JPS63284193A - Production of 2',3'-dideoxycytidine derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a remedy for AIDS with superior yield and convenient isolation ability, by reacting a specific compound with an amine compound. CONSTITUTION:(A) A compound expressed by formula I (X represents halogen atom.; R<1> represents hydroxyl which may be protected or substituted hydroxyl) (e.g. 5'-o-benzoyl-2',3'-dideoxyuridine) is reacted with (B) a compound expressed by the formula YH (Y represents amino group which may be protected or substituted amino group) (e.g. diethylaniline), preferably in an inert solvent, such as chloroform, methanol or DMF, at 0-50 deg.C for 4hr-3 days, and, as necessary, followed by elimination of protecting groups to afford the aimed compound expressed by formula II.

Description

[Detailed description of the invention] 〔the purpose〕 The present invention is useful as a therapeutic agent for AIDS.

This invention relates to an excellent method for producing 3'-dideoxycytidine derivatives.

<Prior art> Conventionally, as a method for synthesizing 2t,3t-dideoxycytidine derivatives from nucleotide Ps, the method of Holpitz et al. (Journal of Organic Chemistry, 32, 817 (1969)) is known. There are, but
Due to the formation of by-products in the final reduction step, it is difficult to isolate the product, making it unsuitable for large-scale synthesis.

Problems to be Solved by the Invention> The present inventors
As a result of extensive research conducted over many years on the synthesis of 2',3'-dideoxycytidine derivatives using Ridenucleosyl groups as raw materials, we have found that the method of the present invention has improved yield and ease of isolation. The present invention was completed based on these findings.

〔composition〕

The method for producing the 27.3/-dideoxycytidine derivative of the present invention is as shown in the following formula: (1) +If) (wherein, R1
and R2 are the same or different and represent an optionally protected hydroxyl group or a substituted hydroxyl group, X represents an atom, and Y represents an optionally protected amino group or a substituted amino group. A compound having the formula (IJ) (indicating a group) is reacted with a compound having the formula (in the formula, Y has the same meaning as above), and if desired, the protecting group is removed. A method for producing a 2',3'-dideoxycytidine derivative represented by (n), or as shown in the following formula, ([1)
A compound having the formula (III) (wherein Hl, R2 and Y have the same meanings as above) is reacted with a norogenating reagent, and then the product is isolated, or Compounds having the formula TH'i (wherein,
Y has the same meaning as above, and if desired],
This is a method for producing a 21.3/-dideoxycytidine derivative represented by formula (II), which is characterized by removing a protecting group.

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

The protecting group for the "optionally protected hydroxyl group" defined by R1 and R2 indicates a protecting group in the reaction, such as formyl, acetyl, tetrapionyl, butyryl,
isobutyryl, pentanoyl, pivaloyl, valeryl,
Alkylcarbonyl groups such as invaleryl, octanoyl, lauroyl, norumitoyl, and stearyl; lower alkoxyalkyl groups such as 4-tetraloacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl; alkylcargonyl groups such as methoxyacetyl; Carbonyl group, +1> Aliphatic acyl group such as unsaturated alkylcarbonyl group such as -2-methyl-2-butenoyl; arylcarbonyl group such as benzoyl, α-naphthoyl, β-naphthoyl, 2-bromobenzoyl, 4 - More halogenated arylcardenyl groups of chlorobenzoyl, 2,4.6-trimethylbenzoyl,
Lower alkylated aryl cargonyl group such as 4-toluoyl, lower alkoxylated aryl cargonyl group such as 4-anisoyl? Nyl group, 4-nitrobensoyl, 2-nitrobensoyl and more nitrated arylcardenyl groups, 2
An aromatic acyl group such as an arylcardenyl group in which a lower alkoxyl is nylated, such as -(methoxycarnonyl)benzoyl, or an arylcargonyl group, such as 4-phenylbenzoyl; tetrahydropyran-2-yl ,
Tetrahydropyranyl or tetrahydro such as 3-bromotetrahydropyran-2-yl, 4-medoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl Thiopyranyl group: Tetrahydrofuranyl or tetrahydrothio7unyl group, such as tetrahydrofuran-2-yl, tetrahydrothio7ran-2-yl:)! j
Tri-lower alkylsilyl groups such as methylsilyl, triethylsilyl, isopropyldimethylsilyl, t-dityldimethylsilyl, methyldiimpropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, Silyl groups such as tri-lower alkylsilyl groups substituted with 1 or 2 aryl groups such as phenyldiisopropylsilyl; methoxymethyl;
Lower alkoxymethyl groups such as 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl groups, such as 2,2.2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, alkoxymethyl groups such as lower alkoxymethyl; 1-ethoxyethyl, 1-methyl-
Lower alkoxylated ethyl groups such as 1-methoxyethyl and 1-(isopropoxy)ethyl, halogenated ethyl groups such as 2.2.2-trichlorophototyl, and esters such as 2-(phenylzelenyl)ethyl. Ether groups such as ruzelenylated ethyl groups; such as benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl a lower alkyl group substituted with 1 to 3 aryl groups,
4-Methylbenzyl, 2.4.6-)limethylbenzyl, 3,4.5-)limethylpenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2
-nido, lopenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanopenol,
4-Cyanohenzoldiphenylmethyl, bis(2-nitrophenyl)methyl, biperonyl, and other aryl rings substituted with lower alkyl, lower alkoxy, nitro, halogen, or cyano groups and substituted with 1 to 3 aryl groups. Aralkyl groups such as lower alkyl groups; methoxycar is nyl, lower alkoxycars are nyl groups such as ethoxycarbonyl, t-butoxymergenyl, imbutoxycarbunyl, 2,2゜2-)'J chlorotetraethoxycar is nyl ,
Alkoxycarginyl groups, such as lower alkoxycar-nyl groups substituted with halogen or tri-lower alkylsilyl groups, such as 2-trimethylsilylethoxycargenyl: pinyloxycargenyl, allyloxycargenyl, etc. Alkenyloxycar is a nyl group: benzyloxycarbonyl, 4-methoxybenzyloxycargenyl, 3.
4-dimethoxypenzyloxycargenyl, 2-ditop
An aralkyloxycar whose aryl ring may be substituted with one or two lower alkoxy or nitro groups, such as benzyloxycargenyl and 4-nitropenzyloxycarbonyl? Mention may be made of protective groups in the reaction such as nyl groups, preferably aliphatic acyl groups and aromatic acyl groups.

Examples of substituents of the "substituted hydroxyl group" defined by R1 and R2 include those having 1 carbon number such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 8-butyl, t-butyl, pentyl, and hexyl. Substituted with 6 to 6 lower alkyl groups or lower alkyl, lower alkoxy, -rogen atoms such as phenyl, 4-tolyl, 4-methoxy7enyl, 4-ritetraphenyl, α- or β-naphthyl Examples include aryl groups which may be substituted.

The "optionally swollen amino group" defined for Y refers to a group in which the amino group may be protected by one or two of the following protecting groups, and the protecting group usually includes an amine group. There is no limitation as long as it is used as a protecting group for, but preferably, for example, the aliphatic acyl group; the aromatic acyl group:
The above alkoxycargenyl group; the above alkenyloxycargenyl group; the above “aralkyloxycargenyl group whose aryl ring may be substituted with 1 to 2 lower alkoxy or nitro groups”; the above silyl group: the above Aralkyl group; or N, N.

Dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylidene, diphenylmethylene, (5
Mention may be made of all substituted methylene groups forming Schiff bases such as -chloro-2-hydroxyphenyl)phenylmethylene, more preferably aralkyl groups.

The "substituted amine group" defined for Y refers to a group in which one or two of the following substituents are substituted for the amino group, and examples of the substituents include the above-mentioned lower alkyl group; the above-mentioned lower alkoxy Alkoxy groups such as lower alkoxylated lower alkoxy groups such as 2-methoxyethoxy, halogenated lower alkoxy groups such as 2-)lichloroethoxy: henzyloxy, phenethyloxy, 3-phenylpropoxy groups , a lower alkoxy group substituted with 1 to 3 aryl groups such as α-naphthylmethoxy, β-naphthylmethoxy, diphenylmethoxy, triphenylmethoxy, α-naphthyldi72nylmethoxy, 9-anthrylmethoxy, 4 -methylbenzyloxy, 2.
4.6-trimethylbenzyloxy, 3.4.5-trimethylbenzyloxy, 4-methoxybenzyloxy,
4-Methoxyphenyldiphenylmethoxy, 2-nitrobenzyloxy, 4-nitrobenzyloxy, 4-chlorobenzyloxy, 4-bromobenzyloxy, 4-cyanobenzyloxy, 4-cyanobenzyldiphenylmethoxy, bis(2-nitrophenyl) ) 1 in which the aryl ring is substituted with lower alkyl, lower alkoxy, nitrogen, halogen, or cyano group such as methoxy, piperonyloxy
Aralkyloxy group such as a lower alkoxy group substituted with 3 to 3 aryl groups: hydroxyl group; hydroxymethyl, 2
-human tetraxy-substituted lower alkyl groups such as hydroxyethyl, 3-hydroxyethyl; 2-aminoethyl, 3-
Examples include amino-substituted alkyl groups such as aminopropyl or the above-mentioned "aryl groups optionally substituted with lower alkyl, lower alkoxy, or halogen", and preferred are lower alkyl groups.

"Halogenating reagent" means, for example, sulfenyl chloride, sulfenyl bromide, sulfenyl iodide P such as sulfenyl chloride, sulfonyl chloride, sulfonyl bromyr1 sulfonyl halides such as sulfonyl iodide P. , phosphorus trihalides such as phosphorus trichloride, phosphorus tribromide, and phosphorus triiodide; phosphorus pentahalides such as phosphorus pentachloride, phosphorus pentabromide, and phosphorus pentaiodide; Oxyhalogenated phosphorus such as phosphorus bromide and phosphorus oxyiodide can be mentioned, and oxyhalogenated phosphorus is preferable.

The first step is to react the compound (ri) with an amine compound in a solvent, and optionally remove the protecting group for the amine group and/or the protecting group for the hydroxyl group, thereby converting the halogen atom at the 4-position into the formula Y. This is a step of extending the compound (II) substituted with the group having the compound (II).

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

The reaction temperature varies depending on the raw materials, solvents and reagents used, but is usually -10°C to 100°C, preferably 0°C to 50°C.
It will be carried out in

The reaction time varies depending on the raw materials, solvents, reagents and reaction time used, but is usually 1 hour to 4 days, preferably 4 days.
It takes from 1 hour to 3 days.

The desired step, the reaction for removing the protecting group, varies depending on the type, but is generally carried out as follows by methods 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 treatment with a compound that generates a fluorine anion, such as tetrabutylammonium fluoride. . The solvent used is not particularly limited, but ethers such as tetrahydrofuran and dioxane are suitable. The reaction is preferably carried out at around room temperature for 10 to 18 hours.

When the protecting group for the hydroxyl group and/or amino group is an aralkyloxycar-nyl group or an aralkyl group, it can be removed by contacting with a reducing agent. For example, /4 radium carbon, platinum Catalytic reduction is carried out at room temperature using a catalyst such as, or an alkali metal sulfide such as sodium sulfide or potassium sulfide is used. There is no particular limitation as long as it does not participate in this reaction, but it may include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, or fatty acids such as acetic acid, and the combination of these organic solvents and water. The reaction temperature at which a mixed solvent is suitable is usually around 0°C to room temperature, and the reaction time varies depending on the type of raw material compound and reducing agent, but is usually 5 minutes to 12 hours.

When the protecting group for a hydroxyl group and/or an 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. can. The solvent to be used is not particularly limited as long as it is used in ordinary hydrolysis reactions, and examples include water, methanol, ethanol, alcohols such as n-7'lonoyanol, tetrahydro7rane, and dioxane. Ethers or mixed solvents thereof are preferred. The base is not particularly limited as long as it does not affect other parts of the two compounds, but preferably alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium hydroxide, potassium hydroxide, etc. The reaction is carried out using an alkali metal hydroxide, an alkali metal alkoxide of an alcohol, or concentrated ammonia-methanol used as a solvent. Suitable reaction conditions include reacting with an alkali metal salt of the alcohol in an alcohol.The reaction temperature is not particularly limited, but is preferably around 0°C to 150°C in order to suppress side reactions. . The reaction time varies depending on the type of raw material compound, reaction temperature, etc., but is usually 5 minutes to 10 hours.

The protecting group for hydroxyl group and/or amino group is alkoxymethyl group, tetrahydropyranyl or tetrahydrothiopyranyl group, tetrahydro7ranyl or tetrahydrothio7
If it is a ranyl group or a substituted ethyl group, it can be removed by treatment with an acid in a solvent.

Preferred acids used include hydrochloric acid, acetic acid-sulfuric acid, and tosylic acid. The solvent 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 a mixed solvent of these organic solvents and water are suitable. A certain zero reaction temperature is usually between 0°C and 50°C.
The reaction time is generally 10 minutes to 18 hours, although the reaction time varies depending on the raw material compound and the type of acid.

When the protecting group for the hydroxyl group and/or the amino group is an alkenyloxycarbunyl group, the protecting group for the hydroxyl group is usually a lower aliphatic acyl group, an aromatic acyl group, or an alkenyloxycarbunyl group.
It can be removed by treatment with a base in the same manner as the removal reaction conditions for the .-co.--1 xycargonyl group. In the case of allyloxycarbunyl, removal using nonoradium, Otriphenylphosphine or nickel tetracargenyl is particularly simple and can be carried out with fewer side reactions.

After completion of the reaction, the target compound can be isolated from the reaction mixture according to conventional methods. For example, it can be purified by recrystallization, preparative thin layer chromatography, column chromatography, etc. to obtain a pure product.

The second step is the method of Honjo et al.
Z/3/-dideoxyuridine compound CDI) prepared according to the method of the invention is reacted with a deoxidizing agent and a norogenating reagent in the presence or absence of a solvent, and then the product is isolated or isolated. In this step, the 2/, 3/-dideoxycytidine rust conductor +Ill is produced by reacting it with an amine compound and, if desired, deprotecting it according to the description of the desired step in the first step.

When using a solvent, the reaction solvent is not particularly limited as long as it does not inhibit the reaction, but preferably esters such as ethyl acetate and ethyl propionate, or chloroforms such as nochloromethane and chloroform. Hydrocarbons.

The deoxidizing agent used is not particularly limited as long as it is an organic base, but aromatic tertiary amines such as diethylaniline and dimethylaniline, or tri-lower alkyl amines such as triethylamine are preferably used. It is.

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

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, 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, an organic solvent that is immiscible with water is added to the reaction mixture, and after washing with water, the solvent is distilled off.

The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, or chromatography.

Examples will be given below to describe in more detail.

26.5M of phosphorus oxychloride, 4.4M of diethylaniline
d was added, and after refluxing for 5 minutes, it was allowed to cool, and this solution f 5'-o
-benzoyl-2/, 3/-cyaoxyuridine 3.
When added to a solution of 02 suspended in 26.5 d of ethyl acetate, it immediately dissolved. After 23 minutes of refluxing, the solvent was distilled off, 1100 l of ethyl acetate and 100 l of ice water were added to dissolve it, and the ethyl acetate layer was separated and washed twice with 100 l of ice water. Further, after washing with 100 volumes of aqueous sodium bicarbonate solution containing ice and twice with 100 parts of ice water, the ethyl acetate layer was dried over anhydrous magnesium sulfate, removed, and the solvent was distilled off.
4-chloro-5'-〇-pensoyl-2',3'-zodeoxyclidine was obtained. The above compound was dissolved in 180 mJ of dry chloroform, cooled to -10 to -15°C, and dried ammonia gas was passed through the solution for 1 hour. Closely @ and bring to room temperature 3
After standing for a day, the solvent was distilled off to obtain crude M5m 0-benzoyl-2/, 3/-dideoxydithizone. This compound was further dissolved in dry methanol'iomt and 1.13 m/i of a solution of 28tin sodium methylate was added thereto, followed by refluxing for 10 minutes. The solvent was distilled off, and the residue was dissolved in 5 Qm of ethyl acetate and 50 m of water, and the aqueous layer was separated and further washed twice with 50 ml of ethyl acetate. After sequentially back-extracting each ethyl acetate layer with 30 d of water, the aqueous layers were combined and adjusted to -7.0 with -normal hydrochloric acid, followed by cHP20P (Hydelas Polymer 75-150μ: manufactured by Mitsubishi Chemical Corporation) 300 m
The mixture was pressurized through nine columns packed with /, and the portion containing compound No. 1 eluted with water was concentrated and lyophilized to obtain compound No. 1.11. (54.9%) Recrystallized with 60ml of ethanol to obtain 0.876F (43.7°). The mother liquor was further concentrated and crystallized from 10 d of ethanol to obtain 0.17 t of second crystals, for a total of 1.046 f (5
2.2%) of the title compound was obtained. The properties of the target compound thus obtained were completely consistent with the compound reported by Horvitz et al.

Under a nitrogen stream, 5'-〇-benzoyl-2',3'-dideoxyuridine 316 was added to a mixture of phosphorus oxychloride Q, 93m, diethylaniline 1.59M, and ethyl acetate 10-.
1+lv was added and heated under reflux for 100 minutes. The solvent was distilled off, 20 df of ethyl acetate and 20 df of ice water were added to the residue, and the ethyl acetate layer was separated and washed sequentially with 15 g each of dilute hydrochloric acid aqueous solution containing ice, sodium bicarbonate aqueous solution containing ice, and ice water. After drying the ethyl acetate layer over anhydrous magnesium sulfate, it was removed and the solvent was distilled off. The residue was separated and purified using silica gel chromatography to obtain the title compound (1% methanol-methylene chloride solution), 250η (74,51).

, THF UV spectrum, λ 275 nm (sh), 2
84nmax (sh), 305nm, 314nm NMR spectrum (δin CDCl2): 7.
4～8.3・(611!.

m, 6-H, phenyl), 6.21 (IEI, d, J=
7, Ocps, 5-H), 6.00 (I Tl
, q, J=2.6°1'-H), 4.3~4.7
(3H, m, 4', 5'-1), 1.7-2.8 (4
H, m, 2', 3'-H) Compound 250 of Example 2
Dissolve Wq in dry chloroform 201, -10 to -1
It was cooled to 5° C. and dry ammonia gas was passed through it for 15 minutes. The container was capped and left at room temperature for 3 days. After evaporating the solvent, crude 51-0-benzoyl-2/,3/-dideoxycytidine was obtained. This compound was dissolved in 10 g of dry methanol and 0.0 g of a solution of 28 titanium methylate.
15N was added and the mixture was refluxed for 10 minutes. The solvent was distilled off, the residue was dissolved in 10 parts of ethyl acetate and 10 parts of water, and the aqueous layer was separated and further washed twice with 10 parts of ethyl acetate. Each ethyl acetate layer was sequentially back-extracted with 51 portions of water. After combining the aqueous layers and adjusting the pH to 7.0 with -normal hydrochloric acid, CI'1P-20P 4
It was passed through a column packed with water and eluted with water. The portion containing the title compound was concentrated and lyophilized to yield 1301q (82,
The title compound of 61) was obtained. It was crystallized with 41 Lt of ethanol to obtain 1091F (6-9, 3%). Further, the mother liquor was concentrated and crystallized with ethanol 1rILt to obtain 9wIf as a second crystal, for a total of 118w (75,3
The title compound of 1) was obtained.

The properties of the target compound obtained here are as shown in Example 1.
The results were consistent with the compound obtained in .

Claims (2)

[Claims] (1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X represents a halogen atom, and R^1 represents an optionally protected hydroxyl group or a substituted hydroxyl group.) is reacted with a compound having the formula YH (wherein Y represents an optionally protected amino group or a substituted amino group), and optionally, the protecting group is removed. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, Y has the same meaning as above, and R^2 represents the same group as R^1.) 2', 3 Method for producing ′-dideoxycytidine derivatives. (2) A compound having the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, R^1 represents an optionally protected hydroxyl group or a substituted hydroxyl group.) and a halogenating reagent and then, with or without isolation of the product, a compound having the formula YH, where Y represents an optionally protected amino group or a substituted amino group. A general formula characterized by reacting and removing a protecting group if desired ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, Y has the same meaning as above, and R^2 is R^1 A method for producing a 2',3'-dideoxycytidine derivative represented by