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WO2007053869A2 - Dérives de furanose à substitution 2,2-dithio, procédé de production et leur utilisation - Google Patents

Dérives de furanose à substitution 2,2-dithio, procédé de production et leur utilisation Download PDF

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WO2007053869A2
WO2007053869A2 PCT/AT2006/000458 AT2006000458W WO2007053869A2 WO 2007053869 A2 WO2007053869 A2 WO 2007053869A2 AT 2006000458 W AT2006000458 W AT 2006000458W WO 2007053869 A2 WO2007053869 A2 WO 2007053869A2
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formula
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carbon atoms
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PCT/AT2006/000458
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WO2007053869A3 (fr
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Gerald Saischek
Ewald Saischek
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Saischek Und Partner Meg
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Publication of WO2007053869A3 publication Critical patent/WO2007053869A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • nucleosides which are used as pharmaceutical products, are of great interest to the medical community.
  • Particularly fluorine-containing nucleosides have gained in importance in recent years. Fluorine atoms have a high binding force to carbon atoms compared to hydroxyl groups; they are chemically largely inactive and have hydrophobic properties.
  • Nucleosides however, also play an extraordinary role in the treatment of various cancers (Chu, CK-Baker, TC, Eds. "Nucelosides and Nucleicides as Antitumor Agents and Antiviral Agents", Plenum Press: New York, 1993) within the class of fluorinated nucleosides to 2 'deoxy-2', 2 'difluoro nucleosides due to your particular property in the activity against numerous viruses and cancers of (EP576230 (1993); EP576227 (1993)).
  • 1, 3-dithiane and 1,3-dithiolane are valuable intermediates for the introduction of geminal difluorides (Susan C. Sondej, John A. Katzenellenbogen, J. ORG CHEM 1986, 51, 3508-3513).
  • the present invention relates to novel 1, 3-disubstituted sulfur compounds of general formula 1 and their preparation and their use
  • R 1 and R 2 are identical or different and independently of one another denote hydrogen or a hydroxy-protecting group, R 3 and R 4, independently of one another, a linear, branched or cyclic alkyl radical having 1-6 carbon atoms, where R 3 and R 4 may be linked to one another by a carbon bridge
  • a 4-7 membered ring preferably 5-6 membered ring, represents the group
  • R 6 and / or R 7 are a hydrogen atom, a substituted or unsubstituted alkyl or alkenyl radical having 1-6 carbon atoms, and n can be 1, 2, 3 or 4, where R 6 and R 7 are preferably hydrogen, n is preferably 2 or 3,
  • R5 is the radical of a base of the general formula. 3
  • radicals R 8 and R 9 independently of one another denote hydrogen or an amino-protecting group and R 10 is hydrogen or a linear saturated or unsaturated alkyl radical having 1 to 4 carbon atoms, optionally substituted by halogen, or halogen.
  • radicals R11 and R12 of the general formula 5 independently of one another denote a linear or branched alkyl radical having 1-4 carbon atoms, or R11 and R12 may be bridged with one another in such a way that the group
  • R 13 and R 14 independently of one another may be a hydrogen atom or an alkyl radical having 1-6 carbon atoms, and n is 1, 2, 3 or 4, preferably a 5 or 6 membered ring.
  • R3 and R4 in the general formula 6 retain the meaning defined above and R15 represents a linear or branched alkyl radical having 1 to 5 carbon atoms.
  • Aldehydes of the general formula 5 can be prepared, for example, from the following references: Barton, Arthur H, R. et al., Tetrahedron Letters (1982), 23, 957-60; Barry, Jean et al., Synthesis (1981), 453-455.
  • Preferred compounds of general formula 6 are 1, 3-dithiolane-2-carboxylic acid ethyl ester and 1, 3-dithiane-2-carboxylic acid ethyl ester.
  • the preparation of these products is described, for example, by Emest L EHeI et al. in J. Org. Chem. (1972), 37, 505-506.
  • the conversion of compounds of general formula 5 with compounds of general formula 6 is carried out in the presence of a solvent or diluent at temperatures of - 100 to + 20 0 C, especially at - 70 to - 40 0 C.
  • a solvent or diluent for the reactions of the aldehyde with 1,3-dithio compounds advantageous to use ethers, such as diethyl ether or tetrahydrofuran.
  • inert solvents under the reaction conditions such as alkanes (n-hexane, n-heptane, cyclohexane), such as aromatic solvents (benzene, ethylbenzene, toluene, xylene), as well as combinations of these solvents are also suitable.
  • alkanes n-hexane, n-heptane, cyclohexane
  • aromatic solvents benzene, ethylbenzene, toluene, xylene
  • combinations of these solvents are also suitable.
  • the deprotonation of the 1, 3-dithio compound of general formula 6 is carried out with organolithium compounds, preferably with lithium diisopropylamide, and subsequent transmetallation with magnesium bromide according to Manfred Braun et al. Ber. (1981), 114, 2924-2928.
  • R1 is hydrogen and R2, R3 and R4 retain the meanings defined above.
  • strongly acidic catalysts are 0.5-5 normal hydrochloric acid, 0.5-5 normal sulfuric acid, organic acids such as. P-toluenesulfonic acid, trifluoroacetic acid, but also strongly acidic ion exchange resins.
  • the acids are generally used in catalytic amounts in the ratio of 0.05 to about 0.5 molar equivalents, relative to the pentanoate.
  • the pentanoate is introduced together with the acidic catalyst in a mixture of a suitable solvent and water, wherein the water content should be 1 to 5 molar equivalents relative to the propionate.
  • suitable solvents are polar solvents such as. Alcohols, for example methanol, ethanol, Isopropanol or similar, acetonitrile or other polar solvents which are inert under the given reaction conditions and keep the starting material or the end product in solutions used.
  • the amount of water required to cleave the protecting groups is kept as low as possible in order not to complicate their removal, which has an accelerating effect on the lactonization.
  • lactonization ring closure
  • the lactonization is carried out by continuously removing the excess water, including the water of reaction, either by supplying an azeotrope with water or by distilling off the mixture of solvent and water while continuously diluting the distilled solvent by fresh solvent.
  • R 1 and R 2 represent a hydroxy-protecting group
  • R 3 and R 4 retain the meaning defined above, obtained by reacting per free hydroxyl group with 1 to 4 equivalents of a protecting agent, optionally in a diluent inert under the reaction conditions such as hydrocarbons, chlorinated hydrocarbons, Carboxylic acid esters, ethers, acetonitrile, or directly in an organic base are reacted directly without diluents.
  • organic bases are preferably tert.
  • Amines, triethylamine or pyridines preferably 2,6-dimethylpyridine or other sterically hindered pyridine bases, and substituted Pyridines such as 4-dimethylaminopyridine, but also inorganic bases, such as alkali metal bicarbonate or alkali metal carbonate in question.
  • inorganic bases such as alkali metal bicarbonate or alkali metal carbonate in question.
  • organic base Preferably 1 to 3 equivalents of organic base are used per hydroxyl group to be protected.
  • Suitable protecting groups are selected according to conventional criteria known to those skilled in the art to protect the primary and secondary alcoholic hydroxyl functions. Such protecting groups must be stable under the reaction conditions prevailing for subsequent reaction steps and should be readily removable once the reaction is complete, if desired.
  • aralkyl groups are introduced as hydroxy protecting groups.
  • Cyclic vinyl ethers preferably 3,4-dihydro-2H-pyran, wherein the reaction in a diluent inert under the reaction conditions, such as halogenated hydrocarbons such as dichloromethane, in the presence of a catalyst such as pyridinium toluene, at temperatures of about - 20 and 50 0 C. takes place, wherein as the hydroxy protecting group, the tetrahydropyranyl group is introduced.
  • a diluent inert under the reaction conditions such as halogenated hydrocarbons such as dichloromethane
  • a catalyst such as pyridinium toluene
  • D) trialkyl, aryl-dialkyl or diaryl-alkyl-silyl halides the reaction being carried out in a diluent such as N, N-Dimehtylformamid in the presence of at least equimolar amounts of a base such as imidazole at temperatures of about - 20 to 25 0 C. in which the trialkyl, aryldialkyl or diarylalkylsilyl group is introduced.
  • the introduction of the silyl protecting groups can also be carried out without solvent only in the presence of an organic base, for example pyridines or 2,6-lutitin or similar sterically hindered bases.
  • a catalyst such as 4-dimethylaminopyridine can be used.
  • Lactones of the general formula 8 are prepared by reduction of the keto group with metal hydrides, such as, for example, diisobutylaluminum hydride, lithium aluminum hydride, preferably lithium aluminum tri-tert-butyloxyhydride, into the protected lactol of the general formula 10
  • metal hydrides such as, for example, diisobutylaluminum hydride, lithium aluminum hydride, preferably lithium aluminum tri-tert-butyloxyhydride
  • the reaction is conducted at low temperatures in the range of - 100 to 0 0 C preferably at - 60 to - 5 ° C is performed.
  • solvents especially ethers such as diethyl ether or tetrahydrofuran, but also toluene or alcohols such as especially ethanol, are used.
  • the preferred solvent is tetrahydrofuran or a mixture of tetrahydrofuran and diethyl ether.
  • L is a general leaving group, such as acyloxy.Sulfonyloxy or alkyloxy, selected from the group alkanoyloxy having 1 to 6 carbon atoms, or Aroyloxyrest having 7 to 15 carbon atoms, optionally substituted by 1 to 2 halogen atoms or by 1 to 2 alkyl groups each with 1 to 4 carbon atoms, or an alkylsulfonyloxy radical having 1 to 4 carbon atoms, an arylsulfonyloxy radical having 6 to 10 carbon atoms optionally substituted by 1 to 2 halogen atoms or 1 to 2 alkyl radicals each having 1 to 4 carbon atoms, or an alkyloxy radical having 1 to 6 carbon atoms, especially but acetyloxy means convicted.
  • acyloxy.Sulfonyloxy or alkyloxy selected from the group alkanoyloxy having 1 to 6 carbon atoms, or Aroyloxyrest having 7 to 15 carbon atoms, optionally substitute
  • the alkyl or arylcarboxylic acid halides or anhydrides which are at least equivalent or in excess, based on the hydroxy group and in the presence of at least equimolar amounts of a base such as an organic base such as 4-dimethylaminopyridine, pyridine, triethylamine, in one of the Reaction conditions inert diluents such as hydrocarbons, for example benzene, toluene, gasoline fractions or chlorinated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride or ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane with one equivalent of a compound of general formula 10 at temperatures of about - 50 bis 50 0 C, preferably at - 10 to 10 0 C, to compounds of general formula. 2
  • a base such as an organic base such as 4-dimethylaminopyridine, pyridine, trie
  • the sulfonylating agent preferably methanesulfonic acid chloride
  • a mixture consisting of an organic base e.g. triethylamine
  • Bases are used in an excess of from 1.05 to 4 equivalents, preferably 1.5 to 3, based on one equivalent of the hydroxy compound of formula 10.
  • alkylsulfonyl halides having 1 to 4 carbon atoms optionally substituted by 3 to 9 fluorine atoms, or alkylsulfonic anhydrides having 2 to 8 carbon atoms, optionally substituted by 6 to 18 fluorine atoms, or Arylsuifonklahalogenide having 6 to 9 carbon atoms, optionally by 1 to 3 alkyl groups or by Substituted 1 to 3 halogen atoms, or arylsulfonic anhydrides, optionally substituted by alkyl groups or by 1 to 3 halogen atoms used.
  • As inert diluents are hydrocarbons, for example benzene, toluene, gasoline fractions or chlorinated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride or ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane or mixtures of solvents used.
  • the sulphonating agents used are used in an excess of from 1.05 to 4 equivalents, preferably 1.5 to 2.5 equivalents, relative to one equivalent of the hydroxy compound.
  • alkylation is the alkylating agent, an alkyl halide having 1 to 6 carbon atoms, preferably alkyl bromide, or a dialkyl sulfate having 2 to 8 carbon atoms, preferably dimethyl sulfate, to a mixture consisting of an inorganic base such as NaH, KH, NaHCO 3 or Na 2 CO , in the presence of a diluent, in a temperature range of - 50 to 70 0 C, preferably - 30 to 30 0 C, brought to Christs.
  • inorganic base such as NaH, KH, NaHCO 3 or Na 2 CO
  • a diluent in a temperature range of - 50 to 70 0 C, preferably - 30 to 30 0 C, brought to Christs.
  • Das used bases are in an excess of 1, 5 to 4 equivalents, preferably 1, 5 bis 3, based on one equivalent of the hydroxy compound used.
  • As inert diluents are hydrocarbons, for example benzene, toluene, gasoline fractions or chlorinated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride or ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane or mixtures of solvents used.
  • the application Alkylating agents are used in an excess of from 1.5 to 4 equivalents, preferably from 1.5 to 3, based on one equivalent of the hydroxy compound of the formula ## STR9 ## Compounds of the general formula 16 are obtained
  • a compound of general formula 2 preferably 1-0-acetyl, or a compound of general formula 16, preferably 1 -O-methyl, or a compound of general formula 17, preferably 1-0-methanesulfonyl
  • a suitable solvent for example CH 2 Cl 2, CICH 2 CH 2 Cl, CHCl 3, benzene, toluene, acetonitrile, dioxane, tetrahydrofuran, chlorobenzene or dimethylformamide, preferably acetonitrile, or in a mixture of the solvents mentioned in the presence of a Lewis catalyst, for example SnCl 4, SnCl 2, TiCl 4, BF 3, ZnCl 2, preferably trimethylsilyl trifluoromethanesulfonate, with a silylated pyrimidine of general formula 12
  • a Lewis catalyst for example SnCl 4, SnCl 2, TiCl 4, BF 3, ZnCl 2, preferably trimethylsilyl trifluoromethanesul
  • R10 retains the meaning defined above and preferably hydrogen and Z is either oxygen, or the radicals NH or N-acyl, wherein acyl is an alkanoyl radical having 2 to 20 carbon atoms, straight or branched, optionally substituted by aryl or aryloxy, or an aroyl radical with 7 to 20 carbon atoms, optionally substituted by 1 to 3 alkyl, alkoxy, cyano-nitro or phenyl radicals, or substituted by 1 to 3 halogen atoms, to obtain a nucleoside of general formula 1
  • silylation of pyrimidine bases of general formulas 3 and 4 is e.g. in patent US-4082911.
  • silylating agent either hexamethyldisilazane, trimethylchlorosilane, N, O-bistrimethylsilylacetamide in the presence of an acidic catalyst, e.g. Ammonium sulfate used.
  • the silylation is advantageously carried out in excess of the silylating agent, after which, after complete silylation, the excess silylating agent is stripped off in vacuo and the silylated pyrimidine base can be used directly without purification step.
  • Nucleosidation is also described, for example, in US Pat. No. 4,082,911. The nucleosidation is carried out at temperatures of from -50 to 100 ° C., preferably at -20 to 40 ° C.
  • the protective groups used in compounds of general formula 1 can be cleaved as needed, according to methods known to those skilled in the art.
  • acyl groups are primarily alkali metal hydroxylates in inert solvents, or even ammoniacal alcohol or water solutions and organic bases, such. Triethylamine, used.
  • Silyl protecting groups can be split off already with contact by water. A variety of deprotection methods are extensively used, e.g. in Greene; "Protective Groups in Organic Synthesis”; John Wiley & Sons, described.
  • R 1 and R 2 are hydrogen, and R 3, R 4 are the same as defined above, and R 5 is either a radical of general formula 3 in R 8 and R 9 is hydrogen, or a radical of general formula 4 in which R 10 is the radical above defined meaning .preferably hydrogen, means.
  • Dithio compounds of the general formula 1 can be converted into geminal difluoride products by oxidative desulfofluorination (Manabu Kuroboshi et al, Adv. Synth. Catal. (2001), 343, 235-250; "Oxidative desulforization - fluorination").
  • the reaction with the oxidation and fluorination agent is advantageously carried out at a temperature of - 100 to 50 0 C, preferably at - 70 to - 20 0 C.
  • oxidizing agent compounds that released halonium equivalents.
  • Typical oxidizing agents are dimethyldibromohydanthoin, N-bromosuccinimide, N-iodosuccinimide, 1,3-dibromo-5,5-dimethylhydanthoin, but also bromine trifluoride.
  • the fluorinating agents customary fluorinating agents can be used.
  • the fluorinating agent is particularly preferably selected from the group of aliphatic and aromatic amine-hydrogen fluoride complexes, for example pyridine-hydrogen fluoride complexes, in particular HF in pyridine with an F content of 50-70%, triethylamine-3HF complex, melamine-HF Complex, polyvinylpyridine-HF complex or tetrabutylammonium dihydrogentrifluoride complex.
  • Suitable solvents are acetonitrile halogenated hydrocarbons, but also ethers such as diethyl ether or THF in question.
  • the reaction is advantageously carried out in the temperature range from - 100 to 50 0 C, preferably in the temperature range of about - 75 to -0 ° C.
  • the reaction is advantageously carried out by the solvent, the fluorinating agent in 4 to 30 molar excess and the oxidizing agent in 1 to 4 molar excess based on one mole of dithio compound is added and the dithio compound dissolved in the respective solvent is slowly added dropwise at low temperature.
  • R1, R2 and R5 retain the meanings defined above.
  • the reaction mixture is cooled to about - 70 0 C.
  • a solution of 10 ml of tetrahydrofuran and 20 g (0.146 mol) of isopropylideneglyceraldehyde is slowly added dropwise.
  • the dosage is carried out in such a way that a temperature of about - 65 0 C can be maintained.
  • stirring is continued for about 2.5 hours at this temperature and the reaction mixture over a period of about one hour at the terminal - heating 10 0 C.
  • the reaction mixture is transferred to a saturated solution of ammonium chloride and ethyl acetate and purified by washing the ethyl acetate phase with distilled water.
  • the organic phase is extracted successively with dilute sulfuric acid, 10% Na 2 CO 3 and H 2 O.
  • the combined organic phases are concentrated to dryness on a rotary evaporator and the residue is recrystallized from 5 ml of ethyl acetate. There are obtained 0.52 g (0.0012 mol) of product.
  • Example 7 3,5-Di-O- (4-chlorobenzoyl) -D'-iythro-pent-2 "(ulosonoethane-1,2-diyldithioacetaQ-1,4-lactone
  • Example 8 3,5-Di-O-pivaloyl-D-erythro-pent-2- (ulosono ethane-1,2-diyl-dithioacetal) -1,4-lactone
  • Example 13 3,5-D ⁇ -O- (4-nitrobenzoyl) -D-erythro-pent-2- (ulosono ethane-1,2-diyl-d ⁇ thioacetal) -1,4-lactone
  • Example 14 3,5-Di-O- (4-methylbenzoyl) -D-erythro-pent-2- (ulosono propane-1,3-diyl-dithioacetal) -1,4-lactone
  • reaction mixture is cooled in an ice bath and to this cooled solution is added a solution consisting of 1 ml of acetonitrile and 0.111 g (0.0005 mol) of trimethylsilyl trifluoromethanesulfonate all at once. Then the ice bath is removed and the reaction solution is allowed to warm to room temperature. The reaction is stopped after about 2 hours. To the reaction mixture are added 50 ml of dichloromethane and the organic phase shaken out in succession with 50 ml of 10% strength NaHCO 3 and 2 ⁇ 50 ml of water. The combined organic phases are concentrated to dryness. It will be 0.169 g
  • the residue is purified by column chromatography on silica gel (cyclohexane: acetone).
  • Example 20 3 ' , 5'-di-O-benzoyl-2 ' - (ethane-1,2-diyl-dithioacetal) ' ⁇ -D-uridine
  • the thus diluted reaction mixture is stirred into a saturated solution of 50 ml of sodium bicarbonate and quickly shaken out, the color turns lightning colorless.
  • the organic phase is shaken a second time with sodium bicarbonate solution and finally shaken out with distilled water again.
  • the organic phase is concentrated to dryness and purified by column chromatography. There are obtained 0.045 g of product.

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Abstract

L'invention concerne des composés de formule (1) dans laquelle : R1, R2, R3 et R4 ont les correspondances indiquées dans le descriptif ; et R5 est soit le radical d'une base de formule générale (3) dans laquelle R8 et R9 sont indépendamment l'un de l'autre hydrogène ou un groupe protecteur amino, de préférence un radical alcanoyle ou aroyle éventuellement substitué, ou le radical d'une base de formule générale (4) dans laquelle R10 est hydrogène, un radical alkyle saturé ou instauré comprenant de 1 à 3 atomes de carbone ou du brome, du fluor, du chlore ou de l'iode. Ces composés peuvent servir de produits intermédiaires adaptés et intéressants pour former des difluoro-nucléosides géminés qui peuvent être utiles dans le cadre de traitements antiviraux et anticarcinogènes. La fluoration est obtenue par une désulfofluoration oxydative qui permet une production économique de fluoro-nucléosides géminés.
PCT/AT2006/000458 2005-11-09 2006-11-08 Dérives de furanose à substitution 2,2-dithio, procédé de production et leur utilisation WO2007053869A2 (fr)

Priority Applications (1)

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AT94452006A AT509773B1 (de) 2005-11-09 2006-11-08 Neue 2,2-dithiosubstituierte furanosederivate, verfahren zu deren herstellung und ihre verwendung

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ATA1837/2005 2005-11-09
AT0183705A AT502635A1 (de) 2005-11-09 2005-11-09 Neue 1,3-dithioverbindungen, verfahren zu deren herstellung und ihre verwendung

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009058800A2 (fr) * 2007-10-29 2009-05-07 President And Fellows Of Harvard College Synthèse de nucléosides

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US4082911A (en) * 1975-02-24 1978-04-04 Schering Aktiengesellschaft Process for the preparation of nucleosides
EP0544010A1 (fr) * 1991-06-14 1993-06-02 Japan Tobacco Inc. Procede de production de 2',3'-didesoxy-beta-nucleosides
EP0576227A2 (fr) * 1992-06-22 1993-12-29 Eli Lilly And Company 2'-désoxy-2',2'-difluoro nucléosides puriniques (substitué en positions 2,6 et 8) avec un activité antiviral et anticancer et leurs intermédiaires
EP0576230A1 (fr) * 1992-06-22 1993-12-29 Eli Lilly And Company 2'-désoxy-2',2'-difluoro(pyrimidine, 4-substitué)nucléosides avec activité antiviral et anticancer et intermédiaires
JPH07278178A (ja) * 1994-04-01 1995-10-24 Japan Tobacco Inc ２’置換−２’，３’−ジデヒドロ−２’，３’−ジデオキシヌクレオシド及びその製造方法

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EP0544010A1 (fr) * 1991-06-14 1993-06-02 Japan Tobacco Inc. Procede de production de 2',3'-didesoxy-beta-nucleosides
EP0576227A2 (fr) * 1992-06-22 1993-12-29 Eli Lilly And Company 2'-désoxy-2',2'-difluoro nucléosides puriniques (substitué en positions 2,6 et 8) avec un activité antiviral et anticancer et leurs intermédiaires
EP0576230A1 (fr) * 1992-06-22 1993-12-29 Eli Lilly And Company 2'-désoxy-2',2'-difluoro(pyrimidine, 4-substitué)nucléosides avec activité antiviral et anticancer et intermédiaires
JPH07278178A (ja) * 1994-04-01 1995-10-24 Japan Tobacco Inc ２’置換−２’，３’−ジデヒドロ−２’，３’−ジデオキシヌクレオシド及びその製造方法

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REINER M ET AL: "Synthesis of 3-deoxy-d-manno-2-octulosonic acid (Kdo) and d-glycero-d-talo-2-octulosonic acid (Ko) and their alpha-glycosides" TETRAHEDRON: ASYMMETRY, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, Bd. 11, Nr. 1, Januar 2000 (2000-01), Seiten 319-335, XP004202388 ISSN: 0957-4166 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009058800A2 (fr) * 2007-10-29 2009-05-07 President And Fellows Of Harvard College Synthèse de nucléosides
WO2009058800A3 (fr) * 2007-10-29 2009-07-16 Harvard College Synthèse de nucléosides

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