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WO2000039144A1 - Procede de preparation de derives fluores de nucleosides et de sucres - Google Patents

Procede de preparation de derives fluores de nucleosides et de sucres Download PDF

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Publication number
WO2000039144A1
WO2000039144A1 PCT/JP1999/006500 JP9906500W WO0039144A1 WO 2000039144 A1 WO2000039144 A1 WO 2000039144A1 JP 9906500 W JP9906500 W JP 9906500W WO 0039144 A1 WO0039144 A1 WO 0039144A1
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Prior art keywords
group
hydroxyl group
hydrogen atom
general formula
derivative
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English (en)
Japanese (ja)
Inventor
Satoshi Takamatsu
Satoshi Katayama
Naoko Hirose
Kunisuke Izawa
Etienne Decock
Marc Demillequand
Geert Schelkens
Jozef Brepoels
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Ajinomoto Co Inc
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Ajinomoto Co Inc
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Priority to AU14082/00A priority Critical patent/AU1408200A/en
Publication of WO2000039144A1 publication Critical patent/WO2000039144A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals
    • 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
    • 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

Definitions

  • the present invention relates to an industrially useful method for producing a nucleoside or saccharide derivative in which a secondary hydroxyl group is substituted by a fluorine atom.
  • INDUSTRIAL APPLICABILITY According to the present invention, 9-1 (2,3-dideoxy-12-fluoro- ⁇ -D-threo-penttofuranosyl) adenine (“F dd A may be abbreviated as “dd A.”) can be industrially advantageously produced.
  • An object of the present invention relates to a method for producing a nucleoside or a sugar derivative in which a secondary hydroxyl group has been substituted with a fluorine atom, and in particular, can be fluorinated in one step, is low in cost, is safe, and is industrially useful.
  • Another object of the present invention is to provide an effective method for producing various useful nucleic acid derivatives such as intermediates for producing the above-mentioned medicines (eg, FddA).
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a secondary hydroxyl group of a nucleotide or a sugar derivative, a perfluoroalkane, norefonynolefnoreolide, or an
  • the secondary hydroxyl group in a nucleoside or sugar derivative is stereospecifically substituted with a fluorine atom in one step by reacting with snorephonylfluoride such as recantholephoninolefnoreolide in the presence of a base. It was found that the present invention was completed. Sulfonyl fluoride is available at a low cost and can be used safely, and the present invention is an industrially excellent production method. As a result, it is expected to be used or used as an intermediate for the production of various drugs as described above. That is, the present invention provides a nucleoside or a sugar derivative represented by the following general formula (I):
  • A is a hydrogen atom or a methyl group having a protected hydroxyl group
  • B is a nucleobase (including a derivative thereof) or a protected hydroxyl group
  • R is a hydroxyl-protecting group
  • Y and X are any.
  • One represents a hydroxyl group and the other represents a hydrogen atom or a protected hydroxyl group; or
  • a and R together form a cyclic acetal represented by the following general formula (III) (R and R-both represent a hydrogen atom or a methyl group, or Represents a hydrogen atom, and the other represents a methyl group or a phenyl group, respectively.), B, Y and X have the same meanings as above.
  • Y represents a hydroxyl group
  • X and B together form a cyclic acetal represented by the following general formula (IV).
  • R 3 and R 4 represent a hydrogen atom or a methyl group. , Or one of them represents a hydrogen atom and the other represents a methyl group or a phenyl group, respectively
  • a and R have the same meanings as described in any of the above-mentioned (a) and (b).
  • AB and R represent the same meaning as described above, and one of Y ′ and X ′ represents a fluorine atom, and the other represents a hydrogen atom or a protected hydroxyl group, respectively.
  • Y ′ represents a fluorine atom
  • X ′ and B may be combined to form a cyclic acetal represented by the above general formula (IV) (R and R are the same as described above).
  • FddA For the preparation of FddA, it is preferred to use as starting material a compound in which B is adenine or 6-logenopurine in the 3-configuration.
  • adenine a compound represented by the general formula ( ⁇ ) (where ⁇ ′ is a hydrogen atom and X ′ is a fluorine atom having 8 positions) is produced, and if a protecting group is present in the hydroxyl group, this is By desorption, it can be easily led to F dc! A.
  • Y ′ is not a hydrogen atom but a hydroxyl group (protected or unprotected)
  • the hydroxyl group is dehydroxylated by a conventional method, and the 5′-position hydroxyl group is protected as necessary.
  • a protecting group when a protecting group is present, it can be desorbed and treated in the same manner to lead to FddA.
  • the obtained compound ( ⁇ ) can be obtained in the same manner by the method described later or other known methods.
  • the present invention also includes the following contents.
  • the produced nucleoside or saccharide derivative represented by the general formula (II) when used and has a protective group in the hydroxyl group, it is preferably produced by subjecting the hydroxyl group to a deprotection step.
  • a fluorinated nucleoside derivative represented by the following general formula (V) and the production method when the produced nucleoside or saccharide derivative represented by the general formula (II) is used and has a protective group in the hydroxyl group, it is preferably produced by subjecting the hydroxyl group to a deprotection step.
  • B ′ represents a nucleic acid base
  • Y ′′ and X ′′ each represent a fluorine atom
  • the other represents a hydrogen atom or a hydroxyl group.
  • the above sugar derivative further includes a condensation step with the nucleic acid base represented by B ′.
  • Fdd A can be easily produced by using the above method. Utilizing such a known method, a desired fluorinated nucleoside derivative such as FddA can be produced.
  • Nucleoside derivative represented by the general formula ( ⁇ ) obtained by the above-mentioned production method (where A is a hydrogen atom, B is 6-logenopurine, Y ′ is a hydrogen atom or a protected hydroxyl group) , X ′ represents a fluorine atom), and the 6-position halogen atom is replaced by a hydrogen atom, an amino group, a hydroxyl group, Azide group, a substituent represented by the formula ⁇ , subjected to the step of substituting with any of substituents represented by the substituents and NHR 4 formula SR 4, a manufacturing method of the described for producing the substituted compound .
  • the method may include a step of deprotecting the protecting group before or after the reaction for substituting with the substituent.
  • R 4 represents a lower alkyl group (C 15) in which a fuunyl group or the like may have a substituent.
  • the nucleoside derivative (when ⁇ ′ represents a protected hydroxyl group and X ′ represents a fluorine atom) obtained by the above production method is further subjected to a step of dehydroxylating the hydroxyl group.
  • a method for producing a 3'-dehydroxylated product is further subjected to a step of dehydroxylating the hydroxyl group.
  • the sugar derivative similarly produced is 3-deoxy-3-fluoro-1,2: 5,6-di-isopropylidene-one-D-dalcofuranose and a fluorinated nucleoside produced using the same. Derivative or FddA.
  • nucleoside or sugar derivative represented by the above general formula (I) used as a starting material of the present invention when the above general formula (I) represents a nucleoside derivative, B is a purine base ⁇ pyrimidine Represents a nucleic acid base such as a base or a derivative thereof.
  • nucleobase includes the nucleic acid base itself and the derivative of such a nucleobase, but in the description of the specification, the terms “nucleobase” and “nucleic acid derivative” in a narrow sense, respectively, are used.
  • terms such as “nucleobase”, “nucleobase (derivative)", and “derivative thereof” are used.
  • pyrimidine bases such as pyrimidine, thymine, cytosine, Peracyl and the like
  • the purin bases include purin, adenine, guanine, xanthine, hypoxanthine and the like.
  • B include a nucleobase derivative in which a hydrogen atom, a hydroxyl group, an amino group, or the like of the nucleobase is substituted with another appropriate substituent.
  • substituent preferably include a hydrogen atom, an amino group, a hydroxyl group, a halogen atom (such as a chlorine atom), an alkyl group having 11 to 10 carbon atoms, and a nitrogen atom.
  • nucleobase derivatives include adenine, guanine, hypoxanthine, 6-halogenoprine, peracyl, thymine and the like, in particular, because of their versatility as intermediates for drug production.
  • these nucleobases or derivatives thereof may be protected with a protecting group generally used in nucleic acid synthesis.
  • the protecting group is a protecting group for a hydroxyl group, for example, an acetyl group such as an acetyl group or a benzoyl group, an alkenyl group such as a methoxymethyl group or an aryl group, or an aralkyl group such as a benzyl group or a triphenylmethyl group. And the like.
  • an amino-protecting group examples thereof include an acetyl group, an benzoyl group and other aralkyl groups, and a benzyl group and other aralkyl groups.
  • These protecting groups may have a suitable substituent such as a halogen atom, an alkyl group having 15 to 15 carbon atoms, or an alkyloxy group having 1 to 5 carbon atoms.
  • B represents a protected hydroxyl group.
  • the hydroxyl-protecting group include acetyl groups such as acetyl group and benzoyl group (having 11 to 10 carbon atoms), alkyl groups such as methyl group and aryl group, and aralkyl groups such as benzyl group and triphenylmethyl group.
  • silyl groups such as trimethylsilyl group and triethylsilyl group.
  • R represents a hydroxyl-protecting group.
  • R represents a hydroxyl-protecting group.
  • the hydroxyl-protecting group as described above, preferably, an acetyl group, an alkyl group such as a benzoyl group, an alkyl group such as a methyl group or an aryl group, an aralkyl group such as a benzyl group or a trimethyl group are preferable.
  • silyl groups such as trimethylsilyl.
  • these protecting groups may have a substituent such as a halogen atom, an alkyl group having 15 to 15 carbon atoms, or an alkyloxy group having 1 to 5 carbon atoms (such as methoxy).
  • a protecting reagent for protecting a reagent known as a reagent for protecting a hydroxyl group, for example, an acylating agent, an alkylating agent, an aralkylating agent, an organic silylating agent and the like are appropriately used.
  • A represents a hydrogen atom or a methyl group having a protected hydroxyl group (that is, R′—O—CH 2 —).
  • hydroxyl-protecting group (R ′) examples include, as described above, for example, an acetyl group, an alkyl group such as a benzoyl group, an alkyl group such as a methyl group and an aryl group, and an aralkyl group such as a benzyl group and a triphenylmethyl group. And the like. That is, when A is a methyl group having a protected hydroxyl group, A is, for example, an acetyloxymethyl group such as an acetyloxymethyl group or a benzoyloxymethyl group, or a benzyloxymethyl group. And an aralkyloxymethyl group such as a trityloxymethyl group.
  • the protective group (R ′) may have a substituent such as a halogen atom, an alkyl group having 115 carbon atoms, or an alkyloxy group having 15 carbon atoms (such as methoxy).
  • R 1 and R 2 both represent a hydrogen atom or a methyl group, or one of them represents a hydrogen atom and the other represents a methyl group or a phenyl group. Further, the above and R 2 may have a substituent such as a halogen atom, an alkyl group having 115 carbon atoms, or an alkyloxy group having 115 carbon atoms.
  • the cyclic acetal represented by the general formula (III) has a form in which an adjacent hydroxyl group is protected by a protecting group.
  • the hydroxyl group can be deprotected by an ordinary method for deprotecting a protecting group.
  • one of Y and X represents a hydroxyl group, and the other represents a hydrogen atom or a protected hydroxyl group.
  • the hydroxyl-protecting group include an acetyl group, an benzoyl group and other such acyl groups, a methyl group and an alkyl group such as an aryl group, and a benzyl group and an aralkyl group such as a triphenylmethyl group.
  • these protecting groups may have a substituent such as a halogen atom, an alkyl group having 115 carbon atoms, or an alkyloxy group having 15 carbon atoms (such as a methoxy group).
  • R., And are both represent represent or either one Ku is Wakashi methyl group the other represents a hydrogen atom phenylene Le based on hydrogen atom or a methylation group Q R and R may have a substituent such as a halogen atom, an alkyl group having 115 carbon atoms, or an alkyloxy group having 115 carbon atoms.
  • the cyclic acetal represented by the general formula (IV) has a form in which an adjacent hydroxyl group is protected by a protecting group. In this case, the hydroxyl group can be deprotected by a usual method for deprotecting a protecting group.
  • the general formula (I) also includes a compound represented by the following formula.
  • B, X, and Y in the above general formula (I) may have any of three or three configurations. Specifically, it is represented by any of the following general formulas (VI) to (XIII).
  • nucleoside derivative When the compound represented by the general formula (I) is a nucleoside derivative, a method generally used in the synthesis of a nucleoside derivative (for example, “Chemistry of Nucleosides ana Nucleotides”, Vol. 1, LB Townsend, According to Ed., Plenum Press, New York (1988), 1-281), any compound can be synthesized.
  • 6-chloro- _9- [3-deoxy-5-O- (triphenylmethyl) -i3-D-erythrotropen-tofurano-sinore] -1 9 H—purine
  • the compound represented by the general formula (I) is a sugar derivative
  • a method used in the synthesis of a sugar derivative eg, “Preparative Carbohydrate Chemistry”, S. Hanessian, Ed., Marcel Dekkei ', New York (1997) 4) Therefore, any compound can be synthesized.
  • sugar derivatives produced here there can be mentioned, for example, 3-deoxy-3-phenylene 1,2: 5,6—di-isopropyridene-hi-D-gunolecofuranose. .
  • sulfonylfluoride used for the fluorinating agent includes, in particular, benzoylfluoride
  • sulfonyl fluoride can be mentioned, it is not particularly limited.
  • Preferred examples thereof include a sulfonyl fluoride compound represented by the following general formula (XXX).
  • R 5 is a saturated or unsaturated, straight-chain or unsaturated, C 1 -C 12 carbon atom
  • compounds representing a branched perfluoroalkyl group can be preferably mentioned.
  • alkanesulfonyl fluoride can also be used.
  • R 5 is a saturated or unsaturated, linear or branched chain having 11 to 12 carbon atoms.
  • a compound which may have a substituent a part of the fluorine atom may be substituted with a hydrogen atom, or may be substituted with a halogen atom other than a fluorine atom, a carboxyl group, or the like.
  • substituent R one or more of the C—C bonds present therein may be a group substituted by a C—O—C bond.
  • tri-norenolenolides such as tri-norenolenolenolides, trinolenolenoleolides, 1-butanesnolehoninolenolenoleolides, and one-octane snorehonolenolenoleolides.
  • sulfonyl fluoride When sulfonyl fluoride is used in the present invention, it is usually used in the range of 0.1 to 10 equivalents to the substrate. Preferably, it is used in the range of 0.5 to 5 equivalents, more preferably 1 to 4 equivalents.
  • the base used in the production method of the present invention is not particularly limited, but preferred examples thereof include amines (including salts thereof), metal hydroxides, metal alkoxides, ion exchange resins, and carbonates. , Phosphates, acetates and the like. Of these, amines and the like are particularly preferable in that there are many types and an optimal one can be selected for the substrate.
  • the amines include hydroxyamine, ammonia or a salt thereof, primary to quaternary organic amine or a salt thereof, an ion exchange resin, and a resin of a polymerized amine. Is mentioned.
  • Specific examples include triethylamine, tributynoleamine, trioctylamine, N, N—dimethinolecyclohexinoleamine, N, N—getinolecyclohexylamine, N-ethylethylisopropylamine, 1,8—diazabicyclo [5,4,0] indecku 7-ene, 1-ethylbiperidine, 2,2,6,6-tetramethylbiperidine, 1,1,3,3-tetramethyldanidine, 2, 4, 6-collidine, polyvinylpyridine and the like.
  • the amines used in the present invention include those in the form of a salt.
  • the salt include a hydrochloride, a tosylate, a tartrate and the like.
  • the base is usually used in the range of 0.1 to 10 equivalents to the substrate. It is preferably used in the range of 0.5 to 5 equivalents, more preferably 1 to 4 equivalents. It is.
  • the fluorination reaction using sulfonyl fluoride can be performed in an appropriate solvent, but is preferably toluene, benzotrifluoride, ethyl acetate, methylene chloride, methyl-t-butyl ether.
  • the reaction can be carried out in an organic solvent such as tetrahydrofuran, acetonitrinole, and acetone.
  • the reaction temperature is usually in the range of ⁇ 40 ° C. to the reflux temperature of the solvent used. Preferably, the temperature is from 20 ° C. to the solvent reflux temperature.
  • reaction mixture is neutralized with a base or sulfonic acid, if necessary, and subjected to the above-mentioned general formula (II ) Can be extracted.
  • the compound represented by the general formula (II) obtained by the production method of the present invention is a compound in which the hydroxyl group in the general formula (I) is stereospecifically substituted with a fluorine atom. Substituents other than the hydroxyl group to be substituted maintain their respective positions and ⁇ or; Specifically, it is represented by any of the following formulas (XVIII) to (XXV).
  • the compound represented by the general formula (I) is a nucleoside derivative, as described above, a compound in which ⁇ is a hydrogen atom and B has 13 configurations is generally used (X and Y are ⁇ or). Any of the three configurations may be held. ).
  • the general formula (II) is represented by any of the following general formulas (XXVI) to (XXIX).
  • the hydroxyl-protecting group of the compound represented by the general formula (II) is an ordinary one. It can be deprotected by law.
  • the hydroxyl-protecting group is an acetyl group, an benzoyl group, or another such acyl group
  • an alcohol such as methanol or a protic solvent such as water, or an alkali such as ammonia or sodium hydroxide is used.
  • aralkyl groups such as benzyl group and triphenylmethyl group
  • deprotection can be easily performed by treating with an acid such as hydrochloric acid or acetic acid, or by reducing in the presence of a reduction catalyst. be able to.
  • the nucleic acid group has a protecting group
  • the protecting group can be similarly deprotected by a usual method.
  • a substituent of a nucleic acid base may be derived to another appropriate substituent, for example, a halogen atom at the 6-position may be substituted with an amino group, or a hydroxyl group of Y ′ or X ′ may be removed.
  • the desired fluorinated nucleoside derivative can be converted to a desired fluorine-containing nucleoside derivative by, for example, dehydroxylating the 3′-hydroxyl group (protected or unprotected).
  • nucleoside or saccharide derivative represented by the general formula (II) produced by the production method of the present invention can be converted into a fluorine derivative represented by the following general formula (V) by a method known to those skilled in the art.
  • Nucleoside derivatives For example, when A is a hydrogen atom and R is a hydroxyl-protecting group in the general formula (I), the 5′-position can be deprotected by an ordinary deprotection method. When any of Y ′ and X ′ is a protected hydroxyl group, it is similarly converted to a hydroxyl group from which the protective group has been removed by the deprotection step.
  • the desired fluorinated nucleoside derivative (V) is obtained by a condensation step of this sugar derivative and a salt represented by B ′ (adenine, 6-halogenoprin, etc.). Can be manufactured.
  • the condensation step can be carried out using a known method (see “Chemistry of Nucleosides and Nucleotides", Vol. 1, LB Townsend, Ed, Plenum Press, New York (1988), 1-281).
  • the base is 6-logenopurine
  • the halogen atom Can be converted into a substituent.
  • FddA when produced, it must be subjected to the following 6-amination step (see, for example, VE Marquez et al., J. Med. Chem., 33, 978 (1990)). ).
  • B ′ represents a nucleobase (including a derivative thereof)
  • Y ′′ and X ′′ each represent a fluorine atom
  • the other represents a hydrogen atom or a hydroxyl group.
  • the compound represented by the general formula (V) is an important compound particularly for pharmaceutical use.
  • Adenine (FddA) is known to have potent antiviral activity against human immunodeficiency virus (HIV). According to the present invention, such an important active ingredient as a medicament can be effectively and easily produced.
  • A is a hydrogen atom
  • B is adenine in a 6-position
  • X ′ is a fluorine atom in a] configuration
  • Y ′ is a hydrogen atom.
  • the above B is 6-halogenoprin in j3 configuration instead of adenine in 3 configuration.
  • FddA can be produced by aminating the halogen atom at the 6-position of the obtained nucleoside derivative by a known method (such as treatment with ammonia / alcohol).
  • ⁇ ′ is not a hydrogen atom but a hydroxyl group (protected or unprotected)
  • a step of dehydroxylating this hydroxyl group is required.
  • the dehydration step may be performed before or after the amination step.
  • the protection and deprotection of the hydroxyl group can be appropriately carried out as required.
  • FddA can be produced by aminating the halogen atom at the 6-position in the same manner.
  • the 6-position amination can be carried out by a halogen atom-amino group substitution reaction step of a nucleoside derivative known per se, in which case the 5′-position hydroxyl group is protected even if it is protected. It may not be protected, and if protected, the 5 ′ position may be subjected to the deprotection step after the amination step.
  • Y ′ is a hydroxyl group protected in place of a hydrogen atom
  • this hydroxyl group (protection) is subjected to a 3′-position dehydroxylation step (for example, Maruyama et al., Chem. Pharm. Bull., 47, 966- 970 (1999)).
  • a 3′-position dehydroxylation step for example, Maruyama et al., Chem. Pharm. Bull., 47, 966- 970 (1999)
  • B may be the above-mentioned halogenoprin, and in such a case, the above-mentioned 6-position amination step is required.
  • the compound described in the general formula (II) can be used to guide FddA according to the method described in Examples below.
  • A is water Compounds in which B is a peracyl or thymine in the
  • the general formula (II) represents a sugar derivative
  • the compound represented by the general formula (II) is useful, for example, as an intermediate of a nucleoside derivative.
  • a target nucleoside derivative By conducting a condensation reaction (coupling reaction) with a nucleobase derivative from such a sugar derivative, a target nucleoside derivative can be obtained. Then, similarly, deprotection of a protecting group of a hydroxyl group or a nucleic acid base, derivation of a substituent to another suitable substituent, or dehydroxylation of a hydroxyl group of X ′ or Y ′ is performed. Thus, it can be converted into a desired fluorine-containing nucleoside derivative represented by the general formula (V).
  • FddA can be derived from a sugar derivative by the method described in VE Marquez et al., Synthesis (1991), 1005 or VE Marquez et al., J. Med. Chem., 33, 978 (1990). it can.
  • the following method can be used to produce FddA and related compounds using a derivative in which B is 6-halogenoprin.
  • the compound represented by the following general formula ( ⁇ -1) may be subjected to the step of substituting the halogen atom at the 6-position with a Z group to remove the 5′-position as necessary, or the 5′-position may be unprotected. Then, FddA or a related compound can be produced by subjecting the halogen atom at the 6-position to a Z group substitution reaction.
  • Q a is halogen atom
  • Z is a hydrogen atom, an amino group, hydroxyl group, azide de group
  • substituents of the formula OR 4 represented by the formula SR 4 substituent
  • R is any of the substituents represented by the formula NH R 4
  • R is a protecting group for a hydroxyl group, and has the same meaning as described above.
  • substitution at the 6-position and the logen atom with the Z group can be carried out using a substitution reaction known per se.
  • the compound represented by the general formula ( ⁇ -1) may be subjected to, for example, the following reaction step.
  • z is a hydrogen atom
  • the compound is treated with hydrogen in the presence of a reduction catalyst such as palladium carbon.
  • a reduction catalyst such as palladium carbon.
  • alkyl amines (Arukiruamin corresponding to substituent to Mechiruamin like object), preferably treated in an inert solvent medium such as dimethyl formamidine de.
  • R 4 may have a substituent such as a fuunyl group, or a lower alkyl group having 15 to 15 carbon atoms (eg, a methyl group, an ethyl group, a propyl group, a butyl group, a benzyl group, etc.). ).
  • a substituent such as a fuunyl group, or a lower alkyl group having 15 to 15 carbon atoms (eg, a methyl group, an ethyl group, a propyl group, a butyl group, a benzyl group, etc.).
  • the compound represented by the general formula ( ⁇ -2) is subjected to a deprotection reaction
  • the scale is an acetyl group such as acetyl or benzoyl
  • the compound is treated with alcohol (sodium hydroxide, potassium hydroxide, etc.).
  • R is an alkyl group such as methoxymethyl or aryl
  • treatment with an acid such as hydrochloric acid or acetic acid results in reduction of palladium carbon or Raney nickel when R is an aralkyl group such as benzyl or trimethylmethyl.
  • R is a silyl group such as trimethylsilyl, it is easily treated with hydrogen or in the presence of a catalyst, if necessary, with an acid such as acetic acid, etc., and then easily treated with tetraammonium fluoride.
  • the nucleoside derivative represented by the formula (III-3) can be produced.
  • the order of the substitution reaction and the deprotection reaction from the compound ( ⁇ -1) is changed, and the compound ( ⁇ -1) is first subjected to the 5′-position deprotection reaction as described above to obtain the compound represented by the general formula
  • the compound represented by ( ⁇ -2 ′) is produced, and then subjected to the reaction of substituting the substituent Q with the Z group as described above, the nucleoside derivative represented by the above general formula ( ⁇ -3) is also obtained.
  • the hydroxyl group (protected or unprotected) is dehydroxylated.
  • the above-mentioned FddA or a related compound can be produced.
  • dehydroxylation a method known per se can be used, but dehydroxylation can also be carried out by introducing an appropriate leaving group.
  • the protecting groups at the 5'-position and the 3'-position should be different from each other so that they cannot be simultaneously deprotected under the same conditions, and those which can deprotect only the 3'-position should be selected.
  • an acetyl group such as an acetyl group or a benzoyl group as a protecting group at the 3′-position
  • an aralkyl group such as a trityl group or a benzyl group which may have a substituent as the protecting group at the 5′-position.
  • Combinations of groups can be employed.
  • 6-Black mouth 9-1 (3-Doxy j8—D—Elitroventfuranosyl) — 9H—Purine 1.38 g (5.1 Ommo 1) is dissolved in 4 mL of dry dimethylformamide, and After adding 2.3 ml (16.5 mm o 1) of triethylamine and 0.424 g (3.47 mm o 1) of 4-dimethylaminopyridine, 4.79 g (16.8 mm o) of trityl chloride o 1) was added, and the mixture was reacted at 50 ° C for about 16.5 hours. After cooling, 8 ml of water was added, and the solvent was distilled off four times.
  • the reaction was stopped by adding 25 milliliters of a 10% aqueous ammonium chloride solution to the reaction mixture, and the organic layer was separated. The organic layer was washed sequentially with 25 milliliters of a 10% aqueous ammonium chloride solution and 25 milliliters of water. When the organic layer was analyzed by HPLC, the desired product was obtained in a yield of 57.6%.
  • 6-Chloro-9— [3-Doxy-d-D-erythro-pentofuranosyl] —9H-purine was reacted with acetyl chloride in dry dimethylformamide in the presence of pyridine at room temperature.
  • the resulting reaction mixture was treated with water, and the product was extracted with methylene chloride.
  • Subjected oily substance obtained by concentrating the extracted organic layer silica force gel strength Ramuku Roma Togurafi one, and eluted with hexane mixed solution to acetic acid Echiruno n scratch.
  • the eluate containing the desired compound was collected, and the residue obtained by concentrating the eluate was recrystallized twice from ethyl acetate and n-hexane to obtain the desired product.
  • the reaction mixture was quenched with 10 milliliters of saturated aqueous sodium bicarbonate solution to terminate the reaction, and then added with 10 milliliters of toluene and 2 ° milliliters of ethyl acetate.
  • the organic layer was separated.
  • the organic layer was washed successively with 10 milliliters of a 5% aqueous solution of citric acid and 10 milliliters of a saturated aqueous solution of sodium bicarbonate.
  • the target product was obtained in a yield of 66.2%.
  • the desired product was isolated and purified by silica gel column chromatography.
  • the regram (0.1 mmo1) was dissolved in 0.5 ml of toluene and 0.5 milliliter of triethylamine, and 0.028 milliliter of triethylamine was added (0.2 mmo1).
  • 38.4 milligrams (0.2 mmo1) of methyl fluorosulfonyl (difluoro) acetate was added dropwise with stirring, and the mixture was heated to 50 ° C and stirred for 74 hours. did.
  • the reaction mixture was analyzed by HPLC, the desired product was obtained in a yield of 28.1%.
  • the 5'-protected hydroxyl group at the target product obtained in this manner is treated with a method known as the 5'-position deprotection method for nucleotides, for example, by treating it with an acid such as hydrochloric acid or acetic acid. Easily converted to 2 ', 3'-didoxy 3'-fluoridine by reduction in the presence of a reduction catalyst Can be
  • the lower layer was extracted with toluene, and the extracted organic layers were combined and washed twice with a saturated aqueous solution of ammonium chloride.
  • the oily substance obtained by concentrating the extracted organic layer was applied to a silica gel column, and eluted with a mixed solution of ethyl acetate and methylene chloride. The eluate containing the desired compound was collected and concentrated to give an oily target in a yield of 47.3%.
  • a compound in which the hydroxyl group is selectively and effectively substituted with a fluorine atom can be easily produced from a nucleoside or a sugar derivative having a secondary hydroxyl group.
  • a fluorine atom can be stereospecifically substituted in one step, and a low-cost, safe, and industrially superior production method is provided.
  • the present invention is extremely useful in the production of various pharmaceutical intermediates including FddA.

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Abstract

L'invention porte sur un procédé efficace de préparation de dérivés fluorés de nucléosides et de sucres dont les groupes hydroxyle secondaires sont sélectivement remplacés par des atomes de fluor. Il consiste à faire réagir un dérivé de nucléoside ou de sucre porteur de groupes hydroxyle secondaires avec un fluorure de sulfonyle tel que le fluorure de perfluoroalkanesulfonyle ou le fluorure d'alkanesulfonyle en présence d'une base. Ce procédé, économique, sûr et avantageux industriellement, permet la fluoruration en une étape des groupes hydroxyle ci-dessus et s'avère extrêmement utile pour la préparation des intermédiaires de différents médicaments dont des antiviraux.
PCT/JP1999/006500 1998-12-25 1999-11-24 Procede de preparation de derives fluores de nucleosides et de sucres Ceased WO2000039144A1 (fr)

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AU14082/00A AU1408200A (en) 1998-12-25 1999-11-24 Process for the preparation of fluorinated derivatives of nucleosides or sugars

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JP37071098A JP2002293792A (ja) 1998-12-25 1998-12-25 ヌクレオシド又は糖のフッ素化誘導体の製造方法
JP10/370710 1998-12-25

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005336151A (ja) * 2004-04-26 2005-12-08 Central Glass Co Ltd ４−フルオロプロリン誘導体の製造方法
JP2006008534A (ja) * 2004-06-22 2006-01-12 Central Glass Co Ltd ４−フルオロプロリン誘導体の製造方法
EP2216337A4 (fr) * 2007-12-12 2014-01-22 Central Glass Co Ltd Procédé de production de dérivé de 4-désoxy-4-fluoro-d-glucose

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0495225A1 (fr) * 1991-01-15 1992-07-22 American Cyanamid Company Procédé de préparation de nucléosides de 3'-fluoropyrimidine
JPH11217396A (ja) * 1998-01-30 1999-08-10 Ajinomoto Co Inc ヌクレオシド誘導体の製造方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0495225A1 (fr) * 1991-01-15 1992-07-22 American Cyanamid Company Procédé de préparation de nucléosides de 3'-fluoropyrimidine
JPH11217396A (ja) * 1998-01-30 1999-08-10 Ajinomoto Co Inc ヌクレオシド誘導体の製造方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MAQBOOL A. SIDDIQUI ET. AL.: 'A New Synthetic Approach to the Clinically Useful, Anti-HIV-Active Nucleoside, 9-(2,3-Dideoxy-2-fluoro-beta-D-threo-pentof uranosyl) adenine (beta-FddA). Introduction of a 2'-beta-Fluoro Substituent via Inversion of a Really Obtainable 2'-alpha-Fluoro Isomer' TETRAHEDRON LETTERS vol. 39, no. 13, 26 March 1998, pages 1657 - 1660, XP002926079 *
VICTOR E. MARQUEZ, ET. AL.: 'Acid-Stable 2'-Fluoro Purine Dideoxynucleosides as Active Agents against HIV.' J. MED. CHEM. vol. 33, no. 3, March 1990, pages 978 - 985, XP002926080 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005336151A (ja) * 2004-04-26 2005-12-08 Central Glass Co Ltd ４−フルオロプロリン誘導体の製造方法
JP2006008534A (ja) * 2004-06-22 2006-01-12 Central Glass Co Ltd ４−フルオロプロリン誘導体の製造方法
EP2216337A4 (fr) * 2007-12-12 2014-01-22 Central Glass Co Ltd Procédé de production de dérivé de 4-désoxy-4-fluoro-d-glucose

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AU1408200A (en) 2000-07-31

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