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  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B61/00—Other general methods
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C327/00—Thiocarboxylic acids
  • C07C327/02—Monothiocarboxylic acids
  • C07C327/04—Monothiocarboxylic acids having carbon atoms of thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C327/06—Monothiocarboxylic acids having carbon atoms of thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of an acyclic saturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
  • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
  • C07C69/618—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety having unsaturation outside the six-membered aromatic ring
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
  • C07D307/20—Oxygen atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
  • C07D309/10—Oxygen atoms
  • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
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  • 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
  • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
  • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
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  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
  • C07H7/04—Carbocyclic radicals

Definitions

• the present invention relates to a thioester derivative and its production method, a ketone derivative and its production method, a production method of a C-aryl-hydroxyglycoside derivative, and a production method of a C-arylglycoside derivative.
• SGLT2 inhibitors are useful as antidiabetic agents.
• “SGLT2” means sodium-glucose cotransporter-2.
• SGLT2 inhibitors include, for example, canagliflozin (1-( ⁇ -D-glycopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene), empagliflozin ( (1S)-1,5-anhydro-1-C- ⁇ 4-chloro-3-[(4- ⁇ [(3S)-oxolan-3-yl]oxy ⁇ phenyl)methyl]phenyl ⁇ -D-glucitol) , ipragliflozin ((1S)-1,5-anhydro-1-C- ⁇ 3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl ⁇ -D-glucitol-(2S)- pyrrolidine-2-carboxylic acid), dapaglif
• Non-Patent Documents 1 and 3 a method of adding an aryl group by reacting an aryllithium with a D-gluconolactone derivative at an ultra-low temperature of -78°C ( Non-Patent Documents 1 and 3), adding an aryl group by reacting a D-gluconolactone derivative with a turbo Grignard reagent such as ArMgBr.LiCl (where Ar represents an aryl group) at a low temperature of -20 to -10°C.
• a turbo Grignard reagent such as ArMgBr.LiCl (where Ar represents an aryl group) at a low temperature of -20 to -10°C.
• Non-Patent Document 2 A reaction method (Non-Patent Document 2), using a magnesiumate complex obtained from lithium tri-n-butyl magnesate (nBu 3 MgLi), under a temperature environment of about -15 ° C., aryl to D-gluconolactone derivative A method of subjecting a group to an addition reaction (Patent Document 2) and the like are known. In addition, it has been reported that a ketone derivative is obtained by reacting a thioester derivative with an organozinc reagent in the presence of a nickel catalyst to cause coupling (Non-Patent Documents 4 and 5).
• Remdesivir represented by the following formula (X) is a compound that can be used as an antiviral drug.
• Remdesivir exhibits antiviral activity against single-stranded RNA viruses such as, for example, respiratory syncytial virus, coronavirus.
• Patent Document 3 discloses a method for producing remdesivir and its intermediates.
• Patent Document 3 discloses that a lactone represented by the following formula (XI) and a bromopyrazole represented by the following formula (Ar'') are treated in the presence of chlorotrimethylsilane (TMSCl) and n-butyllithium. It is described that a hydroxynucleoside represented by the following formula (XII) can be obtained by reacting at °C. This hydroxynucleoside can be used as an intermediate for remdesivir synthesis. "Bn” represents a benzyl group.
• An object of the present invention is to provide a novel thioester derivative and its production method, a novel ketone derivative and its production method, a novel production method of a C-aryl-hydroxyglycoside derivative, and a novel production method of a C-arylglycoside derivative. one purpose.
• W 1 is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted arylalkyl group, or substituted represents an arylalkenyl group that may be R each independently represents an optionally substituted alkyl group, or each independently represents an optionally substituted aryl group, When R each independently represents an optionally substituted alkyl group, R' is an optionally substituted alkylsilyl group, a tetrahydropyranyl group optionally having a substituent, Formula: -CO-L 1 -L 2 [In the formula, L 1 represents an optionally substituted alkylene group or an optionally substituted haloalkylene group, and L 2 is a halogen represents an atom
• a group represented by Formula: -C(-L 3 )(-L 4 )-OL 5 [In the formula, L 3 represents a hydrogen atom or an optionally substituted alkyl group, and L 4 and L 5 , each independently represents an optionally substituted alkyl group.
• R independently represents an optionally substituted aryl group
• R' is an optionally substituted alkylcarbonyl group, an optionally substituted alkylsilyl group, aldehyde group
• Formula: -CO-L 1 -L 2 [In the formula, L 1 and L 2 have the same definitions as above.
• W2 is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted arylalkyl group, or substituted represents an arylalkenyl group that may be R each independently represents an optionally substituted alkyl group, or each independently represents an optionally substituted aryl group, When R each independently represents an optionally substituted alkyl group, R' is an optionally substituted alkylsilyl group, a tetrahydropyranyl group optionally having a substituent, Formula: -CO-L 1 -L 2 [In the formula, L 1 represents an optionally substituted alkylene group or an optionally substituted
• a group represented by Formula: -C(-L 3 )(-L 4 )-OL 5 [In the formula, L 3 represents a hydrogen atom or an optionally substituted alkyl group, and L 4 and L 5 , each independently represents an optionally substituted alkyl group.
• R independently represents an optionally substituted aryl group
• R' is an optionally substituted alkylcarbonyl group, an optionally substituted alkylsilyl group, aldehyde group
• Formula: -CO-L 1 -L 2 [In the formula, L 1 and L 2 have the same definitions as above.
• n represents 1 or 2;
• a ketone derivative (II) represented by [3] The thioester according to [1], wherein each R independently represents an optionally substituted aryl group, and R′ represents an optionally substituted alkylcarbonyl group.
• [5] A method for producing a thioester derivative (I) according to [1], wherein each R independently represents an optionally substituted aryl group, and R' represents an aldehyde group.
• Each R independently represents an optionally substituted aryl group, and R′ represents a group represented by the formula: —CO—L 1 -L 2 [1]
• Each R independently represents an aryl group which may have a substituent
• R′ is represented by the formula: —CO—C(—L 9 )(—L 10 )(—L 11 )
• Each R independently represents an optionally substituted alkyl group, and R′ represents a group represented by the formula: —CO—L 1 -L 2 [1]
• Each R independently represents an optionally substituted alkyl group, and R′ is represented by the formula: —C(—L 3 )(—L 4 )—OL 5
• each R independently represents an optionally substituted alkyl group
• R' 8 A method for producing the thioester derivative (I) according to [1], which represents the group represented by in the presence of a base, Formula (III) below: [In the formula, W 1 and n have the same meaning as in [1], and each R independently represents an optionally substituted alkyl group.
• An acyl-protected lactone derivative (IV) represented by The method according to any one of [3] to [12], comprising the step of producing the thioester derivative (III). [14] In the above step, after the magnesium thiolate is formed by the reaction of the thiol (3) and the Grignard reagent (4), the thioester derivative is formed by the reaction of the magnesium thiolate with the acyl-protected lactone derivative (IV). The method of [13], wherein (III) is formed.
• R each independently represents an optionally substituted alkyl group, or each independently represents an optionally substituted aryl group
• W2 is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted arylalkyl group, or substituted represents an arylalkenyl group that may be R 100 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted alkylcarbonyl group, or a substituted represents a good arylcarbonyl group, n represents 1 or 2;
• a method for producing a C-aryl-hydroxyglycoside derivative (V) represented by The ketone derivative (II) according to [2] is contacted with a first acid and/or base
• W2 is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted arylalkyl group, or substituted represents an arylalkenyl group that may be n represents 1 or 2;
• novel thioester derivatives and production methods thereof, novel ketone derivatives and production methods thereof, novel production methods of C-aryl-hydroxyglycoside derivatives, and novel production methods of C-arylglycoside derivatives are provided.
• inexpensive and efficient industrial production of thioester derivatives, ketone derivatives, C-aryl-hydroxyglycoside derivatives and C-arylglycoside derivatives becomes possible, and raw material costs, facility costs, running costs, etc. can be reduced. can be greatly suppressed.
• Organic solvents examples include nitrile solvents such as acetonitrile and propionitrile; ether solvents such as diisopropyl ether, dimethoxyethane and diglyme; ketone solvents such as acetone, methyl ethyl ketone and diethyl ketone; ester solvents such as methyl acetate, ethyl acetate and butyl acetate; dichloromethane (DCM), chloroform, carbon tetrachloride, Halogenated hydrocarbon solvents such as 1,2-dichloroethane and chlorobenzene; aromatic hydrocarbon solvents such as toluene and xylene; and aliphatic hydrocarbon solvents such as hexane and heptane.
• nitrile solvents such as acetonitrile and propionitrile
• ether solvents such as diisopropyl ether, dimethoxyethane and diglyme
• ketone solvents
• Halogen Atom Halogen is selected from fluorine, chlorine, bromine and iodine.
• Alkyl group The number of carbon atoms in the alkyl group is, for example, 1 to 20, preferably 1 to 15, more preferably 1 to 12 (eg, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 ⁇ 3 or 1 ⁇ 2).
• Alkyl groups may be linear or branched.
• the straight-chain alkyl group has 1 or more carbon atoms, and the branched-chain alkyl group has 3 or more carbon atoms.
• alkenyl group The number of carbon atoms in the alkenyl group is, for example, 2 to 20, preferably 2 to 15, more preferably 2 to 12 (for example, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4 or 2 ⁇ 3).
• An alkenyl group may be linear or branched.
• the straight-chain alkenyl group has 2 or more carbon atoms, and the branched-chain alkenyl group has 3 or more carbon atoms.
• Cycloalkyl Group The cycloalkyl group has, for example, 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms.
• Heterocycloalkyl group is a monocyclic ring containing one or more heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen atoms in addition to carbon atoms as ring-constituting atoms.
• a saturated aliphatic heterocyclic group is an aliphatic heterocyclic group whose ring is composed only of saturated bonds.
• the number of heteroatoms is, for example, 1-4, preferably 1-3, more preferably 1 or 2.
• the number of members of the heterocycloalkyl group is, for example, 3-8 membered, preferably 4-7 membered, more preferably 5-7 membered, even more preferably 5 or 6 membered.
• heterocycloalkyl groups include those containing 1 to 2 oxygen atoms, those containing 1 to 2 sulfur atoms, and those containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms. , those containing 1 to 4 nitrogen atoms, those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms.
• a heterocycloalkyl group preferably contains an oxygen atom as a heteroatom.
• Heterocycloalkyl groups include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, pyrazolidinyl, thiazolidinyl, and tetrahydroisothionyl.
• azolyl group tetrahydrooxazolyl group, tetrahydroisoxazolyl group, piperidinyl group, piperazinyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, morpholinyl group, thiomorpholinyl group (the sulfur atom on the ring may be oxidized, good), azepanyl group, diazepanyl group, oxepanyl group, azocanyl group, diazocanyl group and the like.
• heterocycloalkyl groups are selected from tetrahydrofuranyl and tetrahydropyranyl groups.
• a heterocycloalkyl group is preferably a tetrahydrofuranyl group.
• Aryl group is, for example, a monocyclic or polycyclic (eg, bicyclic or tricyclic) aromatic hydrocarbon ring having 4 to 14, preferably 6 to 14, more preferably 6 to 10 carbon atoms. is the base. Polycyclics are preferably fused rings. Examples of aryl groups include phenyl groups and naphthyl groups. Aryl groups are preferably phenyl groups.
• Heteroaryl Group A heteroaryl group is a monocyclic or polycyclic ring containing, in addition to carbon atoms, one or more heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen atoms as ring atoms. It is a cyclic (eg bicyclic or tricyclic) aromatic heterocyclic group. Polycyclics are preferably fused rings.
• the number of heteroatoms is, for example, 1-4, preferably 1-3, more preferably 1 or 2.
• the number of members of the heteroaryl group is preferably 4-14 membered, more preferably 5-10 membered.
• heteroaryl groups include those containing 1 to 2 oxygen atoms, those containing 1 to 2 sulfur atoms, those containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms, Examples include those containing 1 to 4 nitrogen atoms, those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms.
• Heteroaryl groups are preferably monocyclic or bicyclic 4- to 10-membered, preferably 5- to 10-membered, aromatic heterocyclic groups.
• Examples of monocyclic aromatic heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, Isoxazolyl group, oxadiazolyl group (e.g., 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, etc.), thiadiazolyl group (e.g., 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group) etc.), a triazolyl group (e.g., 1,2,3-triazolyl group, 1,2,4-triazolyl group, etc.), a tetrazolyl group, a 5- to 7-membered monocyclic aromatic heterocyclic group such as a triazinyl group mentioned.
• condensed polycyclic aromatic heterocyclic groups include benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotri solyl group, imidazopyridinyl group, thienopyridinyl group, furopyridinyl group, pyrrolopyridinyl group, pyrazolopyridinyl group, oxazolopyridinyl group, thiazolopyridinyl group, imidazopyrazinyl group, imidazopyrimidinyl group, thienopyrimidinyl group, furopyrimidinyl group, pyrrolopyrimidinyl group, pyrazolopyrimidinyl group, oxazolopyrimidinyl group, thiazolopyrimidinyl group, pyrazolotriazinyl group, naphtho
• heteroaryl groups are selected from thienyl groups, benzothiophenyl groups, furyl groups, pyrrolyl groups, imidazolyl groups and pyridyl groups.
• Heteroaryl groups are preferably selected from thienyl and benzothiophenyl groups.
• Haloalkyl, haloaryl and haloheteroaryl groups are alkyl, aryl and heteroaryl groups respectively having one or more halogen atoms, and alkyl, aryl and hetero A description of the aryl group is provided above.
• the number of halogen atoms possessed by the haloalkyl group, haloaryl group or haloheteroaryl group is, for example, 1 to 3, preferably 1 or 2, more preferably 1.
• Alkylene Groups, Arylene Groups and Heteroarylene Groups Alkylene groups, arylene groups and heteroarylene groups are divalent functional groups generated by removing one hydrogen atom from an alkyl group, an aryl group and a heteroaryl group, respectively. and the descriptions of the alkyl group, the aryl group and the heteroaryl group are as described above.
• Haloalkylene Groups, Haloarylene Groups, and Haloheteroarylene Groups Haloalkylene groups, haloarylene groups, and haloheteroarylene groups are formed by removing one hydrogen atom from haloalkyl groups, haloaryl groups, and haloheteroaryl groups, respectively. It is a divalent functional group, and the description of the haloalkyl group, the haloaryl group and the haloheteroaryl group is as described above.
• Arylalkenyl Group An arylalkenyl group is an alkenyl group having one or more aryl groups, and the descriptions of alkenyl groups and aryl groups are given above.
• the number of aryl groups possessed by the arylalkenyl group is, for example, 1 to 3, preferably 1 or 2, more preferably 1.
• Alkylcarbonyl Group and Arylcarbonyl Group are groups represented by the formula: -CO-alkyl group and -CO-aryl group, respectively. As above.
• Alkyloxy group, haloalkyloxy group, heterocycloalkyloxy group and arylalkyloxy group are each represented by the formula: -O-alkyl group, the formula: -O-haloalkyl groups, groups represented by the formula: -O-heterocycloalkyl group and formula: -O-arylalkyl group, and descriptions of the alkyl group, the haloalkyl group, the heterocycloalkyl group and the arylalkyl group are as follows: As above.
• Alkylthio group, haloalkylthio group, heterocycloalkylthio group and arylalkylthio group are respectively represented by the formula: -S-alkyl group, the formula: -S-haloalkyl group, Groups represented by the formula: -S-heterocycloalkyl group and the formula: -S-arylalkyl group, and the alkyl group, haloalkyl group, heterocycloalkyl group and arylalkyl group are as described above.
• alkyloxycarbonyl group is a group represented by the formula: --CO--O-alkyl group, and the description of the alkyl group is as described above.
• the number of carbon atoms in the alkyl group contained in the alkyloxycarbonyl group is preferably 1 to 10, more preferably 1 to 8, still more preferably 1 to 6, still more preferably 1 to 4, still more preferably 1 to 3. , more preferably 1 or 2.
• Amino Group An amino group is a group (primary amino group) represented by the formula: —NH 2 .
• the monoalkylamino group has the formula: —NH(—Q 1 ) [wherein Q 1 represents an alkyl group. ] and the description of the alkyl group is as described above.
• the number of carbon atoms in the alkyl group represented by Q 1 is preferably 1 to 10, more preferably 1 to 8, still more preferably 1 to 6, still more preferably 1 to 4, still more preferably 1 to 3, More preferably 1 or 2.
• Dialkylamino group has the formula: -N(-Q 2 )(-Q 3 ) [wherein Q 2 and Q 3 each independently represent an alkyl group. ] and the description of the alkyl group is as described above.
• the number of carbon atoms in the alkyl group represented by Q 2 or Q 3 is preferably 1 to 10, more preferably 1 to 8, still more preferably 1 to 6, still more preferably 1 to 4, still more preferably 1 ⁇ 3, more preferably 1 or 2.
• the alicyclic amino group is, for example, a 5- or 6-membered alicyclic amino group.
• the 5- or 6-membered alicyclic amino group include a morpholino group and a thiomorpholino group , pyrrolidin-1-yl group, pyrazolidin-1-yl group, imidazolidin-1-yl group, piperidin-1-yl group and the like.
• the alicyclic amino group has, in addition to the nitrogen atom having the bond of the alicyclic amino group, a heteroatom independently selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom (e.g., one heteroatom atoms).
• a cycloaliphatic amino group is preferably a morpholino group.
• Aminocarbonyl group, monoalkylaminocarbonyl group, dialkylaminocarbonyl group and alicyclic aminocarbonyl group aminocarbonyl group, monoalkylaminocarbonyl group, dialkylaminocarbonyl group and alicyclic aminocarbonyl group are each represented by the formula: -CO -amino group, formula: -CO-monoalkylamino group, formula: -CO-dialkylamino group and formula: -CO-alicyclic amino group, monoalkylamino group, dialkylamino group and The description of the alicyclic amino group is given above.
• Substituent group ⁇ is composed of the following substituents.
• Substituent group ⁇ is composed of the following substituents. ( ⁇ -1) Substituent represented by formula (i) ( ⁇ -2) Substituent represented by formula (ii)
• the number of carbon atoms in the alkyl group is preferably 1 to 10, more preferably 1 to 8, still more preferably 1 to 6, still more preferably 1 to 4, still more preferably 1 to 3. , more preferably 1 or 2.
• the number of carbon atoms in the haloalkyl group is preferably 1 to 10, more preferably 1 to 8, still more preferably 1 to 6, still more preferably 1 to 4, still more preferably 1 to 3. , more preferably 1 or 2.
• the haloalkyl group preferably has 1 to 3 halogen atoms, more preferably 1 or 2, and even more preferably 1.
• a hydroxy group which may be protected by a protecting group The hydroxy group- protecting group can protect the hydroxy group during the desired reaction, and can be removed from the hydroxy group after the desired reaction is completed. It is preferable to be Examples of hydroxy-protecting groups include alkylcarbonyl-type protecting groups, arylcarbonyl-type protecting groups, arylalkyl-type protecting groups, alkyl-type protecting groups, arylalkyloxyalkyl-type protecting groups, alkyloxyalkyl-type protecting groups, and silyl-type protecting groups. groups, oxycarbonyl-type protecting groups, acetal-type protecting groups, aryl-type protecting groups, and the like. These protecting groups may have one or more halogen atoms.
• alkylcarbonyl-type protecting groups include alkylcarbonyl groups having 2 to 10 carbon atoms which may have one or more substituents.
• Substituents include, for example, a halogen atom, a nitro group, a cyano group, a phenyl group, and 1 to 10 carbon atoms (preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms).
• an alkyloxy group having 1 to 10 carbon atoms (preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms), 2 to 11 carbon atoms (preferably carbon It can be selected from alkyloxycarbonyl groups having 2 to 9 carbon atoms, more preferably 2 to 7 carbon atoms, more preferably 2 to 5 carbon atoms, and the like.
• alkylcarbonyl groups having 2 to 10 carbon atoms which may have one or more substituents include acetyl group, propanoyl group, butanoyl group, isopropanoyl group and pivaloyl group.
• the alkylcarbonyl-type protecting group is preferably an alkylcarbonyl group having 2 to 5 carbon atoms, more preferably an acetyl group or a pivaloyl group, and still more preferably an acetyl group.
• arylcarbonyl-type protective groups include arylcarbonyl groups having 7 to 11 carbon atoms which may have one or more substituents. Specific examples of the substituent are the same as those for the alkylcarbonyl type protective group. Examples of the arylcarbonyl group having 7 to 11 carbon atoms which may have one or more substituents include benzoyl group, 4-nitrobenzoyl group, 4-methyloxybenzoyl group, 4-methylbenzoyl group, 4- tert-butylbenzoyl group, 4-fluorobenzoyl group, 4-chlorobenzoyl group, 4-bromobenzoyl group, 4-phenylbenzoyl group, 4-methyloxycarbonylbenzoyl group and the like.
• arylalkyl-type protecting groups include arylalkyl groups having 7 to 11 carbon atoms which may have one or more substituents. Specific examples of the substituent are the same as those for the alkylcarbonyl type protective group. Examples of arylalkyl groups having 7 to 11 carbon atoms which may have one or more substituents include benzyl group, 1-phenylethyl group, diphenylmethyl group, 1,1-diphenylethyl group and naphthylmethyl group. , a trityl group, and the like. Arylalkyl-type protecting groups are preferably benzyl groups.
• alkyl-type protecting groups include alkyl groups having 1 to 10 carbon atoms which may have one or more substituents. Specific examples of the substituent are the same as those for the alkylcarbonyl type protective group.
• the alkyl-type protecting group is preferably an alkyl group having 1 to 5 carbon atoms which may have one or more substituents, more preferably a methyl group, an ethyl group or a tert-butyl group, and more More preferably, it is a methyl group.
• arylalkyloxyalkyl-type protecting group examples include an arylalkyloxymethyl group having 8 to 12 carbon atoms which may have one or more substituents, and an arylalkyloxymethyl group which may have one or more substituents.
• Examples include arylalkyloxyalkyl groups such as 9-13 arylalkyloxyethyl groups and optionally substituted 10-14 carbon atom arylalkyloxypropyl groups.
• substituent are the same as those for the alkylcarbonyl type protective group.
• the arylalkyloxyalkyl-type protecting group is, for example, a benzyloxymethyl group optionally having one or more substituents, preferably substituted with a halogen atom, a nitro group, a cyano group, a methyl group or a methyloxy group.
• benzyloxymethyl group more preferably benzyloxymethyl group.
• alkyloxyalkyl-type protecting groups include alkyloxymethyl groups having 2 to 10 carbon atoms which may have one or more substituents, and alkyloxymethyl groups having 3 to 10 carbon atoms which may have one or more substituents. 10 alkyloxyethyl groups, and alkyloxyalkyl groups such as alkyloxypropyl groups having 4 to 10 carbon atoms which may have one or more substituents. Specific examples of the substituent are the same as those for the alkylcarbonyl type protective group.
• the alkyloxyalkyl-type protecting group is preferably an alkyloxymethyl group having 2 to 10 carbon atoms which may have one or more substituents, more preferably a halogen atom, a nitro group, a cyano group, a methyloxy group. or an alkyloxymethyl group having 2 to 6 carbon atoms which may have an ethyloxy group, more preferably a methyloxymethyl group.
• silyl-type protecting groups include alkyl groups having 1 to 10 carbon atoms which may have one or more substituents, arylalkyl groups having 7 to 11 carbon atoms which may have one or more substituents, and a silyl group having a functional group selected from aryl groups having 6 to 10 carbon atoms which may have one or more substituents.
• substituents are the same as those for the alkylcarbonyl type protective group.
• the silyl-type protecting group is preferably a silyl group having a functional group selected from an alkyl group having 1 to 10 carbon atoms and an aryl group having 6 to 10 carbon atoms, more preferably an alkyl group having 1 to 5 carbon atoms and A silyl group having a functional group selected from a phenyl group, more preferably a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group.
• Examples of the oxycarbonyl-type protecting group include alkyloxycarbonyl groups having 2 to 10 carbon atoms which may have one or more substituents, and 3 to 10 carbon atoms which may have one or more substituents. and an arylalkyloxycarbonyl group having 8 to 12 carbon atoms which may have one or more substituents. Specific examples of the substituent are the same as those for the alkylcarbonyl type protective group.
• the oxycarbonyl type protective group is preferably an alkyloxycarbonyl group having 2 to 6 carbon atoms, an alkenyloxycarbonyl group having 3 to 6 carbon atoms or a benzyloxycarbonyl group, more preferably a methyloxymethyl group, an allyloxycarbonyl group or It is a benzyloxycarbonyl group.
• acetal-type protective group examples include a tetrahydrofuranyl group and a tetrahydropyranyl group.
• Aryl-type protective groups include, for example, aryl groups such as phenyl groups.
• a hydroxy group protected with a protecting group is preferably a group represented by the formula: -OQ.
• Q represents an alkyl group, haloalkyl group, aryl group, haloaryl group, heterocycloalkyl group, alkylcarbonyl group, arylcarbonyl group or arylalkyl group.
• the group represented by the formula: -OQ preferably has 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms.
• Q is preferably an alkyl group, a heterocycloalkyl group, an alkylcarbonyl group or an arylalkyl group, more preferably an ethyl group, a tetrahydrofuranyl group, an acetyl group or a benzyl group.
• a thiol group which may be protected by a protecting group The thiol group- protecting group can protect the thiol group during the target reaction, and can be removed from the thiol group after the target reaction is completed. It is preferable to be Examples of thiol group-protecting groups include alkylcarbonyl-type protecting groups, arylcarbonyl-type protecting groups, arylalkyl-type protecting groups, alkyl-type protecting groups, arylalkyloxyalkyl-type protecting groups, alkyloxyalkyl-type protecting groups, and silyl-type protecting groups. groups, oxycarbonyl-type protecting groups, acetal-type protecting groups, aryl-type protecting groups, and the like. These protecting groups may have one or more halogen atoms. A description of these protecting groups is provided above.
• a thiol group protected with a protecting group is preferably a group represented by the formula: -SQ.
• a description of Q is provided above.
• R 11 , R 12 and R 13 each independently represent an alkyl group, a haloalkyl group, an aryl group, a haloaryl group or a hydroxy group which may be protected by a protecting group.
• the hydroxy group which may be protected by a protecting group is preferably a group represented by the above formula: --OQ. a is 0 or more and 3 or less.
• V 10 represents an alkylene group, haloalkylene group, arylene group, haloarylene group, heteroarylene group, haloheteroarylene group, ester bond, ether bond or carbonyl group.
• the alkylene group or haloalkylene group preferably has 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms.
• the arylene group, haloarylene group, heteroarylene group or haloheteroarylene group preferably has 4 to 14 carbon atoms, more preferably 6 to 14 carbon atoms.
• V 10 is preferably an alkylene group, more preferably a methylene group or an ethylene group.
• b represents 0 or 1. b is preferably one.
• W 10 represents an alkylene group, haloalkylene group, arylene group, haloarylene group, heteroarylene group, haloheteroarylene group, ester bond, ether bond or carbonyl group.
• W 10 is preferably a heteroarylene group, more preferably a 5-membered heteroarylene group containing a sulfur atom as a heteroatom, and even more preferably a thienylene group.
• c represents 0 or 1.
• c is 1.
• X 10 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group represents
• the alkyl group, aryl group or heteroaryl group represented by X 10 may have one or more substituents, and the one or more substituents are each independently selected from the substituent group ⁇ . can be done.
• one or more substituents are each independently selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio groups, haloalkylthio groups, heterocycloalkyloxy groups and heterocycloalkylthio groups; is preferred, more preferably selected from a halogen atom, an alkyloxy group having 1 to 3 carbon atoms and a heterocycloalkyloxy group, and more preferably selected from a fluorine atom, an ethyloxy group and a tetrahydrofuranyloxy group.
• X 10 is preferably an optionally substituted aryl group or an optionally substituted heteroaryl group, wherein a halogen atom, an alkyloxy group having 1 to 3 carbon atoms or an oxygen atom is An aryl group having a heterocycloalkyloxy group containing as a heteroatom or an unsubstituted heteroaryl group is more preferable, and a phenyl group having a fluorine atom, an ethyloxy group or a tetrahydrofuranyloxy group, or an unsubstituted benzo A thiophenyl group is more preferred.
• Thioester derivative (I) is represented by the following formula (I).
• n 1 or 2.
• each R independently represents an optionally substituted alkyl group, or each independently represents an optionally substituted aryl group.
• the thioester derivative (I) in which each R independently represents an optionally substituted aryl group is referred to as a thioester derivative (I-1), and each R is independently Therefore, the thioester derivative (I) representing an optionally substituted alkyl group is sometimes referred to as a thioester derivative (I-2).
• R when each R independently represents an optionally substituted alkyl group, R' an optionally substituted alkylsilyl group, a tetrahydropyranyl group optionally having a substituent, Formula: -CO-L 1 -L 2 [In the formula, L 1 represents an optionally substituted alkylene group or an optionally substituted haloalkylene group, L 2 is a halogen represents an atom. ] A group represented by Formula: -C(-L 3 )(-L 4 )-OL 5 [wherein L 3 represents a hydrogen atom or an optionally substituted alkyl group, and L 4 and L 5 , each independently represents an optionally substituted alkyl group.
• R' is an optionally substituted alkylcarbonyl group, an optionally substituted alkylsilyl group, aldehyde group, Formula: -CO-L 1 -L 2 [In the formula, L 1 and L 2 have the same definitions as above. ]
• a group represented by, or Formula: -CO-C(-L 9 )(-L 10 )(-L 11 ) [wherein L 9 , L 10 and L 11 each independently represent a halogen atom. ] represents the group represented by.
• each R independently represents an optionally substituted alkyl group, and R' represents an optionally substituted alkylsilyl group.
• the alkyl group optionally having substituent(s) and the alkylsilyl group optionally having substituent(s) are described below.
• alkyl Groups which May Have a Substituent The explanations regarding the alkyl groups are as described above.
• the number of carbon atoms in the alkyl group is preferably 1-10, more preferably 1-8, still more preferably 1-6, still more preferably 1-4, and still more preferably 1-3.
• Alkyl groups may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups. It is more preferably selected from an alkyl group, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom and an alkyl group having 1 to 4 carbon atoms.
• alkyloxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t -butyl group, etc.).
• Alkylsilyl group optionally having substituent(s) is represented by the formula: —Si—R 1 (—R 2 )(—R 3 ) is the base.
• R 1 , R 2 and R 3 each independently represent an optionally substituted alkyl group or an optionally substituted aryl group, and R 1 , R 2 and R 3 At least one of represents an optionally substituted alkyl group.
• one of R 1 , R 2 and R 3 represents an optionally substituted alkyl group, and the remaining two represent an optionally substituted aryl group. show.
• R 1 , R 2 and R 3 represent an optionally substituted alkyl group, and the remaining one represents an optionally substituted aryl group.
• R 1 , R 2 and R 3 all represent optionally substituted alkyl groups.
• the number of carbon atoms in the alkyl group is preferably 1-10, more preferably 1-8, even more preferably 1-6, and still more preferably 1-4.
• Alkyl groups may have one or more substituents.
• the number of substituents that the alkyl group has is preferably 1 to 3, more preferably 1 or 2.
• One or more substituents of the alkyl group can be independently selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents of the alkyl group are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups, more preferably selected from an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms; 4 alkyl groups and alkyloxy groups having 1 to 4 carbon atoms, and alkyl groups having 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl group, t-butyl group
• Aryl groups may have one or more substituents.
• the number of substituents on the aryl group is preferably 1-3, more preferably 1 or 2.
• One or more substituents of the aryl group can be independently selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents on the aryl group are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups, more preferably selected from an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms; 4 alkyl groups and alkyloxy groups having 1 to 4 carbon atoms, and alkyl groups having 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl group, t-butyl group, etc.).
• halogen atoms e.g., methyl, ethyl, n-propyl, iso
• R 1 , R 2 and R 3 each independently represent an alkyl group or an aryl group, and when one or more of R 1 , R 2 and R 3 represent an alkyl group,
• the group represented by 1 (-R 2 )(-R 3 ) is an alkylsilyl group.
• alkylsilyl groups include monoalkylsilyl groups such as t-butyldiphenylsilyl group (TBDPS) and methyldiphenylsilyl group (MDPS); dialkylsilyl groups such as dimethylphenylsilyl group; trimethylsilyl group (TMS) and triethylsilyl.
• TES dimethylisopropylsilyl group
• IPDMS dimethylisopropylsilyl group
• DEIPS diethylisopropylsilyl group
• TDS dimethylthexylsilyl group
• TBS t-butyldimethylsilyl group
• TIPS triisopropylsilyl group
• di- Examples include trialkylsilyl groups such as t-butylmethylsilyl group (DTBMS). Among these, a trialkylsilyl group is preferred, TBS or TMS is more preferred, and TBS is even more preferred.
• each R independently represents an optionally substituted alkyl group
• R' represents an optionally substituted tetrahydropyranyl group.
• the description of the optionally substituted alkyl group is as described in (1a) above.
• the tetrahydropyranyl group optionally having a substituent is described below.
• the tetrahydropyranyl group may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups.
• an alkyl group a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom and an alkyl group having 1 to 4 carbon atoms. and an alkyloxy group having 1 to 4 carbon atoms, and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t -butyl group, etc.).
• each R independently represents an optionally substituted alkyl group
• R' represents a group represented by the formula: -CO-L 1 -L 2 .
• the description of the optionally substituted alkyl group is as described in (1a) above.
• the group represented by the formula: -CO-L 1 -L 2 will be described below.
• the group L 1 represented by the formula: -CO-L 1 -L 2 represents an optionally substituted alkylene group or an optionally substituted haloalkylene group.
• the number of carbon atoms in the alkylene group and/or haloalkylene group is preferably 1 to 10, more preferably 1 to 8, still more preferably 1 to 6, still more preferably 1 to 4, and still more preferably 1 to 3. is.
• Each of the alkylene group and the haloalkylene group may have one or more substituents.
• the number of substituents each of the alkylene group and the haloalkylene group has is preferably 1 to 3, more preferably 1 or 2.
• One or more substituents possessed by each of the alkylene group and the haloalkylene group can be independently selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents of the alkylene group and the haloalkylene group are each independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio and a haloalkylthio group, It is more preferably selected from a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom , an alkyl group having 1 to 4 carbon atoms and an alkyloxy group having 1 to 4 carbon atoms, and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropy
• L2 represents a halogen atom.
• a halogen atom is preferably selected from a chlorine atom, a bromine atom and a fluorine atom, and more preferably a chlorine atom.
• the group represented by the formula: -CO-L 1 -L 2 is preferably selected from -CO-CH 2 Cl, -CO-CHCl 2 and -CO-CCl 3 and is -CO-CH 2 Cl is more preferable.
• each R independently represents an optionally substituted alkyl group
• R′ is of the formula: —C(—L 3 )(—L 4 )—O— represents a group represented by L5 ;
• the description of the optionally substituted alkyl group is as described in (1a) above.
• the group represented by the formula: -C(-L 3 )(-L 4 )-OL 5 will be described below.
• the group L 3 represented by the formula (1e): -C(-L 3 )(-L 4 )-OL 5 represents a hydrogen atom or an optionally substituted alkyl group, and L 4 and L5 each independently represent an optionally substituted alkyl group.
• L 3 is preferably an optionally substituted alkyl group.
• L 3 , L 4 and L 5 may be the same alkyl group or different alkyl groups.
• a description of the alkyl group is provided above.
• the number of carbon atoms in the alkyl group is preferably 1-10, more preferably 1-8, still more preferably 1-6, still more preferably 1-4, and still more preferably 1-3.
• Alkyl groups may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups, halogen atoms, C 1-4 It is more preferably selected from an alkyl group, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom and an alkyl group having 1 to 4 carbon atoms.
• alkyloxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t -butyl group, etc.).
• the group represented by the formula: -C(-L 3 )(-L 4 )-OL 5 is -C(-CH 3 ) 2 -O-CH 3 and -CH(-CH 3 )-O- It is preferably selected from CH 2 CH 3 , more preferably -C(-CH 3 ) 2 -O-CH 3 .
• each R independently represents an optionally substituted alkyl group of the formula: —CO—O—C(—L 6 )(—L 7 )(—L 8 ) represents a group represented by The description of the optionally substituted alkyl group is as described in (1a) above. Groups represented by the formulas: —CO—O—C(—L 6 )(—L 7 )(—L 8 ) are described below.
• a description of the alkyl group is provided above.
• the number of carbon atoms in the alkyl group is preferably 1-10, more preferably 1-8, still more preferably 1-6, still more preferably 1-4, and still more preferably 1-3.
• Alkyl groups may have one or more substituents. The number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups, halogen atoms, C 1-4 It is more preferably selected from an alkyl group, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom and an alkyl group having 1 to 4 carbon atoms.
• alkyloxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t -butyl group, etc.).
• the group represented by the formula: —CO—O—C(—L 6 )(—L 7 )(—L 8 ) is preferably —CO—O—C(—CH 3 ) 3 , —CO—O -C(-CH 2 CH 3 ) 3 , -CO-OC(-CH 3 )(-CH 2 CH 3 ) 2 , -CO-OC(-CH 3 ) 2 (-CH 2 CH 3 ) and more preferably —CO—O—C(—CH 3 ) 3 .
• each R independently represents an optionally substituted aryl group
• R' represents an optionally substituted alkylcarbonyl group.
• the aryl group optionally having substituent(s) and the alkylcarbonyl group optionally having substituent(s) are described below.
• Aryl group optionally having a substituent The aryl group is as described above.
• Aryl groups may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups, halogen atoms, C 1-4 It is more preferably selected from an alkyl group, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom and an alkyl group having 1 to 4 carbon atoms.
• alkyloxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t -butyl group, etc.).
• alkylcarbonyl group optionally having substituent(s)
• the description of the alkylcarbonyl group is as described above.
• the number of carbon atoms in the alkyl group contained in the alkylcarbonyl group (-CO-alkyl group) is preferably 1 to 10, more preferably 1 to 8, more preferably 1 to 6, more preferably 1 to 4, more preferably 1 to 3.
• the alkyl group contained in the alkylcarbonyl group may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups, halogen atoms, C 1-4 It is more preferably selected from an alkyl group, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom and an alkyl group having 1 to 4 carbon atoms.
• alkyloxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t -butyl group, etc.).
• each R independently represents an optionally substituted aryl group
• R' represents an optionally substituted alkylsilyl group.
• the description of the optionally substituted aryl group is as described in (1g) above.
• the description of the optionally substituted alkylsilyl group is as described in (1b) above.
• each R independently represents an optionally substituted aryl group
• R' represents an aldehyde group (--CHO).
• the description of the optionally substituted aryl group is as described in (1g) above.
• each R independently represents an optionally substituted aryl group
• R' represents a group represented by the formula: -CO-L 1 -L 2 .
• the description of the optionally substituted aryl group is as described in (1g) above.
• the group represented by the formula: -CO-L 1 -L 2 is as described in (1d) above.
• each R independently represents an optionally substituted aryl group
• R′ is of the formula: —CO—C(—L 9 )(—L 10 )( - represents a group represented by L 11 ).
• the description of the optionally substituted aryl group is as described in (1g) above.
• Groups represented by the formulas: -CO-C(-L 9 )(-L 10 )(-L 11 ) are described below.
• L 9 , L 10 and L 11 may be the same halogen atom or different halogen atoms, but are preferably the same halogen atom.
• a halogen atom is preferably selected from a fluorine atom, a chlorine atom and a bromine atom, and more preferably a fluorine atom.
• n 1
• the three R's may be different, but are the same from the viewpoint of efficient introduction and removal of the group represented by the formula: -CO-R. is preferred.
• all three R are methyl groups.
• all three R are phenyl groups.
• R' is preferably TBS, TMS, a tetrahydropyranyl group, -CO-CH 2 -Cl, -C(-CH 3 ) 2 -O-CH 3 or --CO--O--C(--CH 3 ) 3 , more preferably TBS, tetrahydropyranyl group, --CO--CH 2 --Cl, --C(--CH 3 ) 2 --O--CH 3 or --CO--O —C(—CH 3 ) 3 .
• R' is preferably an acetyl group, TBS, TMS, an aldehyde group, -CO- CH2 -Cl or -CO- CF3 , more preferably an acetyl group, TBS, an aldehyde group, --CO--CH 2 --Cl or --CO--CF 3 .
• n 2
• the four R may be different, but are the same from the viewpoint of efficient introduction and removal of the group represented by the formula: -CO-R. is preferred.
• all four R are methyl groups.
• all four R are phenyl groups.
• R' is preferably TBS, TMS, a tetrahydropyranyl group, -CO-CH 2 -Cl, -C(-CH 3 ) 2 -O-CH 3 or --CO--O--C(--CH 3 ) 3 , more preferably TBS, tetrahydropyranyl group, --CO--CH 2 --Cl, --C(--CH 3 ) 2 --O--CH 3 or --CO--O —C(—CH 3 ) 3 .
• R' is preferably an acetyl group, TBS, TMS, an aldehyde group, -CO- CH2 -Cl or -CO- CF3 , more preferably an acetyl group, TBS, an aldehyde group, --CO--CH 2 --Cl or --CO--CF 3 .
• W 1 is (1) an optionally substituted alkyl group, (2) an alkenyl group optionally having a substituent, (3) a cycloalkyl group optionally having a substituent, (4) a heterocycloalkyl group optionally having a substituent, (5) an aryl group optionally having a substituent, (6) a heteroaryl group optionally having a substituent, (7) an optionally substituted arylalkyl group, or (8) an optionally substituted arylalkenyl group.
• Alkyl Group which May Have a Substituent The description of the alkyl group is as described above.
• Alkyl groups may have one or more substituents. The number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• Alkenyl Group which May Have a Substituent The description of the alkenyl group is as described above.
• Alkenyl groups may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the cycloalkyl group optionally having a substituent is as described above.
• a cycloalkyl group may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• a heterocycloalkyl group may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• Aryl group which May Have a Substituent The aryl group is as described above.
• Aryl groups may have one or more substituents. The number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• a heteroaryl group may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• Arylalkyl Group which May Have a Substituent The arylalkyl group is as described above.
• An arylalkyl group may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• Arylalkenyl Group which May Have a Substituent The arylalkenyl group is as described above.
• An arylalkenyl group may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• one or more substituents are each independently selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups. is preferably selected from a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms.
• halogen atom an alkyl group having 1 to 4 carbon atoms and an alkyloxy group having 1 to 4 carbon atoms
• an alkyl group having 1 to 4 carbon atoms e.g., methyl group, ethyl group, n -propyl group, isopropyl group, n-butyl group, t-butyl group, etc.
• W 1 in formula (I) is an optionally substituted alkyl group, preferably an optionally substituted alkyl group having 1 to 20 carbon atoms, more preferably , an optionally substituted alkyl group having 1 to 16 carbon atoms, more preferably an optionally substituted alkyl group having 1 to 12 carbon atoms.
• the thioester derivative (I) is a thioester derivative (Ia) represented by the following formula (Ia).
• R 1 to R 4 each independently represent a group represented by the formula: --CO--R.
• R has the same definition as in formula (I).
• R 1 to R 4 may be different groups, but from the viewpoint of efficient introduction and removal of the group represented by the formula: --CO--R, they are preferably the same group.
• R 1 -R 4 are all acetyl groups. In another embodiment, R 1 -R 4 are all benzoyl groups.
• R' is preferably TBS, TMS, a tetrahydropyranyl group, -CO-CH 2 -Cl, -C(-CH 3 ) 2 -O-CH 3 or --CO--O--C(--CH 3 ) 3 , more preferably TBS, a tetrahydropyranyl group, --CO--CH 2 --Cl, --C(--CH 3 ) 2 --O--CH 3 or --CO--- OC( -CH3 ) 3 .
• R' is preferably an acetyl group, TBS, TMS, an aldehyde group, --CO--CH 2 --Cl or --CO--CF 3 , more preferably an acetyl group.
• TBS an aldehyde group, —CO—CH 2 —Cl or —CO—CF 3 .
• W1 has the same meaning as in formula (I).
• W 1 in formula (Ia) is an optionally substituted alkyl group, preferably an optionally substituted alkyl group having 1 to 20 carbon atoms, more preferably , an optionally substituted alkyl group having 1 to 16 carbon atoms, more preferably an optionally substituted alkyl group having 1 to 12 carbon atoms.
• Examples of the thioester derivative (Ia) in which W 1 is an optionally substituted alkyl group include the following compounds.
• “Ac” represents an acetyl group
• “Bz” represents a benzoyl group (the same applies throughout the specification).
• R′ is preferably TBS, TMS, a tetrahydropyranyl group, —CO—CH 2 —Cl, —C(—CH 3 ) 2 —O—CH 3 or —CO—O—C( —CH 3 ) 3 , more preferably TBS, a tetrahydropyranyl group, —CO—CH 2 —Cl, —C(—CH 3 ) 2 —O—CH 3 or —CO—OC(—CH 3 ) 3 is.
• R′ is preferably an acetyl group, TBS, TMS, an aldehyde group, —CO—CH 2 —Cl or —CO—CF 3 , more preferably an acetyl group, TBS, an aldehyde group, —CO— CH 2 —Cl or —CO—CF 3 .
• —C 12 H 25 corresponding to W 1 may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups, halogen atoms, C 1-4 It is more preferably selected from an alkyl group, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom and an alkyl group having 1 to 4 carbon atoms.
• alkyloxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t -butyl group, etc.).
• —C 12 H 25 corresponding to W 1 can be changed to other alkyl groups.
• Other alkyl groups include, for example, —C 10 H 21 , —C 11 H 23 and the like.
• Other alkyl groups may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups, halogen atoms, C 1-4 It is more preferably selected from an alkyl group, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom and an alkyl group having 1 to 4 carbon atoms.
• alkyloxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t -butyl group, etc.).
• thioester derivative (I) is thioester derivative (Ib) represented by formula (Ib) below.
• R 1 to R 3 , R′ and W 1 in formula (Ib) have the same definitions as in formula (Ia), and the above explanations regarding R 1 to R 3 , R′ and W 1 also apply to formula (Ib). be done.
• R 1 to R 3 may be different groups, but from the viewpoint of efficient introduction and removal of the group represented by the formula: -CO-R, they should be the same group. is preferred.
• R 1 -R 3 are all acetyl groups. In another embodiment, R 1 -R 3 are all benzoyl groups.
• R' is preferably TBS, TMS, a tetrahydropyranyl group, --CO--CH 2 --Cl, --C(--CH 3 ) 2 --O--CH 3 or --CO--O--C(--CH 3 ) 3 , more preferably TBS, a tetrahydropyranyl group, --CO--CH 2 --Cl, --C(--CH 3 ) 2 --O--CH 3 or --CO--- OC( -CH3 ) 3 .
• R' is preferably an acetyl group, TBS, TMS, an aldehyde group, --CO--CH 2 --Cl or --CO--CF 3 , more preferably an acetyl group.
• TBS an aldehyde group, —CO—CH 2 —Cl or —CO—CF 3 .
• Ketone derivative (II) is represented by the following formula (II).
• R, R' and n have the same definitions as in formula (I), and the above explanations regarding R, R' and n also apply to formula (II).
• the ketone derivative (II) in which each R independently represents an optionally substituted aryl group is referred to as a ketone derivative (II-1), and each R is independently Therefore, the ketone derivative (II) representing an optionally substituted alkyl group is sometimes referred to as the ketone derivative (II-2).
• n 1
• the three R's may be different, but are the same from the viewpoint of efficient introduction and removal of the group represented by the formula: -CO-R. is preferred.
• all three R are methyl groups.
• all three R are phenyl groups.
• R' is preferably TBS, TMS, a tetrahydropyranyl group, -CO-CH 2 -Cl, -C(-CH 3 ) 2 -O-CH 3 or --CO--O--C(--CH 3 ) 3 , more preferably TBS, tetrahydropyranyl group, --CO--CH 2 --Cl, --C(--CH 3 ) 2 --O--CH 3 or --CO--O —C(—CH 3 ) 3 .
• R' is preferably an acetyl group, TBS, TMS, an aldehyde group, -CO- CH2 -Cl or -CO- CF3 , more preferably an acetyl group, TBS, an aldehyde group, --CO--CH 2 --Cl or --CO--CF 3 .
• n 2
• the four R may be different, but are the same from the viewpoint of efficient introduction and removal of the group represented by the formula: -CO-R. is preferred.
• all four R are methyl groups.
• all four R are phenyl groups.
• R' is preferably TBS, TMS, a tetrahydropyranyl group, -CO-CH 2 -Cl, -C(-CH 3 ) 2 -O-CH 3 or --CO--O--C(--CH 3 ) 3 , more preferably TBS, tetrahydropyranyl group, --CO--CH 2 --Cl, --C(--CH 3 ) 2 --O--CH 3 or --CO--O —C(—CH 3 ) 3 .
• R' is preferably an acetyl group, TBS, TMS, an aldehyde group, -CO- CH2 -Cl or -CO- CF3 , more preferably an acetyl group, TBS, an aldehyde group, --CO--CH 2 --Cl or --CO--CF 3 .
• W2 is (1) an optionally substituted alkyl group, (2) an alkenyl group optionally having a substituent, (3) a cycloalkyl group optionally having a substituent, (4) a heterocycloalkyl group optionally having a substituent, (5) an aryl group optionally having a substituent, (6) a heteroaryl group optionally having a substituent, (7) an optionally substituted arylalkyl group, or (8) represents an optionally substituted arylalkenyl group;
• a carbon atom having an aryl group bond that is, -CO- in formula ( II ) (- It is preferred that the carbon atoms located on both sides of the carbon atom bonding to CO—) do not have a substituent. The remaining carbon atoms may have substituents.
• a carbon atom having a heteroaryl group bond i.e., -CO-(-CO-W 2 It is preferred that the carbon atoms or heteroatoms located on both sides of the carbon atom bonding to -CO-) in have no substituents. The remaining carbon atoms or heteroatoms may have substituents.
• W2 may be the same as or different from W1 .
• W2 is preferably represented by the following formula (iv).
• Y 10 represents an optionally substituted alkylene group, an optionally substituted arylene group, or an optionally substituted heteroarylene group.
• the number of carbon atoms in the alkylene group is preferably 1-10, more preferably 1-8.
• the arylene group or heteroarylene group preferably has 4 to 14 carbon atoms, more preferably 6 to 14 carbon atoms.
• the alkylene group, arylene group or heteroarylene group represented by Y 10 may have one or more substituents, and the one or more substituents are each independently selected from the substituent group ⁇ . can be done.
• the one or more substituents are each independently selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio groups and haloalkylthio groups. and an alkyloxy group having 1 to 3 carbon atoms.
• Y 10 is preferably an arylene group having a substituent, more preferably an arylene group having a halogen atom or an alkyl group having 1 to 3 carbon atoms, and a phenylene group having a fluorine atom, a chlorine atom or a methyl group. is even more preferable.
• the carbon atoms located on both sides of the carbon atom bonded to —CO— have no substituents, and the remaining carbon atoms have substituents.
• the arylene group, or the carbon atoms or hetero atoms located on both sides of the carbon atom bonded to -CO- (-CO- in -CO-W 2 ) have no substituents, and the remaining carbon atoms or hetero atoms
• the atom is preferably a heteroarylene group which may have a substituent.
• Y 10 does not have a substituent at the ortho position relative to the carbon atom bonded to —CO— (—CO— in —CO—W 2 ), and has a substituent at the meta and/or para position. It is more preferably a phenylene group which may be
• V 10 , W 10 , X 10 , b and c have the same meanings as in formula (ii).
• W2 is preferably represented by the following formula (vi).
• R 41 and R 42 each independently represent a hydrogen atom or an amino group-protecting group.
• amino-protecting group any protecting group such as carbamate, acyl, amide, sulfonamide, and phthaloyl groups may be used.
• carbamate-based protective groups include tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl and the like.
• Acyl-based protective groups include, for example, an acetyl group, a pivaloyl group, a benzoyl group and the like.
• Amide-based protective groups include, for example, a trifluoroacetyl group and the like.
• sulfonamide-based protecting groups include p-toluenesulfonyl group and 2-nitrobenzenesulfonyl group.
• the amino group-protecting group is preferably an acyl-based or amide-based protecting group. More preferably, the amino-protecting group is a pivaloyl group or a trifluoroacetyl group.
• R 41 and R 42 may combine with each other to form an amino-protecting group such as a phthaloyl group.
• the ketone derivative (II) is a ketone derivative (IIa) represented by the following formula (IIa).
• R 1 to R 4 each independently represent a group represented by the formula: --CO--R.
• R has the same meaning as above.
• R 1 to R 4 may be different groups, but from the viewpoint of efficient introduction and removal of the group represented by the formula: --CO--R, they are preferably the same group.
• R 1 -R 4 are all acetyl groups. In another embodiment, R 1 -R 4 are all benzoyl groups.
• R' is preferably TBS, TMS, a tetrahydropyranyl group, -CO-CH 2 -Cl, -C(-CH 3 ) 2 -O-CH 3 or --CO--O--C(--CH 3 ) 3 , more preferably TBS, a tetrahydropyranyl group, --CO--CH 2 --Cl, --C(--CH 3 ) 2 --O--CH 3 or --CO--- OC( -CH3 ) 3 .
• R' is preferably an acetyl group, TBS, TMS, an aldehyde group, --CO--CH 2 --Cl or --CO--CF 3 , more preferably an acetyl group.
• TBS an aldehyde group, —CO—CH 2 —Cl or —CO—CF 3 .
• W2 has the same definition as in formula (II). In one embodiment, W2 in formula (IIa) is an optionally substituted aryl group.
• Examples of the ketone derivative (IIa) in which W2 is an optionally substituted aryl group include the following compounds.
• “Ph” represents a phenyl group (same throughout the specification).
• R′ is preferably TBS, TMS, a tetrahydropyranyl group, —CO—CH 2 —Cl, —C(—CH 3 ) 2 —O—CH 3 or —CO—O—C( —CH 3 ) 3 , more preferably TBS, a tetrahydropyranyl group, —CO—CH 2 —Cl, —C(—CH 3 ) 2 —O—CH 3 or —CO—OC(—CH 3 ) 3 is.
• R′ is preferably an acetyl group, TBS, TMS, an aldehyde group, —CO—CH 2 —Cl or —CO—CF 3 , more preferably an acetyl group, TBS, an aldehyde group, —CO— CH 2 —Cl or —CO—CF 3 .
• the phenyl group corresponding to W2 may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups, halogen atoms, C 1-4 It is more preferably selected from an alkyl group, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom and an alkyl group having 1 to 4 carbon atoms.
• alkyloxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t -butyl group, etc.).
• W 2 in formula (II) or (IIa) is the same as the functional group possessed by the SGLT-2 inhibitor from the viewpoint of using the ketone derivative (II) or (IIa) as a raw material for producing the SGLT-2 inhibitor or its derivative. or a functional group obtained by derivatizing the functional group of the SGLT-2 inhibitor.
• canagliflozin (1-( ⁇ -D-glycopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene
• empagliflozin ((1S)-1 , 5-anhydro-1-C- ⁇ 4-chloro-3-[(4- ⁇ [(3S)-oxolan-3-yl]oxy ⁇ phenyl)methyl]phenyl ⁇ -D-glucitol)
• ipragliflozin (1S)-1,5-anhydro-1-C- ⁇ 3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl ⁇ -D-glucitol-(2S)-pyrrolidine-2-carvone acid
• dapagliflozin ((2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethyloxybenzyl)phenyl]-6-(
• W2 in formula (II) or (IIa) is preferably a functional group represented by formula (A) below.
• d represents an integer of 0-4.
• d is preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.
• d R a may be the same or different.
• each of d R a can be independently selected from substituent group ⁇ .
• Each of the d R a is preferably independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio and a haloalkylthio group; It is more preferably selected from an alkyl group and an alkyloxy group having 1 to 3 carbon atoms.
• Ar' is a group represented by formula (v) below.
• W 10 , X 10 and c each have the same meaning as in formula (ii).
• Ar' is preferably a group represented by the following formula (Ar'-1), (Ar'-2) or (Ar'-3).
• p is an integer of 0 to 5.
• p is preferably an integer from 0 to 3, more preferably an integer from 0 to 2, even more preferably 0 or 1;
• p R b are each independently one or more selected from substituent group ⁇ and substituent group ⁇ and a heteroaryl group optionally having one or more substituents selected from the substituent group ⁇ .
• Each of the p R b is preferably independently selected from the substituent group ⁇ and an aryl group optionally having one or more substituents selected from the substituent group ⁇ .
• One or more substituents selected from the substituent group ⁇ are each independently a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, a haloalkylthio group, a heterocycloalkyloxy group and It is preferably selected from a heterocycloalkylthio group, more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, an alkyloxy group having 1 to 3 carbon atoms and a heterocycloalkyloxy group, a fluorine atom, ethyloxy It is even more preferred to select from radicals and tetrahydrofuranyloxy radicals.
• p R b When p is 2 or more, p R b may be the same or different.
• R b is preferably an optionally substituted phenyl group, more preferably a phenyl group having a halogen atom. and more preferably a phenyl group having a fluorine atom.
• the position to which the unsubstituted or substituted phenyl group is attached is preferably the 2-position of the thiophene ring.
• the position to which the halogen atom is bonded is preferably the 4-position of the benzene ring.
• p is preferably 0.
• R b is preferably an optionally substituted alkyloxy group or an optionally substituted heterocycloalkyl It is an oxy group.
• the optionally substituted alkyloxy group is preferably an alkyloxy group having 1 to 3 carbon atoms, more preferably a methoxy group or an ethoxy group.
• the optionally substituted heterocycloalkyloxy group is preferably a tetrahydrofuranyloxy group.
• the position to which the optionally substituted alkyloxy group or optionally substituted heterocycloalkyloxy group is preferably bonded is the 4-position of the benzene ring.
• the functional group represented by formula (A) is preferably a group represented by formula (B) below.
• Ra and Ar' have the same meanings as in formula (A).
• the group represented by formula (A) or (B) is preferably a group represented by the following formula (Ar-1), (Ar-2), (Ar-3) or (Ar-4) .
• “Et” represents an ethyl group (same throughout the specification).
• Ketone derivatives (II) or (IIa) are, for example, compounds in which W 2 is a group represented by formula (Ar-1). Examples of such compounds include the following compounds.
• R′ is preferably TBS, TMS, a tetrahydropyranyl group, —CO—CH 2 —Cl, —C(—CH 3 ) 2 —O—CH 3 or —CO—O—C( —CH 3 ) 3 , more preferably TBS, a tetrahydropyranyl group, —CO—CH 2 —Cl, —C(—CH 3 ) 2 —O—CH 3 or —CO—O—C(—CH 3 ) 3 is.
• R′ is preferably an acetyl group, TBS, TMS, an aldehyde group, —CO—CH 2 —Cl or —CO—CF 3 , more preferably an acetyl group, TBS, an aldehyde group, —CO— CH 2 —Cl or —CO—CF 3 .
• the ketone derivative (II) is a ketone derivative (IIb) represented by the following formula (IIb).
• R 1 to R 3 , R' and W 2 have the same definitions as in formula (IIa), and the above explanations regarding R 1 to R 3 , R' and W 2 also apply to formula (IIb). Applies.
• R 1 to R 3 may be different groups, but from the viewpoint of efficient introduction and removal of the group represented by the formula: -CO-R, they should be the same group. is preferred.
• R 1 -R 3 are all acetyl groups. In another embodiment, R 1 -R 3 are all benzoyl groups.
• R' is preferably TBS, TMS, a tetrahydropyranyl group, --CO--CH 2 --Cl, --C(--CH 3 ) 2 --O--CH 3 or --CO--O--C(--CH 3 ) 3 , more preferably TBS, a tetrahydropyranyl group, --CO--CH 2 --Cl, --C(--CH 3 ) 2 --O--CH 3 or --CO--- OC(—CH 3 ) 3 .
• R' is preferably an acetyl group, TBS, TMS, an aldehyde group, --CO--CH 2 --Cl or --CO--CF 3 , more preferably an acetyl group.
• TBS an aldehyde group, —CO—CH 2 —Cl or —CO—CF 3 .
• W 2 , R and n have the same definitions as in formula (II), and the above explanations regarding W 2 , R and n also apply to formula (II').
• the ketone derivative (II') where each R independently represents an optionally substituted aryl group is referred to as the ketone derivative (II'-1), and each R is The ketone derivative (II') independently representing an optionally substituted alkyl group may be referred to as the ketone derivative (II'-2).
• three R may be different, but from the viewpoint of efficient introduction and removal of the group represented by the formula: —CO—R, they are the same.
• all three R are methyl groups.
• all three R are phenyl groups.
• the four R may be different, but from the viewpoint of efficient introduction and removal of the group represented by the formula: —CO—R, they are the same.
• all four R are methyl groups.
• all four R are phenyl groups.
• the ketone derivative (II') is a ketone derivative (IIa') represented by the following formula (IIa').
• R 1 to R 4 and W 2 have the same definitions as in formula (IIa), and the above explanations regarding R 1 to R 4 and W 2 also apply to formula (IIa').
• R 1 to R 4 may be different groups, but from the viewpoint of efficient introduction and removal of the group represented by the formula: -CO-R, they are the same group. is preferred.
• R 1 -R 4 are all acetyl groups. In another embodiment, R 1 -R 4 are all benzoyl groups.
• the ketone derivative (II') is a ketone derivative (IIb') represented by the following formula (IIb').
• R 1 to R 3 and W 2 have the same definitions as in formula (IIb), and the above explanations regarding R 1 to R 3 and W 2 also apply to formula (IIb').
• R 1 to R 3 may be different groups, but from the viewpoint of efficient introduction and removal of the group represented by the formula: -CO-R, they are the same group. is preferred.
• R 1 -R 3 are all acetyl groups. In another embodiment, R 1 -R 3 are all benzoyl groups.
• Thioester derivative (III) is represented by the following formula (III).
• W 1 , R and n have the same definitions as in formula (I), and the above explanations regarding W 1 , R and n also apply to formula (III).
• the thioester derivative (III) in which each R independently represents an optionally substituted aryl group is referred to as a thioester derivative (III-1), and each R is independently Therefore, the thioester derivative (III) representing an optionally substituted alkyl group is sometimes referred to as a thioester derivative (III-2).
• n 1
• the three R's may be different, but are the same from the viewpoint of efficient introduction and removal of the group represented by the formula: -CO-R. is preferred.
• all three R are methyl groups.
• all three R are phenyl groups.
• n 2
• the four R may be different, but are the same from the viewpoint of efficient introduction and removal of the group represented by the formula: -CO-R. is preferred.
• all four R are methyl groups.
• all four R are phenyl groups.
• the thioester derivative (III) is a thioester derivative (IIIa) represented by the following formula (IIIa).
• R 1 to R 4 and W 1 have the same definitions as in formula (Ia), and the above explanations regarding R 1 to R 4 and W 1 also apply to formula (IIIa).
• R 1 to R 4 may be different groups, but from the viewpoint of efficient introduction and removal of the group represented by the formula: -CO-R, they should be the same group. is preferred.
• R 1 -R 4 are all acetyl groups. In another embodiment, R 1 -R 4 are all benzoyl groups.
• the thioester derivative (III) is a thioester derivative (IIIb) represented by the following formula (IIIb).
• R 1 to R 3 and W 1 have the same definitions as in formula (Ib), and the above explanations regarding R 1 to R 3 and W 1 also apply to formula (IIIb).
• R 1 to R 3 may be different groups, but from the viewpoint of efficient introduction and removal of the group represented by the formula: -CO-R, they should be the same group. is preferred.
• R 1 -R 3 are all acetyl groups. In another embodiment, R 1 -R 3 are all benzoyl groups.
• R and n have the same definitions as in formula (I), and the above explanations regarding R and n also apply to formula (IV).
• the acyl-protected lactone derivative (IV) in which each R independently represents an optionally substituted aryl group, is referred to as an acyl-protected lactone derivative (IV-1).
• the acyl-protected lactone derivative (IV) each independently representing an optionally substituted alkyl group may be referred to as an acyl-protected lactone derivative (IV-2).
• n 1
• the three R's may be different, but are the same from the viewpoint of efficient introduction and removal of the group represented by the formula: -CO-R. is preferred.
• all three R are methyl groups.
• all three R are phenyl groups.
• n 2
• the four R may be different, but are the same from the viewpoint of efficient introduction and removal of the group represented by the formula: -CO-R. is preferred.
• all four R are methyl groups.
• all four R are phenyl groups.
• the acyl-protected lactone derivative (IV) is an acyl-protected lactone derivative (IVa) represented by the following formula (IVa).
• R has the same definition as in formula (IV), and the above explanation regarding R also applies to formula (IVa).
• R, W 2 and n have the same definitions as in formula (II), and the above explanations regarding R, W 2 and n also apply to formula (V).
• C-aryl-hydroxyglycoside derivative (V) where each R independently represents an aryl group which may have a substituent is referred to as C-aryl-hydroxyglycoside derivative (V -1), wherein each R independently represents an optionally substituted alkyl group (V) is a C-aryl-hydroxyglycoside derivative (V- 2).
• R 100 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted alkylcarbonyl group, or a substituted represents an arylcarbonyl group which may be substituted.
• an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted alkylcarbonyl group and an optionally substituted arylcarbonyl The group will be explained.
• alkyl group which may have a substituent is as described above.
• Alkyl groups may be linear or branched.
• the number of carbon atoms in the alkyl group is preferably 1-10, more preferably 1-8, still more preferably 1-6, still more preferably 1-4, and still more preferably 1-3.
• Alkyl groups may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups, halogen atoms, C 1-4 It is more preferably selected from an alkyl group, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom and an alkyl group having 1 to 4 carbon atoms.
• alkyloxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t -butyl group, etc.).
• the aryl group which may have a substituent is as described above.
• Aryl groups may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups, halogen atoms, C 1-4 It is more preferably selected from an alkyl group, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom and an alkyl group having 1 to 4 carbon atoms.
• alkyloxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t -butyl group, etc.).
• the alkylcarbonyl group optionally having substituent( s) is as described above.
• the alkyl group contained in the alkylcarbonyl group (-CO-alkyl group) may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups, halogen atoms, C 1-4 It is more preferably selected from an alkyl group, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom and an alkyl group having 1 to 4 carbon atoms.
• alkyloxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t -butyl group, etc.).
• the arylcarbonyl group optionally having substituent( s) is as described above.
• the aryl group contained in the arylcarbonyl group (-CO-aryl group) may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups, halogen atoms, C 1-4 It is more preferably selected from an alkyl group, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom and an alkyl group having 1 to 4 carbon atoms.
• alkyloxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t -butyl group, etc.).
• R 100 is preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t-butyl group, etc.), more preferably hydrogen an atom or a methyl group.
• the C-aryl-hydroxyglycoside derivative (V) is a C-aryl-hydroxyglycoside derivative (V') represented by formula (V') below.
• C-aryl-hydroxyglycoside derivative (V') is an example of C-aryl-hydroxyglycoside derivative (V) in which R 100 is a hydrogen atom.
• W2 has the same meaning as in formula (V).
• C-aryl-hydroxyglycoside derivatives (V′) where each R independently represents an optionally substituted aryl group are referred to as C-aryl-hydroxyglycoside derivatives ( C-aryl-hydroxyglycoside derivative (V′-1), wherein each R independently represents an optionally substituted alkyl group, and C-aryl-hydroxyglycoside derivative (V′) (V'-2) in some cases.
• the C-aryl-hydroxyglycoside derivative (V) is a C-aryl-hydroxyglycoside derivative (Va) represented by formula (Va) below.
• W2 has the same meaning as in formula (V).
• C-aryl-hydroxyglycoside derivative (V) is a C-aryl-hydroxyglycoside derivative (Vb) represented by formula (Vb) below.
• R 101 is a group other than a hydrogen atom, that is, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted alkylcarbonyl group, or , is an arylcarbonyl group which may have a substituent.
• R 101 is preferably an alkyl group having 1 to 4 carbon atoms (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t-butyl group, etc.), more preferably methyl group .
• W2 has the same meaning as in formula (V).
• C-aryl glycoside derivative (VI) is represented by the following formula (VI).
• R, W 2 and n have the same definitions as in formula (II), and the above explanations regarding R, W 2 and n also apply to formula (VI).
• C-aryl glycoside derivative (VI), in which each R independently represents an optionally substituted aryl group is referred to as C-aryl glycoside derivative (VI-1).
• a C-arylglycoside derivative (VI) in which each R independently represents an optionally substituted alkyl group may be referred to as a C-arylglycoside derivative (VI-2).
• the C-aryl glycoside derivative (VI) is a C-aryl glycoside derivative (VIa) represented by formula (VIa) below.
• W2 has the same meaning as in formula (VII).
• Lactone derivative (VII) is represented by the following formula (VII).
• n has the same definition as in formula (I), and the above explanation regarding n also applies to formula (VII).
• the lactone derivative (VII) is a lactone derivative (VIIa) represented by the following formula (VIIa).
• Carboxylic anhydride (1) is represented by the following formula (1).
• each R'' independently represents an optionally substituted alkyl group.
• Alkyl groups may be linear or branched. The number of carbon atoms in the alkyl group is preferably 1-10, more preferably 1-8, still more preferably 1-6, still more preferably 1-4, and still more preferably 1-3. Alkyl groups may have one or more substituents. The number of substituents is preferably 1-3, more preferably 1 or 2. One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ . One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups, halogen atoms, C 1-4 It is more preferably selected from an alkyl group, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom and an alkyl group having 1 to 4 carbon atoms.
• alkyloxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t -butyl group, etc.).
• two R'' may be different, but from the viewpoint of efficient introduction and removal of the group represented by the formula: -CO-R'', they are the same. preferable.
• all two R'' are methyl groups. That is, the carboxylic anhydride (1) according to one embodiment is acetic anhydride.
• each R independently represents an optionally substituted aryl group, and R' has a substituent It corresponds to the group represented by R' in the thioester derivative (I) representing a good alkylcarbonyl group.
• silylating agent (2) is represented by the following formula (2).
• R 1 , R 2 and R 3 each independently represent an optionally substituted alkyl group or an optionally substituted aryl group; , R 2 and R 3 represent an optionally substituted alkyl group, and X represents a halogen atom or a trifluoromethanesulfonyl group.
• —Si—R 1 (—R 2 )(—R 3 ) that is, the alkylsilyl group optionally having substituent(s)
• a group represented by the formula: -Si-R 1 (-R 2 )(-R 3 ) is preferably an alkylsilyl group, more preferably a trialkylsilyl group, still more preferably TBS or TMS, still more preferably It is TBS.
• X represents a halogen atom.
• the halogen atom is preferably selected from a chlorine atom, a bromine atom and an iodine atom, more preferably a chlorine atom and a bromine atom, and even more preferably a chlorine atom.
• silylating agent (2) examples include tert-butyldimethylsilyltrifluoromethanesulfonate (TBSOTf) and chlorotrimethylsilane (TMSCl).
• Thiol (3) is represented by the following formula (3).
• W 1 has the same meaning as in formula (I), and the above description of W 1 also applies to formula (3).
• the Grignard reagent (4) is represented by the following formula (4).
• W3 is (1) an optionally substituted alkyl group, (2) an alkenyl group optionally having a substituent, (3) a cycloalkyl group optionally having a substituent, (4) a heterocycloalkyl group optionally having a substituent, (5) an aryl group optionally having a substituent, (6) a heteroaryl group optionally having a substituent, (7) an optionally substituted arylalkyl group, or (8) represents an optionally substituted arylalkenyl group;
• the remaining carbon atoms or heteroatoms may have substituents.
• W3 may be the same as or different from W1 .
• W3 may be the same as or different from W2 .
• X represents a halogen atom.
• the halogen atom is preferably selected from a chlorine atom, a bromine atom and an iodine atom, more preferably a chlorine atom and a bromine atom, and even more preferably a chlorine atom.
• W3 in formula (4) is an optionally substituted alkyl group.
• Alkyl groups may be linear or branched. The number of carbon atoms in the alkyl group is preferably 1-10, more preferably 1-8, more preferably 1-6, more preferably 1-4, more preferably 1-3. Alkyl groups may have one or more substituents. The number of substituents is preferably 1-3, more preferably 1 or 2. One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ . One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups, halogen atoms, C 1-4 It is more preferably selected from an alkyl group, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom and an alkyl group having 1 to 4 carbon atoms.
• alkyloxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t -butyl group, etc.).
• W3 in formula (4) is an optionally substituted aryl group.
• a description of the aryl group is provided above.
• the number of carbon atoms in the aryl group is preferably 6-14, more preferably 6-10.
• An aryl group is, for example, a phenyl group.
• Aryl groups may have one or more substituents.
• the number of substituents is preferably 1-3, more preferably 1 or 2.
• One or more substituents may each independently be selected from substituent groups ⁇ and ⁇ .
• One or more substituents may be selected from the substituent group ⁇ and one or more substituents may be selected from the substituent group ⁇ .
• the one or more substituents are each independently preferably selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio and haloalkylthio groups, halogen atoms, C 1-4 It is more preferably selected from an alkyl group, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms and a haloalkyloxy group having 1 to 4 carbon atoms, and a halogen atom and an alkyl group having 1 to 4 carbon atoms.
• alkyloxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t -butyl group, etc.).
• Grignard reagents (4) in which W3 is an alkyl group include, for example, alkylmagnesium bromides and alkylmagnesium chlorides, among which alkylmagnesium chlorides are preferred.
• alkylmagnesium bromide examples include methylmagnesium bromide, ethylmagnesium bromide, n-propylmagnesium bromide, isopropylmagnesium bromide, n-butylmagnesium bromide, and isobutylmagnesium bromide.
• alkylmagnesium chloride examples include methylmagnesium chloride, ethylmagnesium chloride, n-propylmagnesium chloride, isopropylmagnesium chloride, n-butylmagnesium chloride, and isobutylmagnesium chloride.
• the Grignard reagent (4) in which W3 is an aryl group includes, for example, arylmagnesium bromide, arylmagnesium chloride, etc. Among these, arylmagnesium chloride is preferred.
• the arylmagnesium bromide includes, for example, phenylmagnesium bromide.
• Arylmagnesium chloride includes, for example, phenylmagnesium chloride.
• the Grignard reagent (5) is selected from a Grignard reagent (5a) represented by the following formula (5a) and a Grignard reagent (5b) represented by the following formula (5b).
• W2 has the same meaning as in formula (II). That is, in equations (5a) and (5b), W2 is (1) an optionally substituted alkyl group, (2) an alkenyl group optionally having a substituent, (3) a cycloalkyl group optionally having a substituent, (4) a heterocycloalkyl group optionally having a substituent, (5) an aryl group optionally having a substituent, (6) a heteroaryl group optionally having a substituent, (7) an optionally substituted arylalkyl group, or (8) represents an optionally substituted arylalkenyl group;
• W2 represents an optionally substituted arylalkenyl group;
• a carbon atom having an aryl group bond i.e., a carbon atom that bonds to Mg in formula (5a) or (5b)
• the carbon atoms located on both sides of do not have a substituent.
• the remaining carbon atoms may have substituents.
• a carbon atom having a heteroaryl group bond i.e., the carbon that binds to Mg in formula (5a) or (5b) It is preferred that the carbon atoms or heteroatoms located on both sides of the atom) have no substituents. The remaining carbon atoms or heteroatoms may have substituents.
• X represents a halogen atom.
• the halogen atom is preferably selected from a chlorine atom, a bromine atom and an iodine atom, more preferably a chlorine atom and a bromine atom, more preferably a bromine atom.
• X in formulas (5a) and (5b) may be the same as or different from X in formula (4).
• the organic zinc compound (6) includes an organic zinc compound (6a) represented by the following formula (6a), an organic zinc compound (6b) represented by the following formula (6b), and an organic zinc compound represented by the following formula (6c). selected from zinc compounds (6c);
• W2 has the same meaning as in formula (II). That is, in equations (6a), (6b) and (6c), W2 is (1) an optionally substituted alkyl group, (2) an alkenyl group optionally having a substituent, (3) a cycloalkyl group optionally having a substituent, (4) a heterocycloalkyl group optionally having a substituent, (5) an aryl group optionally having a substituent, (6) a heteroaryl group optionally having a substituent, (7) an optionally substituted arylalkyl group, or (8) represents an optionally substituted arylalkenyl group;
• W2 represents an optionally substituted arylalkenyl group;
• a carbon atom having an aryl group bond i.e., a bond with Zn in formula (6a), (6b) or (6c
• the carbon atoms located on both sides of the carbon atom that The remaining carbon atoms may have substituents.
• a carbon atom having a heteroaryl group bond i.e., Zn in formula (6a), (6b) or (6c
• the remaining carbon atoms or heteroatoms may have substituents.
• X represents a halogen atom.
• the halogen atom is preferably selected from a chlorine atom, a bromine atom and an iodine atom, more preferably a chlorine atom and a bromine atom, more preferably a bromine atom.
• X in formulas (6a), (6b) and (6c) may be the same as or different from X in formula (4).
• X in formulas (6a), (6b) and (6c) may be the same as or different from X in formulas (5a) and (5b).
• organozinc compound (6a) examples include arylzinc halides (compounds in which W2 is an aryl group and X is a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom in the formula (6a)), alkyl and zinc halide (compound in which W2 is an alkyl group and X is a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom in the formula (6a)).
• organic zinc compound (6b) examples include diarylzinc (compound in which W2 is an aryl group in formula (6b)), dialkylzinc (compound in which W2 is an alkyl group in formula (6b)), and the like. mentioned.
• thioester derivative (I) in which R each independently represents an optionally substituted aryl group is referred to as a thioester derivative (I-1), and each R independently represents a substituent.
• a thioester derivative (I) representing an optionally-containing alkyl group is referred to as a thioester derivative (I-2).
• the first method is a method for producing a thioester derivative (I-1) (hereinafter referred to as "thioester derivative (I-1a)”) in which R' represents an optionally substituted alkylcarbonyl group. .
• the thioester derivative (I-1a) is produced by contacting the thioester derivative (III-1) with the carboxylic anhydride (1) in the presence of a base or Lewis acid to produce the thioester derivative (I-1a). It can be manufactured by a method comprising:
• the thioester derivative (III-1) and carboxylic anhydride (1) may be commercially available products or may be produced according to conventional methods.
• the hydroxy group contained in the thioester derivative (III-1) is represented by the formula: —CO—R′. ' to give a thioester derivative (I-1a).
• the group represented by the formula: --CO--R'' corresponds to the group represented by R' in the thioester derivative (I-1a).
• the contact between the thioester derivative (III-1) and the carboxylic anhydride (1) is preferably carried out in a solvent.
• a solvent By mixing the thioester derivative (III-1) and the carboxylic anhydride (1) in a solvent, the thioester derivative (III-1) and the carboxylic anhydride (1) can be contacted.
• the solvent is preferably an organic solvent. Specific examples of the organic solvent are as described above. One organic solvent may be used alone, or two or more organic solvents may be used in combination.
• the organic solvent is preferably THF, tert-butyl methyl ether, DCM, toluene or a mixed solvent thereof.
• the amount of solvent used is, for example, 1 to 200 mL, preferably 2 to 100 mL, per 1 g of thioester derivative (III-1).
• the contact between the thioester derivative (III-1) and the carboxylic anhydride (1) is carried out in the presence of a base or Lewis acid.
• the amount of carboxylic anhydride (1) used is, for example, 1 to 20 mol, preferably 1 to 10 mol, more preferably 1 to 5 mol, per 1 mol of thioester derivative (III-1).
• bases examples include triethylamine, pyridine, 4-dimethylaminopyridine (4-DMAP), N,N-diisopropylethylamine (DIEA), imidazole, diazabicycloundecene (DBU), organic amines such as diethylaniline, and acetic acid. Sodium, Schottenbaumann conditions, and the like.
• a Grignard reagent eg, Grignard reagent (4)
• the base is preferably selected from triethylamine, pyridine and 4-dimethylaminopyridine (4-DMAP).
• the amount of the base used is, for example, 0.1 to 10 mol, preferably 0.2 to 5 mol, more preferably 0.3 to 3 mol, per 1 mol of the thioester derivative (III-1).
• the Lewis acid is preferably copper(II) trifluoromethanesulfonate (Cu(OTf) 2 ).
• the amount of Lewis acid used is, for example, 0.001 to 1 mol, preferably 0.02 to 0.5 mol, more preferably 0.03 to 0.2 mol, per 1 mol of thioester derivative (III-1). is.
• the contact temperature is, for example, ⁇ 30 to 100° C., preferably ⁇ 10 to 80° C., more preferably 0 to 50. ° C.
• the contact time is, for example, 0.1 to 24 hours, preferably 0.5 to 17 hours, more preferably 0.5 to 5 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• the second method is a method for producing a thioester derivative (I-1) (hereinafter referred to as "thioester derivative (I-1b)”) in which R' represents an optionally substituted alkylsilyl group. be.
• the thioester derivative (I-1b) is produced by a method comprising the step of contacting the thioester derivative (III-1) with a silylating agent (2) in the presence of a base to produce the thioester derivative (I-1b). can do.
• the thioester derivative (III-1) and silylating agent (2) may be commercially available products or may be produced according to conventional methods.
• the contact between the thioester derivative (III-1) and the silylating agent (2) is preferably carried out in a solvent.
• the thioester derivative (III-1) and the silylating agent (2) can be contacted by mixing the thioester derivative (III-1) and the silylating agent (2) in a solvent.
• the solvent is preferably an organic solvent. Specific examples of the organic solvent are as described above. One organic solvent may be used alone, or two or more organic solvents may be used in combination.
• the organic solvent is preferably methylene chloride, chloroform, tetrahydrofuran (THF), 2-methyl-THF, 1,4-dioxane, toluene, N,N-dimethylformamide (DMF), acetonitrile or a mixed solvent thereof.
• the amount of solvent used is, for example, 1-100 mL, preferably 3-30 mL, per 1 g of thioester derivative (III-1).
• the contact between the thioester derivative (III-1) and the silylating agent (2) is carried out in the presence of a base.
• the amount of silylating agent (2) used is, for example, 1 to 10 mol, preferably 1 to 5 mol, more preferably 1 to 3 mol, per 1 mol of thioester derivative (III-1).
• Examples of the base include triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIEA), imidazole, diazabicycloundecene (DBU), diethylaniline, 2,6-lutidine and the like. organic amines, sodium acetate, Schottenbaumann conditions, and the like.
• the base is preferably imidazole.
• the amount of the base used is, for example, 1 to 10 mol, preferably 1 to 5 mol, more preferably 1 to 3 mol, per 1 mol of the thioester derivative (III-1).
• the contact temperature is, for example, -10 to 80°C, preferably -5 to 60°C, more preferably 0 to 40°C.
• the contact time is, for example, 0.1 to 48 hours, preferably 1 to 24 hours, more preferably 2 to 17 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• a third method is a method for producing a thioester derivative (I-1) (hereinafter referred to as "thioester derivative (I-1c)”) in which R' represents an aldehyde group.
• the thioester derivative (I-1c) is produced by a method comprising the step of producing the thioester derivative (I-1c) by contacting the thioester derivative (III-1) with formic acid in the presence of a base and a condensing agent. can be done.
• the thioester derivative (III-1) and formic acid may be commercially available products or may be produced according to conventional methods.
• the thioester derivative (III-1) When the thioester derivative (III-1) is brought into contact with formic acid in the presence of a base and a condensing agent, the hydroxy group contained in the thioester derivative (III-1) is protected with an aldehyde group to give the thioester derivative (I-1c). is obtained.
• the aldehyde group corresponds to the group represented by R' in the thioester derivative (I-1c).
• the contact between the thioester derivative (III-1) and formic acid is preferably carried out in a solvent.
• the thioester derivative (III-1) and formic acid can be brought into contact with each other by mixing the thioester derivative (III-1) and formic acid in a solvent.
• the solvent is preferably an organic solvent. Specific examples of the organic solvent are as described above. One organic solvent may be used alone, or two or more organic solvents may be used in combination.
• the organic solvent is preferably methylene chloride, THF, 2-methyl-THF, toluene, DMF, 1,4-dioxane, acetonitrile or a mixed solvent thereof.
• the amount of solvent used is, for example, 1 to 100 mL, preferably 2 to 50 mL, per 1 g of thioester derivative (III-1).
• the thioester derivative (III-1) is contacted with formic acid in the presence of a base and a condensing agent.
• the amount of formic acid used is, for example, 1 to 20 mol, preferably 1 to 10 mol, more preferably 1 to 5 mol, per 1 mol of the thioester derivative (III-1).
• Examples of the base include triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIEA), imidazole, diazabicycloundecene (DBU), diethylaniline, 2,6-lutidine and the like. organic amines, sodium acetate, Schottenbaumann conditions, and the like.
• the base is preferably selected from DMAP, triethylamine, diisopropylethylamine and pyridine.
• the amount of the base used is, for example, 0.001 to 10 mol, preferably 0.01 to 5 mol, more preferably 0.02 to 2 mol, per 1 mol of the thioester derivative (III-1).
• Condensing agents include N,N'-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC/HCl), ethyl chlorocarbonate, isobutyl chlorocarbonate, diphenyl chlorophosphate, and the like. is mentioned.
• the condensing agent is preferably EDC.HCl.
• the amount of the condensing agent used is, for example, 1-4 mol, preferably 1-3 mol, more preferably 1-2 mol, per 1 mol of the thioester derivative (III-1).
• the contact temperature is, for example, -20 to 60°C, preferably -15 to 50°C, more preferably -10 to 40°C.
• the time is, for example, 0.5 to 48 hours, preferably 1 to 24 hours, more preferably 2 to 17 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• a fourth method is to produce a thioester derivative (I-1) (hereinafter referred to as “thioester derivative (I-1d)”) in which R′ represents a group represented by the formula: —CO—L 1 -L 2 It is a way to
• the thioester derivative (I-1d) is prepared by combining the thioester derivative (III-1) with the formula: J-CO-L 1 -L 2 [wherein L 1 and L 2 are as defined above, J represents a halogen atom. ] to produce the thioester derivative (I-1d).
• the thioester derivative (III-1) and the compound represented by the formula: J—CO—L 1 -L 2 may be commercially available or may be produced according to conventional methods.
• J represents a halogen atom.
• J is preferably selected from chlorine, bromine and iodine, more preferably chlorine.
• J—CO—L 1 -L 2 are Cl—CO—CH 2 Cl (chloroacetyl chloride), Cl—CO—CHCl 2 (dichloroacetyl chloride) and Cl—CO—CCl 3 ( trichloroacetyl chloride), more preferably Cl--CO--CH 2 Cl.
• thioester derivative (III-1) When the thioester derivative (III-1) is brought into contact with a compound represented by the formula: J-CO-L 1 -L 2 in the presence of a base, the hydroxy group contained in the thioester derivative (III-1) is A thioester derivative (I-1d) is obtained by protecting with a group represented by the formula: —CO—L 1 -L 2 .
• the group represented by the formula: -CO-L 1 -L 2 corresponds to the group represented by R' in the thioester derivative (I-1d).
• the contact between the thioester derivative (III-1) and the compound represented by the formula: J—CO—L 1 -L 2 is preferably carried out in a solvent.
• the thioester derivative (III-1) and the compound can be contacted by mixing the thioester derivative (III-1) and the compound in a solvent.
• the solvent is preferably an organic solvent. Specific examples of the organic solvent are as described above. One organic solvent may be used alone, or two or more organic solvents may be used in combination.
• the organic solvent is preferably methylene chloride, THF, 2-methyl-THF, toluene, DMF, 1,4-dioxane, acetonitrile or a mixed solvent thereof.
• the amount of solvent used is, for example, 1 to 100 mL, preferably 3 to 50 mL, per 1 g of thioester derivative (III-1).
• the amount of the compound represented by the formula: J—CO—L 1 -L 2 to be used is, for example, 1 to 5 mol, preferably 1 to 3 mol, more preferably 1 to 1 mol, per 1 mol of the thioester derivative (III-1). 1 to 2 mol.
• Examples of the base include triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIEA), imidazole, diazabicycloundecene (DBU), diethylaniline, 2,6-lutidine and the like.
• organic amines sodium acetate, Schottenbaumann conditions, and the like.
• the base is preferably pyridine.
• the amount of the base used is, for example, 1 to 10 mol, preferably 1 to 5 mol, more preferably 1 to 3 mol, per 1 mol of the thioester derivative (III-1).
• the contact temperature is, for example, ⁇ 30 to 50° C., preferably ⁇ 20° C. to 40° C., more preferably ⁇ 10 to 30° C.
• the contact time is, for example, 0.1 to 17 hours, preferably 0.5 to 8 hours, more preferably 1 to 4 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• a fifth method is a thioester derivative (I- 1 ) (hereinafter referred to as "thioester derivative (I-1e)”).
• the thioester derivative (I-1e) is obtained by combining the thioester derivative (III-1) with the formula: C(-L 9 )(-L 10 )(-L 11 )-CO-O-CO-C(-L 9 )( -L 10 )(-L 11 ) [Wherein, L 9 , L 10 and L 11 are as defined above. ] to produce the thioester derivative (I-1e).
• the represented compounds may be commercially available products or may be produced according to conventional methods.
• C(-L 9 )(-L 10 )(-L 11 )-CO-O-CO-C(-L 9 )(-L 10 )(-L 11 ) is preferably , CF 3 —CO—O—CO—CF 3 (trifluoroacetic anhydride).
• the hydroxy group contained in the thioester derivative (III-1) is represented by the formula: -CO-C (-L 9 ) (-L 10 ) (-L 11 ) group to give the thioester derivative (I-1e).
• the group represented by the formula: --CO--C(-L 9 )(-L 10 )(-L 11 ) corresponds to the group represented by R' in the thioester derivative (I-1e).
• the contact with the compound represented by is preferably carried out in a solvent.
• the thioester derivative (III-1) and the compound can be contacted by mixing the thioester derivative (III-1) and the compound in a solvent.
• the solvent is preferably an organic solvent. Specific examples of the organic solvent are as described above. One organic solvent may be used alone, or two or more organic solvents may be used in combination.
• the organic solvent is preferably methylene chloride, THF, 2-methyl-THF, toluene, DMF, 1,4-dioxane, acetonitrile or a mixed solvent thereof.
• the amount of solvent used is, for example, 1 to 100 mL, preferably 2 to 50 mL, per 1 g of thioester derivative (III-1).
• the amount of the compound represented by the formula: C(-L 9 )(-L 10 )(-L 11 )-CO-O-CO-C(-L 9 )(-L 10 )(-L 11 ) is , for example, 1 to 5 mol, preferably 1 to 3 mol, more preferably 1 to 2 mol, per 1 mol of the thioester derivative (III-1).
• the contact temperature is, for example, -20 to 40 ° C., preferably -10 to 30 ° C., more preferably 0 to 20 ° C.
• the contact time is, for example, 0.5 to 5 hours, preferably 1 to 4 hours, more preferably 1 to 3 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• a sixth method is a method for producing a thioester derivative (I-2) (hereinafter referred to as "thioester derivative (I-2a)”) in which R' represents an optionally substituted alkylsilyl group. be.
• the thioester derivative (I-2a) is produced by a method comprising the step of contacting the thioester derivative (III-2) with a silylating agent (2) in the presence of a base to produce the thioester derivative (I-2a). can do.
• the thioester derivative (III-2) and silylating agent (2) may be commercially available products or may be produced according to conventional methods.
• the contact between the thioester derivative (III-2) and the silylating agent (2) is preferably carried out in a solvent.
• the thioester derivative (III-2) and the silylating agent (2) can be brought into contact with each other by mixing the thioester derivative (III-2) and the silylating agent (2) in a solvent.
• the solvent is preferably an organic solvent. Specific examples of the organic solvent are as described above. One organic solvent may be used alone, or two or more organic solvents may be used in combination.
• the organic solvent is preferably THF, tert-butyl methyl ether, DCM, toluene or a mixed solvent thereof.
• the amount of solvent used is, for example, 1-200 mL, preferably 2-100 mL, per 1 g of thioester derivative (III-2).
• the contact between the thioester derivative (III-2) and the silylating agent (2) is carried out in the presence of a base.
• the amount of silylating agent (2) used is, for example, 1 to 10 mol, preferably 1 to 5 mol, more preferably 1 to 3 mol, per 1 mol of thioester derivative (III-2).
• Examples of the base include triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIEA), imidazole, diazabicycloundecene (DBU), diethylaniline, 2,6-lutidine and the like. organic amines, sodium acetate, Schottenbaumann conditions, and the like.
• the base is preferably imidazole.
• the amount of the base used is, for example, 0.1 to 10 mol, preferably 0.2 to 5 mol, more preferably 0.3 to 3 mol, per 1 mol of the thioester derivative (III-2).
• the contact temperature is, for example, -30 to 100°C, preferably -10 to 80°C, more preferably 0 to 50°C.
• the contact time is, for example, 0.1 to 24 hours, preferably 0.5 to 17 hours, more preferably 0.5 to 5 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• a seventh method is a method for producing a thioester derivative (I-2) (hereinafter referred to as "thioester derivative (I-2b)”) in which R' represents a tetrahydropyranyl group which may have a substituent. is.
• the thioester derivative (I-2b) is prepared by contacting the thioester derivative (III-2) with 3,4-dihydro-2H-pyran optionally having a substituent in the presence of an acid to obtain a thioester derivative ( It can be produced by a method including the step of producing I-2b).
• the thioester derivative (III-2) and optionally substituted 3,4-dihydro-2H-pyran may be commercially available or may be produced according to a conventional method.
• R' represents a tetrahydropyranyl group
• 3,4-dihydro-2H-pyran is used.
• R' represents a substituted tetrahydropyranyl group
• substituted 3,4-dihydro-2H-pyran is used.
• the number and type of substituents possessed by 3,4-dihydro-2H-pyran are the same as the number and type of substituents possessed by the tetrahydropyranyl group.
• the thioester derivative (III-2) and optionally substituted 3,4-dihydro-2H-pyran are brought into contact with the hydroxy group contained in the thioester derivative (III-2). is protected with an optionally substituted tetrahydropyranyl group to obtain a thioester derivative (I-2b).
• the tetrahydropyranyl group which may have a substituent corresponds to the group represented by R' in the thioester derivative (I-2b).
• the contact between the thioester derivative (III-2) and optionally substituted 3,4-dihydro-2H-pyran is preferably carried out in a solvent.
• a solvent By mixing the thioester derivative (III-2) and optionally substituted 3,4-dihydro-2H-pyran in a solvent, the thioester derivative (III-2) and the substituted thioester derivative (III-2) 3,4-dihydro-2H-pyran, which may be used.
• the solvent is preferably an organic solvent. Specific examples of the organic solvent are as described above. One organic solvent may be used alone, or two or more organic solvents may be used in combination.
• the organic solvent is preferably methylene chloride, THF, 2-methyl-THF, toluene, DMF, 1,4-dioxane, acetonitrile or a mixed solvent thereof.
• the amount of solvent used is, for example, 2-100 mL, preferably 3-30 mL, per 1 g of thioester derivative (III-2).
• the amount of 3,4-dihydro-2H-pyran optionally having a substituent to be used is, for example, 1 to 10 mol, preferably 1 to 5 mol, more preferably 1 to 1 mol, per 1 mol of the thioester derivative (III-2). It is preferably 1 to 3 mol.
• the acid is preferably p-toluenesulfonic acid monohydrate (TsOH.H 2 O).
• the amount of acid used is, for example, 0.005 to 1 mol, preferably 0.01 to 0.5 mol, more preferably 0.05 to 0.25 mol, per 1 mol of the thioester derivative (III-2). be.
• the contact temperature is, for example, ⁇ 10 to 100° C., preferably The temperature is 0 to 80° C., more preferably 5 to 60° C.
• the contact time is, for example, 0.5 to 8 hours, preferably 1 to 6 hours, more preferably 2 to 4 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• the eighth method is to produce a thioester derivative (I-2) (hereinafter referred to as "thioester derivative (I-2c)”) in which R' represents a group represented by the formula: -CO-L 1 -L 2 It is a way to
• the thioester derivative (I-2c) is prepared by combining the thioester derivative (III-2) with the formula: J-CO-L 1 -L 2 [wherein L 1 and L 2 are as defined above, J represents a halogen atom. ] to produce the thioester derivative (I-2c).
• the thioester derivative (III-2) and the compound represented by the formula: J—CO—L 1 -L 2 may be commercially available or may be produced according to conventional methods.
• J represents a halogen atom.
• J is preferably selected from chlorine, bromine and iodine, more preferably chlorine.
• J-CO-L 1 -L 2 are Cl-CO-CH 2 Cl (chloroacetyl chloride), Cl-CO-CHCl 2 (dichloroacetyl chloride) and Cl-CO-CCl 3 (trichloroacetyl chloride), more preferably Cl--CO--CH 2 Cl.
• the thioester derivative (III-2) When the thioester derivative (III-2) is brought into contact with the compound represented by the formula: J—CO—L 1 -L 2 in the presence of a base, the hydroxy group contained in the thioester derivative (III-2) is A thioester derivative (I-2c) is obtained by protecting with a group represented by the formula: -CO-L 1 -L 2 .
• the group represented by the formula: -CO-L 1 -L 2 corresponds to the group represented by R' in the thioester derivative (I-2c).
• the contact between the thioester derivative (III-2) and the compound represented by the formula: J—CO—L 1 -L 2 is preferably carried out in a solvent.
• the thioester derivative (III-2) and the compound can be contacted by mixing the thioester derivative (III-2) and the compound in a solvent.
• the solvent is preferably an organic solvent. Specific examples of the organic solvent are as described above. One organic solvent may be used alone, or two or more organic solvents may be used in combination.
• the organic solvent is preferably methylene chloride, THF, 2-methyl-THF, toluene, DMF, 1,4-dioxane, acetonitrile or a mixed solvent thereof.
• the amount of solvent used is, for example, 1 to 100 mL, preferably 2 to 50 mL, per 1 g of thioester derivative (III-2).
• the amount of the compound represented by the formula: J—CO—L 1 -L 2 to be used is, for example, 1 to 5 mol, preferably 1 to 3 mol, more preferably 1 to 3 mol, per 1 mol of the thioester derivative (III-2). 1 to 2 mol.
• Examples of the base include triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIEA), imidazole, diazabicycloundecene (DBU), diethylaniline, 2,6-lutidine and the like.
• organic amines sodium acetate, Schottenbaumann conditions, and the like.
• the base is preferably pyridine.
• the amount of the base used is, for example, 1-5 mol, preferably 1-4 mol, more preferably 1-3 mol, per 1 mol of the thioester derivative (III-2).
• the contact temperature is, for example, ⁇ 30 to 50° C., preferably ⁇ 20° C. to 40° C., more preferably ⁇ 10 to 30° C.
• the contact time is, for example, 0.5 to 17 hours, preferably 1 to 10 hours, more preferably 2 to 8 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• a ninth method is a thioester derivative (I- 2 ) ( hereinafter referred to as "thioester derivative ( I -2d)”).
• K represents a hydrogen atom or an optionally substituted alkyl group.
• L4 represents an alkyl group.
• K represents a substituted alkyl group
• L4 represents a substituted alkyl group.
• the number of carbon atoms in the alkyl group represented by K is one less than the number of carbon atoms in the alkyl group represented by L4 .
• the number and types of substituents possessed by the alkyl group represented by K are the same as the number and types of substituents possessed by the alkyl group represented by L4 .
• the group represented by the formula: -C(-L 3 )(-L 4 )-OL 5 corresponds to the group represented by R' in the thioester derivative (I-2d).
• the thioester derivative (III-2) and the compound can be contacted by mixing the thioester derivative (III-2) and the compound in a solvent.
• the solvent is preferably an organic solvent. Specific examples of the organic solvent are as described above. One organic solvent may be used alone, or two or more organic solvents may be used in combination.
• the organic solvent is preferably methylene chloride, THF, 2-methyl-THF, toluene, DMF, 1,4-dioxane, acetonitrile or a mixed solvent thereof.
• the amount of solvent used is, for example, 1 to 100 mL, preferably 3 to 50 mL, per 1 g of thioester derivative (III-2).
• acids include p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, pyridine paratoluenesulfonic acid (PPTS), and the like.
• the acid is preferably PPTS.
• the amount of acid used is, for example, 0.001 to 1 mol, preferably 0.005 to 0.5 mol, more preferably 0.01 to 0.2 mol, per 1 mol of the thioester derivative (III-2). be.
• the contact temperature is, for example, 0 to 70°C. , preferably 5 to 60° C., more preferably 10 to 40° C.
• the contact time is, for example, 0.5 to 24 hours, preferably 1 to 12 hours, more preferably 2 to 8 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• a tenth method is a thioester derivative (I- 2 ) (hereinafter "thioester derivative (I-2e)”).
• the thioester derivative (I-2e) is prepared by combining the thioester derivative (III-2) with the formula: C(-L 6 )(-L 7 )(-L 8 )-O-CO-O-CO- in the presence of a base. OC(-L 6 )(-L 7 )(-L 8 ) [wherein L 6 , L 7 and L 8 are as defined above. ] to produce the thioester derivative (I-2e).
• the compound represented by L 8 ) may be a commercial product or may be produced according to a conventional method.
• a compound represented by the formula: C(-L 6 )(-L 7 )(-L 8 )-O-CO-O-CO-O-C(-L 6 )(-L 7 )(-L 8 ) is preferably C(--CH 3 ) 3 --O--CO--O--CO--O--C(--CH 3 ) 3 (di-tert-butyl dicarbonate).
• the hydroxy group contained in the thioester derivative (III- 2 ) is transformed into the 7 ) Protected with a group represented by (-L 8 ) to obtain a thioester derivative (I-2e).
• the group represented by the formula: -CO-O-C(-L 6 )(-L 7 )(-L 8 ) corresponds to the group represented by R' in the thioester derivative (I-2e).
• Thioester derivative (III-2) and formula: C(-L 6 )(-L 7 )(-L 8 )-O-CO-O-CO-OC(-L 6 )(-L 7 )( -L 8 ) is preferably carried out in a solvent.
• the thioester derivative (III-2) and the compound can be contacted by mixing the thioester derivative (III-2) and the compound in a solvent.
• the solvent is preferably an organic solvent. Specific examples of the organic solvent are as described above. One organic solvent may be used alone, or two or more organic solvents may be used in combination.
• the organic solvent is preferably methylene chloride, THF, 2-methyl-THF, toluene, DMF, 1,4-dioxane, acetonitrile or a mixed solvent thereof.
• the amount of solvent used is, for example, 1 to 100 mL, preferably 2 to 50 mL, per 1 g of thioester derivative (III-2).
• Thioester derivative (III-2) and formula: C(-L 6 )(-L 7 )(-L 8 )-O-CO-O-CO-OC(-L 6 )(-L 7 )( -L 8 ) is carried out in the presence of a base.
• a compound represented by the formula: C(-L 6 )(-L 7 )(-L 8 )-O-CO-O-CO-O-C(-L 6 )(-L 7 )(-L 8 ) is, for example, 1 to 10 mol, preferably 1 to 5 mol, more preferably 1 to 3 mol, per 1 mol of the thioester derivative (III-2).
• the base is preferably selected from potassium carbonate (K 2 CO 3 ), 4-dimethylaminopyridine (DMAP) and triethylamine (TEA).
• K 2 CO 3 potassium carbonate
• DMAP 4-dimethylaminopyridine
• TAA triethylamine
• the amount of the base used is, for example, 1 to 10 mol, preferably 1 to 5 mol, more preferably 1 to 3 mol, per 1 mol of the thioester derivative (III-2).
• the contact temperature is, for example, ⁇ 10 to 60° C., preferably ⁇ 5 to 50° C., more preferably 0 to 40° C.
• the contact time is, for example, 0.5 to 48 hours, preferably 1 to 24 hours, more preferably 2 to 17 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• thioester derivatives (I-1a) to (I-1e) are collectively referred to as thioester derivatives (I-1), and thioester derivatives (I-2a) to (I-2e) are collectively referred to as thioester derivatives (I-2 ).
• the obtained thioester derivative (I-1) or (I-2) can be isolated by the following method.
• a quenching liquid eg, water, HCl aqueous solution, etc.
• the reaction solution to which the quench solution has been added is stirred to separate into an aqueous layer and an organic layer.
• an organic solvent is added to the aqueous layer to separate the organic layer and the aqueous layer again.
• the organic layer is extracted and combined with the previously extracted organic layer to obtain a total organic layer.
• the total organic layer is washed with a washing solution (e.g., water, HCl aqueous solution, saturated NaHCO 3 aqueous solution, brine, etc.) and then dried using sodium sulfate or the like to give thioester derivative (I-1) or (I-2). ) to give a residue containing the product of
• a washing solution e.g., water, HCl aqueous solution, saturated NaHCO 3 aqueous solution, brine, etc.
• organic solvent added to the aqueous layer are as described above.
• One organic solvent may be used alone, or two or more organic solvents may be used in combination.
• the organic solvent is preferably ethyl acetate, DCM, toluene, hexane or a mixed solvent thereof, more preferably ethyl acetate or DCM.
• the structure of the thioester derivative (I-1) or (I-2) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy.
• the method for producing the thioester derivative (I-1) may include the step of producing the thioester derivative (III-1). In this case, after the step of producing the thioester derivative (III-1), the step of contacting the thioester derivative (III-1) with the carboxylic anhydride (1) to produce the thioester derivative (I-1). done.
• the method for producing the thioester derivative (I-2) may include the step of producing the thioester derivative (III-2). In this case, the step of producing the thioester derivative (III-2) is followed by the step of contacting the thioester derivative (III-2) with the silylating agent (2) to produce the thioester derivative (I-2).
• Thioester derivative (III-1) can be produced by contacting thiol (3) with acyl-protected lactone derivative (IV-1) in the presence of trialkylaluminum.
• Thioester derivative (III-2) can be produced by contacting thiol (3) with acyl-protected lactone derivative (IV-2) in the presence of trialkylaluminum.
• a trialkylaluminum acts as a reactant.
• Trialkylaluminums include, for example, trimethylaluminum, triethylaluminum, and triple aluminum.
• trialkylaluminum such as trimethylaluminum, which has been conventionally used as a reactant, is highly flammable, so care must be taken when handling it. Therefore, it is preferable to produce thioester derivative (III-1) by contacting thiol (3), Grignard reagent (4) and acyl-protected lactone derivative (IV-1). Moreover, it is preferable to produce the thioester derivative (III-2) by contacting the thiol (3), the Grignard reagent (4) and the acyl-protected lactone derivative (IV-2).
• Grignard reagent (4) Since the Grignard reagent (4) is less flammable than trialkylaluminum such as trimethylaluminum, there is relatively no need to pay attention to the usage environment. Therefore, when Grignard reagent (4) is used, thioester derivative (III-1) or (III-2) can be produced more efficiently than when trialkylaluminum such as trimethylaluminum is used. , large-scale production of thioester derivatives (III-1) or (III-2) can be realized.
• Thiol (3), Grignard reagent (4), and acyl-protected lactone derivative (IV-1) or (IV-2) may be commercially available products or may be produced according to conventional methods.
• Thiol (3) includes, for example, ethanethiol, t-butylmercaptan, thiophenol, benzylmercaptan, 1-decanethiol, 1-dodecanethiol and the like.
• the amount of thiol (3) used is, for example, 0.5 to 4 mol, preferably 0.7 to 3 mol, more preferably 0.7 to 3 mol, per 1 mol of acyl-protected lactone derivative (IV-1) or (IV-2). is 0.9 to 2 mol.
• the amount of thiol (3) is preferably larger than the amount of acyl-protected lactone derivative (IV-1) or (IV-2).
• the Grignard reagent (4) acts as a reactant that reacts with the thiol (3) after ring-opening the acyl-protected lactone derivative (IV-1) or (IV-2).
• One type of Grignard reagent (4) may be used alone, or two or more types of Grignard reagents (4) may be used in combination.
• the amount of Grignard reagent (4) used per 1 mol of thiol (3) is, for example, 0.1 to 1 mol, preferably 0.3 to 1 mol, more preferably 0.5 to 1 mol.
• the amount of Grignard reagent (4) used per 1 mol of acyl-protected lactone derivative (IV-1) or (IV-2) is, for example, 0.1 to 1 mol, preferably 0.3 to 1 mol, more preferably 0. .5 to 1 mol.
• the "amount of Grignard reagent (4) used” means the amount of the one Grignard reagent (4) when one Grignard reagent (4) is used, and two or more Grignard reagents ( When 4) is used, it means the total amount of the two or more Grignard reagents (4). The same applies to the amounts of other substances used.
• the contact temperature is, for example, -30 to 50°C, preferably - The temperature is 20 to 40°C, more preferably -10 to 30°C, and the contact time (reaction time) is, for example, 0.1 to 5 hours, preferably 0.2 to 4 hours, more preferably 0.5 to 3 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• the contact between thiol (3), Grignard reagent (4), and acyl-protected lactone derivative (IV-1) or (IV-2) is preferably carried out in a solvent.
• Thiol (3), Grignard reagent (4), and acyl-protected lactone derivative (IV-1) or (IV-2) are mixed in a solvent to give thiol (3), Grignard reagent (4), and acyl-protected lactone.
• Derivatives (IV-1) or (IV-2) can be contacted.
• the solvent is preferably an organic solvent. Specific examples of the organic solvent are as described above. One organic solvent may be used alone, or two or more organic solvents may be used in combination.
• the solvent is preferably THF, dibutyl ether, 2-methyltetrahydrofuran or a mixed solvent thereof.
• the amount of solvent used is, for example, 0.5 to 100 mL, preferably 2 to 50 mL, per 1 g of acyl-protected lactone derivative (IV-1) or (IV-2).
• the thiol (3), the Grignard reagent (4), and the acyl-protected lactone derivative (IV-1) or (IV-2) are contacted in a solvent, the thiol (3), the Grignard reagent (4), the acyl-protected lactone derivative
• the order of adding (IV-1) or (V-2) and the solvent is not particularly limited.
• the Grignard reagent (4) can be added after adding the thiol (3) and solvent to the acyl-protected lactone derivative (IV-1) or (IV-2). Addition of the Grignard reagent (4) can be performed, for example, dropwise.
• Thioester derivative (III-1) is isolated from the reaction mixture obtained by contacting thiol (3), Grignard reagent (4) and acyl-protected lactone derivative (IV-1) followed by carboxylic anhydride ( It may be used in the reaction with 1) or may be used in the reaction with carboxylic anhydride (1) without isolation from the reaction mixture.
• Thioester derivative (III-2) is isolated from the reaction mixture obtained by contacting thiol (3) with Grignard reagent (4) and acyl-protected lactone derivative (IV-2) followed by silylating agent (2 ) or the silylating agent (2) without isolation from the reaction mixture.
• a step of adding carboxylic anhydride (1) to the reaction mixture to bring thioester derivative (III-1) into contact with carboxylic anhydride (1) to produce thioester derivative (I-1) conduct.
• the amount of carboxylic anhydride (1) used is, for example, 0.5 to 10 mol, preferably 0.8 to 5.0 mol, per 1 mol of acyl-protected lactone derivative (IV-1). , more preferably 1.0 to 3.0 mol.
• the thioester derivative (I-1) can be produced by contacting the thioester derivative (III-1) with the carboxylic acid anhydride (1) in the presence of a Grignard reagent (4). can.
• the obtained thioester derivative (III-1) or (III-2) can be isolated, for example, by the following method.
• a quenching liquid eg, water, HCl aqueous solution, etc.
• the quenching liquid preferably contains Bronsted acid, and when the quenching liquid does not contain Bronsted acid, it is preferred to add Bronsted acid to the reaction liquid after addition of the quenching liquid. This can prevent the thioester derivative (III-1) or (III-2) from cyclizing into the structure of the acyl-protected lactone derivative (IV-1) or (IV-2).
• the thioester derivative (III-1) or (III-2) obtained by using the acyl-protected lactone derivative (IV-1) or (IV-2) having a five-membered ring as a substrate has a six-membered ring
• the thioester derivative (III-1) or (III-2) obtained by using the acyl-protected lactone derivative (IV-1) or (IV-2) having a number of members as the substrate it is easily transformed into the structure of the substrate.
• the pH of the reaction solution acidic, the cyclization of the thioester derivative (III-1) or (III-2) can be suppressed and the yield can be increased.
• the amount of Bronsted acid is, for example, 1 mol or more, preferably 3 mol or more, more preferably 5 mol or more, relative to 1 mol of acyl-protected lactone derivative (IV-1) or (IV-2).
• the upper limit of the amount of Bronsted acid is not particularly limited, according to one example, it is 30 mol or less.
• Bronsted acids include, for example, hydrogen halide, sulfuric acid (H 2 SO 4 ), carbonic acid, acetic acid, oxalic acid, citric acid, trifluoroacetic acid (TFA), methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfone acid, phosphoric acid, and the like.
• One Bronsted acid may be used alone, or two or more Bronsted acids may be used in combination.
• Hydrogen halides include, for example, hydrogen fluoride (HF), hydrogen chloride (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), and the like.
• Bronsted acids include, for example, hydrogen chloride, hydrogen bromide, sulfuric acid and the like.
• An acidic solution of Bronsted acid dissolved in water may also be used.
• the amount is preferably 10-30 mL with respect to 1 g of acyl-protected lactone derivative (IV-1) or (IV-2).
• the reaction solution to which the Bronsted acid has been added is stirred to separate into an aqueous layer and an organic layer.
• an organic solvent is added to the aqueous layer to separate the organic layer and the aqueous layer again.
• the organic layer is extracted and combined with the previously extracted organic layer to obtain a total organic layer.
• the total organic layer is washed with a washing solution (e.g., water, HCl aqueous solution, saturated NaHCO 3 aqueous solution, brine, etc.) and then dried using sodium sulfate or the like to give thioester derivative (III-1) or (III-2). ) to give a residue containing the product of
• a washing solution e.g., water, HCl aqueous solution, saturated NaHCO 3 aqueous solution, brine, etc.
• organic solvent added to the aqueous layer are as described above.
• One organic solvent may be used alone, or two or more organic solvents may be used in combination.
• the organic solvent is preferably ethyl acetate, DCM, toluene, hexane or a mixed solvent thereof, more preferably ethyl acetate or DCM.
• the structure of the thioester derivative (III-1) or (III-2) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy.
• a method for producing a thioester derivative (I-1) comprises contacting a thiol (3), a Grignard reagent (4) and an acyl-protected lactone derivative (IV-1) to produce a thioester derivative (III-1).
• the method for producing the thioester derivative (I-1) may comprise the step of producing the acyl-protected lactone derivative (IV-1).
• the thiol (3), the Grignard reagent (4) and the acyl-protected lactone derivative (IV-1) are brought into contact to obtain the thioester derivative (III- 1) is performed.
• a method for producing a thioester derivative (I-2) comprises contacting a thiol (3), a Grignard reagent (4) and an acyl-protected lactone derivative (IV-2) to produce a thioester derivative (III-2).
• the method for producing the thioester derivative (I-2) may comprise the step of producing the acyl-protected lactone derivative (IV-2).
• the thiol (3), the Grignard reagent (4) and the acyl-protected lactone derivative (IV-2) are contacted to obtain the thioester derivative (III- 2) is performed.
• the acyl-protected lactone derivative (IV-1) or (IV-2) is prepared by combining the lactone derivative (VII) with a carboxylic acid anhydride represented by the formula: R—CO—O—CO—R in the presence of a Bronsted acid. It can be manufactured by contacting with.
• each R in the formula: R-CO-O-CO-R independently represents an aryl group which may have a substituent, and the acyl-protected
• each R in the formula: R—CO—O—CO—R independently represents an optionally substituted alkyl group.
• the lactone derivative (VII) is brought into contact with a carboxylic acid anhydride represented by the formula: R—CO—O—CO—R, whereby the hydroxy group contained in the lactone derivative (VII) is , protected with a group represented by the formula: -CO-R to obtain an acyl-protected lactone derivative (IV-1) or (IV-2).
• a carboxylic acid anhydride represented by the formula: R—CO—O—CO—R whereby the hydroxy group contained in the lactone derivative (VII) is , protected with a group represented by the formula: -CO-R to obtain an acyl-protected lactone derivative (IV-1) or (IV-2).
• the amount of the carboxylic anhydride to be used is, for example, 1 to 200 mol, preferably 1 to 100 mol, more preferably 1 to 50 mol, per 1 mol of the lactone derivative (VII).
• the contact between the lactone derivative (VII) and the carboxylic anhydride may be carried out without a solvent, but is preferably carried out in a solvent.
• a solvent By mixing the lactone derivative (VII) and the carboxylic anhydride in a solvent, the lactone derivative (VII) and the carboxylic anhydride can be contacted.
• the solvent is preferably an organic solvent. Specific examples of the organic solvent are as described above. One organic solvent may be used alone, or two or more organic solvents may be used in combination.
• the organic solvent is preferably DCM, toluene or a mixed solvent thereof.
• Bronsted acids include, for example, trifluoroacetic acid (TFA), sulfuric acid, methanesulfonic acid and the like, preferably TFA and sulfuric acid.
• the amount of solvent used is, for example, 0 to 100 mL, preferably 0 to 50 mL, more preferably 0 to 10 mL, relative to 1 g of the lactone derivative (VII).
• the amount of Bronsted acid used is, for example, 0.1 to 100 mL, preferably 0.5 to 50 mL, more preferably 1 to 30 mL, relative to 1 g of lactone derivative (VII).
• the contact between the lactone derivative (VII) and the carboxylic anhydride may be carried out in the presence of a base.
• Specific examples of the base are the same as the specific examples of the base used for contacting the thioester derivative (III-1) and the carboxylic anhydride (1).
• the amount of the base used is, for example, 0 to 10 mol, preferably 0.1 to 5 mol, more preferably 0.5 to 3 mol, per 1 mol of the lactone derivative (VII).
• the contact temperature is, for example, -10 to 50°C, preferably -5 to 40°C, more preferably 0 to 30°C.
• the time is, for example, 0.1 to 10 hours, preferably 1 to 8 hours, more preferably 2 to 5 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• Acyl-protected lactone derivatives (IV-1) or (IV-2) may be concentrated by evaporation.
• the concentrate is used as is (i.e. without isolating the acyl-protected lactone derivative (IV-1) or (IV-2) from the concentrate) for reaction with thiol (3) and Grignard reagent (4). can be done.
• thiol (3), Grignard reagent (4) and acyl-protected lactone derivative (IV-1) are brought into contact to form thioester derivative (III-). 1) is performed.
• the carboxylic anhydride (1) is added to the reaction mixture to obtain a thioester derivative (III-1) and a carboxylic anhydride.
• a step of producing a thioester derivative (I-1) by contacting the substance (1) is carried out.
• the total amount of carboxylic anhydride used (the amount of carboxylic anhydride used for producing acyl-protected lactone derivative (IV) and the amount of carboxylic anhydride used for producing thioester derivative (I-1)
• the total amount of compound (1) used is, for example, 1 to 200 mol, preferably 1 to 100 mol, more preferably 1 to 50 mol, per 1 mol of lactone derivative (VII).
• ketone derivative (II) in which R each independently represents an optionally substituted aryl group is referred to as ketone derivative (II-1), and each R independently represents a substituent.
• a ketone derivative (II) representing an alkyl group which may be present is referred to as a ketone derivative (II-2).
• the ketone derivative (II) is obtained by contacting the thioester derivative (I), a Grignard reagent (5) selected from Grignard reagents (5a) and Grignard reagents (5b), and a copper salt to obtain the ketone derivative (II). It can be manufactured by a method including a manufacturing step.
• the ketone derivative (II-1) is obtained by contacting the thioester derivative (I-1), a Grignard reagent (5) selected from Grignard reagents (5a) and Grignard reagents (5b), and a copper salt to obtain a ketone derivative. It can be produced by a method including the step of producing (II-1).
• the ketone derivative (II-2) is obtained by contacting a thioester derivative (I-2), a Grignard reagent (5) selected from Grignard reagents (5a) and Grignard reagents (5b), and a copper salt to obtain a ketone derivative. It can be produced by a method including the step of producing (II-2).
• either one of the Grignard reagent (5a) and the Grignard reagent (5b) may be selected, or both may be selected.
• a mixture of both may be added to the reaction system, or both may be added to the reaction system separately.
• the Grignard reagent (5a) may be a commercial product or may be produced according to a conventional method.
• the Grignard reagent (5) preferably contains the Grignard reagent (5b).
• the Grignard reagent (5b) is called turbo Grignard reagent.
• the Grignard reagent (5b) may be a commercial product or may be produced according to a conventional method.
• the Grignard reagent (5b) is prepared, for example, in a reaction vessel substituted with an inert gas (e.g., nitrogen, argon, etc.), in the presence of a lithium salt, with magnesium in the formula: W 2 X [wherein W 2 and X has the same meaning as above. ] in an organic solvent.
• an inert gas e.g., nitrogen, argon, etc.
• Grignard reagent (5b) was prepared according to Angew Chem. Int. According to known methods described in Ed. ] with a compound represented by the formula: W 2 —H.
• Copper salts include, for example, copper (I) chloride (CuCl), copper (II) chloride (CuCl 2 ), copper (I) bromide (CuBr), copper (II) bromide (CuBr 2 ), copper cyanide (I) (CuCN), copper (I) 3-methylsalicylate, copper mesitylene (I) (MesCu), copper (I) isopropoxy (iPrOCu), copper (I) iodide (CuI), copper (II) iodide ) (CuI 2 ), copper(I) acetate (CuOAc), copper(II) acetate (Cu(OAc) 2 ), copper(II) sulfate (CuSO 4 ), copper(I) oxide (Cu 2 O), oxidation copper (II) (CuO), copper (I) pivalate (CuOPiv), copper (II) pivalate (Cu(OPiv) 2 ), copper salts containing sulfur (S), and the like.
• Copper salts containing sulfur (S) include, for example, copper (I) thiophene-2-carboxylate (CuTC). S has a high affinity with Cu, and S easily coordinates with Cu in a copper salt. This coordination activates the Cu and increases the yield.
• S copper (I) thiophene-2-carboxylate
• the valence of the copper atom contained in the copper salt is usually monovalent or divalent, preferably monovalent.
• a copper salt in which the valence of the copper atom is monovalent has excellent catalytic activity.
• CuCN, CuCl, CuI, CuBr, CuOAc and CuTC are particularly excellent in catalytic action. Therefore, the copper salt preferably contains at least one selected from CuCN, CuCl, CuI, CuBr, CuOAc and CuTC, more preferably at least one selected from CuCN, CuCl, CuOAc and CuTC. , CuCN and CuCl.
• a ketone derivative (II-1) or (II-2) is obtained in high yield by contacting a thioester derivative (I-1) or (I-2) with a Grignard reagent (5) and a copper salt. be able to.
• the present inventors presume that the reason for this is that an anionic complex (10) represented by the following formula (10) or an anionic complex (11) represented by the following formula (11) is formed. ing. That is, the oxidative addition of the carbon-sulfur bond of the thioester derivative (I-1) or (I-2) is promoted relative to the complex (10) or (11), which is anionic rather than neutral. It is believed that there is.
• the anionic complex (10) is formed when a copper salt other than CuCN (e.g., CuCl, CuBr, CuI, CuOAc, etc.) is used, and the anionic complex (11) is formed using CuCN as the copper salt. It is considered to be formed when a copper salt other than CuCN (e.g., CuCl, CuBr, CuI, CuOAc, etc.) is used, and the anionic complex (11) is formed using CuCN as the copper salt. It is considered to be formed when a copper salt other than CuCN (e.g., CuCl, CuBr, CuI, CuOAc, etc.) is used, and the anionic complex (11) is formed using CuCN as the copper salt. It is considered to be formed when a copper salt other than CuCN (e.g., CuCl, CuBr, CuI, CuOAc, etc.) is used, and the anionic complex (11) is formed using CuCN as the copper salt. It is considered to be formed when a copper salt other than CuCN (
• the amount of CuCN used is preferably 0.2 to 1.2 mol, more preferably 0.5 to 1.1 mol, more preferably 0.5 to 1.1 mol, per 1 mol of the Grignard reagent (5). Preferably 0.9 to 1.1 mol, more preferably 1 mol.
• the amount of CuCl used is preferably 1.3 to 1.5 mol, more preferably 0.4 to 0.95 mol, more preferably 0.4 to 0.95 mol, per 1 mol of the Grignard reagent (5). It is preferably 0.5 to 0.9 mol, more preferably 0.6 to 0.8 mol.
• the amount of the copper salt other than CuCN and CuCl used is preferably 0.1 to 1 mol, more preferably 0.3 to 0.9 mol, more preferably 0.4, per 1 mol of the Grignard reagent (5). ⁇ 0.8 mol.
• the amount of the copper salt other than CuCN and CuCl used is 0.5 to 0.9 mol in one example, and 0.6 to 0.6 mol in another example, per 1 mol of the Grignard reagent (5). 8 mol.
• amount of copper salt other than CuCN and CuCl used means the amount of the one copper salt when one copper salt other than CuCN and CuCl is used, and two copper salts other than CuCN and CuCl are used. When more than one copper salt is used, it means the total amount of the two or more copper salts.
• the amount of the Grignard reagent (5) used is, for example, 1 to 10 mol, preferably 1 to 5 mol, more preferably 1.5 to 4 mol, per 1 mol of the thioester derivative (I-1) or (I-2). Mole.
• the amount of Grignard reagent (5) used does not need to be excessive with respect to the amount of thioester derivative (I-1) or (I-2) used.
• the "amount of Grignard reagent (5) used” means the amount of the one Grignard reagent (5) when one Grignard reagent (5) is used, and two or more Grignard reagents ( When 5) is used, it means the total amount of the two or more Grignard reagents (5).
• the amount of the Grignard reagent (5b) is, for example, the total mass of the Grignard reagent (5a) and the Grignard reagent (5b) 10 to 90% by mass based on.
• the contact between the thioester derivative (I-1) or (I-2), the Grignard reagent (5) and the copper salt is preferably carried out in a solvent.
• the thioester derivative (I-1) or (I-2) and the Grignard reagent (5 ) can be contacted with a copper salt.
• the solvent is preferably an organic solvent. Specific examples of the organic solvent are as described above. One organic solvent may be used, or two or more organic solvents may be used in combination.
• the organic solvent is preferably THF, toluene or a mixed solvent thereof.
• the amount of solvent used is, for example, 1 to 100 mL, preferably 2 to 50 mL, per 1 g of thioester derivative (I-1) or (I-2).
• the contact temperature is, for example, -20 to 150°C, preferably -10 to 100°C. , more preferably 0 to 70°C, even more preferably 0 to 50°C.
• the equipment cost related to temperature control is suppressed, and the ketone derivative (II-1) -1) or (II-2) can be industrially produced at a lower cost. Also, when the contact temperature (reaction temperature) is within the above temperature range, the yield of the ketone derivative (II-1) or (II-2) tends to increase.
• the contact time is, for example, 0.5 to 72 hours, preferably 1 to 48 hours. is.
• the Grignard reagent (5) When the thioester derivative (I-1) or (I-2) is brought into contact with the Grignard reagent (5) and the copper salt, the Grignard reagent (5) is brought into contact with the copper salt to form an organocopper reagent, It is preferable to mix the thioester derivative (I-1) or (I-2) and bring the organocopper reagent and the thioester derivative (I-1) or (I-2) into contact. Thereby, the ketone derivative (II-1) or (II-2) can be obtained in high yield.
• the contact temperature is, for example, ⁇ 20 to 150° C., preferably ⁇ 10 to 100° C., more preferably 0 to 50° C.
• the contact time is, for example, 0.1 to 5 hours, preferably 0.2 to 2 hours, more preferably 0.5 to 1 hour.
• the contact temperature is, for example, -20 to 150°C, preferably -10 to 100°C, more preferably 0. to 50° C.
• the contact time is, for example, 0.1 to 5 hours, preferably 0.2 to 2 hours, more preferably 0.5 to 1 hour.
• organozinc compound (6) When contacting the thioester derivative (I-1) or (I-2) with the Grignard reagent (5) and the copper salt, it is selected from an organic zinc compound (6a), an organic zinc compound (6b) and an organic zinc compound (6c)
• the organozinc compound (6) obtained may be used in combination with a Grignard reagent (5) and a copper salt.
• Organozinc compounds (6) can be used as reagents to introduce group W2 into thioester derivatives (I-1) or (I-2).
• the organic zinc compound (6) one of the organic zinc compound (6a), the organic zinc compound (6b) and the organic zinc compound (6c) may be selected, or two or more thereof may be selected. When two or more are selected, a mixture of two or more organic zinc compounds may be added to the reaction system, or two or more organic zinc compounds may be added separately to the reaction system.
• the organic zinc compound (6) When mixing the thioester derivative (I-1) or (I-2), the Grignard reagent (5) and the copper salt, it is preferable to use the organic zinc compound (6) as little as possible. When the organic zinc compound (6) is used, the yield of the ketone derivative (II-1) or (II-2) tends to decrease.
• the amount of the organic zinc compound (6) used is preferably 10% by mass or less, more preferably 5% by mass or less, more preferably 1% by mass, based on the mass of the thioester derivative (I-1) or (I-2). % or less. The lower bound is zero.
• the organic zinc compound (6) may be a commercial product or may be produced according to a conventional method.
• the organic zinc compound (6a) and/or the organic zinc compound (6b) may be used, for example, together with a lithium salt such as lithium chloride.
• the organozinc compound (6a) may form a complex with a lithium salt.
• the complex of organozinc compound (6a) and lithium salt corresponds to organozinc compound (6c).
• Grignard reagent (5) In addition to the Grignard reagent (5), other Grignard reagents may be used. In this case, the amount of Grignard reagent (5) used is preferably 80% by mass or more, and may be 100% by mass, based on the total mass of Grignard reagent (5) and other Grignard reagents.
• W 2 has no substituents on the carbon atoms located on both sides of the carbon atom having an aryl group bond (the carbon atom bonded to Mg), and the remaining
• the carbon atom is an aryl group that may have a substituent, or the carbon atom or heteroatom located on both sides of the carbon atom having a bond of a heteroaryl group (the carbon atom that binds to Mg) has a substituent
• a Grignard reagent (5a) or (5b) which is a heteroaryl group which does not have and the remaining carbon atoms or heteroatoms may have a substituent.
• the meta positions to the carbon atom bound to MgX have R21 and R23 .
• the para position to the carbon atom bound to MgX has R22 .
• R 21 , R 22 and R 23 are each independently a hydrogen atom or a substituent selected from substituent groups ⁇ and ⁇ . f is 0 or 1;
• the step of producing the ketone derivative (II-1) or (II-2) by contacting the thioester derivative (I-1) or (I-2) with a Grignard reagent (5) and a copper salt,
• the thioester derivative (I-1) or (I-2), the Grignard reagent (5) and the copper salt may be brought into contact in the presence.
• the use of a palladium catalyst is advantageous in that it can reduce the amount of by-products produced by coupling reactions between W 2 groups and the like.
• palladium catalysts include palladium (II) dichloride, palladium (II) dibromide, palladium (II) dichloride bistriphenylphosphine complex, palladium (0) tetrakistriphenylphosphine complex, palladium (II) acetate, and palladium (II) oxide.
• the palladium catalyst may be supported on a carrier.
• the use of a carrier-supported palladium catalyst is advantageous in that the palladium catalyst can be easily separated from the reaction mixture.
• Examples of carriers include activated carbon, alumina, barium sulfate, calcium carbonate, hydroxyapatite, hydrotalcite, aluminum oxide, titanium dioxide, zirconium dioxide, silicon dioxide, clay, silicates, zeolites, and polymer matrices.
• the polymeric matrix may be, for example, a styrene-divinylbenzene resin or a phenol-formaldehyde resin, to which chelating ligands (such as phosphine, 1,10-phenanthroline or 2,2'-bipyridine) are attached.
• chelating ligands such as phosphine, 1,10-phenanthroline or 2,2'-bipyridine
• a ligand that binds to the resin can form a complex with the palladium catalyst, immobilizing the palladium catalyst and making it a heterogeneous catalyst.
• the carrier is preferably activated carbon, alumina, barium sulfate, calcium carbonate, hydroxyapatite and hydrotalcite, aluminum oxide, titanium dioxide and zirconium dioxide, more preferably activated carbon.
• the palladium catalyst is palladium black or palladium on carbon (Pd/C).
• the amount of the palladium catalyst is, for example, 1 to 25 wt%, preferably 3 to 20 wt%, more preferably 4 to 15 wt%, based on the total weight of the palladium catalyst and carrier. %.
• the amount of the palladium catalyst used is, for example, 0.001 to 1 mol, preferably 0.002 to 0.5 mol, more preferably 0.03 to 0.1 mol, per 1 mol of the Grignard reagent (5). .
• the C-aryl-hydroxyglycoside derivative (V) is obtained by contacting the ketone derivative (II) with a first acid and/or base to eliminate the group represented by R' from the ketone derivative (II). After that, if necessary, it is further brought into contact with a second acid to produce the C-aryl-hydroxyglycoside derivative (V).
• C-aryl-hydroxyglycoside derivative (V-1) is converted from ketone derivative (II-1) to R′ by contacting ketone derivative (II-1) with a first acid and/or base. After eliminating the group, if necessary, further contact with a second acid to produce the C-aryl-hydroxyglycoside derivative (V-1).
• C-aryl-hydroxyglycoside derivative (V-2) is converted from ketone derivative (II-2) to R′ by contacting ketone derivative (II-2) with a first acid and/or base. After eliminating the group, contacting with a second acid, if necessary, to produce a C-aryl-hydroxyglycoside derivative (V-2).
• bases include fluorides, alkali metal alkoxides, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and cesium hydroxide.
• fluorides include tetra-n-butylammonium fluoride (TBAF), ammonium fluoride, ammonium bifluoride, hydrofluoric acid and the like.
• alkali metal alkoxides include sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium-t-butoxide, potassium-t-butoxide and the like.
• the base used for removing the group represented by R' from the ketone derivative (II-1) is preferably alkali metal alkoxide, more preferably sodium-t-butoxide or potassium-t-butoxide.
• the base used for removing the group represented by R' from the ketone derivative (II-2) is preferably fluoride, more preferably TBAF.
• the amount of the base used is, for example, 0.01 to 50, preferably 0.1 to 20 mol, more preferably 0.5 to 10 mol, per 1 mol of the ketone derivative (II-1) or (II-2). is.
• the contact between the ketone derivative (II-1) or (II-2) and the base is preferably carried out in a solvent.
• the ketone derivative (II-1) or (II-2) can be brought into contact with the base by mixing the ketone derivative (II-1) or (II-2) and the base in a solvent.
• the solvent is preferably water, an organic solvent or a mixed solvent thereof. Specific examples of the organic solvent are as described above. One organic solvent may be used, or two or more organic solvents may be used in combination.
• Organic solvents are preferably methanol, ethanol, isopropanol (IPA), t-butanol, THF, DCM, chloroform, acetonitrile, N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), acetic acid Ethyl or a mixed solvent thereof.
• the amount of solvent used is, for example, 0.5 to 100 mL, preferably 1 to 80 mL, more preferably 2 to 50 mL, relative to 1 g of ketone derivative (II-1) or (II-2).
• the contact temperature is, for example, ⁇ 20 to 100° C., preferably ⁇ 10 to 70° C., more preferably 0 to 50. ° C.
• the contact time is, for example, 0.1 to 24 hours, preferably 0.2 to 17 hours, more preferably 0.5 to 8 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• Examples of the first acid include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid and hydrogen bromide, and organic acids such as trifluoroacetic acid, trichloroacetic acid, formic acid and phthalic acid.
• inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid and hydrogen bromide
• organic acids such as trifluoroacetic acid, trichloroacetic acid, formic acid and phthalic acid.
• the amount of the first acid used is, for example, 0.01-100 mol, preferably 0.1-50 mol, more preferably 0.1-50 mol, per 1 mol of the ketone derivative (II-1) or (II-2). 5 to 10 mol.
• the contact between the ketone derivative (II-1) or (II-2) and the first acid is preferably carried out in a solvent.
• Contacting the ketone derivative (II-1) or (II-2) with the first acid by mixing the ketone derivative (II-1) or (II-2) and the first acid in a solvent be able to.
• the solvent is preferably water, an organic solvent or a mixed solvent thereof. Specific examples of the organic solvent are as described above. One organic solvent may be used, or two or more organic solvents may be used in combination.
• solvents examples include water, methanol, ethanol, isopropanol (IPA), t-butanol, tetrahydrofuran (THF), methylene chloride, chloroform, acetonitrile, N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone. (NMP), ethyl acetate, or a mixed solvent thereof.
• the contact temperature is, for example, -20 to 60°C, preferably -10 to 50°C, more preferably 0. to 40° C.
• the contact time is, for example, 0.5 to 48 hours, preferably 1 to 24 hours, more preferably 2 to 17 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• the first acid and base may be used together.
• a first acid e.g., inorganic acid such as acetic acid
• a base e.g., fluoride such as TBAF
• a deprotected ketone derivative (II -1) is cyclized to produce a C-aryl-hydroxyglycoside derivative (V-1) in which R 100 is a hydrogen atom, ie a C-aryl-hydroxyglycoside derivative (V'-1).
• a deprotected ketone derivative (II -2) is cyclized to produce a C-aryl-hydroxyglycoside derivative (V-2) in which R 100 is a hydrogen atom, ie a C-aryl-hydroxyglycoside derivative (V'-2).
• R 100 is a group other than a hydrogen atom, that is, an optionally substituted alkyl group, which may have a substituent C-aryl-hydroxyglycoside derivative (V-1) or (V-2) which is an aryl group, an optionally substituted alkylcarbonyl group, or an optionally substituted arylcarbonyl group ) is manufactured.
• Examples of the second acid include alkylsulfonic acids such as methylsulfonic acid, and arylsulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid.
• a carboxylic acid anhydride may be used as the second acid.
• Carboxylic anhydrides include, for example, the formula: R—CO—O—CO—R [wherein each R is independently an optionally substituted alkyl group or having a substituent represents an aryl group that may be ] and the like represented by carboxylic acid anhydrides.
• a carboxylic acid anhydride shall also be included in a 2nd acid.
• R 100 As the second acid, when using an alkylsulfonic acid represented by the formula: R 100 —SO 3 H (wherein R 100 represents an optionally substituted alkyl group), R 100 is substituted A C-aryl-hydroxyglycoside derivative (V-1) or (V-2), which is an alkyl group optionally having a group, is obtained. More specifically, when methylsulfonic acid is used as the second acid, a C-aryl-hydroxyglycoside derivative (V-1) or (V-2) in which R 100 is a methyl group is obtained.
• R 100 As the second acid, when using an arylsulfonic acid represented by the formula: R 100 —SO 3 H (wherein R 100 represents an aryl group which may have a substituent), R 100 is substituted A C-aryl-hydroxyglycoside derivative (V-1) or (V-2), which is an aryl group optionally having a group, is obtained. More specifically, when p-toluenesulfonic acid is used as the second acid, a C-aryl-hydroxyglycoside derivative (V-1) or (V-2) in which R 100 is a methylphenyl group is obtained. be done. Also, when benzenesulfonic acid is used as the second acid, a C-aryl-hydroxyglycoside derivative (V-1) or (V-2) in which R 100 is a phenyl group is obtained.
• the second acid has the formula: R—CO—O—CO—R [wherein each R independently represents an optionally substituted alkyl group. ] may be used.
• R—CO—O—CO—R [wherein each R independently represents an optionally substituted alkyl group. ]
• a C-aryl-hydroxyglycoside derivative (V-1) or (V-2) in which R 100 is an optionally substituted alkylcarbonyl group is obtained.
• the group represented by the formula: —CO—R introduced into the C-aryl-hydroxyglycoside derivative (V′-1) or (V′-2) corresponds to the group represented by R 100 . .
• R—CO—O—CO—R [wherein each R independently represents an aryl group which may have a substituent. ] may be used.
• a C-aryl-hydroxyglycoside derivative (V-1) or (V-2) in which R 100 is an optionally substituted arylcarbonyl group is obtained.
• the group represented by the formula: —CO—R introduced into the C-aryl-hydroxyglycoside derivative (V′-1) or (V′-2) corresponds to the group represented by R 100 . .
• a carboxylic acid anhydride in which R is a phenyl group is used as the second acid, a C-aryl-hydroxyglycoside derivative (V-1 ) or (V-2) is obtained.
• the amount of the second acid used is, for example, 0.01 to 100 mol, preferably 0.1 to 100 mol, per 1 mol of the C-aryl-hydroxyglycoside derivative (V'-1) or (V'-2). 50 mol, more preferably 0.5 to 10 mol.
• the contact between the C-aryl-hydroxyglycoside derivative (V'-1) or (V'-2) and the second acid is preferably carried out in a solvent.
• C-aryl-hydroxyglycoside derivative (V'-1) by mixing C-aryl-hydroxyglycoside derivative (V'-1) or (V'-2) with a second acid in a solvent
• (V'-2) can be contacted with a second acid.
• the solvent is preferably water, an organic solvent or a mixed solvent thereof.
• solvents examples include water, methanol, ethanol, isopropanol (IPA), t-butanol, tetrahydrofuran (THF), methylene chloride, chloroform, acetonitrile, N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone. (NMP), ethyl acetate, or a mixed solvent thereof.
• the contact temperature is, for example, -20 to 60°C, preferably -10. to 50° C., more preferably 0 to 40° C.
• the contact time is, for example, 0.5 to 48 hours, preferably 1 to 24 hours, more preferably 2 to 17 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• C-aryl-hydroxyglycoside derivatives (V-1) or (V-2) is particularly useful.
• the obtained C-aryl-hydroxyglycoside derivative (V-1) or (V-2) may be isolated by silica gel column chromatography, or may be used in the next step as a concentration residue without being purified. .
• the structure of the C-aryl-hydroxyglycoside derivative (V-1) or (V-2) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy.
• the method for producing the C-aryl-hydroxyglycoside derivative (V-1) may include the step of producing the ketone derivative (II-1). In this case, after the step of producing the ketone derivative (II-1), the ketone derivative (II-1) is brought into contact with a first acid and/or base to obtain R' from the ketone derivative (II-1). After elimination of the represented group, a step of producing the C-aryl-hydroxyglycoside derivative (V-1) is performed, optionally further contacting with a second acid.
• the method for producing the C-aryl-hydroxyglycoside derivative (V-2) may include the step of producing the ketone derivative (II-2).
• the ketone derivative (II-2) is brought into contact with a first acid and/or base to convert the ketone derivative (II-2) to R′.
• a step of producing the C-aryl-hydroxyglycoside derivative (V-2) is carried out, optionally further contacting with a second acid.
• the ketone derivative (II-1) or (II-2) is obtained by contacting the thioester derivative (I-1) or (I-2) with a Grignard reagent (5) and a copper salt to obtain the ketone derivative (II-1). Alternatively, it can be produced by a method including the step of producing (II-2). A description of this method is provided above.
• a method for producing a C-aryl-hydroxyglycoside derivative (V-1) or (V-2) comprises contacting a thioester derivative (I-1) or (I-2) with a Grignard reagent (5) and a copper salt. contacting the thioester derivative (I-1) or (I-2) with the Grignard reagent (5) and copper salt After isolating the ketone derivative (II-1) or (II-2) from the reaction mixture obtained by, it may be contacted with a first acid and / or base, or the ketone derivative (II A first acid and/or base may be added to the reaction mixture and contacted with the first acid and/or base without isolating -1) or (II-2).
• the ketone derivative (II-1) or (II-2) is obtained from the reaction mixture obtained by contacting the thioester derivative (I-1) or (I-2) with a Grignard reagent (5) and a copper salt. ), the C-aryl-hydroxyglycoside derivative (V-1) or (V-2) can be produced efficiently.
• Ketone derivative (II′) and/or C-aryl-hydroxyglycoside derivative (V′) are reacted with thioester derivative (I) in the presence of a palladium catalyst, organozinc compound (6a), organozinc compound (6b) and contacting with an organozinc compound (6) selected from organozinc compounds (6c) to produce a ketone derivative (II') and/or a C-aryl-hydroxyglycoside derivative (V').
• a ketone derivative (II′-1) and/or a C-aryl-hydroxyglycoside derivative (V′-1) is reacted with a thioester derivative (I-1), an organic zinc compound (6a), an organic ketone derivative (II'-1) and/or C-aryl-hydroxyglycoside derivative (V' -1) can be produced by a method including the step of producing.
• (II'-1) and/or by a method comprising the step of producing C-aryl-hydroxyglycoside derivative (V'-1) where n 1.
• II'-1 and/or by a method comprising the step of producing C-aryl-hydroxyglycoside derivative (V'-1) where n 2.
• a ketone derivative (II′-2) and/or a C-aryl-hydroxyglycoside derivative (V′-2) is reacted with a thioester derivative (I-2), an organic zinc compound (6a), an organic ketone derivative (II'-2) and/or C-aryl-hydroxyglycoside derivative (V' -2) can be produced by a method including the step of producing.
• the contact between the thioester derivative (I-1) or (I-2) and the organozinc compound (6) is preferably carried out in a solvent.
• the thioester derivative (I-1) or (I-2) and the organic zinc compound (6) are obtained by mixing the thioester derivative (I-1) or (I-2) and the organic zinc compound (6) in a solvent. can be brought into contact with
• the solvent is preferably an organic solvent. Specific examples of the organic solvent are as described above. One organic solvent may be used, or two or more organic solvents may be used in combination.
• the organic solvent is preferably THF, 2-methyl-THF, toluene or a mixed solvent thereof.
• the amount of solvent used is, for example, 1 to 100 mL, preferably 2 to 50 mL, more preferably 3 to 30 mL, relative to 1 g of thioester derivative (I-1) or (I-2).
• the contact temperature is, for example, 0 to 100°C, preferably 5 to 80°C, more preferably The temperature is 10 to 60° C.
• the contact time is, for example, 0.1 to 24 hours, preferably 0.3 to 17 hours, more preferably 0.5 to 8 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• Organozinc compounds (6) can be used as reagents to introduce group W2 into thioester derivatives (I-1) or (I-2).
• the organic zinc compound (6) one of the organic zinc compound (6a), the organic zinc compound (6b) and the organic zinc compound (6c) may be selected, or two or more thereof may be selected. When two or more are selected, a mixture of two or more organic zinc compounds may be added to the reaction system, or two or more organic zinc compounds may be added separately to the reaction system.
• the organic zinc compound (6) may be a commercial product or may be produced according to a conventional method.
• the organic zinc compound (6a) and/or the organic zinc compound (6b) may be used, for example, together with a lithium salt such as lithium chloride.
• the organozinc compound (6a) may form a complex with a lithium salt.
• the complex of organozinc compound (6a) and lithium salt corresponds to organozinc compound (6c).
• the amount of the organic zinc compound (6) used is, for example, 1 to 5 mol, preferably 1.05 to 4 mol, more preferably 1.05 to 4 mol, per 1 mol of the thioester derivative (I-1) or (I-2). 1 to 3 mol.
• the amount of the organic zinc compound (6) used means the amount of the one organic zinc compound (6) when one type of organic zinc compound (6) is used, and two or more types of When the organozinc compound (6) is used, it means the total amount of the two or more organozinc compounds (6).
• the explanation regarding the palladium catalyst is the same as above.
• the use of a palladium catalyst is advantageous in that it can reduce the amount of by-products produced by coupling reactions between W 2 groups and the like.
• the palladium catalyst may be supported on a carrier.
• a carrier-supported palladium catalyst is advantageous in that the palladium catalyst can be easily separated from the reaction mixture.
• the description regarding the carrier is the same as above.
• the amount of the palladium catalyst is, for example, 1 to 25 wt%, preferably 3 to 20 wt%, more preferably 4 to 15 wt%, based on the total weight of the palladium catalyst and carrier. %.
• the amount of the palladium catalyst used is, for example, 0.001 to 1 mol, preferably 0.002 to 0.5 mol, more preferably 0.002 to 0.5 mol, per 1 mol of the thioester derivative (I-1) or (I-2). 03 to 0.1 mol.
• ketone derivative (II') and/or C-aryl-hydroxyglycoside derivative (V') may be isolated by silica gel column chromatography, or used as a concentrated residue in the next step without being purified. good too.
• ketone derivative (II') and/or the C-aryl-hydroxyglycoside derivative (V') can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy.
• the C-aryl-hydroxyglycoside derivative (V') is produced by a method comprising the step of contacting the ketone derivative (II') with a base to produce the C-aryl-hydroxyglycoside derivative (V'). be able to.
• C-aryl-hydroxyglycoside derivative (V'-1) is prepared by contacting ketone derivative (II'-1) with a base to produce C-aryl-hydroxyglycoside derivative (V'-1). It can be produced by a method comprising
• - hydroxyglycoside derivative (V'-1) can be produced by a method comprising the step of producing.
• - hydroxyglycoside derivative (V'-1) can be produced by a method comprising the step of producing.
• C-aryl-hydroxyglycoside derivative (V'-2) is prepared by contacting ketone derivative (II'-2) with a base to produce C-aryl-hydroxyglycoside derivative (V'-2). It can be produced by a method comprising
• V'-2 C-aryl-hydroxyglycoside derivative
• - can be produced by a method comprising the step of producing a hydroxyglycoside derivative (V'-2).
• - can be produced by a method comprising the step of producing a hydroxyglycoside derivative (V'-2).
• the method for producing the C-aryl-hydroxyglycoside derivative (V') may include the step of producing the ketone derivative (II'). In this case, the step of producing the ketone derivative (II') is followed by the step of contacting the ketone derivative (II') with a base to produce the C-aryl-hydroxyglycoside derivative (V').
• the ketone derivative (II′) is prepared by reacting the thioester derivative (I) with an organozinc compound (6a), an organozinc compound (6b) and an organozinc compound (6c) in the presence of a palladium catalyst. ) to produce the ketone derivative (II′).
• an organozinc compound (6a) an organozinc compound (6b) and an organozinc compound (6c) in the presence of a palladium catalyst.
• bases include fluorides, alkali metal alkoxides, alkali metal hydrides, organic bases, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and cesium hydroxide.
• fluorides include tetra-n-butylammonium fluoride (TBAF), ammonium fluoride, ammonium bifluoride, hydrofluoric acid and the like.
• alkali metal alkoxides include sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium-t-butoxide, potassium-t-butoxide and the like.
• Alkali metal hydrides include, for example, sodium hydride and potassium hydride.
• organic bases include triethylamine, diisopropylethylamine, pyridine, lutidine and the like.
• the base is preferably selected from alkali metal alkoxides, alkali metal hydrides and organic bases, more preferably from sodium-t-butoxide, potassium-t-butoxide, sodium hydride and triethylamine.
• the amount of the base used is, for example, 0.1 to 2, preferably 0.3 to 1.5 mol, more preferably 0.3 to 1.5 mol, per 1 mol of the ketone derivative (II'-1) or (II'-2). 5 to 1.2 mol.
• the contact between the ketone derivative (II') and the base is preferably carried out in a solvent.
• the ketone derivative (II') and the base can be contacted by mixing the ketone derivative (II') and the base in a solvent.
• the solvent is preferably an organic solvent. Specific examples of the organic solvent are as described above. One organic solvent may be used, or two or more organic solvents may be used in combination.
• the organic solvent is preferably methylene chloride, THF, 2-methyl-THF, toluene, DMF, 1,4-dioxane, acetonitrile, methanol, IPA or a mixed solvent thereof.
• the amount of solvent used is, for example, 1 to 100 mL, preferably 2 to 50 mL, more preferably 3 to 30 mL, relative to 1 g of ketone derivative (II').
• the contact temperature is, for example, ⁇ 30 to 40° C., preferably ⁇ 20 to 30° C., more preferably ⁇ 10 to 20° C.
• the contact time is, for example, 0.1 to 8 hours, preferably 0.2 to 4 hours, and more preferably 0.3 to 3 hours.
• the contact environment is preferably an inert atmosphere, more preferably an argon atmosphere or a nitrogen atmosphere.
• the obtained C-aryl-hydroxyglycoside derivative (V') may be isolated by silica gel column chromatography, or may be used as a concentrated residue in the next step without being purified.
• the structure of the C-aryl-hydroxyglycoside derivative (V') can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy.
• the C-aryl glycoside derivative (VI) is produced by contacting the C-aryl-hydroxyglycoside derivative (V) or (V') with a silane compound to produce the C-aryl glycoside derivative (VI). It can be manufactured by a method comprising:
• C-aryl glycoside derivative (VI-1) is prepared by contacting C-aryl-hydroxyglycoside derivative (V-1) or (V'-1) with a silane compound to obtain C-aryl glycoside derivative (VI -1) can be produced by a method including the step of producing.
• the C-aryl glycoside derivative (VI-2) is obtained by contacting the C-aryl-hydroxyglycoside derivative (V-2) or (V'-2) with a silane compound to obtain the C-aryl glycoside derivative (VI -2) can be produced by a method including the step of producing.
• the method for producing the C-aryl glycoside derivative (VI) may include the step of producing the C-aryl-hydroxyglycoside derivative (V) or (V'). In this case, after the step of producing the C-aryl-hydroxyglycoside derivative (V) or (V'), the C-aryl-hydroxyglycoside derivative (V) or (V') is brought into contact with the silane compound. , a step of producing a C-aryl glycoside derivative (VI).
• the C-aryl-hydroxyglycoside derivative (V) is obtained by contacting the ketone derivative (II) with a first acid and/or base to eliminate the group represented by R' from the ketone derivative (II). After that, if necessary, it is further brought into contact with a second acid to produce the C-aryl-hydroxyglycoside derivative (V). A description of this method is provided above.
• C-aryl-hydroxyglycoside derivative (V') is prepared by contacting thioester derivative (I) with organozinc compound (6) in the presence of a palladium catalyst to obtain C-aryl-hydroxyglycoside derivative (V').
• the C-aryl-hydroxyglycoside derivative (V') can be prepared by a method comprising the step of contacting the ketone derivative (II') with a base to produce the C-aryl-hydroxyglycoside derivative (V'). can be manufactured. Descriptions of these methods are provided above.
• the silane compound acts as a reducing agent. Therefore, when the C-aryl-hydroxyglycoside derivative (V) or (V') is brought into contact with the silane compound, the reduction reaction of the C-aryl-hydroxyglycoside derivative (V) or (V') proceeds, and C - aryl glycoside derivatives (VI) are obtained.
• silane compounds include triethylsilane, triisopropylsilane, phenylsilane, dimethylphenylsilane, tert-butyldimethylsilane, triisobutylsilane, trichlorosilane, trimethoxyhydrosilane, triethoxyhydrosilane, tetramethyldisiloxane, and the like.
• the silane compound is preferably trimethoxyhydrosilane, triethoxyhydrosilane, tetramethyldisiloxane, etc., and more preferably tetramethyldisiloxane.
• the amount of the silane compound used is preferably 1 to 10 mol, more preferably 1 to 5 mol, per 1 mol of the C-aryl-hydroxyglycoside derivative (V) or (V'), from the viewpoint of sufficiently advancing the reaction. mol, more preferably 1 to 3 mol.
• the contact between the C-aryl-hydroxyglycoside derivative (V) or (V') and the silane compound is preferably carried out in the presence of a Lewis acid.
• Lewis acids examples include BF 3 .Et 2 O (boron trifluoride diethyl ether complex), BF 3 .THF (boron trifluoride tetrahydrofuran), AlCl 3 , ZnCl 2 , FeCl 3 and titanium compounds.
• titanium compounds are preferred.
• Titanium compounds for example, those in which titanium has a valence of zero, those in which titanium has a valence of 2, those in which titanium has a valence of 3, and those in which titanium has a valence of 4 are known. good. Titanium compounds include triisopropoxy titanium (IV) monochloride, diisopropoxy titanium (IV) dichloride, monoisopropoxy titanium (IV) trichloride, titanium (IV) chloride, titanium (IV) bromide, iodide.
• tetravalent titanium salts such as titanium (IV) and titanium oxide (IV) or solvates thereof; trivalent titanium salts such as titanium (III) chloride and titanium (III) bromide or solvates thereof; titanium chloride divalent titanium salts such as (II) or solvates thereof; and zerovalent titanium such as metal Ti or solvates thereof.
• solvates include those coordinated with solvents such as water and tetrahydrofuran.
• R c is preferably a chlorine atom, a bromine atom or an iodine atom
• R d is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms. .
• Titanium compounds are preferably triisopropoxy titanium (IV) monochloride, diisopropoxy titanium (IV) dichloride, monoisopropoxy titanium (IV) trichloride, titanium (IV) chloride, titanium (III) chloride, and the like. and more preferably titanium (IV) chloride. Titanium chloride (IV) has a low melting point and is liquid at room temperature, and is therefore preferable in terms of ease of handling, low cost, and the like.
• the amount of Lewis acid used is, for example, 0.1 to 3 mol, preferably 0.5 to 2 mol, more preferably 1 mol, per 1 mol of the C-aryl-hydroxyglycoside derivative (V) or (V'). ⁇ 1.5 moles.
• the amount of the titanium compound used is, for example, 0.05 to 10 mol, preferably 0.1 to 7 mol, per 1 mol of the C-aryl-hydroxyglycoside derivative (V) or (V'). mol, more preferably 1 to 5 mol.
• the contact between the C-aryl-hydroxyglycoside derivative (V) or (V') and the silane compound is preferably carried out in a solvent.
• the solvent is preferably an organic solvent. Specific examples of the organic solvent are as described above. One solvent may be used alone, or two or more solvents may be used in combination.
• the organic solvent is preferably acetonitrile, DCM or a mixed solvent thereof. These are preferred because they are aprotic polar solvents and are less susceptible to silane reduction.
• the amount of solvent used is, for example, 1 to 100 mL, preferably 1 to 50 mL, more preferably 2 to 20 mL, per 1 g of C-aryl-hydroxyglycoside derivative (V) or (V').
• the contact temperature is, for example, in the range of -100°C to 100°C, more preferably -78°C to -78°C.
• the temperature is 50° C., more preferably ⁇ 60° C. to 10° C.
• the contact time is, for example, 10 minutes to 48 hours, preferably 0.5 to 24 hours, more preferably 1 to 17 hours.
• reaction atmosphere is not particularly limited, it is preferably an inert gas atmosphere or an air atmosphere in order to suppress the contamination of moisture.
• the inside of the reaction system may be under atmospheric pressure, under pressure, or under reduced pressure, but among these, it is preferable to carry out the reaction under atmospheric pressure.
• a C-aryl glycoside derivative (VI-1) or (VI-2) can be obtained by a reduction reaction.
• the products obtained by the reduction reaction are ⁇ -C-arylglycoside derivatives (hereinafter sometimes referred to as “ ⁇ forms”) and ⁇ -C-arylglycoside derivatives (hereinafter sometimes referred to as “ ⁇ forms”).
• ⁇ forms ⁇ -C-arylglycoside derivatives
• ⁇ forms ⁇ -C-arylglycoside derivatives
• the obtained C-aryl glycoside derivative (VI-1) or (VI-2) is preferably removed from the reaction system.
• the C-aryl glycoside derivative (VI-1) or (VI-2) can be prepared, for example, by adding water to the reaction solution, followed by addition of slightly water-soluble organic solvents such as ethyl acetate, toluene, tert-butyl methyl ether and methylene chloride. and extracting the C-aryl glycoside derivative (VI-1) or (VI-2) with the sparingly water-soluble organic solvent, so that it can be removed from the reaction system.
• the obtained C-aryl glycoside derivative (VI-1) or (VI-2) can be further purified using known methods such as column separation and recrystallization.
• column separation and recrystallization it is difficult to separate the ⁇ form and the ⁇ form by column purification using a silica gel column or the like. Therefore, the usefulness of the present invention for producing ⁇ -C-arylglycoside derivatives with high selectivity and high yield is extremely high.
• the resulting C-aryl glycoside derivative (VI-1) or (VI-2) can be suitably used as an SGLT2 inhibitor useful as an antidiabetic agent or a synthetic intermediate thereof.
• the structure of the C-aryl glycoside derivative (VI-1) or (VI-2) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy.
• Example 1 Compound 2 was produced from compound 1 (D-(+)-glucono-1,5-lactone) by the reaction represented by the following formula.
• Ac represents an acetyl group
• iPr represents an isopropyl group (same below).
• reaction mixture was added to a THF solution (0.5 mL) of ZnBr2 (169 mg, 0.750 mmol, 1.00 eq) and LiCl (31.8 mg, 0.750 mmol, 1.00 eq) at room temperature. The mixture was stirred at room temperature for an additional hour and used in the next step (Fukuyama coupling reaction).
• the prepared thiolate solution was added to a THF solution (4 mL) of compound 8 (1.1 g, 1.856 mmol, 1 eq) using a cannula and stirring continued at 0° C. until compound 8 dissolved. After 1 hour, the reaction was quenched with 1M HCl solution, 50 mL of ethyl acetate was added, and the organic layer was washed with 1M HCl, saturated aqueous NaHCO 3 and brine. It was then dried with Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 9.5/0.5 ⁇ 7/3) to obtain compound 10 (1.478 g, yield 91%).
• the reaction was carried out at 40°C for 20 hours. After 20 hours, the reaction was filtered using a silica gel pad with a thin layer of celite. The filtrate was then washed with saturated NaHCO 3 solution (10 mL) to quench the reaction and eluted with ethyl acetate (approximately 20 mL). After eluting with 40 mL of ethyl acetate (4 x 10 mL), the aqueous layer was removed. The organic layer was then washed with brine and dried with Na2SO4 .
• Example 13 Compound 12 was prepared in the same manner as in Example 11, except that the reaction of compound 12 with t-BuOK (12.1 mg, 0.112 mmol, 2.08 eq) was carried out in dichloromethane (DCM) at room temperature for 24 hours. 13 (15.2 mg, 32% yield) was obtained.
• Example 14 Using 20% sodium ethoxide (EtONa) in ethanol (21 ⁇ L, 0.06017 mmol, 1.1 equiv) instead of t-BuOK, the reaction of compound 12 with EtONa was carried out in ethyl acetate (EtOAc). Compound 13 (13.8 mg, yield 29%) was obtained in the same manner as in Example 11, except that the reaction was carried out at room temperature for 30 hours.
• Example 16 Compound 12a was produced from compound 11 by the reaction represented by the following formula.
• Ac represents an acetyl group
• Bz represents a benzoyl group.
• Example 17 The reaction represented by the following formula is performed to convert compound 11 to compound 12aa ((2R,3R,4S,5R)-2-acetoxy-6-(4-chloro-3-(4-(((R)-tetrahydrofuran-3 -yl)oxy)benzyl)phenyl)-6-oxohexane-1,3,4,5-tetrayltetrabenzoate)).
• compound 11 represents compound 11
• compound 12aa ((2R,3R,4S,5R)-2-acetoxy-6-(4-chloro-3-(4-(((R)-tetrahydrofuran-3 -yl)oxy)benzyl)phenyl)-6-oxohexane-1,3,4,5-tetrayltetrabenzoate)).
• Ac represents an acetyl group
• Bz represents a benzoyl group.
• reaction mixture was quenched with THF (1 mL x 2) through another Schlenk column containing a suspension of CuCN (91 mg, 1.02 mmol, 2 eq) and THF (1 mL, 2 volumes). Transferred to a tube, kept at room temperature for 10 minutes and used in the next step.
• reaction mixture was filtered through a celite pad and the bed was washed with ethyl acetate (10 mL x 3). The filtrate was dried over anhydrous sodium sulfate and filtered. The solvent was removed by pulling a vacuum to give the crude compound.
• Example 18 Compound 11b was produced from compound 10 by the reaction represented by the following formula. "Bz” represents a benzoyl group, and “TBS” represents a tert-butyldimethylsilyl group.
• reaction mixture was then diluted with ethyl acetate, washed with saturated aqueous NaHCO 3 (10 mL) and brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated by applying vacuum.
• Example 21 Compound 2 was produced from compound 1b by the reaction represented by the following formula.
• Ac represents an acetyl group
• iPr represents an isopropyl group.
• Example 22 Compound 3b was produced from compound 2 by the reaction represented by the following formula.
• Ac represents an acetyl group
• THP represents a tetrahydropyranyl group.
• Example 23 Compound 4b was produced from compound 3b by the reaction represented by the following formula.
• Ac represents an acetyl group
• THP represents a tetrahydropyranyl group.
• Example 24 Compound 6b was produced from compound 4b by the reaction represented by the following formula.
• Ac represents an acetyl group
• THP represents a tetrahydropyranyl group.
• Example 25 The reaction represented by the following formula is carried out to convert compound 2 to compound 3c ((2R,3R,4S,5R)-2-(2-chloroacetoxy)-6-(dodecylthio)-6-oxohexane-1,3,4 , 5-tetrayltetraacetate) was prepared.
• “Ac” represents an acetyl group.
• Example 26 The reaction represented by the following formula is carried out to convert compound 2 to compound 3d ((2R,3R,4S,5R)-6-(dodecylthio)-2-((2-methoxypropan-2-yl)oxy)-6-oxo hexane-1,3,4,5-tetrayltetraacetate) was prepared.
• "Ac” represents an acetyl group.
• Example 27 The reaction represented by the following formula is carried out to convert compound 2 to compound 3e ((2R,3R,4S,5R)-2-((tert-butoxycarbonyl)oxy)-6-(dodecylthio)-6-oxohexane-1, 3,4,5-tetrayl tetraacetate) was prepared.
• "Ac” represents an acetyl group.
• Example 28 The reaction represented by the following formula is carried out to convert compound 2 to compound 3e ((2R,3R,4S,5R)-2-((tert-butoxycarbonyl)oxy)-6-(dodecylthio)-6-oxohexane-1, 3,4,5-tetrayl tetraacetate) was prepared.
• "Ac” represents an acetyl group.
• Example 29 The reaction represented by the following formula is carried out to convert compound 10 to compound 11d ((2R,3R,4S,5R)-2-(2-chloroacetoxy)-6-(dodecylthio)-6-oxohexane-1,3,4 , 5-tetrayltetrabenzoate) was prepared.
• “Bz” represents a benzoyl group.
• Example 30 The reaction represented by the following formula is performed to convert compound 10 to compound 11e ((2R,3R,4S,5R)-6-(dodecylthio)-6-oxo-2-(2,2,2-trifluoroacetoxy)hexane- 1,3,4,5-tetrayl tetrabenzoate) was prepared.
• “Bz” represents a benzoyl group.
• Trifluoroacetic anhydride (131 mg, 1.25 mmol, 2 eq) was added to an ice-cold DCM solution (10 mL, 20 volumes) containing compound 10 (0.5 g, 0.627 mmol, 1 eq) in an oven dried Schlenk tube. ) at 10-15°C. The reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. Solvent was removed by vacuum to give 0.45 g of compound 11e (80% yield) as a yellow oil.
• Example 31 The reaction represented by the following formula is performed to convert compound 3c to compound 4c ((2R,3R,4S,5R)-2-(2-chloroacetoxy)-6-(3-((5-(4-fluorophenyl)thiophene). -2-yl)methyl)-4-methylphenyl)-6-oxohexane-1,3,4,5-tetrayltetraacetate).
• Ac represents an acetyl group.
• Example 32 The reaction represented by the following formula is carried out to convert compound 3d to compound 4d ((2R,3R,4S,5R)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4 -methylphenyl)-2-((2-methoxypropan-2-yl)oxy)-6-oxohexane-1,3,4,5-tetrayltetraacetate).
• “Ac” represents an acetyl group.
• reaction mixture was quenched with THF (2 mL x 2) into another Schlenk tube containing a suspension of CuCN (288 mg, 3.22 mmol, 2 eq) and THF (2 mL, 2 volumes). at room temperature, kept for 10 minutes and used in the next step.
• Example 33 A reaction represented by the following formula is performed to convert compound 11d to compound 12d ((2R,3R,4S,5R)-2-(2-chloroacetoxy)-6-(3-((5-(4-fluorophenyl)thiophene). -2-yl)methyl)-4-methylphenyl)-6-oxohexane-1,3,4,5-tetrayltetrabenzoate)).
• “Bz” represents a benzoyl group.
• reaction mixture was quenched with THF (3.6 mL x 2) into a suspension of CuCN (369 mg, 4.12 mmol, 2 eq) and THF (3.6 mL, 2 volumes). Transfer to another Schlenk tube at room temperature, keep for 10 minutes and use in next step.
• Example 34 The reaction represented by the following formula is carried out to convert compound 3e to compound 4e ((2R,3R,4S,5R)-2-((tert-butoxycarbonyl)oxy)-6-(3-((5-(4-fluoro phenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-oxohexane-1,3,4,5-tetrayltetraacetate).
• “Ac” represents an acetyl group.
• reaction mixture was quenched with THF (6 mL x 2) into another Schlenk tube containing a suspension of CuCN (829 mg, 9.24 mmol, 2 eq) and THF (6 mL, 2 volumes). at room temperature, kept for 10 minutes and used in the next step.
• Example 35 The reaction represented by the following formula is carried out to give compound 6 ((2R,3R,4S,5R)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4 from compound 4d. -methylphenyl)-2-hydroxy-6-oxohexane-1,3,4,5-tetrayltetraacetate). "Ac” represents an acetyl group.
• Example 36 The reaction represented by the following formula is carried out to convert compound 4e to compound 6 ((2R,3R,4S,5R)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4 -methylphenyl)-2-hydroxy-6-oxohexane-1,3,4,5-tetrayltetraacetate).
• "Ac” represents an acetyl group.
• Example 37 The reaction represented by the following formula is performed to convert compound 6 to compound 5 ((3R,4S,5R,6R)-6-(acetoxymethyl)-2-(3-((5-(4-fluorophenyl)thiophene-2 -yl)methyl)-4-methylphenyl)-2-hydroxytetrahydro-2H-pyran-3,4,5-triyltriacetate).
• "Ac” represents an acetyl group.

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