WO2015125781A1 - チオラン骨格型糖化合物の製造方法およびチオラン骨格型糖化合物 - Google Patents
チオラン骨格型糖化合物の製造方法およびチオラン骨格型糖化合物 Download PDFInfo
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- 0 *=C[C@]([C@]([C@](COC(c(cc1)ccc1-c1ccccc1)=O)O)OC(c(cc1)ccc1-c1ccccc1)=O)OC(c(cc1)ccc1-c1ccccc1)=O Chemical compound *=C[C@]([C@]([C@](COC(c(cc1)ccc1-c1ccccc1)=O)O)OC(c(cc1)ccc1-c1ccccc1)=O)OC(c(cc1)ccc1-c1ccccc1)=O 0.000 description 12
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- WPPGXQZWWLNDAZ-AUJHIJEMSA-N COC([C@H]1OC(c(cc2)ccc2-c2ccccc2)=O)O[C@@H](COC(c(cc2)ccc2-c2ccccc2)=O)[C@@H]1OC(c(cc1)ccc1-c1ccccc1)=O Chemical compound COC([C@H]1OC(c(cc2)ccc2-c2ccccc2)=O)O[C@@H](COC(c(cc2)ccc2-c2ccccc2)=O)[C@@H]1OC(c(cc1)ccc1-c1ccccc1)=O WPPGXQZWWLNDAZ-AUJHIJEMSA-N 0.000 description 1
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- KBBIRIROVCTCST-QGBCWPEESA-N CS(O[C@@H](COC(c1cc(cccc2)c2cc1)=O)[C@@H]([C@H](C=O)OC(c1cc2ccccc2cc1)=O)OC(c1cc2ccccc2cc1)=O)(=O)=O Chemical compound CS(O[C@@H](COC(c1cc(cccc2)c2cc1)=O)[C@@H]([C@H](C=O)OC(c1cc2ccccc2cc1)=O)OC(c1cc2ccccc2cc1)=O)(=O)=O KBBIRIROVCTCST-QGBCWPEESA-N 0.000 description 1
- NPSJHLBWKNFPPU-KWXIBIRDSA-N Cc(cc1)ccc1C(OC[C@@H]([C@@H]([C@@H](C=O)OC(c1ccc(C)cc1)=O)OC(c1ccc(C)cc1)=O)OS(C)(=O)=O)=O Chemical compound Cc(cc1)ccc1C(OC[C@@H]([C@@H]([C@@H](C=O)OC(c1ccc(C)cc1)=O)OC(c1ccc(C)cc1)=O)OS(C)(=O)=O)=O NPSJHLBWKNFPPU-KWXIBIRDSA-N 0.000 description 1
- MZUWXJCUSAZDMP-QWHCGFSZSA-N Cc(cc1)ccc1C(OC[C@H](C=C1)O[C@H]1OC)=O Chemical compound Cc(cc1)ccc1C(OC[C@H](C=C1)O[C@H]1OC)=O MZUWXJCUSAZDMP-QWHCGFSZSA-N 0.000 description 1
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- GAKJJSAXUFZQTL-ZAKLUEHWSA-N NC(C=CN1[C@@H]([C@@H]2O)S[C@@H](CO)[C@@H]2O)=NC1=O Chemical compound NC(C=CN1[C@@H]([C@@H]2O)S[C@@H](CO)[C@@H]2O)=NC1=O GAKJJSAXUFZQTL-ZAKLUEHWSA-N 0.000 description 1
- RDPSEHUWZIZIMP-JEBCDFCZSA-N NC(C=CN1[C@@H]([C@@H]2OC(c(cc3)ccc3-c3ccccc3)=O)S[C@@H](COC(c(cc3)ccc3-c3ccccc3)=O)[C@@H]2OC(c(cc2)ccc2-c2ccccc2)=O)=NC1=O Chemical compound NC(C=CN1[C@@H]([C@@H]2OC(c(cc3)ccc3-c3ccccc3)=O)S[C@@H](COC(c(cc3)ccc3-c3ccccc3)=O)[C@@H]2OC(c(cc2)ccc2-c2ccccc2)=O)=NC1=O RDPSEHUWZIZIMP-JEBCDFCZSA-N 0.000 description 1
- PDPPKLQTDRKBMB-HMVVSKLPSA-N O=C(c(cc1)ccc1-c1ccccc1)OC[C@@H]([C@@H]1OC(c(cc2)ccc2-c2ccccc2)=O)OC[C@H]1OC(c(cc1)ccc1-c1ccccc1)=O Chemical compound O=C(c(cc1)ccc1-c1ccccc1)OC[C@@H]([C@@H]1OC(c(cc2)ccc2-c2ccccc2)=O)OC[C@H]1OC(c(cc1)ccc1-c1ccccc1)=O PDPPKLQTDRKBMB-HMVVSKLPSA-N 0.000 description 1
- GFSOUIYUWLYVNT-QGZVFWFLSA-N O=CCC[C@H](COC(c(cc1)ccc1-c1ccccc1)=O)Br Chemical compound O=CCC[C@H](COC(c(cc1)ccc1-c1ccccc1)=O)Br GFSOUIYUWLYVNT-QGZVFWFLSA-N 0.000 description 1
- KRKFCCPCJACZNF-ZOFHGUTNSA-N OC([C@H]1OC(c(cc2)ccc2-c2ccccc2)=O)O[C@@H](COC(c(cc2)ccc2-c2ccccc2)=O)[C@@H]1OC(c(cc1)ccc1-c1ccccc1)=O Chemical compound OC([C@H]1OC(c(cc2)ccc2-c2ccccc2)=O)O[C@@H](COC(c(cc2)ccc2-c2ccccc2)=O)[C@@H]1OC(c(cc1)ccc1-c1ccccc1)=O KRKFCCPCJACZNF-ZOFHGUTNSA-N 0.000 description 1
- OUIVYQLWUFSIBI-AEKUSUEZSA-N OC[C@@H]([C@H]([C@@H](COC(c(cc1)ccc1-c1ccccc1)=O)Br)OC(c(cc1)ccc1-c1ccccc1)=O)OC(c(cc1)ccc1-c1ccccc1)=O Chemical compound OC[C@@H]([C@H]([C@@H](COC(c(cc1)ccc1-c1ccccc1)=O)Br)OC(c(cc1)ccc1-c1ccccc1)=O)OC(c(cc1)ccc1-c1ccccc1)=O OUIVYQLWUFSIBI-AEKUSUEZSA-N 0.000 description 1
Classifications
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- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
-
- 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
- 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
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 or an acyl group
- R 2 represents a hydrogen atom, a fluorine atom, an acyloxy group, an arylmethyloxy group, an allyloxy group, an arylmethyloxycarbonyloxy group.
- R 3 represents a hydrogen atom or an acyloxy group
- R 5 represents an alkyl group or an aryl group
- X represents a leaving group.
- R 2 is a fluorine atom, an acyloxy group, an arylmethyloxy group, an allyloxy group, an arylmethyloxycarbonyloxy group or an allyloxycarbonyloxy group
- R 3 is an acyloxy group.
- R 1 and R 5 have the same meanings as R 1 and R 5 in the general formula (II).
- R 2a and R 3a each independently represents an alkyl group or an aryl group.
- R 2b represents —CH 2 —Ar, an allyl group, —C ( ⁇ O) OCH 2 —Ar, or an allyloxycarbonyl group.
- Ar represents an aryl group. Note that a broken-line bond having a constant thickness that is bonded to the thiolane ring is located on either the ⁇ side or the ⁇ side.
- R 5 is an aryl group
- R 3 or —O—C ( ⁇ O) —R 3a is an arylcarbonyloxy group.
- R 5 is a phenyl group, a 4-methylphenyl group, a 4-phenylphenyl group or a 2-naphthyl group
- R 3 or —O—C ( ⁇ O) —R 3a is a phenylcarbonyloxy group
- R 2, R 3 and R 5 have the same meanings as R 2, R 3 and R 5 in the general formula (II).
- R 1a represents an acyl group.
- R 1 or R 1a is an acetyl group or an arylcarbonyl group.
- X is a halogen atom, an alkylsulfonyloxy group, or an arylsulfonyloxy group.
- R 1 represents a hydrogen atom or an acyl group
- R 2a and R 3a each independently represents an alkyl group or an aryl group
- R 5 represents an alkyl group or Represents an aryl group
- R 2b represents —CH 2 —Ar, an allyl group, —C ( ⁇ O) OCH 2 —Ar, or an allyloxycarbonyl group.
- Ar represents an aryl group. Note that a broken-line bond having a constant thickness that is bonded to the thiolane ring is located on either the ⁇ side or the ⁇ side.
- R 1 is a hydrogen atom, an acetyl group, or an arylcarbonyl group
- R 2a , R 3a, and R 5 are each independently an aryl group.
- R 2a , R 3a and R 5 are each independently a phenyl group, a 4-methylphenyl group, a 4-phenylphenyl group or a 2-naphthyl group.
- R 1 , R 1b and R 1c each independently represent a hydrogen atom or an acyl group.
- R 2a and R 3a each independently represents an alkyl group or an aryl group.
- R 2b represents —CH 2 —Ar, an allyl group, —C ( ⁇ O) OCH 2 —Ar, or an allyloxycarbonyl group.
- Ar represents an aryl group.
- R 5 , R 5b , R 5c , R 5d and R 5e each independently represents an alkyl group or an aryl group. However, when R 1b and R 1c are acetyl groups, R 5b is an aryl group, and R 5c is an aryl group substituted with an alkyl group or a substituent.
- R 1 is a hydrogen atom, an acetyl group, a 4-methylbenzoyl group, a 4-phenylbenzoyl group or a 2-naphthoyl group
- R 1b and R 1c are each independently a hydrogen atom, a 4-methylbenzoyl group, 4-phenylbenzoyl group or 2-naphthoyl group
- R 2a , R 3a , R 5 , R 5b and R 5c are each independently a 4-methylphenyl group, a 4-phenylphenyl group or a 2-naphthyl group
- R 2b is a phenylmethyl group
- R 5d and R 5e are each independently a phenyl group, a 4-methylphenyl group, a 4-phenylphenyl group, or a 2-naphthyl group.
- each substituent may be further substituted with a substituent unless otherwise specified.
- a production method for producing a thionucleoside synthesis intermediate in a simple and high yield under mild conditions a production capable of synthesizing a compound having a thiosugar skeleton with few steps A method can be provided. Furthermore, it is possible to provide a thiolane skeleton type sugar compound useful as a thionucleoside synthesis intermediate exhibiting antiviral activity or antitumor activity, or a compound of the synthesis intermediate thereof.
- 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. It goes through the process of making it.
- R 1 represents a hydrogen atom or an acyl group
- R 2 represents a hydrogen atom, a fluorine atom, an acyloxy group, an arylmethyloxy group, an allyloxy group, an arylmethyloxycarbonyloxy group.
- R 3 represents a hydrogen atom or an acyloxy group
- R 5 represents an alkyl group or an aryl group
- X represents a leaving group.
- R 2 is a fluorine atom, an acyloxy group, an arylmethyloxy group, an allyloxy group, an arylmethyloxycarbonyloxy group or an allyloxycarbonyloxy group
- R 3 is an acyloxy group.
- R 2 , R 3 and CH 2 —O—C ( ⁇ O) —R 5 in the general formulas (I) and (II) is an asymmetric carbon atom
- R 2 , R 3 and The configuration substituted by CH 2 —O—C ( ⁇ O) —R 5 is substantially either R or S on each asymmetric carbon atom.
- R 2 is substantially located on either the ⁇ side or the ⁇ side
- R 3 is substantially located on either the ⁇ side or the ⁇ side
- CH 2 —O—C ( ⁇ O) —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. It means that the step of acylating the compound synthesized in the step of reacting the compound with a sulfur compound may be included.
- R 1 in the general formula (II) is a hydrogen atom, it can be produced only by the step of reacting the compound represented by the general formula (I) with a sulfur compound.
- R 1 is an acyl group, after the step of reacting a sulfur compound, it can be prepared by carrying out the step of acylation. In the present invention, it is preferable to acylate the OH form obtained by the reaction with the sulfur compound.
- 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 (IIB).
- R 2, R 3 and R 5 have the same meanings as R 2, R 3 and R 5 in the general formula (II).
- R 1a represents an acyl group.
- the compound represented by the general formula (II) in the present invention has 2 to 4 asymmetric carbon atoms as carbon atoms constituting the thiolane ring which is a basic skeleton. Specifically, when R 2 and R 3 are hydrogen atoms, there are 2 asymmetric carbon atoms, when one of R 2 or R 3 is a hydrogen atom, 3 asymmetric carbon atoms, otherwise It has 4 asymmetric carbon atoms.
- the term “sterically controlled” means that a compound represented by the general formula (II) is produced by setting the configuration present in an asymmetric carbon atom to a specific configuration.
- R 1 , R 5 and X have the same meanings as R 1, R 5 and X in the general formula (I) and (II).
- R 2a and R 3a each independently represents an alkyl group or an aryl group.
- 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 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.
- 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.
- acylating agent used in the step of acylating the compound represented by the general formula (IIA) examples include acyl halides and acid anhydrides.
- R 1a in the acylating agent an acyl unit and the general formula (IIB) compounds represented by is the same meaning as the acyl group for R 1 described below, the preferred range is also the same.
- acylating agents are preferably 0.5 to 10 times mol, more preferably 0.8 to 5 times mol, and further preferably 1 to 2 times mol based on 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. These solvents may be used as a mixture.
- 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 0.2 to 5 moles compared to the compound represented by the general formula (IIA).
- the reaction temperature is preferably ⁇ 20 to 100 ° C., more preferably ⁇ 10 to 80 ° C., and further preferably 0 to 50 ° 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 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 or an acyl group
- R 2 represents a hydrogen atom, a fluorine atom, an acyloxy group, an arylmethyloxy group, an allyloxy group, an arylmethyloxycarbonyloxy group, or an allyloxycarbonyl.
- R 3 represents a hydrogen atom or an acyloxy group
- R 5 represents an alkyl group or an aryl group.
- R 2 is a fluorine atom, an acyloxy group, an arylmethyloxy group, an allyloxy group, an arylmethyloxycarbonyloxy group or an allyloxycarbonyloxy group
- R 3 is an acyloxy group.
- R 2 is substantially located on either the ⁇ side or the ⁇ side
- R 3 is substantially located on either the ⁇ side or the ⁇ side
- CH 2 —O—C ( ⁇ O) —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.
- the number of carbon atoms of the acyl group in R 1 is preferably 1-20, more preferably 2-20, and even more preferably 2-16.
- 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, and 4-methylbenzoyl, 4-phenylbenzoyl or 2-naphthoyl is preferable.
- 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 1 is preferably a hydrogen atom, an acetyl group or an arylcarbonyl group.
- Examples of the acyl moiety of the acyloxy group in R 2 and R 3 include the acyl moieties exemplified for the acyl group in R 1 .
- the alkyl group in R 5 preferably has 1 to 19 carbon atoms, and the aryl group preferably has 6 to 19 carbon atoms, and more preferably 6 to 15 carbon atoms.
- 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.
- alkyl group examples include methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, n-hexyl, 2-ethylhexyl, dodecyl and octadecyl.
- aryl group examples include phenyl, 4-chlorophenyl, 4-methylphenyl, 4-phenylphenyl and 2-naphthyl.
- the acyloxy group in R 3 and the acyloxy group represented by —O—C ( ⁇ O) —R 5 in the 5-position are benzoyloxy, 4-methylbenzoyl, 4-chlorobenzoyl, 4-phenylbenzoyl or 2-naphthoyl. preferable.
- the number of carbon atoms of the arylmethyloxy group in R 2 is preferably 7-20, more preferably 7-16, such as phenylmethyloxy, 4-chlorophenylmethyloxy, 4-methylphenylmethyloxy, 4-phenylphenylmethyloxy and 2-naphthylmethyloxy is mentioned.
- the arylmethyloxycarbonyloxy group in R 2 preferably has 8 to 21 carbon atoms, more preferably 8 to 17 carbon atoms such as phenylmethyloxycarbonyloxy, 4-chlorophenylmethyloxycarbonyloxy, 4-methylphenylmethyloxycarbonyloxy 4-phenylphenylmethyloxycarbonyloxy and 2-naphthylmethyloxycarbonyloxy.
- R 2 is preferably a hydrogen atom, a fluorine atom, an acyloxy group or an arylmethyloxy group.
- R 5 is preferably an aryl group, and R 3 is preferably an arylcarbonyloxy group.
- R 5 is more preferable that R 5 is an aryl group and R 3 is an arylcarbonyloxy group, and R 5 is a phenyl group, a 4-methylphenyl group, a 4-phenylphenyl group or 2 More preferably, it is a naphthyl group and R 3 is a phenylcarbonyloxy group, a 4-methylphenylcarbonyloxy group, a 4-phenylphenylcarbonyloxy group or a 2-naphthylcarbonyloxy group.
- 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-14).
- R 1 and R 5 have the same meanings as R 1 and R 5 in general formula (II), and the preferred ranges are also the same.
- R 2a and R 3a each independently represents an alkyl group or an aryl group.
- R 2b represents —CH 2 —Ar, an allyl group, —C ( ⁇ O) OCH 2 —Ar, or an allyloxycarbonyl group.
- Ar represents an aryl group. Note that a broken-line bond having a constant thickness that is bonded to the thiolane ring is substantially located on either the ⁇ side or the ⁇ side.
- the compounds represented by the general formulas (II-1), (II-2) and (II-4) to (II-7) having a bond having a constant thickness and bonded to the thiolane ring are as follows: In general formulas (II-1A), (II-1B), (II-2A), (II-2B), (II-4A) to (II-7A) and (II-4B) to (II-7B) expressed.
- R 2a and R 3a are synonymous with the alkyl group and aryl group in R 5 , and the preferred range is also the same.
- R 2a and R 3a are preferably each independently an aryl group.
- the aryl group in Ar is synonymous with the aryl group in R ⁇ 5 > of general formula (II), and its preferable range is also the same.
- R 2b is preferably —CH 2 —Ar, more preferably a phenylmethyl group.
- R 5 is preferably an aryl group
- R 3a is preferably an aryl group
- R 5 is an aryl group
- R 3a is an aryl group. More preferred.
- R 5 is a phenyl group, a 4-methylphenyl group, a 4-phenylphenyl group or a 2-naphthyl group
- R 3a is a phenyl group, a 4-methylphenyl group, a 4-phenylphenyl group or a 2-naphthyl group
- R 5 is preferably an aryl group.
- R 1 is preferably a hydrogen atom, an acetyl group or an arylcarbonyl group, and R 2a , R 3a and R 5 are each independently preferably an aryl group, and R 1 Is more preferably a compound in which is a hydrogen atom, an acetyl group or an arylcarbonyl group, and R 2a , R 3a and R 5 are each independently an aryl group. More preferred are compounds wherein R 2a , R 3a and R 5 are each independently a phenyl group, a 4-methylphenyl group, a 4-phenylphenyl group or a 2-naphthyl group.
- R 1b and R 1c represent a hydrogen atom or an acyl group.
- R 5b , R 5c , R 5d and R 5e each represents an alkyl group or an aryl group. However, when R 1b and R 1c are acetyl groups, R 5b is an aryl group, and R 5c is an aryl group substituted with an alkyl group or a substituent.
- the acyl group in R 1b and R 1c is synonymous with the acyl group in general formula (II), and the preferred range is also the same.
- the alkyl group and aryl group in R 5b , R 5c , R 5d and R 5e have the same meaning as R 5 in formula (II), and the preferred range is also the same.
- the acyl group is preferably an arylcarbonyl group, and the aryl part of the arylcarbonyl group is also preferably an aryl part substituted with a substituent.
- substituent for substituting the aryl moiety examples include the aforementioned halogen atom, alkyl group, aryl group, heterocyclic group, alkoxy group, aryloxy group, alkylthio group, and arylthio group.
- the halogen atom, alkyl group, or aryl group is Preferably, an alkyl group or an aryl group is more preferable, and a methyl group or a phenyl group is further preferable.
- R 1b and R 1c are also preferably a 2-naphthylcarbonyl group.
- R 1 is a hydrogen atom, an acetyl group, a 4-methylbenzoyl group, a 4-phenylbenzoyl group or a 2-naphthoyl group
- R 1b and R 1c is a hydrogen atom, 4-methylbenzoyl group, 4-phenylbenzoyl group or 2-naphthoyl group
- R 2a , R 3a , R 5 , R 5b and R 5c are each independently a 4-methylphenyl group, 4-phenylphenyl group or 2-naphthyl group
- R 2b is phenylmethyl group
- R 5d and R 5e are phenyl group, 4-methylphenyl group, 4-phenylphenyl
- 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 2a, R 2b, R 3a and R 5 has the general formula (II-1) R 2a in ⁇ (II-14), R 2b, R 3a And R 5 , 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 compound represented by the following general formula (i) is a compound included in the general formula (I-1B), and can be synthesized by the following synthesis scheme.
- R 2a, R 3a and R 5 have the general formula (I-1B) R 2a in the same meaning as R 3a and R 5, the preferred range is also the same.
- the compound represented by the general formula (e) is converted to an oxime compound represented by the general formula (f) with O-methylhydroxylamine, and then converted to the general formula (g) with 2,4,5-trichlorobenzenesulfonyl chloride. Is synthesized.
- the compound represented by the general formula (g) is reacted with lithium bromide to synthesize the compound represented by the general formula (h).
- the oxime is converted to an aldehyde to synthesize a compound represented by the general formula (i).
- the compound represented by the general formula (II) is 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or 1- (4-thio) useful as an antitumor agent.
- - ⁇ -D-arabinofuranosyl) cytosine and its peripheral compounds are useful compounds.
- Examples of the use of the compound represented by the general formula (II) include a compound represented by the general formula (V).
- the thionucleoside represented by the general formula (V) is represented by the general formula (IV) directly from the compound represented by the general formula (II) or via the compound represented by the general formula (III).
- Compounds can be synthesized and synthesized by deprotection. That is, the compound represented by the general formula (V) can be synthesized 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 have the same meanings as R 2, R 3 and R 5 in formula (II), and their preferable ranges are also the same.
- X 1 represents a halogen atom (preferably a bromine atom).
- R 2, R 3 and R 5 have the same meanings as R 2, R 3 and R 5 in formula (II), and their preferable ranges are also the same.
- B ′ represents a nucleobase or a group obtained by protecting an amino group in a nucleobase with an acyl group.
- R 2 'and R 3' represents the general formula (II)
- R 2 is acyloxy, arylmethyloxycarbonyl group, allyloxycarbonyl group, arylmethyl group or an allyloxy group
- R 3 represents an acyloxy group, it represents a hydroxy group, and otherwise, it has the same meaning as R 2 and R 3 in formula (II).
- 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).
- nucleobases in the general formulas (IV) and (V) are adenine which may be substituted, guanine which may be substituted, cytosine which may be substituted, thymine which may be substituted or substituted. It means good uracil and represents the following groups, for example.
- * shows the part couple
- the compound represented by the general formula (III) can be synthesized by halogenating the compound represented by the general formula (II).
- the compound represented by the general formula (IV) 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) or (III), It can be synthesized by introducing a group protector.
- the amino group may be acylated to improve the crystallinity for purification.
- the thionucleoside represented by the general formula (V) can be synthesized by deprotecting the compound represented by the general formula (IV). This method is described, for example, in Protective Groups in Organic Synthesis, 4th edition, pages 696-926 (2007), John Willy & Sons (John Wiley & Sons. INC).
- the organic layer was washed successively with 750 mL of 10% aqueous sodium hydrogen carbonate solution, 750 mL of water and 750 mL of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate.
- the organic layer was washed with a 10% sodium chloride aqueous solution three times, once with a sodium hydrogen carbonate aqueous solution once, and then with a saturated sodium chloride aqueous solution three times, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
- microwave reactor Initiator Sixty (trade name, manufactured by Biotage)
- (2R, 3R, 4R) -4-Bromo-1-oxo-3,5-bis ((naphthalen-2-yl) carbonyloxy) pentan-2-yl naphthalene-2-carboxylate is prepared as follows. (3R, 4R, 5S) -2-hydroxy-4-((naphthalen-2-yl) carbonyloxy) -5-((((naphthalen-2-yl) carbonyloxy) methyl) reacted with 15% sodium hydrogen sulfide ) Thioran-3-yl naphthalene-2-carboxylate was obtained and further synthesized by reacting with (naphthalen-2-yl) carbonyl chloride.
- the organic layer was washed with a 10% sodium chloride aqueous solution three times, once with a sodium hydrogen carbonate aqueous solution once, and then with a saturated sodium chloride aqueous solution three times, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
- the organic layer was washed with a 10% sodium chloride aqueous solution three times, once with a sodium hydrogen carbonate aqueous solution once, and then with a saturated sodium chloride aqueous solution three times, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
- the organic layer was washed with a 10% sodium chloride aqueous solution three times, once with a sodium hydrogen carbonate aqueous solution once, and then with a saturated sodium chloride aqueous solution three times, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
- the organic layer was washed with a 10% sodium chloride aqueous solution three times, once with a sodium hydrogen carbonate aqueous solution once, and then with a saturated sodium chloride aqueous solution three times, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
- (2R, 3R, 4S) -4- (Methanesulfonyloxy) -1-oxo-3,5-bis ((naphthalen-2-yl) carbonyloxy) pentan-2-yl naphthalene-2 was prepared as follows. -Carboxylate is reacted with 15% sodium hydrogen sulfide to give (3R, 4R, 5R) -2-hydroxy-4-((naphthalen-2-yl) carbonyloxy) -5-(((naphthalen-2-yl) Carbonyloxy) methyl) thiolan-3-yl naphthalene-2-carboxylate was obtained and further synthesized by reacting (naphthalen-2-yl) carbonyl chloride.
- the organic layer was washed with a 10% sodium chloride aqueous solution three times, once with a sodium hydrogen carbonate aqueous solution once, and then with a saturated sodium chloride aqueous solution three times, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
- reaction mixture was distilled off under reduced pressure, 1000 mL of toluene was added, and the organic layer was washed successively with 500 mL of water, 500 mL of saturated aqueous sodium hydrogen carbonate solution, 500 mL of water and 200 mL of saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure to give (2R, 3R, 4R) -4-hydroxy-5-methoxy-2-((4-methylbenzoyloxy) methyl) oxolan-3-yl 4-methylbenzoate as a colorless oil. 215 g of crude product was obtained. This crude product was used in the next step without purification. As a result of measuring 1 H-NMR, it was an anomeric mixture of about 59:41.
- (2S) -5- (methoxyimino) -2-((2,4,5-trichlorobenzenesulfonyl) oxy) pentyl 4-methylbenzoate 0.67 g of 1,3-dimethyl-2-imidazolidinone 2.6 mL
- 0.23 g of lithium bromide was added in three portions at room temperature, and the mixture was stirred at 40 ° C. for 2 hours.
- the reaction mixture was purified by silica gel column chromatography to obtain 0.41 g of (2R) -2-bromo-5- (methoxyimino) pentyl 4-methylbenzoate as a colorless oil.
- (2R) -2-bromo-5-oxopentyl 4-phenylbenzoate was synthesized by reacting with an aqueous solution of sodium hydrogen sulfide.
- (2S) -2-Hydroxy-5- (methoxyimino) pentyl 4-phenylbenzoate 0.26 g of acetonitrile, 0.24 g of 2,4,5-trichlorobenzenesulfonyl chloride and 96 ⁇ L of N-methylimidazole were added at room temperature And stirred for 135 minutes at room temperature. Then, 0.14 g of 2,4,5-trichlorobenzenesulfonyl chloride and 96 ⁇ L of N-methylimidazole were added and stirred for 75 minutes. Ethyl acetate and water were added to the reaction mixture, the insoluble material was filtered off, and the organic layer was separated.
- (2S) -5- (methoxyimino) -2-((2,4,5-trichlorobenzenesulfonyl) oxy) pentyl 4-phenylbenzoate 0.35 g in 1,3-dimethyl-2-imidazolidinone 2 mL solution Then, 0.11 g of lithium bromide was added at room temperature, and the mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was purified by silica gel column chromatography to obtain 0.18 g of (2R) -2-bromo-5- (methoxyimino) pentyl 4-phenylbenzoate as a colorless oil.
- (2S) -2-Hydroxy-5-((tris (propan-2-yl) silyl) oxy) pentyl benzoate 2.98 g and triethylamine 4.5 mL in 60 mL ethyl acetate at 0-10 ° C. 24 mL was added dropwise and stirred at room temperature for 30 minutes. Ethyl acetate and a saturated aqueous sodium chloride solution were added to the reaction mixture, and the organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
- (2S) -2- (Methanesulfonyloxy) -5-((tris (propan-2-yl) silyl) oxy) pentylbenzoate 3.41 g of methanol 40 mL of p-toluenesulfonic acid monohydrate 0.70 g Added and stirred at room temperature for 1 hour. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
- (2S) -5-Hydroxy-2- (methanesulfonyloxy) pentyl benzoate 1.84 g of 1,4-triacetoxy-1,1-dihydro-1,2-benziodoxol 3.9 g of 3 (1H) -one (Dess-Martin periodinane) was added and stirred at room temperature for 1 hour.
- Ethyl acetate, saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes.
- (2S) -2- (methanesulfonyloxy) -5-oxopentyl 4-phenylbenzoate was synthesized by reacting with an aqueous solution of sodium hydrogen sulfide.
- (2S) -2-Hydroxy-5- (methoxyimino) pentyl 4-phenylbenzoate 1.0 g of methanesulfonyl chloride 0.46 mL was added dropwise at 0 to 10 ° C. to a mixed solution of 20 g of ethyl acetate and 1.67 mL of triethylamine at room temperature. For 100 minutes. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.39 g of (2S) -2- (methanesulfonyloxy) -5- (methoxyimino) pentyl 4-phenylbenzoate as a colorless oil.
- (2S) -2- (Methanesulfonyloxy) -5- (methoxyimino) pentyl 4-phenylbenzoate 1.39 g of acetone in 15 mL solution was added with 37% formaldehyde aqueous solution 2.4 mL and 9% hydrochloric acid 0.1 mL at room temperature. And stirred for 60 minutes at room temperature. Subsequently, 5 mL of 37% formaldehyde aqueous solution was added and stirred for 70 minutes. Subsequently, 5 mL of 37% formaldehyde aqueous solution was added and stirred for 30 minutes.
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Abstract
Description
例えば、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンは、優れた抗腫瘍活性を有し、腫瘍治療剤として有用であることが知られている(特許文献1参照)。
そのため、チオヌクレオシドを合成するルートおよび合成中間体の研究が盛んに行われている。
このうち、チオラン環を形成する反応も多く検討され、提案されている(例えば、特許文献2~8参照)。
一方、糖化合物ではないものの、ベンゾテトラヒドロチオフェン環の合成(特許文献8参照)や、イミノ糖の合成反応(特許文献9、非特許文献1参照)も知られている。
従って、本発明では、チオラン環を形成する反応において、穏和な条件で、簡便、かつ高収率で、チオヌクレオシド合成中間体を製造する製造方法、少ない工程で、チオ糖骨格を有する化合物を合成できる製造方法を提供することを課題とする。
さらには、抗ウイルス活性または抗腫瘍活性を示すチオヌクレオシド合成中間体として有用なチオラン骨格型糖化合物もしくはその合成中間体の化合物を提供することを課題とする。
<1>下記一般式(I)で表される化合物を硫黄化合物と反応させる工程を経由する下記一般式(II)で表される化合物の製造方法。
ただし、R2がフッ素原子、アシルオキシ基、アリールメチルオキシ基、アリルオキシ基、アリールメチルオキシカルボニルオキシ基またはアリルオキシカルボニルオキシ基の場合、R3はアシルオキシ基である。
<2>一般式(II)で表される化合物が、下記一般式(II-1)~(II-14)のいずれかで表される<1>に記載の製造方法。
<3>R5がアリール基であり、かつR3または-O-C(=O)-R3aがアリールカルボニルオキシ基である<1>または<2>に記載の製造方法。
<4>R5が、フェニル基、4-メチルフェニル基、4-フェニルフェニル基または2-ナフチル基であり、かつR3または-O-C(=O)-R3aがフェニルカルボニルオキシ基、4-メチルフェニルカルボニルオキシ基、4-フェニルフェニルカルボニルオキシ基もしくは2-ナフチルカルボニルオキシ基である<1>~<3>のいずれか1つに記載の製造方法。
<5>一般式(I)で表される化合物を硫黄化合物と反応させる工程で、下記一般式(IIA)で表される化合物を合成した後、一般式(IIA)で表される化合物をアシル化する工程で、下記一般式(IIB)で表される化合物を合成する<1>~<4>のいずれか1つに記載の製造方法。
<6>R1またはR1aがアセチル基またはアリールカルボニル基である<1>~<5>のいずれか1つに記載の製造方法。
<7>Xが、ハロゲン原子、アルキルスルホニルオキシ基またはアリールスルホニルオキシ基である<1>~<6>のいずれか1つに記載の製造方法。
<8>硫黄化合物が、Mがアルカリ金属であるMSHまたはM2Sである<1>~<7>のいずれか1つに記載の製造方法。
<9>下記一般式(II-1)~(II-14)のいずれかで表される化合物。
<10>R1が、水素原子、アセチル基またはアリールカルボニル基であり、R2a、R3aおよびR5が各々独立に、アリール基である<9>に記載の化合物。
<11>R2a、R3aおよびR5が各々独立に、フェニル基、4-メチルフェニル基、4-フェニルフェニル基または2-ナフチル基である<9>または<10>に記載の化合物。
<12>下記一般式(II-1A’)、(II-1B)、(II-2A)、(II-2B’)、(II-3)、(II-6B)、(II-9)、(II-13’)または(II-14’)のいずれかで表される化合物。
<13>R1が水素原子、アセチル基、4-メチルベンゾイル基、4-フェニルベンゾイル基または2-ナフトイル基であり、R1bおよびR1cが各々独立に、水素原子、4-メチルベンゾイル基、4-フェニルベンゾイル基または2-ナフトイル基であり、R2a、R3a、R5、R5bおよびR5cが各々独立に、4-メチルフェニル基、4-フェニルフェニル基または2-ナフチル基であり、R2bが、フェニルメチル基であり、R5dおよびR5eが各々独立に、フェニル基、4-メチルフェニル基、4-フェニルフェニル基または2-ナフチル基である<12>に記載の化合物。
<14>化合物が、チオヌクレオシド合成中間体である<9>~<13>のいずれか1つに記載の化合物。
なお、「-O-C(=O)-R3aがアリールカルボニルオキシ基である」とは、-O-C(=O)-R3aが全体でアリールカルボニルオキシ基を表すことを意味する。すなわち、R3aがアリール基である。
さらには、抗ウイルス活性または抗腫瘍活性を示すチオヌクレオシド合成中間体として有用なチオラン骨格型糖化合物もしくはその合成中間体の化合物を提供することができる。
本発明の上記及び他の特徴及び利点は、下記の記載からより明らかになるであろう。
本発明のチオラン骨格型糖化合物の製造方法は、下記一般式(II)で表される立体制御された化合物の製造方法であり、下記一般式(I)で表される化合物を硫黄化合物と反応させる工程を経由する。
ただし、R2がフッ素原子、アシルオキシ基、アリールメチルオキシ基、アリルオキシ基、アリールメチルオキシカルボニルオキシ基またはアリルオキシカルボニルオキシ基の場合、R3はアシルオキシ基である。
一般式(II)におけるR1が水素原子の場合、一般式(I)で表される化合物を硫黄化合物と反応させる工程のみで製造することができる。
また、R1がアシル基の場合、硫黄化合物と反応させる工程の後に、アシル化する工程を実施することにより製造することができる。
なお、本発明では、硫黄化合物との反応で得られたOH体をアシル化することが好ましい。
本発明において、「立体制御された」とは、不斉炭素原子において存在する立体配置を特定の配置にして、一般式(II)で表される化合物を製造するものである。
好ましい溶媒は、部分構造にアミド部分またはスルホニル基を有する溶媒、すなわち、アミド類、環状アミド類、尿素類、環状尿素類またはスルホキシド類である。
具体的には、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチルピロリドン、N-エチルピロリドン、1,3-ジメチル-2-イミダゾリジノンおよびジメチルスルホキシドが挙げられる。
硫化水素の塩は、例えば、アルカリ金属塩およびアルカリ土類金属塩が挙げられる。
硫黄化合物は、Mがアルカリ金属であるMSHまたはM2Sが好ましい。
硫黄化合物は、例えば、硫化水素、硫化水素ナトリウム、硫化ナトリウム、硫化水素カリウム、硫化水素カルシウムおよび硫化マグネシウムが挙げられ、硫化水素ナトリウムが好ましい。
硫黄化合物は、水和物でもよく、水溶液に溶解させて使用することもできる。
反応時間は、5分間~50時間が好ましく、5分間~24時間がより好ましく、5分間~6時間がさらに好ましい。
なお、アシル化剤のアシル部および一般式(IIB)で表される化合物におけるR1aは、後述のR1におけるアシル基と同義であり、好ましい範囲も同じである。
また、塩基の使用量は、一般式(IIA)で表される化合物に対し、0.2~5倍モルが好ましい。
反応時間は、5分間~50時間が好ましく、10分間~24時間がより好ましく、30分間~6時間がさらに好ましい。
本発明のチオラン骨格型糖化合物は、前述の一般式(II)で表される化合物である。
一般式(II)において、R1は、水素原子またはアシル基を表し、R2は、水素原子、フッ素原子、アシルオキシ基、アリールメチルオキシ基、アリルオキシ基、アリールメチルオキシカルボニルオキシ基またはアリルオキシカルボニルオキシ基を表し、R3は水素原子またはアシルオキシ基を表し、R5は、アルキル基またはアリール基を表す。
ただし、R2がフッ素原子、アシルオキシ基、アリールメチルオキシ基、アリルオキシ基、アリールメチルオキシカルボニルオキシ基またはアリルオキシカルボニルオキシ基の場合、R3はアシルオキシ基である。
なお、一般式(II)において、R2は実質的にα側またはβ側のいずれか一方に位置し、R3は実質的にα側またはβ側のいずれか一方に位置し、かつ、CH2-O-C(=O)-R5は実質的にα側またはβ側のいずれか一方に位置する。
アルキルカルボニル基は、例えば、アセチル、プロピオニル、ブチリル、イソブチリル、バレリル、イソバレリル、ピバロイル、ラウロイル、ミリストイル、パルミトイルおよびステアロイルが挙げられる。なお、R1におけるアシル基はホルミルも含む。
アリールカルボニル基は、例えば、ベンゾイル、4-メチルベンゾイル、4-クロロベンゾイル、4-フェニルベンゾイルおよび2-ナフトイルが挙げられ、4-メチルベンゾイル、4-フェニルベンゾイルまたは2-ナフトイルが好ましい。
R5におけるアルキル基の炭素数は、1~19が好ましく、アリール基の炭素数は、6~19が好ましく、6~15がより好ましい。
アルキル基やアリール基は置換基を有していてもよく、例えば、ハロゲン原子、アルキル基、アリール基、ヘテロ環基、アルコキシ基、アリールオキシ基、アルキルチオ基およびアリールチオ基が挙げられる。
アルキル基は、例えば、メチル、エチル、イソプロピル、n-プロピル、n-ブチル、t-ブチル、n-ヘキシル、2-エチルヘキシル、ドデシルおよびオクタデシルが挙げられる。
アリール基は、例えば、フェニル、4-クロロフェニル、4-メチルフェニル、4-フェニルフェニルおよび2-ナフチルが挙げられる。
一般式(II)において、R5がアリール基であって、かつR3がアリールカルボニルオキシ基である場合がより好ましく、R5がフェニル基、4-メチルフェニル基、4-フェニルフェニル基または2-ナフチル基であって、かつR3がフェニルカルボニルオキシ基、4-メチルフェニルカルボニルオキシ基、4-フェニルフェニルカルボニルオキシ基または2-ナフチルカルボニルオキシ基である場合がさらに好ましい。
R2aおよびR3aは各々独立に、アリール基が好ましい。
R2bは-CH2-Arが好ましく、フェニルメチル基がより好ましい。
なお、一般式(II-13)および(II-14)においては、R5はアリール基が好ましい。
R2a、R3aおよびR5が各々独立に、フェニル基、4-メチルフェニル基、4-フェニルフェニル基または2-ナフチル基である化合物がさらに好ましい。
R5b、R5c、R5dおよびR5eにおけるアルキル基およびアリール基は、一般式(II)におけるR5と同義であり、好ましい範囲も同じである。
なお、R1bおよびR1cにおいて、アシル基は、アリールカルボニル基が好ましく、アリールカルボニル基のアリール部は、置換基で置換されたアリール部も好ましい。
アリール部を置換する置換基は、前述のハロゲン原子、アルキル基、アリール基、ヘテロ環基、アルコキシ基、アリールオキシ基、アルキルチオ基およびアリールチオ基等が挙げられ、ハロゲン原子、アルキル基またはアリール基が好ましく、アルキル基またはアリール基がより好ましく、メチル基またはフェニル基がさらに好ましい。
また、R1bおよびR1cは、2-ナフチルカルボニル基も好ましい。
一般式(I)で表される化合物のうち、一般式(II-1)~(II-14)で表される化合物を合成するための化合物は、下記一般式(I-1)~(I-14)で表される。
ハロゲン原子は、フッ素原子、塩素原子、臭素原子およびヨウ素原子が挙げられる。
アルキルスルホニルオキシ基における炭素数は1~10が好ましく、1~6がより好ましく、1~3がさらに好ましく、1が特に好ましい。
アルキルスルホニルオキシ基は、例えば、メチルスルホニルオキシ、エチルスルホニルオキシ、プロピルスルホニルオキシ、イソプロピルスルホニルオキシ、n-ブチルスルホニルオキシ、t-ブチルスルホニルオキシ、オクチルスルホニルオキシおよびドデシルスルホニルオキシが挙げられる。
アリールスルホニルオキシ基における炭素数は、6~16が好ましく、6~12がより好ましく、6~10がさらに好ましい。
アリールスルホニルオキシ基は、例えば、ベンゼンスルホニルオキシ、トルエンスルホニルオキシ、ナフチルスルホニルオキシ、4-クロロベンゼンスルホニルオキシおよび2,4,5-トリクロロベンゼンスルホニルオキシが挙げられる。
なお、一般式(I-1A)および(I-2)~(I-14)においても同様に、下記に示す離脱基を適用した化合物が挙げられる。
下記一般式(i)で表される化合物は、一般式(I-1B)に含まれる化合物であり、下記合成スキームで合成することができる。
一般式(II)で表される化合物は、抗腫瘍剤として有用な1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンや1-(4-チオ-β-D-アラビノフラノシル)シトシンおよびその周辺化合物の製造などに有用な化合物である。
一般式(V)で表されるチオヌクレオシドは、一般式(II)で表される化合物から直接もしくは一般式(III)で表される化合物を経由して、一般式(IV)で表される化合物を合成し、脱保護により合成できる。
すなわち、一般式(V)で表される化合物は、一般式(II)で表される化合物をシリル化された核酸塩基と反応させ、さらに、脱保護することで合成できる。
一般式(IV)において、R2、R3およびR5は一般式(II)におけるR2、R3およびR5と同義であり、好ましい範囲も同じである。B’は核酸塩基または核酸塩基中のアミノ基をアシル基で保護した基を表す。
一般式(V)において、R2’およびR3’は、一般式(II)においてR2がアシルオキシ基、アリールメチルオキシカルボニルオキシ基、アリルオキシカルボニルオキシ基、アリールメチルオキシ基もしくはアリルオキシ基を表す場合またはR3がアシルオキシ基を表す場合はヒドロキシ基を表し、それ以外の場合は、一般式(II)におけるR2およびR3と同義である。Bは核酸塩基を表す。
なお、B’-SiR3は、シリル化された核酸塩基または核酸塩基中のアミノ基をアシル化して保護した基を表し、Rはアルキル基(好ましくはメチル)を表す。
なお、*はチオラン環の1位に結合する部分を示す。
ここで、一般式(IV)で表される化合物を合成した後、アミノ基をアシル化することにより結晶性を向上させて精製してもよい。
カラムクロマトグラフィー
測定機器:山善株式会社製の分取クロマト装置 W-Prep 2XY(商品名)
クロマト担体:シリカゲル
測定機器:Bruker社製のAVANCE 300(商品名)
全δ値をppmで示した。
測定機器:ウオーターズ社製のSQD(商品名)
カラム:ウオーターズ社製のBEH C18(商品名) 1.7μm,2.1×30mm
溶媒:A液:0.1%ギ酸/水
B液:0.1%ギ酸/アセトニトリル
グラジエントサイクル:0.00min(A液/B液=95/5)、2.00min(A液/B液=5/95)、3.00min(A液/B液=5/95)、3.01min(A液/B液=100/0)、3.80min(A液/B液=100/0)
流速:0.5mL/min
カラム温度:室温
イオン化法:電子スプレーイオン化法(Electron Spray Ionization:ESIポジティブおよびネガティブイオンピークを検出)
検出波長:254nm
〔A〕(3S,4R,5S)-2,4-ビス(4-メチルベンゾイルオキシ)-5-[(4-メチルベンゾイルオキシ)メチル]チオラン-3-イル 4-メチルベンゾアートの合成
1H-NMR(CDCl3)δ値:
2.31(3H,s)、2.36(3H,s)、2.42(3H,s)、2.44(3H,s)、4.29(1H,dt,J=8.6,5.8Hz)、4.53(1H,dd,J=5.9,11.6Hz)、4.70(1H,dd,J=5.7,11.5Hz)、6.00(1H,dd,J=3.6,8.6Hz)、6.17(1H,dd,J=1.8,3.5Hz)、6.28(1H,d,J=1.8Hz)、6.96(2H,d,J=8.0Hz)、7.13(2H,d,J=8.0Hz)、7.24-7.27(4H,m)、7.79(2H,d,J=8.3Hz)、7.80(2H,d,J=8.3Hz)、7.96(2H,d,J=8.2Hz)、7.97(2H,d,J=8.2Hz)
1H-NMR(CDCl3)δ値:
2.36(3H,s)、2.40(3H,s)、2.41(3H,s)、2.43(3H,s)、4.16(1H,dt,J=2.2,6.5Hz)、4.56(2H,d,J=6.5Hz)、5.91(1H,t,J=4.7Hz)、6.07(1H,dd,J=2.2,4.4Hz)、6.69(1H,d,J=4.9Hz)、7.10(2H,d,J=8.5Hz)、7.16(2H,d,J=7.9Hz)、7.24-7.27(4H,m)、7.82(2H,d,J=8.2Hz)、7.86(2H,d,J=8.2Hz)、7.98(2H,d,J=8.2Hz)、7.99(2H,d,J=8.3Hz)
なお、原料である上記(2S,3R,4R)-4-ブロモ-1-オキソ-3,5-ビス((4-メチルフェニル)カルボニルオキシ)ペンタン-2-イル 4-メチルベンゾアートは、以下のように、複数の工程で合成した。
2.35-2.45(9H,m)、3.40(2.4H,s)、3.47(0.6H,s)、4.49(0.8H,d,J=6.2,12.8Hz)、4.56-4.63(0.4H,m)、4.68-4.73(1.8H,m)、5.13(0.8H,s)、5.30(0.2H,dd,J=4.4,7.1Hz)、5.37(0.2H,d,J=4.4Hz)、5.64(0.8H,d,J=4.8Hz)、5.69(0.2H,dd,J=3.4,7.1Hz)、5.84(0.8H,dd,J=4.8,6.6Hz)、7.10-7.32(6H,m)、7.77-8.04(6H,m)
2.36-2.40(9H,m)、3.32-3.34(1H,m)、4.51-4.79(3H,m)、5.48(0.33H,dd,J=4.4,6.2Hz)、5.61(0.67H,d,J=2.4Hz)、5.65(0.67H,d,J=4.9Hz)、5.75-5.79(0.66H,m)、5.86(0.67H,dd,J=5.0,6.2Hz)、7.10-7.27(6H,m)、7.77-7.98(6H,m)
2.38-2.41(9H,m)、3.09(0.75H,d,J=5.8Hz)、3.25(0.25H,d,J=6.0Hz)、3.91(2.25H,s)、4.02(0.75H,s)、4.26-4.43(2H,m)、4.59-4.64(1H,m)、5.76(0.75H,dd,J=3.3,7.9Hz)、5.82(0.25H,dd,J=2.8,8.6Hz)、6.13(0.75H,dd,J=3.3,6.9Hz)、6.53(0.25H,dd,J=2.8,6.1Hz)、6.90(0.25H,d,J=6.1Hz)、7.12-7.26(6H,m)、7.59(0.75H,d,J=6.9Hz)、7.84-7.93(6H,m)
2.41-2.43(9H,m)、3.84(2.25H,s)、3.96(0.75H,s)、4.60(0.25,dd,J=7.6,12.8Hz)、4.65(0.75dd,J=7.7,12.7Hz)、4.81(0.75H,dd,J=2.9,12.7Hz)、4.93(0.28H,dd,J=2.7,12.8Hz)、5.40-5.45(0.25H,m)、5.48-5.52(0.75H,m)、5.92(0.75H,dd,J=3.6,5.4Hz)、6.98-6.02(1H,m)、6.52(0.25H,dd,J=4.8,5.6Hz)、6.89(0.25H,d,J=5.6Hz)、7.19-7.35(7H,m)、7.53(0.75H,d,J=6.3Hz)、7.75-8.00(7H,m)
2.41-2.43(9H,m)、3.70(2.31H,s)、3.80(0.69H,s)、4.50-4.77(3H,m)、5.91-6.01(1.75H,m)、6.50(0.25H,t,J=6.4Hz)、6.80(0.25H,d,J=6.2Hz)、7.22-7.28(6H,m)、7.45(0.75H,d,J=6.3Hz)、7.90-8.00(6H,m)
2.41-2.43(9H,m)、(1H,dd,J=6.4,10.4Hz)、4.72-4.82(2H,m)、5.64(1H,dd,J=1.0,7.4Hz)、5.98(1H,dd,J=3.1,7.4Hz)、7.23-7.29(6H,m)、7.92-7.99(6H,m)、9.69(1H,d,J=0.96Hz)
〔A〕(3S,4R,5S)-2,4-ビス(4-フェニルベンゾイルオキシ)-5-[(4-フェニルベンゾイルオキシ)メチル]チオラン-3-イル 4-フェニルベンゾアートの合成
4.26(0.4H,dt,J=1.8,6.4Hz)、4.38(0.6H,dt,J=8.6,5.3Hz)、4.59-4.67(1.4H,m)、4.75(0.6H,dd,J=6.0,11.7Hz)、6.02(0.4H,t,J=4.6Hz)、6.14(0.6H,dd,J=3.6,8.6Hz)、6.22(0.4H,dd,J=1.9,4.3Hz)、6.28(0.6H,dd,J=1.7,3.5Hz)、6.37(0.6H,d,J=1.7Hz)、6.78(0.4H,d,J=4.9Hz)、7.27-7.77(28H,m)、7.96-8.04(4H,m)、8.15-8.26(4H,m)
なお、原料である上記(2S,3R,4R)-4-ブロモ-1-オキソ-3,5-ビス((4-フェニルフェニル)カルボニルオキシ)ペンタン-2-イル 4-フェニルベンゾアートは、以下のように、複数の工程で合成した。
3.46(2.61H,s)、3.53(0.39H,s)、4.56-4.62(1H,m)、4.68-4.80(2H,m)、5.20(0.87H,s)、5.39-5.44(0.26H,m)、5.73(0.87H,d,J=4.8Hz)、5.77(0.13H,dd,J=3.5,6.8Hz)、5.93(0.87H,dd,J=4.8,6.6Hz)、7.26-7.77(21H,m)、7.95-8.18(6H,m)
3.28(1H,brs)、4.60-4.86(3H,m)、5.57(0.43H,dd,J=4.4,6.3Hz)、5.6(0.57H,brs)、5.75(0.57H,dd,J=0.8,4.8Hz)、5.84-5.87(0.86H,m)、5.96(0.57H,dd,J=4.8,6.2Hz)、7.37-7.70(21H,m)、7.96-8.22(6H,m)
3.08(0.77H,brs)、3.27(0.23H,brs)、3.94(2.31H,s)、4.06(0.69H,s)、4.32-4.53(2H,m)、4.66-4.72(1H,m)、5.87(0.77H,dd,J=3.3,7.9Hz)、5.92(0.23H,dd,J=2.7,8.7Hz)、6.21(0.77H,dd,J=3.3,6.8Hz)、6.62(0.23H,dd,J=2.8,6.1Hz)、6.97(0.23H,d,J=6.1Hz)、7.38-7.68(21.77H,m)、8.04-8.12(6H,m)
3.88(2.16H,s)、4.00(0.84H,s)、4.68(0.28H,dd,J=7.4,12.8Hz)、4.73(0.72H,dd,J=7.5,12.7Hz)、4.91(0.72H,dd,J=2.9,12.7Hz)、4.93(0.28H,dd,J=2.7,12.8Hz)、5.49-5.54(0.28H,m)、5.56-5.61(0.72H,m)、6.02(0.72H,dd,J=3.7,5.2Hz)、6.07-6.11(1H,m)、6.62(0.28H,dd,J=4.8,5.6Hz)、6.97(0.28H,d,J=5.6Hz)、7.38-7.72(22.72H,m)、7.95-8.18(7H,m)
1H-NMRを測定した結果、約74:26のオキシム異性体混合物であった。
3.75(2.22H,s)、3.86(0.78H,s)、4.60-4.66(1H,m)、4.73-4.78(1H,m)、4.81-4.87(1H,m)、6.01-6.10(1.74H,m)、6.59(0.26H,t,J=6.3Hz)、6.88(0.26H,d,J=6.2Hz)、7.39-7.71(21.74H,m)、8.09-8.19(6H,m)
4.65(1H,dd,J=6.7,11.0Hz)、4.80-4.91(2H,m)、5.74(1H,dd,J=0.8,7.3Hz)、6.08(1H,dd,J=3.1,7.2Hz)、7.39-7.72(21H,m)、8.10-8.19(6H,m)、9.77(1H,d,J=0.8Hz)
〔A〕(3R,4R,5S)-2,4-ビス(4-メチルベンゾイルオキシ)-5-[(4-メチルベンゾイルオキシ)メチル]チオラン-3-イル 4-メチルベンゾアートの合成
1H-NMR(CDCl3)δ値:
2.38-2.42(12H,m)、4.23(1H,dt,J=3.6,7.5Hz)、4.54(1H,dd,J=7.3,11.3Hz)、4.74(1H,dd,J=7.9,11.3Hz)、5.90(1H,t,J=3.3Hz)、6.14(1H,dd,J=2.0,3.2Hz)、6.43(1H,d,J=1.6Hz)、7.15-7.28(8H,m)、7.90-7.98(8H,m)
1H-NMR(CDCl3)δ値:
2.31(3H,s)、2.34(3H,s)、2.38(3H,s)、2.42(3H,s)、3.91(1H,dt,J=7.7,6.2Hz)、4.52(1H,dd,J=6.2,11.5Hz)、4.67(1H,dd,J=6.1,11.5Hz)、5.85(1H,dd,J=4.5,9.8Hz)、6.31(1H,dd,J=7.8,9.8Hz)、6.50(1H,d,J=4.5Hz)、6.95(2H,d,J=8.0Hz)、7.14(2H,d,J=8.0Hz)、7.19(2H,d,J=8.0Hz)、7.22(2H,d,J=8.0Hz)、7.77(2H,d,J=8.2Hz)、7.85(2H,d,J=8.1Hz)、7.87(2H,d,J=8.2Hz)、7.91(2H,d,J=8.2Hz)
なお、原料である上記(2R,3R,4R)-4-ブロモ-1-オキソ-3,5-ビス((4-メチルフェニル)カルボニルオキシ)ペンタン-2-イル 4-メチルベンゾアートは、以下のように、複数の工程で合成した。
2.37-2.43(9H,m)、3.36(0.75H,s)、3.48(2.25H,s)、4.43-4.48(0.25H,m)、4.53-4.57(0.75H,m)、4.59-4.69(1H,m)、4.74(0.25H,dd,J=4.5,11.7Hz)、4.83(0.75H,dd,J=3.3,11.7Hz)、5.16(0.75H,s)、5.33(0.25H,d,J=4.5Hz)、5.46(0.25H,dd,J=4.5,6.9Hz)、5.49(0.75H,d,J=1.2Hz)、5.55(0.75H,d,J=5.1Hz)、5.93(0.25H,dd,J=5.1,6.9Hz)、7.16-7.28(6H,m)、7.86-7.98(6H,m)
2.35-2.41(9H,m)、3.36(0.75H,brs)、3.63(0.25H,brs)、4.41-4.46(0.25H,m)、4.62(0.75H,dd,J=5.0,11.3Hz)、4.73-4.83(2H,m)、5.51-5.55(1.75H,m)、5.66(0.75H,d,J=3.9Hz)、5.79-5.86(0.5H,m)、7.13-7.28(6H,m)、7.86-7.98(6H,m)
2.39-2.43(9H,m)、3.41(1H,d,J=5.4Hz)、3.79(2.25H,s)、3.96(0.75H,s)、4.18-4.29(1H,m)、4.34-4.42(1H,m)、4.52-4.60(1H,m)、5.66(0.75H,dd,J=3.4,8.3Hz)、5.84(0.25H,dd,J=2.7,8.4Hz)、6.18(0.75H,dd,J=3.4,6.0Hz)、6.57(0.25H,dd,J=2.7,5.4Hz)、6.76(0.25H,d,J=5.4Hz)、7.19-7.29(6H,m)、7.45(0.75H,d,J=6.0Hz)、7.88-8.01(6H,m)
1H-NMRを測定した結果、約75:25のオキシム異性体混合物であった。
2.40-2.42(9H,m)、3.83(2.25H,s)、3.91(0.75H,s)、4.63-4.78(2H,m)、5.39-5.45(0.25H,m)、5.46-5.53(0.75H,m)、5.93-5.99(1.5H,m)、6.04(0.25H,dd,J=5.1,4.3Hz)、6.34(0.25H,dd,J=4.3,5.1Hz)、6.72(0.25H,d,J=5.1Hz)、7.19-7.27(67H,m)、7.48(0.75H,d,J=5.4Hz)、7.75-7.97(67H,m)
1H-NMRを測定した結果、約80:20のオキシム異性体混合物であった。
2.33-2.41(9H,m)、3.84(2.4H,s)、3.88(0.6H,s)、4.47(0.8H,dd,J=9.9,13.3Hz)、4.57-4.61(0.4H,m)、4.68-4.76(1.8H,m)、6.04-6.12(1.8H,m)、6.43(0.2H,t,J=5.3Hz)、6.76(0.2H,d,J=5.5Hz)、7.10-7.26(6H,m)、7.53(0.8H,d,J=4.7Hz)、7.77-8.00(6H,m)
〔A-1〕(3R,4R,5S)-2-ヒドロキシ-4-((4-フェニルフェニル)カルボニルオキシ)-5-(((4-フェニルフェニル)カルボニルオキシ)メチル)チオラン-3-イル 4-フェニルベンゾアートおよびそのアセチル体
2.67(1H,d,J=4.1Hz)、3.93(1H,dd,J=7.0,13.4Hz)、4.67-4.88(2H,m)、5.67(1H,dd,J=4.1,9.1Hz)、5.70(1H,t,J=4.1Hz)、6.34(1H,dd,J=7.0,9.1Hz)、7.26-7.64(21H,m)、8.00-8.13(6H,m)
2.10(1H,s)、3.94(1H,dd,J=7.2,13.6Hz)、4.60(1H,dd,J=6.0,11.3Hz)、4.72(1H,dd,J=7.1,11.3Hz)、5.79(1H,dd,J=4.5,9.9Hz)、6.30(1H,dd,J=7.7,9.9Hz)、6.40(1H,d,J=4.5Hz)、7.35-7.70(21H,m)、7.96-8.13(6H,m)
1H-NMR(CDCl3)δ値:
4.31-4.37(1H,m)、4.66(1H,dd,J=6.8,11.3Hz)、4.82(1H,dd,J=8.3,11.2Hz)、6.02(1H,t,J=3.4Hz)、6.25(1H,dd,J=2.2,3.1Hz)、6.51(1H,d,J=1.8Hz)、7.35-7.72(28H,m)、8.06-8.17(8H,m)
1H-NMR(CDCl3)δ値:
4.02(0.88H,dt,J=7.9,5.7Hz)、4.32-4.38(0.12H,m)、4.61-4.74(1.88H,m)、4.83(0.12H,dd,J=8.2,11.3Hz)、5.94(0.88H,dd,J=4.5,10.0Hz)、6.03(0.12H,t,J=3.4Hz)、6.25(0.12H,dd,J=2.1,3.3Hz)、6.45(0.88H,dd,J=8.0,10.0Hz)、6.51(0.12H,d,J=1.8Hz)、6.60(0.88H,dd,J=4.5Hz)、7.25-7.72(28H,m)、7.95-8.17(8H,m)
保持時間:2.61min
[M+H] 800.7
なお、得られた1H-NMRスペクトルはブロードであり、δ値を求めることはできなかった。
保持時間:0.21min
[M+H] 260.3
3.57-3.69(2H,m),3.86-3.98(2H,m),4.09(1H,t,J=6.6Hz),5.94(2H,d,J=7.9Hz),6.02(2H,d,J=6.6Hz),8.06(1H,d,J=7.3Hz)
なお、原料である上記(2R,3R,4R)-4-ブロモ-1-オキソ-3,5-ビス((4-フェニルフェニル)カルボニルオキシ)ペンタン-2-イル 4-フェニルベンゾアートは、以下のように、複数の工程で合成した。
3.53(3H,s)、4.60(1H,dd,J=3.8,8.5Hz)、4.78(1H,dd,J=4.1,12.0Hz)、4.92(1H,dd,J=3.3,12.0Hz)、5.24(1H,s)、5.56(1H,d,J=1.2Hz)、5.67(1H,d,J=5.0Hz)、7.31-7.70(21H,m)、8.06(2H,d,J=8.6Hz)、8.12(2H,d,J=8.6Hz)、8.16(2H,d,J=8.6Hz)
4.84-5.00(3H,m)、5.73(1H,d,J=4.1Hz)、6.01(1H,s)、6.69(1H,s)、7.32-7.74(21H,m)、8.02(2H,d,J=8.6Hz)、8.12(2H,d,J=8.6Hz)、8.22(2H,d,J=8.6Hz)
3.06(0.77H,d,J=3.7Hz)、3.41(0.23H,d,J=5.5Hz)、4.49-4.54(0.23H,m)、4.72-4.89(2.77H,m)、5.59-5.63(1H,m)、5.67(0.77H,d,J=4.5Hz)、5.74(0.77H,d,J=3.7Hz)、5.87(0.23H,t,J=5.0Hz)、5.95(0.23H,t,J=5.3Hz)、7.33-7.70(21H,m)、8.05-8.18(6H,m)
3.44-3.47(1H,m)、3.83(2.1H,s)、4.00(0.9H,s)、4.26-4.37(1H,m)、4.46-4.52(1H,m)、4.61-4.68(1H,m)、5.76(0.7H,dd,J=3.5,8.1Hz)、5.93(0.3H,dd,J=2.8,8.3Hz)、6.26(0.7H,dd,J=3.5,6.0Hz)、6.66(0.3H,dd,J=2.8,5.2Hz)、6.84(0.3H,d,J=5.2Hz)、7.38-7.73(21.7H,m)、8.05-8.21(6H,m)
3.87(2.1H,s)、3.97(0.9H,s)、4.71-4.87(2H,m)、5.48-5.53(0.3H,m)、5.55-5.59(0.7H,m)、6.02-6.09(1.4H,m)、6.12(0.3H,dd,J=4.4,5.1Hz)、6.42(0.3H,dd,J=4.4,5.2Hz)、6.79(0.3H,d,J=5.2Hz)、7.38-7.71(22.7H,m)、7.94-8.17(7H,m)
3.88(2.4H,s)、3.93(0.6H,s)、4.56(0.8H,dd,J=10.0,13.5Hz)、4.64-4.69(0.4H,m)、4.78-4.85(1.8H,m)、6.11-6.22(1.8H,m)、6.52(0.2H,t,J=5.5Hz)、6.83(0.2H,d,J=5.5Hz)、7.36-7.68(21.8H,m)、7.96-8.19(6H,m)
4.70(1H,dd,J=7.1,11.6Hz)、4.81-4.91(2H,m)、5.90(1H,d,J=5.5Hz)、6.08(1H,dd,J=3.6,5.5Hz)、7.39-7.66(21H,m)、8.04-8.15(6H,m)、9.79(1H,s)
〔A〕(3R,4R,5S)-2,4-ビス((ナフタレン-2-イル)カルボニルオキシ)-5-[((ナフタレン-2-イル)カルボニルオキシ)メチル]チオラン-3-イル ナフタレン-2-カルボキシラートの合成
1H-NMR(CDCl3)δ値:
4.43-4.50(1H,m)、4.76(1H,dd,J=6.9,11.3Hz)、4.97(1H,dd,J=8.4,11.2Hz)、6.16(1H,t,J=2.8Hz)、6.38(1H,dd,J=1.9,2.7Hz)、6.64(1H,d,J=1.2Hz)、7.31-8.14(28H,m)、8.56(1H,s)、8.64(1H,s)、8.66(1H,s)、8.71(1H,s)
1H-NMR(CDCl3)δ値:
4.08-4.17(1H,m)、4.76(1H,dd,J=5.7,11.5Hz)、4.85(1H,dd,J=6.9,11.5Hz)、6.08(1H,dd,J=4.5,9.7Hz)、6.58(1H,dd,J=8.9,9.8Hz)、6.71(1H,d,J=4.5Hz)、7.38-8.04(24H,m)、8.41(1H,s)、8.41(1H,s)、8.56(1H,s)、8.59(1H,s)
なお、原料である上記(2R,3R,4R)-4-ブロモ-1-オキソ-3,5-ビス((ナフタレン-2-イル)カルボニルオキシ)ペンタン-2-イル ナフタレン-2-カルボキシラートは、以下のように、複数の工程で合成した。
3.44(0.45H,s)、3.57(2.55H,s)、4.62-4.67(0.15H,m)、4.71(0.85H,dd,J=4.4,8.5Hz)、4.76-4.87(1.15H,m)、5.01(0.85H,dd,J=3.5,12.0Hz)、5.31(0.85H,s)、5.46(0.15H,d,J=4.3Hz)、5.59-5.66(0.15H,m)、5.66(0.85H,d,J=1.2Hz)、5.78(0.85H,d,J=4.9Hz)、6.12-6.20(0.15H,m)、7.41-8.21(18H,m)、8.54-8.79(3H,m)
3.13(0.75H,brs)、3.45(0.25H,brs)、4.59-4.64(0.25H,m)、4.79-4.98(2.75H,m)、5.70-5.73(1H,m)、5.77(0.75H,d,J=4.7Hz)、5.81(0.75H,brs)、5.94(0.25H,brs)、6.06(0.25H,t,J=5.4Hz)、7.31-8.12(18H,m)、8.53-8.69(3H,m)
3.53-3.57(1H,m)、3.82(2.1H,s)、4.01(0.9H,s)、4.39-4.48(1H,m)、4.54-4.61(1H,m)、4.68-4.75(1H,m)、5.86(0.7H,dd,J=3.7,8.0Hz)、6.02(0.3H,dd,J=2.9,8.1Hz)、6.35(0.7H,dd,J=3.7,6.0Hz)、6.74(0.3H,dd,J=2.9,5.2Hz)、6.92(0.3H,d,J=5.2Hz)、7.46-8.16(18.7H,m)、8.57-8.71(3H,m)
1H-NMRを測定した結果、約70:30のオキシム異性体混合物であった。
3.86(2.1H,s)、3.95(0.9H,s)、4.81-4.93(2H,m)、5.58-5.69(1H,m)、6.12-6.21(1.7H,m)、6.52(0.3H,dd,J=4.0,5.1Hz)、6.88(0.3H,d,J=5.2Hz)、7.50-8.10(20.7H,m)、8.59-8.70(3H,m)
3.86(2.4H,s)、3.92(0.6H,s)、4.65(0.8H,dd,J=9.8,13.3Hz)、4.70-4.91(2.2H,m)、6.19-6.27(1.8H,m)、6.60(0.2H,t,J=5.5Hz)、6.90(0.2H,d,J=5.6Hz)、7.25-8.14(18.8H,m)、8.43-8.69(3H,m)
4.79(1H,dd,J=7.2,11.7Hz)、4.89-5.00(2H,m)、5.97(1H,d,J=5.5Hz)、6.16(1H,dd,J=3.7,5.5Hz)、7.43-8.09(18H,m)、8.51(1H,s)、8.53(1H,s)、8.65(1H,s)、9.84(1H,s)
〔A〕(3S,4R,5R)-2,4-ビス(4-フェニルベンゾイルオキシ)-5-[(4-フェニルベンゾイルオキシ)メチル]チオラン-3-イル 4-フェニルベンゾアートの合成
4.31(0.4H,dd,J=7.1,12.3Hz)、4.50(0.6H,dd,J=6.7,13.1Hz)、4.66-4.97(2H,m)、5.81(0.4H,t,J=4.4Hz)、6.21-6.28(1.2H,m)、6.47-6.52(1H,m)、6.71(0.4H,d,J=5.0Hz)、7.36-7.77(28H,m)、7.93-8.26(8H,m)
なお、原料である上記(2S,3R,4S)-4-(メタンスルホニルオキシ)-1-オキソ-3,5-ビス((4-フェニルフェニル)カルボニルオキシ)ペンタン-2-イル 4-フェニルベンゾアートは、以下のように、複数の工程で合成した。
3.17(0.75H,s)、3.21(2.25H,s)、3.91(2.25H,s)、4.01(0.75H,s)、4.56(0.25H,dd,J=6.5,12.8Hz)、4.62(0.75H,dd,J=6.8,12.6Hz)、4.98(0.75H,dd,J=2.9,12.6Hz)、5.02(0.25H,dd,J=2.8,12.8Hz)、5.53-5.55(1H,m)、6.07-6.17(1.75H,m)、6.60(0.25H,dd,J=3.9,5.4Hz)、6.97(0.25H,d,J=5.4Hz)、7.39-7.72(21.75H,m)、8.08-8.20(6H,m)
3.17(3H,s)、4.55(1H,dd,J=5.2,12.9Hz)、5.00(1H,dd,J=2.7,12.8Hz)、5.64-5.69(1H,m)、5.93(1H,d,J=2.8Hz)、6.18(1H,dd,J=2.8,8.1Hz)、7.38-7.75(21H,m)、8.07-8.28(6H,m)、9.79(1H,s)
〔A〕(3S,4R,5R)-2-ヒドロキシ-4-((4-メチルフェニル)カルボニルオキシ)-5-(((4-メチルフェニル)カルボニルオキシ)メチル)チオラン-3-イル 4-メチルベンゾアートおよびそのアシル体
2.37-2.43(9H,m)、2.71(0.79H,brs)、2.87(0.21H,d,J=11.7Hz)、4.06-4.12(0.21H,m)、4.44(0.79H,dd,J=7.1,13.5Hz)、4.55-4.70(2H,m)、5.43(0.21H,dd,J=3.8,5.8Hz)、5.65(0.79H,dd,J=3.8,5.8Hz)、5.74-5.75(1H,m)、6.12(0.79H,dd,J=3.7,6.1Hz)、6.33(0.21H,t,J=4.6Hz)、7.12-7.28(6H,m)、7.76-7.93(6H,m)
1H-NMR(CDCl3)δ値:
2.37(3H,s)、2.39(3H,s)、2.41(3H,s)、2.42(3H,s)、4.39(1H,dd,J=7.2,13.2Hz)、4.62(1H,dd,J=7.4,11.1Hz)、4.75(1H,dd,J=7.2,11.1Hz)、6.10-6.17(2H、m)、6.41(1H,d,J=3.4Hz)、7.13(2H,d,J=8.0Hz)、7.17(2H,d,J=8.1Hz)、7.24-7.27(4H,m)、7.78(2H,d,J=7.8Hz)、7.85(2H,d,J=8.2Hz)、7.94-7.97(4H,m)
1H-NMR(CDCl3)δ値:
2.34(3H,s)、2.38(6H,s)、2.43(3H,s)、4.16-4.22(1H,m)、4.58-4.70(2H,m)、5.71(1H,dd,J=4.0,5.1Hz)、6.38(1H,t,J=4.6Hz)、6.62(1H,d,J=5.1Hz)、7.03(2H,d,J=8.0Hz)、7.11(2H,d,J=8.0Hz)、7.15(2H,d,J=8.0Hz)、7.19(2H,d,J=8.0Hz)、7.77(4H,t,J=8.1Hz)、7.83(2H,d,J=8.2Hz)、7.98(2H,d=8.2Hz)
なお、原料である上記(2S,3R,4S)-4-(メタンスルホニルオキシ)-1-オキソ-3,5-ビス((4-メチルフェニル)カルボニルオキシ)ペンタン-2-イル 4-メチルベンゾアートは、以下のように、複数の工程で合成した。
2.40-2.42(9H,m)、3.11(0.72H,s)、3.16(2.28H,s)、3.87(2.28H,s)、3.97(0.72H,s)、4.47(0.24H,dd,J=6.7,12.7Hz)、4.53(0.76H,dd,J=7.1,12.6Hz)、4.89(0.76H,dd,J=2.7,12.6Hz)、4.94(0.24H,dd,J=2.8,12.8Hz)、5.43-5.49(1H,m)、5.98-6.08(1.76H,m)、6.51(0.24H,dd,J=4.1,5.5Hz)、6.90(0.24H,d,J=5.5Hz)、7.22-7.27(6H,m)、7.54(0.76H,d,J=6.1Hz)、7.88-7.80(6H,m)
2.40-2.44(9H,m)、3.10(3H,s)、4.46(1H,dd,J=5.4,12.9Hz)、4.92(1H,dd,J=2.5,12.8Hz)、5.55-5.61(1H,m)、5.83(1H,d,J=2.9Hz)、6.07(1H,dd,J=2.8,8.0Hz)、7.21-7.31(6H,m)、7.87-8.08(6H,m)、9.72(1H,s)
〔A〕(3R,4R,5R)-2,4-ビス(4-メチルベンゾイルオキシ)-5-[(4-メチルベンゾイルオキシ)メチル]チオラン-3-イル 4-メチルベンゾアートの合成
2.35-2.45(12H,m)、4.26(0.62H,dt,J=8.3,7.0Hz)、4.40-4.47(1H,m)、4.61(1H,dd,J=6.5,11.6Hz)、4.76(0.38H,dd,J=7.2,10.7Hz)、5.96(0.38H,t,J=4.6Hz)、6.09(0.62H,dd,J=4.5,10.0Hz)、6.17(0.62H,dd,J=7.3,10.0Hz)、6.25(0.38H,dd,J=2.0,4.0Hz)、6.32(0.38H,d,J=1.8Hz)、7.05-7.28(8H,m)、7.76-8.01(8H,m)
なお、原料である上記(2R,3R,4S)-4-(メタンスルホニルオキシ)-1-オキソ-3,5-ビス((4-メチルフェニル)カルボニルオキシ)ペンタン-2-イル 4-メチルベンゾアートは、以下のように、複数の工程で合成した。
1H-NMRを測定した結果、約70:30のオキシム異性体混合物であった。
2.38-2.41(9H,m)、3.02(0.9H,s)、3.08(2.1H,s)、3.83(2.1H,s)、3.95(0.9H,s)、4.50-4.59(1H,m)、4.79-4.87(1H,m)、5.38-5.50(1H,m)、6.02(0.7H,s)、6.02(0.7H,dd,J=5.3,13.9Hz)、6.10(0.3H,dd,J=4.0,5.9Hz)、6.38(0.3H,dd,J=4.1,5.1Hz)、6.73(0.3H,d,J=5.2Hz)、7.20-7.27(6H,m)、7.47(0.7H,d,J=5.3Hz)、7.91-8.00(6H,m)
2.41-2.43(9H,m)、3.04(3H,s)、4.54(1H,dd,J=6.0,12.7Hz)、4.87(1H,dd,J=2.8,12.7Hz)、5.47-5.52(1H,m)、5.72(1H,d,J=2.7Hz)、6.05(1H,dd,J=2.7,7.0Hz)、7.23-7.30(6H,m)、7.94(4H,d,J=8.2Hz)、8.01(2H,d,J=8.2Hz)、9.68(1H,s)
〔A〕(3R,4R,5R)-2,4-ビス(4-フェニルベンゾイルオキシ)-5-[(4-フェニルベンゾイルオキシ)メチル]チオラン-3-イル 4-フェニルベンゾアートの合成
1H-NMR(CDCl3)δ値:
4.33-4.39(0.77H,m)、4.44-4.53(1H,m)、4.68-4.79(1H,m)、4.90(0.23H,dd,J=7.4,11.5Hz)、6.03-6.06(0.23H,m)、6.19(0.77H,dd,J=4.5,10.2Hz)、6.28(0.77H,dd,J=7.3,10.2Hz)、6.40-6.42(0.46H,m)、6.63(0.77H,d,J=4.5Hz)、7.36-7.71(28H,m)、7.91-8.18(8H,m)
1H-NMR(CDCl3)δ値:
4.33-4.39(0.23H,m)、4.44-4.53(1H,m)、4.68-4.79(1H,m)、4.92(0.77H,dd,J=7.4,11.4Hz)、6.03-6.06(0.77H,m)、6.19(0.23H,dd,J=4.6,10.2Hz)、6.28(0.23H,dd,J=7.3,10.2Hz)、6.40-6.41(1.54H,m)、6.63(0.23H,d,J=4.5Hz)、7.36-7.71(28H,m)、7.91-8.18(8H,m)
なお、原料である上記(2R,3R,4S)-4-(メタンスルホニルオキシ)-1-オキソ-3,5-ビス((4-フェニルフェニル)カルボニルオキシ)ペンタン-2-イル 4-フェニルベンゾアートは、以下のように、複数の工程で合成した。
3.09(0.9H,s)、3.15(2.1H,s)、3.87(2.1H,s)、4.00(0.9H,s)、4.59-4.68(1H,m)、4.87-4.93(1H,m)、5.47-5.57(1H,m)、6.10(0.7H,s)、6.10(0.7H,dd,J=5.4,14.3Hz)、6.18(0.3H,dd,J=4.1,6.0Hz)、6.47(0.3H,dd,J=4.1,5.2Hz)、6.79(0.3H,d,J=5.2Hz)、7.39-7.71(21.7H,m)、8.10-8.19(6H,m)
3.11(3H,s)、4.64(1H,dd,J=5.7,12.7Hz)、4.96(1H,dd,J=3.0,12.7Hz)、5.56-5.61(1H,m)、5.81(1H,d,J=2.6Hz)、6.15(1H,dd,J=2.6,7.2Hz)、7.40-7.73(21H,m)、8.11-8.23(6H,m)、9.75(1H,s)
〔A〕(3R,4R,5R)-2,4-ビス((ナフタレン-2-イル)カルボニルオキシ)-5-[((ナフタレン-2-イル)カルボニルオキシ)メチル]チオラン-3-イル ナフタレン-2-カルボキシラートの合成
1H-NMRを測定した結果、約71:29のアノマー混合物であった。
4.33-4.39(0.71H,m)、4.56-4.64(1H,m)、4.77-4.86(1H,m)、4.99(0.29H,dd,J=7.4,11.4Hz)、6.19-6.22(0.29H,m)、6.33-6.42(1.42H,m)、6.51-6.52(0.58H,m)、6.74(0.71H,d,J=4.2Hz)、7.24-8.12(24H,m)、8.37-8.69(4H,m)
なお、原料である上記(2R,3R,4S)-4-(メタンスルホニルオキシ)-1-オキソ-3,5-ビス((ナフタレン-2-イル)カルボニルオキシ)ペンタン-2-イル ナフタレン-2-カルボキシラートは、以下のように、複数の工程で合成した。
3.08(0.99H,s)、3.15(2.01H,s)、3.87(2.01H,s)、3.99(0.99H,s)、4.69-4.78(1H,m)、4.96-5.04(1H,m)、5.55-5.60(0.33H,m)、5.62-5.67(0.67H,m)、6.17-6.24(1.34H,m)、6.26(0.33H,dd,J=4.2,5.5Hz)、6.56(0.33H,dd,J=4.3,5.2Hz)、6.88(0.33H,d,J=5.2Hz)、7.49-7.63(6.67H,m)、7.81-7.95(9H,m)、8.02-8.12(3H,m)、8.62-8.68(3H,m)
3.09(3H,s)、4.75(1H,dd,J=6.0,12.6Hz)、5.04(1H,dd,J=3.1,12.6Hz)、5.70(1H,m)、5.92(1H,d,J=2.8Hz)、6.22(1H,dd,J=2.8,6.6Hz)、7.46-8.15(18H,m)、8.62(1H,s)、8.68(1H,s)、8.72(1H,s)、9.82(1H,s)
〔A〕(3S,4S,5S)-2-ヒドロキシ-4-(4-メチルベンゾイルオキシ)-5-[(4-メチルベンゾイルオキシ)メチル]チオラン-3-イル 4-メチルベンゾアートおよびそのアセチル体
保持時間:1.99,2.02min
[M+H-H2O] 503.4
保持時間:2.17min
[M+H-AcOH] 503.4
2.08(1H,s),2.34(3H,s),2.38(3H,s),2.38(3H,s),4.15-4.23(1H,m),4.37-4.43(1H,m),4.54-4.60(1H,m),5.94(1H,dd,J=4.5,10.5Hz),6.06(1H,dd,J=7.6,17.7Hz),6.31(1H,d,J=4.5Hz),7.10-7.24(6H,m),7.75-7.92(6H,m)
保持時間:1.77min
[M+H] 614.5
2.34(3H,s),2.37(3H,s),2.39(3H,s),4.28-4.36(1H,m),4.62(1H,dd,J=11.9,4.0Hz),4.91(1H,d,J=6.6Hz),5.79(1H,d,J=7.3Hz),5.97(1H,dd,J=7.9,6.6Hz),6.23(1H,t,J=7.3Hz),6.47(1H,d,J=6.6Hz),7.8(6H,t,J=8.6Hz),7.26(6H,d,J=7.9Hz),7.78(4H,t,J=8.6Hz),7.88(2H,d,J=7.9Hz),8.12(1H,d,J=7.9Hz)
保持時間:0.21min
[M+H] 260.2
3.73-3.81(1H,m),3.84-4.02(2H,m),4.17-4.25(2H,m),5.86(1H,d,J=7.3Hz),5.95(1H,d,J=3.3Hz),8.37(1H,d,J=7.3Hz)
なお、原料である上記(2R,3S,4S)-2-((メタンスルホニル)オキシ)-5-オキソペンタン-1,3,4-トリイル トリス(4-メチルベンゾアート)は、以下のように、複数の工程で合成した。
保持時間:2.05min
[M+H] 612.5
2.35-2.45(9H,m),3.02(0.96H,s),3.08(2.04H,s),3.83(2.04H,s),3.95(0.96H,s),4.49-4.61(1H,m),4.76-4.88(1H,m),5.36-5.56(1H,m),5.97-6.11(1.68H,m),6.35-6.41(0.32H,m),6.72(0.32H,d,J=5.3Hz),7.17-7.31(6H,m),6.72(0.68H,d,J=5.3Hz),7.88-8.01(6H,m)
保持時間:1.90min
[M+H]:583.4
〔A〕(2R,3R,4R)-4-(ベンジルオキシ)-5-ヒドロキシ-2-((4-メチルベンゾイルオキシ)メチル)チオラン-3-イル 4-メチルベンゾアートおよびそのアセチル体
1.94(2.22H,s)、2.16(0.78H,s)、2.33-2.48(6H,m)、4.17-4.32(1H,m)、4.37-4.58(1H,m)、4.58-4.78(3H,m)、5.71(0.74H,dd,J=4.6、5.3Hz)、5.77(0.26H,dd,J=7.6、9.6Hz)、6.04(0.74H,d,J=2.0Hz)、6.16(0.26H,d,J=4.0Hz)、7.04-7.37(9H,m)、7.76-7.95(4H,m)
なお、原料である上記(2S,3R,4R)-4-(ベンジルオキシ)-2-ブロモ-3-(4-メチルベンゾイルオキシ)-5-オキソペンチル 4-メチルベンゾアートは、以下のように、複数の工程で合成した。
2.40(6H,s)、2.85(0.59H,d,J=3.3Hz)、2.97(0.41H,d,J=7.3Hz)、3.45(1.77H,s)、3.54(1.23H,s)、4.34-4.38(0.59H,m)、4.40-4.69(2.41H,m)、4.70-4.78(0.41H,m)、4.82-4.91(0.59H,m)、4.98(0.59H,d,J=2.0Hz)、5.07(0.41H,d,J=4.6Hz)、5.36(0.59H,dd,J=2.6,6.6Hz)、5.52(0.41H,dd,J=5.3,5.9Hz)、7.16-7.25(4H,m)、7.85-7.96(4H,m)
2.36-2.44(6H,m)、2.89-2.94(0.8H,m)、3.01-3.05(0.2H,m)、3.78(0.6H,s)、3.87(2.4H,s)、4.27-4.51(4H,m)、4.56-4.74(1.8H,m)、5.09(0.20H,dd,J=5.3,6.6Hz)、5.50(0.8H,dd,J=2.0,5.9Hz)、5.56(0.2H,dd,J=2.6,5.3Hz)、6.85(0.2H,d,J=6.6Hz)、7.13-7.34(9H,m)、7.44(0.80H,d,J=7.9Hz)、7.80-8.00(4H,m)
〔A〕(2S,3S,4S)-3-(ベンゾイルオキシ)-4-フルオロ-5-ヒドロキシチオラン-2-イル)メチル ベンゾエートおよびそのアセチル体
8.04-7.87(4H,m),7.63-7.50(2H,m),7.48-7.34(4H,m),5.98(0.44H,dq,J=6.0,8.7Hz),5.91(0.56H,ddd,J=4.2,5.1,10.8Hz),5.65(0.44H,ddd,J=3.9,8.1,9.6Hz),5.56(0.56H,ddd,J=1.1,8.7,13.1Hz),5.35(0.56H,ddd,J=1.6,3.5,47.8Hz),5.22(0.44H,ddd,J=3.9,6.1,50.6Hz),4.67(1.12H,d,J=6.9Hz),4.55-4.33(1.32H,m),4.28(0.56H,dd,J=6.9,12.3Hz),2.73(0.44H,dd,J=2.4,8.1Hz),2.52(0.56H,d,J=8.7Hz)
8.07-7.95(3.12H,m),7.87-7.81(0.88H,m),7.62-7.30(6H,m),6.20(0.44H,dd,J=2.2,4.5Hz),6.11(0.56H,dd,J=2.4,16.5Hz),6.01-5.90(0.44H,m),5.91-5.82(0.56H,m),5.54(0.56H,ddd,J=2.4,5.1,48.9Hz),5.44(0.44H,ddd,J=4.5,9.3,50.7Hz),4.67(0.56H,dd,J=6.9,11.7Hz),4.58-4.47(1H,m),4.37(0.44H,dd,J=5.1,11.7Hz),4.24-4.17(1H,m),2.19(1.32H,s),2.01(1.68H,s)
なお、原料である上記(2R,3R,4S)-3-(ベンゾイルオキシ)-4-フルオロ-2-(メタンスルホニルオキシ)-5-オキソペンチル ベンゾエートは、以下のように、複数の工程で合成した。
8.11-8.03(4H,m),7.66-7.55(2H,m),7.52-7.38(4.75H,m),6.85(0.25H,dd,J=4.5,11.1Hz),6.09-6.00(0.25H,m),5.99-5.74(1H,m),5.56-5.35(1.75H,m),4.87(0.75H,dd,J=2.8,12.8Hz),4.86(0.25H,dd,J=2.8,12.8Hz),4.48(0.75H,dd,J=6.0,12.6Hz),4.46(0.25H,dd,J=6.6,12.6Hz),3.92(0.75H,s),3.85(2.25H,s),3.14(2.25H,s),3.13(0.75H,s)
9.75(1H,d,J=6.9Hz),8.10-8.00(4H,m),7.66-7.55(2H,m),7.51-7.41(4H,m),5.93(1H,ddd,J=1.9,7.1,24.8Hz),5.47(1H,ddd,J=2.8,5.8,7.1Hz),5.30(1H,dd,J=1.9,46.4Hz),4.91(1H,dd,J=2.8,12.9Hz),4.48(1H,dd,J=5.8,12.9Hz),3.14(3H,s)
〔A〕((2S)-5-ヒドロキシチオラン-2-イル)メチル 4-メチルベンゾエートおよびそのアセチル体
7.96-7.90(2H,m),7.28-7.22(2H,m),5.63-5.55(1H,m),4.54(0.55H,dd,J=6.6,11.1Hz),4.40(0.55H,dd,J=6.9,11.1Hz),4.27-4.17(0.90H,m),3.99-3.77(1H,m),2.45-1.95(8H,m)
7.96-7.89(2H,m),7.27-7.20(2H,m),6.20-6.14(1H,m),4.54(0.52H,dd,J=6.4,11.1Hz),4.33(0.52H,dd,J=7.2,11.1Hz),4.28-4.16(0.96H,m),3.91-3.75(1H,m),2.43-1.89(10H,m)
なお、原料である上記(2R)-2-ブロモ-5-オキソペンチル 4-メチルベンゾエートは、以下のように、複数の工程で合成した。
4.98(1H,s),4.84(1H,d,J=5.9Hz),4.59(1H,d,J=5.9Hz),4.44(1H,t,J=2.7Hz),3.74-3.57(2H,m),3.44(3H,s),3.22(1H,dd,J=2.9,10.4Hz),1.49(3H,s),1.32(3H,s)
7.96(2H,d,J=8.1Hz),7.24(2H,d,J=8.1Hz),5.02(1H,s),4.77(1H,dd,J=0.6,6.0Hz),4.65(1H,d,J=6.0Hz),4.53(1H,dt,J=0.6,6.9Hz),4.36(1H,dd,J=6.9,13.9Hz),4.32(1H,dd,J=6.9,13.9Hz),3.34(3H,s),2.41(3H,s),1.50(3H,s),1.34(3H,s)
7.96(2H,d,J=8.1Hz),7.24(2H,d,J=8.1Hz),4.88(1H,br),4.56(1H,dd,J=3.9,11.9Hz),4.47-4.38(2H,m),4.28-4.21(1H,m),4.11-4.06(1H,m),3.33(3H,s),2.59(1H,d,J=3.3Hz),2.53(1H,d,J=7.1Hz),2.41(3H,s)
7.97(2H,d,J=8.1Hz),7.24(2H,d,J=8.1Hz),6.37(1H,dd,J=5.0,6.3Hz),6.16(1H,dd,J=0.9,5.0Hz),5.16(1H,d,J=0.9Hz),4.74-4.68(1H,m),4.62(1H,dd,J=4.1,11.9Hz),4.45(1H,dd,J=4.7,11.9Hz),3.38(3H,s),2.59(3H,s),2.55(3H,s),2.41(3H,s)
7.97(2H,d,J=8.1Hz),7.23(2H,d,J=8.1Hz),6.23-6.18(1H,m),5.96-5.91(1H,m),5.76-5.73(1H,m),5.06-4.99(1H,m),4.44(1H,dd,J=4.2,11.6Hz),4.36(1H,dd,J=5.6,11.6Hz),3.41(3H,s),2.41(3H,s)
7.98(2H,d,J=8.4Hz),7.24(2H,d,J=8.4Hz),5.03(1H,d,J=3.6Hz),4.49-4.24(3H,m),3.24(3H,s),2.41(3H,s),2.11-1.86(4H,m)
8.00-7.90(2H,m),7.28-7.20(2H,m),5.64(0.5H,d,J=3.9Hz),5.46(0.5H,d,J=3.6Hz),4.64-4.55(0.5H,m),4.47-4.34(2H,m),4.26(0.5H,dd,J=6.0,11.4Hz),2.72(0.5H,br),2.62(0.5H,br),2.41(3H,s),2.33-1.71(4H,m)
7.96-7.90(2H,m),7.44(0.60H,t,J=5.7Hz),7.28-7.22(2H,m),6.72(0.40H,t,J=5.9Hz),4.41-4.21(2H,m),4.07-3.92(1H,m),3.88(1.20H,s),3.82(1.80H,s),2.64-2.31(5H,m),1.84-1.67(2H,m)
8.06(1H,s),7.71(2H,d,J=8.1Hz),7.42-7.36(1.58H,m),7.21(2H,d,J=8.1Hz),6.70(0.42H,t,J=5.5Hz),5.11(0.58H,ddd,J=3.3,6.7,12.8Hz),5.03(0.42H,ddd,J=3.2,6.4,12.8Hz),4.50-4.34(2H,m),3.87(1.26H,s),3.82(1.74H,s),2.58-2.35(5H,m),2.12-1.98(2H,m)
7.98-7.92(2H,m),7.41(0.58H,t,J=5.6Hz),7.29-7.22(2H,m),6.68(0.42H,t,J=5.4Hz),4.63-4.45(2H,m),4.35-4.17(1H,m),3.87(1.26H,s),3.81(1.74H,s),2.70-1.89(7H,m)
9.84(1H,s),7.95(2H,d,J=8.0Hz),7.26(2H,d,J=8.0Hz),4.55(2H,ddd,J=6.3,11.7,28.2Hz),4.36-4.25(1H,m),2.90-2.68(2H,m),2.46-2.32(4H,m),2.18-2.03(1H,m)
〔A〕((2S)-5-ヒドロキシチオラン-2-イル)メチル 4-フェニルベンゾエートおよびそのアセチル体
8.14-8.08(2H,m),7.70-7.59(4H,m),7.51-7.36(3H,m),5.64-5.56(1H,m),4.58(0.53H,dd,J=6.6,11.1Hz),4.44(0.53H,dd,J=6.9,11.1Hz),4.32-4.20(0.94H,m),4.02-3.80(1H,m),2.42-1.97(5H,m)
8.14-8.07(2H,m),7.70-7.59(4H,m),7.51-7.36(3H,m),6.21-6.16(1H,m),4.58(0.54H,dd,J=6.4,11.0Hz),4.42-4.20(1.46H,m),3.94-3.78(1H,m),2.42-1.91(7H,m)
なお、原料である上記(2R)-2-ブロモ-5-オキソペンチル 4-フェニルベンゾエートは、以下のように、複数の工程で合成した。
8.09(1H,s),7.94-7.88(2H,m),7.71-7.60(4H,m),7.52-7.37(4.65H,m),6.70(0.35H,t,J=5.4Hz),5.19-5.01(1H,m),4.54-4.39(2H,m),3.88(1.05H,s),3.82(1.95H,s),2.63-2.38(2H,m),2.14-1.99(2H,m)
8.16-8.10(2H,m),7.71-7.59(4H,m),7.52-7.37(3.59H,m),6.69(0.41H,t,J=5.5Hz),4.67-4.49(2H,m),4.37-4.20(1H,m),3.88(1.23H,s),3.82(1.77H,s),2.71-1.94(4H,m)
9.85(1H,s),8.16-8.09(2H,m),7.71-7.59(4H,m),7.51-7.37(3H.m),4.68-4.49(2H,m),4.39-4.24(1H,m),2.92-2.70(2H,m),2.48-1.97(2H,m)
〔A〕((2R)-5-ヒドロキシチオラン-2-イル)メチル ベンゾエートおよびそのアセチル体
8.08-8.01(2H,m),7.62-7.54(1H,m),7.48-7.42(2H,m),5.63-5.53(1H,m),4.56(0.53H,dd,J=6.6,11.0Hz),4.42(0.53H,dd,J=6.9,11.0Hz),4.30-4.17(0.94H,m),4.00-3.92(0.47H,m),3.90-3.78(0.53H,m),2.41-1.92(5H,m)
8.08-8.01(2H,m),7.61-7.53(1H,m),7.49-7.41(2H,m),6.20-6.14(1H,m),4.56(0.54H,dd,J=6.5,11.0Hz),4.39-4.18(1.46H,m),3.93-3.76(1H,m),2.41-1.90(7H,m)
なお、原料である上記(2S)-2-(メタンスルホニルオキシ)-5-オキソペンチル ベンゾエートは、以下のように、複数の工程で合成した。
8.07-8.01(2H,m),7.63-7.56(1H,m),7.50-7.43(2H,m),4.93-4.83(1H,m),4.55(1H,dd,J=3.2,12.2Hz),4.45(1H,dd,J=5.3,12.2Hz),2.73-2.07(4H,m)
8.08-8.04(2H,m),7.62-7.55(1H,m),7.49-7.43(2H,m),5.22(0.22H,ddd,J=3.6,6.1,12.6Hz),4.40(0.78H,dd,J=3.6,11.4Hz),4.28(0.78H,dd,J=7.0,11.4Hz),4.08-3.99(0.78H,m),3.90-3.67(2.44H,m),1.92-1.53(4H,m)
8.09-8.04(2H,m),7.61-7.54(1H,m),7.48-7.41(2H,m),4.37(1H,dd,J=4.2,11.3Hz),4.29(1H,dd,J=6.3,11.3Hz),4.08-3.96(1H,m),3.84-3.70(2H,m),3.16(1H,d,J=4.2Hz),1.87-1.59(4H,m),1.18-1.01(21H,m)
8.10-8.04(2H,m),7.62-7.55(1H,m),7.49-7.43(2H,m),5.09(1H,ddd,J=3.2,6.9,12.9Hz),4.56(1H,dd,J=3.1,12.3Hz),4.43(1H,dd,J=6.9,12.3Hz),3.83-3.70(2H,m),3.03(3H,s),2.01-1.63(4H,m),1.15-0.97(21H,m)
8.10-8.04(2H,m),7.63-7.55(1H,m),7.50-7.42(2H,m),5.11(1H,ddd,J=3.1,6.6,13.1Hz),4.57(1H,dd,J=3.1,12.4Hz),4.43(1H,dd,J=6.9,12.4Hz),3.75(1H,br),3.05(3H,s),1.98-1.70(4H,m),1.41(1H,br)
9.83(1H,s),8.08-8.03(2H,m),7.64-7.56(1H,m),7.51-7.43(2H,m),5.10-5.02(1H,m),4.55(1H,dd,J=3.3,12.4Hz),4.43(1H,dd,J=6.6,12.4Hz),3.04(3H,s),2.82-2.72(2H,m),2.26-1.97(2H,m)
〔A〕((2R)-5-ヒドロキシチオラン-2-イル)メチル 4-フェニルベンゾエートおよびそのアセチル体
8.14-8.08(2H,m),7.70-7.60(4H,m),7.51-7.36(3H,m),5.64-5.56(1H,m),4.59(0.53H,dd,J=6.6,11.1Hz),4.44(0.53H,dd,J=6.9,11.1Hz),4.28(0.47H,dd,J=8.7,11.1Hz),4.23(0.47H,dd,J=6.6,11.1Hz),4.03-3.93(0.47H,m),3.92-3.80(0.53H,m),2.43-1.94(5H,m)
8.14-8.07(2H,m),7.70-7.69(4H,m),7.51-7.36(3H,m),6.22-6.16(1H,m),4.58(0.54H,dd,J=6.6,11.1Hz),4.41-4.20(1.46H,m),3.94-3.79(1H,m),2.42-1.92(7H,m)
なお、原料である上記(2S)-2-(メタンスルホニルオキシ)-5-オキソペンチル 4-フェニルベンゾエートは、以下のように、複数の工程で合成した。
8.15-8.08(2H,m),7.71-7.59(4H,m),7.52-7.37(3.52H,m),6.74(0.48H,t,J=5.7Hz),4.46-4.37(1H,m),4.33-4.24(1H,m),4.10-3.94(1H,m),3.89(1.44H,s),3.83(1.56H,s),2.67-2.37(3H,m),1.87-1.71(2H,m)
8.17-8.08(2H,m),7.71-7.58(4H,m),7.50-7.36(3.58H,m),6.72(0.42H,t,J=5.5Hz),5.15-5.00(1H,m),4.62-4.41(2H,m),3.88(1.26H,s),3.83(1.74H,s),3.08(1.74H,3H),3.07(1.26H,m),2.63-2.37(2H,m),2.11-1.97(2H,m)
9.84(1H,s),8.15-8.09(2H,m),7.72-7.59(4H,m),7.51-7.37(3H,m),5.13-5.03(1H,m),4.57(1H,dd,J=3.3,12.3Hz),4.46(1H,dd,J=6.6,12.3Hz),3.06(3H,s),2.88-2.67(2H,m),2.25-2.00(2H,m)
なお、本発明の一般式(II)で表される化合物を出発原料とし、常法またはそれに準じた方法により、有用な生理活性物質として期待されるチオヌクレオシドを合成することができる。このように、本発明の一般式(II)で表される化合物の製造方法ならびに本発明の一般式(II)で表される化合物は、有用である。
Claims (14)
- 下記一般式(I)で表される化合物を硫黄化合物と反応させる工程を経由する下記一般式(II)で表される化合物の製造方法。
ただし、R2がフッ素原子、アシルオキシ基、アリールメチルオキシ基、アリルオキシ基、アリールメチルオキシカルボニルオキシ基またはアリルオキシカルボニルオキシ基の場合、R3はアシルオキシ基である。 - 前記R5がアリール基であり、かつR3または-O-C(=O)-R3aがアリールカルボニルオキシ基である請求項1または2に記載の製造方法。
- 前記R5が、フェニル基、4-メチルフェニル基、4-フェニルフェニル基または2-ナフチル基であり、かつR3または-O-C(=O)-R3aがフェニルカルボニルオキシ基、4-メチルフェニルカルボニルオキシ基、4-フェニルフェニルカルボニルオキシ基または2-ナフチルカルボニルオキシ基である請求項1~3のいずれか1項に記載の製造方法。
- 前記R1またはR1aがアセチル基またはアリールカルボニル基である請求項1~5のいずれか1項に記載の製造方法。
- 前記Xが、ハロゲン原子、アルキルスルホニルオキシ基またはアリールスルホニルオキシ基である請求項1~6のいずれか1項に記載の製造方法。
- 前記硫黄化合物が、Mがアルカリ金属であるMSHまたはM2Sである請求項1~7のいずれか1項に記載の製造方法。
- 前記R1が、水素原子、アセチル基またはアリールカルボニル基であり、R2a、R3aおよびR5が各々独立に、アリール基である請求項9に記載の化合物。
- 前記R2a、R3aおよびR5が各々独立に、フェニル基、4-メチルフェニル基、4-フェニルフェニル基または2-ナフチル基である請求項9または10に記載の化合物。
- 下記一般式(II-1A’)、(II-1B)、(II-2A)、(II-2B’)、(II-3)、(II-6B)、(II-9)、(II-13’)または(II-14’)のいずれかで表される化合物。
- 前記R1が水素原子、アセチル基、4-メチルベンゾイル基、4-フェニルベンゾイル基または2-ナフトイル基であり、前記R1bおよびR1cが各々独立に、水素原子、4-メチルベンゾイル基、4-フェニルベンゾイル基または2-ナフトイル基であり、前記R2a、R3a、R5、R5bおよびR5cが各々独立に、4-メチルフェニル基、4-フェニルフェニル基または2-ナフチル基であり、前記R2bが、フェニルメチル基であり、前記R5dおよびR5eが各々独立に、フェニル基、4-メチルフェニル基、4-フェニルフェニル基または2-ナフチル基である請求項12に記載の化合物。
- 前記化合物が、チオヌクレオシド合成中間体である請求項9~13のいずれか1項に記載の化合物。
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