Method for producing enriched beta-anomer nucleoside

 

(57) Abstract:

The invention relates to a method for obtaining enriched beta-anomer nucleoside of the formula I, where T is fluorine and R is the corresponding nucleoside described in paragraph (1 formulas. How is that carried out SN2replacement is not necessary in a suitable solvent sulfonyloxy (Y) from enriched monomer carbohydrate formula II, where X is independently selected from hydroxyamine groups, T is the specified value, at least Monomeric equivalent to the corresponding nucleobase at a temperature 17-120oWith and release with the formation of compounds of formula I. this method is stereoselective. 19 C. p. F.-ly, 4 PL.

< / BR>

This invention relates to a process for stereoselective glycosylation to obtain 2'-methoxyphenylazo and intermediate products of this process.

Continuous interest for the synthesis of 2'-methoxyphenylazo and their analogues, based on their successful use as therapeutic agents for the treatment of viral diseases and cancers. The compound of particular interest is gemcitabine; see Euro which there is a need to provide such compounds in high yields.

A significant stage in the process of synthesis of 2'-methoxyphenylazo is condensation or glycosylation of nucleobase and carbohydrate (carbohydrate) with the formation of N-glycosidic bonds.

However, the processes of synthesis of 2'-deoxynucleosides, as a rule, are asterionellopsis and lead to the formation of mixtures of alpha - and beta-nucleosides. For example, the process for U.S. patent 4526988 not resulted in stereoselective obtain 2-deoxy-2,2-debtor-beta-nucleosides, and instead gave a 4:1 anomeric ratio of 2-deoxy-2,2-deformalized. Even the optimization of protective groups were not able to increase the ratio of alpha and beta beyond 1: 1; see U.S. patent 4965374, which was used carbohydrate with benzoline protective or blocking groups.

According to the present invention offers a stereoselective process glucosylceramide to obtain enriched beta-anomer nucleoside of the formula:

< / BR>
where T is selected from hydrogen or fluorine, and R is a nucleoside selected from the group consisting of

< / BR>
where R1selected from the group consisting of hydrogen, alkyl, substituted alkyl and halogen;

R2selected from the group consisting of hydroxy, halogen, azido, ne
R4, R5and R6independently selected from the group consisting of hydrogen, -OH, -NH2N (alkyl), halogen, alkoxy and thioalkyl;

R7selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkoxy, alkoxycarbonyl, thioalkyl, thiocarboxamide and carboxamide;

Q is selected from the group consisting of CH, CR8and N;

where R8selected from the group consisting of halogen, carboxamide, thiocarboxamide, alkoxycarbonyl and nitrile, including SA2nucleophilic substitution of sulfonyloxy group (Y) is enriched in alpha-anomer of carbohydrate formula:

< / BR>
where X is independently selected from hydroxyamine groups, and

T has the values defined above; with at least a molar equivalent of nucleobase (R) selected from the group consisting of

< / BR>
< / BR>
< / BR>
where R1-R7and Q have the meanings defined above;

Z represents hydroxyamino group (i.e. a group protecting the hydroxy-group);

W represents aminosidine group; and

Mrepresents a cation;

the release with the formation of the compounds of formula (I).

Throughout this specification, all temperatures are expressed in degrees Celsius, all the proportions, pesano otherwise. Anomeric mixture expressed as the ratio of weight/weight or percentage.

The term "lactol" alone or in combination with other refers to 2-deoxy-2,2-debtor-D-ribofuranose or 2-deoxy-2-fluoro-D-ribofuranose. The term "xylene" by itself or in combination refers to all of the isomers of xylene and their mixtures. The term "carbohydrate" alone or in combination refers to an activated lactose, in which the hydroxy-group at C-1 position is substituted desired to be deleted or leaving group. The term "halogen", either alone or in combination refers to chlorine, iodine, fluorine or bromine. The term "alkyl" by itself, in combination, refers to an aliphatic hydrocarbon group with a straight, cyclic and branched chain, containing from 1 to 7 carbon atoms, and preferably contain up to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, 3-metalcenter, and similar groups, or substituted aliphatic hydrocarbon group with a straight, cyclic or branched chain, such as chloroethyl, 1,2-dichloroethyl and similar. The term "alkoxy" alone or in combination refers to compounds of General formula AO, where A is alkyl. The term "aryl" alone or in combination refers to carbonyl alkyl" alone or in combination refers to the total BS formula: where B is alkyl or hydrogen. The term "ester" alone or in combination refers to the General formula EOOC, where E is alkyl or aryl. The term "aromatic" alone or in combination refers to benzoline/similar structures containing (4n+2) delocalized electrons. The terms "sulfonate" or "sulfonyloxy" by themselves or in combination, refers to compounds of General formula BSO3where B is alkyl, substituted alkyl, aryl or substituted aryl. The term "substituted" one or in combination refers to the substitution of one or more groups selected from cyano, halogen, carbalkoxy, toluoyl, nitro, alkoxy, alkyl, dialkylamino. The phrase "enriched anomer" alone or in combination refers to an anomeric mixture in which the ratio of specific anomer is higher than 1:1 and comprises essentially pure anomer. The term "concentrated" alone or in combination refers to a solution in which the weight content of carbohydrate dissolved in the solvent is higher than 20% by weight per unit volume of solvent. For example, the dissolving 100 grams of carbohydrate in 200 milliliters of solvent will give a 50% solution of carbohydrate. The term "conjugate anion" refers to the anion of the General formula BSO3- where B is snakenirvanero derived.

In accordance with the present glycosylation process enriched beta-anomer of 2'-deoxy-2', 2'-deformalized and 2'-deoxy-2'-formulised formula (I) is retrieved using the interaction enriched alpha-anomer of carbohydrate formula (II) with at least a molar equivalent of nucleobase (R") and release of the resulting nucleoside, as shown below

< / BR>
where Y, X, T, R" and R have the values defined above.

Read that the glycosylation reaction proceeds through SN2substituted (preemption). Therefore, enriched with beta-anomer nucleoside products of the present invention are obtained stereoselective in the reaction of nucleobase c enriched alpha-anomer carbohydrate.

Lactaline source materials suitable for use in obtaining enriched alpha-anomeric carbohydrate formula (II) used in the present glycosylation process are known and freely synthesized using standard procedures commonly used by experts in the field of technology.

For example, in U.S. patent 4562988 mentioned here for information, disclosed the synthesis of 2,2-debtor-2-deoxy-D-ri the tx2">

In addition, the authors Reichman and others , Cornohydr. Res., 42, 233 (1975) discloses the synthesis of 2-deoxy-2-fluoro-D-ribofuranose formula

< / BR>
where X represents hydroxyamino group.

In the preferred embodiment of the present process is applied enriched alpha-anomer 2,2-debtor-2-deoxy-D-ribofuranose-3,5-dibenzoate intermediate compound of formula (III).

A key principal of the present invention is the discovery that the new enriched alpha-anomer carbohydrate intermediate compound of formula (III) or (IV) may be injected into the reaction under the conditions of nucleophilic substitution, which is favored by inversion (since SN2), giving enriched beta-anomer nucleosides of formula (I).

To achieve an effective reaction between nucleosomal and enriched alpha-anomer by carbohidratos formula (II) to lactose must be attached stereoselective of the deleted group (V) to activate lactol and generate enriched alpha-anomer of carbohydrate formula (II). However, the specific selected to be deleted, the group is dependent on the selected nucleobase and selected reaction conditions glycosylation.

Obtaining enriched alpha-anomer ka the two that are together pending applications U.S. 07/902301 and 07/902305.

In the application N 07/902301 describes the stereoselective process for producing enriched - anomer of the intermediate compounds of formula (II), where T represents fluorine, with the cooperation of lactol formula (III) with aminoven base with indicator pKa of 8 to 20, antifreeze inert solvent; adjusting the temperature of the reaction mixture to about -120 -40 ... oC; and adding sulphurouses reagent.

Amine base, preferably selected from the group consisting of triethylamine, tributylamine, dibutylamine, Diethylenetriamine, dimethylethylamine, benzylmethylamine, N - methylmorpholine, Tripropylamine, dipropylacetamide, N, N - dimethylbenzylamine, diisopropylethylamine, diethylamine, 1,8 - diazabicyclo (5.4.0) undec-7-ene and 1,5-diazabicyclo-(4.3.0)non-5-ene. The amount of base is preferably used, ranges from about 1 molar equivalent to 2 molar equivalents, and more preferably from about 1.2 molar equivalent to 1.5 molar equivalents.

The reaction is carried out in an inert solvent having a freezing point preferably below -78oC. Preferred solvents are selected from the group consisting of dichloromethane, 1,2-d is and solvents is preferably below about -78oC. for Example, the compound of formula III in which X represents benzoyl, was added to dichloromethane and triethylamine at room temperature for 30 minutes. Then the reaction temperature was lowered. Data19F NMR was filmed at various temperatures and showed that as the temperature is decreased, there was an increase : anomeric relations ionized lactol:

Temperature is the Ratio of alpha/beta

19oC - 2.0:1

-3oC - 2.3:1

-23oC - 2.5:1

-43oC - 3.0:1

-63oC - 3.6:1

-83oC - 3.4:1

Ionized lactol then is captured in the solution at a lower temperature and a higher ratio of alpha-anomer adding sulphurouses (sulfurous) agent, forming an enriched - anomer carbohydrate of the formula (II).

Thus, by using the appropriate selection of the temperature is possible to vary the ratio to carbohydrates intermediate source material.

Remove the group (Y) is connected in lactose by sulfonation. Sulfureuse the reagents are preferably selected from the group consisting of substituted and unsubstituted sulferous of alkylhalogenide, substituted and unsubstituted aryl-with organogenic, ethanolgasoline, 2-chloro-1-ethanolgasoline, p-nitrobenzenesulfonate, 2,4-dinitrobenzenesulfonyl, bromobenzosulfonyl, dibromoanthracene, the anhydride of benzosulfimide, the anhydride of n-bromobenzonitrile and the anhydride of methansulfonate, and substituted and unsubstituted foralkyl and ferril sulfurous halides and anhydrides of foralkyl and FERRYL-sulphonic acids, such as triftormetilfullerenov, triftormetilfullerenov, 1,1,1-triftoratsetilatsetonom, 1,1,1-cryptgethashparam anhydride, galoyanized octatitanate acid anhydride octatitanate acid, galoyanized and anhydride nonattitudinal acid, depending on the desired delete group; more preferred is methysulfonylmethane. Enriched - anomer carbohydrate intermediate products derived from ionized lakelaw, especially carbohydrates containing tripterocalyx are unstable at room temperature and therefore is preferably subjected to reaction with nucleosomal in place.

Due to the reactivity of sulfurous reagents may also be galatassaray.

Enriched - anomer of the intermediate compounds of formula (II), in which T is hydrogen, can be obtained similarly, except that the starting material used lactol formula (IV).

In the application of the U.S. 07/902305 describes another stereoselective process for producing enriched - anomer of the intermediate compounds of formula (II), where T represents fluorine, through processing of the beta-anomer ribofuranosylpurine formula

< / BR>
where Y is a sulfonate, and each X is independently selected from hydroxyamine groups, the source of conjugate anion of a sulfonic acids, at elevated temperatures, in an inert solvent.

A conjugate anion of a sulfonic acids can be obtained using a number of techniques known to experts in this field. They include:

(a) neutralization of the alkyl - or arylsulfonate, such as 1-methanesulfonate, p-methylbenzenesulfonate, econsultation, p-toluensulfonate, benzosulfimide, p-bromobenzonitrile and camphorsulfacid, melodramaticheskim base, such as sodium hydroxide, sodium hydride, potassium hydroxide, tert-butyl potassium, sodium methylate and similar;

(b) neutralization or N-methylmorpholine, or aromatic nitrogen base, such as pyridine.

Examples of conjugate anions of sulfonic acids obtained by this method include triethylammonium-methanesulfonate, trimethylammonium methanesulfonate, methanesulfonate N, N-dimethylbenzylamine, pyridinemethanol, triethylamine (p-Brabanthal)sulfonate, tetraethylammonium (p-Brabanthal)sulfonate, tetraethylammonium (p-toluene)sulfonate, pyridine(p-toluene)sulfonate and pirigyi-3-nitrobenzenesulfonate; more preferred is methanesulfonate of triethylamine; and finally

(c) a conjugate anion of a sulfonic acids can be obtained by the reaction of 2-deoxy-2,2-debtor-D-ribofuranose with a sulfonic anhydride, such as benzosulfimide anhydride, p-bromobenzophenone anhydride or methansulfonate, VA base, such as triethylamine. The products of the reaction are, for example, 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-di-O-benzyl-1-methanesulfonate and dietilaminoetanola.

Beta-anomeric ribofuranosylpurine and a conjugate anion of a sulfonic acids are heated at a temperature of from about 50 to 130oC and more preferably to a temperature of reflux distilled solvent mixture.

the conditions of the reaction; preferred are acetonitrile, 1,2 - dichloride, 1,1,2-trichloroethane, chlorobenzene, Brabanthal, dichlorobromomethane, anisole, glyme, diglyme, methyl tert-butyl ether, tetrahydrofuran, dioxane, ethyl acetate, toluene, xylenes, pyridine, N-methylpyrrolidinone, N,N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, N,N-dimethylacetamide, and mixtures thereof; most preferred are anisole, toluene, glyme, acetonitrile and mixtures thereof.

To increase the solubility and nucleoplasty metal salts used as the source of conjugate anion of a sulfonic acids may be added catalyst selected from crown ethers or catalysts in the transfer phase, the preferred catalysts are selected from the 18-crown-6, 15-crown-5, 12-crown-4 and Tris[2-(2-methoxyethoxy)-ethyl]amine.

This process is carried out under atmospheric conditions and is preferably anhydrous and essentially completed during the period from about 15 minutes to 24 hours. The resulting enriched - anomer carbon hydrates of the formula (II) are obtained with the anomeric ratio of from about 2.3:1 to 3.0:1 alpha to beta.

Enriched - anomer of the intermediate compounds of formula (II), where T is hydrogen, may be analogous to some fragment (glycosylation usually require protection of the hydroxy groups lactol before using them for in order to prevent the reaction of their hydroxyl groups with nucleocounter, or decay in any way. Hydroxyamine groups (X), are suitable for use in the present glycosylation process are groups independently selected from known protective groups used in synthetic organic chemistry. Each selected hidroxizina group preferably able to be entered in lactol and easily removed from it after the glycosylation reaction is completed. Hydroxyamine group, known in the art, are described in Chapter 3 operation Protective Groups in Organic Chemistry, Mc Omie ed. Plenum Press; new York (1973) and Chapter 2 operation Protective Groups in Organic Synthesis, Green, John, J. Wiley and Sons, new York (1981); preferred are complex afrobrazilian groups, such as formyl, acetyl, substituted acetyl, propionyl, butenyl, pialligo, 2-chloroacetyl, benzoyl, substituted benzoyl, phenoxycarbonyl, methoxyacetyl; carbonate derivatives such as phenoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl, vinyloxycarbonyl, 2,2,2-trichlorocyanuric and benzyloxycarbonyl; alkyl simple epioblasma groups such as benzyl, diphenylmethyl, triphenylmethyl, tert-butyl, methoxymethyl, tetrahedr as trialkylsilyl, trimethylsilyl, isopropylalcohol, alkyldiethanolamine, triisopropylsilyl, tert-butyldimethylsilyl and 1,1,3,3-tetraisopropyldisiloxane; carbamates, such as N-phenylcarbamate and N-imidazol-carbamate; however, more preferred are benzoyl, monosubstituted and disubstituted benzoyl benzoyl, acetyl, pivaloyl, triphenylmethyl ethers, and silyl simple epioblasma group, especially tert-butylmethylether; and most preferred is benzoyl.

When attaching hydroxyamine groups to lactose apply the usual reaction conditions, depending on the nature of the selected specifically hydroxyamino group. Typical reaction conditions are described in U.S. patent 4526988.

In accordance with the present process is used in at least equimolar amount of nucleobase (R) relative to the amount applied carbohydrate. However, it is more preferable to use an excess of nucleobase within about 1 molar equivalent to 30 molar equivalents; more preferably from about 10 molar equivalents to 20 molar equivalents, and most preferably from about 15 to 20 molar equivalents.

Used WKO, to be useful in the present glycosylation process, nucleobase or their tautomeric equivalents, which are amino or hydroxy groups, preferably contain a protective group, such as primary aminosidine group (W) and/or hydroxyamine group (Z), depending on the nature of nucleosome. Protecting groups hinder the hydroxy or amino groups to enable competitive reaction sites for enriched - anomer of carbohydrate. Protective groups attached to nucleosomal (R") before it is subjected to reaction with enriched alpha-anomer carbohydrate of formulas II, and after that they are deleted. The procedure of attaching the protective groups to nucleobases described in U.S. patent 4526988.

Preferred aminosidine group (W) for pyrimidine nucleobase selected from the group consisting of silyl forming a simple ether groups, such as trialkylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl; carbamates, such as tert-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzeneboronic and 4-nitrobenzenesulfonyl; formyl, acetyl, benzoyl, pialligo; forming a simple ether groups, such as Metock. Preferred aminosidine group (W) for purine nucleobase selected from the group consisting of alkylcarboxylic, galoiduglyerodov and arylcarboxamide, such as 2-dialkyldithiocarbamate, 4-methoxybenzyl, 3,4-dimethoxybenzyl, tert-butyl, phthalimido, tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl ether, methoxycoumarin, trityl, pialligo, tert-butyldimethylsilyl, tert-existimatio, triisopropylsilyl, trichlorocyanuric, TRIFLUOROACETYL, Naftoli, formyl, acetyl; sulfonamides, such as sulfonamide, arylsulfonamides, and more preferred is pialligo. Besides the fact that it serves as a group protecting the amino group, palmizana group increases the solubility obviously insoluble derivatives of purine nucleobase and directs the reaction of N-glycosidic combination of purine bases in the direction 9 regioisomer, as opposed to 7 regioisomer.

Preferred hydroxyamine groups (Z) for pyrimidine nucleobase selected from silyl forming a simple ether groups, such as trialkylsilyl; carbamates, such as tert-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzeneboronic and 4-nlnoy is trimethylsilyl. Preferred hydroxyamine groups (Z) for purine nucleobase selected from the group consisting of forming a simple ester groups such as benzyl, tert-butyl, trityl, tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, trityl; esters, such as formyl, acetylphenyl, pialligo, benzoyl, substituted benzoyl; carbonates, such as carbobenzoxy, tert-butoxycarbonyl, carbethoxy, vinyloxycarbonyl; carbamates, such as N, N-dialkylamino; trialkylsilyl esters, such as tert-butyldimethylsilyl, tert-existimatio, triisopropyl-silyl; more preferred is pialligo.

Giving protective group nucleobases of this process, these protective groups may themselves be protected. For example, N-acetylcytosine can be protected by trimethylsilyl, giving bis-trimethylsilyl-N-acetylcytosine.

In addition to the above, it is often advisable to turn any keto-oxygen atoms nucleobase in the enol form. This makes nucleobase more aromatic and enhances the reactivity of nucleobase towards enriched alpha-anomer to the carbohydrate of the formula (II). It is most convenient to analyze keto-color is, to the reaction between enriched - / - anomer carbohydrate of the formula (II) and nucleosomal was carried out in a dry atmosphere, such as dry air, nitrogen or argon. This is because some derivatives nucleobase, such as siciliane derivatives nucleobase are sensitive to moisture.

Any solvents used to obtain nucleobase can before the reaction glycosylation removed or mixed with the reaction solvent, provided that the mixture is inert to the reaction glycosylation.

When the glycosylation reaction is carried out in the reaction solvent, the solvent must be inert to the reaction glycosylation.

However, as mentioned previously, the specific solvent used for the reaction will depend on the reaction conditions glycosylation (e.g. reaction temperature, solvent), remove the group and applied nucleobase.

The glycosylation reaction can be carried out at a temperature in the range from about 170oC to -120oC under atmospheric conditions and is usually basically ends after about 5 minutes the Stam in the art, such as liquid chromatography high pressure (HPLC) or thin layer chromatography, which can be used to detect the formation of nucleoside product.

When the reaction is carried out in solution, it is preferable to use a high-boiling inert solvent and the solution having a concentration of carbohydrate at least 20 percent of carbohydrate. Preferred concentration of carbohydrate from about 20 to 70%; and most preferably from about 30 to 50%. A suitable interval, the reaction temperature is from about 70 to 170oC.

High-boiling solvent preferably has a boiling point above about 70oC and is selected from the group consisting of denuclearising, aromatic, haloalkyl, alkoxy and galijasevic aromatic solvents, and mixtures thereof. Preferred solvents are 1,2-dichloroethane, 1,1,2-trichloroethane, glyme, diglyme, toluene, xylenes, anisole, dichloromethane, chlorobenzene, dibromochloromethane, tribromomethane, dibromethane, acetonitrile, propionitrile, dioxane and mixtures thereof; and more preferred is anisole.

Enriched with alpha-anomer carbohydrate of the formula (II) used with heights, replaced alkylsulfonate and substituted arylsulfonate, such as methanesulfonate, 2-chloro-1-econsultancy, toluensulfonate, p-nitrobenzenesulfonate and p-bromobenzonitrile.

Nucleobase (R"), preferred for use with the high-boiling solvent is a compound selected from the group consisting of

< / BR>
< / BR>
where R1, R3, Z and N have the meanings given above.

When enriched - anomer carbohydrate of the formula (II) contains persulfonic, it is unstable at temperatures above room temperature. Therefore, the glycosylation reaction using these sulfonyloxy should be carried out at a temperature equal to or below room temperature. When the reaction glycosylation takes place in these conditions, the solvent should be antifreeze. The preferred temperature range for the reaction is from 25 to -120oC. In this case, the preferred solvents are selected from the group consisting of dichloromethane, 1,2-dichloroethane, dichloromethane, acetone, toluene, anisole, chlorobenzene, and mixtures thereof; more preferred is dichloromethane. However, the optimal is V).

For example, when the deleted group is tripterocalyx, the preferred interval, the reaction temperature is about -50 to 25oC; and more preferred is a temperature of about -20 to 25oC. However, when the deleted group is 1,1,1-triftoratsetofenona, octafluorocyclopentene or nanoformulations, the preferred reaction temperature ranges from about -20 to 25oC and a more preferred temperature is from about 0 to 25oC.

Nucleobase (R"), preferred for use in low temperatures, are compounds selected from the group consisting of

< / BR>
where R1, R2, R3, Z and W have the meanings given above.

Nucleobase (R) may not necessarily turn into a salt of the cation of the metal to enhance its nucleophilic reactivity with enriched - / - anomer carbohydrate of the formula (II) (i.e., anionic glycosylation). These cationic salts nucleobase prepared by adding to nucleosomal in a solvent base.

The base can be selected from the group consisting of tert-butyl sodium, the I, ethylate and potassium t-butyl potassium. Alternatively, the base may be selected from trialkylamine or tetraalkylammonium. Suitable inert solvents for the reaction can be selected from the group consisting of acetonitrile, dimethylformamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, tetrahydrofuran, sulfolane, N-methylpyrrolidinone, dimethyl sulfoxide and mixtures thereof. The solvent may be removed before the reaction glycosylation or mixed with a solvent for the reaction glycosylation, provided that the mixture is essentially inert to the reaction glycosylation. Suitable reaction temperatures vary from approximately 23oC to 130oC.

Nucleobase (R") preferably is selected from the group consisting of the following

< / BR>
where R1- R7, Q, Z, W and M+have the meanings given above.

Enriched with alpha-anomer carbohydrate of the formula (II) in these conditions contains sulfonyloxy group selected from alkylsulfonate, resultname, substituted alkyl, sulfonyloxy, replaced arylsulfonate, fluorine-alkylsulfonate and fluorine-arylsulfonate, such as tripterocalyx, 1,1,1-triftoratsetofenona, such is sulfonyloxy, n-nitrobenzenesulfonate and p-bromobenzonitrile.

As noted earlier, the fluorine-sulfonyloxy group of the formula (II) tend to be unstable at higher temperatures, and the above reaction with the salt of nucleobase with the cation of the metal should be carried out using antifreeze inert solvent such groups. The preferred temperature for the reaction will vary from about 25 to -120oC.

The glycosylation reaction can also be carried out in the absence of solvent (i.e., glycosylation in the melt). Obviously, the applied temperature should be sufficient for the conversion of enriched - anomer carbohydrate intermediate compounds of formula (II) and nucleobase in the melt phase. Preferred reaction temperatures range from about 100 to 160oC; however, a more preferred temperature is from about 110 to 160oC; and the most preferred temperature is from about 130 to 150oC.

Enriched/ anomer carbohydrate of the formula (II) in the conditions of the condensation contains sulfonyloxy group selected from alkylsulfonate, arylsulfonate, replaced alkylsulfonate and Zam is nitrobenzanthrone and p-Brabanthal - sulfonyloxy.

Nucleobase (R"), suitable for use in conditions of low, preferably selected from the group consisting of

< / BR>
where R1, R3, Z and W have the meanings given above.

This process can also promotionals catalyst. When used, the catalyst, it significantly reduces the number of required nucleobase, stereoselectivity increases, reduces the processing cost, increases productivity, facilitates the selection of the product and reduces the required reaction temperature, allowing you to use less heat-resistant carbohydrates. Therefore, in the present process preferably is used a catalyst which is a salt containing nucleophilic anion. Preferred are salts of metals of group IA, IIA or Quaternary ammonium salt. The catalyst must be soluble in the reaction solvent and vysokoorganizovannym.

Preferred are salt catalyst selected from the group consisting of potassium, barium, cesium and dialkylammonium salts triftoratsetata, nanoformulation, sulfuric acid, perchloric, nitric and triperoxonane the reaction temperature is in the range of from about 50 to 100oC.

The solvent preferably is selected from polar denuclearising solvent such as glyme, diglyme, anisole, acetonitrile, propionitrile, dioxane and mixtures thereof; more preferred is acetonitrile.

Enriched - anomer carbohydrate of the formula (II) in the catalytic conditions preferably contains sulfonyloxy selected from alkylsulfonate and arylsulfonate, such as methanesulfonate, 2-chloro-1-econsultancy, toluensulfonate, p-nitrobenzenesulfonate and p-bromobenzonitrile.

Nucleobase (R") for use in catalytic conditions, preferably selected from

< / BR>
< / BR>
where R1, R2, R3, Z and W have the meanings given above.

The final phase of the reaction sequence is the removal of the protective groups X, Z and/or W (i.e., release) of the blocked nucleoside of the formula (I). After removal of the protective groups obtained the same anomeric ratio of nucleosides.

Most silyl and siliconising groups are easily cleaved using proton solvent, such as water or alcohol. Acyl protective group, t is e from approximately 0 to 100oC.

Strong or moderately strong bases for use in this reaction are the reasons, which have pKa (at 25oC) from about 8.5 to 20. Such bases include hydroxides of alkali metals such as sodium hydroxide or potassium; an alkali metal alcoholate such as sodium methylate or tert-butyl potassium; amides of alkali metals; amines, such as diethylamine, geocillin, ammonia and similar; and other conventional bases, such as hydrazine and similar. For each protective group requires at least one equivalent of base.

Acyl protective group can also be removed using acid catalysts, such as methanesulfonate, hydrochloric, Hydrobromic, sulphuric acid or with acidic ion-exchange resins. It is preferable to carry out this hydrolysis at relatively high temperatures, such as temperature reflux distilled mixture, but can be used such low temperature as ambient temperature, when applied particularly strong acid.

Removal of ether protective groups is carried out using known methods, for example, using ethanthiol and aluminum chloride.

Removing the protective groups may conveniently be carried out in alcoholic solvents, especially aqueous alcohols, such as methanol. However, the reaction of the release can also be carried out in any suitable solvent, such as polyols including ethylene glycol, ethers such as tetrahydrofuran, ketones such as acetone and methyl ethyl ketone or dimethyl sulfoxide.

In the preferred embodiment, the reaction release applies ammonia to remove bentilee protective group of the hydroxy-group at a temperature of about 10oC. it is Preferable, however, to use an excess of base in this reaction, although the number of excess base is not significant.

In accordance with this process enriched beta-anomer nucleoside analog drugs are obtained when the anomeric ratio higher than 1:1 to 1:9.

The resulting enriched - anomer nucleoside of the formula (I) can be extracted and/or to stand out from the reaction mixture as described in U.S. patent 4965374, which is included here for information.

The following examples illustrate specific aspects of the present invention, but they are not intended to limit its about the value of enriched beta-anomer 1-(2'-deoxy-2', 2'-debtor-3'-, 5'-di-O-benzoyl-D-ribofuranosyl)-4 - aminopyrimidine-2-it with 10 equivalents of bis-trimethylsilylacetamide.

Bio-trimethylsilylmethyl was obtained by combining 2.44 cytosine, 5.15 ml hexamethyldisilazane and 580 mg of ammonium sulfate and 5 ml of xylene, and heating the solution under reflux at 120oC for 1 hour. Added an additional 5 ml hexamethyldisilazane for the formation of a homogeneous solution, which was heated under reflux for 30 minutes. The xylene and excess hexamethyldisilazane was removed, and formed glutinously bio-trimethylsilylmethyl. 5.6 g of bis-trimethylsilylacetamide were placed in 20 ml of xylenes. The xylenes were removed, and bis-trimethylsilylmethyl again were placed in 20 ml of xylenes. Bis-trimethylsilylmethyl was evaporated to dryness and placed in 5 ml of xylenes. 1 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 -- methanesulfonate was subjected to reaction with bis-trimethylsilylethynyl solution at 127oC for 3.5 hours.

Analysis of liquid chromatography high resolution (HPLC) confirmed the completion of reaction.

For extraction of the nucleoside product, the reaction mixture was cooled to 60oC, R the which was formed, are divided. The organic layer was washed successively with 100 ml of 5% sodium bicarbonate and 100 ml of saturated solution of sodium chloride, then dried over magnesium sulfate. Quantitative HPLC analysis an ethyl acetate layer showed that the yield of blocked beta-anomeric nucleoside was 50%.

Anomeric ratio of beta to alpha blocked nucleoside was 2.2 to 1.

Example 2

Obtaining enriched beta-anomer 1-(2'-deoxy-2',2'-debtor-3'5'-di-O - benzoyl-D-ribofuranosyl)-4-aminopyrimidine-2-one with 5 equivalents of bis-trimethylsilylacetamide.

To 2.8 g of bis-trimethylsilylacetamide was added 3 ml of xylene, and the solution was heated to 120oC up until bis-trimethylsilylmethyl not solubilizers. 1 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-methane - sulfonate dissolved in 2 ml of xylenes was heated and subjected to reaction with bis-trimethylsilylethynyl solution at 130oC for 16 hours. The HPLC analysis confirmed completion of the reaction. Anomeric ratio of beta to alpha blocked nucleoside was 1.1:1.

For extraction of the nucleoside product, the reaction mixture was diluted to 15 ml of ethyl acetate and was washed with 150 ml of 1 N. hydrochloric acid. Had seats is water and 100 ml of 5% sodium bicarbonate, then were dried over magnesium sulfate. For a more precise analysis HPLC 1 ml organic layer was evaporated to dryness and placed in 1 ml of acetonitrile. Quantitative HPLC analysis of the organic layer in acetonitrile pointed to the fact that the yield of blocked beta-anomeric nucleoside amounted to 36%.

Example 3

Obtaining enriched beta-anomer 1-(2'-deoxy-2',2-debtor-3',5'-di-O-benzoyl-D-ribofuranosyl)-4 - aminopyrimidine-2-it is in the form chlorhydrate salt 15 equivalents of bis-trimethylsilylacetamide.

Bis-trimethylsilylmethyl were prepared by combining 18.33 g of cytosine and 10 ml of anisole from 64.3 ml of N-methyl-N-cytosine-(trimethylsilyl)-trifurcated and heating the solution at 80oC for 30 minutes.

5.0 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 -- methansulfonate dissolved in 10 ml of anisole were interacting with the solution of bis-trimethylsilylacetamide at 105oC for 5 hours. Anomeric ratio of beta to alpha blocked nucleoside was 5.4:1.

To highlight the nucleoside product, the reaction mixture was cooled to 60oC, was diluted with 75 ml ethyl acetate and was washed with 200 ml of 1 N. hydrochloric acid. Formed a translucent solution, the solid was washed sequentially with 20 ml of ethyl acetate, then were dried in a vacuum oven at 40oC for 16 hours. The resulting nucleoside product weighed 4.0 g, so pl. 252 - 256oC. Quantitative HPLC analysis confirmed that the product was clorhidrato Sol blocked beta-anomeric nucleoside with a yield of 75 percent.

Example 4

Obtaining enriched beta-anomer 1-(2'-deoxy-2',2'-debtor-3',5'-di-O-benzoyl-D-ribofuranosyl)-4 - aminopyrimidine-2-it with 10 equivalents of bis-trimethylsilylacetamide.

Bis-trimethylsilylmethyl were prepared using the procedure described in example 1, except that used was 20 g of cytosine, 380 ml hexamethyldisilazane, 1.18 g of ammonium sulfate and 48 ml of xylenes. Bis-trimethylsilylmethyl was dissolved in 24 ml of xylene. 9.6 g of 2-deoxy-2,2-debtor-D - ribofuranosyl-3,5-Dibenzoyl-1-toluensulfonate in the ratio of alpha to beta 70: 30 was dissolved in 24 ml of xylene and subjected to reaction with a solution of bis-trimethylsilylacetamide for 1 hour. The HPLC analysis confirmed the completion of reaction.

For extraction of the nucleoside product, the reaction mixture was cooled to 65oC and was added 100 ml of ethyl acetate. The solution was maintained at 65oC and were washed with 200 ml of 1 N. hydrochloric sour is sodium carbonate, then were dried over magnesium sulfate. Anomeric ratio of beta to alpha blocked nucleoside was 1.1:1. Quantitative HPLC analysis indicated that the yield of blocked beta-anomer nucleoside was 27 percent.

Example 5.

Obtaining enriched beta-anomer 1-(2'-deoxy-2',2'-debtor-3',5'-di-O-benzoyl-D-ribofuranosyl)-4 - aminopyrimidine-2-one with 20 equivalents trimethylsilylacetamide.

Bis-trimethylsilylmethyl were prepared by mixing 10 g of cytosine with 175 ml hexamethyldisilazane and 25 mg of ammonium sulfate under nitrogen atmosphere and heating the solution at 120oC for 2 hours. The mixture was cooled to 80oC and was diluted with 100 ml of ethyl acetate. Hexamethyldisilazane and ethyl acetate atmospheric subsequently distilled at a temperature of 145oC. This procedure was repeated twice, then the resulting bis-trimethylsilyloxy was added to 15 ml of anisole and cooled to 100-115oC.

5.75 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 -- -methansulfonate dissolved in 10 ml of anisole were mixed at 45oC as long, until it formed a homogeneous solution, and subjected to reaction with a solution of bis-trimethylsilylacetamide when 11 is to alpha blocked nucleoside amounted to 7.3 : 1.

To highlight the nucleoside product, the reaction mixture was cooled to 88oC, was diluted 34 ml of ethyl acetate and was washed 125 ml 4 N. hydrochloric acid. Formed suspension containing solid particles, stirred for 1.5 hours at 80oC and filtered. The filtrate was washed with 50 ml of 4 N. hydrochloric acid and dried in a vacuum oven at 45oC. the Resulting nucleoside product weighed 4,6 kg Quantitative HPLC analysis showed that the yield of blocked beta-anomer nucleoside was 79.5 percent.

Example 6.

Obtaining enriched beta-anomer chlorhydrate salt 1-/2'-deoxy-2', 2'-debtor-3', 5'-di-O-benzoyl-D-ribofuranosyl/ -4-aminopyrimidine-2-it with 20 equivalents of bis-trimethylsilylacetamide.

Bis-trimethylsilylmethyl were prepared using the procedure described in example 5. The solution was cooled to 100oC.

5.75 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 -- methansulfonate dissolved in 10 ml of anisole were mixed at 45oC as long, until it formed a homogeneous solution, and subjected to interaction with bis-trimethylsilylethynyl solution at 110 - 115oC for 16 hours. The HPLC analysis confirmed that the number ratio of beta to alpha blocked nucleoside was 7.2 : 1.

For extraction of the nucleoside product, the reaction mixture was cooled and diluted 69 ml of ethyl acetate at 65oC. the Reaction mixture was then merged with 185 ml of 4 N. hydrochloric acid. The mixture was heated under reflux for 1 hour at 78oC to form a suspension. The suspension was filtered, and the solid was washed with 60 ml of 4 N. hydrochloric acid and dried in a vacuum oven at 45oC. Nucleoside product weighed 3.62, Quantitative HPLC analysis confirmed that the product was clorhidrato Sol blocked beta-anomer nucleoside with the release of 64.2%.

Example 7.

Obtaining enriched beta-anomer 9-/2'-deoxy-2',2'-debtor - 3',5-di-O-benzoyl-D-ribofuranosyl/-5-aminopurine with 15 equivalents bestemmingsplannen.

Bis-trimethylsilylethynyl were prepared by combining 7 g of adenine and 109 ml hexamethyldisilazane with 250 mg of ammonium sulfate and heating the mixture at 100-115oC for 8 hours. The solution was heated under reflux for an additional 30 minutes, and the excess hexamethyldisilazane subsequently was removed, and 14.5 g of bis-trimethylsilylacetamide was dissolved in 3 ml of anisole. 1.58 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibene 24 hours.

The HPLC analysis confirmed the completion of reaction.

For extraction of the nucleoside product, the reaction mixture was cooled to 30oC, was diluted with 50 ml ethyl acetate and was washed with 75-ml 4 N. hydrochloric acid. Formed emulsion, and the organic layer was separated and was washed successively with 75 ml of 5% sodium bicarbonate and 75 ml of saturated sodium chloride solution, then dried over magnesium sulfate.

Anomeric ratio of beta to alpha blocked nucleoside was 6: 1.

In table. 1, provided at the end of the description that shows how the concentration of carbohydrate and selected carbohydrate affect anomeric ratio of nucleoside product.

/N/D/ denotes not determined. Carbohydrates (Carbo) are gidrosistemi and include ...- or - OMS is alpha - or beta-2,2-debtor-2-deoxy-D-ribofuranosyl-3,5-Dibenzoyl-1-methanesulfonate; and / or - OTs is beta - or alpha-2,2-debtor-2-des-hydroxy-D-ribofuranosyl-3,5-Dibenzoyl-1 - toluensulfonate; and - or - OBs is alpha - or beta-2,2-debtor-2-deoxy-D-ribofuranosyl-3,5-Dibenzoyl-1-bromo - bansilalpet. 70: 30 : - -OTs carbohydrates was obtained through isomerization - -OTs salt of p-toluenesulfonic acid. The outputs are given per kaloudi peak of a solution of the product was compared with the standard, 1-(2'-deoxy - 2', 2'-debtor-3'-,5'-di-O-benzoyl -- -D-ribofuranosyl)-4-aminopyrimidine-2-one, except in the case of (a), which gives the output of the selected product. (G) the Concentration of carbohydrate (Carbo.Conc.) expressed in percent of carbohydrate by weight (grams) per unit volume of solvent (ml). The group that protects nucleobase, in each example is trimethylsilyl.

Example 8.

Obtaining enriched beta-anomer 1-(2'-deoxy-2',2'-debtor-3',5'-di-O-benzoyl-D-ribofuranosyl)-4 - aminopyrimidine-2-one with 20 equivalent bis-trimethylsilylacetamide.

To 5.78 g of cytosine was added 112 ml hexamethyldisilazane and 100 mg of ammonium sulfate. The solution was heated to 115 - 120oC for 1.5 hours with stirring, and the excess hexamethyldisilazane subsequently removed. The mixture was cooled to 60oC and dissolved in 40 ml of 1,2-dichloromethane, forming a homogeneous solution of bis-trimethylsilylacetamide.

To 1 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-N-3,5-dibenzoate was added 10 ml of dichloromethane and 0.54 ml of triethylamine. This solution was mixed with 23oC for 30 minutes, cooled to -78oC and subjected to reaction with 0.57 ml trifloromethyl-anhydride, in 0.50 ml of dichloromethane, obrazujuce compound in solution. Measures were taken to maintain the temperature of the reaction mixture below -65oC. Analysis19F demominator resonance (NMR) enriched alpha-anomer 2-deoxy-2,2-debtor-D - ribofuranosyl-3,5-Dibenzoyl-1-triftormetilfosfinov intermediate connection 65oC gave the following data:

19F NMR (300 MHz, CDCl3), -77 (C., 3F, CF3SO2- III (D., J=257 Hz, 1F, alpha-anomer), -122 (D., J=242 Hz, 1F, beta-anomer), -124 (D., J=257 Hz, 1F, alpha-anomer), -126 million dollars (D., J=242 Hz, 1F, beta-anomer). It should be noted that all shifts19F NMR peaks are relative to hexaferrite, which prescribed frequency -162,9 million dollars. Range19F NMR also indicated the fluorine-proton combinations, but the nature of these combinations have not been determined.

The solution enriched alpha-anomer 2-deoxy-2,2-debtor - D-ribofuranosyl-3,5-Dibenzoyl-1-triftoratsetata was subjected to reaction with a solution of bis-trimethylsilylacetamide at -65oC, and the reaction temperature was allowed to rise to 23oC, and was formed named in the header of the blocked nucleoside, which was confirmed by the analysis of the HRLC. Anomeric ratio of beta to alpha blocked nucleoside was 1.9:1.

For the extraction nucleoside is delalla was filtered and 200 ml of 5% sodium bicarbonate. The organic layer was again separated and washed with 200 ml saturated sodium chloride. The target nucleoside product precipitated from the organic layer. Quantitative HPLC analysis showed a yield of blocked beta-anomer nucleoside 42 percent.1H NMR (DMSO); = 4.74 (4'H), 4.79 (5'H), 5.84 (5H), 5.88 (3'H), 6.44 (1'H), 7.56 (NH2), 7.68 (6H).13C NMR (DMSO): = 63,46 (5'C), 71.80 (3'C), 75.71 (4'C), 84.64 (1'C), 95.12 (5'C), 121.86 (2'C), 141.93 (6'C), 154.48 (2C), 165.87 (4C).

Example 9

Obtaining enriched beta-anomer 1-(2'-deoxy-2',2'-debtor-3',5'-di-O-benzoyl-D-ribofuranosyl)- 4-aminopyrimidine-2-it with 20 equivalents of bis-trimethylsilylacetamide.

A solution of bis-trimethylsilylacetamide were prepared by suspendirovanie 5.78 g of cytosine in 75 ml of dichloromethane and adding 20.57 ml of N-methyl-N-trimethylsilyltrifluoroacetamide and cooling the resulting solution to -30oC.

To 1 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 10 ml of dichloromethane and 0.55 ml of triethylamine. This solution was mixed with 23oC for 30 minutes, cooled to -78oC and subjected to reaction with 0.57 ml trifloromethyl-anhydride in 1 ml dichloromethane, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl - 3,5-Dibenzoyl-1-cryptomelane alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl - 3,5-Dibenzoyl-1-triftorbyenzola in the form of a solution was subjected to reaction with a solution of bis-trimethylsilylacetamide at -30oC, forming a target blocked nucleoside, which was confirmed data analysis HPLC. Anomeric ratio of beta to alpha blocked nucleoside amounted to 2.3:1.

For the extraction nucleoside product from the reaction mixture were added 200 ml of 1 N. hydrochloric acid. The organic layer was separated and was washed with 5% sodium carbonate. Quantitative HPLC analysis of the organic layer showed a yield of blocked beta-anomeric nucleoside 45%.

Example 10

Obtaining enriched beta-anomer 1-(2'-deoxy-2',2'-debtor-3',5'-di-benzoyl-D-ribofuranosyl)- 4-aminopyrimidine-2-it with 20 equivalents of bis-trimethylchitosan.

A solution of bis-trimethylsilylacetamide were prepared using the procedure described in example 8, and was cooled to -15oC.

To 1 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 10 ml of dichloromethane and 0.54 ml of triethylamine. This solution was mixed with 23oC for 30 minutes, cooled to -78oC and subjected to reaction with 0.57 ml trifloromethyl-anhydride in 0.5 ml of dichloromethane, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl - 3,5-Dibenzoyl-1-triftorbyenzola in solution. Measures were taken to maintain the 3.5-Dibenzoyl-1-triftoratsetata the solution was subjected to reaction with a solution of bis-trimethylsilylacetamide at -15oC, forming a target blocked nucleoside, which was confirmed data analysis HPLC. Anomeric ratio of beta to alpha blocked nucleoside amounted to 2.3:1.

For the extraction nucleoside product from the reaction mixture dichloromethane was removed and the resulting residue was dissolved in 21 ml of anisole, and then 40 ml of water, and then was heated to 90oC. the Solids that formed were removed from the solution. Organic and aqueous layers were separated, and the organic layer was subsequently washed with additional 10 ml of water. From the organic layer to precipitate the beta-anomeric nucleoside product. Quantitative HPLC analysis found the exit blocked beta-anomer nucleoside 58%.

Example 11

Obtaining enriched beta-anomer 1-(2'-deoxy-2',2'-debtor-3',5'-di-O-benzoyl-D-ribofuranosyl)- 4-aminopyrimidine-2-it with 20 equivalents of bis-trimethylsilylacetamide.

A solution of bis-trimethylsilylacetamide were prepared by suspension 5.78 g of cytosine in 20 ml of dichloromethane and adding 20.57 ml of N-methyl-N-trimethylsilyltrifluoroacetamide in 10 ml of dichloromethane and cooling the resulting solution to 0oC.

To 1 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3 is for 30 minutes, was cooled to -78oC and subjected to reaction with 0.57 ml trifloromethyl-anhydride in 1 ml dichloromethane, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl - 3,5-/Dibenzoyl-1-triftormetilfullerenov in solution. Measures were taken to maintain the temperature of the reaction mixture below -65oC. Enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl - 3,5-Dibenzoyl-1-triftorbyenzola in the solution was subjected to reaction with a solution bdis-trimethylsilylacetamide at 0oC, forming a target blocked nucleoside, which was confirmed by HPLC analysis. Anomeric ratio of beta to alpha blocked nucleoside was 2.5:1.

For the extraction nucleoside product from the reaction mixture is added 250 ml of 1 N. hydrochloric acid. The organic layer was separated and washed with 200 ml of 5% sodium carbonate. Quantitative HPLC analysis of the organic layer were found the exit blocked beta-anomeric nucleoside 49 percent.

Example 12

Obtaining enriched beta-anomer 1(2'-deoxy-2',2'-debtor-3',5'-di-O-benzoyl-D-ribofuranosyl)-4 - acetamidophenyl-2-it with 10 equivalents of bis-trimethylsilyl-N - acetylcytosine.

To 4 g of N-acetylcytosine was added 56 ml HEXAMETHYL the Institute, and excess hexamethyldisilazane subsequently removed. The mixture was cooled to -50oC and dissolved in 50 ml of 1,2-dichloroethane. 1,2-dichloroethane was removed and the resulting solid residue was dissolved again in 50 ml of 1,2-dichloroethane. 1,2-dichloroethane was again removed, and the formed oily residue. The oily residue was taken in 2.5 ml of 1,2-dichloroethane, forming a homogeneous solution of bis-trimethylsilyl-N-acetylcytosine. To 1 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 2 ml of dry dichloromethane. This solution was cooled to -78oC and subjected to reaction with 0.55 ml of triethylamine and 0.58 ml trifloromethyl-anhydride, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 - triftorbyenzola in solution. Measures were taken to maintain the temperature of the reaction mixture below -65oC. the Solution is enriched in alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 - triftoratsetata was subjected to reaction with a solution of bis-trimethylsilyl-N-acetylcytosine at the 23oC.

The reaction mixture is stirred at -60oC for one and a half hours, forming a target blocked nucleoside, which was confirmed by HPLC analysis. Anomeric ratio of beta to alpha art was added 50 ml of dichloromethane. The organic layer was separated and was washed successively with 50 ml of 5% sodium bicarbonate, then with 50 ml of 1 N. hydrochloric acid and 50 ml saturated sodium chloride. Quantitative HPLC analysis of the organic layer showed a yield of blocked beta-anomeric nucleoside 15 percent.

Example 13

Obtaining enriched beta-anomer 1-(2'- deoxy-2',2'-debtor-3', 5'-di-O-benzoyl-D-ribofuranosyl)-4 - aminopyrimidine-2-it with 20 equivalents of bis-trimethylsilylacetamide.

To 5.78 g of cytosine was added 112 ml hexamethyldisilazane 50 mg of ammonium sulfate. The mixture was heated to 115-120oC for 3 hours under stirring, and the excess hexamethyldisilazane subsequently removed. This solution is then cooled until the 27oC, and formed a solid residue, which was placed in 35 ml of dichloromethane, forming a homogeneous solution of bis-trimethylsilylacetamide.

To 1 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 10 ml of dichloromethane and 0.54 ml of triethylamine. The solution was cooled to -78oC and subjected to reaction with 0.57 ml trifloromethyl-anhydride (0.50 ml dichloromethane, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl - 1-triftorbyenzola in solution. The principles of the alpha-anomer of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl - 1-triftoratsetata was subjected to reaction with a solution of bis-trimethylsilylacetamide at the 27oC, forming a target blocked nucleoside, which was confirmed data analysis HPLC and pointed to what remained 11 percent unreacted enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl - 1-triftoratsetata.

Anomeric ratio of beta to alpha blocked nucleoside was 2.2:1. Quantitative HPLC analysis showed a yield of blocked beta-anomeric nucleoside 54%.

Example 14

Obtaining enriched beta-anomer 1-(2'- deoxy-2',2'-debtor-3', 5'-di-O-benzoyl-D-ribofuranosyl)-4 - aminopyrimidine-2-it with 20 equivalents of bis-trimethylsilylacetamide.

To 5.78 g of cytosine was added 112 ml hexamethyldisilazane and 50 mg of ammonium sulfate. This solution was heated to 115-120oC for 2 hours under stirring, and the excess hexamethyldisilazane subsequently removed. The resulting oil was cooled to 23oC, forming a solid residue, which was placed in 35 ml of dichloromethane, forming a homogeneous solution of bis-trimethylsilylacetamide, and was cooled to 0oC.

To 1 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 9 ml of dichloromethane and 0.54 ml of triethylamine. The solution was cooled to -78oC, padvergoldeter-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl - 1-triftorbyenzola in solution. Measures were taken to maintain the temperature of the reaction mixture below -65oC.

The solution enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl - 1-triftoratsetata was subjected to reaction with a solution of bis-trimethylsilylacetamide at the 23oC, forming a target blocked nucleoside, which was confirmed by HPLC analysis. Anomeric ratio of beta to alpha blocked nucleoside amounted to 2.2:1.

For the extraction nucleoside product from the reaction mixture and the mixture was washed twice with 150 ml of 1 N. hydrochloric acid. The organic layer was separated, washed with 150 ml of 5% sodium bicarbonate and washed again with 150 ml saturated sodium chloride. Quantitative HPLC analysis of the organic layer showed a yield of blocked beta-anomeric nucleoside 49 percent.

Example 15

Obtaining enriched beta-anomer 1-(2'-deoxy-2','2-debtor-3',5'-di-O-benzoyl-D-ribofuranosyl)-4 - aminopyrimidine-2-it with 30 equivalents of bis-trimethylsilylacetamide.

To 5.9 g of cytosine was added 112 ml hexamethyldisilazane and 25 mg of ammonium sulfate. The solution was heated to 120-125oC for 3 hours under stirring, and the excess hexamethyldisilazane subsequently removed. The floor is built solution of bis-trimethylsilylacetamide.

To 655 mg of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 0.55 ml of dichloromethane and 0.36 ml of triethylamine. The solution was mixed with 23oC for 30 minutes, cooled to -78oC and subjected to reaction with 0.35 ml trifloromethyl-anhydride (0.50 ml dichloromethane, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl - 1-triftorbyenzola in solution. Measures were taken to maintain the temperature of the reaction mixture below -65oC.

The solution enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl - 1-triftoratsetata was subjected to reaction with a solution of bis-trimethylsilylacetamide at 10oC, forming a target blocked nucleoside, which was confirmed data analysis HPLC. Anomeric ratio of beta to alpha blocked nucleoside was 2.7:1. Quantitative HPLC analysis showed a yield of blocked beta-anomeric nucleoside 60 percent.

Example 16

Obtaining enriched beta-anomer 1-(2'-deoxy-2','2-debtor-3',5'-di-O-benzoyl-D-ribofuranosyl)-4 - aminopyrimidine-2-it with 20 equivalents of bis-trimethylsilylacetamide.

To 5.78 g of cytosine was added 112 ml hexamethyldisilazane and 50 mg of ammonium sulfate. the on subsequently removed. The resulting solid residue was placed in 40 ml of 1,2-dichloromethane at 23oC, forming a homogeneous solution of bis-trimethylsilylacetamide.

To 1 mg of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 10 ml of dichloromethane with 1.2 ml of triethylamine. The solution was cooled to -78oC and subjected to reaction with 0.57 ml trifloromethyl-anhydride (0.50 ml dichloromethane, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl - 1-triftorbyenzola in solution.

Measures were taken to maintain the temperature of the reaction mixture below -65oC. the Solution is enriched in alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl - 1-triftoratsetata was subjected to reaction with a solution of bis-trimethylsilylacetamide at the 23oC, forming a target blocked nucleoside, which was confirmed by HPLC analysis.

Anomeric ratio of beta to alpha blocked nucleoside amounted to 2.8: 1. Quantitative HPLC analysis showed a yield of blocked beta-anomeric nucleoside 50%.

Example 17

Obtaining enriched beta-anomer 1-(2'-deoxy-2',2'-debtor-3',5'-di-O-benzoyl-D-ribofuranosyl)-4 - aminopyrimidine-2-it with 20 equivalents of bis-trimethylsilyltriflate to 115-120oC for 1.5 hours with stirring, and the excess hexamethyldisilazane subsequently removed. The resulting solid residue was placed in 40 ml dichloromethane at 23oC, forming a homogeneous solution of bis-trimethylsilylacetamide.

To 1 mg of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 10 ml of dichloromethane and 0.54 ml of triethylamine. The solution was mixed with 23oC for 30 minutes, cooled to -78oC and subjected to interaction with 0.57 ml trifloromethyl-anhydride (0.50 ml dichloromethane, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl - 1-triftorbyenzola in solution. Measures were taken to maintain the temperature of the reaction mixture below -65oC.

The solution enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl - 1-triftoratsetata was subjected to reaction with a solution of bis-trimethylsilylacetamide in solution at 23oC, forming a target blocked nucleoside, which was confirmed by HPLC analysis.

Anomeric ratio of beta to alpha blocked nucleoside amounted to 2.5: 1. Quantitative HPLC analysis showed a yield of blocked beta-anomeric nucleoside 68 percent.

To 5.78 g of cytosine was added 5 ml of dichloromethane, 20.6 ml of N-methyl-N-trimethylsilyltrifluoroacetamide and 5 ml of dichloromethane, forming a homogeneous solution of bis-trimethylsilylacetamide.

To 1 mg of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 3 ml of dichloromethane and 0.55 ml of triethylamine. This solution was mixed with 23oC for 30 minutes, cooled to -78oC and subjected to reaction with 0.57 ml trifloromethyl-anhydride in 1 ml dichloromethane, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl - 1-triftorbyenzola in solution. Measures were taken to maintain the temperature of the reaction mixture below -65oC. the Solution is enriched in alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl - 1-triftoratsetata was subjected to reaction with a solution of bis-trimethylsilylacetamide at 25oC, forming a target blocked nucleoside, which was confirmed by HPLC analysis. Anomeric ratio of beta to alpha blocked nucleoside was 2.5:1.

For the extraction nucleoside product from the reaction mixture was added 250 ml of 1 N. hydrochloric acid. The organic layer was separated and washed with 250 ml of 5% sodium carbonate. Quantitative HPLC analysis of the see at the end of the description) shows how the solvent, the number of molar equivalents pyrimidine-nucleoside derivatives affect anomeric ratio and the output of the nucleoside product.

The carbohydrate used to get blocked nucleosides, the table was enriched alpha-anomer 2-deoxy-2,2 - debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-triftorbyenzola. (N/D) means not determined. Data output is presented in relation to the number of carbohydrate and was calculated from the results of quantitative analysis HPLC reverse phase, in which the peak corresponding solution of the product was compared with the standard. A protective group for the above nucleoside base is trimethylsilyl

Example 19

Obtaining enriched beta-anomer 1-(2-'-deoxy-2',2'-debtor - 3', 5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidine-2-it.

Cytosine (12.0 g), hexamethyldisilazane (60 ml) and ammonium sulfate (10 mg) was heated under reflux at 125oC for 30 minutes, forming a homogeneous solution. Hexamethyldisilazane was removed by distillation, forming bis-trimethylsilylmethyl. 2-deoxy-2',2'-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-methanesulfonate (1.15 g) was subjected to Rhea potassium salt nanovor-1-butanesulfonic acid (0.5 g) for 16 hours.

The HPLC analysis confirmed completion of the reaction, and pointed to the exit in situ 33 percent. Anomeric ratio of beta to alpha target compound was 3: 1.

Example 20

Obtaining enriched beta-anomer 1-(2'-deoxy-2', 2'-debtor - 3', 5'-di-O-benzyl-D-ribofuranosyl)-4-aminopyrimidine-2-one with potassium sulfate.

2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-methanesulfonate (1.15 g) was subjected to reaction with bis-trimethylsilylethynyl (6.89 g, 10 equiv.) obtained as described in example 19, in acetonitrile (2.0 ml) at 80oC in the presence of potassium sulfate (0.5 g) for 72 hours.

The HPLC analysis confirmed completion of the reaction and showed out in situ 65 percent. Anomeric ratio of beta to alpha target compound was 4.7:1.

Example 21

Obtaining enriched beta-anomer 1-(2'-deoxy-2', 2'- debtor-3', 5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidine-2-she tetrabutylammonium salt triftoratsetata.

2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-methanesulfonate (0.29 ml) was subjected to reaction with bio trimethylsilylcyanation (6.89 g, 10 EQ. ), obtained as described in example 19, in acetonitrile (3.0 ml) at 80oC in the presence of tetrabutylammonium salt triptime solution in methanol) triftormetilfullerenov (0.13 ml)), then distillation to remove methanol for 4 hours.

The HPLC analysis confirmed completion of the reaction and showed out in situ 45 percent. Anomeric ratio of beta to alpha target compound was 7.1:1.

Example 22

Obtaining enriched beta-anomer 1-(2'-deoxy-2', 2'- debtor-3', 5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidine-2-one with barium sulphate.

2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-methanesulfonate (1.15 g) was subjected to interaction with bis-trimethylsilylacetamide (6.89 g, 10 EQ. ), obtained as described in example 19, in acetonitrile (3.0 ml) at 75oC in the presence of barium sulfate (1.0 g) for 20.5 hours. The HPLC analysis showed output in situ 36 percent of the Anomeric ratio of beta to alpha target compound was 11.2:1.

Example 23

Obtaining enriched beta-anomer 1-(2'-deoxy-2', 2'- debtor-3', 5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidine-2-she cesium sulfate.

2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-methanesulfonate (1.15 g) was subjected to reaction with bis-trimethylsilylacetamide (6.89 g, 10 equiv.) obtained as described in example 19, in acetonitrile (3.0 ml) at 75oC in the presence of cesium sulfate (1.0 g) in 21 hours.

The HPLC analysis p is p 24

Obtaining enriched beta-anomer 1-(2'-deoxy-2', 2'-debtor - 3', 5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidine-2-she cesium salt triftormetilfullerenov acid.

2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-methanesulfonate (1.15 g) was subjected to interaction with bis-trimethylsilylacetamide (6.89 g, 10 EQ. ), obtained as described in Example 19, in acetonitrile (3.0 ml) at 75oC in the presence of a cesium salt triftormetilfullerenov acid (obtained in situ by using the processing 0.13 ml triftormetilfullerenov acid with an excess of cesium carbonate) for 20.5 hours.

The HPLC analysis confirmed completion of the reaction and showed out in situ 65 percent. Anomeric ratio of beta to alpha target compound was 7.2:1.

Example 25

Obtaining enriched beta-anomer 1-(2'-deoxy-2', 2'-debtor - 3', 5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidine-2-the barium salt triftormetilfullerenov acid.

2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-methanesulfonate (1.15 g) was subjected to interaction with bis-trimethylsilylacetamide (6.89 g, 10 EQ. ), obtained as described in example 19, in acetonitrile (3.0 ml) at 75oC in the presence of barium salt triptoreline 20.5 hours.

The HPLC analysis showed output in situ 25 percent. Anomeric ratio of beta to alpha target compound of 14.4:1.

Example 26

Obtaining enriched beta-anomer 1-(2'-deoxy-2', 2'-debtor - 3', 5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidine-2-the potassium salt of triftoratsetata.

2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-methanesulfonate (2.3 g, 12,6 EQ.) subjected to reaction with bistrimethylammonium (16,1 g), obtained as described in example 19, in acetonitrile (8.0 ml) at 75oC and in the presence of potassium salt triftormetilfullerenov acid (0,26 ml) with potassium carbonate (1.0 g) within 45 hours. The HPLC analysis indicates the output 69,8% in situ. The ratio of beta to alpha isomers in the target product is 7.2:1.

Extract the nucleoside, the reaction mixture was cooled to 70-80oand combined with 40 ml of 4N hydrochloric acid. Quantitative HPLC analysis indicates that the output of the selected product is about 62.4 per cent

Example 27

Receiving beta-anomer enriched 1-(2-deoxy-2,2-debtor-3,5-O - benzoyl-D-ribofuranosyl)-4-amino-pyrimidine-2-he with potassium salt triftormetilfullerenov acid.

2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-methanesulfonate (2.3 g) is subjected to regcreatekey potassium salt of triftoratsetata (obtained in situ by treatment of triftoratsetata (0.26 ml), potassium carbonate (1.0 g) in 21 hours.

The HPLC analysis confirmed completion of the reaction. Anomeric ratio of beta to alpha target compound was 6.7:1.

For extraction of the nucleoside product, the reaction mixture was cooled to a temperature between 70 and 80oC and were combined with 40 ml of 4 N. hydrochloric acid. The product precipitated, was filtered and dried. Quantitative HPLC analysis showed the output of the selected product 59.3%.

Comparative example 28

Obtaining enriched 1-(2'-deoxy-2',2'-debtor-3',5'-di-O - benzoyl-D-ribofuranosyl)-4-aminopyrimidine-2-it is without a catalytic Converter.

2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-methanesulfonate (1.15 g) was subjected to reaction with bistrimethylammonium (6.09 g, 10 equiv.) obtained as described in example 19, in anisole (4 ml) at 110oC for 20 hours.

The HPLC analysis confirmed completion of the reaction and showed out in situ 77 percent. Anomeric ratio of beta to alpha target compound was 3.4:1.

Comparative example 39

Obtaining enriched 1-(2'-deoxy-2',2'-debtor-3',5'-di-O - benzoyl-D-ribofuranosyl)-4-aminopyrimidine-2-it is without a catalytic Converter.

2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-methanesulfonate (1.15 g) was subjected to reaction with bistromathics the AI cesium salts triftoratsetata (obtained in situ by using the processing triftoratsetata (0.13 ml) with an excess of cesium carbonate) for 20 hours.

The HPLC analysis confirmed completion of the reaction and showed out in situ 70 percent. Anomeric ratio of beta to alpha target product was 6.7: 1.

Example 30

Obtaining enriched beta-anomer 9-[1-(2'-deoxy-2',2'-debtor - 3', 5'-di-O-benzoyl-D-ribofuranosyl)] -2,6-dipivaloylmethane with 2 equivalents of potassium salt of 2,6-dipivaloylmethane.

To 100 mg of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 1 ml of dichloromethane and 0.036 ml of triethylamine. This solution was mixed with 23oC for 15 minutes, cooled to -40oC and subjected to reaction with 0.045 ml triftormetilfullerenov anhydride, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D - ribofuranosyl-3,5-Dibenzoyl-1-triftorbyenzola in solution.

185 mg of a suspension of 2,6-dipivaloylmethane were prepared in 1.5 ml of acetonitrile and maintained in anhydrous atmosphere Altanbulag. To the suspension was added 65 mg of potassium tert-butylate, and the resulting mixture stirred at 23oC for 10 minutes, forming a potassium salt of 2,6-dipivaloylmethane. Sol was cooled to 0oC and subjected to reaction with enriched alpha-anomer solution of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-DIBI blocked nucleoside, that was confirmed by HPLC analysis.

Anomeric ratio of beta to alpha blocked nucleoside was 2:1.

For the extraction nucleoside product from the reaction mixture were added 25 ml of ethyl acetate, 1 ml water, 1 ml of 1 N. hydrochloric acid and 2 ml of a saturated aqueous solution of sodium chloride. The organic layer was separated, washed with 5 ml saturated aqueous sodium bicarbonate solution, 5 ml of saline solution and dried over magnesium sulfate.

Quantitative HPLC analysis showed the combined yield of blocked beta - and alpha-anomer nucleoside 42 percent.

Example 31

Obtaining enriched beta-anomer 9-[1-(2'-deoxy-2',2'-debtor - 3', 5'-di-O-benzoyl-D-ribofuranosyl)] -2,6-dipivaloylmethane with 2 equivalents of potassium salt of 2,6-dipivaloylmethane.

To 1 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 0.55 ml of triethylamine and 8.33 ml of dichloromethane at 23oC. the Mixture was cooled to -78oC and subjected to reaction with 0.53 ml triftormetilfullerenov anhydride in 0.50 ml of dichloromethane, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl - 3,5-dibenzoate-1-triftorbyenzola in solution. Measures were taken to maintain was tangalos in 30 ml of acetonitrile and kept in anhydrous nitrogen atmosphere. To this suspension was added 651 mg of potassium tert-butylate, and the resulting mixture stirred at 23oC for 15 minutes, forming a potassium salt of 2,6-dipivaloylmethane. The salt suspension was added to 20 ml of dry dichloromethane, cooled to 0oC and subjected to reaction with enriched alpha-anomer solution of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate-1 - triftoratsetata, stirred for 1 hour and heated to 23oC, forming a target blocked nucleoside, which was confirmed by HPLC analysis.

Anomeric ratio of beta to alpha blocked nucleoside was 2:1.

For the extraction nucleoside product from the reaction mixture were added 50 ml of ethyl acetate and 50 ml of 1 N. hydrochloric acid. The organic layer was separated and was washed with 50 ml of 5% sodium bicarbonate. The organic layer was separated and was washed with 50 ml saturated aqueous sodium chloride and dried over magnesium sulfate.

Example 32

Obtaining enriched beta-anomer 9-[1-(2'-deoxy-2,2-debtor - 3', 5'-di-O-benzoyl-D-ribofuranosyl)] -6-chloropurine with 2 equivalents of potassium salt of 6-chloropurine.

To 1.4 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate added 14 m is -40oC and subjected to reaction with 0.621 ml triftormetilfullerenov anhydride, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D - ribofuranosyl-3,5-Dibenzoyl-1-triftorbyenzola in solution.

155 mg of a suspension of 6-chloropurine were prepared in 3 ml of acetonitrile and maintained in anhydrous nitrogen atmosphere. To the suspension was added 130 mg of potassium tert-butylate, and the resulting mixture stirred at 23oC for 10 minutes, forming a potassium salt of 6-chloropurine. The salt suspension was cooled to 0oC and subjected to reaction with 2 ml of a solution enriched in alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 - triftoratsetata, stirred for 1 hour and heated to 22oC, forming a target blocked nucleoside, which was confirmed by HPLC analysis.

Anomeric ratio of beta to alpha blocked nucleoside was 2:1.

For extracted nucleoside product from the reaction mixture were added 25 ml of ethyl acetate, 1 ml water, 1 ml of 1 N. hydrochloric acid and 2 ml of a saturated aqueous solution of sodium chloride. The organic layer was separated, washed with 5 ml saturated aqueous sodium bicarbonate solution and 5 ml of saline solution and sushils is aside 27%.

Example 33

Obtaining enriched beta-anomer 9-[1-(2'-deoxy-2',2'-debtor - 3', 5'-di-O-benzoyl-D-ribofuranosyl)]-2,6-dichloro-3-deazapurine with 2 equivalents of potassium salt of 2,6-dichloro-3-deazapurine.

To 1.4 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 14 ml of dichloromethane and 0.515 ml of triethylamine. This solution was mixed with 23oC for 15 minutes, cooled to -40oC and subjected to reaction with 0.621 ml triftormetilfullerenov anhydride, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D - ribofuranosyl-3,5-Dibenzoyl-2,2-triftorbyenzola in solution.

82 mg of a suspension of 2,6-dichloro-3-deazapurine was obtained in 1.5 ml of acetonitrile and kept in anhydrous conditions in an atmosphere of nitrogen. 49 mg of potassium tert-butylate were added to the suspension, and the resulting mixture stirred at 23oC for 10 minutes, forming a potassium salt of 2,6-dichloro-3-deazapurine. The salt suspension was cooled to 0oC and subjected to interaction with enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 - triftoratsetata in solution, stirred for 1 hour and heated to 20oC, forming a target blocked nucleoside that is confirmed by the tx2">

For the extraction nucleoside product from the reaction mixture were added 25 ml of ethyl acetate, 1 ml water, 1 ml of 1 N. hydrochloric acid and 2 ml of a saturated aqueous solution of sodium chloride. The organic layer was separated, washed with 5 ml saturated aqueous sodium bicarbonate solution and 5 ml of saline solution and dried over magnesium sulfate.

Quantitative HPLC analysis showed the combined yield of blocked beta-anomeric nucleoside 21 percent, so pl. 127-129oC.

Example 34

Obtaining enriched beta-anomer 9-[1-(2'-deoxy-2',2'-debtor - 3', 5'-di-O-benzoyl-D-ribofuranosyl)] -2,6-dichloropurine with 2 equivalents of potassium salt of 2,6-dichloropurine.

To 1.4 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 14 ml of dichloromethane and 0.515 ml of triethylamine. This solution was mixed with 23oC for 15 minutes, then cooled to -40oC and subjected to reaction with 0.621 ml triftormetilfullerenov anhydride, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 - triftorbyenzola in solution.

Were prepared suspension of 220 mg of 2,6-dichloropurine in 3 ml of acetonitrile and kept in anhydrous nitrogen atmosphere. Was added 130 mg of tert-yewww salt of 2,6-dichloropurine. The salt suspension was cooled to 0oC and subjected to reaction with enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 - triftoratsetata solution, stirred for 1 hour and heated to 22oC, forming a target blocked nucleoside, which was confirmed by HPLC analysis. Anomeric ratio of beta to alpha blocked nucleoside amounted to 2.5:1.

For the extraction nucleoside product from the reaction mixture were added 25 ml of ethyl acetate, 1 ml water, 1 ml of 1 N. hydrochloric acid and 2 ml of a saturated aqueous solution of sodium chloride. The organic layer was separated, washed with 5 ml saturated aqueous sodium bicarbonate solution, 5 ml of saline solution and dried over magnesium sulfate.

Quantitative HPLC analysis showed a yield of blocked beta-anomeric nucleoside 22 percent.

Example 35

Obtaining enriched beta-anomer 1-[1-(2'-deoxy-2',2'-debtor - 3', 5'-di-O-benzoyl-D-ribofuranosyl)] -3-carboethoxy-1,2,4-triazole with 2 equivalents of potassium salt of 3-carboethoxy-1,2,4-triazole.

To 1.4 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 14 ml of dichloromethane and 0.515 ml of triethylamine. This solution was mixed with 23

Were prepared suspension of 164 mg of ester triazole in 3 ml of acetonitrile and maintained in anhydrous nitrogen atmosphere. Added 131 mg of potassium tert-butylate, and the resulting mixture stirred at 23oC for 10 minutes, forming a potassium salt of 3-carboethoxy-1,2,4-triazole. The salt suspension was cooled to 0oC and subjected to reaction with 2 ml of a solution enriched in alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 - triftoratsetata, stirred for 40 minutes and was heated to 15oC, forming a target blocked nucleoside, which was confirmed by HPLC analysis.

Anomeric ratio of beta to alpha blocked nucleoside was 2.5:1.

For the extraction nucleoside product from the reaction mixture were added 25 ml of ethyl acetate, 1 ml water, 1 ml of 1 N. hydrochloric acid and 2 ml of a saturated aqueous solution of sodium chloride. The organic layer was separated, washed with 5 ml saturated aqueous sodium bicarbonate solution, 5 ml of saline solution and dried over magnesium sulfate.

Quantitative HPLC analysis showed the beta-anomer 9-[1-(2'-deoxy-2',2'-debtor-3', 5'-di-O-benzoyl-D-ribofuranosyl)] -2 - amino-6 - chloropurine with 2 equivalents of potassium salt of 2-amino-6-chloropurine.

To 1.4 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 14 ml of dichloromethane and 0.515 ml of triethylamine. This solution was mixed with 23oC for 15 minutes, cooled to -40oC and subjected to reaction with 0.621 ml triftormetilfullerenov anhydride, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 - triftorbyenzola in solution.

Were prepared suspension 197 mg of 2-amino-6-chloropurine in 3 ml of acetonitrile and maintained in anhydrous nitrogen atmosphere. Was added 130 mg of potassium tert-butylate, and the resulting mixture stirred at 23oC for 10 minutes, forming a potassium salt of 2-amino-6-chloropurine.

The salt suspension was cooled to 0oC and subjected to reaction with 2 ml of a solution enriched in alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-triptorelin - sulfonate were mixed for 1 hour and heated to 22oC, forming a target blocked nucleoside, which was confirmed by HPLC analysis.

Anomeric ratio of beta to alpha blocked nucleoside was 2: 1.

what was vyvanse sediment. The precipitate was filtered off, was washed with 5 ml saturated aqueous sodium bicarbonate solution, 5 ml of saline solution and dried over magnesium sulfate.

Quantitative HPLC analysis showed a yield of blocked beta-anomer nucleoside 14 percent.

Example 37

Obtaining enriched beta-anomer 9-[1-(2'-deoxy-2',2'-debtor-3', 5'-di-O-benzole-D-ribofuranosyl)] -2,6 - dipivaloylmethane with 2 equivalents of potassium salt of 2,6-dipivaloylmethane.

To of 3.78 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 30 ml of dichloromethane and 1.39 ml of triethylamine. This solution was mixed with 23oC for 15 minutes, cooled to -40oC and subjected to reaction with 1.68 ml triftormetilfullerenov anhydride, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-triftorbyenzola in solution.

Suspension 6.99 g of 2,6-dipivaloylmethane were prepared in 100 ml of acetonitrile and maintained in anhydrous nitrogen atmosphere. Added 2.46 g of potassium tert-butylate, and the resulting mixture stirred at 23oC for 10 minutes and was dried to constant weight in vacuum at 40oC, forming the potassium salt of 2,6-dipivaloylmethane. With Ogadenia alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 - triftoratsetata, stirred for 1 hour and heated to 22oC, forming a target blocked nucleoside, which was confirmed data analysis HPLC.

For the extraction nucleoside product from the reaction mixture were added 500 ml of ethyl acetate, 20 ml of ice, 20 ml of 1 N. hydrochloric acid and 35 ml of a saturated aqueous solution of sodium chloride. The organic layer was separated, washed with 25 ml of a saturated aqueous solution of sodium bicarbonate, 25 ml of brine and dried over magnesium sulfate. Anomeric ratio of beta to alpha blocked nucleoside was 1.8 : 1.

Quantitative HPLC analysis showed a yield of blocked beta-anomer nucleoside 28 percent, so pl. 138-239oC.

Example 38

Obtaining enriched beta-anomer 9-[1-(2'-deoxy-2',2'-debtor-3', 5'-di-O-benzoyl-D-ribofuranosyl)]-6 - jalanidhipuja with 2 equivalents of potassium salt of 6-jalanidhipuja.

To 1.4 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 14 ml of dichloromethane and 0.515 ml of triethylamine. This solution was mixed with 23oC for 15 minutes, cooled to -40oC and subjected to reaction with 0.621 ml triftormetilfullerenov anhydride, forming an enriched alpha-anomer 2-the camping suspension 255 mg 6-jalanidhipuja in 3 ml of acetonitrile and maintained in anhydrous nitrogen atmosphere. Added 131 mg of potassium tert-butylate, and the resulting mixture stirred at 23oC for 10 minutes, forming a potassium salt of 6-jalanidhipuja. The salt suspension was cooled to 0oC and subjected to reaction with a solution enriched with alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 - triftoratsetata, stirred for 1 hour and heated to 22oC, forming end-blocked nucleides that was confirmed by the data of HPLC analysis.

Anomeric ratio of beta to alpha blocked nucleoside was 2:1.

For the extraction nucleoside product from the reaction mixture were added 25 ml of ethyl acetate, 1 ml water, 1 ml of 1 N. hydrochloric acid and 2 ml of a saturated aqueous solution of sodium chloride. The organic layer was separated, washed with 5 ml saturated aqueous sodium bicarbonate solution, 5 ml of saline solution and dried over magnesium sulfate.

Quantitative HPLC analysis showed the combined yield of blocked beta - and alpha-anomer nucleoside 28 percent.

Example 39

Obtaining enriched beta-anomer 9-[1-(2'-deoxy-2',2'-debtor-3'-, 5'-di-O-benzoyl-D-ribofuranosyl)]- 8-bromo-7-cyano-deaza-6-palmettopride with 2 equivalent of the 3,5-bientot was added 14 ml of dichloromethane and 0.515 ml of triethylamine. This solution was mixed with 23oC for 15 minutes, cooled to -40oC and subjected to reaction with 0.621 ml triftormetilfullerenov anhydride forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 - triftorbyenzola in solution.

Were prepared suspension 187 ml of 8-bromo-7-cyano-7-deaza-6-paulminneapolis in 3 ml of acetonitrile and maintained in anhydrous nitrogen atmosphere. Was added 65 mg of potassium tert-butylate, and the resulting mixture stirred at 23oC for 10 minutes, forming a potassium salt of 8-bromo-7-cyano-7-deaza-6-pivalamidine. The salt suspension was cooled to 0oC and subjected to the reaction with 1 ml of a solution enriched in alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-1-triftoratsetata, stirred for 1 hour and heated to 20oC, forming a target blocked nucleoside, which was confirmed data analysis HPLC.

Anomeric ratio of beta to alpha blocked nucleoside was 2:1.

For the extraction nucleoside product from the reaction mixture were added 25 ml of ethyl acetate, 1 ml water, 1 ml of 2 N. hydrochloric acid and 2 ml of a saturated aqueous solution of sodium chloride. The organic layer on the d magnesium sulfate.

Quantitative HPLC analysis showed the combined yield of blocked beta - and alpha-anomer nucleoside 24 percent.

Example 40

Obtaining enriched beta-anomer 9-[1-(2'-deoxy-2','2'- debtor-3', 5'-di-O-benzoyl-D-ribofuranosyl)] -2,6 - dipivaloylmethane with 2 equivalents of potassium salt of 2,6-dipivaloylmethane in different reaction solvents.

To 1 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 10 ml of dichloromethane and 0.36 ml of triethylamine. This solution was mixed with 23oC for 15 minutes, cooled to -40oC and subjected to reaction with 0.45 ml triftormetilfullerenov anhydride, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 - triftorbyenzola in solution.

Were prepared suspension of 1.85 g of 2,6-dipivaloylmethane in 30 ml of acetonitrile and maintained in anhydrous nitrogen atmosphere. Was added 0.65 g of potassium tert-butylate, and the resulting mixture stirred at 25oC for 10 minutes, forming a potassium salt of 2,6-dipivaloylmethane. The salt suspension was dried in vacuum at 40oC, forming a white solid with a constant weight. 207 mg of purine salt suspendibility 1.5 was restaurados reaction with 1 ml of enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 - triftoratsetata, the mixture was mixed for 1 hour and heated to 0oC, forming a target blocked nucleoside, which was confirmed data analysis HPLC.

Anomeric relations beta to alpha blocked nucleoside is shown below.

For the extraction nucleoside product from the reaction mixture were added 25 ml of ethyl acetate, 1 ml water, 1 ml of 1 N. hydrochloric acid and 2 ml of a saturated aqueous solution of sodium chloride. The organic layer was separated, was washed with 2 ml of saturated aqueous sodium bicarbonate solution, 5 ml of saline solution and dried over magnesium sulfate.

Quantitative HPLC analysis showed a yield of blocked beta-anomer nucleoside, are given in table. 3 (see the end of the description).

Example 41

Obtaining enriched beta-anomer 9-[1-(2'-deoxy-2','2'- debtor-3', 5'-di-O-benzoyl-D-ribofuranosyl)] -2-acetamido-6 - diphenylchlorosilane with 2 equivalents of potassium salt of 2-acetamido-6-diphenylchlorosilane.

To 1.4 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 14 ml of dichloromethane and 0.515 ml of triethylamine. This solution was mixed with 23oC for 15 minutes, cooled to -40oC and subjected to reaction with 0.621 ml triftoratsetilatsetonom in solution.

Was prepared a solution of 2.56 g of 2-acetamido-6-diphenylchlorosilane in 50 ml of hot dimethylformamide and maintained in anhydrous nitrogen atmosphere. The solution was cooled to 25oC, was added 0.74 g of potassium tert-butylate. The resulting mixture was mixed at 23oC for 10 minutes and was evaporated to an oil, which was pulverized with ether, collected on a filter and dried in vacuum at 40oC, giving potassium salt of 2-acetamido-6-diphenylchlorosilane. 496 mg of purine salt suspendibility in 3 ml of dichloromethane, and the suspension was cooled to 5oC and subjected to reaction with a solution enriched with alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 - triftoratsetata, stirred for 1 hour and heated to 25oC, forming a target blocked nucleoside, which was confirmed data analysis HPLC.

Anomeric relations beta to alpha blocked nucleoside was 1.8:1.

For the extraction nucleoside product from the reaction mixture were added 25 ml of ethyl acetate, 1 ml water, 1 ml of 1 N. hydrochloric acid and 2 ml of a saturated aqueous solution of sodium chloride. The organic layer was separated, washed with 5 ml saturated aqueous solution of bicarbonate by 5.8%.

Example 42

Obtaining enriched beta-anomer 9-[1-(2'-deoxy-2','2'- debtor-3', 5'-di-O-benzoyl-D-ribofuranosyl)] -2,6 - dipivaloylmethane with 7 equivalents of 2,6-potassium salt of 2,6-dipivaloylmethane.

To 100 mg of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate was added 3 ml of dichloromethane and 0.036 ml of triethylamine. This solution was mixed with 23oC for 15 minutes, cooled to -78oC and subjected to reaction with 0.045 ml triftormetilfullerenov anhydride, forming an enriched alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 - triftorbyenzola in solution.

Were prepared suspension of 1.85 g of 2,6-dipivaloylmethane in 30 ml of acetonitrile and maintained in anhydrous nitrogen atmosphere. Was added 0.65 g of potassium tert-butylate, and the resulting mixture stirred at 23oC for 10 minutes and dried in vacuum at 40oC, forming the potassium salt of 2,6-dipivaloylmethane, which was cooled to -78oC. Purine salt was subjected to reaction with a solution enriched with alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 - triftoratsetata at the 23oC, stirred for 1.5 hours and heated to 22oC, forming casinogo product from the reaction mixture were added 25 ml of ethyl acetate, 1 ml of ice, 1 ml of 1 N. hydrochloric acid and 2 ml of a saturated aqueous solution of sodium chloride.

The organic layer was separated, washed with 5 ml saturated aqueous sodium bicarbonate solution, 5 ml of saline solution and dried over magnesium sulfate.

Anomeric ratio of beta to alpha blocked nucleoside was 2.7:1.

Example 43

Obtaining enriched beta-anomer 1-(2'-deoxy-2', 2'- debtor-3', 5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidine-2-one with 3 equivalents of bis-trimethylsilylacetamide.

Bis-trimethylsilylmethyl were prepared by combining 292 mg of cytosine with 2 ml hexamethyldisilazane, 11 mg of ammonium sulfate and 5 ml of xylene, and heating the solution under reflux for one hour with the formation of a homogeneous solution. The excess xylene and hexamethyldisilazane was removed, leaving the fused residue of bis-trimethylsilylacetamide. Molten bis-trimethylsilylacetamide was added 400 mg of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 -- methansulfonate dissolved in 2 ml of xylene and the xylene was removed. The temperature of the reaction mixture was maintained at 160oC for 15 minutes.

The HPLC analysis confirmed the completion reane nucleoside product, the reaction mixture was cooled, it was diluted with 50 ml ethyl acetate and was washed with 50 ml of 1 N. hydrochloric acid.

Example 44

Obtaining enriched beta-anomer 9-(2'-deoxy-2', 2'- debtor-3', 5'-di-O-benzoyl-D-ribofuranosyl)-4-Ketobemidone-2-one with 3 equivalents of bis-trimethylsilylmethyl.

Bis-trimethylsilylmethyl were prepared by combining 295 mg of uracil with 5 ml hexamethyldisilazane, 11 mg of ammonium sulfate and 10 ml of 1,2-dichloroethane. The solution was heated to 110oC for one hour, forming a homogeneous solution, and the excess xylene and hexamethyldisilazane was removed, giving the fused bis-trimethylsilylmethyl.

Molten bis-trimethylsilylmethyl was added 200 mg of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 -- methansulfonate. The temperature of the reaction mixture was maintained at 150oC within 2 hours.

The HPLC analysis confirmed completion of the reaction. Anomeric ratio of alpha to beta blocked nucleoside was 1:1.8.

For extraction of the nucleoside product, the reaction mixture was cooled, it was diluted with 50 ml ethyl acetate and was washed with 50 ml of 1 N. hydrochloric acid.

Example 45

Obtaining enriched beta-anomer 1-(2'-deoxy-2', 2'- debtor-3', 5'-di-O-rasplavlennogo bis-trimethylsilylethynyl was added 200 mg of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 -- methansulfonate. The temperature of the reaction mixture was maintained at 130oC for 1 hours.

The HPLC analysis confirmed completion of the reaction. Anomeric ratio of the blocked nucleoside product of beta to alpha blocked nucleoside was 1.7:1.

For extraction of the nucleoside product, the reaction mixture was diluted with 100 ml ethyl acetate and was washed with 100 ml of 1 N. hydrochloric acid. Quantitative HPLC analysis of the organic layer showed that the yield of blocked beta-anomer nucleoside was 50%.

Example 46

Obtaining enriched beta-anomer 1-(2'-deoxy-2', 2'- debtor-3', 5'-di-O-benzoyl-D-ribofuranosyl)-4-acetamidophenyl-2-one with 3 equivalents of bis-trimethylsilyl-N-acetylcytosine.

To 500 ml of bis-trimethylsilyl-N-acetylcytosine was added to 980 mg of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 -- methansulfonate. The temperature of the reaction mixture was maintained at 100oC for 3 hours.

The HPLC analysis confirmed completion of the reaction. Anomeric ratio of beta to alpha blocked nucleoside amounted to 1.4:1.

For extraction of the nucleoside product, the reaction mixture was cooled, it was diluted with 25 ml ethyl acetate was filtered and 25 ml of 1 N. hydrochloric to the od of blocked beta-anomer nucleoside was 34 percent.

Example 47

Obtaining enriched beta-anomer 1-(2'-deoxy-2', 2'- debtor-3', 5'-di-O-benzoyl-D-ribofuranosyl)-4-acetamidophenyl-2-one with 3 equivalents of bis-trimethylsilyl-N-acetylcytosine.

To 393 ml of bis-trimethylsilyl-N-acetylcytosine was added 200 mg of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 -- methansulfonate. The temperature of the reaction mixture was maintained at 100oC for 1 hour.

Anomeric ratio of beta to alpha blocked nucleoside product was 2.3:1.

For extraction of the nucleoside product, the reaction mixture was diluted with 40 ml ethyl acetate was filtered and 25 ml of 1 N. hydrochloric acid. Quantitative HPLC analysis of the organic layer showed that the release of the beta-anomer nucleoside was 27 percent.

Example 48

Obtaining enriched beta-anomer 1-(2'-deoxy-2',2'-debtor-3',5'-di-O-benzoyl-D-ribofuranosyl)-4 - aminopyrimidine-2-it with 20 equivalents of bis-trimethylsilylacetamide.

Bis-trimethylsilylmethyl was obtained by combining 4.9 g of cytosine with 90 ml hexamethyldisilazane, 581 mg of ammonium sulfate and 2 ml of xylene and heating the solution for two hours with the formation of a homogeneous solution. Excess hexamethylditin the 2-debtor-D-ribofuranose-3,5-Dibenzoyl - 1 -- methanesulfonate, dissolved in 5 ml of acetonitrile, and the acetonitrile was removed. The temperature of the reaction mixture was maintained at 130oC under vacuum for 1 hour.

The HPLC analysis showed complete reaction. Anomeric ratio of beta to alpha blocked nucleoside product was 3.9:1.

For extraction of the nucleoside product, the reaction mixture was diluted with 100 ml of dichloromethane and washed successively with 100 ml of 1 N. hydrochloric acid and 200 ml of 5% sodium bicarbonate, and then 200 ml of saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and evaporated to 1.03 g of yellow solid.

Quantitative HPLC analysis showed that the yield of beta-anomer nucleoside amounted to 43 percent.

In table. 4 (see below) shows how the selected carbohydrate, the reaction temperature and the molar amount equivalent nucleoside affect the output, and the anomeric ratio nucleoside product.

(N/D)means not determined. Carbohydrates (Carbo.) are hydroxybudesonide. Designations or - OMs are alpha - or beta-2,2-debtor-2-deoxy-D-ribofuranosyl-3,5-Dibenzoyl-1 - methanesulfonate and - or - OTs are beta - or alpha-2,2-debtor-2-the creation of carbohydrate and calculated by quantitative HPLC analysis in reverse phase, at which the peak of the corresponding solution of the product was compared with a standard, 1-(2'-deoxy-2',2'- debtor-3',5'-di-O-benzoyl-beta-D-ribofuranosyl)-4 - aminopyrimidine-2-one. The protective group of the nucleoside bases in each example is trimethylsilyl.

Example 49

Obtaining enriched beta-anomer 1-(2'-deoxy-2', 2'-debtor - 3', 5'-di-O-benzoyl-D-ribofuranosyl)-4-palmitoylated-2-she's in acetonitrile.

N-palmitoylation (1.0 g, 5.5 mmol) was suspensible in acetonitrile (15.0 ml) and was treated with tributyltin potassium (0.062 g, 5.5 mmole) and stirred under nitrogen atmosphere at 25oC, forming the potassium salt of N-evalualtion.

2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1 -- (n-brabanthallen (2.99 g, 5.0 mmol) in acetonitrile (10.0 ml) was added to the aforementioned salt, and the whole mixture was subjected to reaction for 5.5 hours at 65oC, forming a blocked nucleoside.

The HPLC analysis confirmed completion of the reaction and showed the anomeric ratio of beta to alpha 3.9:1.

To highlight the nucleoside product, the reaction mixture was distributed between ethyl acetate and water, and the organic layer was washed with sodium bicarbonate and dried over magnesium sulfate. Chromatogra is SUP>oC.

Example 50

Obtaining enriched beta-anomer 1-(2'-deoxy-2', 2'-debtor - 3', 5'-di-O-benzoyl-D-ribofuranosyl)-4-(N-pialligo)aminopyridin-2-she's in acetonitrile.

N-palmitoylation (0.098 g, 0.5 mmole) was suspenderbelt in acetonitrile (1.5 ml) and processed tert-butyl potassium (0.062 g, 0.55 mmole) and stirred under nitrogen atmosphere at 25oC, giving potassium salt of N-evalualtion.

The above salt was added 2-deoxy-2,2-debtor-D - ribofuranosyl-3,5-Dibenzoyl-1-iodide (0.244 g, 0.5 mmole) in acetonitrile (1.5 ml), and the mixture was subjected to interaction within 24 hours at 60oC, giving a blocked nucleoside.

The HPLC analysis confirmed completion of the reaction and showed the anomeric ratio of beta to alpha 1.13:1.

Example 51

obtaining enriched beta-anomer 1-(2'-deoxy-2', 2'-debtor - 3', 5'-di-O-benzoyl-D-ribofuranosyl)-1,2,4-triazole-3-carbonitrile and aconitine.

1,2,4-triazole-3-carbonitrile (0,101 g, 1.03 mmole) was suspenderbelt in acetonitrile (10 ml) and was treated with sodium hydride) (0.445 g, 1.12 mmole) and stirred under nitrogen atmosphere at 25oC with the formation of the corresponding sodium salt of the triazole. The above salt was added 2-deoxy-2,2-debtor-D 78 hours at 82oC, forming a blocked nucleoside.

The HPLC analysis confirmed completion of the reaction and showed the anomeric ratio of beta to alpha 1.2:1.

To highlight the nucleoside product, the reaction mixture was evaporated, leaving an oily solid, which was diluted with ethyl acetate, washed with sodium bicarbonate and dried over magnesium sulfate and concentrated. The residue is crystallized from the pattern, giving 30 mg of the desired product with a yield of 6%, so pl. 225 - 226oC. MC (FD) M/Z 455 (M+I).

Elemental analysis for C22H16F2N4O5: (Theoretical) C 58.15, H 3.55, N, 12.33. (Empirical) C With 58.36, H 3.79, N 12.10.

Example 52

Obtaining enriched beta-anomer 1-(2'-deoxy-2',2'-debtor-3',5'-di-O-benzoyl-D-ribofuranosyl)-1,2,4 - triazole-3-carbonitrile in acetonitrile.

1,2,4-triazole-3-carbonitrile (0.272 g, 2.89 mmole) was suspenderbelt in acetonitrile 20 ml) was treated with sodium hydride (0.094 g, 2.7 mmole) and stirred under nitrogen atmosphere at 25oC, forming a sodium salt of a triazole.

To this salt was added 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-iodide (0.941 g, 1.9 mmole) in acetonitrile (20 ml), and the mixture was subjected to reaction for 48 hours at 82oC, fellowship beta to alpha 3.5:1.

To highlight the nucleoside product, the reaction mixture was evaporated, leaving an oily solid, which was diluted with ethyl acetate, washed with sodium bicarbonate, dried over magnesium sulfate and concentrated. The residue is crystallized from ethanol, giving 0.421 g of the target product; so pl. 225-226oC with the release of 48%.

MC/FD/M/Z455/M+1/.

Elemental analysis for C22H16F2N4O5: (Theoretical) C 58.15. H 3.55, N, 12.33. (Empirical) C At 58.35, H 3.65 , N, 12.33.

Example 53

Obtaining enriched (9) regioisomer-beta-anomer 1-(2'-deoxy-2'2, 2'-debtor-3', 5'-di-O-benzoyl-D-ribofuranosyl)-6-cyanobutane in N,N-dimethylacetamide.

6-Canouan (0.92 g, 6.35 mmol) was suspenderbelt in N,N-dimethylacetamide (12 ml) and treated with sodium hydrate (0.396 g, 8.25 mmol) and stirred under nitrogen atmosphere at 25oC, giving the sodium salt of 6-cyanobutane.

The above salt was added 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-iodide (3.09 g, 6,35 ml) in N,N-dimethylacetamide (4 ml), the mixture was subjected to reaction for 5 hours at 70oC, forming a blocked nucleoside.

The HPLC analysis confirmed completion of the reaction and showed the anomeric ratio of beta to 1.2:1.

To highlight the nucleoside product, the reaction mixture was cooled, the solvent was removed in vacuo, the residue was dissolved in ethyl acetate, was filtered by a 0.2 M solution of lithium chloride, dried over magnesium sulfate and concentrated. Chromatography on a column (silica gel, toluene/ethyl acetate 9:1/ gave 0.21 g of the desired product with a yield of 6.5% MC (FD) 506 (M+1). Elemental analysis for C25H17F2N5O5: (Theoretical) C 59.41, H 3.39, N At 13.86. (Empirical) C 59.85, H 3.49 , N, 13.48.

Example 54

Obtaining enriched (9) regioisomer-beta-anomer 1-(2'-desoxy-2, '2' -debtor-3',5'-di-O-benzoyl-D-Returnil)-2,6-(devalued)diaminopurine in N,N-dimethylacetamide.

2,6-(diivanid/diaminopurine) 0.159 g 0.5 mmole) was suspenderbelt in N, N-dimethylacetamide (1.0 ml) and processed tert-butyl potassium (0.062 g, 0.55 mmol) and stirred under nitrogen atmosphere at 25oC, forming the potassium salt of 2,6-(tipuloid)diaminopurine.

The above salt was added 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-- (n-Brabanthal)sulfonate (0.299 g, 0.5 mmole) in N,N-dimethylacetamide (0.5 ml), and the mixture was subjected to reaction for 6 hours at 60oC, forming a blocked nucleoside.

The HPLC analysis padta selection nucleoside product, the reaction mixture was cooled, and the solvent was removed under vacuum. The residue was diluted with ethyl acetate, washed with sodium bicarbonate, dried over magnesium sulfate and concentrated to oil. Chromatography on a column (silikagelya/ethyl acetate 1:1) gave forms 0.141 g as alpha and beta nucleoside products with an output of 28%. MC (FD) 679 (M+1).

Example 55

Obtaining enriched (9)-regioisomer-beta-anomer 1-(2'-deoxy-2', 2'-debtor-3',5'-di-O-benzoyl-D-ribofuranosyl)-2,6 -(devalued)diaminopurine in acetonitrile

2,6-(diivanid/diaminopurine/0.159 g, 0.5 mmole/ suspenderbelt in acetonitrile /1.5 ml and processed tert-butyl potassium (0.062 g, 0.55 mmole) and stirred under nitrogen atmosphere at 25oC with the formation of the potassium salt of 2,6-(devalued)diaminopurine.

To this salt was added 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1- -- iodide (0.244 g, 0.5 mmole) in acetonitrile (1.5 ml), and the mixture was subjected to reaction for 16 hours at 60oC, forming a blocked nucleoside.

The HPLC analysis confirmed completion of the reaction, and pointed to the anomeric ratio of beta to alpha 2.2:1.

To highlight the nucleoside product, the reaction mixture was diluted with ethyl acetate, the organic layer was filtered by bicorporeal, toluene/ethyl acetate 1:1) followed by recrystallization gave 0.085 g of the desired product with a yield of 25%. MC (FD) 679 (M+1).

Example 56

Obtaining enriched beta-anomer 1-(2'-deoxy-2',2'-debtor-3',5'-di-O-benzoyl-D-ribofuranosyl)-4-(benzylamino) pyrimid-2-it is in N,N-dimethylacetamide.

N-benzyliden (0.099 g, 0.493 mmole) was suspenderbelt in N,N-dimethylacetamide (2.0 ml) and treated with sodium hydride (0.0256 g, 0.534 mmole) were mixed in a nitrogen atmosphere at 25oC with the formation of the sodium salt of N-benzylacetone.

To this salt was added 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-iodide (0.201 g, 0.411 mmole) in N,N-dimethylacetamide (1.5 ml), and the mixture was subjected to reaction for 5 hours at 23oC with the formation of the blocked nucleoside.

The HPLC analysis confirmed the completion of reaction was indicated on the anomeric ratio of beta to alpha 1.9:1.

The reaction solvents were removed under vacuum, and the residue was dissolved in ethyl acetate, washed with sodium bicarbonate, dried over magnesium sulfate and concentrated to oil. Chromatography on a column (silica gel, toluene/ethyl acetate 9: 1) gave 0.015 mg of the desired product with a yield of 6.5 percent. MC (FD) 562 (M+2).

Example 57

Ethyl 1,2,4-triazole-3-carboxylate (0.723 g, 5.13 mmol) was suspenderbelt in N, N-dimethylacetamide (2.5 ml) was treated with sodium hydride (0.123 g, 5.13 mmol) and stirred under nitrogen atmosphere at 25oC with the formation of the sodium salt of a triazole.

To this salt was added 2-deoxy-2,22-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-iodide (2.0 g, 4.11 mmole) in N,N-dimethylacetamide (2.5 ml), and the mixture was subjected to reaction for 24 hours at 23oC, forming a blocked nucleoside. The HPLC analysis confirmed completion of the reaction and showed the anomeric ratio of beta to alpha 3:1.

The crude reaction mixture was purified by removing the solvent under reduced pressure and the use of chromatography on a column (silica gel, toluene/ethyl acetate 9:1). Combined theoretical yield of alpha and beta regioisomers (A and B below) of the blocked nucleoside was 67 percent.

A.

Ethyl 1-(2'-deoxy-2,2'-debtor-3', 5'-di-O-benzoyl-a-D-ribofuranosyl)-1,2,4-triazole-3-carboxylate (436 mg, 21.2% yield).

< / BR>
Recrystallization "A" from a mixture of ethyl acetate : isooctane gave 267 mg of pure beta-anomer with the release of 13%.

B.

Ethyl 1-(2'-deoxy-2', 2'-debtor-3', 5'-di-O-benzoyl-a-D-ribofuranosyl)-1,2,4-triazole-5-carefor-D-ribofuranosyl-1 -- (2-amino-6-chloropurine) in dimethylacetamide.

To a suspension of 2-amino-6-chloropurine (82.6 mmole, 14.0 g) in dimethyl-ndimethylacetamide (900 ml) at 0oC in an atmosphere of nitrogen was added powdered potassium hydroxide (99.12 mmole, 5.5 g). The mixture was mixed for 30 minutes, forming a solution. Was added 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-iodide (82.6 mmole, 40.31 g) in dimethylacetamide (450 ml). The reaction mixture was left to warmed to room temperature and stirred under nitrogen atmosphere over night.

The product was extracted by adding ethyl acetate and brine. The organic layer was washed successively 1 N. HCl, saturated sodium bicarbonate solution, water and brine. The organic layer was then dried over sodium sulfate and evaporated in vacuum.

The crude product was purified using chromatography on silica gel, giving a 3:1 anomeric ratio of beta to alpha 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-Dibenzoyl-1-(2-amino - 6-globulin).

1H NMR (300 MHz, CD3CD), 4.68 (m, 2H), 4'-H, 5'- a-H), 4.90 (m, 1H, 5' b-H), 6.02 (m, 1H, 3'-H), 6.29 (m, 1H, 1'-H), 7.53 (m, 6H, Bz), 7.92 (C., 1H, 8'-H), 8.05 (m, 4H, Bz).

Dibenzyline intermediate compound (0.49 mmole, 260 mg) was deblokirovkoj suspendirovanie him in methanol at 0oC and nasishennokrasnie night. The solution was then flushed with nitrogen and was evaporated. The target product was then purified by washing non-polar solvent, such as methylene chloride, to remove benzoate products. Beta-anomer was separated using HPLC in reverse phase.

1H NMR (300 MHz, CD3CD), 3.90 (m, 3H, 4'-H, 5'-H), 4,58 (m, 1H, 3'-H), 6.27 (DD., 1H, 1'-H), 8.31 C., 1H, 8-H).

Getting 1

Enriched with alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-di-O-benzoyl-1 - methanesulfonate.

To a solution of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-dibenzoate (40 mg) in methylene chloride (0.5 mg) was added triethylamine (0.025 ml). After stirring at room temperature for 30 minutes the mixture was cooled to -78oC, then added methanesulfonamide (0.01 ml). The reaction temperature was maintained between -78oC and -80oC for 30 min, then was warmed up to room temperature.

The HPLC analysis showed that the reaction was completed. Anomeric ratio of target compound alpha to beta according to the definition using the 19F NMR analysis: it was 4:1.

Getting 2

Alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl - 3,5-di-O-benzoyl-1-methanesulfonate.

To a solution of 2-deoxy-2,2-debtor-D-ribofuranose is emiliania at room temperature for 30 minutes, the mixture was cooled to -78oC. After 5 minutes, to the mixture was added methanesulfonamide (14 ml, 1.2 EQ.) in dichloromethane (140 ml). The reaction temperature was maintained between -78oC and -80oC in nitrogen atmosphere for one hour.

The HPLC analysis showed that the reaction was completed. Anomeric ratio of the target compounds according to the HPLC analysis was 3.53:1 alpha to beta.

For selection of the target compounds, the reaction mixture was washed with water, 1 N. HCl solution and 5% sodium bicarbonate solution (30 ml each). The organic layer was separated and dried over anhydrous magnesium sulfate. The target compound (31.5 g) was obtained with a yield of 46%, so pl. 88-89oC; []D(1.01, CHCl3) + 84.2; []365am+302.0o. Elemental analysis: C20H18O8SF2:

Calculated: C, 52.63, H 3.98, F 8.33, S 7.02 (456.4).

Found: C, 52.92, H 3.82, F 8.33, S 7.30;

1H NMR (CDCl3), = 3.17 (CH3), 4.66 and 4.76 (C-5H), 4.84 (C-4H), 5.57 (C-3H), 6.13 (C-1H),13C NMR (CDCl3), = 40.22 (CH3), 62.51 (C-5H), 71.03 (C-3H), JC,F= 18.3, 38,5 Hz), 82.75 (C-4H), 99.59 (C-1H, JC,F= 25.5, 48.3 Hz), 122.24 (C-2H, JC,F= 259, 286 Hz).

Getting 3

Enriched with alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5-di-O-benzoyl - 1-methanesulfonate.

To anonemail) was added N,N-dimethylbenzylamine-methanesulfonate (100 mg). The mixture is stirred and heated up to the temperature of reflux distilled. The HPLC analysis was used to determine the ratio of alpha to beta of the target product and showed the following:

Time/clock - alpha/beta

0 - 1:32

16 - 1.0:1.4

24 - 2.3:1.0

Getting 4

Enriched with alpha-anomer 2-deoxy-2,2-debtor-D-ribofuranosyl - 3,5-di-O-benzoyl-1-methanesulfonate.

To anomeric mixture of 2-deoxy-2,2-debtor-D-ribofuranosyl - 3,5-di-O-benzoyl-1-methanesulfonate (29.1 g, 50% beta-anomer) in dichloromethane and n-propyl ... was heated to 90oC to remove dichloromethane. The mixture was cooled to 50-60oC, was added a mixture of triethylamine (5.33 ml, 0.55 EQ.) and methansulfonate (2.04 ml, 0.55 equiv.). The resulting mixture was heated to 95 to 97oC was mixed. The mixture contained 23.2 g of 2-deoxy-2,2-debtor-D-ribofuranosyl-3,5 - di-O-benzoyl-1-methanesulfonate. To determine the ratio of alpha to beta of the target product was used for HPLC analysis and showed the following:

Time (hours) - alpha/beta

4 - 3:1G

1. Method for producing enriched beta-anomer nucleoside of the General formula I

< / BR>
where T is fluorine;

R is a nucleoside selected from the group consisting of radicals

< / BR>
< / BR>
< / BR>
< / BR>
the group, consisting of hydroxy, halogen, primary amine or secondary amine;

R4, R5and R6independently selected from the group consisting of hydrogen, - OH, -NH2N(alkyl)W halogen;

Q is selected from the group consisting of CH, CR8or N, where R8selected from the group consisting of halogen or cyano,

characterized in that conduct SN2replacement is not necessary in a suitable solvent sulfonyloxy (Y) - rich alpha-anomer of carbohydrate formula II

< / BR>
where X is independently selected from hydroxyamine groups;

T has the meanings given above,

at least the molar equivalent of nucleobase (R) selected from the group consisting of

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where R1, R2, R4, R5, R6and Q have the meanings defined above;

Z represents hydroxyamino group;

W represents aminosidine group;

Mrepresents a cation,

moreover, SN2the substitution is carried out at a temperature of 17 ... -120oWith and release with the formation of compounds of formula I.

2. The method according to p. 1, wherein R" is selected from the group consisting of


Z represents hydroxyamino group;

W represents aminosidine group;

Y is selected from the group consisting of alkylsulfonate, arylsulfonate, replaced alkylsulfonate and replaced arylsulfonate group,

moreover, the process is carried out in a solution having a concentration of carbohydrate more than 20 wt.% per unit volume of solvent, and the solvent is an inert solvent with a boiling point of more than 70oC.

3. The method according to p. 1, wherein R" is selected from the group consisting of

< / BR>
< / BR>
< / BR>
where R1selected from the group consisting of hydrogen, alkyl, substituted alkyl and halogen;

R2selected from the group consisting of hydroxy, halogen, primary amino or secondary amino;

Z represents hydroxyamino group;

W represents aminosidine group;

Y is selected from the group consisting of tripterocalyx, 1,1,1-triftoratsetofenona, octafluorocyclopentene, nonatherosclerotic,

moreover, SN2the substitution is carried out at a temperature of from -120 25oWith using antifreeze inert solvent.

4. The method according to p. 1, wherein R" is chosen substituted alkyl and halogen;

Z represents hydroxyamino group;

W represents aminosidine group;

Y is selected from the group consisting of alkylsulfonate, arylsulfonate, replaced alkylsulfonate and replaced arylsulfonate,

moreover, the process is carried out in the presence of a catalyst.

5. The method according to p. 4, characterized in that the catalyst is chosen from vysokointegrirovannyh salts, which are essentially soluble in the solvent and contain dinucleophiles anion.

6. The method according to p. 4 or 5, characterized in that the solvent is selected from polar, denuclearising solvents.

7. The method according to p. 1, wherein R" is selected from the group consisting of

< / BR>
< / BR>
< / BR>
< / BR>
where R2selected from the group consisting of hydroxy, halogen, primary amino or secondary amino;

R4, R5, R6independently selected from the group consisting of hydrogen, - OH, NH2N(alkyl)W halogen;

Q is selected from the group consisting of CH, CR8and N, where R8selected from the group consisting of halogen or cyano;

Z represents hydroxyamino group;

W represents aminosidine group;

Mrepresents a cation;

Y is selected from onafterinitialise;

and the solvent is an inert solvent with a freezing point below the 26oC.

8. The method according to p. 1, wherein the process is carried out in the absence of solvent and R" are selected from the group consisting of

< / BR>
< / BR>
< / BR>
< / BR>
where R1selected from the group consisting of hydrogen, alkyl, substituted alkyl and halogen;

Z represents hydroxyamino group;

W represents aminosidine group, where Y is selected from the group consisting of alkylsulfonate, arylsulfonate, replaced alkylsulfonate and replaced arylsulfonate.

9. The method according to p. 8, characterized in that the reaction is carried out at a temperature of from 100 to 160oC.

10. The method according to p. 1, wherein R" is chosen from the group consisting of

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where R1selected from the group consisting of hydrogen, alkyl, substituted alkyl and halogen;

R2selected from the group consisting of hydroxy, halogen, primary amino and secondary amino;

R4, R5, R6independently selected from the group consisting of hydrogen, - OH, NH2N(alkyl)W halogen;

Q is selected from the group consisting of CH, CR8and N, where R8selected from the group with the second group;

Y is selected from the group consisting of alkylsulfonate, arylsulfonate, replaced alkylsulfonate and replaced arylsulfonate.

11. The method according to any of paragraphs.1 to 10, characterized in that hidroxizina group X in the compounds of formula II is benzoyl.

12. The method according to any of paragraphs.1 to 10, characterized in that sulfonyloxy Y of the compounds of formula II represents methanesulfonate.

13. The method according to p. 2, characterized in that sulfonyloxy Y of the compounds of formula II represents methanesulfonate.

14. The method according to p. 4, characterized in that sulfonyloxy Y of the compounds of formula II represents methanesulfonate.

15. The method according to p. 5, characterized in that sulfonyloxy Y of the compounds of formula II represents methanesulfonate.

16. The method according to p. 6, characterized in that sulfonyloxy Y of the compounds of formula II represents methanesulfonate.

17. The method according to p. 8, characterized in that sulfonyloxy Y of the compounds of formula II represents methanesulfonate.

18. The method according to p. 9, characterized in that sulfonyloxy Y of the compounds of formula II predstavljaet methansulfonate.

19. the XI.

20. The method according to p. 1, characterized in that sulfonyloxy Y of the compounds of formula II represents tripterocalyx.

 

Same patents:
The invention relates to the synthesis of nucleosides and relates to an improved method for the preparation of 3'-azido-2',3'-dideoxythymidine with the ability to suppress the reproduction of human immunodeficiency virus and finds application in medical practice for the treatment of AIDS

The invention relates to new compounds of formula I Nu-O-Fa, where O is oxygen, Nu is a nucleoside or nucleoside analogue, including such nitrogen base, as adenine, Esenin, cytosine, uracil, thymine; Fa - acyl monounsaturated C18YPD C20-9-fatty acids, which fatty acid etherification hydroxyl group in 5-position of the sugar portion of the nucleoside or nucleoside analog, or a hydroxyl group, an acyclic chain of an analogue of the nucleoside

The invention relates to the chemistry of nucleosides, in particular to the compounds used in medicine as anti-viral drugs for the treatment of diseases caused by, for example, human immunodeficiency virus (HIV), myeloblastosis birds (VMP)

The invention relates to the field of organic chemistry and Virology and applies to new nucleoside analogues containing the carbohydrate components of the 3-oximino-2-deoxyribofuranosyl, 3 Allexinno-2-deoxyribofuranosyl (acyl= acetyl, propionyl, isobutyryl, pivaloyl, benzoyl and other) or a 3-methoxyimino-2-deoxyribofuranosyl possessing antiviral activity of a broad spectrum of activity against the human immunodeficiency viruses (HIV), herpes simplex (HSV) and hepatitis B (VHB), which can find application in medicine

The invention relates to chemical technology for acyclic guanosine analogues with antiviral activity, in particular, to the drug Acyclovir [9-(2'-hydroxyethoxymethyl )guanine] , used in medicine as an effective means Antiherpes virus effect

The invention relates to organic chemistry, in particular to an improved method of synthesis of 2'-deoxythymidine [1-(2'-deoxy--D-threo-pentofuranose)thymine]

The invention relates to Virology and relates to new biologically active compounds, namely salts 5 N-phosphonate 3'-azido-3'- deoxythymidine General formula given in the description

The invention relates to new biologically active compounds-nitroxyl derivatives of azidothymidine General formula

< / BR>
where R1radical containing nitroxyl group >NO, and R2=R1or H, which possess antiviral activity against RNA-containing viruses (human immunodeficiency virus and vesicular stomatitis virus) and DNA-containing virus (cytomegalovirus)

The invention relates to the field of organic chemistry, and in particular to methods of obtaining derivatives of nucleosides, in particular to obtain 5'-0-benzoyl-2,3'-anhidrosis-thymidine
The invention relates to the chemistry of nucleosides, in particular, to obtain 3'-azido-2', 3'-dideoxythymidine (azidothymidine, AZT), used in medicine as an antiviral drug for the treatment of acquired immunodeficiency syndrome (AIDS)

FIELD: organic chemistry, biochemistry, medicine, virology.

SUBSTANCE: invention relates to derivatives of 2'=amino-2'-deoxynucleosides of the formula:

wherein R means hydrogen atom (H), alkyl, aminoalkyl; R1 means -(R2NR3) wherein R2 and/or R3 means H, -OH, -NH2, alkyl, benzyl under condition that R doesn't represent H or methyl when R2 and R3 mean H. Compounds elicit an antiviral activity with respect to measles and Marburg viruses exceeding that of ribavirin.

EFFECT: valuable properties of compounds.

4 tbl, 2 dwg, 18 ex

FIELD: medicine, pharmacology, bioorganic chemistry, pharmacy.

SUBSTANCE: invention relates to the effective using amount of β-L-2'-deoxynucleoside of the formula (I) or (II) used in manufacturing a medicinal agent used in treatment of hepatitis B, pharmaceutical compositions containing thereof, and methods for treatment of hepatitis B. Proposed agent shows the enhanced effectiveness in treatment of hepatitis B.

EFFECT: enhanced and valuable medicinal properties of agent.

83 cl, 6 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to method of gemcitabine hydrochloride purification, which includes enriching gemcitabine hydrochloride with its p-anomer, according to which solution of gemcitabine hydrochloride in water is taken with ratio of water to gemcitabine hydrochloride from 3:1 to 12:1 (wt/vol); solution is processed with activated coal, activated coal being taken in amount from 0.1 to 10 wt % of gemcitabine hydrochloride amount in solution; activated coal is removed from solution with formation of filtered solution; concentration of gemcitabine hydrochloride in filtered solution is increased until ratio of filtered solution to gemcitabine hydrochloride equals from 1:1 to 1:5 (wt/vol), efficient for gemcitabine hydrochloride sedimentation; deposited gemcitabine hydrochloride is isolated; and in case admixture content in deposited gemcitabine hydrochloride is not reduced to required level, stages (a)-(e) are repeated. Claimed invention also relates to method of obtaining gemcitabine hydrochloride using claimed purification method.

EFFECT: creation of efficient method of gemcitabine hydrochloride purification.

5 cl, 1 tbl, 5 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to (2'R)-2'-dezoxy-2'-fluoro-2'-C-methylnucleoside (β-D or (β-L) , where X represents O; R1 and R7 independently represent H; R3 represents hydrogen and R4 represents NH2; or its pharmaceutically acceptable salt. The invention also pertains to the method of producing the said compounds, which involves glycosylation of N4-benzoylcytosine with a compound of formula 1-4, where R represents methyl, Pg is chosen from C(O)Ph, CH2Ph or both Pg groups can be included in 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene); with further removal of protection of 3'-OPg and 5'-OPg and N-benzoyl of the obtained product.

EFFECT: invented compounds or their pharmaceutically acceptable salts are used as active ingredients against Flaviviridae family viruses in pharmaceutical compositions and liposomal pharmaceutical compositions.

4 cl, 9 tbl, 5 ex, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining enriched with β-anomer 2'-desoxy-2',2'-difluorocytidine of formula (I)

, which includes stages: (i) interaction of enriched with α-anomer compound of 1-halogenribofuranose of formula (III) with nucleic base of formula (IV) in solvent obtaining enriched with β-anomer nucleoside of formula (II) , with constant removal of formed in reaction process silylhalogenide of formula R3SiX (V) by distillation using carrier or running inert gas through reaction mixture; and (ii) removal of protective group from enriched with β-anomer nucleoside of formula (II). Invention also relates to method of obtaining hydrate of enriched with β-anomer 2'-desoxy-2',2'-difluorocytidine of formula (I), which at stage (ii) after removal of protective group additionally includes stages of dissolving formula (I) nucleoside in water; heating of obtained solution to temperature from 40 to 60°C; cooling of solution to temperature ranging from 10 to 25°C with or without mixing and without changing pH; and filtering of deposited solid substances.

EFFECT: method improvement.

17 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the method of producing 2'-desoxy-β-L-thymidine, which involves reacting 5'-O-trityl- or 5'-O-dimethoxytrityl- substituted 2,2' -anhydro-1 -β-L- arabinofuranosylthymine with a reducing agent RedAl and a complexing agent 15-crown-5-ether in a polar solvent 1,2-dimethoxyethane (DME) or tetrahydrofuran, obtaining 5'-O-trityl- or 5'-O-dimethoxytrityl- substituted 2,2'-desoxy-β-L-thymidine, subjected to protection removal if necessary. The invention also relates to the method of producing 2'-desoxy-β-L-thymidine, which involves reacting L-arabinose with cyanamide with subsequent reaction of the intermediate product - L-arabinofuranosylaminooxazoline - with a cycling or condensing agent, forming 2,2' -anhydro-1-β-L-arabinofuranosylthymine; reaction of the latter with a reducing agent RedAl and a complexing agent 15-crown-5-ether in a polar solvent 1,2-dimethoxyethane (DME) or tetrahydrofuran, obtaining 2'-desoxy-β-L-thymidine, where L-arabinofuranosylaminooxazoline can be protected by trityl or dimethoxytrityl in position 5' before or after reaction with the cycling or condensing agent; and protection removal of optionally protected 2'-desoxy-β-L-thymidine, if this is necessary or desired. Use in the given methods of such a reducing agent as Red-Al, and such a complexing agent as 15-crown -5-ether, causes a reaction of intramolecular protection and production of the required nucleoside product with good output.

EFFECT: compound is of great importance as an antiviral or antineoplastic preparation.

13 cl, 29 dwg, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a pyrimidine nucleoside compound of general formula (1) , in which one of X and Y is a cyano group and the other is hydrogen; R1 is hydrogen, (R3)(R4)(R5)Si- or a carbonyl group which includes an alkyl monosubstituted with an amino group; R2 is hydrogen or (R6)(R7)(R8)Si-, provided that at least one of R1 and R2 is not hydrogen; or R1 and R2 together form a 6-member cyclic group -Si(R9)(R10)-, where each of R9 and R10 is a straight or branched alkyl; R3, R4 and R5 denote a straight or branched alkyl optionally substituted alkoxy, or cycloalkyl; R6, R7 and R8 denote a straight or branched alkyl optionally substituted alkoxy, cycloalkyl or phenyl, or to pharmacologically acceptable salts thereof. The invention also relates to a range of specific compounds of formula (1) or to their pharmacologically acceptable salts: 5'-O-triisopropylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-diethylisopropylsilyl-2'-cyano-2,-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-dimethylthexylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-(dimethyl-n-octylsilyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-dimethylthexylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-diethylisopropylsilyl -2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-(tert-butyldimethylsily)-2'-cyano-2'-desoxy-1-β-O-arabinofuranosylcytosine; 3'-O-triisopropylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-dimethylthexylsilyl-5'-O-(L-valyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-(L-valyl)-3'-O-(tert-butyldimethylsilyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; and 3'-O-cyclopropyl-diisopropylsilyl-2'-cyano-2'-desoxy-1-β-D- arabinofuranosylcytosine.

EFFECT: obtaining formula (1) compounds or their pharmacologically acceptable salts for preparing a medicinal agent for treating tumours.

9 cl, 20 tbl, 1 dwg, 73 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) where R1 is chosen from ethyl, n-propyl, isopropyl or isobutyl, and to its pharmaceutically acceptable salts. Besides, the invention refers to a pharmaceutical composition on the basis of said compounds used for treating a hepatitis C virus (HCV) mediated disease, and also to a method of treating the hepatitis C virus (HCV) mediated disease, and to the method of selective O-acylation nucleoside II for producing O-acyl nucleoside I in an alkaline reaction medium including the stages: (i) dissolution of II and DMAP in a heterogeneous mixture of water and a solvent and addition of a water base for pH control between approximately 7.5 to approximately 12; (ii) optional addition of a sufficient amount of saturated aqueous NaCl for preparing a diphase reaction mixture; (iii) addition of an acidating agent and an accessory base sufficient for pH preservation between approximately 7.5 to approximately 12; (iv) reaction monitoring and interruption of adding said acidating agent and said base after sufficient conversion provided; (v) optional contact of O-acylnucleoside with the pharmaceutically acceptable acid to produce a pharmaceutically acceptable salt.

EFFECT: production of the pharmaceutical composition for treating the hepatitis C virus (HCV) mediated disease.

9 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5'-urethane AZT derivatives of general formula

where X = -NH2, -NHMe, -NHEt, .

EFFECT: compounds have low toxicity, can efficiently inhibit reproduction of the immunodeficiency virus type 1 virus in a CEM SS cell culture.

1 cl, 2 tbl, 7 ex

Up!