloroform using a silica gel column, the fractions corresponding to the target compound were collected, and concentrated to dryness to obtain a powder of the target compound at 2.83 CI (7
7%).

'H-NMR (CDCQ3) δ: 8.68 (6H, m, Cs-H, 7.2 of pyridine ring
7 (1H,S, 03-H of pyridine ring)6.20 (
1H,t,J=6Hz,C+'-H)4.25-4
．． 07 (4H, m, C3' + 4' + 5'H>2.6
0 2.20 (5H, m, C2' -H and -COC on the pyridine ring) 2.09 (3H, S, -COC at the 5' position) Example 73 5'-〇-acetyl3 - (3-(4-benzoyloxy-5-chloro-2-pyridyloxycarbonyl)benzoyl)-3' -0-benzyl-21-deoxy-
Production of 5-fluorouridine 0.42 Cl of isophthaloyl chloride is added to a solution of 0.60 q of 5'-〇-acetyl-3'-〇-benzyl-2'-deoxy-5-fluorouridine in 30 mQ of dry dioxane.
and triethylamine were added and refluxed for 2 hours.

Then 4-benzoyloxy-5-chloro-2(1H)
-0.60 g of pyridone and 1.11 mQ of triethylamine
was added, and the mixture was washed away for 1 hour. The generated precipitate was removed, concentrated, and the residue was filtered using a silica gel column.
Elution with 40% ethyl acetate-benzene yielded 0.0% of the target compound.
450 (37%).

"HNMR (CDC93) δ: 8.66-7.28 (17H, m, phenyl-HlC
s H and 03,6 H of the pyridine ring) 6.19 (
1H,t,J=6Hz,C+'H)4.27-4
．． 01 (4H, m.

C3'#4'+5' H) 2.66-1.90 (5H, m1C2' -H and C0
CH5) Example 74 Production of 5'-〇-acetyl-3-(3-(4-acetyloxy-5-chloro-2-pyridyloxycarbonyloxy-2'-deoxy-5-fluorouridine) In Example 73, 4-benzoyloxy -5-chloro-2(
4-acetoxy-5-chloro- instead of 1H)-pyridone
Using 2(1H)-pyridone, the reaction and post-treatment were carried out in the same manner to obtain the target compound in a yield of 51%.

'H-NMR (CDCQ3) δ: 8, 65-7.17 (12HSm, phenyl-H
lCs H and pyridine ring 03,6 H)6,19
(IH, t, J=6Hz, C+ '-H>4, 26
-4.1 2 (4HXm, C3' + 4' + 5"H) 2,55-2.07 (8H, m., C2'H and COC
H3
-3'-0-Benzyl-2'-deoxy-5-fluorouridine Production Example 73 4-benzoyloxy-5-chloro-2(
IH)-pyridone was replaced with 4-benzoyloxy-2(1
Using H)-pyridone, the reaction and post-treatment were carried out in the same manner to obtain the target compound in a yield of 55%.

1H NMR (CDC93) δ: 8.66-7.25 (18H, m, phenyl-HlC
s H and pyridine ring 03,5.6 H>6.21
(IH, t, J=6Hz, C+,'-H)4.2
9-4.07 (4H, m.

C3' e 4' + 5' H)2, 76-1.
98 (5H, m, COCH3 and C'2' H) Example 76 5'-〇-acetyl-3- (3-(2-benzoyloxy-4-pyridyloxycarbonyl 2'-deoxy-
Production of 5-fluorouridine In Example 73, 4-benzoyloxy-5-chloro-2(
'IH)-2-benzoyloxy-4- instead of pyridone
The reaction and post-treatment were carried out in the same manner using hydroxypyridine to obtain the target compound in a yield of 42%.

'H NMR (CDCQ3) δ: 8, 66-7, 23 (18H, m, phenyl-H, C
6 H and pyridine ring 03+5+6 H)6,22
(1H, ↑, J-6Hz, C+ '-H) 4, 52
(2H,s,-Cdan2be=))4,30-4.06 (
4H, m, C3' l 4' l s' -H)2, 72
2.04 (5H1m, C2'H and COCH3
) Example 77 Production of 5'-〇-acetyl-3-(3- (2- (2-methylbenzoyloxy)-4-pyridyloxycarbonyl-benzyl-2'-deoxy-5-fluorouridine) In Example 73, 4- Benzoyloxy-5-chloro-2 (
Using 2-(2-methylbenzoyloxy)-4-hydroxypyridine in place of 1H)-pyridone, the reaction and post-treatment were carried out in the same manner to obtain the target compound in a yield of 31%.

'H NMR (CDCQ3) δ: 8,66-7,20 (17H,m, phenyl-H,
Ca H and pyridine ring 03,5.6 H>6,2
1 (1H, ↑, J=6Hz, C+ 'H>4, 2
8-4.07 (4H, m, C3' l 4', s'-H> 2,68 2.02 (8H, m, C2' -H
, Example 78 5'-〇-acetyl-3'-〇-benzyl-3- (3
- (5-chloro-2-ethoxycarbonyloxy-4
-pyridyloxycarbonyl)benzoyl)-2' -
Production of deoxy-5-fluorouridine In Example 73, 4-benzoyloxy-5-chloro-2 (
Using 5-chloro-2-ethoxycarbonyloxy-lysine in place of IH)-pyridone, the reaction and post-treatment were carried out in the same manner to obtain the target compound in a yield of 52%.

'H NMR (CDCQ3) δ: 8, 66-7,
26 (1 2H, m, phenyl-H2O2 H and C3,6 H of pyridine ring) 6, 22 (1H, t, J
=6Hz,C+'H)-0-CH2CH3 and C3',',s'H) 2.75-2.11 (5H,m,C2'H and C0
CH5) 1.40 (3H, t, J=7Hz.

-OC)12 CH3) Example 79 5'-〇-acetyl-3-(3-(4-benzoyloxy-5-chloro-2-pyridyloxycarbonyl(4-chlorobenzyl)-2'-deoxy-5-fluoro Production of Uridine In Example 73, 5' was used instead of 5'-〇-acetyl-3'-0-benzyl-2'-deoxy-5-fluorouridine.
Using -0-acetyl-3' -0- (4-chlorobenzyl)-2'-deoxy-5-fluorouridine, the reaction and post-treatment were carried out in the same manner to obtain the target compound in a yield of 50%.

'H-NMR (CDCQ3) δ: 8, 65-7.22 (16H, m, phenyl-H, C
s H and pyridine ring 03,6 H)6,18 (
1H,t,J=6Hz,C+'-H)4,27-4
．． 11 (4H, m, C3' * t', s' H) 2, 70 2. 00 (5H, m, COCH
3 and C2' H) Example 80 5'-〇-acetyl-3- (3- (2-acetoxy-5-chloro-4-pyridyloxycarbonyl)benzoyl)-3' -0- (4-chlorobenzyl)-2 ′
Production of -deoxy-5-fluorouridine In Example 73, replacing 5'-〇-acetyl-3'-0-benzyl-2'-deoxy-5-fluorouridine with 5'
Using -O-acetyl-3'-0-(4-chlorobenzyl)-2'-deoxy-5-fluorouridine, 4
-Benzoyloxy-5-chloro-2(IH)-pyridone was replaced with 2-acetoxy-5-chloro-4-hydroxylysine, and the reaction and post-treatment were carried out in the same manner to obtain the target compound in a yield of 43%. .

'H-NMR (CDCQ3) δ: 8, 67-7, 24 (1 H, m, phenyl-Hl
Cs H and pyridine ring 03,6 H>6,20
(1H, t, J=6Hz, C+'H>4, 30-
4.08 (4H, m, C3' t 4' l s' H) 2,62 2.1 1 (8H, m, C2' -H
and COCH3X2> Example 81 5'-〇-acetyl-3- (3- (4-acetoxy-5-chloro-2-pyridyloxycarbonyl)benzoyl)-3' -0- (4-chlorobenzyl)-2'
-Production of -deoxy-5-fluorouridine In Example 73, 5'-O-acetyl-3'-〇-benzyl-2'-deoxy-5-fluorouridine was replaced with 5'
-O-acetyl-3' -〇- (4-chlorobenzyl)-2'-deoxy-5-fluorouridine was replaced with 4-benzoyloxy-5-chloro-2(IH)-pyridone, and 4-acetoxy-5 -Chloro-2(1H)-pyridone was used for reaction and post-treatment in the same manner to obtain the target compound in a yield of 52%.

'H-NMR (CD093) δ: 8, 65-7. 1 8 (1 1 H, m, phenyl-H, Cs H and 03,6 H of pyridine ring)
6, 18 (1H, t, J-6Hz, C+'-H)
4.28-4.07 (4H, m.

C3' l 4' l S' H)2.5
4-2.09 (8H, m, C2'H and COCH3
'X2> Example 82 5'-〇-acetyl-3-(3-(2-benzoyloxy-5-chloro-4-pyridyloxycarbonyl)benzoyl)-3'-0-(4-chlorobenzyl)-2
' -Deoxy-5-fluorouridine Production Example 73 In place of 5'-〇-acetyl-3'-0-benzyl-2'-deoxy-5-fluorouridine,5'
-〇-acetyl-3' -0-(4-chlorobenzyl)
-2'-Deoxy-5-fluorouridine was replaced with 4-benzoyloxy-5-chloro-2(1H)-pyridone using 2-benzoyloxy-5-chloro-4-hydroxypyridine, and the reaction and post-treatment were carried out in the same manner. After treatment, the target compound was obtained in a yield of 53%.

'H-NMR (CDCG3) δ: 8.68-7.26 (16H,m, phenyl-H2O
2H and C3,6H of pyridine ring) 6.20 (1H, t, J = 6H2, C+ ' -H)
4.30-4.08 (4H, m.

C3' l 4' l 5' H) 2.73-2.05 (5H, m, C2' H and CO
CH3) Example 83 5'-〇-acetyl-3-. C3-(2-acetoxy-
Production of 5-chloro-4-pyridyloxycarbonyl)-3-pyridylcarbonyl-3'-〇-benzyl-2'-deoxy-5-fluorouridine 5'-〇-acetyl-3'-〇-benzyl-2'- To a solution of 1.00 Q of deoxy-5-fluorouridine in 5011 G of dry dioxane were added 3.26 ml of triethylamine and pyridine-3,5-dicarbonyl chloride o, aog, and the mixture was refluxed for 1 hour. The produced precipitate was removed, and the two solutions were concentrated under reduced pressure. The residue was dissolved in 50 ml of acetonitrile (2), and triethylamine 1.83111Q and 2
-acetoxy-5-chloro-4-hydroxypyridine 0
．． 59 (7) was added, and the mixture was stirred at air temperature for 2.5 hours. The solvent was concentrated under reduced pressure, and the residue was eluted with chloroform using a silica gel column to obtain 0.22 g (12%) of the target compound.

'HNMRCCDCQ3) δ 7.83 (IH, d, J=6Hz, Cs H)7.
30 (5H,s, phenyl-H)6,19(1HS
t, J=6Hz, C+'-H)4.28-4.1
2 (4H, m, C3' * t-' e s ' H) 2.3
8-2.09 (8H, m, C2'H and COCH3
X2> Example 84 5'-〇-acetyl-3'-〇-benzyl-3-(4-
(Production of 5-chloro-4-hydroxy-2-pyridyloxycarbonyl-2'-deoxy-5-fluorouridine 5'-〇-acetyl-3'-〇-benzyl-2'-deoxy-5-fluorouridine 1.00q 2.88 mQ of triethylamine and 0.80 Q of terephthaloyl chloride were added to a 50 mf2 solution of dry dioxane and refluxed for 1.5 hours. After distilling off the solvent, the residue was dissolved in 50 mQ of acetonitrile. (limethylsilyloxy)
1.53 c+ of -5-chloropyridine was added and stirred overnight at air temperature. After evaporating the solvent, the residue was eluted with 0.5% ethanol-chloroform using a silica gel column to obtain the target compound 0.18C1 (10%).

'H-NMR (CDCQ3) δ: 8.25 (IH,s, 06H of pyridine ring)8.
17-7.93 (4H, m, 7.80 (1H, d, J=6H2, Cs H) 6.7
'9 (IH,s, C3H of pyridine ring) 6.20 (
1H,t,J=6H2,C+'-H>4.44-4
．． 09 (4H, m, C3', t', 5', -H) 2.75 2.10 (5H, m, C2' H and CO
CH3> Example 85 3-(3-(4-acetoxy-5-chloro-2-pyridyloxycarbonyl 3'-〇-benzyl-5-fluoro-5'-〇-nicotinoyl uridine) In Example 73, 5 '-〇-acetyl-3'-〇-benzyl-2'-deoxy-3' in place of 5-fluorouridine
-〇-benzyl-2'-deoxy-5-fluoro-5'
-〇- Nicotinoyl uridine was replaced with 4-acetoxy-5-chloro-2(1H)-pyridone, and the reaction and post-treatment were carried out in the same manner. The target compound was obtained in a yield of 41%.

'H NMR (CDCQ3) δ: 9, 21-7.29 (1 5H, m, phenyl-H,
6, 18 (IH, t, J=6Hz, C+ ' -H
)03'et' - s'H>2, 80
2.03 (5HSm, C2', H and COC
H3) Example 86 3-(3-(4-acetoxy-5-chloro-2-pyridyloxycarbonyl)benzoyl]-3'-0-
Benzyl-2'-deoxy-5-fluoro-5'-0-
(3.4-methylenedioxybenzoyl)uridine I
n In Example 73, 3' was substituted for 5'-〇-acetyl-3'-0-benzyl-2'-deoxy-5-fluorouridine.
-〇-benzyl-2'-deoxy-5-fluoro-5'
-0- (3.4-methylenedioxybenzoyl)uridine was converted to 4-benzoyloxy-5-chloro-2(I
4-acetoxy-5-chloro-2 instead of H)-pyridone
Using (1H)-pyridone, the reaction and post-treatment were carried out in the same manner to obtain the target compound in a yield of 42%.

'H-NMR (CDC93) δ: 8, 65-8.17 and 7.79-7.527, 25 (
1H,S,03H)6,20(1H
,t,J=6Hz,C+'-H)6.03 (2H
SS, 0CH20>4.55-4.12 (6H
, m.

2.70-2.51 and 2.25-2.02 (2H, m,
C2' -H) 2.38 (3H,S, COCH3) Example 87 3- (3-(4-acetoxy-5-chloro-2-pyridyloxycarbonyl-3'-0-benzyl-5' -0- (Production of 4-chlorobenzoyl-2'-deoxy-5-fluorouridine In Example 73, replacing 5'-〇-acetyl-3'-0-benzyl-2'-deoxy-5-fluorouridine with 3'
-〇-pencil-5'-6- (4-chlorobenzoyl)-2'-deoxy-5-fluorouridine, 4-
Using 4-acetoxy-5-chloro-2(1H)-pyridone in place of benzoyloxy-5-chloro-2(1H)-pyridone, the reaction and post-treatment were carried out in the same manner to obtain the target compound in a yield of 61%. .

'H-NMR (CDCQ3) δ: 8, 64-7.1 7 (1 6H, m, phenyl-H
, Cs H and pyridine ring 03,6 H)6,19
(1H,t,J=6Hz,C+'-H)4,55
-4.18 (6H, m.

2,62-2.13 (5H,m,C2'H and -COCH3) Example 88 3'-〇-benzyl-2'-deoxy-5-fluoro-
Production of 5'-0-(3.4-methylenedioxybenzoyl)uridine The reaction and post-treatment were carried out in the same manner as in Example 26 to obtain the target compound in a yield of 72%.

mp: 1 69-1 71℃'H-NMR (CDC93) δ: 9, 72 (IH, bs, -NH-, disappears with addition of D20) 7, 71 7.52 (2H, m, Cs H and 6 ,
23 (1H, t, J=6Hz, C+ ' -H)6
, 03 (2H,S, OCH20> and C3' *
' + s' H) 2, 75-2.49 and 2.19-
1.89(2H,m,C2'H> Example 89 Production of 3'-〇-benzyl-5'-0-(4-chlorobenzoyl)-2'-deoxy-5-fluorouridine Reaction in the same manner as in Example 26 and post-treatment to obtain the target compound in a yield of 53%.

'H NMR (DMSO-ds) δ: 1 1, 9
(1H, bs, -NH-, disappeared by addition of D20) 7,95 (2HSd, J=9Hz.

7, 92 (1H, d, J-6Hz, Cs H) 7,
59 (2H, d, J=9Hz, 6, 15 (IH, t, J=6Hz, C+ 'H
>4,58-4.31 (6H,m, 2,42 2.31 (2H,m,C2'H) Example 90 3'-0-(3-chlorobenzyl)-2'-deoxy-5- Preparation of fluorouridine 2.00 g of potassium hydroxide was dissolved in a mixture of 75 ml of water and 40 mQ of dioxane, and 1.
0OC1 and 3-chloropensyl chloride 2.50CI
and stirred at 4.5°C for 3 days. After washing the reaction solution twice with 200 ml of ether, the aqueous layer was neutralized with 6N-HCQ and concentrated to about 200 ml. Repeat this with 6N-H
l) Adjust H to about 3-4 with CQ, ethyl acetate 10011
Extracted twice with 112. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and then concentrated. The oily residue was purified by silica gel column chromatography eluting with chloroform-2% methanol-chloroform to obtain the target compound (0.21%).
g (yield 14%) was obtained.

Melting point 153-155°C Example 91 Production of 3'-0-(2-chlorobenzyl)-2'-deoxy-5-fluorouridine 3.75 g of potassium hydroxide was dissolved in a mixed solution of 150 mQ of water and 40 mQ of dioxane. , to which 2'-deoxy-5-fluorouridine i,
oog and 10 mQ of 2-chlorobenzyl chloride were added, and the mixture was stirred at 30°C for 3 days. After reaction, Examples 4 and 5
The residue was worked up in the same manner as above, and subjected to silica gel column chromatography eluting with 2% methanol-chloroform to obtain the target compound 0.340 (yield 23%).

Melting point 78-80°C Example 92 Production of 2'-deoxy-5-fluoro-3'-0-(4-fluorobenzyl)uridine 7.59 potassium hydroxide was dissolved in a mixture of 300 ml of water and 80 ml of dioxane, To this, 2'-deoxy-5-fluorouridine 2.00 (] and ]4-fluorobenzyl chloride 49
r++Q was added and stirred at 35°C for 2 days. After the reaction, the reaction mixture was post-treated in the same manner as in Examples 4 and 5, and subjected to silica gel column chromatography eluted with 2% methanol-chloroform to obtain 0.57 g of the target compound (yield: 20%).

Melting point 130-131°C Example 93 Production of 2'-deoxy-5-fluoro-3'-0-(1-naphthylmethyl)uridine Potassium hydroxide 1.3 g
, 2'-deoxy-5-fluorouridine 1.00Cl
and 2.7 g of 1-naphthylmethyl bromide, and in the same manner as in Examples 4 and 5, 0.28 (1 (yield: 18%)) of the target compound was obtained.

Melting point 159-160°C Example 94 5'-〇-acetyl-3-0-benzoyl-3'-0
Production of -(4-chlorobenzyl)-2'-deoxy-5-fluorouridine 3'-0-(4-chlorobenzyl)
-5'-〇-acetyl-2'-deoxy-5-fluorouridine 0.250 in dioxane 30mg solution, benzoyl chloride 0.269 and triethylamine 0.51
mf2 was added and stirred at 90°C for 2 hours.

The reaction solution was concentrated, the residue was dissolved in 50 mQ of ethyl acetate, washed three times with saturated aqueous sodium bicarbonate solution and then three times with saturated brine, dried over anhydrous sodium Wft,
Ethyl acetate was distilled off, and the residue was subjected to silica gel column chromatography and eluted with chloroform to obtain the target compound 0.
．． 29CI (yield 92%) was obtained.

N MR (CD CQ 3 ) δ 7.77 (1H, d, J=6Hz, Hs)7.
27 (4) (,d, J=3Hz, phenyl-H)
6.21 (1H, t, J=4H2,H+'>4
．． 90 (2H,d, J=1Hz.

-C Gogo JcQ> 4.32 4.03 (4H, m, H3', H4
', H5') 2,72 1.96 (5H,m, H2 and CH3C
O> Example 95 5'-〇-acetyl-3-(4-chlorobenzoyl)-
Production of 3'-0-(4-chlorobenzyl)-2'-deoxy-5-fluorouridine 3'-0-(4-chlorobenzyl)-5'-0-acetyl-2'-deoxy-5-fluoro Uridine 0.30
0.38 CI of 4-chlorobenzoyl chloride and 0.61 Cl of triethylamine in 30 ml of dioxane solution of ()
++1f2 and stirred at 40"C for 3 hours. Insoluble matter was removed, the residue was dissolved in ethyl acetate, washed with water, dried, ethyl acetate was distilled off, and the residue was subjected to silica gel column chromatography. 0.33 g (yield: 82%) of the target compound was obtained by elution with chloroform-〇-hexane (3:2).

NMR (CDC93) δ 7.86 (2H, d, J-9Hz.

7.77 (1H, d, J=7Hz, H6) 7.4
8 (2H,d, J=91-1z.

7.27 (4H-1d, J-4H1゜6.20 (
1H,j 5J=6Hz, H1')4,49
(2H,s, -Crou(toca >4.32 4
．． 03 (4H, m, H3', Ht', H5'
) 2,75-1.95 (5H, m 1H2' and CH3C
O) Example 96 5'-〇-acetyl-3-(4-n-propoxybenzoyl)-3'-〇-(4-chlorobenzyl)-2'-
Production of deoxy-5-fluorouridine 3'-〇-(4-chlorobenzyl)-5'-0-acetyl-2'-deoxy-5-fluorouridine 0.30
4-n-propoxybenzoyl chloride 0.44 () and triethylamine 0.0 g in 30 ml of dioxane solution
．． 61mQ was added thereto, and the mixture was stirred at 70'C for 3 hours. Insoluble matter was removed in an oven, the residue was dissolved in ethyl acetate, washed with water, dried, ethyl acetate was distilled off, and the residue was subjected to silica gel column chromatography and purified with chloroform-petroleum ether (1
:1> and the target compound was eluted at 0.15 (1 (yield 36%).
> obtained.

NMR (CDCQ3) δ 7.87 (2H, d, J-9H2,7,74 (1H
, d , J=6Hz , Hs )7.27 (4H, d
, J-3Hz.

6゜21 (1H, t, J=4H2,H+'>4
, 49 (2H,s , -〇5×nCQ>4.31
3.93 (6H, m, H3', H4', Hs
' and -〇-CFiLCH20H3)2.72-1.6
5 (7H,m, H2, CH3Co- and -〇-CH2
CH2-CH3) 1.04 (3H,t, J-7H2
, -0CH2CH2CHL) Example 97 3-benzoyl-3'-0-(4-chlorobenzyl)
Production of -2'-deoxy-5-fluorouridine 3' Using 0.50 g of -0-(4-chlorobenzyl)-2'-deoxy-5-fluorouridine, Example 4
In the same manner as in 1, 0.46 g (yield 72%) of the target compound in powder form was obtained.

Melting point - (powder) NMR (CDCQ3) δ 8.19 (1H, d, J=6Hz, Hs)7.
90 (2H, bd, J=7Hz.

7.65-7.35 (3H, m.

6.24 (1H,j, J=6Hz, H+'>
4, 42 (2H, S, CH2<paar C9) 4.2
4 4.15 (2H, m, H3', H4'>3.
95 3.60 (2H, m, Hs') 2.59 1.
98 (2H, m, H2') Example 98 3-benzoyl-5'-〇-benzoyl-3' -0-
Production of (4-chlorobenzyl)-2'-deoxy-5-fluorouridine 3'-0-(4-chlorobenzyl)
-2'-deoxy-5-fluorouridine 0.25CI
0.23 mQ of benzoyl chloride was added to the pyridine solution, and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent, ethyl acetate and water were added to the residue, and the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography and eluted with chloroform to obtain 0.27 g (yield 70%) of the target compound.

NMR (CDC93) δ 7.71 (IH, d, J=6H2, Hs >7.6
3-7.32 (6H,m, 6.21 (1H,t, J=4Hz, H+'
)4.63-4.20 (6H,m,H3',H
4', H5' and -CHL+CQ) 2.77 2.02 (2H, m, H2') Example 99 3'-〇-benzyl-2'-deoxy-5-fluoro-
Production of 3-nicotinoyl-5'-〇-nicotinoyluridine To a dioxane 40 mg solution of 0.50 () of 3'-〇-benzyl-2'-deoxy-5-fluorouridine, 0.40 C1 of nicotinoyl hydrochloride and 1 triethylamine,
0ml of the mixture was added, and the mixture was refluxed for 6 hours.

After distilling off the solvent, the residue was subjected to silica gel column chromatography and eluted with 1% methanol-chloroform.
0.23 CI (yield 29%) of the target compound was obtained.

NMR (DMSOd s ) δ 8.57 8.16 (3H, m, Hs and 6.10 (1
H,m,J=6H2,H+')4.54 4.
33 (4H, III, H3', H4', H
5') 2.37-2.20 (2H,m,H2') Example 100 3-(3-(4-acetoxy-5-chloro-2-pyridyloxycarbonyl)benzoyl]-3'-〇-benzyl 5-fluoro2'-deoxy-5' -〇-
Production of (1-naphthoyl)uridine 3'-〇-benzyl-2'-deoxy-5-fluoro-
5'-0-('1-naphthoyl)uridine 0.50C
Using I, 0.05 (1 (yield 6%)) of the target compound in powder form was obtained in the same manner as in Example 73.

N'MR (CDCQ3) δ 7.16 (1H,S, H3 of pyridine ring) 6.24 (
IH,t, J=6Hz, H+'>4.70
4.24 (6H, m, H3', HA', 2,75-
2.03 (5H,m, H2' and CH3Co-) Example 101 3- (3-(4-acetoxy-5-chloro-2-pyridyloxycarbonyl-3'-0-benzyl-2'-deoxy-5 -Production of fluorouridine 3'-0-Benzyl-21-deoxy-5-fluorouridine 1.50mf2 of trimethylchlorosilane and 4.20mi2 of triethylamine were added to a solution of 1.00CI of dry dioxane and stirred for 20 minutes at room temperature.The precipitate formed was removed, the filtrate was concentrated, and the residue was dissolved in 30 mf2 of dry dioxane.

This solution was stirred for 45 minutes with 724 m of isophthaloyl chloride and 22.4 m of totriethyluane.

After further cooling this reaction solution to room temperature, 0.84 (l) of 4-acetyloxy-5-chloro-2-pyridone was added thereto, and the mixture was stirred at room temperature for 2 hours.
Concentrate the solution, dissolve the residue in 50 mf2 of ethyl acetate,
Washed three times with 30 mQ of saturated saline. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. To the residue were added 50 methanol and 1.0 m (2 m) of acetic acid, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off, and the residue was subjected to silica gel column chromatography and eluted with 1% acetone-chloroform to obtain the target compound. 74 g (yield 38%) was obtained.

NMR (CDCQ3) δ 8,45 (1H,s, H6 of pyridine ring) 8,1
1 (1H, d, H6, J=7Hz)7, 1
8 (IH,s, 1 of the pyridine ring 3〉6, 24
(1H, t, H+', J=4Hz >4, 5
2 (IH16, -〇53 J=1Hz> 4, 29 4.1 1 (2H, m, H3',
H4'>4,04 3.67 (2H,m,H
s')2,57-2.04 (2H,m,H2
)2,39 (3H,s, CH3Co
) Example 102 3'-〇-benzyl-3- (3- (5-chloro-1
, 2-dihydro-2-oxo-pyridyloxycarbonyldeoxy-5-fluorouridine production 3'-〇-benzyl-2'-deoxy-5-fluorouridine 0.50
( ) was silylated and isophthaloylated in the same manner as in Example 101. After removing the insoluble matter, the solvent was distilled off, and the residue was dissolved in pyridine 100ITII2. Pyridone (0.35%) was added, and the apparatus was kept at room temperature overnight. Pyridine was distilled off, and the residue was subjected to silica gel column chromatography, eluting with chloroform-4% methanol-chloroform to obtain the target compound, 0.23% (1%). A yield of 25% was obtained.

NMR (DMSOds) δ 12, 04 (1H, bs, -NH-) 8, 62 8
．． 26 (4H,m, Hs and Hs of pyridine ring
) 6,'63 (1H,s, H3 of pyridine ring)6,'
11 (1H,i, J=6H2,H+')5.2
9 (1H, t, J=5Hz, 5' -〇H)4.
35 4.08 (2H, m, H3', H, t')
3.70-3.61 (2H, m, Hs')
2.51-2.08 (2H,m, H2') Example 103 3- (3-(4-benzoyloxy-5-chloro-2
-pyridyloxycarbonyl>benzoyl)-3'-
Production of 〇-benzy-2'-deoxy-5-fluorouridine 0.29 g of powder of the target compound was prepared in the same manner as in Example 101 using 0.50 () of 3'-〇-benzy-2'-deoxy-5-fluorouridine ( A yield of 27% was obtained.

NMR (CDC('3)δ 7.39 (IH,s, H3 of pyridine ring) 6.21
(1H,t, J-4H2,H+')4.5
5 (2H,d, J=1Hz.

4.46 4.12 (2H-m, H3', Ha'
>4.03 3.66 (2H, m, Hs')2.
67 2.07 (2H, m, H2') Example 10
4 3'-〇-benzyru-3- (3-(5-chloro-4-
Production of hydroxy-2-pyridyloxycarbonyl)benzoyl]-2'-deoxy-5-fluorouridine 3'-〇-benzyl-2'-deoxy-5-fluorouridine 0.50! J was silylated and isophthaloylated in the same manner as in Example 101. After removing the insoluble matter, the solvent was distilled off, and the residue was dissolved in 50 mQ of dichloromethane. This was added with 0.57O of 2,4-bis(trimethylsilyloxy)-5-chloropyridine and 0-10-1O of stannic chloride.
was added and stirred at room temperature for 6 hours. After neutralizing with triethylamine, the mixture was concentrated, the residue was extracted with ethyl acetate, the extract was washed with water, dried, and concentrated. The residue was suspended in 40 methanol and stirred at room temperature overnight. The solvent was distilled off, and the residue was subjected to silica gel column chromatography and eluted with 1% methanol-chloroform to obtain a powder of the target compound (0.1%).
9p (yield 21%) was obtained.

NMR (CDC93) δ 8.05 (1H, d, J=6H2, Hs) 7.2
9 (5H,S, phenyl-H)6.78 (IH,
s, H3 of pyridine ring)6.19 (1H,E,J
=6H2,H+' )4.32 3.78 (4H
, m, H3', Ht', H5') 2.49 2.09 (2H, m, H2') Example 105 3- (3-(4-benzoyloxy-5-chloro-2
-pyridyloxycarbonylzoyl]-3'-〇-(4-chlorobenzyl)-2'-
Production of deoxy-5-fluorouridine 3'-0-(4-chlorobenzyl)-2'-deoxy-5-fluorouridine and 4-benzoyloxy-5-chloro-2-pyridone were used in the same manner as in Example 101. reacted to.

For desilylation, the residue of the above reaction solution was dissolved in chloroform 5
1TIQ, methanol'+omQ was added thereto, and the mixture was left at air temperature for 16 hours. The solvent was distilled off, and the residue was subjected to silica gel column chromatography eluting with 1% acetone-chloroform to obtain 0.24 g of powder of the target compound.
(yield 24%).

NMR (CDC93) δ 8,1 1 (1H,'d, Hs, J=6Hz
)7,39 (1H,s, H3 of pyridine ring)J-
2Hz) 6, 24 (IH,t, J=4Hz, H+')
4, 48 (2H, s, -C hill + CQ > 4, 36
4.15 (2H, III, H3', Hs')4
, 10 3.73 (2H,m,Hs')2,7
0 2.10 (2H, mS H2') Example 10
6 3'-〇-benzyru-3-(3- (5-chloro-4-
Preparation of dimethylaminobenzoyloxy-2-pyridyloxycarbonyl-2'-deoxy-5-fluorouridine 3'-〇-benzyl-2'-deoxy-5-fluorouridine 1. Using OOq, 0.48q of powder of the target compound (yield: 21%) was obtained in the same manner as in Example 101.

N M R ( C D C Q 3 ) δ8,00
7.76 (4H, m , H6, 6, 82 (2H,
d, J=9Hz, 6, 12 (1H,t, J=7H
z, H+') 5, 30 (1H, t, J=5
Hz, 5'-OH)4, 53 (2H, s
, -C near (Y4, 42 3.63 (4H, m, H3
' , H4' , H5' ) 3,07 (6H,S , -N (CH3)2 >2,
56-2.20 (2H, m, H2') Example 107 3- (3- (4-acetoxy-2-pyridyloxycarbonyl-acetyl-3'-〇-benzyl-2'-deoxy-5
-Production of fluorouridine The target compound was obtained in a yield of 46% in the same manner as in Example 73.

N M R (CD CQ 3 ) δ 7.80 (1H, d, J=6H2, H6) 7.31
(5H,S, phenyl-H)7.22-7.09
(2H,m, H3 of pyridine ring, Hs) 6.20 (1H,t, J=6Hz, H+'
>4.52 and 4.50 (1H, S, -0CHp<■) 4.44 4.08 (4H, m, H3', H4'
, H5') 2,69 2.02 (8H,m, H2' and CH3
Co X2> Example 1'08 5'-〇-acetyl-3'-〇-benzyl-3-(3-
Production of (5-chloro-1,2-dihydro-2-oxo-4-pyridyloxycarbonyl)benzoyl]-2'-deoxy-5-fluorouridine 5'-〇-acetyl-3'-〇-benzyl-2' - Deoxy-5-fluorouridine 0.50 CI in dioxane 50111 CI solution with 0.4 isophthaloyl chloride
0 (l) and 1.0 ml of triethylamine were added and refluxed for 1 hour. After cooling, insoluble materials were removed and the furnace liquid was concentrated.
The residue was dissolved in 100 mQ of pyridine. To this was added 0.38 CI of 5-chloro-4-hydroxy-2-pyridone, and the mixture was stirred at air temperature overnight.

The solvent was distilled off, and the residue was subjected to silica gel column chromatography and eluted with 2% methanol-chloroform to obtain the target compound 0.23 (1 (yield 27%)).

NMR (DMSOd6) δ 12,00 (1H, bs, -NH-) 8.67-7
．． 88 (6H,m, Hs, CO 6,63 (1H,S, H3 of pyridine ring) 6.10
(1H,C,J=6H2,H+'>4.24 (
4H, bs, H13', HA', H5')2,
46-2.01 (5H, m, H2' and CH3CO> Example 109 5'-〇-acetyl-3'-〇-benzyl-3-(3-
(5-chloro-4-n-hexanoyloxy-2-pyridyloxycarbonylbenzoyl-2'-deoxy-
Production of 5-fluorouridine Powder of the target compound was produced in the same manner as in Example 73 with a yield of 75%.
I got it.

100Hs) 7,18 (1H,s, H3 of pyridine ring)6,2
1 (1H,t, J=6Hz, H+'>4,
44 4.09 (4H, III, H3', H4'
H5') 2,65 (2H,t, J=7Hz, -COCdan2C
H2>2.22-0.93 (14H,m, COCH3-
1H2' and -COCH2 (CH2>3 CH3) Example 110 5'-〇-acetyl-3'-〇-pencyl-3-(3-
(5-chloro-4-octadecanoyloxy-2-pyridyloxycarbonylbenzoyl-2'-deoxy-
Production of 5-fluorouridine Powder of the target compound was produced in the same manner as in Example 73 with a yield of 17%.
I got it.

7, 18 (1H,s, 83 of the lysine ring) 6, 19
(1H,t, J=6Hz, H+')4,3
0 4.10 (4H, m, H3', H4'H5'
) 2,67 (2H,t S J = 7Hz.

-COC Dan2CH2> 2,58 2.05 (5H, m, COCH3- and H2') 1,26 (30H, bs, COCH2 (CH2) + s CH3
)0,88 (3H,t, J=7Hz, CH2
C Dan L> Example 111 5'-〇-acetyl-3'-〇-benzyl-3-(3-
Production of (5-chloro-4-(2-furoyloxy)-2-pyridyloxycarbonylbenzoyl)-2'-deoxy-5-fluorouridine The target compound was obtained in a yield of 57% in the same manner as in Example 73.

H6 of the pyridine ring and Hs of the furan ring) and Hs) 7, 49 (I H, dd, J 3,4=4Hz
, J 3,5 = 1Hz, H3 of furan ring) 6, 64 (1 H, dd, J 3,4 = 4Hz
, J4,5=2Hz, H4 of the furan ring) 6,21 (1H,t, J-6Hz, H+'
>4, 53 and 4.51 (each 1H,S, 4, 30-4.09 (4H,m, H3',
H4', H5') 2, 58-2. 09 (5H, m, H2'
and CH3CO) Example 112 5'-〇-acetyl-3'-〇-benzyl-3- (3
- (5-chloro-4-(2-thenoyloxy)-2-
Production of (pyridyloxycarbonylbenzoyl)-2'-deoxy-5-fluorouridine The target compound was obtained in a yield of 59% in the same manner as in Example 73.

H6 of the pyridine ring, H3 of the thiophene ring, H5 of the thiophene ring and 16) 7.38 (1HSs, H3 of the pyridine ring and Ha of the thiophene ring) 6.21 (1H,j, J=6H2,H+') 4.
52 and 4.50 (each 1H, S, 4.28 4.09 (4H, m, +3', Ha'
, H5') 2,72-2.05 (5H,m, H2' and CH3
C0) Example 113 5'-〇-acetyl-3'-〇-benzyl-3-(3-
Preparation of (5-chloro-4-(3,4,5-trimethoxybenzoyloxy)-2-pyridyloxycarbonyl]benzoyl)-2'-deoxy-5-fluorouridine The target compound was prepared in the same manner as in Example 73. Powder yield 71%
I got it.

NMR (CDCQ3) δ Hs of pyridine ring) 7.38 (1H,S, H3 of pyridine ring) 6.21
(1H, t, J=6H2,H+'>4.53 and 4
．． 50 (each 1H, S, 4.29 4.08 (4H, m, +3', H4'H
5') 3.96 and 3.93 (9H, 5l each -OCH3X3) 2,50-2.05 (5H,m, H2' and CH3
Co-) Example 114 Production of 2'-deoxy-5-fluoro-3'-0-(4-carboxybenzyl=R3=H,R'=4-carboxybenzyl group) 2'-deoxy-5-fluoro- To a 200 mf2 solution of 5'-〇-trityluridine 3.OOCI in dioxane were added 4.30 CI of potassium hydroxide and 1.70 C of 4-methoxycarbonylbenzyl bromide, and the mixture was stirred for 1 day under air temperature.The reaction solution was concentrated under reduced pressure to obtain a residue. 200 r of water for dipping
nQ was added and stirred for 15 minutes under air temperature.

After the reaction solution was made acidic with acetic acid, extraction with ethyl acetate was performed. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was dissolved in 50 mQ of an 80% aqueous acetic acid solution and heated at 100'C for 2 hours. When the solvent was distilled off and the residue was subjected to silica gel column chromatography using 3% methanol-chloroform as the developing solvent, the target compound was found at 650%.
+ng (28%) was obtained.

'H NMR (DMSO-da) δ: 1 1, 8
3 (1H, bs, N:] ]l-1, disappeared by addition of D20) 8, 19 (1H, d, J=7Hz, C6-H) 7, 9
4 (2H, d, J=8Hz, 6, 14 (1H, t, J=6Hz, C+ 'H)
5, 20 (1H.bs, Cs' OH, D2 0
disappears upon addition) 4,63 (2H,s, -CH2-(D-CO)4
, 22-3.64 (4H, m, C3'14' + 5' H) 2.35-2.04 (2H, m, C2' H) Example 115 2'-deoxy-3'-〇-benzyru 5 -Fluorouridine (R'=Cs H5CH2, R2=R3=H)
Preparation of 10C1 of 2'-deoxy-5'-0-trityl-5-fluorouridine was dissolved in 50m12 of dioxane, 2.9mQ of benzyl bromide and 14.6C1 of fine powder of potassium hydroxide were added thereto, and 10C1 of 2'-deoxy-5'-0-trityl-5-fluorouridine was dissolved at room temperature. Stir for hours. water 40+
After adding nQ and adjusting the pH to about 3 to 4 with acetic acid, extraction was performed with ethyl acetate, and the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate.

The sodium sulfate was filtered off and the solvent was distilled off to obtain 2'-deoxy-3'-〇-benzy-5'-〇-trityl-5-fluorouridine 16, OC] as an intermediate.

This compound was dissolved in 80 Tgl of 80% acetic acid and
After reacting at 60°C for 2 hours, cooling with water for 1 hour, 5.10
After concentrating the trityl alcohol solution, ethanol was added and stirred, and the precipitated crystals were separated and dried to obtain 5.3 g (75.7%) of the target compound.

The 'H-NMR analysis result of the compound having a melting point of 138-139° was consistent with that of the compound obtained in Example 2.

Example 116 2'-deoxy-3'-〇-benzy-5-fluorouridine (R' -Cs Hs CH2, R2=R3-H
) Production of the target compound was obtained in the same manner as in Example 115 using 2'-deoxy-5'-0-(diphenyl-p-methoxyphenyl)methyl-5-fluorouridine.

Yield: 63% The 'H-NMR analysis results of the compound with a melting point of 138-139° were consistent with those of the compound obtained in Example 115.

Example 117 2'-deoxy-3'-〇-benzy-5-fluorouridine (R' = C6Hs CH2, R2 = R3 = H
) Production of 2'-deoxy-5'-0-trityl-5-fluorouridine (10 Cl) was dissolved in 100 mO of dioxane, and to this was added 2.9 m of benzyl chloride (2, 6.9 g of fine powder of potassium hydroxide and 6.9 g of sodium iodide). Add 3.560, 40'
After stirring at C for 4 hours, 2.9 ml of benzyl chloride and 1.15 Cl of potassium hydroxide were further added, and the mixture was stirred for 1 hour.

After adding water and dissolving potassium hydroxide, adjust lI to about 3 with acetic acid, extract with ethylene dichloride, wash with water,
Dry the ethylene dichloride layer over anhydrous sodium sulfate.
-deoxy-3'-〇-benzyl-5'-〇-trityl-5-fluorouridine 8q was obtained.

This compound was dissolved in 80% acetic acid, 80+ nG, and 50-6
After reacting at 0'C for 2 hours, ice-cooling for 1 hour, trityl alcohol was poured out, concentrated, and recrystallized from ethanol to obtain primary crystals of the target compound (yield: 70.
6%).

The ethanol mother liquor was concentrated in a colander, and the smallest amount of ethanol was added and recrystallized to obtain secondary crystals of the target compound (yield: 15,
9%).

Yield: 86.5% The 'H-NMR analysis result of the compound with a melting point of 138-139° was consistent with that of the compound obtained in Example 115.

Example 118 2'-deoxy-3'-〇-benzy-5-fluorouridine (R' = Cs H5 CH2, R2 = R3 = H
) Preparation of 2'-deoxy-5'-0-trityl-5-fluorouridine 10C] was dissolved in 50 mf2 of dioxysan,
Add to this 2.9% of benzyl bromide and 14% of fine powder of potassium hydroxide. ．． 6Cl was added and stirred at air temperature for 1 hour. The solvent was distilled off, and the residue was dissolved in 80 mQ of 80% acetic acid.
After reacting at 0°C for 2 hours, cooling on ice for 1 hour, removing trityl alcohol and concentrating the mother liquor, ethanol was added and stirred, and the precipitated crystals were filtered and dried to obtain the target compound 5.
0 g (yield 72%) is obtained.

The 'H-NMR analysis result of the compound with a melting point of 138-139° was consistent with that of the compound obtained in Example 115.

Examples 119-147 In the same manner as Example 115, Examples 1 and 3-2
Each compound described in 5.90 to 93.114 was obtained.

Examples 148-176 Example 1 and Examples 3-2 in the same manner as Example 117
Each compound described in 5.90 to 93.114 was obtained.

Example 177 3'-〇-benzy-2'-deoxy-5-fluoro-
Preparation of 5'-O-stearoyluridine The reaction and post-treatment were carried out in the same manner as in Example 26 to obtain the desired compound as an oil in a yield of 78%.

1HNMR (CDCQ3) δ near, 65 (1H, d, J=6H2, CB -H)7.
32 (5H,S, phenyl-H)6.23 (1H,
t, J=6Hz, C+'H)4.54 (2H,
d, J=2Hz, 4.29-4.01 (4H, m, C3' * t' + s' H) 2.33-1.
83 (4H, m, C2' -H and -COCH2>1.25 (30H, bs, -(Cdan2>15)0
．． 88 (3H, t, -CdanL) Example 178 5'-0-cyclohexanoyl-2'-deoxy-3
' -0-(2,4-Dichlorobenzyl)-5-fluorouridine Production The reaction and post-treatment were carried out in the same manner as in Example 26 to obtain a powder of the target compound in a yield of 77%.

'H-NMR (CDCQ3) δ: 9.50 (1H, b, NH) 7.67 (1H, d, J=6H2, C6H) 7.40
-7.16 (3H,m, phenyl-H)6.25 (
1H,t, J=6zz,C+'H)4.37
-4.08 (4H, m, C3', 4', 5' H > 2.77-2.51 and 2.48-1.04 (13H, m
, C2'-H and cyclohexyl-H) Example 179 Production implementation of 2'-deoxy-5-fluoro-3'-〇-(4-methoxybenzyl)-5'-0-(2-thenoyl)uridine The reaction and post-treatment were carried out in the same manner as in Example 26 to obtain a powder of the target compound in a yield of 91%.

'HNMR (CDCQ3) δ: 9.20 (1H, bs, NH) 7.82 (1H, dd, JA, s = 4H2,7,
63 (1H, d, J = 6H2, Cs H) 7.59
(1H, dd, J3.4 =5H2,6,87(2H,
d, J=9Hz, 6.25 (1H, t, J=6H2, (g'H)
4.56-4.10 (6H, m, C3', 4', 5' H and 3.78 (3H, S, 0CH3) 2.74-2.
48 and 2.22-1.78 (2H, mXC2'H
) Example 180 Production of 2'-deoxy-5-fluoro-3'-(3-methylbenzyl)-5'-0-(2-furoyl)uridine The target compound was obtained by reaction and post-treatment in the same manner as in Example 26. A powder of 85% was obtained.

'HNMR (CDC93) δ: 9.14 (1H, bs, NH) 7.93 (1H, d, J=6H2, Cs H)7.
29-7.10 (5H,m, furanyl-H16,55
(IH, dd, J3.4 = 4Hz, 6.35 (IH
, t, J=6Hz, C+'-H)4.77-4.1
0 (6H, m, 2.71-2.44 and 2.34-1.97 (5H, m,
C2'-H and CH3) Example 181 3'-〇-benzyl-5'-〇-crotonoyl-2'-
Production of deoxy-5-fluorouridine The reaction and post-treatment were carried out in the same manner as in Example 54 to obtain a powder of the target compound in a yield of 75%.

'HNMR (CDCQ3) δ: 8.63 (IHSbs, NH>7.67 (1H, d, J=6H2, Cs H)7.
32 (5H,s, phenyl-H)7.14-6.89
(1H, m.

-CH=CdanCH3) 6.24 (IH, t, J=6Hz, C+'-H>
5y84 (1H, dd, Jα, β=16Hz, 4.4
2-4.05 (4H, m, C3' + 4' + 5' H) 2.73-2.44 and 2.20-2.02 (2H, m,
C2' H) 1.90 (3H, dd, Jβ, 7=7Hz, Jα, r
=2H1, -CH=CHCdanL) Example 182 3'-(2-bromobenzyl>-2'-deoxy-5
Production of '-〇-ethoxyacetyl-5-fluorouridine 3'-(2-bromobenzyl)-2'-deoxy-5
- Add DCCl and 24 CJ to a solution of 1 g of fluorouridine and 0.63 CI of ethoxyacetic acid in 10 mf2 of pyridine,
Stirred at room temperature for 24 hours. The insoluble materials were removed, the filtrate was concentrated, and the residue was purified with isopropanol-ether to obtain 1.06 g (80%) of the desired compound as a powder.

'H-NMR (CDCQ3) δ: 9.49 (1H, bs, NH>7, '74 (1H, d, J=6H2, CIS H
)7.60-7.06 (4H,m, phenyl-H)6
．． 34 (1H, t, J=6H2,C+ 'H>
4,60 (2H,s, -C5(1 4,39-4,13(6H,m, CGZ4Z5' H and -COCH20) 3.59 (
2H, Q, J=7Hz, -〇CC20CH3) 2.73-2.48.2.31-2.00 (2H, m,
C2'-H) 1.22 (3H, t, J=7Hz.

'0CH2CdanL) Example 183 2'-deoxy-5-fluoro-3'-0-(2,4
, 6-drimethylbenzyl) uridine 2'-deoxy-5-fluoro-5'-〇-trityl uridine 4.0 OCI, potassium hydroxide 2.30 C] and sodium iodide 1.47 C] in dry dioxane 50 m
2.4.6-Dolimethylbenzyl chloride 1.
66C] and stirred at 60'C for 3 hours. The solvent was distilled off, ethyl acetate and water were added to the residue, and the ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off, and the residue was dissolved in 50 mQ of 80% acetic acid and left at 70'C for 2 hours. The reaction solution was concentrated, water was added to the residue, and the mixture was made weakly basic with an aqueous sodium hydroxide solution and washed with ether. The aqueous layer was made weakly acidic with 6N-hydrochloric acid and extracted with ethyl acetate.

The ethyl acetate layer was washed with water, dried and concentrated over anhydrous sodium sulfate. Ether was added to the residue to solidify it, and then recrystallized from ethanol to obtain 1.69 CI (55%) of the target compound.

Melting point 179-181°C 'H-NMR (DMS○-ds) δ: 11.82 (
IHSbs, NH) 8.20 (IH, d, J=7H2, C6H) 6.07
(1H,bt,',J-6H2,C+'-H)5
．． 19 (IH, bt, J=5Hz, 5'-0H)C
H3 4,204,10 (1H, m, C3'H) 4.0
2-3.91 (1H,m,C4'-H)3.6
9 3.57 (281m, Cs' H) 2.2
9-2.12 (11H, m, CH3X3 and C2'
H) Example 184 2'-deoxy-3-(3-(6-(2,4-dichlorobenzoyloxy)-2-pyridineoxycarbonyl)
Production of (benzoyl)-5-fluoro-3'-0-(3-methylbenzyl)-5'-〇-(2-furoyl)uridine The reaction and post-treatment were carried out in the same manner as in Example 73 to obtain a powder of the target compound. The yield was 24%.

'H-NMR (CDCQ3) δ: 8.14-7.92 (31-1, m, C4H of ring) 7.60 (1H, bs, Cs H of furanyl) 7.
53 (1H, d, J=2Hz, 7.36, (1H, dd, J=8Hz, J=2Hz,
7.30-7.11 (7H, m.

03 H of furanyl) 6.55 (IH, dd, J=4Hz, J=2Hz, C4H of furanyl) 6.34 (1H, t, J=6Hz, C+ 'H)
4.75-4.15 (6H, m, 2.77 2.01 (5H, C2' H and CH3)
Example 185 5'-〇-cyclohexanoyl-2'-deoxy-3'
-〇-(2,4-dichlorobenzyl-5-fluoro-3
-(3-(3-cyano-6-(3-methylbenzoyl)
-2-Pyridyloxycarbonylene was reacted and post-treated in the same manner as in Example 73 to obtain a powder of the target compound in a yield of 13%.

'H NMR (CDC93) δ near, 86 7.65 (2H, m, 06 H and 7,
49-7.16 (6HSm, CH3 of pyridine ring 6, 22 (1H, t, J = 6Hz, C+ ' -H
) 4, 42-4.09 (4H, m, C3' + 4' + 5' H) 2, 8
5-1.10 (16H,m,C2'H,CH
3, cyclohexyl) Example 186 3'-〇-benzyl-3- (3- (5-chloro-1
,2-dihydro-1-ethoxymethyl-2-oxo-4
-Production of pyridyloxycarbonylluorouridine The reaction and post-treatment were carried out in the same manner as in Example 101 to obtain a powder of the target compound in a yield of 49%.

'H-NMR (CDC93 > δ: 8, 67 8.19 (4H, m, Cs H and 1C
06 H of the pyridine ring) 6, 66 (IH,S, C3 H of the pyridine ring>6,
20 (IH, t, J-6Hz, C+'-H>5,
34 (2H,s,N CH2 0 )4,32-
3.81 (4H, m, C3'+4'+5' H) 3,64 (2H,Q,J=7Hz, -OCH2 CH3) 3,10 (1H, bs, Cs' OH)2,52
-2.19 (2H,m,C2'-H>1,24
(3H, t, J=7Hz, OCH2CdanL) Example 187 3- (3- (6-penzoyloxy-3-rero-2-pyridyloxysulfonyl)benzoyl)-3'-
Production of 0-pencyl-2'-deoxy-5-fluorouridine The reaction and post-treatment were carried out in the same manner as in Example 101 to obtain a powder of the target compound in a yield of 39%.

'HNMR (CDC93) δ: 8.71 8.10 (6H, m, Cs H and 7.9
7 (1H, d, J = -8 Hz, O- of the pyridine ring 7,25 (1H, d, J = 8 Hz, H') syn ring (DC
s H) 6.23 (1H, t, J=6H2, C+' -H)
4.26-3.66 (4H, m, C3' + 4' + 5' H) 3.0
7 (1H, bs, Cs' 0H) 2.52 2
．． 12 (2H, m, C2' -H) Example 188 3- (3-(6-penzoyloxy-3-chloro-2
-pyridyloxycarbonylzoyl)-3' -〇- (4-chlorobenzyl)-2
Preparation of '-deoxy-5-fluorouridine The reaction and post-treatment were carried out in the same manner as in Example 101 to obtain a powder of the target compound in a yield of 45%.

'H-NMR (CD093) δ near, 98 (1H, d, J = 8Hz, C4 of pyridine ring
H) 7,76-7,39 (4H,m, 7,30-7.1 1 (5H,m,6,22 (1
H, t, J=6Hz, C+'-H)4, 23-3
．． 75 (4H, m, C3' + '#5'H)3,06
(1H,bs,Cs'-OH)2,66 2.
02 G2H,m,C2'H>Example 189 3- (4- (6-penzoyloxy-3-cyano-
2-pyridyloxycarbonyl)-3-furoyl)-3
Preparation of '-0-benzyl-2'-deoxy-5-fluorouridine The reaction and post-treatment were carried out in the same manner as in Example 101 to obtain a powder of the target compound in a yield of 31%.

'H-NMR (CD093) δ: 8, 1 8-7.94 (4H, m, Cs H and Piri 6, 12 (1H, t, J=6Hz, C+ 'H
) 4.39 and 4.37 (1H, S, 4, 25-3 respectively)
．． 55 (4H, m, C 3' l 4' l s H > 2, 78 (1H, bs, Cs' -OH) 2, 60
-2.1 1 (2H, m, C2' -H) Example 1
90 3- (3- (6-penzoyloxy-3-cy7no-2-pyridyloxycarbonyl)benzoyl)-3'-
Preparation of 0-benzyl-2'-deoxy-5-fluorouridine The reaction and post-treatment were carried out in the same manner as in Example 101 to obtain a powder of the target compound (19) with a yield of 33%.

'HNMR (CD093) δ: 8.71 8.12 (7H, m, Cs H and Pyri 6
．． 23 (IH, t, J-6H2, C+ 'H) 4
．． 29-3.66 (4H, m, C3' l 4', 5'-H> 3.47 (IH, bs, Cs' 0H) 2.6
8-2.19 (2H,m,C2'H) Example 1
91 3-(3-(6-penzoyloxy-3-cyano-2
-pyridyloxycarbonyl)benzoyl)-3'-0
~Production of (2-chlorobenzyl)-2'-deoxy-5-fluorouridine The reaction and post-treatment were carried out in the same manner as in Example 101 to obtain a powder of the target compound in a yield of 43%.

Cs H of pyridine ring) 6.26 (1H, bt, J=6Hz, C+'
H) 4.33-4.17 (2H, m, C3', 4' H) 4.01-3.71 (2H, m, Cs' H) 2.8
6 (1H, bs, Cs' 0H) 2.68-2.
14 (2H,m,C2'-H) Example 192 3- (3-(6-penzoyloxy-3-cyano-2
-pyridyloxycarbonylzoyl]-2'-deoxy-5-fluoro-3' -0
- Production of (4-fluorobenzyl)uridine The reaction and post-treatment were carried out in the same manner as in Example 101 to obtain a powder of the target compound in a yield of 57%.

'H NMR (CDC93) δ: 6, 22 (1
H,bt,J=6Hz,C+'H)4, 45
(2H, s, -CHL+F)4, 31-4.10
(2H,m, C3'.4'H> 4,00-3.63 (2H,m,Cs' -H)
2,80-2.00 (3H,m,C5'OH
, C2' H) Example 193 3- (3- (6-penzoyloxy-3-chloro-
2-pyridyloxycarbonylzoyl]-2'-deoxy-5-fluoro3'-
Production of 0-(2,4,6-drimethylbenzyl)uridine The reaction and post-treatment were carried out in the same manner as in Example 101 to obtain a powder of the target compound in a yield of 47%.

'H-NMR (CDC93) δ near, 97 (1H, d, J = 8Hz, Ca of pyridine ring
H) 7.25 (1H, d, J = 8Hz, Cs of pyridine ring
, H) Jibar3 6.27 (1H,btS J=6HzS C+'
-H) 4.27-4.02 (2H, m.

C3', 4' H > 4.00-3.71 (2H, m, Cs' -H
)2.72-2.05 (12H,m,5'-O
H.

C2' -H, CH3 The reaction and post-treatment were carried out in the same manner as in Production Example 104 to obtain a powder of the target compound in a yield of 33%.

'HNMR (DMSO-ds) δ: 11.45 (1H, bslNH>Cs H) 7.33 (5H, s, phenyl-H) 6.81 and 6.
64 (2H1 each d, J = 8H2, 03 of the pyridone ring
,5 H) 6.11 (1H,t,J=7H2,C+'H
)5.29 (IH, t, J=6Hz, Cs'
0H) 4.29-4.10 (2H, m, C3', -' H) 3.74 3.63 (2H, m, Cs' H)
2.45-2.23 (2H,m,C2'-H) Example 195 3-(3-(6-penzoyloxy-3-cyano-2-
pyridyloxycarbonyl)benzoyl)-3'-0
-Preparation of benzyl-2'-deoxy-5-fluorouridine 6-penzoyloxy-3-cyano-2-hydroxypyridine 1. 2.88 mQ of triethylamine and 1.0 isophthaloyl chloride in 50 ml of dioxane solution of OOQ
1C1 was added, and the mixture was stirred for 1.5 hours under air temperature.

Separately, 2.88 m of triethylamine (2) and 0.69 m of trimethylsilyl chloride were added to a solution of 1.40 C1 of 3'-〇-benzyl-2'-deoxy-5-fluorouridine in 50 m of dioxane, and the mixture was stirred for 1 hour under air temperature. The reaction solution was filtered. The residue was added to the previously prepared reaction solution and stirred at 80°C for 30 minutes.The reaction solution was filtered and concentrated, and the residue was dissolved in 20 mQ of acetone and added with 5 m of water.
f2 was added and stirred at 75°C for 1 hour. After concentrating the acetone, 50 ml of ethyl acetate was added for extraction. After washing the organic layer with water, it was dried on a sulfuric acid magne column, then concentrated, and the residue was subjected to column chromatography using benzene:ethyl acetate (4:1) as a mobile phase and florisil as a stationary phase, and the target compound was obtained as 801+1. (1 (3%) obtained.

When the obtained compound was analyzed by thin layer chromatography and liquid chromatography, it was found to be the same as the compound obtained in Example 190.

Example 196 Production of 2'-deoxy-5-fluoro-3'-0-(4-methoxycarbonylbenzylene) The above compound was obtained in the same manner as in Example 114.

Melting point 169-170'C'H-NMR (CD093) δ: 9,85 (1H, bs, N3H)8,04 7
．． 94 (3H, m, Cs H and 7, 37 (2H,
d, J = 8Hz, 6, 24 (IH, t, J = 6Hz, C, I' -
H>4,58 (2H,s,3'-O-Ωdan,-)4,
31-3.70 (7H, m, C3Z4'15' H and -COCH3 >3, 19
(1H, bs, Cs'OH>2, 66-2.
04 (2H,m,C2'H) Example 197 Production of 2'-deoxy-3'-〇-cinnamyl-5-fluorouridine The above compound was obtained in the same manner as in Example 114.

Yield 23% 'H NMR (DMSO-ds) δ: 1 1, 7
5 (1H, bs, N3 H)8, 20 (1H
, d, J=7Hz, C6H>7, 53-7.
24 (5H, m.

6, 64 (1H, d, J = 16Hz.

6, 47-6, 08 (2H, m, C+ '-H and 5
, 20 (IH, bs, Cs' -OH) 4, 1
7 (2H, d, J=5Hz, C3'O-Ωdan1) 4,20 ~4.03 (2H, m.

C3'. 4'H) 3,74-3.59 (2H,m,Cs'-H)
2,34~2.2 1 (2H,m,C2'
H) Example 198 Preparation of 2'-deoxy-3'-0-(4-dimethylaminobenzyl)-5-fluorouridine 4-dimethylaminobenzyl alcohol 1, 60 g of benzene 20n12 solution with pyridine 0, 86mf2 and tri-odor 1.19n+2 phosphorus chloride was added and stirred at 80'C for 1 hour. The reaction solution was concentrated, and the residue was dissolved in 50 g of a water-acetonitrile mixed solvent (2:1), and potassium hydroxide was added thereto to adjust the DH to 11. Furthermore, 2'-deoxy-5-
Fluorouridine 1. OOCI was added and stirred at room temperature for 2 days.

The reaction solution was poured into ice water and extracted with ethyl acetate.

After drying the organic layer with magnesium sulfate, concentrate the residue to 1%.
When subjected to silica gel column chromatography using methanol/chloroform as a developing solvent, 70 mg (5%) of the target compound was obtained.

'H-NMR (DMSO-d6) δ:1 1,98
(IH, bs, N3 H) 8, 18 (1H, d, J
=7Hz,Cs-H>6,69 (2H,d,J=9
Hz.

6.09 (1H, t, J=6H2,C+'
-H) 5.18 (IH, bs, Cs' 0H
) 4.18~3.96 (2H, m, C3', 4' H) 3.7C) ~ 3.58 (2H, m, Cs'
H) 2.88 (6H,S,CH:l X2>2.2
8'-2,09(2H,m,C2'H) Example 1
99 Production of 2'-deoxy-5-fluoro-3'-0-(3-phenylpropyl)uridine 2'-deoxy-3'-〇-cinnamyl-5-fluoro5' obtained as an intermediate in Example 197 -0-trityluridine 500
50 mg of 5% palladium-carbon was added to a 30-mCl solution in methanol, and catalytic reduction was carried out under air temperature for 1 hour.

The reaction solution was filtered and concentrated, and the residue was dissolved in 80% acetic acid (20 rlIQ).
) The mixture was stirred in a container at 65°C for 2 hours.

The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography using 1% methanol-chloroform as a developing solvent to obtain 190 mCl of the desired compound.

Yield 63% 'HNMR (DMSOd6) δ: 11,80 (1H,bs, N3H>6,12 (
1H, t, J-6H2,C+ 'H) 5, 18 (
IH, t, J=5H2, Cs'=-OH)4,06
~3.93 (2H,m, C3', L'H) 3,66~3.62 (2H,m, Cs'-H>
3, 41 (2H, t, J=6Hz, C3'O-□-
) 2.72-1.66 (6H, m, C2' H and pharmacological test example ■ Sarcoe subcultured in ICR mice as ascites? (
3arcoma>-180 was diluted with physiological saline to 1
An amount of 2×10 7 cells per mouse was subcutaneously transplanted into the back of syngeneic mice and used for experiments. Starting 24 hours after tumor implantation, a drug suspended in 5% gum arabic was orally administered once a day for 7 days.

On the 10th day after tumor transplantation, a solid tumor under the skin of the back was excised, and the tumor weight was measured. C) is determined, and the drug dose and the dose of the ratio (T/C) are determined, and the 50% tumor-inhibiting dose (ED50
value) was calculated. The results are shown in Table 1.

Table 1 Pharmacological Test Example ■ (Acute Toxicity) The compounds of the present invention obtained in Example 2 and Example 54 were each
The drug was orally administered to week-old ICR male mice (8 mice per group), and general symptoms, changes in body weight, and whether they were alive or dead were observed for 14 days after administration. Further, the LD50 value was determined from the mortality rate according to the Litchfield-Wilcoxon method. The results are shown in Table 2 below.

Table 2 Formulation Example 1 Compound of Example 54 50 mCl Milk
Sugar 97mQ Crystalline cellulose 50rrlQ Magnesium stearate 3mQ Capsules containing 200 mC per capsule are prepared using the above side combinations.

Formulation Example 2 Compound of Example 54 10 mg Lactose 184 mq Crystalline Cellulose 100 mc + Magnesium Stearate 6 mg Capsules containing 300 mCl per capsule are prepared using the above blending ratio.

Formulation Example 3 Compound of Example 54 10 mg Lactose 240 mCl Corn starch 340 mc + Hydroxypropyl cellulose 10 mg 6 per package at the above blending ratio
Prepare 00 mCl granules.

Formulation Example 4 Compound of Example 54 10 mCl Macrogol 300 500 mCl Distilled Water for Injection
Prepare an injectable preparation of 5 m (2) per ampoule using the appropriate amount and the above-mentioned mixing ratio.

Formulation Example 5 1000 tablets for oral use each containing 10 mC1 of the compound of Example 54 are prepared according to the following formulation.

Compound of Example 54 '10cI Lactose (Japanese Pharmacopoeia) 45g Cornstarch (
25g crystalline cellulose (Japanese Pharmacopoeia crystal) 25q methyl cellulose (Japanese Pharmacopoeia crystal>1.
5CI Magnesium Stearate (Japanese Pharmacopoeia Crystal) 1Ω Example 5
Compound No. 4, lactose, cornstarch and crystalline cellulose are thoroughly mixed, granulated with a 5% aqueous solution of methylcellulose, passed through a 200 mesh sieve and carefully dried. The dried granules are passed through a 200 mesh sieve, mixed with magnesium stearate and pressed into tablets.

(that's all)

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 and R^2 are lower alkyl groups, lower alkoxy groups, halogen atoms, carboxyl groups, lower alkoxycarbonyl groups on the phenyl ring. and a phenyl lower alkyl group which may have a substituent selected from a di(lower alkyl)amino group, or a phenyl lower alkyl group, a phenyl lower alkenyl group, or a naphthyl lower alkyl group having a lower alkylenedioxy group or a phenyl group as a substituent. and the other represents a hydrogen atom or an acyl group. R^3 represents a hydrogen atom, an acyl group or a tetrahydrofuranyl group] A 2'-deoxy-5-fluorouridine derivative represented by: