WO2015125782A1 - Procédé de production d'un composé saccharidique de type à squelette de thiolane ainsi que composé saccharidique de type à squelette de thiolane - Google Patents

Procédé de production d'un composé saccharidique de type à squelette de thiolane ainsi que composé saccharidique de type à squelette de thiolane Download PDF

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WO2015125782A1
WO2015125782A1 PCT/JP2015/054306 JP2015054306W WO2015125782A1 WO 2015125782 A1 WO2015125782 A1 WO 2015125782A1 JP 2015054306 W JP2015054306 W JP 2015054306W WO 2015125782 A1 WO2015125782 A1 WO 2015125782A1
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group
general formula
compound represented
compound
alkyl group
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PCT/JP2015/054306
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伊藤　孝之
渡辺　徹
玲 武田
英希 岡田
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富士フイルム株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
    • 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
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/08—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to sulfur, selenium or tellurium
    • C07H5/10—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to sulfur, selenium or tellurium to sulfur

Definitions

  • the present invention relates to a method for producing a thiolane skeleton type sugar compound and a thiolane skeleton type sugar compound.
  • thionucleosides in which an oxygen atom is replaced by a sulfur atom exhibit antiviral activity or antitumor activity.
  • 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine has excellent antitumor activity and is known to be useful as a tumor therapeutic agent.
  • Patent Document 1 2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl
  • Conventional methods for synthesizing a thiosugar by a reaction for forming a thiolane ring are mainly a dithioketal method and a pumeler method.
  • the dithioketal method uses a relatively low-grade mercaptan such as dibenzyl mercaptan, so it has a strong malodor and is not preferable from an environmental and health viewpoint.
  • the Pummerer method is not preferable in terms of yield and suitability for mass production because regioisomers are inevitably produced in the Pummerer rearrangement step.
  • a method for producing a thionucleoside synthesis intermediate is produced in a simple and high yield under mild conditions, and a compound having a thiosugar skeleton is synthesized with few steps. It is an object to provide a manufacturing method that can be used. Furthermore, it is an object of the present invention to provide a thiolane skeleton-type sugar compound or a synthetic intermediate compound useful as a thionucleoside synthesis intermediate exhibiting antiviral activity or antitumor activity.
  • R 1 represents a hydrogen atom, an alkyl group or an acyl group
  • R 2 represents —O—R 2a or a fluorine atom
  • R 2 ′ represents —O—R 2a
  • R 2a represents a hydrogen atom, —CH 2 —R 2b or an acyl group
  • R 2b , R 3 and R 5 each independently represents a hydrogen atom, an alkyl group, a vinyl group or an aryl group
  • X represents a leaving group.
  • the bond from R 2 ′ to the thiolane ring represents a single bond or a double bond.
  • R 1, R 2b, R 3 and R 5 are R 1, R 2b in the formula (II), and R 3 and R 5 synonymous.
  • R 2c represents an alkyl group or an aryl group.
  • R 11 represents an alkyl group or an acyl group
  • R 21 , R 31 and R 51 each independently represents an alkyl group.
  • R 2 ′ in the general formula (II) is —O—CH 2 —R 2b or an arylcarbonyloxy group, and R 2b is a hydrogen atom, an alkyl group, a vinyl group or an aryl group,
  • the production method according to ⁇ 1> or ⁇ 2> wherein the compound represented by the general formula (II) is represented by the general formula (II-1) or (II-2), and R 2c is an aryl group .
  • R 11 is a methyl group or an acetyl group
  • R 21 , R 31, and R 51 are each independently an alkyl group having 1 to 10 carbon atoms.
  • ⁇ 5> The production method according to ⁇ 2> or ⁇ 4>, wherein R 21 , R 31, and R 51 are all the same substituent.
  • ⁇ 6> In the step of reacting the compound represented by the general formula (I) with a sulfur compound, the compound represented by the following general formula (IIA) is synthesized, and then the compound represented by the general formula (IIA) is alkylated.
  • R 2, R 3 and R 5 have the same meanings as R 2, R 3 and R 5 in the general formula (I).
  • R 2 ′ in the general formula (II) is a hydroxy group, or when the compound represented by the general formula (II) is represented by the general formula (II-3), it is represented by the general formula (I).
  • the step of dealkylating the compound represented by the following general formula (II-a) obtained through the step of reacting the compound obtained with the sulfur compound, or represented by the following general formula (II-b) The method according to ⁇ 1> or ⁇ 2>, wherein a compound represented by the following general formula (II-c) is produced in the step of deacylating the compound:
  • R 1, R 3 and R 5 have the same meanings as R 1, R 3 and R 5 in the general formula (II).
  • R 2b has the same meaning as R 2b in the general formula (II-1).
  • R 2c have the same meanings as R 2c in the formula (II-2).
  • the compound represented by the following general formula (II-d) is obtained through the step of oxidizing the compound represented by the following general formula (II-c ′) obtained through the step of reacting the compound obtained with the sulfur compound.
  • R 1 , R 3 and R 5 have the same meanings as R 1, R 3 and R 5 in the general formula (II).
  • R 1 ′ represents an alkyl group or an acyl group.
  • R 1 represents a hydrogen atom, an alkyl group or an acyl group
  • R 1b represents an unsubstituted alkyl group or an arylcarbonyl group
  • R 20b , R 30 and R 50 each independently represents an aryl group
  • R 2c represents an alkyl group or an aryl group.
  • R 11 represents an alkyl group or an acyl group
  • R 21 , R 31 and R 51 each independently represents an alkyl group.
  • R 11a represents an alkyl group or an acyl group
  • R 21a , R 31a and R 51a each independently represents an alkyl group.
  • R 11a is an acyl group
  • at least one of R 21a , R 31a and R 51a is an unsubstituted alkyl group.
  • R 11b represents an alkyl group or an acyl group
  • R 21b , R 31b and R 51b each independently represents an alkyl group.
  • the total number of these carbon atoms is 5 or more.
  • R 1 is a hydrogen atom, a methyl group or an acetyl group
  • R 1b is a methyl group
  • R 20b , R 30 and R 50 are phenyl groups
  • R 2c is a chlorine atom, an alkyl group or an alkoxy group
  • ⁇ 12> The compound according to ⁇ 12>, which is a phenyl group which may have a group.
  • ⁇ 14> The compound according to ⁇ 12> or ⁇ 13>, wherein the compound is selected from the following.
  • R 11 , R 11a and R 11b are a methyl group or an acetyl group
  • R 21 , R 21a , R 21b , R 31 , R 31a , R 31b , R 51 , R 51a and R 51b are The compound according to ⁇ 12>, wherein each independently represents an alkyl group having 1 to 10 carbon atoms.
  • R 21, R 31 and R 51, R 21a, R 31a and R 51a and R 21b,, R 31b and R 51b are, according to which each independently the same substituent ⁇ 12> or ⁇ 15> Compound.
  • ⁇ 17> The compound according to any one of ⁇ 12>, ⁇ 15>, or ⁇ 16>, wherein the compound is selected from the following.
  • R x1 represents an acetyl group or a methyl group
  • R x2 represents a methyl group, a propyl group, a butyl group, or a pentyl group.
  • each substituent may be further substituted with a substituent unless otherwise specified.
  • a compound having a thiosugar skeleton in a reaction for forming a thiolane ring, can be synthesized by a production method for producing a thionucleoside synthesis intermediate in a simple and high yield under mild conditions, and with fewer steps.
  • a manufacturing method can be provided.
  • the method for producing a thiolane skeleton type sugar compound of the present invention is a method for producing a stereocontrolled compound represented by the following general formula (II), and reacts the compound represented by the following general formula (I) with a sulfur compound.
  • R 1 represents a hydrogen atom, an alkyl group or an acyl group
  • R 2 represents —O—R 2a or a fluorine atom
  • R 2 ′ represents —O—R 2a
  • R 2a represents a hydrogen atom, —CH 2 —R 2b or an acyl group
  • R 2b , R 3 and R 5 each independently represents a hydrogen atom, an alkyl group, a vinyl group or an aryl group
  • X represents a leaving group.
  • the bond from R 2 ′ to the thiolane ring represents a single bond or a double bond.
  • R 2 ′ When the carbon atom substituted by R 2 , R 2 ′, O—CH 2 —R 3 and CH 2 —O—CH 2 —R 5 in the general formulas (I) and (II) is an asymmetric carbon atom,
  • the configuration substituted by R 2 , R 2 ′, O—CH 2 —R 3 and CH 2 —O—CH 2 —R 5 is substantially either R or S on each asymmetric carbon atom. It is.
  • R 2 ′ is substantially located on either the ⁇ side or the ⁇ side, except when ⁇ O, and O—CH 2 —R 3 is substantially ⁇ And CH 2 —O—CH 2 —R 5 is substantially located on either the ⁇ side or the ⁇ side.
  • passing means that, even if it is only the step of reacting the compound represented by the general formula (I) with the sulfur compound, it is further represented by the general formula (I) after the step of reacting with the sulfur compound.
  • the compound synthesized in the step of reacting the compound with the sulfur compound may include a step of alkylating or acylating the compound.
  • the compound represented by the general formula (I) is reacted with the sulfur compound. It is preferable to perform the process of alkylating the OH body obtained by reaction with a sulfur compound, or the process of acylating after the process to make. It is also preferable to perform a step of oxidizing —OH to ⁇ O.
  • R 1 in the general formula (II) is an acyl group
  • the compound represented by the following general formula (IIA) is synthesized in the step of reacting the compound represented by the general formula (I) with a sulfur compound.
  • the step of acylating the compound represented by the general formula (IIA) it is preferable to produce the compound represented by the following general formula (II).
  • R 2, R 3 and R 5 have the same meanings as R 2, R 3 and R 5 in the general formula (I).
  • the carbon atom constituting the thiolane ring as the basic skeleton has three asymmetric carbon atoms when R 2 ′ is ⁇ O, and in other cases, It has 4 asymmetric carbon atoms.
  • the term “sterically controlled” means that a compound represented by the general formula (II) is produced by changing the configuration existing in the asymmetric carbon atom to a specific configuration.
  • M represents an alkali metal.
  • MSH performs a nucleophilic attack on the carbon atom substituted by X via the following reaction route. Since this nucleophilic substitution reaction is an S N 2 reaction, only the arrangement of the thiolane ring on the 4-position carbon atom is inverted (valden inversion), and the arrangement of asymmetric carbon atoms other than the 4-position is fixed without change. ing. In addition, in the following reaction route, it is the arrangement
  • the compound in which R 2 ′ is a hydroxy group can be produced, for example, by the following steps. That is, a step of dealkylating a compound represented by the following general formula (II-a) obtained via a step of reacting a compound represented by the general formula (I) with a sulfur compound, or the following general formula
  • a step of dealkylating a compound represented by the following general formula (II-a) obtained via a step of reacting a compound represented by the general formula (I) with a sulfur compound or the following general formula
  • the step of deacylating the compound represented by (II-b) the compound represented by the following general formula (II-c) can be produced.
  • R 1, R 3 and R 5 have the same meanings as R 1, R 3 and R 5 in the general formula (II).
  • R 2b has the same meaning as R 2b in the general formula (II-1).
  • R 2c have the same meanings as R 2c in the formula described below (II-2).
  • R 1 , R 3 and R 5 have the same meanings as R 1, R 3 and R 5 in the general formula (II).
  • R 1 ′ represents an alkyl group or an acyl group.
  • the solvent used for the reaction in the step of reacting the compound represented by the general formula (I) with the sulfur compound is not particularly limited as long as it does not affect the reaction.
  • Examples include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons, ureas and water. These solvents may be used as a mixture.
  • Preferred solvents are solvents having an amide moiety or a sulfonyl group in the partial structure, that is, amides, cyclic amides, ureas, cyclic ureas or sulfoxides.
  • the amount of the solvent used is not particularly limited, and may be 1 to 50 times (v / w) with respect to the compound represented by the general formula (I). / W) is preferred.
  • Examples of the sulfur compound used in this reaction include hydrogen sulfide or a salt thereof.
  • Examples of the hydrogen sulfide salt include alkali metal salts and alkaline earth metal salts.
  • the sulfur compound is preferably MSH or M 2 S in which M is an alkali metal.
  • M is an alkali metal.
  • Examples of the sulfur compound include hydrogen sulfide, sodium hydrogen sulfide, sodium sulfide, potassium hydrogen sulfide, calcium hydrogen sulfide, and magnesium sulfide, and sodium hydrogen sulfide is preferable.
  • the sulfur compound may be a hydrate or may be used by dissolving in an aqueous solution.
  • the amount of the sulfur compound used is preferably 0.2 to 10-fold mol, more preferably 0.5 to 2.0-fold mol, and 0.7 to 1.times. Mol with respect to the compound represented by the general formula (I). A 5-fold mole is more preferred.
  • the reaction temperature is preferably ⁇ 20 to 100 ° C., more preferably ⁇ 10 to 80 ° C., and further preferably ⁇ 5 to 60 ° C.
  • the reaction time is preferably 5 minutes to 50 hours, more preferably 5 minutes to 24 hours, and even more preferably 5 minutes to 6 hours.
  • the compound in which R 1 is an alkyl group causes the compound represented by the general formula (IIA) to react with an alcohol represented by R 1 OH in the presence of an acid.
  • R 1 is an alkyl group
  • the alkyl part of alcohol and the alkyl group in R ⁇ 1 > of general formula (II) are synonymous with the alkyl group in below-mentioned R ⁇ 1 >, and its preferable range is also the same.
  • the acids used are Bronsted acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid and trifluoromethanesulfonic acid, as well as aluminum chloride, aluminum bromide, tetrachloride Mention may be made of Lewis acids such as tin, titanium tetrachloride, titanium (IV) isopropoxide, zinc chloride and trimethylsilyl trifluoromethanesulfonate.
  • Preferred acids include hydrochloric acid, sulfuric acid, aluminum chloride, tin tetrachloride and trimethylsilyl trifluoromethanesulfonate.
  • Hydrochloric acid may be supplied from a gas cylinder or may be generated by reacting R 1 OH and acyl chloride (preferably acetyl chloride) in the system.
  • the amount of these acids used is preferably 0.01 to 100 times mol, more preferably 0.1 to 10 times mol, and 0.5 to 5 times mol based on the compound represented by the general formula (IIA). Is more preferable.
  • reaction solvent aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, amides, sulfoxides, aromatic hydrocarbons and ureas are preferable, and alcohols represented by R 1 OH are more preferable. preferable.
  • the reaction temperature is preferably ⁇ 20 to 100 ° C., more preferably ⁇ 10 to 80 ° C., and further preferably ⁇ 5 to 60 ° C.
  • the reaction time is preferably 5 minutes to 50 hours, more preferably 5 minutes to 24 hours, and even more preferably 5 minutes to 6 hours.
  • Examples of the acylating agent in the step of acylating the compound represented by the general formula (IIA) include acyl halides and acid anhydrides.
  • the acyl part of an acylating agent and the acyl group in R ⁇ 1 > of general formula (II) are synonymous with the acyl group in R ⁇ 1 > mentioned later, and its preferable range is also the same.
  • acylating agents are preferably 50 to 1000 mol%, more preferably 80 to 500 mol%, still more preferably 100 to 200 mol%, relative to the compound represented by the general formula (IIA).
  • the reaction solvent is preferably aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons or ureas, ethers, esters , Ketones, nitriles, amides, sulfoxides or aromatic hydrocarbons are more preferred.
  • a base is preferably used.
  • pyridines, trialkylamines optionally having a ring structure, N, N-dialkylanilines, N-alkyl-N-arylanilines , Triarylamines, guanidines, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates and alkali metal hydrogen carbonates, pyridines or trialkylamines are preferred.
  • the amount of the base used is preferably 20 to 500 mol% with respect to the compound represented by the general formula (IIA).
  • the reaction temperature is preferably ⁇ 20 to 100 ° C., more preferably ⁇ 10 to 80 ° C.
  • the reaction time is preferably 5 minutes to 50 hours, more preferably 10 minutes to 24 hours, and even more preferably 30 minutes to 6 hours.
  • the acylating step is the same without synthesizing the compound represented by the general formula (IIA) from the compound represented by the general formula (I), and then removing the compound represented by the general formula (IIA). It is preferable to synthesize in a container.
  • the compound represented by the general formula (II-c) can be synthesized by dealkylating the compound represented by the general formula (II-a) with a Lewis acid.
  • Lewis acids include triisobutylaluminum, trimethylaluminum, aluminum chloride, aluminum bromide, tin tetrachloride, titanium tetrachloride, titanium (IV) isopropoxide, zinc chloride, and trimethylsilyl trifluoromethanesulfonate.
  • Triisobutylaluminum is more preferred.
  • These Lewis acids are preferably 0.01 to 100-fold mol, more preferably 0.1 to 50-fold mol, and 0.5 to 10-fold mol based on the compound represented by the general formula (II-a). Further preferred.
  • Reaction solvents are preferably aliphatic hydrocarbons, halogenated hydrocarbons, ethers, amides, sulfoxides, aromatic hydrocarbons and ureas, more preferably aliphatic hydrocarbons, halogenated carbons. Hydrogens, ethers or aromatic hydrocarbons.
  • the reaction temperature is preferably ⁇ 20 to 100 ° C., more preferably ⁇ 10 to 80 ° C., and further preferably ⁇ 5 to 60 ° C.
  • the reaction time is preferably 5 minutes to 50 hours, more preferably 5 minutes to 24 hours, and even more preferably 5 minutes to 6 hours.
  • the compound represented by the general formula (II-c) can also be synthesized by deacylating the compound represented by the general formula (II-b) by acting a nucleophile.
  • Preferred nucleophiles are alcohols (eg methanol, ethanol, propanol and butanol), water, ammonia, primary amines (eg methylamine, ethylamine, propylamine and butylamine) and secondary amines (eg dimethyl). Amine and diethylamine).
  • alcohols or water it is more preferable to use an alkali or alkaline earth metal salt thereof. More preferred nucleophiles are methanol, water or their alkali metal salts, ammonia or methylamine.
  • the reaction solvent is preferably aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons, ureas or water, More preferred are alcohols, ethers, amides, sulfoxides or water, and still more preferred are alcohols (particularly preferably methanol) or water.
  • the nucleophile is preferably 0.1 to 100 times mol, more preferably 0.8 to 50 times mol, and further preferably 1 to 30 times mol based on the compound represented by the general formula (II-b). preferable.
  • the alkali metal alkoxide in the case of using an alkali metal alkoxide (preferably sodium methoxide) as a nucleophile in an alcohol solvent (preferably methanol) is preferably 0.001 to 0.5 times mol, more preferably 0. It may be used in an amount of 0.01 to 0.3 moles, more preferably 0.05 to 0.2 moles.
  • the reaction temperature is preferably ⁇ 20 to 100 ° C., more preferably ⁇ 10 to 80 ° C., and further preferably ⁇ 5 to 60 ° C.
  • the reaction time is preferably 5 minutes to 50 hours, more preferably 5 minutes to 24 hours, and even more preferably 5 minutes to 6 hours.
  • the oxidizing agent in the step of oxidizing the compound represented by the general formula (II-c ′) to the compound represented by the general formula (II-d) is 1,1,1-triacetoxy-1,1-dihydro- 1,2-benziodoxol-3 (1H) -one, o-iodoxybenzoic acid, dimethyl sulfoxide / acetic anhydride, etc., among which 1,1,1-triacetoxy-1,1-dihydro -1,2-benziodoxol-3 (1H) -one or o-iodoxybenzoic acid is preferred, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one is more preferred.
  • the oxidizing agent is represented by the general formula (II-c ′ ) Is preferably 50 to 500 mol%, more preferably 75 to 300 mol%, still more preferably 90 to 200 mol%.
  • reaction solvent dichloromethane is usually used.
  • the reaction temperature is preferably 0 to 80 ° C, more preferably 10 to 30 ° C.
  • the reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 12 hours, and even more preferably 60 minutes to 6 hours.
  • R 1 in the compound represented by the general formula (II-d) is the same as R 1 ′ in the general formula (II-c ′).
  • the alkyl group or acyl group in R 1 ′ may be led to a hydrogen atom.
  • the thiolane skeleton type sugar compound of the present invention is a compound represented by the aforementioned general formula (II).
  • R 1 represents a hydrogen atom, an alkyl group or an acyl group
  • R 2 ′ represents —O—R 2a , a fluorine atom or ⁇ O.
  • R 2a represents a hydrogen atom, —CH 2 —R 2b or an acyl group
  • R 2b , R 3 and R 5 each independently represents a hydrogen atom, an alkyl group, a vinyl group or an aryl group
  • X represents a leaving group.
  • R 2 ′ When the carbon atom substituted by R 2 ′, O—CH 2 —R 3 and CH 2 —O—CH 2 —R 5 in the general formula (II) is an asymmetric carbon atom, R 2 ′ is ⁇ O And O—CH 2 —R 3 is substantially located on either the ⁇ side or the ⁇ side, and CH 2. —O—CH 2 —R 5 is substantially located on either the ⁇ side or the ⁇ side.
  • substantially means, for example, the asymmetric purity of each asymmetric carbon (other than the anomeric position) [when the S form is excessive, (S form / (S form + R form) ⁇ 100) ] Is 95% or more, preferably 97% or more, more preferably 99% or more.
  • R 1 is preferably an alkyl group among a hydrogen atom, an alkyl group, and an acyl group.
  • the number of carbon atoms of the alkyl group in R 1 is preferably 1 to 20, more preferably 1 to 10, still more preferably 1 to 4, and particularly preferably 1.
  • Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, octyl and dodecyl, preferably methyl or ethyl, and more preferably methyl.
  • the alkyl group in R 1 is preferably an unsubstituted alkyl group.
  • the acyl group preferably has 1 to 20 carbon atoms, more preferably 2 to 20 carbon atoms, and still more preferably 2 to 12 carbon atoms.
  • the acyl group is preferably an alkylcarbonyl group or an arylcarbonyl group. Examples of the alkylcarbonyl group include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, myristoyl, palmitoyl and stearoyl.
  • the acyl group in R 1 includes formyl.
  • arylcarbonyl group examples include benzoyl, 4-methylbenzoyl, 4-chlorobenzoyl, 4-phenylbenzoyl and 2-naphthoyl.
  • the acyl group for R 1 is more preferably an alkylcarbonyl group, and even more preferably an acetyl group.
  • R 1 is preferably a hydrogen atom, an acetyl group or a methyl group, and more preferably an acetyl group or a methyl group.
  • acyl groups may be substituted with a substituent, and examples of the substituent include a halogen atom, an alkyl group, an aryl group, a heterocyclic group, an alkoxy group, an aryloxy group, an alkylthio group, and an arylthio group.
  • R 2b and R 3 and R 5 in R 2 ′ each independently represent a hydrogen atom, an alkyl group, a vinyl group or an aryl group.
  • the alkyl group preferably has 1 to 10 carbon atoms, more preferably 1 to 3, and examples thereof include methyl, ethyl, isopropyl, n-propyl and 2-ethylhexyl.
  • the aryl group preferably has 6 to 20 carbon atoms, more preferably 6 to 16 carbon atoms, still more preferably 6 to 12 carbon atoms, and examples thereof include phenyl and naphthyl.
  • the alkyl group and the aryl group may have a substituent, and examples thereof include a halogen atom, an alkyl group, an aryl group, a heterocyclic group, an alkoxy group, an aryloxy group, an alkylthio group, and an arylthio group.
  • R 2a in R 2 ′ is an acyl group
  • examples of the acyl group include an alkylcarbonyl group and an arylcarbonyl group, and an arylcarbonyl group is preferable.
  • the specific acyl groups include acyl groups mentioned in R 1, other than an aryl group is preferred, the same as the preferable range of the acyl groups in R 1.
  • R 2 ′ is preferably —O—CH 2 —R 2b or an arylcarbonyloxy group among the above groups.
  • R 2b , R 3 and R 5 are preferably aryl groups.
  • the compound represented by the general formula (II) is preferably a compound represented by any one of the following general formulas (II-1) to (II-10).
  • R 1, R 2b, R 3 and R 5 are R 1, R 2b in the formula (II), and R 3 and R 5 synonymous.
  • R 2c represents an alkyl group or an aryl group.
  • the aryl group of R 2c may be substituted with a substituent, and examples of the substituent include a halogen atom, an alkyl group, an aryl group, a heterocyclic group, an alkoxy group, an aryloxy group, an alkylthio group, and an arylthio group.
  • R 2c is preferably an aryl group, more preferably phenyl, 4-halogen-substituted phenyl, 4-methylphenyl, 4-phenylphenyl, 4-alkoxyphenyl or 2-naphthyl.
  • the compound represented by the general formula (II) is more preferably a compound represented by the above general formula (II-1) or (II-2), wherein R 2c is an aryl group.
  • the compound represented by any one of the general formulas (II-1) to (II-5) is preferably a compound represented by any one of the following general formulas (II-1 ′) to (II-5 ′).
  • R 1 represents a hydrogen atom, an alkyl group or an acyl group
  • R 1b represents an unsubstituted alkyl group or an arylcarbonyl group
  • R 20b , R 30 and R 50 each independently represents an aryl group
  • R 2c represents an alkyl group or an aryl group.
  • the alkyl group or arylcarbonyl group in R 1b is synonymous with the alkyl group or arylcarbonyl group in R 1 of the general formula (II), and the preferred range is also the same.
  • the aryl group in R 20b , R 30 and R 50 has the same meaning as the aryl group in R 2b , R 3 and R 5 in formulas (II-1) to (II-5), and the preferred range is also the same. is there.
  • R 1 is a hydrogen atom, a methyl group or an acetyl group
  • R 1b is a methyl group
  • R 20b , R 30 and R 50 are phenyl groups
  • R 2c has a chlorine atom, an alkyl group or an alkoxy group. It is preferably a phenyl group. It is represented by the general formulas (II-3 ′) to (II-5 ′) having a specific substituent, which does not have O—CH 2 —R 20b or O—C ( ⁇ O) R 2c at the 2-position.
  • the preferred ranges of R 1 , R 30 and R 50 also apply to the compounds that are made.
  • R 11 represents an alkyl group or an acyl group
  • R 21 , R 31 and R 51 each independently represents an alkyl group.
  • the number of carbon atoms of the alkyl group in R 11 is preferably 1-20, more preferably 1-10, still more preferably 1-4, and particularly preferably 1.
  • Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, octyl and dodecyl, preferably methyl or ethyl, and more preferably methyl.
  • the alkyl group in R 11 is preferably an unsubstituted alkyl group.
  • the acyl group preferably has 1 to 20 carbon atoms, more preferably 2 to 20 carbon atoms, and still more preferably 2 to 12 carbon atoms.
  • the acyl group is preferably an alkylcarbonyl group or an arylcarbonyl group. Examples of the alkylcarbonyl group include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, myristoyl, palmitoyl and stearoyl.
  • the acyl group in R 1 includes formyl.
  • arylcarbonyl group examples include benzoyl, 4-methylbenzoyl, 4-chlorobenzoyl, 4-phenylbenzoyl and 2-naphthoyl.
  • the acyl group in R 11 is more preferably an alkylcarbonyl group, and even more preferably an acetyl group.
  • R 11 is particularly preferably a methyl group or an acetyl group.
  • the number of carbon atoms of the alkyl group in R 21 , R 31 and R 51 is preferably 1 to 10, more preferably 2 to 10, and still more preferably 3 to 7.
  • Examples of the alkyl group include methyl, ethyl, isopropyl, n-propyl and 2-ethylhexyl.
  • the alkyl group may have a substituent, and examples thereof include a halogen atom, an alkyl group, an aryl group, a heterocyclic group, an alkoxy group, an aryloxy group, an alkylthio group, and an arylthio group.
  • Examples of the aryl group include phenyl and naphthyl.
  • R 11 is a methyl group or an acetyl group
  • R 21 , R 31 and R 51 are each independently an alkyl group having 1 to 10 carbon atoms. It is particularly preferable that R 21 , R 31 and R 51 are all the same substituent.
  • the compound represented by any one of the general formulas (II-6) to (II-10) is represented by the following general formula (II-6 ′) or (II-8 ′) or the above general formula (II-7), A compound represented by either (II-9) or (II-10) is preferred.
  • R 11a represents an alkyl group or an acyl group
  • R 21a , R 31a and R 51a each independently represents an alkyl group.
  • R 11a is an acyl group
  • at least one of R 21a , R 31a and R 51a is an unsubstituted alkyl group.
  • R 11b represents an alkyl group or an acyl group
  • R 21b , R 31b and R 51b each independently represents an alkyl group.
  • the total number of these carbon atoms is 5 or more.
  • the alkyl group or acyl group in R 11a and R 11b has the same meaning as the alkyl group or acyl group in R 11 , and the preferred range is also the same.
  • the alkyl group in R 21a, R 31a, R 51a , R 21b, R 31b and R 51b are the same meaning as the alkyl group in R 21, R 31 and R 51, the preferred range is also the same.
  • R 11 , R 11a and R 11b are each a methyl group or an acetyl group
  • R 21 , R 21a , R 21b , R 31 , R 31a , R 31b , R 51 , R 51a and R 51b are each independently An alkyl group having 1 to 10 carbon atoms is preferable.
  • R 21 , R 31 and R 51 are the same substituent
  • R 21a , R 31a and R 51a are the same substituent
  • R 21b , R 31b and R 51b are the same substituent. It is more preferable.
  • R x1 represents an acetyl group or a methyl group
  • R x2 represents a methyl group, a propyl group, a butyl group, or a pentyl group.
  • R x2 is preferably a propyl group, a butyl group or a pentyl group, more preferably a butyl group or a pentyl group, and even more preferably a butyl group.
  • the compound represented by the general formula (II) of the present invention is synthesized through a step of reacting the compound represented by the general formula (I) with a sulfur compound.
  • R 3 and R 5 has the same meaning as R 3 and R 5 in the general formula (II), and preferred ranges are also the same.
  • R 2 represents —O—R 2a or a fluorine atom, and R 2a has the same meaning as R 2a in formula (II), and the preferred range is also the same.
  • X represents a leaving group.
  • X is preferably a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group.
  • the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the number of carbon atoms in the alkylsulfonyloxy group is preferably 1 to 10, more preferably 1 to 6, still more preferably 1 to 3, and particularly preferably 1.
  • alkylsulfonyloxy group examples include methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, n-butylsulfonyloxy, t-butylsulfonyloxy, octylsulfonyloxy and dodecylsulfonyloxy.
  • the number of carbon atoms in the arylsulfonyloxy group is preferably 6 to 16, more preferably 6 to 12, and still more preferably 6 to 10.
  • arylsulfonyloxy group examples include benzenesulfonyloxy, toluenesulfonyloxy, naphthylsulfonyloxy, 4-chlorobenzenesulfonyloxy and 2,4,5-trichlorobenzenesulfonyloxy.
  • the compounds for synthesizing the compounds represented by the general formulas (II-1) to (II-5) are represented by the following general formulas (I-1) to (I -5).
  • R 2b, R 2c, R 3 and R 5 have the general formula (II-1) ⁇ (II -5) in R 2b, R 2c, R 3 and It is synonymous with R 5 and the preferred range is also the same.
  • X is synonymous with X in general formula (I), and its preferable range is also the same.
  • the compounds for synthesizing the compounds represented by the general formulas (II-6) to (II-10) are represented by the following general formula (I-6) to It is represented by (I-10).
  • R 21, R 31 and R 51 are the general formula (II-6) ⁇ (II -10) has the same meaning as R 21, R 31 and R 51 in The preferred range is also the same.
  • X is synonymous with X in general formula (I), and its preferable range is also the same.
  • the compound represented by the general formula (I) is disclosed in Chinese Patent Application No. 1010585855, Synlett, 2010, No3, p. 488-492, Journal of Organic Chemistry, 1992, 57, p. 5899-5907, Biomacromolecules, 2010, 11, p. 2415-2421 and Tetrahedron, 1994, 50, p. It can be synthesized according to the method described in 5361-5368.
  • the compound represented by the following general formula (h) or (h ′) is included in the compound represented by the general formula (I-1) or (I-2), and is synthesized by the following synthesis scheme, for example. can do.
  • R 2b, R 2c, R 3, R 5 and X have the general formula (I-1) and (I-2) in R 2b, R 2c, R 3 , It has the same meanings as R 5 and X, and the preferred range is also the same.
  • the compound represented by the general formula (h ′) can also be synthesized from the compound represented by the general formula (d ′) in the same manner as the compound represented by the general formula (h).
  • the compound represented by the general formula (II) is 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine, 1- (2-deoxy, which is useful as an antitumor agent. -2-methylene-4-thio- ⁇ -D-arabinofuranosyl) cytosine, 1- (2-deoxy-2,2-difluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine and / or It is a useful compound for the production of these peripheral compounds.
  • Examples of the use of the compound represented by the general formula (II) include a compound represented by the general formula (V).
  • the compound represented by the general formula (V) can be synthesized, for example, by reacting the compound represented by the general formula (II) with a silylated nucleobase and further deprotecting the compound.
  • R 2 ', R 3 and R 5 has the general formula (II) R 2 in the' have the same meanings as R 3 and R 5, the preferred range is also the same.
  • B ′ represents a nucleobase or a group obtained by protecting an amino group in a nucleobase with an acyl group. The bond from R 2 ′ to the thiolane ring represents a single bond or a double bond.
  • R 22 represents a hydroxy group when R 2 ′ represents —O—R 2a in the general formula (II), and R 2 ′ in the general formula (II) otherwise. It is synonymous with.
  • B represents a nucleobase.
  • the bond from R 22 to the thiolane ring represents a single bond or a double bond.
  • B′-SiR 3 represents a silylated nucleobase or a group obtained by acylating and protecting an amino group in a nucleobase, and R represents an alkyl group (preferably methyl).
  • R represents an alkyl group (preferably methyl).
  • the nucleobase in the general formulas (IV) and (V) has the same meaning as the nucleobase in the general formulas (IV-4) and (V-4) described later.
  • X 1 represents a halogen atom (preferably a bromine atom).
  • B ′ represents a nucleobase or a group obtained by protecting an amino group in a nucleobase with an acyl group.
  • B represents a nucleobase.
  • B′-SiR 3 represents a silylated nucleobase or a group obtained by acylating and protecting an amino group in a nucleobase, and R represents an alkyl group (preferably methyl).
  • B (X 2 ) 3 is boron trihalide, and X 2 represents a halogen atom, preferably a chlorine atom or a bromine atom.
  • nucleobases in the general formulas (IV-4) and (V-4) are adenine which may be substituted, guanine which may be substituted, cytosine which may be substituted, thymine which may be substituted or It means uracil which may be substituted, and represents, for example, the following groups.
  • * shows the part couple
  • the compound represented by the general formula (III-4) can be synthesized by halogenating the compound represented by the general formula (II-4) with a halogenating agent.
  • the compound represented by the general formula (IV-4) is obtained by reacting a nucleobase or a silylated compound which is a protected amino group thereof with a compound represented by the general formula (II-4) or (III-4).
  • the amino group may be acylated to improve the crystallinity for purification.
  • R 1, R 3 and R 5 in the general formula (II-11) ⁇ (II -14) has the same meaning as R 1, R 3 and R 5 in the general formula (II), and preferred ranges are also the same.
  • B in the thionucleoside represented by the general formulas (V-11) to (V-14) is a nucleobase group, and is synonymous with B in the general formula (V-4), and the preferred range is also the same. It is.
  • the compound represented by the general formula (II-5) can be synthesized by oxidizing the compound represented by the general formula (II-3).
  • the compound represented by the general formula (II-11) can be synthesized from the compound represented by the general formula (II-5) by the Wittig reaction, and the compound represented by the general formula (II-12) is deoxygenated. It can be synthesized from the compound represented by formula (II-5) by fluorination reaction.
  • the compounds represented by the general formulas (II-13) and (II-14) can be synthesized by reacting the compound represented by the general formula (II-5) with a Grignard reagent.
  • 4-amino-1-[(3S, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methylthiolan-2-yl] -1,2-dihydropyrimidine was prepared as follows. -2-one and 4-amino-1-[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methylthiolan-2-yl] -1,2-dihydro Pyrimidin-2-one was synthesized.
  • the reaction solution was slowly added to a mixed solution of 100 mL of ethyl acetate / 100 mL of water / 30 g of sodium bicarbonate while stirring, and the aqueous layer was removed.
  • the organic layer was washed successively with 50 mL of aqueous sodium hydrogen carbonate solution, 50 mL of water and 50 mL of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Methyl ((2R, 3R, 4S) -2,3,5-tris (benzyloxy) -4-hydroxypentylidene) amine (2.9 g) in 30 mL of ethyl acetate at 1.5 ° C. and 1.5 mL of triethylamine and methanesulfonyl chloride 0.75 mL was added and it stirred at 25 degreeC for 7 hours. 50 mL of ethyl acetate and 100 mL of 1N hydrochloric acid water were added to the reaction mixture, and the aqueous layer was removed.
  • the organic layer was washed successively with 100 mL of aqueous sodium hydrogen carbonate solution, 100 mL of water and 100 mL of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the first reaction is performed by, for example, Journal of Organic Chemistry, 1992, 57, p. 5899-5907
  • the second reaction is described, for example, in Biomacromolecules, 2010, 11, p. In 2415-2421
  • the third reaction is described in, for example, Tetrahedron, 1994, 50, p. 5361-5368.
  • the organic layer was washed successively with 10% aqueous sodium chloride solution (twice), 1N aqueous hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the synthesis was performed by reacting (2R, 3R, 4R) -1,3,4-tripropoxy-5-oxopentan-2-yl methanesulfonate with a 15% aqueous sodium hydrogen sulfide solution as follows.
  • the synthesis was carried out by reacting (2R, 3R, 4R) -1,3,4-tributoxy-5-oxopentan-2-yl methanesulfonate with a 15% aqueous sodium hydrogen sulfide solution as follows.
  • the synthesis was performed by reacting (2S, 3S, 4S) -1,3,4-tributoxy-5-oxopentan-2-yl methanesulfonate with a 15% aqueous sodium hydrogen sulfide solution as follows.
  • the synthesis was performed by reacting (2S, 3R, 4R) -1,3,4-tributoxy-5-oxopentan-2-yl methanesulfonate with a 15% aqueous sodium hydrogen sulfide solution as follows.
  • the synthesis was performed by reacting (2S, 3R, 4S) -1,3,4-tributoxy-5-oxopentan-2-yl methanesulfonate with a 15% aqueous sodium hydrogen sulfide solution as follows.
  • Examples 6 to 10 are the corresponding 3,4-dialkoxy-5-alkoxymethyloxolane-2-o according to conditions known in the literature or similar conditions as in the route described in Example 4. This was obtained by synthesizing the corresponding 1,3,4-trialkoxy-5-oxoalkane-2-yl methanesulfonate by the same method as in Example 5.
  • the synthesis was performed by reacting (2R, 3S, 4S) -4-bromo-2,3,5-tributoxypentanal with a 15% aqueous sodium hydrogen sulfide solution as follows.
  • a thionucleoside expected as a useful physiologically active substance can be synthesized by a known technique or a method according thereto.
  • the method for producing the compound represented by the general formula (II) of the present invention and the compound represented by the general formula (II) of the present invention are useful.

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Abstract

　L'invention concerne un composé et un procédé de fabrication d'un composé représenté par la formule générale (II), et obtenu par une étape de mise en réaction d'un composé représenté par la formule générale (I) avec un composé sulfuré.　Dans les formules générales (I) et (II): R1 représente un atome d'hydrogène, un groupe alkyle ou un groupe acyle; R2 représente -O-R2a ou un atome de fluor; R2' représente -O-R2a, un atome de fluor ou =O. Ici, R2a représente un atome d'hydrogène, - CH2R2b ou un groupe acyle. R2b, R3 et R5 représentent un atome d'hydrogène, un groupe alkyle, un groupe vinyle ou un groupe aryle, et X représente un groupe partant. Ici, la liaison atomique à partir de R2' vers le cycle thiolane représente une liaison unique ou une liaison double.
PCT/JP2015/054306 2014-02-18 2015-02-17 Procédé de production d'un composé saccharidique de type à squelette de thiolane ainsi que composé saccharidique de type à squelette de thiolane WO2015125782A1 (fr)

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