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WO2009058800A2 - Synthèse de nucléosides - Google Patents

Synthèse de nucléosides Download PDF

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Publication number
WO2009058800A2
WO2009058800A2 PCT/US2008/081499 US2008081499W WO2009058800A2 WO 2009058800 A2 WO2009058800 A2 WO 2009058800A2 US 2008081499 W US2008081499 W US 2008081499W WO 2009058800 A2 WO2009058800 A2 WO 2009058800A2
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process according
group
protecting group
alkyl
hydrogen
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PCT/US2008/081499
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WO2009058800A3 (fr
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Gregory L. Verdine
Seongmin Lee
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President And Fellows Of Harvard College
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    • 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
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • 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
    • C07H19/16—Purine radicals
    • C07H19/167—Purine radicals with ribosyl as the saccharide radical

Definitions

  • This disclosure relates to the synthesis of nucleoside analogues, and more particularly to the synthesis of 4'-fluoronucleoside analogues.
  • nucleosides In addition to encoding genetic information, nucleosides play a central role in cell metabolism. The binding motifs of these nucleosides are associated with a broad array of targets of therapeutic importance in biological systems. Thus, nucleoside analogues can be used for example as inhibitors of these processes, for example DNA biosynthesis, a process that is essential for cell growth and viral replication.
  • Naturally occurring nucleoside analogs demonstrate selective activities such as protein synthesis inhibition (puromycin), glycosyl transferase inhibition (tunicamycin) and methyltransferase inhibition (sinefungin).
  • non-naturally occurring nucleoside analogues are known to be therapeutically useful, for example as antipsychotics, cardiotonics, diuretics, analgesic, anti-inflammatory agents, anticonvulsants, antihypertensives, antibiotics, antivirals, and anticancer agents. Many of these nucleoside analogues are either on the market or in advanced clinical stages.
  • Nucleocidin, 4'-fluoro-5'-O-sulfamoyladenosine, an antimicrobial agent effective against trypanosomes, amoebae and gram negative and gram positive bacteria is produced by cultures of Streptomyces calvus. Blackus, et al., Antibiot. Chemother., 1957, 7, 532; Morton, et al, J. Am. Chem. Soc, 1969, 1535; Jenkins, et al., J. Am. Chem. Soc, 1971, 93, 4323; Jenkins, et al., J. Am. Chem. Soc, 1976, 98, 2346.
  • 5'- Deoxy-4',5-difluorouridine has been synthesized as a prodrug of the anticancer drug 5- fluorouracil.
  • 4'-Fluoroadenosine has been prepared as an inhibitor of S-adenosyl-L-homocysteine hydrolase, a target that has been investigated for potential antiviral agents, and inhibition of which induces immunosuppression.
  • R A is heterocyclic base linked via a nitrogen atom;
  • R B is selected from the group consisting of hydrogen, OR 2 , O(Ci-C 3 )alkyl,
  • R 2 is selected from the group consisting of hydrogen and an alcohol protecting group
  • R 3 is selected from the group consisting of hydrogen and an alcohol protecting group
  • R 4 is selected from the group consisting of hydrogen and an alcohol protecting group; with a brominating agent; and (b) reacting the product of step (a) with a fluorinating agent to form a compound according to formula II:
  • R B is selected from the group consisting of hydrogen, OR 2 , O(Ci-C 3 )alkyl, F, and (Ci-C 3 )alkylene0(Ci-C 3 )alkyl; the symbol indicates that the stereochemistry of OR 1 and R B are independently ⁇ or ⁇ ;
  • R 1 is selected from the group consisting of hydrogen and an alcohol protecting group
  • R 2 is selected from the group consisting of hydrogen and an alcohol protecting group
  • R 3 is selected from the group consisting of hydrogen and an alcohol protecting group
  • R 4 is selected from the group consisting of hydrogen and an alcohol protecting group; with a brominating agent; and (b) reacting the product of step (a) with a fluorinating agent to form a compound according to formula IV;
  • step (c) optionally converting the product of step (b) into a compound according to formula V:
  • step (d) reacting the product of step (b) wherein OR 1 is a leaving group or the product of step (c) with a nitrogen-containing heterocyclic base to form a compound according to formula II:
  • R A is a heterocyclic base linked via a nitrogen atom; and R B , R 3 , and R 4 are as defined above for formula III.
  • (C x -C y )alkyl denotes a straight or branched hydrocarbon radical containing x to y carbons.
  • An alkyl group formally corresponds to an alkane with a C-H bond replaced by a point of attachment of the alkylene group to the remainder of the compound.
  • Some embodiments have 1 to 6 carbons, some embodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons, and some embodiments are 1 or 2 carbons. Examples include methyl and ethyl.
  • Alkyl groups having 3 or more carbon atoms may be straight-chained (e.g. n-propyl, n-butyl, n- pentyl etc.), branched (isopropyl, isobutyl, t-butyl etc.), or cyclic (e.g. cyclopropyl, cyclobutyl, cyclopropylmethyl, methylcyclopropyl, etc.).
  • (C x -C y )alkylene denotes a straight or branched hydrocarbon diradical containing x to y carbons.
  • An alkylene group formally corresponds to an alkane with two C-H bond replaced by points of attachment of the alkylene group to the remainder of the compound.
  • Some embodiments have 1 or 2 to 6 carbons, some embodiments are 1 or 2 to 4 carbons, some embodiments are 1 or 2 to 3 carbons, and some embodiments are 1 or 2 carbons. Examples include methylene -(CH 2 )- and 1 , 1 -ethylene (-(CH(CH 3 )-) or 1 ,2-ethylene (-(CH 2 CH 2 )-) .
  • Alkylene groups having may be straight-chained (e.g. -(CH 2 ) n - where n is an integer), branched (e.g. (-(CH(CH 3 )-, -(C(CH 3 ) 2 - etc.), or cyclic (e.g. cyclopropylidene).
  • halogen means fluorine, chlorine, bromine, or iodine.
  • a protecting group is a derivative of a chemical functional group which is often used when the group would otherwise be incompatible with the conditions required to perform a particular reaction which, after the reaction has been carried out, can be removed to re generate the original functional group, which is thereby considered to have been "protected", but may also be useful for other purposes (such as improving the solubility of a compound in organic solvents or facilitating purification).
  • protecting groups are indicated, is familiar with protecting groups used to protect a particular chemical functionality, how to select such groups, and knows processes that can be used for selectively introducing and selectively removing them, because methods of selecting and using protecting groups have been extensively documented in the chemical literature.
  • Suitable protecting groups are those which are stable and thereby able to protect a particular functional group under conditions for the reaction required to be performed upon the protected compound while being able to be selectively removed when protection is no longer desired or required.
  • Techniques for selecting, incorporating and removing chemical protecting groups may be found, for example, in Protective Groups in Organic Synthesis by Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons Ltd. (3 rd Edition, 1999), and Protecting Groups by Philip Kocienski, Georg Thieme Verlag (3 rd Edition, 2003), the entire disclosures of which are incorporated herein by reference. Stereochemistry is indicated herein by means of projection formulae.
  • ⁇ or ⁇ The stereochemistry of ring substituents herein (or, equivalently, the configuration of the carbon to which such a substituent is attached) is designated ⁇ or ⁇ by analogy to the standard designations of stereochemistry of an anomeric carbon of a carbohydrate: a substituent attached to a ring by means of a bond which projects above the plane of the ring (as indicated by the symbol ⁇ ) is designated ⁇ while the stereochemistry of a substituent attached to a ring by means of a bond which projects below the plane of the ring (as indicated by the symbol ) is designated ⁇ .
  • a substituent which may be either ⁇ or ⁇ is indicated by the symbol > ⁇ , .
  • the stereochemistry of W and Z is ⁇
  • the stereochemistry of Y is ⁇
  • the stereochemistry of X may be either ⁇ or ⁇ .
  • the processes described below may be conducted in any reactor suitable for performing chemical processes. Continuous, semi-continuous, and batch reactors can be employed.
  • the reagents are mixed in a batch, preferably with a solvent, and the resulting mixture is maintained at a temperature and pressure to perform the reaction.
  • the reactions are generally preferably performed under an inert and/or dry atmosphere although rigorous exclusion of oxygen is not always necessary. If it is desirable or necessary to remove air, the solvent and reaction mixture can be sparged with a non-reactive gas, such as nitrogen, helium, or argon, or the reaction may be conducted under anaerobic conditions.
  • the process conditions can be any operable conditions which yield the desired products.
  • the solvents be used in the process of the invention are selected to solubilize the reagents and not interfere with either the formation of the desired products or react with the desired products.
  • the amount of solvent which is employed may be any amount, preferably an amount sufficient to at least partially solubilize all the reactants.
  • a suitable quantity of solvent typically ranges from about 1 to about 100 grams solvent per gram reactants. Other quantities of solvent may also be suitable, as determined by the specific process conditions and by the skilled artisan.
  • the final product is isolated from the reaction mixture and purified. In some embodiments it may be desirable or necessary to isolate and/or purify intermediate products before proceeding to the next step, although in some embodiments it may be acceptable to take a crude product forward to a subsequent step without purification of intermediates.
  • the intermediates and final products can be isolated and/or purified by conventional methods known to those skilled in the art, including, for example, distillation, crystallization, sublimation, and gel chromatography. The yield of product will vary depending upon the specific reagents and conditions used.
  • the final product may be converted to another useful product, e.g., a monophospate, diphosphate or triphosphate nucleotide, by reaction without the intermediate isolation and/or purification of the final products of the processes.
  • a useful product e.g., a monophospate, diphosphate or triphosphate nucleotide
  • R is heterocyclic base linked via a nitrogen atom
  • R B is selected from the group consisting of hydrogen, OR 2 , O(Ci-C 3 )alkyl, F, and (Ci-C 3 )alkylene0(Ci-C 3 )alkyl; the symbol > ⁇ - indicates that the stereochemistry of R B is ⁇ or ⁇ ;
  • R 2 is selected from the group consisting of hydrogen and an alcohol protecting group
  • R 3 is selected from the group consisting of hydrogen and an alcohol protecting group; and R 4 is selected from the group consisting of hydrogen and an alcohol protecting group; with a brominating agent; and (b) reacting the product of step (a) with a fluorinating agent to form a compound according to formula II:
  • R A , R B , R 3 , and R 4 are as defined above for formula I.
  • the heterocyclic bases (R A ) of the nucleoside analogues used as reagents and made in the aforementioned process are in general the nucleobases which occur in naturally occurring nucleosides, or an analogue and/or derivative thereof, and comprise either a 6-memberered ring linked via nitrogen (“a pyrimidine” or “pyrimidine analogue”) or a 5,6-fused ring system having a nitrogen at the 1-position of the 5- membered ring (“a purine or purine analogue”), i.e. a ring system defined by:
  • the heterocyclic base is a nucelobase or an analogue thereof which can mimic a naturally occurring nucleobases in interations with biological molecules.
  • R A is a purine or pyrimidine, or an aza and/or deaza analogue thereof, i.e., an analogue wherein one or more carbon atoms of the ring system is replaced by nitrogen and/or one or more nitrogen atoms of the ring system is replaced by carbon.
  • R A is a nucleobase or nucleobase analogue selected from the group consisting of adenine, 7-deazaadenine, 7- deaza-8-azaadenine, 3,7-dideazaadenine, 8-deazaadenine, guanine, 3-deazaguanine, 7- deaza-8-azaguanine, 3,7-dideazaaguanine, 3,7-dideaza-8-azaguanine, 7-deazaguanine, 8- azaguanine, purine, 2-aminopurine, azapurine, 2,6-diaminopurine, ethenoadenine, hypoxanthine, uracil, 5-azauracil, 6-azauracil, 5-fluorouracil, 5-bromouracil, 5- iodouracil, thymine, 6-azathymine, cytosine, 6-azacytosine, 5-azacytosine, pyrimidine, azapyrim
  • a (Ci-Ce)alkyl and/or halogen-substituted derivative of one of the nucleobase or nucleobase analogues described in the preceding paragraph means that the nucleobase is derivatized by substitution with one or more (Ci-Ce)alkyl substituents and/or one or more halogen substituents.
  • An alkyl group substituent may be attached to any substitutable position of the nucleobase or nucleobase analogue, including any substitutable heteroatom as well as substitutable carbon atoms.
  • N-(Ci-Ce)alkyl and O- (Ci-Ce)alkyl derivatives are included.
  • a halogen substituent is attached to a carbon atom.
  • heteroatom-protected-derivative it is meant that a heteroatom-containing group of the nucleobase or nucleobase analogue (or its (Ci-Ce)alkyl and/or halogen-substituted derivative)) is protected by a protecting group.
  • groups that are used for the protection of nitrogen-containing functional groups include groups suitable for the protection of amino groups, as described, for example, in Chapter 7 of Protective Groups in Organic Synthesis by Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons Ltd. (3rd Edition, 1999). Protection of nucleosides specifically is described in Current Protocols in Nucleic Acid Chemistry (John Wiley & Sons, Updated as of Supplement 30, September 2007).
  • R B is selected from the group consisting of OR 2 , O(Ci-C 3 )alkyl, F, and (Ci-C 3 )alkylene0(Ci-C 3 )alkyl. In particular embodiments thereof, R B is OR 2 .
  • each of OR 2 , OR 3 and OR 4 is an optionally protected hydroxy group.
  • Any protecting group used to protect alcohols and which is compatible with the conditions used for the processes may be used as a protecting group, and it is not necessary that all the protecting groups be the same. Suitable protecting groups are those described in Protective Groups in Organic Synthesis by Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons Ltd. (3 rd Edition, 1999).
  • protecting groups useful in the process include any suitable hydroxyl protecting group ether groups, for example methyl ether, substituted methyl ethers, benzyl ethers, silyl ethers; ester groups, for example carboxylates such as acetate and benzoate; and carbonate groups, for example methyl, ethyl and benzyl carbonates.
  • Typical hydroxyl protecting groups include methyl ethers, substituted methyl ethers, substituted ethyl ethers, substitute benzyl ethers, and silyl ethers, and esters, particularly carboxylates, including carbonates.
  • substituted methyl ethers include methyoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4- methoxyphenoxy)methyl, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2- chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxido, 1 -[(2-chloro-4
  • substituted ethyl ethers include 1-ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1- methoxyethyl, 1 -methyl- 1-benzyloxyethyl, 1 -methyl- l-benzyloxy-2-fluoroethyl, 2,2,2- trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p- chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
  • substituted benzyl ethers include p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p- nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4- picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p'-dinitrobenzhydryl, 5- dibenzosuberyl, triphenylmethyl, .alpha.-naphthyldiphenylmethyl, p- methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p- methoxyphenyl)methyl, 4-(4'-bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4
  • silyl ethers examples include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p- xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenylsilyl.
  • esters include formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-phenylacetate, 3-phenylpropionate, 4- oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate(mesitoate), 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4- methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl carbonate, 4-(
  • carbonate protecting groups include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o- nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-l-naphthyl, and methyl dithiocarbonate.
  • R 2 and R 3 or R 3 and R 4 are together protected by a 1,2- or 1,3-diol protecting group such that R 2 and R 3 or R 3 and R 4 form a cyclic protecting group.
  • Examples include cyclic acetals and ketals.
  • Typical 1,2- and 1,3-diol protecting groups include cyclic acetals and ketals (methylene, ethylidene, 1-t-butylethylidene, 1-phenylethylidene, (4- methoxyphenyl)ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p- methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, 2- nitrobenzylidene); cyclic ortho esters (methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1,2- dimethoxyethylidene, alpha-methoxy
  • each of R 2 , R 3 and R 4 is a protecting group.
  • each of R 2 , R 3 and R 4 is a carboxyl (i.e. an ester) protecting group.
  • each of R 2 , R 3 and R 4 is an optionally substituted benzoyl protecting group.
  • the optionally benzoyl group is either unsubstituted or substituted at any substitutable position with one or more substituents by a substituent such as alkyl, heteroalkyl, fluoroalkyl, halo, or alkoxy. Any brominating agent suitable for the bromination of aliphatic C-H bonds may be used in the aforementioned process.
  • Free radical brominating agents are particularly useful for use as brominating agents in the process. While not being limited by theory, it is believed that such agents act via a mechanism in which bromine atoms (i.e. bromine radicals, Br-) abstract the hydrogen atom of the C-H bond to form a free radical, which then abstracts bromine from atom donor.
  • the bromine atom donor is believed to be typically bromine which may be formed from a bromine precursor such as a compound containing an N-Br bond.
  • the brominating agent comprises bromine atoms, or a precursor thereof.
  • Suitable brominating agents which are suitable for use in the aforementioned process include N-bromoimides, N-bromoimines, N-bromocarboxamides, bromine, and bromine chloride. Particular brominating agents which may be used include N- bromosuccinimide and N-bromoacetamide. N-Bromosuccinimide is preferred.
  • the free radical mechanism believed to be involved in bromination by at least some of the above-mentioned brominating agents the skilled artisan will appreciate that it may be advantageous to perform the reaction under particular conditions to promote the desired result.
  • Light may be supplied, for example, in the form of ambient light or by irradiation with a lamp.
  • free radical initiators include peroxides such as dibenzoyl peroxide and azo compounds such as azoisobutyronitrile.
  • the reaction is preferably performed in a suitable solvent which is capable of dissolving the substrates and reagents and which is preferably selected to be inert under the reaction conditions.
  • suitable solvents include halogenated hydrocarbons, particularly perhalogenated hydrocarbons such as carbon tetrachloride and hexachloroethane.
  • the preferred solvent is carbon tetrachloride.
  • the reaction is preferably performed at a temperature in the range from about 0 0 C to about 150 0 C, preferably about 50 0 C to about 120 0 C.
  • the reaction is preferably performed in the presence of light.
  • Any fluorinating agent suitable for the substitution of aliphatic C-Br bonds by fluorine may be used in the aforementioned process. While not being limited by theory, it is believed that nucleophilic fluorinating agents, which donate fluorine as a fluoride anion and causing the bromine to depart as a bromide anion will be particularly useful in the above mentioned process. Particularly useful fluorinating agents are those comprising fluoride and/or tetrafluoroborate anions.
  • suitable fluorinating agents include in the reagent mixture an agent that enhances the leaving group ability of the bromine, for example agents that have an affinity for bromine, for example late transition metal ions such as silver and zinc. Therefore, in particular embodiments of the aforementioned process, suitable fluorinating agents include those that further comprise silver ions.
  • Particular agents that are useful as fluorinating agents for use in the aforementioned processes include metal fluoride salts, for example lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, silver fluoride, manganese trifluoride, organic fluoride salts, for example tetraalkylammonium (e.g. tetrabutylammonium) fluoride and pyridinium hydrofluoride, and diethylaminosulfur trifluoride.
  • the fluoride salts may be advantageously coupled with the use of Lewis acids (e.g. boron trifluoride, titanium chloride, aluminum chloride), a silver compound
  • a chelating agent which complexes the metal to increase the nucleophilicity of the fluoride e.g. potassium fluoride / 18- crown-6.
  • the fluorinating agent comprises silver fluoride and/or silver tetrafluoroborate.
  • each of R 2 , R 3 and R 4 is a carboxyl protecting group, the brominating agent an N-bromoimide, and the fluorinating agent comprises fluoride and/or tetrafluoroborate anions.
  • each of R 2 , R 3 and R 4 is an optionally substituted benzoyl protecting group, the brominating agent an N- bromosuccinimide, and the fluorinating agent comprises silver fluoride and/or silver tetrafluoroborate .
  • the fluorination reaction is preferably performed in a suitable solvent which is capable of dissolving the substrates and reagents and which is preferably selected to be inert under the reaction conditions.
  • Suitable solvents include ether solvents such as diethylether, 1 ,2-dimethoxyethane, 1 ,4-dioxane, and t-butyl methyl ether.
  • the preferred solvent is diethyl ether.
  • the reaction is preferably performed at a temperature in the range from about - 10 0 C to about 100 0 C, preferably about - 10 0 C to about 20 0 C, preferably at about 0 0 C.
  • the final stage of 4'-fluoro nucleoside synthesis involves the deprotection of the protecting groups.
  • deprotection is performed using standard conditions for performing the deprotections, as described in Protective Groups in Organic Synthesis by Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons Ltd. (3rd Edition, 1999), having due regard to selecting the protecting groups and conditions such that the reaction conditions for deprotection are compatible with the stability of the product, as described in greater detail below.
  • R B is selected from the group consisting of hydrogen, OR 2 , 0(Ci-C3)alkyl, F, and (Ci-C 3 )alkylene0(Ci-C 3 )alkyl; the symbol ⁇ r ⁇ indicates that the stereochemistry of OR 1 and R B are independently ⁇ or ⁇ ;
  • R 1 is selected from the group consisting of hydrogen and an alcohol protecting group
  • R 2 is selected from the group consisting of hydrogen and an alcohol protecting group
  • R 3 is selected from the group consisting of hydrogen and an alcohol protecting group
  • R 4 is selected from the group consisting of hydrogen and an alcohol protecting group; with a brominating agent;
  • step (b) reacting the product of step (a) with a fluorinating agent to form a compound according to formula IV;
  • R B , R 1 , R 3 , and R 4 are as defined above for formula III;
  • step (c) optionally converting the product of step (b) into a compound according to formula V:
  • step (d) reacting the product of step (b) wherein OR 1 is a leaving group or the product of step (c) with a nitrogen-containing heterocyclic base to form a compound according to formula II:
  • R A is a heterocyclic base linked via a nitrogen atom; and R B , R 3 , and R 4 are as defined above for formula III.
  • the nitrogen-containing heterocyclic bases used as reagents in step (d) of the above process and incorporated into the synthesized nucleoside analogues as R A generally the nucleobases which occur in naturally occurring nucleosides or analogues and/or derivatives thereof and comprise either a nitrogen-containing 6-memberered ring ("a pyrimidine” or "pyrimidine analogue”) or a 5,6-fused ring system having a nitrogen at the 1-position of the 5-membered ring ("a purine or purine analogue”) which become linked via the nitrogen atom to yield a ring system defined by:
  • R A Pyrimidine analogue as R A , wherein each A atom independently represents either an sp 2 -hybridized carbon or nitrogen atom.
  • the heterocyclic base is a nucelobase or an analogue thereof which can mimic a naturally occurring nucleobases in interations with biological molecules.
  • R A is a purine or pyrimidine, or an aza and/or deaza analogue thereof, i.e. an analogue wherein one or more carbon atoms of the ring system is replaced by nitrogen and/or one or more nitrogen atoms of the ring system is replaced by carbon.
  • R A is a nucleobase or nucleobase analogue selected from the group consisting of adenine, 7-deazaadenine, 7- deaza-8-azaadenine, 3,7-dideazaadenine, 8-deazaadenine, guanine, 3-deazaguanine, 7- deaza-8-azaguanine, 3,7-dideazaaguanine, 3,7-dideaza-8-azaguanine, 7-deazaguanine, 8- azaguanine, purine, 2-aminopurine, azapurine, 2,6-diaminopurine, ethenoadenine, hypoxanthine, uracil, 5-azauracil, 6-azauracil, 5-fluorouracil, 5-bromouracil, 5- iodouracil, thymine, 6-azathymine, cytosine, 6-azacytosine, 5-azacytosine, pyrimidine, azapyrim
  • R B is selected from the group consisting of OR 2 , O(Ci-C 3 )alkyl, F, and (Ci-C 3 )alkylene0(Ci-C 3 )alkyl. In particular embodiments thereof, R B is OR 2 .
  • each of OR 1 , OR 2 , OR 3 and OR 4 is an optionally protected hydroxy group.
  • Any protecting group used to protect alcohols and which is compatible with the conditions used for the processes may be used as a protecting group, and it is not necessary that all the protecting groups be the same. Suitable protecting groups are those described in Protective Groups in Organic Synthesis by Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons Ltd. (3 rd Edition, 1999).
  • protecting groups useful in the process include any suitable hydroxyl protecting group ether groups, for example methyl ether, substituted methyl ethers, benzyl ethers, silyl ethers; ester groups, for example carboxylates such as acetate and benzoate; and carbonate groups, for example methyl, ethyl and benzyl carbonates as described in greater detail for the process described for the bromination-fluorination of nucleosides described in section (H)(I) above.
  • R 4 is a protecting group.
  • each of R 1 , R 2 , R 3 and R 4 is a carboxyl (i.e. an ester) protecting group.
  • R 1 is an acetyl group and each of R 2 , R 3 and R 4 is an optionally substituted benzoyl protecting group.
  • the optionally benzoyl group is either unsubstituted or substituted at any substitutable position with one or more substituents by a substituent such as alkyl, heteroalkyl, fluoroalkyl, halo, or alkoxy.
  • brominating agent suitable for the bromination of aliphatic C-H bonds may be used in the aforementioned process.
  • the reagents and conditions suitable for performing the bromination step described for the bromination- fluorination of nucleosides described in section (H)(I) above will also in general be suitable for the bromination of carbohydrate derivatives in the process described herein.
  • the brominating agent comprises bromine atoms, or a precursor thereof.
  • Suitable brominating agents include N- bromoimides, N-bromoimines, N-bromocarboxamides, bromine, and bromine chloride.
  • Particular brominating agents which may be used include N-bromosuccinimide and N- bromoacetamide. N-Bromosuccinimide is preferred.
  • any fluorinating agent suitable for the substitution of aliphatic C-Br bonds by fluorine may be used in the aforementioned process.
  • the reagents and conditions suitable for performing the fluorination step described for the bromination-fluorination of nucleosides described in section (H)(I) above will also in general be suitable for the fluorination of brominated carbohydrate derivatives in the process described herein.
  • the fluorinating agent is a nucleophilic fluorinating agent.
  • Suitable fluorinating agents include those wherein the fluorinating agent comprises fluoride and/or tetrafluoroborate anions.
  • suitable fluorinating agents include those that further comprise silver ions.
  • agents that are useful as fluorinating agents for use in the aforementioned processes include metal fluoride salts, for example lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, silver fluoride, manganese trifluoride, organic fluoride salts, for example tetraalkylammonium (e.g. tetrabutylammonium) fluoride and pyridinium hydrofluoride, and diethylaminosulfur trifluoride.
  • metal fluoride salts for example lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, silver fluoride, manganese trifluoride
  • organic fluoride salts for example tetraalkylammonium (e.g. tetrabutylammonium) fluoride and pyridinium hydrofluoride, and diethylaminosulfur trifluoride.
  • the fluoride salts may be advantageously coupled with the use of Lewis acids (e.g., boron trifluoride, titanium chloride, aluminum chloride), a silver compound (e.g., silver carbonate, silver nitrate, or silver oxide) or a chelating agent which complexes the metal to increase the nucleophilicity of the fluoride (e.g., potassium fluoride / 18-crown-6).
  • Lewis acids e.g., boron trifluoride, titanium chloride, aluminum chloride
  • a silver compound e.g., silver carbonate, silver nitrate, or silver oxide
  • a chelating agent which complexes the metal to increase the nucleophilicity of the fluoride
  • the fluorinating agent comprises silver fluoride and/or silver tetrafluoroborate.
  • Completion of the 4'-fluoronucleoside synthesis then requires performing a glycosylation sequence to replace the OR 1 group of the carbohydrate derivative with the heterocyclic base R A .
  • This conversion is performed by converting the OR 1 group of the carbohydrate derivative to a leaving group as described in step (c), followed by displacement of the leaving group by the heterocyclic base as described in step (d).
  • leaving groups for displacement by the heterocyclic base are univalent groups (-L) which, when attached to hydrogen, are acids (H-L) with a pKa of about 5 or lower.
  • a leaving group is a group which, in a nucleophilic substitution reaction may be expelled to give, typically, a stable anion while the carbon to which the leaving group was attached forms a new bond to the nucleophile.
  • leaving groups include carboxylate, for example acetate or benzoate, halogen, for example chloride, bromide, and iodide, and sulfonate groups, for example trifluoromethanesulfonate (-OTf), arenesulfonates (such as phenylsulfonate, p-toluenesulfonate (-OTs), and naphthalenesulfonate), or alkanesulfonates (such as mesylate).
  • the conversion of the OR 1 group to a suitable leaving group may be performed using conditions known to the person skilled in the art for performing such functional group transformations. See, e.g., Comprehensive Organic Transformations by R.C. Larock, VCH Publishers (1989). It may be necessary or desirable to deprotect the OR 1 group prior to performing the conversion to the leaving group.
  • the glycosylation reaction described in step (d) is performed. If the OR 1 group itself can function as a leaving group, then it may not be necessary to perform the conversion of OR 1 into a leaving group since the glycosylation reaction can in such cases be performed on the product of step (b) directly.
  • the glycosylation reaction is performed by reacting the heterocyclic base, or a suitable derivative thereof, with the carbohydrate derivative from step (b) (wherein OR 1 is a leaving group) or step (c) under conditions suitable for effecting the glycosylation reaction. The presence of an acid or a base may promote the desired glycosylation.
  • step (d) is performed by reacting the product of step (b) with a nucleobase, preferably a purine or pyrimidine, under acidic conditions.
  • a nucleobase preferably a purine or pyrimidine
  • the acid used is preferably a Lewis acid such as tin tetrachloride, titanium tetrachloride, or trimethylsilyltriflate.
  • a Lewis acid as described herein may still be beneficial and salts with affinity for halogen (e.g. silver salts) may also be useful to promote the desired substitution.
  • the nucleobase is preferably derivatized as a silyl derivative, preferably a trialkylsilyl derivative, most preferably a persilylated derivative.
  • step (d) is performed by reacting the product of step (b), preferably wherein OR 1 is a carboxylate group, preferably acetate, with a purine or pyrimidine derivatized as a silylated derivative, preferably a trialkylsilyl derivative, and preferably persilylated, and the reaction is performed in the presence of a Lewis acid, preferably a trialkylsilyl triflate.
  • the glycosylation reaction is preferably performed in a suitable solvent which is capable of dissolving the substrates and reagents and which is preferably selected to be inert under the reaction conditions.
  • suitable solvents include aprotic solvents such as toluene, acetonitrile, benzene, or a mixture of any or all of these solvents.
  • the reaction is preferably performed at a temperature in the range from about 20 0 C to about 150 0 C, preferably about 50 0 C to about 120 0 C, preferably at about 100 0 C.
  • the final stage of 4'-fluoro nucleoside synthesis involves the deprotection of the protecting groups.
  • deprotection is performed using standard conditions for performing the deprotections, as described in Protective Groups in Organic Synthesis by Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons Ltd. (3rd Edition, 1999), having due regard to selecting the protecting groups and conditions such that the reaction conditions for deprotection are compatible with the stability of the product, as described in greater detail below.
  • N- glycosylation takes place slowly ( ⁇ 16 h) compared to that of non-fluorinated substrate ( ⁇ 3 h), presumably due to retardation of the oxocarbenium intermediate for N- glycosylation, by the inductive effect of the 4'-fluoro substituent.
  • CD 3 OD no decomposition no decomposition. no decomposition. no after 1 day decomposition.
  • Reagents such as BF 3 -OEt 2 , TMSOTf, nucleobases, AgF, AgBF 4 , and N, O- bis(trimethylsilyl)trifluoro acetamide, purchased were used as received.
  • Methylene chloride was distilled from calcium hydride.
  • N-Bromosuccinimide was recrystalized from boiling water.
  • Sodium sulfate (Na 2 SO 4 ) was anhydrous. All recrystalization, chromatographic, and workup solvents were distilled.
  • TLC visualizing solutions were: (i) /?-anisaldehyde solution (1350 mL absolute ethanol, 50 mL concentrated H 2 SO 4 , 37 mL/?-anisaldehyde), and (ii) permanganate solution (weight percents of 1 % KMnO 4 and 2 % Na 2 CO 3 in water).
  • Analytical samples were obtained from flash silica gel chromatography, using silica gel of 230-400 mesh ASTM. 1 H NMR and 13 C NMR spectra were recorded on Bruker AM 500 (500 MHz).
  • NMR spectra were determined in chloroform-di (CDCl 3 ), DMSO-d ⁇ or methanol ⁇ (CD 3 OD) solution and are reported in parts per million (ppm) from the residual chloroform (7.24 ppm and 77.0 ppm) and benzene (7.16 ppm and 128.39 ppm) standard respectively. Peak multiplicates in 1 H-NMR spectra, when reported, are abbreviated as s (singlet), d (doublet), t (triplet), m (multiplet), and/or ap
  • silver tetrafluoroborate was prepared from the reaction of silver fluoride (189 mg, 1.5 mmol) with borontrifluoride-diethyl ether (377 ⁇ L, 3.0 mmol) in anhydrous diethyl ether (10 mL) for 30 minutes at 25 0 C.
  • An ethyl acetate (5 mL) solution of the bromide mixture was added to the solution OfAgBF 4 and the mixture was stirred for 30 minutes at 0 0 C.
  • the reaction mixture was diluted with diethyl ether, washed with aqueous saturated sodium bicarbonate, water, and brine, and dried over anhydrous sodium sulfate.
  • 4'-Fluoro inosine 7b was prepared by similar procedures used for the synthesis of 7a.
  • 1 H NMR 500 MHz, CD 3 OD
  • 13 C MMR 125 MHz, CD 3 OD 140.5, 138.5, 133.0, 130.2, 129.3, 128.4, 115.0.

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Abstract

L'invention porte sur un procédé de synthèse d'analogues de nucléosides.
PCT/US2008/081499 2007-10-29 2008-10-29 Synthèse de nucléosides WO2009058800A2 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9211300B2 (en) 2012-12-19 2015-12-15 Idenix Pharmaceuticals Llc 4′-fluoro nucleosides for the treatment of HCV
US9243022B2 (en) 2012-12-21 2016-01-26 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US9422323B2 (en) 2012-05-25 2016-08-23 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
US9447132B2 (en) 2013-04-12 2016-09-20 Achillion Pharmaceuticals, Inc. Highly active nucleoside derivative for the treatment of HCV
WO2019173602A1 (fr) * 2018-03-07 2019-09-12 Emory University Compositions thérapeutiques à base de nucléosides et de nucléotides contenant 4-halogène et utilisations associées
CN113929724A (zh) * 2021-11-02 2022-01-14 周雨恬 一种核苷类化合物及其药物组合物和用途
CN114891048A (zh) * 2022-05-16 2022-08-12 浙江晟格生物科技有限公司 一种制备1-氧-氟基-2,3,5-三氧苯甲酰基-l-核糖的方法
US11628181B2 (en) 2014-12-26 2023-04-18 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US11903959B2 (en) 2017-12-07 2024-02-20 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999043691A1 (fr) * 1998-02-25 1999-09-02 Emory University 2'-fluoronucleosides
US20050130274A1 (en) * 2001-09-05 2005-06-16 O'hagan David Enzymatic process for the synthesis of organo-fluorine compounds
WO2007053869A2 (fr) * 2005-11-09 2007-05-18 Saischek Und Partner Meg Dérives de furanose à substitution 2,2-dithio, procédé de production et leur utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999043691A1 (fr) * 1998-02-25 1999-09-02 Emory University 2'-fluoronucleosides
US20050130274A1 (en) * 2001-09-05 2005-06-16 O'hagan David Enzymatic process for the synthesis of organo-fluorine compounds
WO2007053869A2 (fr) * 2005-11-09 2007-05-18 Saischek Und Partner Meg Dérives de furanose à substitution 2,2-dithio, procédé de production et leur utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JUNG, M. E. ET AL.: 'Preparation of 4'-substituted thymidines by substitution of the thymidine 5'-esters.' J. ORG. CHEM. vol. 66, 2001, pages 2624 - 2635 *

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US10487104B2 (en) 2012-12-21 2019-11-26 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
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