CA1065315A - Process for producing nucleosides - Google Patents
Process for producing nucleosidesInfo
- Publication number
- CA1065315A CA1065315A CA246,368A CA246368A CA1065315A CA 1065315 A CA1065315 A CA 1065315A CA 246368 A CA246368 A CA 246368A CA 1065315 A CA1065315 A CA 1065315A
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- Canada
- Prior art keywords
- tri
- process according
- beta
- benzoyl
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
Abstract
ABSTRACT OF THE DISCLOSURE
A nucleoside is produced by reacting a sugar derivative containing an -O-acyl or -O-alkyl group or a halogen atom in the 1-position with a silylated organic base in the presence of an ester selected from the group consisting of trialkylsilyl esters of mineral acids and trialkylsilyl esters of strong organic acids.
For example, 2,4-bis-(trimethylsilyloxy)-pyrimidine is reacted with 1-O-acetyl-2,3,5-tri-0-benzoyl-.beta.-D-ribofuranose in the presence of trimethylsilyl perchlorate to produce uridine 2',3',5'-tri-O-benzoate.
A nucleoside is produced by reacting a sugar derivative containing an -O-acyl or -O-alkyl group or a halogen atom in the 1-position with a silylated organic base in the presence of an ester selected from the group consisting of trialkylsilyl esters of mineral acids and trialkylsilyl esters of strong organic acids.
For example, 2,4-bis-(trimethylsilyloxy)-pyrimidine is reacted with 1-O-acetyl-2,3,5-tri-0-benzoyl-.beta.-D-ribofuranose in the presence of trimethylsilyl perchlorate to produce uridine 2',3',5'-tri-O-benzoate.
Description
10653~
This invention relates to a new process for producing nucleosides.
Processes for the manufacture of nucleosides are known.
Thus, for example, from Y. Furukawa et al (Chem. Pharm. Bull. 16, 1067/1968) it is known that purines can be reacted with a l-O-acyl-or l-O~alkyl-derivative of a sugar in the presence of a Friedel-Crafts catalyst to form the corresponding N-glycosides, and German Patent DBP No. 1,919,307 describes a process for the manufacture of nucleosides in which silylated N-heterocycles are reacted with protected 1-halo-, 1-O-alkyl- and especially l-acyl-s~ars in the presence of Friedel-Crafts catalysts.
The industrial use of the known processes has been dis-advantageous, because the separation of the salts of Lewis acids or Friedel-Crafts catalysts formed during the reaction often gives rise to difficulties in working up the reaction mixture, and additional chemical operations are necessary. In particular, such disadvantages also cause a reduction in the yield of the desired end product.
It has now been found that the Friedel-Crafts catalysts, for example, SnC14 can be replaced with known trimethylsilyl esters of perchloric acid or trifluoromethane sulphonic acid.
The present invention accordingly provides a process for producing a nucleoside, wherein a sugar derivative that contains an -O-acyl or -O-aklyl group or a halogen atom in the l-position, and selected from ribose, desoxyribose, arabinose and glucose, where all the hydroxyl groups are protected, is reacted with a silylated 5 or 6 membered N-containing heterocyclic organic base, in the presence of an ester selected from trimethylsilyl perchlorate and the trimethylsilyl ester of trifluoromethane sulphonic acid and, if desired, any protected hydroxyl group in the resulting nucleoside is converted into a free hydroxyl group.
1()~;53~5 ` The trialkylsilyl esters are easily accessible trimethylsilyl perchlorate [(CH3)3Si-OC103] and the trimethyl-silyl ester of trifluoromethane sulphonie acid [(CH3)3Si-OCOCF3]
By the replacement of, for example, SnC14 with the trimethylsilyl ester of the mineral acid, the harmful formation of emulsions and eolloids during working up is avoided and the yields are inereased.
In aecordance with the process of the present invention, all silylated 5 or 6 membered heterocyclie N-containing organie bases known generally to those skilled in the art can be used.
There are suitable, for example, organie bases of the formula 1 i Rl ~ N = (f C~ n = f - R2 3 4 IX (Ia) y or R~ C = lC)n 2 3 4 (Ib) in whieh X represents an oxygen or sulphur atom, n represents O
or 1, Rl and R2 eaeh represents an unsubstituted or substituted organie hydroearbon group (whieh may be saturated or unsaturated) or together represent a divalent organic group (whieh may contain one or two nitrogen atoms), R3 and R4 each represents a hydrogen atom or an alkyo, alkoxycarbonyl or alkylaminocarbonyl group or together represent either a divalent group of the formula .C3 - 2 -10~;S315 ~ ' \ ~ ' ~ ' ~N ~ ~ N~ ~ ~
j ~1 3 ~ 3 ~ ` ~
H H H
or ~ O' ~S
or a corresponding divalent group that is substituted (for example, in the usual manner), and Y represents a trialkylsilyl group, especially a trimethylsilyl group.
When Rl and R2 represent any desired separate organic groups, they represent more especially lower alkyl groups, pre-ferably containing 1 to 4 carbon atoms, for example, methyl, ethyl, propyl and butyl groups, and aryl or aralkyl groups.
The divalent groups represented by Rl and R2 together and by R3 and R4 together may contain substitutents selected from the group consisting of lower alkyl, trifluoromethyl, acyl, hydroxyl, alkoxy, acyloxy, carboxyl, carboxamide, alkoxycarbonyl, dialkylaminocarbonyl, amino, nitro and nitriloxo groups and halo-gen atoms.
Preferred starting bases are silylated organic bases in -a ~ which Rl and R2 in the above formulae are connected together in a ring and capccially in such a manner that the heterocyclic base contains five or six atoms in the ring, of which one to three are nitrogen atoms.
The silylated organic bases having the formulae Ia and Ib are thus preferably derived from heterocyclic bases, namely uracil, cytosine, 6-azauracil, 2-thio-6-azauracil, thymine, N-acyladenine, guanine, lumazine, imidazole, pyrazine, thiazole which may be substituted by one or more of the above mentioned substituents listed for the divalent groups represented by R
and R2 together, and R3 and R4 together.
For the case in which Rl and R2 are connected together in a ring, the divalent group represented by Rl and R2 together is more especially a Il NIH2 lXI 75 75 76 - C - NH - , - C = N - C - , - N = C - - C = C -- CH = N = , - CH = N - or - O - CO - group, when n = 1, and a -NH - CO - CH = N - , - N = C - N = C - or - N = C - N = CH -group, when n = O, in which X has the above meaning, and R5 and R6 each represents a hydrogen atom or an alkyl, alkoxycarbonyl or alkylaminocarbonyl group.
The sugar derivatives used in the process of the present C invention are p~Y~ *X~t derived from ribose, desoxyribose, ara-binose and glucose.
AdVQ.~L~geOUS1Y~ all the free hydroxyl groups of the sugar are protected. As sugar protecting groups, the protecting groups customarily used in sNgar chemistry are suitable, for example, acyl, benzoyl, para-chlorobenzoyl, para-nitrobenzoyl, para-toluyl and benzyl groups.
In the nucleosides obtained in accordance with the process of the present invention, the free or protected sugar group is preferably connected to the nitrogen atom in a ~-glycoside manner.
When, in accordance with the process of the present invention, nucleosides which contain O-acyl-protected sugar groups are to be made, there come into consideration in addition to the protecting groups already mentioned the groups of propionic acid, butyric acid, valeric acid, caproic acid, oenanthic acid, undecanoic acid, oleic acid, pivalic acid, cyclopentyl-propionic acid, phenylacetic acid and adamantan carboxylic acid.
~0~5315 The process of the present invention can be used in general for the preparation of nucleosides. Preferred products of the process are nucleosides of the general formula II
1 7 'T I )n ~ ~ R2 (II) 3 4 \XJm in which Rl, R2, R3, R4, X and n have the above meanings, Z
represents a free or protected sugar group, and m represents O
or 1. The nucleosides that can be prepared in accordance with the process and especially the products of the general formula II are biologically active. By virtue of their specific solubility they can be administered, depending on the choice of the substi-tuents, either systemically as aqueous or alcoholic solutions, or locally as salves or jellies.
The nucleosides, depending on the starting compounds used, have, for example, an enzyme-inhibiting, antibacterial, antiviral, cytostatic, antipsoriatic or inflammation-inhibiting action.
The reaction of the silylated organic base, for example, a base of the general formula Ia or Ib, with a l-O-acyl-, 20 C ~-O-alkyl- or l-ha ~geno-derivative of a free or protected sugar in the presence of a catalyst in accordance with the process of the present invention is carried out in a suitable solvent, for example, methylene chloride (CH2C12), 1-2-dichlorethane (ClCH2CH2Cl), chloroform, benzene, toluene, acetonitrile, ethylene chloride, dioxan, tetrahydrofuran, dimethylformamide, carbon disulphide, chlorobenzene, sulpholan or molten dimethyl sulphone.
The reaction may be carried out at room temperature or at a higher or lower temperature, but preferably at a temperature within the range of 0 to 100C. The reactants are generally used in the reaction in approximately equimolar quantities;
however, a silylated heterocycle is often used in a small excess in order to obtain a conversion of the sugar component that is lO~S315 as far as possible quantitative. Often 0.1 equivalent of the catalyst suffices, for each equivalent of the sugar component.
The catalysts used for the new process, as compared with the formerly used Lewis acids or Friedel-Crafts catalysts, have the great advantage that they can be immediately and quantita-tively removed by simple agitation with a bicarbonate solution without the formation of emulsions or colloids, becuase they are immediately hydrolyzed to a salt and hexamethyl-disiloxane (boiling point 98C), which is removed during withdrawal of the solvent.
The catalysts can be prepared in accordance with the literature, for example, from AgC104 with (CH3)3SiCl which gives (CH3)3Si-OC103 together with AgCl [U. Wannagat and W. Liehr, Angew. Chemie 69, 783 (1957)], or, as in the case of the trimethyl-silyl ester of trifluoromethane sulphonic acid, easily from CF3S03H and (CH3)3SiCl [H.C. Marsmann and H.G. Horn, Z. Natur-forschung B 27, 4448 (1972)] using a neutral solvent, for example, benzene, or without a solvent. Filtration of any salts formed with the exclusion of moisture leads to stable solutions of the silyl esters used as catalysts.
From acylated l-O-alkyl- and l-O-acyl-sugars and the catalyst, in the reaction of the process of the present invention a sugar cation contained in, for example, a mineral acid salt and also a silylated O-alkyl- or O-acyl-derivative are formed.
The sugar salt then reacts with, for example, a silylated pyrimi-dine with the formiation of a nucleoside and the renewed formation of the silyl ester of the mineral acid, so that catalytic quantities of the silyl ester of the mineral acid suffice.
The yields obtained in the process of the present invention are higher than those of the aforesaid known processes. Moreover, ~- derivatives of the sugars are preponderantly formed and the undesired ~-anomers are formed only in minor auantities or not at 106s~lS
.`!
all.
For the preparation of nucleosides containing free hydroxyl groups, the hydroxyl-protecting groups can be removed in the usual manner, for example, by alcoholic solutions of ammonia or alcoholates, a~ueous or alcoholic alkali and, also in the case of the benzyl ethers, by reduction or hydrogenation.
The following examples illustrate the invention:
Example 1
This invention relates to a new process for producing nucleosides.
Processes for the manufacture of nucleosides are known.
Thus, for example, from Y. Furukawa et al (Chem. Pharm. Bull. 16, 1067/1968) it is known that purines can be reacted with a l-O-acyl-or l-O~alkyl-derivative of a sugar in the presence of a Friedel-Crafts catalyst to form the corresponding N-glycosides, and German Patent DBP No. 1,919,307 describes a process for the manufacture of nucleosides in which silylated N-heterocycles are reacted with protected 1-halo-, 1-O-alkyl- and especially l-acyl-s~ars in the presence of Friedel-Crafts catalysts.
The industrial use of the known processes has been dis-advantageous, because the separation of the salts of Lewis acids or Friedel-Crafts catalysts formed during the reaction often gives rise to difficulties in working up the reaction mixture, and additional chemical operations are necessary. In particular, such disadvantages also cause a reduction in the yield of the desired end product.
It has now been found that the Friedel-Crafts catalysts, for example, SnC14 can be replaced with known trimethylsilyl esters of perchloric acid or trifluoromethane sulphonic acid.
The present invention accordingly provides a process for producing a nucleoside, wherein a sugar derivative that contains an -O-acyl or -O-aklyl group or a halogen atom in the l-position, and selected from ribose, desoxyribose, arabinose and glucose, where all the hydroxyl groups are protected, is reacted with a silylated 5 or 6 membered N-containing heterocyclic organic base, in the presence of an ester selected from trimethylsilyl perchlorate and the trimethylsilyl ester of trifluoromethane sulphonic acid and, if desired, any protected hydroxyl group in the resulting nucleoside is converted into a free hydroxyl group.
1()~;53~5 ` The trialkylsilyl esters are easily accessible trimethylsilyl perchlorate [(CH3)3Si-OC103] and the trimethyl-silyl ester of trifluoromethane sulphonie acid [(CH3)3Si-OCOCF3]
By the replacement of, for example, SnC14 with the trimethylsilyl ester of the mineral acid, the harmful formation of emulsions and eolloids during working up is avoided and the yields are inereased.
In aecordance with the process of the present invention, all silylated 5 or 6 membered heterocyclie N-containing organie bases known generally to those skilled in the art can be used.
There are suitable, for example, organie bases of the formula 1 i Rl ~ N = (f C~ n = f - R2 3 4 IX (Ia) y or R~ C = lC)n 2 3 4 (Ib) in whieh X represents an oxygen or sulphur atom, n represents O
or 1, Rl and R2 eaeh represents an unsubstituted or substituted organie hydroearbon group (whieh may be saturated or unsaturated) or together represent a divalent organic group (whieh may contain one or two nitrogen atoms), R3 and R4 each represents a hydrogen atom or an alkyo, alkoxycarbonyl or alkylaminocarbonyl group or together represent either a divalent group of the formula .C3 - 2 -10~;S315 ~ ' \ ~ ' ~ ' ~N ~ ~ N~ ~ ~
j ~1 3 ~ 3 ~ ` ~
H H H
or ~ O' ~S
or a corresponding divalent group that is substituted (for example, in the usual manner), and Y represents a trialkylsilyl group, especially a trimethylsilyl group.
When Rl and R2 represent any desired separate organic groups, they represent more especially lower alkyl groups, pre-ferably containing 1 to 4 carbon atoms, for example, methyl, ethyl, propyl and butyl groups, and aryl or aralkyl groups.
The divalent groups represented by Rl and R2 together and by R3 and R4 together may contain substitutents selected from the group consisting of lower alkyl, trifluoromethyl, acyl, hydroxyl, alkoxy, acyloxy, carboxyl, carboxamide, alkoxycarbonyl, dialkylaminocarbonyl, amino, nitro and nitriloxo groups and halo-gen atoms.
Preferred starting bases are silylated organic bases in -a ~ which Rl and R2 in the above formulae are connected together in a ring and capccially in such a manner that the heterocyclic base contains five or six atoms in the ring, of which one to three are nitrogen atoms.
The silylated organic bases having the formulae Ia and Ib are thus preferably derived from heterocyclic bases, namely uracil, cytosine, 6-azauracil, 2-thio-6-azauracil, thymine, N-acyladenine, guanine, lumazine, imidazole, pyrazine, thiazole which may be substituted by one or more of the above mentioned substituents listed for the divalent groups represented by R
and R2 together, and R3 and R4 together.
For the case in which Rl and R2 are connected together in a ring, the divalent group represented by Rl and R2 together is more especially a Il NIH2 lXI 75 75 76 - C - NH - , - C = N - C - , - N = C - - C = C -- CH = N = , - CH = N - or - O - CO - group, when n = 1, and a -NH - CO - CH = N - , - N = C - N = C - or - N = C - N = CH -group, when n = O, in which X has the above meaning, and R5 and R6 each represents a hydrogen atom or an alkyl, alkoxycarbonyl or alkylaminocarbonyl group.
The sugar derivatives used in the process of the present C invention are p~Y~ *X~t derived from ribose, desoxyribose, ara-binose and glucose.
AdVQ.~L~geOUS1Y~ all the free hydroxyl groups of the sugar are protected. As sugar protecting groups, the protecting groups customarily used in sNgar chemistry are suitable, for example, acyl, benzoyl, para-chlorobenzoyl, para-nitrobenzoyl, para-toluyl and benzyl groups.
In the nucleosides obtained in accordance with the process of the present invention, the free or protected sugar group is preferably connected to the nitrogen atom in a ~-glycoside manner.
When, in accordance with the process of the present invention, nucleosides which contain O-acyl-protected sugar groups are to be made, there come into consideration in addition to the protecting groups already mentioned the groups of propionic acid, butyric acid, valeric acid, caproic acid, oenanthic acid, undecanoic acid, oleic acid, pivalic acid, cyclopentyl-propionic acid, phenylacetic acid and adamantan carboxylic acid.
~0~5315 The process of the present invention can be used in general for the preparation of nucleosides. Preferred products of the process are nucleosides of the general formula II
1 7 'T I )n ~ ~ R2 (II) 3 4 \XJm in which Rl, R2, R3, R4, X and n have the above meanings, Z
represents a free or protected sugar group, and m represents O
or 1. The nucleosides that can be prepared in accordance with the process and especially the products of the general formula II are biologically active. By virtue of their specific solubility they can be administered, depending on the choice of the substi-tuents, either systemically as aqueous or alcoholic solutions, or locally as salves or jellies.
The nucleosides, depending on the starting compounds used, have, for example, an enzyme-inhibiting, antibacterial, antiviral, cytostatic, antipsoriatic or inflammation-inhibiting action.
The reaction of the silylated organic base, for example, a base of the general formula Ia or Ib, with a l-O-acyl-, 20 C ~-O-alkyl- or l-ha ~geno-derivative of a free or protected sugar in the presence of a catalyst in accordance with the process of the present invention is carried out in a suitable solvent, for example, methylene chloride (CH2C12), 1-2-dichlorethane (ClCH2CH2Cl), chloroform, benzene, toluene, acetonitrile, ethylene chloride, dioxan, tetrahydrofuran, dimethylformamide, carbon disulphide, chlorobenzene, sulpholan or molten dimethyl sulphone.
The reaction may be carried out at room temperature or at a higher or lower temperature, but preferably at a temperature within the range of 0 to 100C. The reactants are generally used in the reaction in approximately equimolar quantities;
however, a silylated heterocycle is often used in a small excess in order to obtain a conversion of the sugar component that is lO~S315 as far as possible quantitative. Often 0.1 equivalent of the catalyst suffices, for each equivalent of the sugar component.
The catalysts used for the new process, as compared with the formerly used Lewis acids or Friedel-Crafts catalysts, have the great advantage that they can be immediately and quantita-tively removed by simple agitation with a bicarbonate solution without the formation of emulsions or colloids, becuase they are immediately hydrolyzed to a salt and hexamethyl-disiloxane (boiling point 98C), which is removed during withdrawal of the solvent.
The catalysts can be prepared in accordance with the literature, for example, from AgC104 with (CH3)3SiCl which gives (CH3)3Si-OC103 together with AgCl [U. Wannagat and W. Liehr, Angew. Chemie 69, 783 (1957)], or, as in the case of the trimethyl-silyl ester of trifluoromethane sulphonic acid, easily from CF3S03H and (CH3)3SiCl [H.C. Marsmann and H.G. Horn, Z. Natur-forschung B 27, 4448 (1972)] using a neutral solvent, for example, benzene, or without a solvent. Filtration of any salts formed with the exclusion of moisture leads to stable solutions of the silyl esters used as catalysts.
From acylated l-O-alkyl- and l-O-acyl-sugars and the catalyst, in the reaction of the process of the present invention a sugar cation contained in, for example, a mineral acid salt and also a silylated O-alkyl- or O-acyl-derivative are formed.
The sugar salt then reacts with, for example, a silylated pyrimi-dine with the formiation of a nucleoside and the renewed formation of the silyl ester of the mineral acid, so that catalytic quantities of the silyl ester of the mineral acid suffice.
The yields obtained in the process of the present invention are higher than those of the aforesaid known processes. Moreover, ~- derivatives of the sugars are preponderantly formed and the undesired ~-anomers are formed only in minor auantities or not at 106s~lS
.`!
all.
For the preparation of nucleosides containing free hydroxyl groups, the hydroxyl-protecting groups can be removed in the usual manner, for example, by alcoholic solutions of ammonia or alcoholates, a~ueous or alcoholic alkali and, also in the case of the benzyl ethers, by reduction or hydrogenation.
The following examples illustrate the invention:
Example 1
2.5 moles of trimethylsilyl perchlorate [(CH3)3Si-O-C103]
in 20 ml of benzene were added to 5.15 mmoles of 2,4-bis-(tri-methylsilyloxy)-pyrimidine and 5 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 20 ml of 1,2-dichlorethane, and the whole was allowed to stand for 1 week at 24C. After the addition of 50 ml of chloroform, the mixture was agitated with 50 ml of an ice-cold saturated solution of sodium bicarbonate, and separated, and the aqueous phase was then agitated with a small amount of chloroform. After drying with sodium sulphate and evaporation, 2.8 g of crude product were obtained which, after recrystalliz-ation from 40 ml of benzene, gave 2.1 g (75.5% of the theoretical yield) of pure uridine 2',3',5'-tri-O-benzoate melting at 138 -140C.
Example 2 The procedure was the same as that described in Example 1, except there was added only 0.5 mmole of trimethylsilyl per-chlorate (in 5 ml of benzene) and boiling was carried out for 4 hours at a 100C bath temperature under argon. After working up and crystallization, 2.238 (80.4% of the theoretical yield) of uridine 2',3',5'-tri-O-benzoate were obtained.
Example 3 1 mmole of trimethylsilyl perchlorate in 7 ml of benzene were added to 10 mmoles of 3-trimethylsilylthio-5-trimethylsilyloxy-1,2,4-triazine and 10 mmoles of ~-glucose-penta-acetate in 25 ml lO~S31s of 1,2-dichlorethane, and the whole was boiled for 3 hours at a 100C bath temperature. After the usual working up as described in Example 1, there were obtained 3.5 g of crude product, from which there were obtained, from ethanol, 3 g (65~ of the theore-tical yield) of 2-(2,3,4,6-tetra-O-acetyl-~-D-glucopyranosyl)-3-thio-2,3,4,5-tetrahydro-1,2,4-triazin-5-one melting at 226C.
Example 4 t~;rl~or~an~ s ~ ¦~n~t ~r~ 0.5 mmole of trimethylsilyl~æ~lat~ in 1 ml of benzene was added to 5 mmoles of 2-trimethylsilyloxy-pyridine and 5 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 25 ml of i 1,2-dichlorethane, and the whole was boiled for 1.5 hours at a 100C bath temperature and worked up as described in Example 1.
After crystallization of the resulting residue (2.8 g) from 75 ml of carbon tetrachloride, 2.28 g (85~ of the theoretical yield) of 1-(2,3,5-tri-O-benzoyl-~-D-ribofuranosyl)-1,2-dihydro-pyridin-2-one melting at 140C were obtained.
Example 5 12 mmoles of the trimethylsilyl ester of trifluoromethane sulphonic acid [(CH3)3Sio-So2CF3] in 24 ml of benzene were added to 10 mmoles of 2-O-trimethylsilyloxy-4-trimethylsilylamino-pyrimidine and 10 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 35 ml of 1,2-dichlorethane and the whole was heated for 1 hour at 100C. Working up as described in Example 1 gave 3.869 g (85~ of the theoretical yield) of amorphous cytidine 2',3',5'-tri-O-benzoate.
Example 6 1 mmole of trimethylsilyl perchlorate in 7 ml of benzene was added to 10 mmoles of 6-benzoyl-trimethylsilylamino-9-trimethyl-silyl-purine and 10 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 35 ml of 1,2-dichlorethane. After 12 hours at a bath temperature of 100C and working up as described in Example 1, amorphous adenosine tetrabenzoate was obtained, and was hydrolyzed lO~S3~5 with 250 ml of methanolic ammonia for 16 hours at 22C. By evapor-ation and extraction with methylene chloride, 2.3 g (86.4~ of the theoretical yield) of pure adenosine, melting at 230 - 232C was obtained from methanol - H2O.
Example 7 4 mmoles of trimethylsilyl perchlorate in 20 ml of ben-zene were added to 40 mmoles of 2,4-bis-(trimethylsilyloxy)-lumazine and 40 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 75 ml of 1,2-dichlorethane, and the whole was boiled for 4 hours at a bath temperature of 100C. By working up as described in Example 1, 20.2 g (84% of the theoretical yield) of l-(2,3,5-tri-O-benzoyl-~-D-ribofuranosyl)-lumazine were obtained.
Example 8 5 mmoles of (CH3)3SiO-SO2CF3 in 20 ml of benzene were added to 55 mmoles of 1-trimethylsilyl-3-carboxymethyl-1,2,4-triazole and 55 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 100 ml of 1,2-dichlorethane and the whole was boiled for 4 hours at a bath temperature of 100C. By working up as described in Example 1, 24 g (85.5% of the theoretical yield) of 1-(2,3,5-tri-O-benzoyl-~-D-ribofuranosyl)-3-carboxy-methyl-1,2,4-triazole were obtained.
Example 9 11 mmoles of (CH3)3SiO-SO2CF3 in 20 ml of benzene were added to 10 mmoles of 2,4-bis-(trimethylsilyloxy)-5-morpholino-pyrimidine and 10 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 35 ml of 1,2-dichlorethane, and the whole was stirred for 20 hours at room temperature under argon. Working up as described in Example 1 yielded 6.36 g (99% of the theo-retical yield) of amorphous 5-morpholino-uridine 2',3',5'-tri-O-benzoate.
Example 10 11 mmoles of 2,4-bis-(trimethylsilyloxy)-5-methoxy-pyrimidine and 12 mmoles of (CH3)3SiO-SO2CF3 dissolved in absolute 1,2-dichlorethane were added to 5.04 g (10 mmoles) of l-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 75 ml of 1,2-dichlorethane, and the whole was stirred for 4 hours at room temperature. Working up as described in Example 1 yielded, from ethyl acetate/hexane, 5.24 g (89.3~ of the theoretical yield) of 5-methoxy-uridine 2',3',5'-tri-O-benzoate.
Example 11 11 mmoles of 2,4-bis-(trimethylsilyloxy)-5,6-dimethyl-pyrimidine and 12 mmoles of (CH3)3SiO-SO2CF3 dissolved in absolute 1,2-dichlorethane were added, under argon, to 5.04 g (10 mmoles) of l-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 75 ml of 1,2-dichlorethane, and the whole was stirred for 3.5 hours at room temperature. Working up as described in Example 1 yielded, from methylene chloride/hexane, 4.8 g (82.2% of the theoretical yield) of 5,6-dimethyl-uridine 2',3',5'-tri-O-benzoate.
Example 12 11 mmoles of 2,4-bis-(trimethylsilyloxy)-6-methyl-pyrimidine and 12 mmoles of (CH3)3SiO-SO2CF3 in absolute acetoni-trile were added to a solution of 5.04g ~0 mmoles) of l-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 100 ml of absolute acetoni-trile under argon, and the whole was stirred for 3 hours at room temperature. Working up in accordance with Example 1 and column chromatography with ethyl acetate/hexane, yielded, from ethyl acetate/hexane, 4.04 g (70.9% of the theoretical yield) of 6-methyl-uridine 2',3',5'-tri-O-benzoate.
Example 13 In a manner analogous to that described in Example 12, 5.04 g (10 mmoles) of 1-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribo-furanose, 11 mmoles of 1-(trimethylsilyloxy)-1,2,4-triazole lO~S315 and 12 mmoles of (CH3) 3Sio-So2CF3 were reacted. Working up as described in Example 1 yielded 2.94 g (57.2% of the theoretical yield) of l-(1,2,4-triazolyl)-~-D-ribofuranoside 2',3',5'-tri-O-benzoate melting at 105 - 106C.
In the formulae (Ia) and (Ib) referred to hereinbefore, Rl and R2 together may represent a group selected from -IC=N- , -N=N-CH=f , -C4H4- , -CH=CH-C=N-OSi_ OSi~ NH
-CH=N- , -CH=N-f=N- , -f=N-CH=f- and -CH=N-CH=N-CH2-COOH f ~N~
--si-- o
in 20 ml of benzene were added to 5.15 mmoles of 2,4-bis-(tri-methylsilyloxy)-pyrimidine and 5 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 20 ml of 1,2-dichlorethane, and the whole was allowed to stand for 1 week at 24C. After the addition of 50 ml of chloroform, the mixture was agitated with 50 ml of an ice-cold saturated solution of sodium bicarbonate, and separated, and the aqueous phase was then agitated with a small amount of chloroform. After drying with sodium sulphate and evaporation, 2.8 g of crude product were obtained which, after recrystalliz-ation from 40 ml of benzene, gave 2.1 g (75.5% of the theoretical yield) of pure uridine 2',3',5'-tri-O-benzoate melting at 138 -140C.
Example 2 The procedure was the same as that described in Example 1, except there was added only 0.5 mmole of trimethylsilyl per-chlorate (in 5 ml of benzene) and boiling was carried out for 4 hours at a 100C bath temperature under argon. After working up and crystallization, 2.238 (80.4% of the theoretical yield) of uridine 2',3',5'-tri-O-benzoate were obtained.
Example 3 1 mmole of trimethylsilyl perchlorate in 7 ml of benzene were added to 10 mmoles of 3-trimethylsilylthio-5-trimethylsilyloxy-1,2,4-triazine and 10 mmoles of ~-glucose-penta-acetate in 25 ml lO~S31s of 1,2-dichlorethane, and the whole was boiled for 3 hours at a 100C bath temperature. After the usual working up as described in Example 1, there were obtained 3.5 g of crude product, from which there were obtained, from ethanol, 3 g (65~ of the theore-tical yield) of 2-(2,3,4,6-tetra-O-acetyl-~-D-glucopyranosyl)-3-thio-2,3,4,5-tetrahydro-1,2,4-triazin-5-one melting at 226C.
Example 4 t~;rl~or~an~ s ~ ¦~n~t ~r~ 0.5 mmole of trimethylsilyl~æ~lat~ in 1 ml of benzene was added to 5 mmoles of 2-trimethylsilyloxy-pyridine and 5 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 25 ml of i 1,2-dichlorethane, and the whole was boiled for 1.5 hours at a 100C bath temperature and worked up as described in Example 1.
After crystallization of the resulting residue (2.8 g) from 75 ml of carbon tetrachloride, 2.28 g (85~ of the theoretical yield) of 1-(2,3,5-tri-O-benzoyl-~-D-ribofuranosyl)-1,2-dihydro-pyridin-2-one melting at 140C were obtained.
Example 5 12 mmoles of the trimethylsilyl ester of trifluoromethane sulphonic acid [(CH3)3Sio-So2CF3] in 24 ml of benzene were added to 10 mmoles of 2-O-trimethylsilyloxy-4-trimethylsilylamino-pyrimidine and 10 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 35 ml of 1,2-dichlorethane and the whole was heated for 1 hour at 100C. Working up as described in Example 1 gave 3.869 g (85~ of the theoretical yield) of amorphous cytidine 2',3',5'-tri-O-benzoate.
Example 6 1 mmole of trimethylsilyl perchlorate in 7 ml of benzene was added to 10 mmoles of 6-benzoyl-trimethylsilylamino-9-trimethyl-silyl-purine and 10 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 35 ml of 1,2-dichlorethane. After 12 hours at a bath temperature of 100C and working up as described in Example 1, amorphous adenosine tetrabenzoate was obtained, and was hydrolyzed lO~S3~5 with 250 ml of methanolic ammonia for 16 hours at 22C. By evapor-ation and extraction with methylene chloride, 2.3 g (86.4~ of the theoretical yield) of pure adenosine, melting at 230 - 232C was obtained from methanol - H2O.
Example 7 4 mmoles of trimethylsilyl perchlorate in 20 ml of ben-zene were added to 40 mmoles of 2,4-bis-(trimethylsilyloxy)-lumazine and 40 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 75 ml of 1,2-dichlorethane, and the whole was boiled for 4 hours at a bath temperature of 100C. By working up as described in Example 1, 20.2 g (84% of the theoretical yield) of l-(2,3,5-tri-O-benzoyl-~-D-ribofuranosyl)-lumazine were obtained.
Example 8 5 mmoles of (CH3)3SiO-SO2CF3 in 20 ml of benzene were added to 55 mmoles of 1-trimethylsilyl-3-carboxymethyl-1,2,4-triazole and 55 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 100 ml of 1,2-dichlorethane and the whole was boiled for 4 hours at a bath temperature of 100C. By working up as described in Example 1, 24 g (85.5% of the theoretical yield) of 1-(2,3,5-tri-O-benzoyl-~-D-ribofuranosyl)-3-carboxy-methyl-1,2,4-triazole were obtained.
Example 9 11 mmoles of (CH3)3SiO-SO2CF3 in 20 ml of benzene were added to 10 mmoles of 2,4-bis-(trimethylsilyloxy)-5-morpholino-pyrimidine and 10 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 35 ml of 1,2-dichlorethane, and the whole was stirred for 20 hours at room temperature under argon. Working up as described in Example 1 yielded 6.36 g (99% of the theo-retical yield) of amorphous 5-morpholino-uridine 2',3',5'-tri-O-benzoate.
Example 10 11 mmoles of 2,4-bis-(trimethylsilyloxy)-5-methoxy-pyrimidine and 12 mmoles of (CH3)3SiO-SO2CF3 dissolved in absolute 1,2-dichlorethane were added to 5.04 g (10 mmoles) of l-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 75 ml of 1,2-dichlorethane, and the whole was stirred for 4 hours at room temperature. Working up as described in Example 1 yielded, from ethyl acetate/hexane, 5.24 g (89.3~ of the theoretical yield) of 5-methoxy-uridine 2',3',5'-tri-O-benzoate.
Example 11 11 mmoles of 2,4-bis-(trimethylsilyloxy)-5,6-dimethyl-pyrimidine and 12 mmoles of (CH3)3SiO-SO2CF3 dissolved in absolute 1,2-dichlorethane were added, under argon, to 5.04 g (10 mmoles) of l-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 75 ml of 1,2-dichlorethane, and the whole was stirred for 3.5 hours at room temperature. Working up as described in Example 1 yielded, from methylene chloride/hexane, 4.8 g (82.2% of the theoretical yield) of 5,6-dimethyl-uridine 2',3',5'-tri-O-benzoate.
Example 12 11 mmoles of 2,4-bis-(trimethylsilyloxy)-6-methyl-pyrimidine and 12 mmoles of (CH3)3SiO-SO2CF3 in absolute acetoni-trile were added to a solution of 5.04g ~0 mmoles) of l-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in 100 ml of absolute acetoni-trile under argon, and the whole was stirred for 3 hours at room temperature. Working up in accordance with Example 1 and column chromatography with ethyl acetate/hexane, yielded, from ethyl acetate/hexane, 4.04 g (70.9% of the theoretical yield) of 6-methyl-uridine 2',3',5'-tri-O-benzoate.
Example 13 In a manner analogous to that described in Example 12, 5.04 g (10 mmoles) of 1-O-acetyl-2,3,5-tri-O-benzoyl-~-D-ribo-furanose, 11 mmoles of 1-(trimethylsilyloxy)-1,2,4-triazole lO~S315 and 12 mmoles of (CH3) 3Sio-So2CF3 were reacted. Working up as described in Example 1 yielded 2.94 g (57.2% of the theoretical yield) of l-(1,2,4-triazolyl)-~-D-ribofuranoside 2',3',5'-tri-O-benzoate melting at 105 - 106C.
In the formulae (Ia) and (Ib) referred to hereinbefore, Rl and R2 together may represent a group selected from -IC=N- , -N=N-CH=f , -C4H4- , -CH=CH-C=N-OSi_ OSi~ NH
-CH=N- , -CH=N-f=N- , -f=N-CH=f- and -CH=N-CH=N-CH2-COOH f ~N~
--si-- o
Claims (26)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing a nucleoside, wherein a sugar derivative containing an -O-acyl or -O-alkyl group or a halogen atom in the1-position and selected from ribose, desoxy-ribose arabinose and glucose, where all the hydroxyl groups are protected, is reacted with a silylated 5 or 6 member N-containing heterocyclic base in the presence of an ester selected from trimethylsilyl perchlorate and the trimethylsilyl ester of tri-fluoromethane sulphonic acid.
2. A process according to claim 1, wherein the ester is trimethylsilyl perchlorate.
3. A process according to claim 1, wherein the ester is the trimethylsilyl ester of trifluoromethane sulphonic acid.
4. A process according to claim 1, 2 or 3 wherein any protected hydroxyl group in the nucleoside is converted into a free hydroxyl group.
5. A process according to claim 1, 2 or 3 wherein the sugar is ribose or desoxyribose.
6. A process according to claim 1, 2 or 3 wherein the sugar is arabinose or glucose.
7. A process according to claim 1, wherein the silylated organic base is a compound of the general formula (Ia) or (Ib) in which n represents O or 1, X represents an oxygen or sulphur atom, Rl and R2 each represents an unsubstituted or substituted organic hydrocarbon group or together represent a divalent organic group, R3 and R4 each represents a hydrogen atom or an alkyl, alkoxycarbonyl or alkylaminocarbonyl group or together represent a divalent group of the formula , , , , , , , , , , , , or or a corresponding divalent group that is substituted, and Y
represents a trialkylsilyl group.
represents a trialkylsilyl group.
8. A process according to claim 7 wherein the divalent organic group represented by R1 and R2 together contains 1 or 2 nitrogen atoms.
9. A process according to claim 7 wherein the silylated organic base is a compound of the general formula (Ia) in which n represents 1, R3, R4, X and Y have the meanings given in claim 7, and R1 and R2 together represent a , , , , , group in which X represents an oxygen or sulpher atom and R5 and R6 each represents a hydrogen atom or an alkyl, alkoxycarbonyl or alkylaminocarbonyl group.
10. A process according to claim 7 wherein the silylated organic base is a compound of the general formula (Ib) in which n represents O, R3, R4 and Y have the meanings given in claim 7, and R1 and R2 together represent a , or group in which R5 represents a hydrogen atom or an alkyl, alkoxy-carbonyl or alkylaminocarbonyl group.
11. A process according to claim 7, 8 or 9 wherein Y represents a trimethylsilyl group.
12. A process according to claim 1, 2 or 3 wherein the reaction is carried out at a temperature within the range of from 0 to 100°C.
13. A process according to claim 1, wherein 2,4-bis-(trimethylsilyloxy)-pyrimidine and 1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-D-ribofuranose are reacted in the presence of trimethylsilyl perchlorate to produce uridine 2',3',5'-tri-O-benzoate.
14. A process according to claim 1, wherein 3-trimethyl-silylthio-5-trimethylsilyloxy-1,2,4-triazine and .beta.-glucose-penta-acetate are reacted in the presence of trimethylsilyl perchlorate to produce 2-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyl)-3-thio-2,3,4,5-tetrahydro-1,2,4-triazin-5-one.
15. A process according to claim 1, wherein 2-trimethyl-silyloxy-pyridine and 1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-D-ribo-furanose are reacted in the presence of trimethylsilyl trifluor-methanesulfonate to produce 1-(2,3,5-tri-O-benzoyl-.beta.-D-ribo-furanosyl)-1,2-dihydropyridine-2-one.
16. A process according to claim 1, wherein 2-O-tri-methylsilyloxy-4-trimethylsilylamino-pyridine and 1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-D-ribofuranose are reacted in the presence of the trimethylsilyl ester of trifluoromethane sulphonic acid to produce cytidine 2',3',5'-tri-O-benzoate.
17. A process according to claim 1, wherein 6-benzoyl-trimethylsilylamino-9-trimethylsilyl-purine and 1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-D-ribofuranose are reacted in the presence of trimethylsilyl perchlorate to produce adenosine tetrabenzoate.
18. A process according to claim 17, wherein said adenosine tetrabenzoate is hydrolyzed with methanolic ammonia to produce adenosine.
19. A process according to claim 1, wherein 2,4-bis-(trimethylsilyloxy)-lumazine and 1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-D-ribofuranose are reacted in the presence of trimethylsilyl perchlorate to produce 1-(2,3,5-tri-O-benzoyl-.beta.-D-ribofuranosyl)-lumazine.
20. A process according to claim 1, wherein 1-trimethyl-silyl-3-carboxymethyl-1,2,4-triazole and 1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-D-ribofuranose are reacted in the presence of the tri-methylsilyl ester of trifluoromethane sulphonic acid to produce 1-(2,3,5-tri-O-benzoyl-.beta.-D-ribofuranosyl)-3-carboxymethyl-1,2,4-triazole.
21. A process according to claim 1, wherein 2,4-bis-(trimethylsilyloxy)-5-morpholino-pyrimidine and 1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-D-ribofuranose are reacted in the presence of the trimethylsilyl ester of trifluoromethane sulphonic acid to pro-duce 5-morpholino-uridine 2',3',5'-tri-O-benzoate.
22. A process according to claim 1, wherein 2,4-bis-(trimethylsilyloxy)-5-methoxy-pyrimidine and 1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-D-ribofuranose are reacted in the presence of the trimethylsilyl ester of the trifluoromethane sulphonic acid to produce 5-methoxy-uridine 2',3',5'-tri-O-benzoate.
23. A process according to claim 1, wherein 2,4-bis-(trimethylsilyloxy)-5,6-dimethyl-pyrimidine and 1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-D-ribofuranose are reacted in the presence of the trimethylsilylester of trifluoromethane sulphonic acid to produce 5,6-dimethyl-uridine 2',3',5'-tri-O-benzoate.
24. A process according to claim 1, wherein 2,4-bis-(trimethylsilyloxy)-6-methyl-pyrimidine and 1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-D-ribofuranose are reacted in the presence of the tri-methylsilyl ester of trifluoromethane sulphonic acid to produce 6-methyl-uridine 2',3',5'-tri-O-benzoate.
25. A process according to claim 1, wherein 1-(trimethyl-silyloxy)-1,2,5-triazole and 1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-D-ribofuranose are reacted in the presence of the trimethylsilyl ester of trifluoromethane sulphonic acid to produce 1-(1,2,4-tri-azolyl)-.beta.-D-ribofuranoside-2',3',5'-tri-O-benzoate.
26. A process according to claim 7, 9 or 10 wherein R1 and R2 together represent a group selected from , , -C4H4- , , , and -CH=N-CH=N-.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19752508312 DE2508312A1 (en) | 1975-02-24 | 1975-02-24 | NEW PROCESS FOR THE PRODUCTION OF NUCLEOSIDES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1065315A true CA1065315A (en) | 1979-10-30 |
Family
ID=5939872
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA246,368A Expired CA1065315A (en) | 1975-02-24 | 1976-02-23 | Process for producing nucleosides |
Country Status (12)
| Country | Link |
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| US (1) | US4082911A (en) |
| JP (1) | JPS51125382A (en) |
| BE (1) | BE838879A (en) |
| CA (1) | CA1065315A (en) |
| CH (1) | CH626093A5 (en) |
| DE (1) | DE2508312A1 (en) |
| DK (1) | DK138900C (en) |
| FR (1) | FR2301536A1 (en) |
| GB (1) | GB1542442A (en) |
| LU (1) | LU74411A1 (en) |
| NL (1) | NL7601625A (en) |
| SE (1) | SE7602109L (en) |
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| JPS53108986A (en) * | 1977-03-02 | 1978-09-22 | Mitsui Toatsu Chem Inc | Preparation of nucleosides and nucleotides |
| DE2721466A1 (en) * | 1977-05-12 | 1978-11-16 | Robugen Gmbh | PROCESS FOR THE PREPARATION OF 2'-DESOXYRIBOFURANOSYL NUCLEOSIDES |
| US4195176A (en) * | 1977-10-11 | 1980-03-25 | Warner-Lambert Company | Imidazole compounds, methods for their production and conversion of said compounds into (R)-3-(2-deoxy-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazol[4,5-d][1,3]diazepin-8-ol |
| DE2757365A1 (en) * | 1977-12-20 | 1979-06-21 | Schering Ag | NEW PROCESS FOR THE PRODUCTION OF NUCLEOSIDES |
| JPH029511U (en) * | 1988-06-21 | 1990-01-22 | ||
| CA2091732C (en) * | 1992-07-08 | 1998-07-21 | Anica Markovac | A process for the preparation of 2-fluoro-9-(2,3,5-tri-o-benzyl-beta-d-arabinofuranosyl) adenine |
| JPH07276137A (en) * | 1994-03-31 | 1995-10-24 | Osaka Diamond Ind Co Ltd | Tool for cutting and grinding |
| DE19513330A1 (en) * | 1995-04-03 | 1996-10-10 | Schering Ag | New process for the production of nucleosides |
| MY164523A (en) | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
| KR20080021797A (en) | 2000-05-26 | 2008-03-07 | 이데닉스(케이만)리미티드 | Methods and compositions for treating flaviviruses and pestiviruses |
| CA2489552A1 (en) | 2002-06-28 | 2004-01-08 | Idenix (Cayman) Limited | 2'-c-methyl-3'-o-l-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections |
| US7608600B2 (en) | 2002-06-28 | 2009-10-27 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
| MXPA05005192A (en) | 2002-11-15 | 2005-09-08 | Idenix Cayman Ltd | 2aCOE-BRANCHED NUCLEOSIDES AND FLAVIVIRIDAE. |
| US7038038B2 (en) * | 2003-03-17 | 2006-05-02 | Pharmion Corporation | Synthesis of 5-azacytidine |
| US6887855B2 (en) | 2003-03-17 | 2005-05-03 | Pharmion Corporation | Forms of 5-azacytidine |
| US6943249B2 (en) | 2003-03-17 | 2005-09-13 | Ash Stevens, Inc. | Methods for isolating crystalline Form I of 5-azacytidine |
| EP1620451A4 (en) | 2003-04-28 | 2009-02-18 | Novartis Ag | Industrially scalable nucleoside synthesis |
| KR20060035652A (en) | 2003-06-30 | 2006-04-26 | 이데닉스 (케이만) 리미티드 | SYNTHESIS OF beta-L-2-DEOXY NUCLEOSIDES |
| AT502635A1 (en) * | 2005-11-09 | 2007-05-15 | Saischek Und Partner Meg | NEW 1,3-DITHIUM COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
| WO2007075876A2 (en) | 2005-12-23 | 2007-07-05 | Idenix Pharmaceuticals, Inc. | Process for preparing a synthetic intermediate for preparation of branched nucleosides |
| EP2048151A1 (en) * | 2007-10-10 | 2009-04-15 | Cilag AG | Method for producing nucleosides by direct glycosylation of the nucleoside base |
| EP2050757A1 (en) * | 2007-10-10 | 2009-04-22 | Cilag AG | Method of producing 2' -deoxy-5-azacytidine (Decitabine) |
| DK2695609T3 (en) | 2008-05-15 | 2020-02-10 | Celgene Corp | Oral formulations of cytidine analogues and methods for their use |
| WO2010014883A2 (en) | 2008-08-01 | 2010-02-04 | Dr. Reddy's Laboratories Ltd. | Azacitidine process and polymorphs |
| EP2324042B1 (en) * | 2008-08-06 | 2012-11-28 | Sicor, Inc. | Process for preparing azacytidine intermediate |
| JP5650643B2 (en) * | 2008-08-08 | 2015-01-07 | サイノファーム タイワン リミテッド | Method for producing 5-azacytosine nucleoside and derivatives thereof |
| EP2424845A4 (en) * | 2009-04-27 | 2014-03-05 | Reddys Lab Ltd Dr | Preparation of decitabine |
| CN103619864A (en) | 2011-03-31 | 2014-03-05 | 细胞基因国际有限公司 | Systhesis of 5-azacytidine |
| CN108239128B (en) * | 2016-12-23 | 2019-03-29 | 江苏奥赛康药业股份有限公司 | The preparation method of beta-nucleosides class compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3354160A (en) * | 1965-07-22 | 1967-11-21 | Hoffmann La Roche | Tri-lower alkyl-silyl-5-fluoropyrimidines |
| US3352849A (en) * | 1965-10-24 | 1967-11-14 | Merck & Co Inc | 6-aza-2'-deoxyuridines |
| CH541566A (en) * | 1969-04-11 | 1973-09-15 | Schering Ag | Process for the preparation of nucleosides |
| DE2122991C2 (en) * | 1971-05-04 | 1982-06-09 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Process for the preparation of cytosine and 6-azacytosine nucleosides |
-
1975
- 1975-02-24 DE DE19752508312 patent/DE2508312A1/en active Granted
-
1976
- 1976-02-18 NL NL7601625A patent/NL7601625A/en not_active Application Discontinuation
- 1976-02-23 US US05/660,675 patent/US4082911A/en not_active Expired - Lifetime
- 1976-02-23 SE SE7602109A patent/SE7602109L/en unknown
- 1976-02-23 CA CA246,368A patent/CA1065315A/en not_active Expired
- 1976-02-23 LU LU74411A patent/LU74411A1/xx unknown
- 1976-02-23 GB GB767006A patent/GB1542442A/en not_active Expired
- 1976-02-24 BE BE164585A patent/BE838879A/en not_active IP Right Cessation
- 1976-02-24 CH CH227476A patent/CH626093A5/de not_active IP Right Cessation
- 1976-02-24 FR FR7605030A patent/FR2301536A1/en active Granted
- 1976-02-24 JP JP51019810A patent/JPS51125382A/en active Granted
- 1976-02-24 DK DK77176A patent/DK138900C/en active
Also Published As
| Publication number | Publication date |
|---|---|
| GB1542442A (en) | 1979-03-21 |
| DE2508312C2 (en) | 1987-10-29 |
| JPS6139318B2 (en) | 1986-09-03 |
| DK138900B (en) | 1978-11-13 |
| DK138900C (en) | 1979-04-30 |
| FR2301536B1 (en) | 1979-07-27 |
| SE7602109L (en) | 1976-08-25 |
| CH626093A5 (en) | 1981-10-30 |
| US4082911A (en) | 1978-04-04 |
| DK77176A (en) | 1976-08-25 |
| NL7601625A (en) | 1976-08-26 |
| BE838879A (en) | 1976-08-24 |
| DE2508312A1 (en) | 1976-09-02 |
| LU74411A1 (en) | 1976-08-13 |
| FR2301536A1 (en) | 1976-09-17 |
| JPS51125382A (en) | 1976-11-01 |
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