JPS62258396A - 5-fluorouridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<1> is group shown by formula II; one of R<2> and R<3> is H and the other is H, halogen or acyloxy; R<4> is H or -OSO2R<6> (R<6> is lower alkyl or aryl); R<5> is phenyl lower alkyl which may be replaced with halogen, etc., naphthyl lower alkoxy, etc.)]. EXAMPLE:2'-O-Acetyl-3',5'-di-O-tosyl-5-fluorouridine. USE:An intermediate for synthesizing anti-cancer drugs. PREPARATION:For example, a starting compound shown by formula III is treated with a sulfonyl halide shown by formula R<6>O2SOX in an inert solvent such as THF, etc., in the presence of a deoxidizer such as pyridine, etc., at -80-200 deg.C to give a compound shown by formula IV. Then, the compound is acylated to give a compound shown by formula V, which is reacted with a compound shown by formula VI in an inert solvent such as THF, etc., in the presence of Lewis acid such as ferric chloride, etc. The compound shown by formula IV is a novel compound.

Description

[Detailed description of the invention] Industrial applications The present invention relates to 5-fluorouridine derivatives.

DISCLOSURE OF THE INVENTION The 5-fluorouridine derivative of the present invention is a novel compound that has not been described in any literature and is represented by the following general formula (1).

○ 1RI 5 R3 ■ is a hydrogen atom, usage is hydrogen atom, halogen atom or acyloxy group, R4 is a hydrogen atom or group 0302 R6 (R6
is a lower alkyl group or an aryl group), R5 is a hydrogen atom,
Hydroxyl group, acyloxy group, phenyl lower alkoxy group which may have a substituent selected from the group consisting of lower alkyl group, lower alkoxy group, halogen atom and carboxyl group on the phenyl ring, lower alkylene dioxy group or phenyl as a substituent represents a phenyl lower alkoxy group or a naphthyl lower alkoxy group. However, R1 may also be indicated. ] The 5-fluorouridine derivative represented by the general formula (1) of the present invention has the following general formula [wherein Rsa is selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, and a carboxyl group on the phenyl ring] Indicates a phenyl lower alkoxy group which may have a substituent, a phenyl lower alkoxy group having a lower alkylene dioxy group or a) engineering group as a substituent, or a naphthyl lower alkoxy group. ] It is useful as an intermediate for synthesizing the compound represented by. The compound represented by the general formula (2) not only has an anticancer effect itself, but also has the following formula (
It is an important compound as an intermediate for synthesizing the compound represented by 3).

In this specification, halogen atoms include fluorine atoms,
Examples include chlorine atom, bromine atom, and iodine atom.

The acyl group of the acyloxy group includes those belonging to the following groups.

(1) Straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms:
For example, formyl, acetyl, propionyl, butyryl,
Isobutyryl, pentanoyl, hexanoyl groups, etc.

(2) Arylcarbonyl group which may have a substituent The aryl ring has 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, and a nitro group as a substituent, or phenyl group or naphthyl group, etc.

More specifically, for example, benzoyl, α-naphthylcarbonyl, β-naphthylcarbonyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methylbenzoyl, 2,
4-dimethylbenzoyl, 3,4.5-trimethylbenzoyl, 4-ethylbenzoyl, 2-propylbenzoyl, 3-hexylbenzoyl, 2-chlorobenzoyl,
3-chlorobenzoyl, 4-chlorobenzoyl, 2,3
-dichlorobenzoyl, 2,4゜6-drichlorobenzoyl, 2-bromobenzoyl, 4-fluorobenzoyl, 2-nitrobenzoyl, 3-nitrobenzoyl, 4-
Nitrobenzoyl, α-methyl-β-naphthylcarbonyl β-nitro-α-naphthylcarbonyl group.

(3) Straight-chain or branched alkoxy-substituted carbonyl group having 1 to 6 carbon atoms: for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl group, etc. .

(4) Lower alkyl substituted or unsubstituted carbamoyl group: mono- or di-lower alkyl substituted carbamoyl or unsubstituted carbamoyl group, etc. More specifically, for example, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-tel"t-butylcarbamoyl, N,N-
Dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl, N,N-diethylcarbamoyl, N-ethyl-
N-butylcarbamoyl carbamoyl group, etc.

Lower alkyl groups include methyl, ethyl, propyl,
Isopropyl, butyl, tert-butyl, pentyl,
Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms such as hexyl group.

Examples of lower alkoxy groups include those having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, impropoxy, butoxy, te-butoxy, pentyloxy, and hexyloxy groups.
Examples include straight chain or branched alkoxy groups.

A phenyl lower alkoxy group that may have a substituent selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, and a carboxyl group on the phenyl ring may have 1 to 3 of the above substituents. A phenyl group and a fullyleneoxy group having 1 to 6 carbon atoms, such as methyleneoxy, ethyleneoxy, trimethyleneoxy,
1-methylethyleneoxy, tetramethyleneoxy, 2
-methyltrimethyleneoxy, pentamethyleneoxy,
An example is a phenylalkoxy group bonded to a hexamethyleneoxy group or the like. A specific example thereof is as follows.

Benzyloxy, 2-methylbenzyloxy, 3-methylbenzyloxy, 4-methylbenzyloxy, 2-ethylbenzyloxy, 3-ethylbenzyloxy, 4-
Ethylbenzyloxy, 2-propylbenzyloxy,
3-propylbenzyloxy, 4-propylbenzyloxy, 2-butylbenzyloxy, 3-butylbenzyloxy, 4-butylbenzyloxy, 2-tert-
Butylbenzyloxy, 3-tert-butylbenzyloxy, 4-tert-butylbenzyloxy, 2-pentylbenzyloxy, 3-pentylbenzyloxy, 4-pentylbenzyloxy, 2-hexylbenzyloxy, 3-hexylbenzyl oxy, 4-hexylbenzyloxy, 2,3-dimethylbenzyloxy, 2,4-dimethylbenzyloxy, 2,5-dimethylbenzyloxy, 2,6-dimethylhenzyloxy, 3
,4-dimethylbenzyloxy,benzyloxy,3,
5-dimethylbenzyloxy, 2,3.4-trimethylbenzyloxy, 2.4.5-trimethylbenzyloxy, 2゜3.5-trimethylbenzyloxy, 2,4゜6-trimethylbenzyloxy, 3.4. 5-trimethylbenzyloxy, 2,3-diethylbenzyloxy,
2,4-diethylbenzyloxy, 2,5-diethylbenzyloxy, 2゜6-diethylbenzyloxy, 2.
4.6-triethylbenzyloxy, 3,4.5-triethylbenzyloxy, 2.4-dipropylbenzyloxy, 3-methyl-4-ethylbenzyloxy, 1-phenylethoxy, 2-phenylethoxy, 2-phenyl -1-methylethoxy, 1-(2-methylphenyl)ethoxy, 2-(2-methylphenyl)ethoxy, 2-
(3-Methylphenyl)ethoxy, 2-(4-methylphenyl)ethoxy, 1-(2,4-dimethylphenyl)ethoxy, 2-(2,4-dimethylphenyl)ethoxy, 1-(2, 4,6-trimethylphenyl)ethoxy, 2-<2.4.6-trimethylphenyl)ethoxy, 3-phenylpropoxy, 3-(4-methylphenyl)propoxy, 4-phenylbutoxy, 4- (2-
methylphenyl)butoxy, 5-phenylpentyloxy, 5-(3-methylphenyl)pentyloxy, 6
-phenylhexyloxy, 6-(4-methylphenyl)hexyloxy, 2-methoxybenzyloxy, 3-
Methoxybenzyloxy, 4-methoxybenzyloxy, 2゜3-dimethoxybenzyloxy, 2,4-dimethoxybenzyloxy, 2,5-dimethoxybenzyloxy, 3-methoxy-4-ethoxybenzyloxy, 2,
6-dimethoxybenzyloxy, 3,4-dimethoxybenzyloxy, 3゜5-dimethoxybenzyloxy, 2
, 3.4-trimethoxybenzyloxy, 2,4.5-
trimethoxybenzyloxy, 2,4.6-trimethoxybenzyloxy, 2-ethoxybenzyloxy, 4-
Propoxybenzyloxy, 3-butoxybenzyloxy, 2-tert-butoxybenzyloxy, 3-pentyloxybenzyloxy, 4-hexyloxybenzyloxy, 2.3-jethoxybenzyloxy, 1-
(4-methoxyphenyl)ethoxy, 2-(3,4-dimethoxyphenyl)ethoxy, 3-(4-methoxyphenyl)propoxy, 4-(2-methoxyphenyl)butoxy, 5-(4-methoxyphenyl)pentyloxy ,
6-(4-methoxyphenyl)hexyloxy, 6-
(3,4゜5-tripentyloxyphenyl)hexyloxy, 2-fluorobenzyloxy, 3-fluorobenzyloxy, 4-fluorobenzyloxy, 2.3-
Difluorobenzyloxy, 2゜4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 2-fluoro-3-chlorobenzyloxy, 2-fluoro-3
-bromobenzyloxy, 2,6-difluorobenzyloxy, 2,3.4-trifluorobenzyloxy, 2
, 4.5-trifluorobenzyloxy, 2,4.6-
Trifluorobenzyloxy, 3,4.5-1-lifluorobenzyloxy, 1-(2-fluorophenyl)ethoxy, 2-(2-fluorophenyl)ethoxy, 3-
(3-fluorophenyl)propoxy, 4-(2-fluorophenyl)butoxy, 5-(2-fluorophenyl)pentyloxy, 6-(3-fluorophenyl)hexyloxy, 2-bromobenzyloxy, 3-bromobenzyl oxy, 4-bromobenzyloxy, 2,3-dibromobenzyloxy, 2,4-dibromobenzyloxy, 2,5-dibromobenzyloxy, 2-fluoro-
3-bromobenzyloxy, 2,6-dibromobenzyloxy, 2,3,4-tribromobenzyloxy, 2,
3.5-tribromobenzyloxy, 2,4.5-tribromobenzyloxy, 2,4.6-tribromobenzyloxy, 3,4.5-tribromobenzyloxy, 1
-(2-bromophenyl)ethoxy, 2-(2-bromophenyl)ethoxy, 3-(2-bromophenyl)propoxy, 4-(3-bromophenyl)butoxy, 5-(
2-bromophenyl)pentyloxy, 6-(4-bromophenyl)hexyloxy, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 2,3-dichlorobenzyloxy, 2,4-dichloro Benzyloxy, 2,5-dichlorobenzyloxy, 2,6-dichlorobenzyloxy, 2-bromo-4-
Chlorobenzyloxy, 2-fluoro-4-chlorobenzyloxy, 2,3.4-trichlorobenzyloxy,
2,3.5-trichlorobenzyloxy, 2,4.5-
Trichlorobenzyloxy, 2,4.6-trichlorobenzyloxy, 3.4.5-trichlorobenzyloxy, 1-(4-chlorophenyl)ethoxy, 2-(4-chlorophenyl)ethoxy, 3-(2-chlorophenyl)propoxy , 4-(4-chlorophenyl)butoxy,
5-(3-chlorophenyl)pentyloxy, 6-(4
-chlorophenyl)hexyloxy, 2-iodobenzyloxy, 3-iodobenzyloxy, 4-iodobenzyloxy, 3,4-shortbenzyloxy, 3.4
．． 5-triiodobenzyloxy, 2-(3-iodophenyl)ethoxy, 6-(2-iodophenyl)hexyloxy, 2-carboxybenzyloxy, 3-carboxybenzyloxy, 4-carboxybenzyloxy,
3゜4-dicarboxybenzyloxy, 2,4-dicarboxybenzyloxy, 2,3,4-tricarboxybenzyloxy, 3,4.5-tricarboxybenzyloxyxyphenyl)ethoxy, 3-(4-carboxy phenyl)propoxy, 6-(4-carboxyphenyl)hexyloxy, etc.

The lower alkylene dioxy group or the phenyl lower alkoxy group having a phenyl group is 2.

3-methylenedioxybenzyloxy, 3,4-methylenedioxybenzyloxy, 2,3-ethylenedioxybenzyloxy, 3,4-ethylenedioxybenzyloxy, 3,4-trimethylenedioxybenzyloxy,
3,4-tetramethylenedioxybenzyloxy, go(3,4-methylenedioxyphenyl)ethoxy, 2-
(3.4-methylenedioxyphenyl)ethoxy, 3
-(3,4-methylenedioxyphenyl)propoxy,
4-(3,4-methylenedioxyphenyl)butoxy,
5- (3,4-methylenedioxyphenyl)pentyloxy, 6- (3,4-methylenedioxyphenyl)
Hexyloxy, 3- (3.

4-trimethylenedioxyphenyl)propoxy, 2-
Phenylbenzyloxy, 3-phenylbenzyloxy, 4-phenylbenzyloxy, 2-(3-phenylphenyl)ethoxy, 1-(4-phenylphenyl)ethoxy, 3-(4-phenylphenyllenyl)butoxy, 5-( A phenyl group bonded to an alkylene dioxy group having 1 to 4 carbon atoms such as 4-phenylphenyl)pentyloxy or 6-(4-phenylphenyl)hexyloxy group or a phenyl group and a linear or branched chain having 1 to 6 carbon atoms. An example is a phenylalkoxy group bonded to a branched alkoxy group.

Naphthyl lower alkoxy groups include α-naphthylmethoxy, α-naphthyl ethoxy, α-naphthylpropoxy, α-su7tylbutoxy, α-naphthyl-tert-butoxy, α-naphthylpentyloxy, α-naphthylhexyloxy, β- Examples include naphthylmethoxy, β-naphthyl ethoxy, β-naphthylpropoxy, β-naphthylbutoxy, β-naphthyl-tert-butoxy, β-naphthylpentyloxy, and β-naphthylhexyloxy groups.

Examples of the aryl group include phenyl, α-naphthyl,
β-naphthyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl,
3,4.5-trimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2,4-
Diethylphenyl, 2-isopropylphenyl, 2.3
-diisopropylphenyl, 2,4.6-dolyisopropylphenyl, 2-methyl-4-hexylphenyl, 2
-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2.4.6-dolichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-fluorophenyl, 2,4. lotrifluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl,
3-butoxyphenyl, 4-hexyloxyphenyl,
2.4-dimethoxyphenyl, 2,4.6-driethoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, β-methyl-α-naphthyl, α
-Ethoxy-β-naphthyl, α-chloro-β-naphthyl, β-nitro-α-naphthyl, etc. as a substituent on the heptadyl ring selected from the group consisting of a lower alkyl group, a halogen atom, a lower alkoxy group, and a nitro group. A phenyl group or a naphthyl group having or not having 1 to 3 groups can be exemplified.

The compound of the present invention can be produced, for example, by the method shown in the reaction scheme below.

Reaction scheme-1 ○R7 ■ 3a ○ 3a [In the formula, R6 is the same as above. R3a represents an acyloxy group. R7 represents a lower alkyl group or a trialkylsilyl group. According to reaction scheme-1, tetrahedron, 37°1685 (198
Known or new general formula (6) according to the method shown in 1)
A compound represented by is produced, and then the compound (6)
A compound represented by the general formula (7) is produced by acylating the compound (7), and the compound represented by the general formula (1a) is further reacted with a known 5-fluoropyrimidine derivative (8). the compound of the invention is produced;
Furthermore, the compound of the present invention represented by the general formula (1b) is produced by treating the compound (1a) with a known alcoholade.

The reaction for obtaining compound (6) from compound (4) can be carried out by adding a lower alkanesulfonyl halide or an arylsulfonyl halide [i.e. Compound (5)] at a temperature of -80 to 200'C for 30 to 50 minutes.
It is carried out by reacting for about a period of time. The inert solvent used here is not particularly limited, and a wide range of known inert solvents can be used as long as it does not adversely affect the above reaction. aromatic hydrocarbons such as benzene, toluene, xylene, saturated hydrocarbons such as hexane, pentane, cyclohexane, petroleum ether, ligroin, diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, diisopropyl ether, diglyme, etc. ethers, ketones such as acetone, methyl ethyl ketone, diisobutyl ketone, dimethylformamide, N-methylpyrrolidone, N,N'-dimethylimidazolidine, N
, N-dimethylacetamide, amides such as hexamethylphosphoamide, dimethylsulfoxide, ethyl acetate, acetonitrile, and the like. The deoxidizing agent is not particularly limited; a wide range of conventionally known basic compounds can be used, such as triethylamine, pyridine,
Examples include potassium carbonate and sodium carbonate. The amount of such a deoxidizing agent to be used is usually at least twice the molar amount, preferably about 2 to 3 times the molar amount of compound (4). The lower alkanesulfonyl halides used in this reaction include, for example, methanesulfonyl chloride, ethanesulfonyl chloride, propanesulfonyl chloride, do, butanesulfonyl chloride, hexanesulfonyl chloride, etc., and the arylsulfonyl halides include, for example, benzenesulfonyl Chloride, 2-methylbenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 3
Examples include -methoxybenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, α-naphthalenesulfonyl chloride, and 2°4.6-drimethylbenzenesulfonyl chloride. The amount of compound (5) to be used relative to compound (4) is usually at least twice the molar amount, preferably about 2 to 3 times the molar amount.

The acylation reaction of compound (6) is described in the Journal of the
American Chemical Society 1 ship, 524
7 (1958) in a suitable solvent,
It is carried out in the presence of an acid anhydride and a suitable catalyst. As the acid anhydride, acid anhydrides corresponding to the acyl groups to be introduced into the 1st and 2nd positions of the compound (5) are preferably used,
Specific examples include acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride, and the like. These acid anhydrides are generally used in an amount of at least twice the molar amount of compound (6), preferably about 2 to 3 times the molar amount. As the catalyst, a wide range of catalysts commonly used in acid hydrolysis reactions can be used, such as inorganic acids such as hydrochloric acid and Fa acid, sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, and trifluoromethanesulfonic acid, etc. organic acids and the like. The amount of such catalyst to be used is usually from a catalytic amount to an excess amount, preferably an excess amount.

As the solvent, it is desirable to use an organic acid that corresponds to the acid anhydride used. When an organic acid is used as the catalyst, it also acts as a solvent, so there is no need to use any other solvent. The above reaction is usually -30 to 10
The process progresses suitably at about 0"C, preferably about -5 to 20C, and generally ends in 3 to 50 minutes.

The reaction between compound (7) and compound (8) is described in Chemical and Pharmaceutical Industry Bulletin, 26.2.
990 (1978), by reacting both in the presence of a Lewis acid in a suitable inert solvent. Examples of the inert solvent include the halogenated hydrocarbons, the aromatic hydrocarbons, the saturated hydrocarbons, the ethers, and the Ketones, the above amides, dimethyl sulfoxide, ethyl acetate,
Acetonitrile etc. can be used. Examples of the Lewis acid include stannic chloride, aluminum chloride, ferric chloride, titanium tetrachloride, and zinc chloride. The amount of Lewis acid used is usually a catalytic amount to an excess amount, preferably an equimolar amount. As the compound (8), any known compound can be used as long as it corresponds to the general formula (8), and specific examples include 2,4-bistrimethylsilyloxy-5-fluoropyrimidine and the like.
Examples include 2,4-dialkyloxy-5-fluoropyrimidine such as trialkylsilyloxy-5-fluoropyrimidine and 2,4-dimethyloxy-5-fluoropyrimidine. The ratio of compound (7) and compound (8) to be used is usually at least about the same mole of the former, preferably about 3 times the mole of the latter. The above reaction normally proceeds suitably at about -30 to 100'C, preferably at about -5 to 50'C, and generally
Completes in minutes to 50 hours.

The reaction for obtaining compound (1b) from compound (1a) is carried out in an inert solvent in the presence of a suitable catalyst. As the inert solvent, the above-mentioned ethers, the above-mentioned ketones, used in the reaction between the above-mentioned compound (4) and compound (5),
In addition to the above-mentioned amides, dimethyl sulfoxide, ethyl acetate, acetonitrile, etc., lower alcohols such as methanol, ethanol, isopropanol, propatool, butanol, nitromethane, etc. can be used.

It is preferable to use anhydrous inert solvents. As the catalyst, a wide range of catalysts can be used that are commonly used in alkaline hydrolysis reactions, and representative examples thereof include alcoholades such as sodium methylate, sodium ethylate, and potassium tert-butoxide. Such a catalyst is usually preferably used in an excess amount relative to compound (1a). The above reaction proceeds either under cooling, at room temperature, or under heating, but usually proceeds suitably near room temperature, and is generally completed in about 3 minutes to 3 hours.

Reaction Scheme-2 [In the formula, R5, RG and X are the same as above. R3b represents a halogen atom. R5a' is a phenyl lower alkyl group which may have a substituent selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom and a carboxyl group on the phenyl ring, a lower alkylene dioxy group or a phenyl group as a substituent; phenyl lower alkyl group or naphthyl lower alkyl group. ] According to reaction scheme-2, compound (9) is added to compound (1b).
) to produce the compound of the present invention represented by the general formula (1c), and then reacting the compound (1C) with hydrogen halide to produce the compound of the present invention represented by the general formula (1d). A compound is produced, and the compound (1d) is further dehalogenated to produce the compound of the present invention represented by the general formula (1e).

The reaction between compound (1b) and compound (9) is carried out in a suitable inert solvent in the presence of an acid absorbing agent.

The inert solvent is not particularly limited, and a wide range of ordinary solvents can be used as long as it does not adversely affect the reaction. Examples include hydrogens, the above aromatic hydrocarbons, the above saturated hydrocarbons, the above ethers, the above ketones, the above amides, dimethyl sulfoxide, ethyl acetate, and acetonitrile. As a deoxidizing agent, a wide range of ordinary basic compounds can be used, including metal hydroxide compounds such as sodium hydroxide and potassium hydroxide, alkali metal hydrides such as sodium hydride and potassium hydride, etc. Organic bases such as tertiary amines such as pyridine and triethylamine can be exemplified. Examples include organic bases such as compounds. The ratio of compound (1b) and compound (9) to be used is not particularly limited and can be appropriately selected within a wide range, but usually the latter is at least equimolar to the former, preferably equimolar to 3 times the molar ratio. It is better to set it as a degree. The above reaction is usually -3
The reaction proceeds suitably at a temperature of about 0 to 100'C, preferably about 0 to 30'C, and is generally completed in about 3 minutes to 1 hour.

The reaction for obtaining compound (1d) from compound (1C) is carried out by reacting compound (1C) with trialkylchlorosilane and an alkali metal halide in a suitable inert solvent. The inert solvent is not particularly limited, and a wide range of common solvents can be used as long as it does not adversely affect the reaction. For example, when the compound (4) and the compound (
Use the above halogenated hydrocarbons, the above aromatic hydrocarbons, the above saturated hydrocarbons, the above ethers, the above ketones, the above amides, dimethyl sulfoxide, ethyl acetate, acetonitrile, etc. used in the reaction with 5). can do. As trialkylchlorosilane,
For example, trimethylchlorosilane can be used. The ratio of compound (1C) and trialkylchlorosilane to be used is not particularly limited and can be appropriately selected from a wide range, but usually the latter is at least equimolar to the former, preferably equimolar to 5 times the molar ratio. It is better to

Examples of the alkali metal halide include sodium bromide and sodium iodide. Compound (1G)
The proportion of the alkali metal halide and the alkali metal halide is not particularly limited and can be appropriately selected within a wide range, but it is usually at least equimolar to the former, preferably about equimolar to twice the molar amount of the latter. good. The above reaction is usually O~
The reaction proceeds suitably at about 200'C, preferably at air temperature to about 100'C, and is generally completed in about 10 minutes to 3 hours.

The reaction for obtaining compound (1e) from compound (1d) is carried out by reducing compound (1d) in a suitable inert solvent in the presence or absence of a basic compound. The inert solvent is not particularly limited, and a wide range of common solvents can be used as long as it does not adversely affect the reaction.
For example, the halogenated hydrocarbons, aromatic hydrocarbons, saturated hydrocarbons, ethers, ketones, amides, dimethyl used in the reaction between compound (4) and compound (5) Sulfoxide, ethyl acetate, acetonitrile, etc., methanol, ethanol,
Examples include lower alcohols such as propatool, isopropanol, and butanol. Basic compounds include, for example, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, calcium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, hydroxide. Inorganic bases such as calcium, sodium acetate, pyridine, triethylamine, picoline, collidine, dimethylaniline, 4-dimethylaminopyridine, quinoline, isoquinoline, diazabicycloundecene, diazabicyclononane, diazabicyclooctane, diimpropylethylamine, Examples include organic bases such as tertiary amines such as tributylamine. As the reducing agent used in the reaction, a wide variety of conventionally known reducing agents can be used, such as sodium borohydride, sodium cyanoborohydride, triethylsilyl hydride, trialkyltin, triphenyltin, trialkyltin halide-hydrogenation ( 71
Examples include sodium II, lithium aluminum hydride, triphenyltin halide-sodium borohydride, lithium aluminum hydride, and catalytic reduction catalysts.

As the catalytic reduction catalyst, a wide variety of catalysts commonly used in this type of reaction can be used, such as palladium-barium sulfate, Raney nickel, palladium-activated carbon, and the like. The above reaction normally proceeds suitably at about 0 to 100°C, preferably about 5 to 40'C, and is generally completed in about 30 minutes to 30 hours under atmospheric pressure.

Reaction scheme-3 5b [In the formula, R3b and R6 are the same as above. R5b represents an acyloxy group. ] According to Reaction Scheme-3, the compound of the present invention represented by the general formula (1f) is produced by reacting the compound (1b) with an acyl halide, and then the compound (1f)
The compound of the present invention represented by the general formula (1g) is produced by dehalogenating, and further the compound (1g)
The compound of the present invention represented by general formula (1g) is produced by hydrolyzing .

The reaction between compound (1b) and acyl halide is carried out in a suitable inert solvent. The inert solvent is not particularly limited, and a wide range of common solvents can be used as long as it does not adversely affect the reaction.
The above halogenated hydrocarbon layer, the above aromatic hydrocarbons, the above saturated hydrocarbons, the above ethers, the above ketones, the above amides, dimethyl sulfoxide, ethyl acetate, acetonitrile used in the reaction between and compound (5) etc. can be used. As an acyl halide,
A wide variety of conventionally known compounds can be used, such as lower alkanoyl halides such as acetyl chloride, acetyl bromide, acetyl iodide, propionyl chloride, butyryl bromide, aryl carbonyl halides such as benzoyl chloride, benzoyl bromide, α-naphthyl carbonyl chloride, and methoxy Examples include lower alkoxycarbonyl halides such as carbonyl chloride, ethoxycarbonyl chloride, propoxycarbonyl chloride, carbamoyl chloride, carbamoyl bromide, and N-methyl-N-ethylcarbamoyl chloride halides. The ratio of compound (1b) and acyl halide to be used is not particularly limited and can be appropriately selected within a wide range, but usually the latter is at least equimolar to the former, preferably about equimolar to twice the molar amount. It is better to do so. In the reaction system of the above reaction, an alkali metal halide salt such as sodium bromide or sodium iodide may be present, and the amount of the alkali metal salt used is preferably at least the same as that of the acyl halide. .

The above reaction normally proceeds suitably at a temperature of about 0 to 200"C, preferably from a very low temperature to about 100"C, and generally takes about 10 minutes to 30 minutes.
The reaction is completed in about an hour.

The reaction for obtaining compound (1Ω) from compound (1f) is carried out by reducing compound (1f) in a suitable inert solvent in the presence or absence of a basic compound. The inert solvent is not particularly limited, and a wide range of common solvents can be used as long as it does not adversely affect the reaction.
For example, the halogenated hydrocarbons, aromatic hydrocarbons, saturated hydrocarbons, ethers, ketones, amides, dimethyl used in the reaction between compound (4) and compound (5) Sulfoxide, ethyl acetate, acetonitrile, etc., methanol, ethanol,
Examples include lower alcohols such as propatool, impropatool, and butanol. Basic compounds include, for example, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, calcium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, hydroxide. Inorganic bases such as calcium, sodium acetate, pyridine, triethylamine, picoline, collidine, dimethylaminone, 4-dimethylaminolysine, quinoline, isoquinoline, diazabicycloundecene, diazabicyclononane, diazabicyclooctane, diisopropylethylamine, Examples include organic bases such as tertiary amines such as tributylamine. As the reducing agent used in this reaction, a wide variety of conventionally known reducing agents can be used, such as sodium borohydride, triethylsilyl hydride, metal-acids such as zinc and tin, trialkyltin, triphenyltin, trialkyltin halide. Examples include - sodium borohydride or lithium aluminum hydride, triphenyltin halide - fM sodium hydride or lithium aluminum hydride, and catalytic reduction catalysts. As the catalytic reduction catalyst, a wide variety of catalysts commonly used in this type of reaction can be used, such as 5% palladium-barium sulfate, Raney nickel, palladium-activated carbon, and the like. The above reaction normally proceeds suitably at about 0 to 150°C, preferably about 0 to 40'C, and is generally completed in about 1 to 3 hours under atmospheric pressure.

For the hydrolysis reaction of compound (1q), a wide range of reaction conditions for ordinary ester hydrolysis reactions can be applied.

Examples of the basic compound used include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates and hydrogen carbonates such as potassium carbonate, sodium carbonate, and sodium hydrogen carbonate, ammonia, and the like. Examples of acids that can be used include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid. The above reaction normally proceeds suitably at about -10 to 200'C, preferably at air temperature to about 100'C, and generally
It will be completed in about 0 minutes to 30 hours.

Reaction Scheme-4 3C [In the formula, R6 and X are the same as above. R8 represents a tosyl group or a mesyl group. ] The compound (1b) of the present invention can also be produced by the method shown in Reaction Scheme-4 above.

In the above reaction scheme-4, the reaction to obtain compound (12) from compound (4) via compound (10) and compound (11) can be carried out using a known method, such as the Journal of the
American Chemical Society, DanΩ, 524
7 (1958).

Further, from compound (12) via compound (13), compound (
The reaction for obtaining 14) can also be carried out using known methods, such as those described in Chemical and Pharmaceutical Industry Bulletin.

15, 2990 (1978).

The reaction between compound (14) and compound (5) is carried out in a suitable inert solvent in the presence of a basic compound. The inert solvent is not particularly limited and a wide range of common solvents can be used as long as it does not adversely affect the reaction, such as aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, Examples include ethers such as dimethoxyethane, diisopropyl ether, and diglyme, pyridine, and triethylamine. Basic compounds include, for example, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, calcium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, hydroxide. Inorganic bases such as calcium, sodium acetate, pyridine, triethylamine, picoline, collidine, dimethylaniline, 4-dimethylaminopyridine, quinoline, isoquinoline, diazabicycloundecene, diazabicyclononane, diazabicyclooctane, diisopropylethylamine, tri Examples include organic bases such as tertiary amines such as butylamine. The ratio of compound (14) and compound (5) to be used is not particularly limited and can be appropriately selected within a wide range, but usually the latter is at least equimolar to the former, preferably equimolar - 1.5 times. It is preferable to set it to about mol. The above reaction is usually carried out at about -5 to 100'C, preferably from O to 30'C.
The reaction proceeds suitably at about C and is generally completed in about 5 minutes to 30 hours.

The compound of the present invention represented by the above general formula (1) can be derived into a compound (2) useful as an anticancer agent, for example, according to the method shown in Reaction Scheme-5 below.

Reaction Scheme-5 a [In the formula, R, R5, Re and X are the same as above. R9 represents an acyl group, and M represents an alkali metal atom. ] According to Reaction Scheme-5, the compound of the present invention represented by the general formula (1h) is passed through the compound represented by the general formula (15), or from the compound of the present invention represented by the general formula (1e) to the general formula A compound represented by (16) is produced, and then a compound (2) is produced from the compound (16).

The reaction to obtain compound (15) from compound (1h) is carried out by converting compound (1h) with the general formula R90M in a suitable inert solvent.
This is carried out by reacting a compound represented by (for example, an alkali salt of a lower fatty acid such as sodium acetate or sodium propionate, an aromatic carboxylate such as sodium benzoate, etc.). As the inert solvent, a wide variety of conventionally known solvents can be used as long as there is no particular restriction and it does not adversely affect the reaction, such as lower alcohols such as methanol, ethanol, propatool, impropatol, butanol, benzene, toluene, Examples include aromatic hydrocarbons such as xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diisopropyl ether, and diglyme.

The amount of the compound represented by the above general formula R90M to be used is generally about 1 molar to 20 times the molar amount of compound (1h), preferably about 4 times the molar equivalent to 3 times the molar amount of compound (1h). The above reaction normally proceeds suitably at a temperature of about 0 to 300"C, preferably about 100 to 200"C, and generally
The reaction is completed in about 30 hours.

The reaction for obtaining compound (16) from compound (15) is carried out by reacting compound (15) with compound (9) in an appropriate inert solvent in the presence of a catalyst. As the inert solvent, there are no particular restrictions and a wide range of conventionally known solvents can be used as long as they do not adversely affect the reaction, such as aromatic hydrocarbons such as benzene, toluene, and xylene, diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane. , diisopropyl ether, ethers such as diglyme, acetonitrile, and the like. Examples of catalysts include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates and hydrogen carbonates such as potassium carbonate, sodium carbonate, and sodium hydrogen carbonate, and inorganic metals such as silver oxide and silver hydroxide. Examples include bases. The ratio of compound (15) and compound (9) to be used is usually about 1 to 10 times the molar equivalent of the former, preferably about 2 to 2 times the molar amount of the latter. The above reaction normally proceeds suitably at about 0 to 200'C, preferably at about 0 to 100'C, and generally
The reaction is completed in about 0 minutes to 30 hours.

The reaction for obtaining compound (16) from compound (1e) can be carried out under the same reaction conditions as the reaction for obtaining compound (15) from compound (1h).

Compound (1e) also has compound (9) added to compound (1h).
It can also be produced by reacting.

The reaction between compound (1h) and compound (9) can be carried out under the same conditions as the reaction between compound (15) and compound (9).

For the hydrolysis reaction of compound (16), a wide range of reaction conditions for ordinary ester hydrolysis reactions can be applied. Examples of the basic compounds used include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, potassium carbonate,
Examples include alkali metal carbonates and hydrogen carbonates such as sodium carbonate and sodium hydrogen carbonate, and ammonia. Examples of acids that can be used include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid.

The above reaction normally proceeds suitably at about -10 to 200°C, preferably at air temperature to about 100°C, and generally for 30 minutes to 30 minutes.
The reaction is completed in about 0 hours.

Compound (16) obtained in the above reaction scheme-5 can also be produced by the method shown in the following reaction scheme-6.

Reaction Scheme-6 [In the formula, R3b, R5a, R5a', R9 and X are the same as above. According to Reaction Scheme-6, compound (17) is produced by acylating compound (14), and then compound (18) is produced by reacting compound (17) with compound (9). The compound (19) is then produced by reacting the compound (18) with hydrogen halide, and the compound (16) is further produced by dehalogenating the compound (19).

Acylation of compound (14) is carried out in the presence of a basic compound,
This is carried out by reacting compound (14) with an acylating agent in a suitable inert solvent.

As the inert solvent, a wide variety of conventionally known solvents can be used as long as there is no particular restriction and it does not adversely affect the reaction, such as aromatic hydrocarbons such as benzene, toluene, xylene, etc.
diethyl ether, tetrahydrofuran, dioxane,
Examples include ethers such as dimethoxyethane, diisopropyl ether, and diglyme, saturated hydrocarbons such as hexane, pentane, cyclohexane, petroleum ether, and ligroin, pyridine, and triethylamine.

Basic compounds include sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate,
potassium bicarbonate, lithium bicarbonate, calcium bicarbonate,
Sodium hydroxide, potassium hydroxide, lithium hydroxide,
Inorganic bases such as calcium hydroxide and silver oxide, triethylamine, pyridine, picoline, collidine, dimethylaniline, 4-dimethylaminopyridine, quinoline, isoquinoline, diazabicycloundecene, diazabicyclononane, diazabicyclooctane, diisopropylethylamine , organic bases such as tertiary amines such as tributylamine, and the like. As the acylating agent, a wide variety of conventionally known acylating agents can be used, such as acid anhydrides such as acetic anhydride, lower alkanoyl halides such as acetyl chloride and acetyl bromide, benzoyl chloride,
- Aromatic carbonyl halides such as methylbenzoyl chloride, and the like. The amount of such acylating agent to be used is generally about 1 to 5 times the molar amount of compound (14), preferably about 1.5 times the molar amount of compound (14). The above reaction normally proceeds suitably at about -10 to 100'C, preferably around air temperature, and generally takes about 30 minutes to 30 minutes.
The reaction is completed in about 0 hours.

The reaction for obtaining compound (18) from compound (17) can be carried out under the same reaction conditions as the reaction for obtaining compound (16) from compound (15). The reaction to obtain compound (19) from compound (18) can be carried out under the same reaction conditions as the reaction to obtain compound (1d) from compound (1G). Further, the reaction for obtaining compound (16) from compound (19) can be carried out under the same reaction conditions as the reaction for obtaining compound (1e) from compound (1d).

In the above reaction scheme-6, compound (17) and compound (18) are produced from compound (1b) and compound (1C), respectively, under the same reaction conditions as the reaction to obtain compound (16) from compound (1e). be done.

Compound (2) obtained by the above reaction scheme-5 has the general formula [wherein X represents a halogen atom]. ] By reacting the compound represented by the following, a compound (3) having extremely excellent anticancer activity is produced.

The above 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, for example, an acid chloride method.

According to the acid chloride method, compound (2) is added to compound (2).
The target compound (3) can be obtained by reacting 0) in an appropriate solvent in the presence of an acid deoxidizing agent. In the above, the deoxidizing agent includes, for example, sodium hydrogen carbonate,
Sodium carbonate, potassium carbonate, pyridine, triethylamine, etc. can be used. Examples of solvents used include benzene, chloroform, methylene chloride, carbon tetrachloride, dioxane, and tetrahydrofuran. Compound (20
) is usually used in an amount of at least about 5 molar equivalents, preferably about 3 times the molar amount of compound (2). The reaction temperature is usually about -30 to 100°C, preferably from air temperature to about 80'C, and generally about 20°C.
It can be completed in about 20 minutes to 20 hours.

In the above reaction, the 5'-position of compound (2) is also acylated at the same time as the 3-position. Therefore, in the above-mentioned acylation of these compounds, it is preferable to protect the 5'-position hydroxyl group in advance, and then remove the protecting group after the acylation.

The protection of the hydroxyl group at the 5' position of compound (2) is carried out by introducing a trimethylsilyl group into the 5' position of compound (2), and examples of reagents for introducing this protecting group include chlorotrimethylsilane, etc. halides are used.

This reaction is carried out under conventional dehydrohalogenation reaction conditions.

As the hydrogen halide agent, any of various basic compounds commonly used in this type of reaction can be used.

Specific examples include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, alkali metals such as sodium and potassium, and alkali hydrides such as sodium hydride and potassium hydride. Examples include metals. The reaction can be carried out without a solvent or in the presence of a solvent. As the solvent, any ordinary inert solvent can be used, such as water, ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, ketones such as acetone and methyl ethyl ketone, Acetonitrile, propionitrile and the like are advantageously used. The ratio of compound (2) and the above-mentioned halide to be used is not particularly limited and may be appropriately selected from a wide range, but usually the latter is at least equivalent to 2 times the former, preferably equivalent to 1. , 5 times the molar maximum. The reaction temperature for the above reaction is usually -30
It is preferable to set the temperature to about 80'C.

The elimination reaction of the protecting group can be carried out using a suitable catalyst commonly used in ordinary acid hydrolysis reactions, such as inorganic acids such as hydrochloric acid, 5Iit acid, and perchloric acid, lower alkanoic acids such as formic acid, acetic acid, and propionic acid, It is usually carried out in a suitable solvent using a suitable amount of an organic acid such as benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, organic sulfonic acid such as 4-methylbenzenesulfonic acid. As a solvent, common inert solvents such as water, lower alcohols such as methanol, ethanol, and impropatol, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, tetrahydrofuran, and dioxane, bempine,
Aromatic hydrocarbons such as toluene, xylene, and 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 usually O
-100'C1, preferably about 80°C, and the reaction is generally completed in about 3 minutes to 20 hours.

In addition, the acid used is usually in a catalytic amount to an excessive amount,
Preferably, the amount is about an excessive amount.

The target compounds obtained in each of the above steps are easily isolated and purified from the reaction mixture by conventional separation means. Examples of such separation means include solvent extraction, solvent dilution, recrystallization, column chromatography, and preparative thin layer chromatography.

Incidentally, the present invention naturally includes optical isomers and stereoisomers of D, 1 and d, 9.

Inner style Reference examples and working examples are listed below.

Reference Example 1 1. Synthesis of 2-0-isopropylidene-3,5-di-O-mesylxylofuranose 64 Cl of xylose monoacetonide and 81.6 g of triethylamine were dissolved in 320 m of methylene chloride [2].
The mixture was cooled in an ice-methanol bath, and a solution of 77 g of methanesulfonyl chloride in 120 methylene chloride was added dropwise (below 10° C.) for about 1 hour. After dropping, remove the bath and
Continue stirring at air temperature for 1.5 hours. After the reaction was completed, water was added, the methylene chloride layer was separated, and washed with a 5% aqueous sulfuric acid solution.
After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the target compound 106°2Cl (91%) as an oil.

NMR spectrum (CDCQ3, δppm>5°96
(1H1d, J=3.8Hz) 5, 07 (1H
, d, J=3. 6Hz>4.80 (1H, d,
J=3.8Hz) 4.7-4.5 (1H, m) 4, 40 (2H, m>, 3.10
(3t1, S)3, 08 (3H,s)
, '1. 50 (3H,s)1.32 (3t-
(,s) Reference Example 2 Synthesis of 1,2-di-0-acetyl-3,5-di-methylxylofuranose 1,2-0-isopropylidene-3,5-di-O obtained in Reference Example 1 above -Mesyl xylofuranose (106q) is dissolved in 300 mQ of acetic acid and 100 mQ of acetic anhydride, and 90 mQ of sulfuric acid is added dropwise over water cooling. After the dropwise addition, the reaction solution was left at air temperature overnight, poured into 1Q of water and 500ml of brine, and extracted with 400ml of ethyl acetate. The extract was washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 66 g (55%) of the target compound as an oil.

NMR spectrum (CDCQ3, δppm>6.45
(0,5H, d, J=4Hz)6.20 (0,5H
, s > 5.5-4.0 (5H, m) 3.3-3.0 (6H, m > 2.2-1.9 (6H, m) From the results of the above NMR spectrum, the above obtained The compound was a mixture of α and β isomers.

Reference Example 3 Synthesis of 1.2-di-0-acetyl-3,5-di〇-tosylxylofuranose 1.2-0-isopropylidene-3,5-di〇-tosylxylofuranose 7, Oq to acetic acid 98- and dissolved in 11.2 mf2 of acetic anhydride, and 7.0 mf of sulfuric acid was added dropwise over water-cooled solution. After dropping, leave it at air temperature overnight, and pour the reaction solution into 500ml of water.
12 and extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate, dried over anhydrous 11 magnesium, and the solvent was distilled off under reduced pressure to obtain 7.0 g (92%) of the target compound as an oily substance.

NMR spectrum (CDCQ3.δppm) 7.9-7
．． 7 (5H, m> 7, 5~7.3 (4 to 1, m) 6.20
(0,5H, d, J=6Hz) 6, 0 (0,5t(,S) 5.3~5.1 (1,5H, m> 4.92 <0.5H, dd, J=3 .6Hz)4.5
5 (1H,m) 4.2~4.0 (3H,m) 2.50 (3H,s) 2.48 (3H1s) 2.2~2.0 (6H,m> From the above NMR spectrum results The compound obtained above was a mixture of α and β isomers.

Example 1 2'-〇-acetyl-3', 5'-di-O-mesyl-5-fluorouridine and 5'-〇-tosyyl-2,2
'-Anhi bite-1-β-D-arabinofuranosilu 5
-Synthesis of fluorouracil 1,2-di-0-acetyl-3 obtained in Reference Example 2 above
, 5-di-O-mesylxylofuranose 66Q was dissolved in 120 mQ of acetonitrile, and 47 g of 2゜4-bistrimethylsilyloxy-5-fluoropyrimidine was added.
Add 20 mQ of anhydrous tin tetrachloride while cooling on ice. After stirring for 4 hours at ￥ temperature, the reaction solution was poured into water and extracted with ethyl acetate.

The extract was washed with aqueous sodium bicarbonate, and the solvent was distilled off to obtain 2'-0-acetyl-3',5'-di-O-mesyl-5-fluorouridine as an oily substance.

Dissolve this oily substance in 200 mQ of methanol, add 24 g of sodium methylate, and stir for about 2 Q minutes.
5'-0-tosyl-2,2'-anhydro-1-β-D
-Arabinofuranosil-5-fluorouracil precipitates as crystals. This was washed with acetone to remove the compound.
2g (59%) obtained.

NMR spectrum (d6DMSO, δpp
m>8, 33 (1t(, d, J=4.8H
z) 6.33 (1H, d, J=5.6Hz)5,
33 (1t(,d, J=5.6t1z
)4.5~4.3 (2H, m) 4.25 (1H, dd, J=3.8.13.5H2) 4.05 (1H, dd, J=7.5.13.51 (Z
) 3.13 (3H,s> Example 2 Synthesis of 2'-〇-acetyl-3',5'-di〇-tosy-5-fluorouridine 1,2-di-O-acetyl-3 obtained in Reference Example 3 above
, 7 g of 5-di-o-tosylxylofuranose was dissolved in 50 g of acetonitrile, 3.59 g of 2,4-bistrimethylsilyloxy-5-fluoropyrimidine was added, and 3.4 g of anhydrous tin tetrachloride was added under ice cooling. After stirring at air temperature for 4 hours, the reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with aqueous sodium bicarbonate, drying with anhydrous magnesium sulfate,
When the solvent is distilled off, 2'-0-acetyl-3' is obtained.

5'-G〇-tosyl-5-fluorouridine 6.6g
(83%) is obtained as an oil, which crystallizes after a few days.

NMR spectrum (d s DMSO, δpp
m>7.9~7.7 (5H, m) 7.6~7.4 (4H, m) 5.82 (1H, dd, J=#, 5.4.6Hz> 5.35 (1H, t, J=4.6l-1z)5.25
(1H, t, J=4.6Hz) 4.55 (IH, m
> 4.32 (1H, dd, J=8.12H2) 4.20
(1)-1, dd, J=4, 12Hz)2
．． 4 (6HXs) '1.90 (3H,S) Example 3 5'-0-tosyl-2,2' -anhydro-1-β-
Synthesis of D-arabinofuranosyl-5-fluorouracil 2'-〇-acetyl-3' obtained in Example 2 above
, 5'-di-0-tosyl-5-fluorouridine 12
．． Suspend 2g in 120ml of anhydrous methanol, add 3.20ml of sodium methylate, and leave at air temperature.
The whole solidifies within about 30 minutes.

This was collected for 1 month, washed with acetone, and 5'-0-tosyl-2,2'-anhydro-1-β-D-arabinofuranosyl-5-fluorouracil 6°4Q (80%
).

NMR spectrum (d s DMSO, δpp
m>8. 20 (1H, d, J=4.
2 t1z) 7.65 (2H, d), 7.42 (
2+-1, d>6.25 (1H, d, J=5°4Hz
>5.24 (1H, d, J=5.4Hz>4.30
(2HSbrs) 4.13 (IH, dd, J=4.11Hz>3.70
(1H, dd, J-8,111-(Z)2.40
(3H,s> Example 4 Synthesis of 2'-deoxy-2'-bromo-3'-〇-acetyl-5'-mesyl-5-fluorouridine 2,2'-anhydro-2 given by 1 in Example 1 above ′
-deoxy-5'-〇-mesyl-5-fluorouridine 1.4 g with 1 heel of acetyl bromide and 14 acetonitrile
Boil for 2 hours in m1. After adding water, extract with ethyl acetate. After washing with sodium bicarbonate solution, drying over anhydrous magnesium sulfate and distilling off the solvent, 1.0 g (52%) of 2'-deoxy-2'-bromo-3'-〇-acetyl-5'-mesyl-5-fluorouridine was obtained. is obtained as an oily substance,
This is recrystallized from methanol.

NMR spectrum (CDCQ3.δppm>7.65
(1H, d, J=5Hz> 6.21 (1H, dd, J-1, 2, 6, 6Hz> 5.22 (IH, dd, J-4, 2, 5, 4 to I Z
) 4.7~4.3 (4H, m> 3.12 (3)-1, s), 2.17 (3H, s)
Example 5 Synthesis of 2'-deoxy-2'-iodo-3'-〇-acetyl-5'-〇-mesyl-5-fluorouridine 5'-0-tosyl-2゜2' obtained in Example 1 above
-Anhydro-1-β-D-arabinofuranosyl-5-
9.6 g of fluorouracil, 6.0 g of sodium iodide and 34 mQ of acetyl chloride were added to 50 n+1 of acetonitrile.
Reflux in 2 ml for 1 hour. After adding water to the reaction solution, it is extracted with ethyl acetate. After washing with aqueous sodium bicarbonate and drying over anhydrous magnesium sulfate, the solvent was distilled off to give 2'-deoxy-2'
-Iodo-3'-〇-acetyl-5'-〇-methyl-5
- Fluorouridine is obtained as an oil which is recrystallized from methanol.

NMR spectrum (d s DMSO, δpp
m) 8.00 (1H, d, J=6.8Hz) 6, 17
(1H, dd, J=1.5.8.0Hz) 5.10 (1H, ddX J=1.8.6.01-
I Z ) 4.76 (1H, ddS J=6.0.8.0H
z> 4.42 (3H, m> , 3.22 (3H, s>2
．． 13 (3H,s> Example 6 Synthesis of 2'-deoxy-2'-bromo-3'-〇-acetyl-5'-0-tosyl-5-fluorouridine 5'-0- obtained in Example 3 above Toshiru-2゜2'
-Anhydro-1-β-D-arabinofuranosyl-5-
Fluorouracil 28.9 CI to acetonitrile 145
Suspend in a spoon, add 17ml of acetyl bromide, and add 3
Reflux for 0 minutes. Then, after adding water, the mixture is extracted with ethyl acetate. After washing with sodium bicarbonate solution, drying over anhydrous magnesium sulfate and distilling off the solvent, 32.0 g of 2'-deoxy-2'-bromo-3'-0-acetyl-5'-0-tosyl-5-fluorouridine was obtained. (85%) is obtained as an oil, which is recrystallized from methanol.

NMR spectrum (d 6D MSO, δppm>
7.89 (1H, d, J-6Hz) 7-80 (2H, d), 7. 45
(2 t1, d) 6°04 (1H, d, J=7
．． 2Hz) 5.12 (IH, m> 4.93 (1H, t, J=5.4Hz>4.5~4.
2 (3H,m>2.40 (3H,s>,2゜08 (3H,s>Example 7 2'-deoxy-2'-iodo-3'-〇-acetyl-5'-0-tosyl-5 -Synthesis of fluorouridine 5'-〇-tosyl-2゜2' obtained in Example 3 above
-Anhydro-1-β-D-arabinofuranosyl-5-
Fluorouracil 3.98CI to acetyl chloride 51t2
and 50ml of acetonitrile with 1.70CI of sodium iodide? It refluxes inside. Thereafter, in the same manner as in Example 6, 2'-deoxy-2'-iodo-3'-0-acetyl-5'-〇-tosy-5-fluorouridine 4.5
Obtain 5 g (80%).

NMR spectrum (ds DMSO, δppm>7.
85 (1H, d-1J=6Hz) 7°79 (2H,
d), 7.45 (2H, d) 6.10 (1H, dd
, J=1.5.8. ○Hz＞4.96 (1H, dd, J-2,0,6,0Hz＞4.70 (IH, dd, J=7.6.8.0Hz) 4゜4~4.2 (3H, m >2.40 (3H,s), 2.10 (3H1s>Example 8 2'-deoxy-3'-〇-acetyl-5'-o-tosy-5-fluorouridine and 2'-deoxy-5'-
Synthesis of 〇-tosylated-5-fluorouridine 5.7 g of 2'-deoxy-2'-iodo-3'-〇-acetyl-5'-〇-tosylated-5-fluorouridine obtained in Example 7 was added to methanol at a rate of 100%. suspended in
Catalytic reduction using 5% palladium-barium sulfate 570mc+ as a catalyst in the presence of 1.7q sodium acetate (1
atmospheric pressure, room temperature, 4 hours). A catalyst? 2'-deoxy-3'-〇-acetyl-5'-〇-tosy-5-fluorouridine was obtained, and without isolating it, 10% sodium hydroxide was added to the furnace solution and allowed to stand. Let it precipitate 2
5.2 g (approximately 65%) of '-deoxy-5'-0-tosyl-5-fluorouridine are obtained.

NMR spectrum (ds DMSO, δppm)7.
78 (2H, m), 7.48 (2H, m>6.1
0 ('IH, m), 4.40-4.10 (3H, m), 3.87 (1H, m), 2.40 (3H, s)2
．． 30-2. ．． O(2H,m> Example 9 5'-0-tosyl-3'-〇-benzyru2゜2'-
Synthesis of anhydro-1-β-D-arabinofuranosyl-5-fluorouracil 5'-0-tosyl-2゜2' obtained in Example 3 above
-Anhydro-1-β-D-arabinofuranosyl-5-
Fluorouracil 3,98Cl and benzyl bromide 2.0
Suspend CI in 30mf2 of dimethylformamide, 1.
Add 2 equivalents of sodium hydride (0,3Q). When stirred at room temperature for 30 minutes, a precipitate appears again after dissolution. A 5% aqueous sodium hydroxide solution was added to the mixture, washed with water, dried and 5'-〇-tosyl-3'-〇-benzyl-2,2'-anhydro-1-β-D-arabinofuranosyl. 4.90 of 5-fluorouracil is obtained.

NMR spectrum (d s DMSO, δpp
m) 8.20 (IH, d1J=5Hz) 7.64 (2H, d) 7.42~7.33 (7H,, m> 6°31 (1H, d, J=5.4Hz>5, 50
(1H, d, J=5.4 t1z)4.
60 (2H, d>, 4.52 (1H, m) 4.27
(1H, d, J=1.5Hz) 4.14 (IH, d
d, J=4.14Hz) 3.76 (IH, dd, J=
8.14Hz>2.38 (3H,s> Example 10 Synthesis of 2'-deoxy-2'-bromo-3'-〇-acetyl-5'-0-tosyl-5-fluorouridine obtained in Example 3 above. 2,2'-anhydro-2'-
Deoxy-5′-0-tosyl-5-fluorouridine 7, Op was suspended in HBr-saturated acetic acid at a threshold of 35 and
Heat to 85°C for approximately 50 minutes.

The reaction solution was poured into saturated sodium bicarbonate solution, extracted with methylene chloride,
After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the oily substance 2'-deoxy-2'-bromo-3'-〇-acetyl-5'-0-tosyl-5-fluorouridine was extracted with 8
．． 0g (87%) obtained.

This is further purified using a silica gel column to obtain the above compound as crystals.

The NMR spectrum of the compound was consistent with that of Example 6 above.

Example 11 Synthesis of 2'-deoxy-2'-iodo-3'-〇-benzyl-5'-〇-tosyl-5-fluorouridine 5'-〇-tosyl-3'-〇-benzyl obtained in the above example 1 g of 2,2'-anhydro-1-β-D-arabinofuranosyl-5-fluorouracil was suspended in 10 ml of acetonitrile, 0.4 C1 of sodium iodide and 1 mQ of trimethylchlorosilane were added, and the mixture was refluxed for about 1 hour. do. After the reaction, water is added and extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium bicarbonate solution and a small amount of an aqueous solution of sodium sulfite, and then dried. When the solvent is distilled off, TL
C-hihabo single spot 2'-deoxy-2'-
Iodo-3'-〇-benzyru-5'-0-tosyl-5
- 500 mg (40%) of fluorouridine are obtained as an amorphous powder.

NMR spectrum (CDC93, δppm 7.78
(2H, m> 7.51 (1H, d, J=6Hz> 7.38~7.25 (7H, m) 6.28 (IH, Q, J=1.2.5.2H2) 4.70 ~4.21 (6HSm) 3.62 (IH, m> 2.44 (3H, s> 2 g of 2'-deoxy-2'-iodo-3'-〇-benzyl-5'-0-tosyl-5-fluorouridine obtained in Example 11 was suspended in 30 mQ of methanol, and 300 mQ of sodium acetate was added.
catalytic reduction using 5% palladium-barium sulfate as a catalyst in the presence of 1 atm, 40'C, 4 hours). The catalyst was removed, the solution was concentrated, and the resulting residue was subjected to HtJ using silica gel column chromatography to give 2'-deoxy-3'-〇-benzyl-5'-〇-tosy-5-
320n+g (21%) of fluorouridine is obtained.

NMR spectrum (CDCQ3, δppm) 9.23
(1H, bs), 7.78 (2H, m) 7.49
(1H, d, J=5Hz) 7°45~7.23 (7H,m>6.25 (1H,m) 4.53 (2H,d, J-11Hz) 4.32~4
．． 05 (4H, m> 2゜60-2.26 (4H, m> 2゜10-1.80 (1H, m> D
Synthesis of -arabinofuranosyl-5-fluorouracil 2.2' -Anhydro-1-β-D-arabinofuranosyl-5-fluorouracil 2.49 and 1 equivalent of p-toluenesulfonyl chloride (1,90C1) were combined with pyridine 30TIIQ The mixture was dissolved in water and left overnight at room temperature, and the reaction solution was poured into water and extracted with methylene chloride. 5 extracts
% sulfuric acid, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give an oily substance of 5'-〇-tosyl-2,2'-
Anhydro-1-β-D-arabinofuranosyl-5-fluorouracil 3°15C] (79%) is obtained. This is further purified using a silica gel column to obtain the above compound as crystals.

The NMR spectrum of the compound was consistent with that of Example 3 above.

Example 14 Synthesis of 2'-deoxy-3'-〇-benzyl-5'-〇-tosylated-5-fluorouridine 2'-deoxy-5'-〇-tosylated-5-fluorouridine obtained in Example 8 above4. After dissolving Oq in 100 mQ of dimethylformamide and adding 2.59 mQ of silver oxide, 2.0 mQ of benzyl bromide was added.
Add CI. After stirring overnight at room temperature and removing insoluble matter, the solvent was distilled off to give an oily substance of 2'-deoxy-3'-〇-.
About 2 g (about 40%) of benzy-5'-0-tosyl-5-fluorouridine is obtained. This is further purified using a silica gel column to obtain the above compound as crystals.

Example 15 Synthesis of 2'-deoxy-3'-〇-benzyl-5'-〇-tosy-5-fluorouridine 2'-deoxy-2'
-Iodo-3'-〇-Benzyl-5' -0-Tosyl-
5-Fluorouridine 6.1'? Q was suspended in 50 methanol of ethanol, and 50 m of α,α'-azobisisobutyronitrile and 2.0 n12 of tributyltin chloride were added and heated.

Add dimethylformamide until homogeneous.

Add 500m of sodium borohydride for 10 minutes,
After refluxing for 10 minutes and cooling, 5% RJM acid was added and extracted with methylene chloride. After drying with magnesium sulfate, the solvent is distilled off. The residue was purified by silica gel column chromatography, and the 2'
3.52 q (72%) of -deoxy-3'-〇-benzy-5'-〇-tosy-5-fluorouridine are obtained.

The NMR spectrum of this compound matched that of the compound obtained in Example 12 above.

Example 16 Synthesis of 2'-deoxy-5'-0-tosyl-5-fluorouridine 2'-deoxy-2'-iodo-3'-〇-acetyl-5'-0-tosyl-5-fluorouridine 250m(
1 is suspended in ethanol 3IT12, and about 10 m
q of α,α'-azobisisobutyronitrile and 0.05 ml of tributyltin chloride are added and refluxed. When it becomes uniformly clear in about 10 minutes, add 150 ml of sodium borohydride.
Add mq as is at once.

After 10 minutes, stop heating and cool to room temperature. Add 5% aqueous sulfuric acid solution and extract with methylene chloride. After drying with magnesium sulfate, the solvent was distilled off and the resulting residue was dissolved in ethanol 5
Dissolve in mG, add 0.5 - of aqueous ammonia and stir at room temperature to 1.
Leave it overnight. When acidified with hydrochloric acid and further left overnight, crystals precipitate. Add this to i number and get 2'-deoxy-5'
-0-tosyl-5-fluorouridine 120 mg (71
%).

The NMR spectrum of this compound matched that of the compound obtained in Example 8 above.

Reference Example 4 Synthesis of 2'-deoxy-3'-〇-benzyl-5'-〇-acetyl-5-fluorouridine 2'-deoxy-3'-〇-benzyl-5'- obtained in Example 12 above
2.45 C] of 0-tosyl-5-fluorouridine is dissolved in 100 mQ of dimethylformamide and 5 equivalents of sodium acetate (2.05 g) are added. After refluxing for 3 hours, the solvent was distilled off to give an oily substance of 2'-deoxy-3'-〇-benzyl-5'-〇-acetyl-5-fluorouridine 2.
．． Obtain 3 g (61%). This is further purified using a silica gel column.

Reference Example 5 Synthesis of 2'-deoxy-5'-〇-acetyl-5-fluorouridine 4.0 CI of 2'-deoxy-5'-〇-tosyl-5-fluorouridine obtained in Example 8 above was added to 150 m2 of dimethylformamide. Dissolve and add 5 parts sodium acetate (4,1 parts). After refluxing for 3 hours, the solvent was distilled off to obtain 1.63 g (57%) of 2'-deoxy-5'-〇-acetyl-5-fluorouridine as an oil. This is further purified using a silica gel column.

Reference Example 6 Synthesis of 2'-deoxy-3'-〇-benzyl-5'-〇-acetyl-5-fluorouridine 2'-deoxy-5'-〇-acetyl-5-fluorouridine 2 obtained in Example 6 above .889 in dimethylformamide 50mQ
After adding 2.4 g of silver oxide, dissolve benzyl bromide 1
．． Add 8g. After stirring overnight at room temperature and removing insoluble matter, the solvent was distilled off to give an oily substance of 2'-deoxy-3'-
1.5C1 (40%) of 〇-benzy-5'-〇-acetyl-5-fluorouridine is obtained. This is further purified using a silica gel column to obtain the above compound as crystals.

Reference Example 7 Synthesis of 2'-deoxy-3'-〇-benzyl-5-fluorouridine 2'-deoxy-3' obtained in Reference Examples 4 and 6 above
-〇-Benzyl-5'-〇-acetyl-5-fluorouridine 3.80% in 10% sodium hydroxide solution 5mf2
When added to 50 mQ of methanol and allowed to stand, 363 g of 2'-deoxy-3'-0-benzyl-5-fluorouridine was obtained.

Reference example 8 5'-〇-acetyl-2,2'-anhydro-1-β-
Synthesis of D-arabinofuranosyl-5-fluorouracil 2. 2.44 g of 2'-anhydro-1-β-D-arabinofuranosyl-5-fluorouracil was dissolved in 20 times of pyridine, and 1.020 g of acetic anhydride was added. After standing overnight at room temperature, the reaction solution was diluted with water and extracted with methylene chloride. The extract was washed with dilute sulfuric acid, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give an oily substance of 5'-〇-acetyl-2゜2'-anhydro-1-β-D-arabino7lanosyl-5- 1.77 g (62%) of fluorouracil are obtained. This is further purified using a silica gel column to obtain the above compound as crystals.

Reference example 9 5'-〇-acetyl-3'-〇-benzyl-2゜2'-
Synthesis of anhydro-1-β-D-arabinofuranosyl-5-fluorouracil 5'-〇-acetyl-2.2' obtained in Reference Example 8 above
-Anhydro-1-β-D-arabinoflazzi-5-
Fluorouracil 2.860 to dimethylformamide 5
Dissolve in 0 mQ, add 2.5 g of silver oxide, and then add 1°8 g of benzyl bromide. After stirring overnight at room temperature and removing insoluble matter, the solvent was distilled off to give an oily substance of 5'-〇-7cetyl-3'-〇-benzyl-2,2'-anhydro-1-
β-D-arabinofuranosyl-5-fluorouracil 1
．． 7a (45%). This is further purified using a silica gel column to obtain the above compound as crystals.

Reference Example 10 Synthesis of 2'-deoxy-2'-iodo-3'-〇-benzyl-5'-〇-acetyl-5-fluorouridine 5'-0-acetyl-3'- obtained in the above reference example
〇-benzyru-2,2'-anhydro-1-β-D-
Arabinofuranosil-5-fluorouracil 3.76C
1 is suspended in 100 ml of acetonitrile, 1.5 g of sodium iodide and 3 mQ of acetyl chloride are added to this, and about 1
Time passes away. After the reaction, water is added and extracted with ethyl acetate. After washing the extract, it was dried over magnesium sulfate and the solvent was distilled off to give an oily substance of 2'-deoxy-2'-iodo-3'-〇-benzyl-5'-〇-acetyl-5-fluorouridine4. Obtain 03C7 (80%).

Reference Example 11 Synthesis of 2'-deoxy-3'-〇-benzyl-5'-〇-acetyl-5-fluorouridine 2'-deoxy-2'-iodo-3'-〇-benzyl obtained in Reference Example 10 above 5'-0-acetyl-5-fluorouridine 5
．． 04C] was suspended in 50 m2 of methanol and 500 m2 of 5% palladium-barium sulfate was added in the presence of sodium acetate.
Catalytic reduction using 111CI as a catalyst (1 atm, room temperature,
4 hours). The catalyst was removed, and the 2' solution was concentrated to obtain crude 2'
-deoxy-3'-〇-benzyl-5'-〇-acetyl-5-fluorouridine is obtained. This was separated using a silica gel column and 2'-deoxy-3'-O-benzyl-5
'-〇-acetyl-5-fluorouridine 390ma (
10%).

Reference example 12 5'-〇-acetyl-2,2'-anhydro-1-β-
Synthesis of D-arabinofuranosyl-5-fluorouracil 5'-〇-tosyl-2゜2' obtained in Example 3 above
-Anhydro-1-β-D-arabinofuranosyl-5-
4.0 g of fluorouracil and 10 g of dimethylformamide
0 m[2] and add 4.1 g of sodium acetate.

After refluxing for about 3 hours, the solvent was distilled off to give an oily substance of 5'-〇-acetyl-2,2'-anhydro-1-β-D-arabinofuranosyl-5-fluorouracil (1.820
64%). This is further purified using a silica gel column to obtain the above compound as crystals.

Reference example 13 5'-〇-acetyl-3'-〇-benzyl-2゜2'-
Synthesis of anhydro-1-β-D-arabinofuranosyl-5-fluorouracil 5'-0-tosyl-3'-〇-benzyl-2,2'-anhydro-1-β-D- obtained in Example 9 above 4.9 g of arabinofuranosil-5-fluorouracil is dissolved in 100 mQ of dimethylformamide, and 4.1 g of sodium acetate is added. After refluxing for about 3 hours, the solvent was distilled off,
Oily substance 5'-〇-acetyl-3'-〇-benzyl-
2,2'-ambitro-1-β-D-arabinofuranosyl-5-fluorouracil 2.17Ω (58%) is obtained. This is further purified using a silica gel column to obtain the above compound as crystals.

Reference Example 14 Synthesis of 2'-deoxy-3'-〇-benzyl-5-fluorouridine 2'-deoxy-2'-iodo-3'-〇-benzyl-5'-〇-acetyl-5-fluorouridine 5.04 g
was suspended in 50 mf2 of ethanol, and 50 mg of α,α'-azobisinbutyronitrile and 1.0 mQ of tributyltin chloride were added thereto and refluxed. When the mixture becomes homogeneous and clear, 300 mg of sodium borohydride is added at once. Continue refluxing for 10 minutes and cool. Add 5% aqueous sulfuric acid solution and extract with methylene chloride. After drying with magnesium FtL acid, the solvent was distilled off, and the resulting residue was dissolved in methanol 1
Dissolve in 0mf2, add 2wQ of aqueous ammonia, and leave at room temperature overnight. The mixture was acidified with hydrochloric acid, the solvent was distilled off, and the residue was recrystallized from isopropyl alcohol to give 2'-deoxy-3'-〇-benzy-5-fluorouridine 2.18
g (65%).

(that's all)

Claims (1)

[Claims] (1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is a group▲There are mathematical formulas, chemical formulas, tables, etc.▼,
One of R^2 and R^3 is a hydrogen atom, the other is a hydrogen atom,
Halogen atom or acyloxy group, R^4 is hydrogen atom or group -OSO_2R^6 (R^6 is lower alkyl group or aryl group), R^5 is hydrogen atom, hydroxyl group, acyloxy group, lower alkyl group on phenyl ring , a phenyl lower alkoxy group which may have a substituent selected from the group consisting of a lower alkoxy group, a halogen atom and a carboxyl group, a phenyl lower alkoxy group having a lower alkylene dioxy group or a phenyl group as a substituent, or a naphthyl lower alkoxy group. Indicates the group. However, R^1 and R^2 may be combined with each other to represent a group ▲a mathematical formula, a chemical formula, a table, etc.▼. ] 5-fluorouridine derivative represented by these.