JPH0686448B2 - Process for producing 2 ', 3'-dideoxycytidine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Object] The present invention relates to an excellent method for producing a 2 ′, 3′-dideoxycytidine derivative useful as a therapeutic agent for AIDS.

<Prior Art> Conventionally, 2 ', 3'-dideoxycytidine derivative, as a method for synthesizing the ribonucleosides include, Horubitsutsu et al. (Journal Of Oganitsuku Chemistry, 32, 817 (1969)) is known However, since a by-product is formed in the final reduction step, it is difficult to isolate the product and it is not suitable for large-scale synthesis.

<Problems to be Solved by the Present Invention> The inventors of the present invention have used 2 ', which uses ribonucleosides as a raw material.
As a result of intensive research over many years on the synthesis of the 3'-dideoxycytidine derivative, the method of the present invention was found to be excellent in terms of yield and isolation, and the present invention was completed. did.

〔Constitution〕

The method for producing the 2 ', 3'-dideoxycytidine derivative of the present invention is as shown in the following formula: (In the formula, R ¹ and R ² are the same or different and each represents an optionally protected hydroxyl group or a substituted hydroxyl group, X is a halogen atom, and Y is an optionally protected amino group or a substituted hydroxyl group. A compound having the formula (I) is reacted with a compound having the formula YH (wherein Y has the same meaning as defined above), and if desired, the protecting group is removed. Or a process for producing a 2 ', 3'-dideoxycytidine derivative represented by the formula (II) or as shown in the following formula: (In the formula, R ¹ , R ² and Y have the same meanings as described above.) Formula (II
Reacting the compound having I) with a halogenating reagent,
The product is then isolated with or without isolation of the formula YH
A 2 ′, 3′-dideoxycytidine derivative represented by the formula (II), which comprises reacting with a compound having the formula (wherein Y has the same meaning as defined above) and, if desired, removing a protecting group. Is a manufacturing method.

In the above formula, the "halogen atom" defined by X represents fluorine, chlorine, bromine or iodine.

“An optionally protected hydroxyl group” defined by R ¹ and R ²
The protecting group of represents a protecting group in the reaction, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, palmitoyl, alkylcarbonyl group such as stearoyl, chloroacetyl, Dichloroacetyl, trichloroacetyl,
Aliphatic acyl groups such as halogenated alkylcarbonyl groups such as trifluoroacetyl, lower alkoxyalkylcarbonyl groups such as tomexacetyl, unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl; Arylcarbonyl groups such as benzoyl, α-naphthoyl, β-naphthoyl, halogenated arylcarbonyl groups such as 2-bromobenzoyl, 4-chlorobenzoyl, lower such as 2,4,6-trimethylbenzoyl, 4-toluoyl Alkylated arylcarbonyl group, lower alkoxylated arylcarbonyl group such as 4-anisoyl, nitrated arylcarbonyl group such as 4-nitrobenzoyl and 2-nitrobenzoyl, lower alkoxycarbonyl such as 2- (methoxycarbonyl) benzoyl Arylcarbonyl group, 4-phenylben Aromatic acyl groups such as arylated arylcarbonyl group such as benzoyl; tetrahydropyran-2-yl, 3-bromo-tetrahydropyran-2
A tetrahydropyranyl or tetrahydrothiopyranyl group such as yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran-2-yl, tetrahydro A tetrahydrofuranyl or tetrahydrothiofuranyl group such as thiofuran-2-yl; a trihydrofuranyl group such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl Silyl such as lower alkylsilyl group, triphenylalkylsilyl group substituted with 1 or 2 aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, and phenyldiisopropylsilyl. Group; methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, iso-propoxymethyl, butoxymethyl, t-
Lower alkoxymethyl group such as butoxymethyl, lower alkoxylated lower alkoxymethyl group such as 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,
Alkoxymethyl groups such as halogenated lower alkoxymethyl such as bis (2-chloroethoxy) methyl; lower alkoxylated ethyl such as 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1- (isopropoxy) ethyl Base, 2,
Halogenated ethyl group such as 2,2-trichloroethyl, 2-
A substituted ethyl group such as an arylzenylated ethyl group such as (phenylenyl) ethyl; benzyl, phenethyl,
3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α
-Lower alkyl groups substituted with 1 to 3 aryl groups such as naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,
4,5-Trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-
Lower alkyl such as nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl, piperonyl, lower alkoxy, nitro, halogen, cyano group An aralkyl group such as a lower alkyl group substituted by 1 to 3 aryl groups in which the aryl ring is substituted with; a lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, 2, Alkoxycarbonyl groups such as halogen such as 2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl or lower alkoxycarbonyl groups substituted with tri-lower alkylsilyl groups; alkenyloxy such as vinyloxycarbonyl and allyloxycarbonyl Rubonyl group; 1 to 2 lower alkoxy or nitro groups such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl And a protecting group in the reaction such as an aralkyloxycarbonyl group in which the aryl ring may be substituted may be mentioned, and an aliphatic acyl group and an aromatic acyl group are preferable.

Examples of the substituent of the “substituted hydroxyl group” defined by R ¹ and R ² include carbon such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl and hexyl. Number 1 to 6 lower alkyl group or phenyl, 4-tolyl, 4-methoxyphenyl, 4-
Mention may be made of lower alkyl such as chlorophenyl, α- or β-naphthyl, lower alkoxy, aryl groups optionally substituted by halogen atoms.

The "optionally protected amino group" defined by Y is a group in which the following protecting group may protect one or two amino groups, and the protecting group is usually an amino group. There is no limitation as long as it is used as a protecting group, but preferably, for example, the above-mentioned aliphatic acyl group; the above-mentioned aromatic acyl group; the above-mentioned alkoxycarbonyl group; the above-mentioned alkenyloxycarbonyl group; An aralkyloxycarbonyl group in which the aryl ring may be substituted with a lower alkoxy or nitro group; the silyl group; the aralkyl group; or N, N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene,
Examples thereof include a substituted methylene group forming a Schiff base such as salicylidene, 5-chlorosalicylidene, diphenylmethylene and (5-chloro-2-hydroxyphenyl) phenylmethylene, and more preferably It is an aralkyl group.

The “substituted amino group” defined by Y means a group in which the following substituent substitutes 1 or 2 amino groups, and examples of the substituent include the above lower alkyl group and the above lower alkoxy. Groups, lower alkoxylated lower alkoxy groups such as 2-methoxyethoxy, halogenated lower alkoxy groups such as 2,2,2-trichloroethoxy, and other alkoxy groups;
Benzyloxy, phenethyloxy, 3-phenylpropoxy, α-naphthylmethoxy, β-naphthylmethoxy,
Lower alkoxy group substituted with 1 to 3 aryl groups such as diphenylmethoxy, triphenylmethoxy, α-naphthyldiphenylmethoxy, 9-anthrylmethoxy, 4-methylbenzyloxy, 2,4,6- Trimethylbenzyloxy, 3,4,5-trimethylbenzyloxy, 4-methoxybenzyloxy, 4-methoxyphenyldiphenylmethoxy, 2-nitrobenzyloxy, 4-nitrobenzyloxy, 4-chlorobenzyloxy, 4-bromo 1 to 1 in which the aryl ring is substituted with lower alkyl such as benzyloxy, 4-cyanobenzyloxy, 4-cyanobenzyldiphenylmethoxy, bis (2-nitrophenyl) methoxy, piperonyloxy, lower alkoxy, nitro, halogen, cyano group Aralkyloxy groups such as lower alkoxy groups substituted with 3 aryl groups; hydroxy ; Hydroxymethyl, 2-hydroxyethyl, hydroxy-substituted lower alkyl groups such as 3-hydroxypropyl; 2-aminoethyl, 3-
Examples thereof include amino-substituted alkyl groups such as aminopropyl and the above-mentioned "lower alkyl, lower alkoxy, aryl group optionally substituted by halogen", and lower alkyl groups are preferable.

The "halogenating reagent" is, for example, sulfenyl chloride, sulfenyl bromide, sulfenyl halides such as sulfenyl iodide, sulfonyl chloride, sulfonyl bromide, sulfonyl halides such as sulfonyl iodide, Phosphorus trihalides such as phosphorus trichloride, phosphorus tribromide, phosphorus triiodide, phosphorus pentahalides such as phosphorus pentachloride, phosphorus pentabromide, phosphorus pentaiodide or phosphorus oxychloride, oxyodor Phosphorus oxyhalides such as phosphorus oxychloride and phosphorus oxyiodide can be mentioned, and phosphorus oxyhalides are preferable. In the first step, the compound (I) is reacted with an amine compound in a solvent and, if desired, the amino-protecting group and / or the hydroxyl-protecting group is removed, so that the halogen atom at the 4-position is converted to the formula Y A compound substituted with a group having
This is the process of manufacturing I).

The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but preferably chloroform, halogenated hydrocarbons such as dichloromethane, lower alcohols such as methanol and ethanol, N, N-dimethylformamide, N,
Amides such as N-dimethylacetamide or polar solvents such as dimethylsulfoxide, hexamethylphosphoramide, triethylphosphate are used.

The reaction temperature will differ depending on the starting materials, solvent and reagents used, but is usually −10 ° C. to 100 ° C., and preferably 0 ° C. to 50 ° C.

The reaction time will differ depending on the starting materials, solvent, reagents and reaction time used, but is usually 1 hour to 4 days, and preferably 4
Time to 3 days.

The desired step, the reaction of removing the protecting group, varies depending on its type, but is generally carried out as follows by a method well known in the art.

When the protecting group for the hydroxyl group and / or amino group is a silyl group, the protecting group can be removed by treating with a compound that produces a fluorine anion such as tetrabutylammonium fluoride. The solvent used is not particularly limited, but ethers such as tetrahydrofuran and dioxane are preferable. The reaction is preferably carried out by treating at around room temperature for 10 to 18 hours.

When the protective group for the hydroxyl group and / or the amino group is an aralkyloxycarbonyl group or an aralkyl group, it can be removed by bringing it into contact with a reducing agent. For example, catalytic reduction is carried out at room temperature using a catalyst such as palladium carbon or platinum, or an alkali metal sulfide such as sodium sulfide or potassium sulfide is used. The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, or acetic acid. Fatty acids such as and mixed solvents of these organic solvents and water are preferred. The reaction temperature is usually from 0 ° C. to room temperature, and the reaction time is usually from 5 minutes to 12 hours, varying depending on the kinds of the raw material compounds and the reducing agent.

When the protective group for the hydroxyl group and / or the amino group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it can be removed by treatment with a base in the presence of an aqueous solvent. The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction, and water, alcohols such as methanol, ethanol and n-propanol, ethers such as tetrahydrofuran and dioxane, or these Mixed solvents are preferred. The base is not particularly limited as long as it does not affect other parts of the compound, but it is preferably an alkali metal carbonate such as sodium carbonate or potassium carbonate, sodium hydroxide or potassium hydroxide. It is carried out using an alkali metal hydroxide, an alkali metal alkoxide of alcohol used as a solvent, or concentrated ammonia-methanol. Suitable reaction conditions are to react with an alkali metal salt of the alcohol in an alcohol. Although the reaction temperature is not particularly limited, it is preferably 0 ° C. to 150 ° C. in order to suppress side reactions. The reaction time varies depending on the kind of the raw material compound and the reaction temperature, but is usually 5 minutes to 10 hours.

When the protective group for the hydroxyl group and / or the amino group is an alkoxymethyl group, a tetrahydropyranyl or a tetrahydrothiopyranyl group, a tetrahydrofuranyl or a tetrahydrothiofuranyl group or a substituted ethyl group, it is treated with an acid in a solvent. It can be removed by treatment.
The acid used is preferably hydrochloric acid, acetic acid-sulfuric acid, tosylic acid or the like. The solvent is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, tetrahydrofuran, ethers such as dioxane or a mixed solvent of these organic solvents and water is preferable. is there. Reaction temperature is usually 0 ℃ to 50 ℃
The reaction time is usually 10 minutes to 18 hours, though it varies depending on the kind of the raw material compound and the acid.

When the protective group for the hydroxyl group and / or the amino group is an alkenyloxycarbonyl group, usually, the removal reaction conditions when the protective group for the hydroxyl group is a lower aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group and Similarly, it can be eliminated by treating with a base.
In the case of allyloxycarbonyl, a method of removing it particularly using palladium and triphenylphosphine or nickel tetracarbonyl is simple and can be carried out with few side reactions.

After completion of the reaction, the target compound can be isolated from the reaction mixture by a conventional method. For example, a pure product can be obtained by purification by recrystallization, preparative thin-layer chromatography, column chromatography, or the like.

The second step is the 2 ', 3'-dideoxyuridine compound (III) produced according to the method of Honjo et al. (Chemical Pharmaceutical Brutein, 18 , 554 (1970)).
With a deoxidizing agent and a halogenating reagent in the presence or absence of a solvent, and then the product is isolated or, without isolation, is reacted with an amine compound, optionally with a first By deprotecting according to the description of the desired step, a 2 ', 3'-dideoxycytidine derivative (II)
Is a process of manufacturing.

The reaction solvent in the case of using a solvent is not particularly limited as long as it does not inhibit the reaction, but is preferably an ester such as ethyl acetate or ethyl propionate, or a halogenated carbonic acid such as dichloromethane or chloroform. It is hydrogen.

The deoxidizing agent used is not particularly limited as long as it is an organic base, but it is preferable to use aromatic tertiary amines such as diethylaniline and dimethylaniline or tri-lower alkylamines such as triethylamine. Is.

The reaction temperature will differ depending on the raw materials, the presence or absence of solvent, the type of solvent used and the halogenating reagent used, but it is usually from 30 ° C to
It is carried out at 200 ° C., preferably at the boiling point of the reaction liquid.

The reaction time varies depending on the raw materials, the presence or absence of a solvent, the type of solvent used, the halogenating reagent used and the reaction temperature, but is usually 10 minutes to 5 hours, and preferably 20 minutes to 4 hours.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1 2 ', 3'-dideoxycytidine To 26.5 ml of phosphorus oxychloride, 4.4 ml of diethylaniline was added, and the mixture was refluxed for 5 minutes and then allowed to cool. This solution was mixed with 3.0 g of 5'-o-benzoyl-2 ', 3'-dideoxyuridine and ethyl acetate
When added to a solution suspended in 6.5 ml, it immediately dissolved. Reflux 23
After the minutes, the solvent was distilled off, and 100 ml of ethyl acetate and 100 ml of ice water were added to dissolve it. The ethyl acetate layer was separated and washed twice with 100 ml of ice water. Further, after washing with 100 ml of a 5% sodium hydrogen carbonate aqueous solution containing ice water, and then washing twice with 100 ml of ice water, the ethyl acetate layer was dried over anhydrous magnesium sulfate and then removed, the solvent was distilled off, and 4-chloro-5 '-O-benzoyl-2',
3'-dideoxyuridine was obtained. The above compound was dissolved in 180 ml of dry chloroform, cooled to -10 to -15 ° C, and dried ammonia gas was passed for 1 hour. After sealing and leaving at room temperature for 3 days, the solvent was distilled off to obtain crude 5'-o-benzoyl-2 ', 3'-dideoxycytidine. This compound was further dissolved in 70 ml of dry methanol, 1.8 ml of 28% sodium methylate solution was added, and the mixture was refluxed for 10 minutes. The solvent was distilled off, the residue was dissolved in 50 ml of ethyl acetate and 50 ml of water, the aqueous layer was separated, and washed twice with 50 ml of ethyl acetate. After sequentially back-extracting each ethyl acetate layer with 30 ml of water, the aqueous layers were combined and adjusted to pH 7.0 with 1N hydrochloric acid, and then CHP20P (high-porous polymer 75 to 150 μ: manufactured by Mitsubishi Chemical Corporation) 300
It was passed through a column packed with ml and eluted with water. The portion containing the title compound was concentrated and freeze-dried to obtain 1.1 g of the title compound. (54.9%) 0.876 g when recrystallized with 60 ml of ethanol
(43.7%) was obtained. The mother liquor was further concentrated and crystallized from 10 ml of ethanol to obtain 0.17 g of second crystals,
A total of 1.046 g (52.2%) of the title compound was obtained. The properties of the target compound thus obtained were completely in agreement with those of the compound reported by Horbits et al.

Example 2 4-chloro-5'-o-benzoyl-2 ', 3'-
Dideoxyuridine 0.93 ml of phosphorus oxychloride and diethylaniline under nitrogen stream
To a mixed solution of 1.59 ml and 10 ml of ethyl acetate, 316 mg of 5'-o-benzoyl-2 ', 3'-dideoxyuridine was added, and the mixture was heated under reflux for 100 minutes. The solvent was distilled off, and ethyl acetate was added to the residue.
After adding 0 ml and 20 ml of ice water and collecting the ethyl acetate layer, dilute hydrochloric acid aqueous solution containing ice, sodium hydrogen carbonate aqueous solution containing ice,
After successively washing with 15 ml of ice water each time, the ethyl acetate layer was dried over anhydrous magnesium sulfate and then removed, and the solvent was distilled off. The residue was separated and purified by silica gel chromatography (1% methanol-
Methylene chloride solution), 250 mg (74.5%) of the title compound were obtained.

NMR spectrum (δ in CDCl ₃ ): 7.4 to 8.3 (6H, m, 6-H, phenyl), 6.21 (1H, d, J = 7.0cps, 5-H), 6.00 (1H, q, J)
= 2.6,1'-H), 4.3 to 4.7 (3H, m, 4 ', 5'-H), 1.7
~ 2.8 (4H, m, 2 ', 3'-H) Example 3 2', 3'-dideoxycytidine 250 mg of the compound of Example 2 was dissolved in 20 ml of dry chloroform, cooled to -10 to -15 ° C, and dried ammonia gas was added to 15 ml.
It was connected for a minute. The container was tightly closed and left at room temperature for 3 days. Removal of the solvent gave crude 5'-o-benzoyl-2 ', 3'-
Dideoxycytidine was obtained. This compound was dissolved in 10 ml of dry methanol, and a 28% sodium methylate solution of 0.
15 ml was added and refluxed for 10 minutes. The solvent was distilled off, the residue was dissolved in 10 ml of ethyl acetate and 10 ml of water, the aqueous layer was dispersed, and further washed twice with 10 ml of ethyl acetate. 5 ml of water for each ethyl acetate layer
Then, back extraction was carried out sequentially. Combine the aqueous layers and adjust to pH 7 with 1N hydrochloric acid.
After setting to 0, it was passed through a column packed with 40 ml of CHP-20P and eluted with water. The portion containing the title compound was concentrated and freeze-dried to obtain 130 mg (82.6%) of the title compound. Ethanol 4
Crystallization with ml gave 109 mg (69.3%). Further, the mother liquor was concentrated and crystallized with 1 ml of ethanol to obtain 9 mg of a second crystal, and 118 mg (75.3%) of the desired compound was obtained in total. The properties of the notational target compound obtained here were in agreement with those of the compound obtained in Example 1.

Claims (2)

[Claims] 1. A general formula (Wherein, X represents a halogen atom, R ¹ represents a hydroxyl group which may be protected or a substituted hydroxyl group), and a compound having the formula YH (wherein Y is protected) Is an amino group or a substituted amino group.)
A general formula characterized by reacting with and optionally removing a protecting group (In the formula, Y has the same meaning as described above and R ² represents the same group as R ^1. ) A process for producing a 2 ′, 3′-dideoxycytidine derivative represented by the formula: 2. General formula (Wherein, R ¹ represents an optionally protected hydroxyl group or a substituted hydroxyl group) is reacted with a halogenating reagent, and then the product is isolated or without isolation. A compound having the formula YH, wherein Y represents an optionally protected amino group or a substituted amino group.
A general formula characterized by reacting with and optionally removing a protecting group (In the formula, Y has the same meaning as described above and R ² represents the same group as R ^1. ) A process for producing a 2 ′, 3′-dideoxycytidine derivative represented by the formula: