WO2020050361A1 - PROCÉDÉ DE FABRICATION DE DÉRIVÉ D'ARYLE β－C-GLYCOSIDE - Google Patents

PROCÉDÉ DE FABRICATION DE DÉRIVÉ D'ARYLE β－C-GLYCOSIDE Download PDF

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WO2020050361A1
WO2020050361A1 PCT/JP2019/034981 JP2019034981W WO2020050361A1 WO 2020050361 A1 WO2020050361 A1 WO 2020050361A1 JP 2019034981 W JP2019034981 W JP 2019034981W WO 2020050361 A1 WO2020050361 A1 WO 2020050361A1
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substituents
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雅彦 関
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株式会社トクヤマ
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    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a method for producing a SGLT2 inhibitor useful as an antidiabetic agent or a ⁇ -C-arylglycoside derivative which is a synthetic intermediate thereof. Specifically, the present invention relates to a method for efficiently producing a SGLT2 inhibitor useful as an antidiabetic agent or a ⁇ -C-arylglycoside derivative which is a synthetic intermediate thereof under mild conditions.
  • ⁇ -C-aryl glycoside derivative means a compound represented by the formula (1) described below
  • C-aryl-hydroxyglycoside derivative means a compound represented by the formula (2) described later. Means a compound represented by
  • SGLT2 inhibitors are useful as antidiabetic agents.
  • “SGLT2” means sodium-glucose cotransport carrier-2.
  • Examples of SGLT2 inhibitors include 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-
  • Non-Patent Document 1 and Patent Document 1 As one method for producing a ⁇ -C-aryl glycoside derivative, a method for producing a ⁇ -C-aryl glycoside derivative by reducing a C-aryl-hydroxy glycoside derivative has been reported (Non-Patent Documents 1 and 2). And Patent Document 1).
  • Non-patent Documents 1 and 2 disclose that a C-aryl-hydroxyglycoside derivative is reduced using triethylsilane in the presence of boron trifluoride diethyl ether complex (BF 3 .OEt 2 ) to give ⁇ -C-aryl Methods for producing glycoside derivatives have been described.
  • Patent Document 1 discloses that a C-aryl-hydroxyglycoside derivative is prepared by converting BF 3 .OEt 2 , boron trifluoride tetrahydrofuran (BF 3 ) in the presence of silanes such as triethylsilane, triisopropylsilane, and tetramethyldisiloxane
  • a process for producing a ⁇ -C-arylglycoside derivative by reacting with a Lewis acid such as THF (THF) and aluminum chloride is described.
  • reaction vessel is corroded because boron trifluoride is corrosive.
  • aluminum chloride requires a relatively high temperature for the reaction to proceed because of its low Lewis acidity. However, as the reaction temperature increases, the stereoselectivity ( ⁇ selectivity) of the reaction decreases. Further, aluminum chloride is a solid Lewis acid, and it is necessary to weigh it under anhydrous conditions, so that handling is difficult.
  • an object of the present invention is to provide a method for producing a ⁇ -C-aryl glycoside derivative with high selectivity and high yield, in which the reduction reaction of the C-aryl-hydroxyglycoside derivative proceeds rapidly at a low temperature. I do.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems. As a result, by bringing the C-aryl-hydroxyglycoside derivative into contact with the silane compound in the presence of the titanium compound, the reduction reaction of the C-aryl-hydroxyglycoside derivative rapidly proceeds at a low temperature, and the ⁇ -C-arylglycoside They have found that derivatives can be produced with high selectivity and high yield, and have completed the present invention.
  • the present invention includes the following inventions.
  • the following formula (1) [Wherein, R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom or a hydroxyl-protecting group, and Ar is an unsubstituted or substituted aromatic ring group and an unsubstituted or substituted aromatic ring group. It is an organic group containing a group selected from a group heterocyclic group as a group bonded to an oxane ring in the formula.
  • the method comprising the step of contacting a C-aryl-hydroxyglycoside derivative represented by the formula with a silane compound in the presence of a titanium compound to produce the ⁇ -C-arylglycoside derivative.
  • R 1 , R 2 , R 3 and R 4 are each independently a hydroxyl protecting group selected from a methyl group, a benzyl group, an acetyl group, a pivaloyl group, a trimethylsilyl group and a tert-butyldimethylsilyl group.
  • the titanium compound is selected from triisopropoxy titanium monochloride (IV), diisopropoxy titanium dichloride (IV), monoisopropoxy titanium trichloride (IV), titanium chloride (III) and titanium (IV) chloride. The method according to [1] or [2], which is selected.
  • the silane compound is selected from triethylsilane, triisopropylsilane, phenylsilane, dimethylphenylsilane, tert-butyldimethylsilane, triisobutylsilane, trichlorosilane, trimethoxyhydrosilane, triethoxyhydrosilane and tetramethyldisiloxane.
  • the method according to any one of [1] to [3].
  • Ar is the following formula (A): [Where, Ra is each independently a halogen atom, an amino group, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted heteroalkyl group, an unsubstituted or substituted heteroalkoxy group, Substituted or substituted monoalkylamino group, unsubstituted or substituted dialkylamino group, unsubstituted or substituted aliphatic ring group, unsubstituted or substituted aliphatic ring oxy group, unsubstituted or substituted aliphatic heterocyclic group, Selected from an unsubstituted or substituted aliphatic heterocyclic oxy group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyloxy group, an unsubstituted or substituted phenylalkyl group,
  • Group n is an integer from 0 to 4
  • Ar ′ is a group selected from an unsubstituted or substituted aromatic ring group, an unsubstituted or substituted aromatic heterocyclic group, and an unsubstituted or substituted aliphatic heterocyclic ring.
  • Ar ′ is represented by the following formula (Ar′-1), (Ar′-2) or (Ar′-3): [Where, R b is independently a halogen atom, an amino group, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted heteroalkyl group, an unsubstituted or substituted heteroalkoxy group, Substituted or substituted monoalkylamino group, unsubstituted or substituted dialkylamino group, unsubstituted or substituted aliphatic ring group, unsubstituted or substituted aliphatic ring oxy group, unsubstituted or substituted aliphatic heterocyclic group, Selected from an unsubstituted or substituted aliphatic heterocyclic oxy group
  • a method for producing a desired ⁇ -C-aryl glycoside derivative with high selectivity and high yield in which the reduction reaction of the C-aryl-hydroxyglycoside derivative proceeds rapidly at a low temperature.
  • the obtained ⁇ -C-arylglycoside derivative is a SGLT2 inhibitor useful as an antidiabetic drug or a synthetic intermediate thereof, and therefore, the industrial utility value of the present invention is very high.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • an unsubstituted or substituted alkyl group means an alkyl group or an alkyl group having one or more substituents.
  • the “alkyl group” means an unsubstituted alkyl group unless otherwise specified.
  • Alkyl group means a linear alkyl group or a branched alkyl group.
  • the number of carbon atoms of the linear alkyl group is usually 1 to 20, preferably 1 to 10, more preferably 1 to 8, still more preferably 1 to 6, even more preferably 1 to 5, and still more preferably 1 to 5. To 4, more preferably 1 to 3, even more preferably 1 or 2.
  • the number of carbon atoms of the branched alkyl group is usually 3 to 20, preferably 3 to 10, more preferably 3 to 8, still more preferably 3 to 6, still more preferably 3 to 5, and even more preferably 3 to 5. Or 4.
  • alkyl group examples include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, isohexyl, heptyl, , 4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl and the like.
  • the alkyl group is preferably an alkyl group having 1 to 6 carbon atoms.
  • the “alkyl group having 1 to 6 carbon atoms” means a linear alkyl group having 1 to 6 carbon atoms or a branched alkyl group having 3 to 6 carbon atoms.
  • the one or more substituents are each substituted with a hydrogen atom of the alkyl group.
  • the number of substituents that the alkyl group may have is preferably 1 to 3, more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different.
  • the one or more substituents that the alkyl group may have may each independently be selected from halogen atoms.
  • unsubstituted or substituted alkylene group means an alkylene group or an alkylene group having one or more substituents.
  • the “alkylene group” means an unsubstituted alkylene group unless otherwise specified.
  • Alkylene group means a divalent functional group generated by removing one hydrogen atom from an alkyl group.
  • alkyl group also applies to the alkyl group from which the alkylene group is derived (the alkyl group from which one hydrogen atom is removed).
  • the one or more substituents are each substituted with a hydrogen atom of the alkylene group.
  • the number of substituents that the alkylene group may have is preferably from 1 to 3, more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different.
  • One or more substituents that the alkylene group may have may be each independently selected from halogen atoms.
  • an unsubstituted or substituted alkoxy group means an alkoxy group or an alkoxy group having one or more substituents.
  • the “alkoxy group” means an unsubstituted alkoxy group unless otherwise specified.
  • Alkoxy group means a group represented by an alkyl group -O-.
  • alkyl group also applies to the alkyl group included in the alkoxy group.
  • the one or more substituents are each substituted with a hydrogen atom of the alkoxy group.
  • the number of substituents that the alkoxy group may have is preferably from 1 to 3, more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different.
  • the one or more substituents that the alkoxy group may have may each independently be selected from halogen atoms.
  • unsubstituted or substituted heteroalkyl group means a heteroalkyl group or a heteroalkyl group having one or more substituents.
  • heteroalkyl group means an unsubstituted heteroalkyl group unless otherwise specified.
  • Heteroalkyl group means a straight-chain heteroalkyl group or a branched-chain heteroalkyl group. “Heteroalkyl group” means an alkyl group having an oxygen atom (—O—) between carbon atoms. The number of oxygen atoms is preferably one or two, more preferably one. The carbon number of the linear heteroalkyl group is usually 2 to 20, preferably 2 to 10, more preferably 2 to 8, still more preferably 2 to 6, still more preferably 2 to 5, and still more preferably It is 2 to 4, more preferably 2 or 3.
  • the number of carbon atoms of the branched heteroalkyl group is usually 3 to 20, preferably 3 to 10, more preferably 3 to 8, still more preferably 3 to 6, still more preferably 3 to 5, and still more preferably. 3 or 4.
  • the heteroalkyl group include -CH 2 -O-CH 3 , -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -CH 2 -O-CH 3 , -CH (-CH 3 ) —CH 2 —O—CH 3 , —CH 2 —O—CH 2 —CH 3 , —CH 2 —CH 2 —O—CH 2 —CH 3 , —CH 2 —CH 2 —CH 2 —O—CH 2- CH 3 , -CH (-CH 3 ) -CH 2 -O-CH 2 -CH 3 , -CH 2 -O-CH 2 -CH 2 -CH 3 , -CH 2 -CH 2 -O-CH 2 —CH
  • the one or more substituents are each substituted with a hydrogen atom of the heteroalkyl group.
  • the number of substituents that the heteroalkyl group may have is preferably from 1 to 3, more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different.
  • One or more substituents that the heteroalkyl group may have may each independently be selected from halogen atoms.
  • an unsubstituted or substituted heteroalkoxy group means a heteroalkoxy group or a heteroalkoxy group having one or more substituents.
  • a heteroalkoxy group means an unsubstituted heteroalkoxy group unless otherwise specified.
  • Heteroalkoxy group means a group represented by heteroalkyl group -O-.
  • the above description regarding the “heteroalkyl group” also applies to the heteroalkyl group included in the heteroalkoxy group.
  • the one or more substituents are each substituted with a hydrogen atom of the heteroalkoxy group.
  • the number of substituents that the heteroalkoxy group can have is preferably from 1 to 3, more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different.
  • One or more substituents that the heteroalkoxy group may have may be each independently selected from halogen atoms.
  • an unsubstituted or substituted monoalkylamino group means a monoalkylamino group or a monoalkylamino group having one or more substituents.
  • the “monoalkylamino group” means an unsubstituted monoalkylamino group unless otherwise specified.
  • a “monoalkylamino group” has the formula: —NH (—Q 1 ), wherein Q 1 is an alkyl group. ].
  • the above description regarding the “alkyl group” also applies to the alkyl group contained in the monoalkylamino group.
  • the alkyl group contained in the monoalkylamino group is preferably an alkyl group having 1 to 6 carbon atoms.
  • the one or more substituents are each substituted with a hydrogen atom of the monoalkylamino group.
  • the number of substituents that the monoalkylamino group may have is preferably from 1 to 3, more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different.
  • One or more substituents that the monoalkylamino group may have may be each independently selected from halogen atoms.
  • an unsubstituted or substituted dialkylamino group means a dialkylamino group or a dialkylamino group having one or more substituents.
  • dialkylamino group means an unsubstituted dialkylamino group unless otherwise specified.
  • Dialkylamino group has the formula: —N (—Q 2 ) (— Q 3 ) wherein Q 2 and Q 3 are each independently an alkyl group. ].
  • the above description regarding the “alkyl group” also applies to the alkyl group included in the dialkylamino group.
  • the alkyl group contained in the dialkylamino group is preferably an alkyl group having 1 to 6 carbon atoms.
  • the carbon number of the dialkylamino group is usually 2 to 20, preferably 2 to 12, more preferably 2 to 8, still more preferably 2 to 6, even more preferably 2 to 5, and still more preferably 2 to 4, Even more preferably, it is 2 or 3.
  • the one or more substituents are each substituted with a hydrogen atom of the dialkylamino group.
  • the number of substituents that the dialkylamino group may have is preferably from 1 to 3, more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different.
  • One or more substituents that the dialkylamino group may have may be each independently selected from halogen atoms.
  • unsubstituted or substituted aliphatic cyclic group means an aliphatic cyclic group or an aliphatic cyclic group having at least one substituent.
  • the “aliphatic ring group” means an unsubstituted aliphatic ring group, unless otherwise specified.
  • aliphatic ring group means a functional group generated by removing one hydrogen atom from a monocyclic aliphatic hydrocarbon ring.
  • the aliphatic ring group is preferably a cycloalkyl group having 3 to 10 carbon atoms, more preferably a cycloalkyl group having 3 to 8 carbon atoms, and still more preferably a cycloalkyl group having 3 to 6 carbon atoms.
  • Examples of the cycloalkyl group having 3 to 10 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
  • the one or more substituents are each substituted with a hydrogen atom of the aliphatic ring group.
  • the number of substituents which the aliphatic ring group may have is preferably 1 to 3, more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different.
  • One or more substituents that the aliphatic ring group may have may be each independently selected from halogen atoms.
  • an unsubstituted or substituted aliphatic ring oxy group means an aliphatic ring oxy group or an aliphatic ring oxy group having one or more substituents.
  • the “aliphatic ring oxy group” means an unsubstituted aliphatic ring oxy group, unless otherwise specified.
  • Aliphatic ring oxy group means a group represented by an aliphatic ring group -O-.
  • the above description regarding the “aliphatic ring group” also applies to the aliphatic ring group included in the aliphatic ring oxy group.
  • the one or more substituents are each substituted with a hydrogen atom of the aliphatic ring oxy group.
  • the number of substituents that the aliphatic ring oxy group may have is preferably from 1 to 3, more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different.
  • One or more substituents that the aliphatic ring oxy group may have may be each independently selected from halogen atoms.
  • unsubstituted or substituted aliphatic heterocyclic group means an aliphatic heterocyclic group or an aliphatic heterocyclic group having at least one substituent.
  • the “aliphatic heterocyclic group” means an unsubstituted aliphatic heterocyclic group unless otherwise specified.
  • Aliphatic heterocyclic group is a monocyclic monocyclic ring containing, as a ring-constituting atom, one or more heteroatoms independently selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, in addition to a carbon atom. It means a functional group formed by removing one hydrogen atom from an aliphatic heterocycle (non-aromatic heterocycle).
  • the number of hetero atoms contained in the aliphatic heterocyclic group is usually 1 to 4, preferably 1 to 3, more preferably 1 or 2.
  • the number of members of the aliphatic heterocyclic group is usually 3 to 8, preferably 4 to 8, more preferably 5 to 7 members, and still more preferably 5 or 6 members.
  • the number of ring-constituting carbon atoms in the aliphatic heterocyclic group is appropriately determined according to the number of heteroatoms and the number of members in the aliphatic heterocyclic group.
  • the aliphatic heterocyclic group is preferably a saturated aliphatic heterocyclic group.
  • the saturated aliphatic heterocyclic group is an aliphatic heterocyclic group in which a ring is constituted only by a saturated bond.
  • the aliphatic heterocyclic group for example, 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 And 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, and the like.
  • two carbon atoms constituting the ring may be bridged with an alkylene group.
  • the aliphatic heterocyclic group In the aliphatic heterocyclic group, two adjacent carbon atoms among the carbon atoms constituting the ring may form a double bond. In the aliphatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may be substituted with an oxo group.
  • the number of oxo groups that the aliphatic heterocyclic group may have is preferably one or two. When the aliphatic heterocyclic group contains a sulfur atom, the aliphatic heterocyclic group may be in the form of a dioxide.
  • Examples of the aliphatic heterocyclic group include, for example, an aziridinyl group, an oxiranyl group, a thiranyl group, an azetidinyl group, an oxetanyl group, a thietanyl group, a tetrahydrothienyl group, a tetrahydrofuranyl group, a pyrrolinyl group, a pyrrolidinyl group, an imidazolinyl group, an imidazolidinyl group, and an oxazolinyl group.
  • a 3- to 8-membered aliphatic heterocyclic group such as a morpholinyl group, a thiomorpholinyl group (a sulfur atom on the ring may be oxidized), an azepanyl group, a diazepany
  • the aliphatic heterocyclic group is preferably a tetrahydrofuranyl group.
  • the one or more substituents are each substituted with a hydrogen atom of the aliphatic heterocyclic group.
  • the number of substituents that the aliphatic heterocyclic group may have is preferably from 1 to 3, more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different.
  • One or more substituents that the aliphatic heterocyclic group may have may be each independently selected from halogen atoms.
  • an unsubstituted or substituted aliphatic heterocyclic oxy group means an aliphatic heterocyclic oxy group or an aliphatic heterocyclic oxy group having at least one substituent.
  • the “aliphatic heterocyclic oxy group” means an unsubstituted aliphatic heterocyclic oxy group unless otherwise specified.
  • Aliphatic heterocyclic oxy group means a group represented by an aliphatic heterocyclic group -O-.
  • the above description regarding the “aliphatic heterocyclic group” also applies to the aliphatic heterocyclic group included in the aliphatic heterocyclic oxy group.
  • the aliphatic heterocyclic oxy group is preferably a tetrahydrofuranyloxy group.
  • the one or more substituents are each substituted with a hydrogen atom of the aliphatic heterocyclic oxy group.
  • the number of substituents that the aliphatic heterocyclic oxy group may have is preferably from 1 to 3, more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different.
  • One or more substituents that the aliphatic heterocyclic oxy group may have may be each independently selected from halogen atoms.
  • Unsubstituted or substituted phenyl group means a phenyl group or a phenyl group having one or more substituents.
  • phenyl group means an unsubstituted phenyl group unless otherwise specified.
  • the one or more substituents are each substituted with a hydrogen atom of the phenyl group.
  • the number of substituents that the phenyl group may have is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different.
  • the one or more substituents that the phenyl group may have can be independently selected from the substituent group ⁇ described below.
  • the total number of carbon atoms in the phenyl group having one or more substituents is preferably 10 or less, more preferably 9 or less, even more preferably 8 or less. Hereinafter, it is even more preferably 7 or less.
  • Unsubstituted or substituted phenyloxy group means a phenyloxy group or a phenyloxy group having at least one substituent.
  • the “phenyloxy group” means an unsubstituted phenyloxy group unless otherwise specified.
  • Phenyloxy group means a group represented by phenyl group -O-.
  • the one or more substituents are each substituted with a hydrogen atom of the phenyloxy group.
  • the number of substituents that the phenyloxy group may have is preferably 1 to 4, more preferably 1 to 3, and still more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different.
  • One or more substituents that the phenyloxy group may have can be independently selected from the substituent group ⁇ described below. When one or more substituents are selected from groups containing carbon atoms, the total carbon number in the phenyloxy group having one or more substituents is preferably 12 or less, more preferably 10 or less, even more preferably 8 or less.
  • Unsubstituted or substituted phenylalkyl group means a phenylalkyl group or a phenylalkyl group having one or more substituents.
  • the “phenylalkyl group” means an unsubstituted phenylalkyl group, unless otherwise specified.
  • Phenylalkyl group means a group represented by a phenyl-alkylene group.
  • the above description regarding the “alkylene group” also applies to the alkylene group included in the phenylalkyl group.
  • the alkylene group contained in the phenylalkyl group is preferably a linear alkylene group having 1 to 4 carbon atoms or a branched alkylene group having 3 to 4 carbon atoms, and more preferably 1 to 4 carbon atoms. Is a linear alkylene group.
  • the number of carbon atoms in the linear alkylene group is preferably from 1 to 3, more preferably 1 or 2.
  • the phenylalkyl group preferably has 7 to 10 carbon atoms.
  • the one or more substituents are each substituted with a hydrogen atom of the phenylalkyl group.
  • the hydrogen atom to be substituted may be a hydrogen atom on a benzene ring or a hydrogen atom in an alkylene portion, but is preferably a hydrogen atom on a benzene ring.
  • the number of substituents that the phenylalkyl group may have on the alkylene moiety is preferably 1 to 3, more preferably 1 or 2, and the number of substituents that the phenylalkyl group may have on the benzene ring is preferably It is 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2.
  • the one or more substituents that the phenylalkyl group may have can be independently selected from the substituent group ⁇ described below.
  • the total carbon number in the phenylalkyl group having one or more substituents is preferably 16 or less, more preferably 14 or less, even more preferably 12 or less.
  • an unsubstituted or substituted phenylalkyloxy group means a phenylalkyloxy group or a phenylalkyloxy group having one or more substituents.
  • the “phenylalkyloxy group” means an unsubstituted phenylalkyloxy group unless otherwise specified.
  • Phenylalkyloxy group means a group represented by phenylalkyl group -O-. The above description regarding the “phenylalkyl group” also applies to the phenylalkyl group included in the phenylalkyloxy group.
  • the one or more substituents are each substituted with a hydrogen atom of the phenylalkyloxy group.
  • the hydrogen atom to be substituted may be a hydrogen atom on a benzene ring or a hydrogen atom in an alkylene portion, but is preferably a hydrogen atom on a benzene ring.
  • the number of substituents that the phenylalkyloxy group may have on the alkylene moiety is preferably from 1 to 3, more preferably 1 or 2.
  • the number of substituents that the phenylalkyloxy group may have on the benzene ring is It is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different.
  • the one or more substituents that the phenylalkyloxy group may have can be independently selected from the substituent group ⁇ described below. When one or more substituents are selected from groups containing a carbon atom, the total carbon number in the phenylalkyloxy group having one or more substituents is preferably 16 or less, more preferably 14 or less, even more preferably. Is 12 or less.
  • an unsubstituted or substituted aromatic ring group means an aromatic ring group or an aromatic ring group having at least one substituent.
  • aromatic ring group means an unsubstituted aromatic ring group, unless otherwise specified.
  • Aromatic ring group means a group formed by removing one hydrogen atom from a monocyclic or condensed polycyclic aromatic hydrocarbon ring.
  • the aromatic ring group is usually a 1 to 4 ring, preferably 1 to 3 ring, more preferably a 1 or 2 ring aromatic ring group.
  • the number of ring-constituting carbon atoms in the aromatic ring group is usually from 6 to 18, preferably from 6 to 14, and more preferably from 6 to 10.
  • Examples of the monocyclic aromatic ring group include a phenyl group.
  • Examples of the condensed polycyclic aromatic ring group include 2- to 4-cyclic aromatic ring groups such as a naphthyl group, an anthryl group, a phenanthrenyl group, a tetracenyl group, and a pyrenyl group.
  • the fused polycyclic aromatic ring group may be a partially saturated fused polycyclic aromatic ring group.
  • the partially saturated condensed polycyclic aromatic ring group is a condensed polycyclic aromatic ring group in which some of the bonds constituting the ring are hydrogenated.
  • the aromatic ring group is preferably a phenyl group.
  • the one or more substituents are each substituted with a hydrogen atom of the aromatic ring group.
  • the number of substituents that the aromatic ring group may have can be appropriately determined according to the number of carbon atoms, the number of members, and the like of the aromatic ring group.
  • the number of substituents that the aromatic ring group may have is preferably 1 to 4, more preferably 1 to 3, and still more preferably 1 or 2.
  • the number of substituents is two or more, the two or more substituents may be the same or different.
  • One or more substituents that the aromatic ring group may have can be independently selected from the substituent group ⁇ described below.
  • the total number of carbon atoms in the aromatic ring group having one or more substituents is preferably 20 or less, more preferably 19 or less, and still more preferably. Is 18 or less, even more preferably 17 or less.
  • an unsubstituted or substituted aromatic heterocyclic group means an aromatic heterocyclic group or an aromatic heterocyclic group having at least one substituent.
  • the “aromatic heterocyclic group” means an unsubstituted aromatic heterocyclic group unless otherwise specified.
  • “Aromatic heterocyclic group” is a monocyclic or heterocyclic group containing, as a ring-constituting atom, one or more heteroatoms independently selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, in addition to a carbon atom. It means a group formed by removing one hydrogen atom from a condensed polycyclic aromatic heterocycle.
  • the aromatic heterocyclic group is usually a 1 to 4 cyclic, preferably 1 to 3 cyclic, more preferably a 1 or 2 cyclic aromatic heterocyclic group.
  • the number of heteroatoms contained in the aromatic heterocyclic group is usually 1 to 4, preferably 1 to 3, and more preferably 1 or 2.
  • the number of aromatic heterocyclic groups is preferably from 5 to 14 members, more preferably from 5 to 10 members.
  • the number of ring-constituting carbon atoms in the aromatic heterocyclic group is appropriately determined according to the number of heteroatoms and the number of members in the aromatic heterocyclic group.
  • two hydrogen atoms bonded to the same carbon atom may be substituted with an oxo group.
  • the aromatic heterocyclic group is, for example, a monocyclic aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group is, for example, a 5- to 7-membered monocyclic aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group includes, for example, those containing 1 to 2 oxygen atoms, those containing 1 to 2 sulfur atoms, 1 to 2 oxygen atoms and 1 to 2 sulfur atoms. Examples include an atom-containing compound, a compound containing 1 to 4 nitrogen atoms, a compound containing 1 to 3 nitrogen atoms, 1 to 2 sulfur atoms, and / or 1 to 2 oxygen atoms.
  • the monocyclic aromatic heterocyclic group for example, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, thienyl group, pyrrolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, imidazolyl group, furyl group, oxazolyl group, Isoxazolyl group, oxadiazolyl group (eg, 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, etc.), thiadiazolyl group (eg, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group) And a 5- to 7-membered monocyclic aromatic heterocyclic group such as a triazolyl group (eg, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group), a tetrazolyl group, a triazin
  • the monocyclic aromatic heterocyclic group two hydrogen atoms bonded to the same carbon atom may be substituted with an oxo group.
  • the number of oxo groups that the monocyclic aromatic heterocyclic group may have is preferably 1 or 2.
  • the aromatic heterocyclic group is, for example, a condensed polycyclic aromatic heterocyclic group.
  • the fused polycyclic aromatic heterocyclic group is, for example, an 8- to 14-membered bicyclic or tricyclic aromatic heterocyclic group.
  • Examples of the condensed polycyclic aromatic heterocyclic group include those containing 1 to 3 oxygen atoms, those containing 1 to 3 sulfur atoms, 1 to 3 oxygen atoms and 1 to 3 A compound containing a sulfur atom, a compound containing 1 to 5 nitrogen atoms, a compound containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, and the like. .
  • Examples of the condensed polycyclic aromatic heterocyclic group include a benzothiophenyl group, a benzofuranyl group, a benzoimidazolyl group, a benzooxazolyl group, a benzoisoxazolyl group, a benzothiazolyl group, a benzoisothiazolyl group, and a benzotria Zolyl group, imidazopyridinyl group, thienopyridinyl group, flopyridinyl group, pyrrolopyridinyl group, pyrazolopyridinyl group, oxazolopyridinyl group, thiazolopyridinyl group, imidazopyrazinyl group, imidazopyrimidinyl group, Thienopyrimidinyl group, furopyrimidinyl group, pyrrolopyrimidinyl group, pyrazolopyrimidinyl group, oxazolopyrimidinyl group,
  • the aromatic heterocyclic group is preferably a thienyl group, a benzothiophenyl group, a furyl group, a pyrrolyl group, an imidazolyl group or a pyridyl group, and more preferably a thienyl group or a benzothiophenyl group.
  • the one or more substituents are each substituted with a hydrogen atom of the aromatic heterocyclic group.
  • the number of substituents that the aromatic heterocyclic group may have can be appropriately determined according to the number of carbon atoms, the number of members, and the like of the aromatic heterocyclic group.
  • the number of substituents that the aromatic heterocyclic group may have is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different.
  • One or more substituents that the aromatic heterocyclic group may have can be independently selected from the substituent group ⁇ described below.
  • the total number of carbon atoms in the aromatic heterocyclic group having one or more substituents is preferably 20 or less, more preferably 19 or less, and even more. It is preferably 18 or less, more preferably 17 or less.
  • Substituent group ⁇ is composed of the following substituents.
  • Halogen atom "unsubstituted or substituted alkyl group”, “unsubstituted or substituted alkoxy group”, “unsubstituted or substituted heteroalkyl group”, “unsubstituted or substituted heteroalkoxy group”, “unsubstituted” Or a substituted monoalkylamino group, an unsubstituted or substituted dialkylamino group, an unsubstituted or substituted aliphatic ring group, an unsubstituted or substituted aliphatic ring oxy group, an unsubstituted or substituted.
  • aliphatic heterocyclic group and “unsubstituted or substituted aliphatic heterocyclic oxy group” also applies to the substituent group ⁇ .
  • Substituent group ⁇ is a halogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted heteroalkyl group, an unsubstituted or substituted heteroalkoxy group, an unsubstituted or substituted aliphatic It is preferable that the heterocyclic group is composed of a heterocyclic group and an unsubstituted or substituted aliphatic heterocyclic oxy group, a halogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted hetero group.
  • it is composed of an alkyl group and an unsubstituted or substituted heteroalkoxy group, and more preferably it is composed of a halogen atom, an unsubstituted or substituted alkyl group, and an unsubstituted or substituted alkoxy group. preferable.
  • Substituent group ⁇ is composed of the following substituents. ( ⁇ -1) Substituent group ⁇ ( ⁇ -2) unsubstituted or substituted phenyl group ( ⁇ -3) unsubstituted or substituted phenyloxy group ( ⁇ -4) unsubstituted or substituted phenylalkyl group ( ⁇ -5) unsubstituted or substituted phenylalkyl Oxy group
  • ( ⁇ -2) is preferably a phenyl group having at least one substituent selected from a halogen atom.
  • the number of halogen atoms is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2.
  • ( ⁇ -3) is preferably a phenyloxy group having at least one substituent selected from a halogen atom.
  • the number of halogen atoms is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2.
  • ( ⁇ -4) is preferably a phenylalkyl group having at least one substituent selected from a halogen atom.
  • the number of halogen atoms is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2.
  • ( ⁇ -5) is preferably a phenylalkyloxy group having at least one substituent selected from a halogen atom.
  • the number of halogen atoms is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2.
  • the substituent group ⁇ is preferably composed of a halogen atom, an aliphatic heterocyclic oxy group, a phenyl group, and a phenyl group having at least one substituent selected from a halogen atom and an aliphatic heterocyclic oxy group.
  • the method for producing a ⁇ -C-aryl glycoside derivative of the present invention includes a step of producing a ⁇ -C-aryl glycoside derivative by contacting the C-aryl-hydroxy glycoside derivative with a silane compound in the presence of a titanium compound. .
  • ⁇ -C-aryl glycoside derivatives have the following formula (1): It is a compound represented by these.
  • R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom or a hydroxyl protecting group.
  • R 1 , R 2 , R 3 and R 4 are all hydrogen atoms.
  • R 1 , R 2 , R 3 and R 4 are all hydroxyl protecting groups.
  • one to three of R 1 , R 2 , R 3 and R 4 are hydroxyl protecting groups and the rest are hydrogen atoms.
  • R 1 , R 2 , R 3 and R 4 is a hydroxyl-protecting group in that the ⁇ -C-aryl glycoside derivative to be produced is easily separated from the reaction system.
  • R 2, 2 or more of R 3 and R 4 are hydroxyl-protecting group, it is preferably further all R 1, R 2, R 3 and R 4 are hydroxyl protecting group .
  • R 1 , R 2 , R 3 and R 4 are hydroxyl-protecting groups
  • these hydroxyl-protecting groups may be the same or different. It is preferable that they are the same from the viewpoint of efficient introduction and removal.
  • the hydroxyl-protecting group is not particularly limited and can be appropriately selected as long as it can protect the hydroxyl group when performing the desired reaction and can be eliminated from the hydroxyl group after the completion of the desired reaction.
  • Examples of the hydroxyl group-protecting group include ester-type protecting groups, arylalkyl-type protecting groups, alkyl-type protecting groups, arylalkyloxyalkyl-type protecting groups, alkyloxyalkyl-type protecting groups, silyl-type protecting groups, and oxycarbonyl-type protecting groups. Is mentioned.
  • ester-type protecting group examples include acetyl, propanoyl, butanoyl, isopropanoyl, pivaloyl, benzoyl, 4-nitrobenzoyl, 4-methyloxybenzoyl, 4-methylbenzoyl, Examples include a tert-butylbenzoyl group, a 4-fluorobenzoyl group, a 4-chlorobenzoyl group, a 4-bromobenzoyl group, a 4-phenylbenzoyl group, and a 4-methyloxycarbonylbenzoyl group.
  • the ester-type protecting groups are preferably an acetyl group and a pivaloyl group.
  • arylalkyl-type protecting group examples include a benzyl group, a 1-phenylethyl group, a diphenylmethyl group, a 1,1-diphenylethyl group, and a naphthylmethyl group.
  • the arylalkyl-type protecting group is preferably a benzyl group.
  • alkyl-type protecting group examples include a methyl group, an ethyl group and a tert-butyl group.
  • the alkyl-type protecting group is preferably a methyl group.
  • arylalkyloxyalkyl type protecting group examples include a benzyloxymethyl group.
  • alkyloxyalkyl-type protecting group examples include a methyloxymethyl group.
  • silyl-type protecting group examples include a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, and a tert-butyldiphenylsilyl group.
  • the silyl-type protecting group is preferably a trimethylsilyl group and a tert-butyldimethylsilyl group.
  • Examples of the oxycarbonyl-type protecting group include an alkyloxycarbonyl group such as methyloxycarbonyl and an arylalkyloxycarbonyl group such as benzyloxycarbonyl.
  • the hydroxyl protecting group is preferably selected from a methyl group, a benzyl group, an acetyl group, a pivaloyl group, a trimethylsilyl group and a tert-butyldimethylsilyl group, and more preferably selected from a benzyl group, an acetyl group and a pivaloyl group.
  • These hydroxyl group-protecting groups are preferable in that the protection and deprotection of the hydroxyl group are easy and the reagent is inexpensive.
  • Ar is an organic group containing a group selected from an unsubstituted or substituted aromatic ring group and an unsubstituted or substituted aromatic heterocyclic group as a group bonded to the oxane ring in the formula. is there.
  • Ar is an organic group that contains an unsubstituted or substituted aromatic ring group as a group that bonds to the oxane ring in Formula (1).
  • Ar may be an unsubstituted or substituted aromatic ring group.
  • Ar is an organic group containing an unsubstituted or substituted aromatic heterocyclic group as a group bonded to the oxane ring in the formula (1).
  • Ar may be an unsubstituted or substituted aromatic heterocyclic group.
  • Examples of the organic group containing an unsubstituted or substituted aromatic ring group as a group bonded to the oxane ring in the formula (1) include, for example, a compound represented by the formula: -J 1 -J 2 [wherein J 1 is an unsubstituted Or a substituted alkylene group; J 2 is an unsubstituted or substituted aromatic ring group, an unsubstituted or substituted aromatic heterocyclic group, or an unsubstituted or substituted aliphatic heterocyclic group. And an aromatic ring group having a substituent represented by the formula: J 1 is preferably an unsubstituted alkylene group. J 2 is preferably an unsubstituted or substituted aromatic ring group or an unsubstituted or substituted aromatic heterocyclic group.
  • Examples of the organic group containing an unsubstituted or substituted aromatic heterocyclic group as a functional group bonded to a carbon atom of an oxane ring in the formula (I) include, for example, a compound represented by the formula: -K 1 -K 2 1 is an unsubstituted or substituted alkylene group, and K 2 is an unsubstituted or substituted aromatic ring group, an unsubstituted or substituted aromatic heterocyclic group or an unsubstituted or substituted aliphatic heterocyclic group. .
  • an aromatic heterocyclic group having a substituent represented by the formula: K 1 is preferably an unsubstituted alkylene group.
  • K 2 is preferably an unsubstituted or substituted aromatic ring group or an unsubstituted or substituted aromatic heterocyclic group.
  • the organic group represented by Ar is the same as the aromatic ring group or the aromatic heterocyclic group of the SGLT-2 inhibitor, or the aromatic group or the aromatic heterocyclic group of the SGLT-2 inhibitor. It is preferable that the group is derived from a group.
  • 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 ”) and dapagliflozin (“ (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (4-
  • Ar is of the following formula (A): Is an organic group represented by
  • n is an integer of 0 to 4. n is preferably 1 to 3, more preferably 1 or 2, and still more preferably 1.
  • n pieces of R a are each independently a halogen atom, an amino group, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, substituted or unsubstituted heteroalkyl group, non Substituted or substituted heteroalkoxy group, unsubstituted or substituted monoalkylamino group, unsubstituted or substituted dialkylamino group, unsubstituted or substituted aliphatic ring group, unsubstituted or substituted aliphatic ring oxy group, unsubstituted Or a substituted aliphatic heterocyclic group, an unsubstituted or substituted aliphatic heterocyclic oxy group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyloxy group, an unsubstituted or substituted phenylalkyl group, and It is a group
  • n pieces of R a may be the same or different.
  • n Ra are each independently a halogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted heteroalkyl group, an unsubstituted or substituted A heteroalkoxy group, an unsubstituted or substituted aliphatic ring group, an unsubstituted or substituted aliphatic ring oxy group, an unsubstituted or substituted aliphatic heterocyclic group, an unsubstituted or substituted aliphatic heterocyclic oxy group, It is preferably a substituted or substituted phenyl group, an unsubstituted or substituted phenyloxy group, an unsubstituted or substituted phenylalkyl group, and a group selected from an unsubstituted or substituted phenylalkyloxy group, a halogen atom, A group selected from an unsubstituted or
  • Ar ' is a group selected from an unsubstituted or substituted aromatic ring group, an unsubstituted or substituted aromatic heterocyclic group, and an unsubstituted or substituted aliphatic heterocyclic group.
  • Ar ′ is preferably a group selected from an unsubstituted or substituted aromatic ring group and an unsubstituted or substituted aromatic heterocyclic group, and is 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 of 0 to 3, more preferably an integer of 0 to 2, and even more preferably 0 or 1.
  • p R b are each independently a halogen atom, an amino group, an unsubstituted or substituted alkyl group, Substituted or substituted alkoxy group, unsubstituted or substituted heteroalkyl group, unsubstituted or substituted heteroalkoxy group, unsubstituted or substituted monoalkylamino group, unsubstituted or substituted dialkylamino group, unsubstituted or substituted fat Aliphatic group, unsubstituted or substituted aliphatic ring oxy group, unsubstituted or substituted aliphatic heterocyclic group, unsubstituted or substituted aliphatic heterocyclic oxy group, unsubstituted or substituted phenyl group, unsubstituted or substituted A phenyloxy group, an unsubstituted or substituted phenylalkyl
  • p R b When p is 2 or more, p R b may be the same or different.
  • R b is preferably an unsubstituted or substituted phenyl group, more preferably a phenyl group having a halogen atom. Preferably, it is a phenyl group having a fluorine atom.
  • the position where the unsubstituted or substituted phenyl group is bonded is preferably the 2-position of the thiophene ring.
  • the position where the halogen atom is bonded is preferably the 4-position of the benzene ring.
  • p is preferably 0.
  • R b is preferably an unsubstituted or substituted alkoxy group or an unsubstituted or substituted aliphatic heterocyclic oxy group.
  • the unsubstituted or substituted alkoxy group is preferably an alkoxy group having 1 to 3 carbon atoms, and more preferably a methoxy group or an ethoxy group.
  • the unsubstituted or substituted aliphatic heterocyclic oxy group is preferably a tetrahydrofuranyloxy group.
  • the position to which the unsubstituted or substituted alkoxy group or unsubstituted or substituted aliphatic heterocyclic oxy group is bonded is preferably the 4-position of the benzene ring.
  • Ar is represented by the following formula (B): It is preferably an organic group represented by
  • Ra and Ar ′ have the same meaning as in the formula (A).
  • Ar is preferably an organic group represented by the following formula (Ar-1), (Ar-2), (Ar-3) or (Ar-4).
  • the C-aryl-hydroxyglycoside derivative has the following formula (2): It is a compound represented by these.
  • R 1 , R 2 , R 3 , R 4 and Ar have the same meanings as in the formula (1).
  • R 5 is a hydrogen atom, a methyl group, a trimethylsilyl group or an acetyl group.
  • R 5 is preferably a methyl group, a trimethylsilyl group or an acetyl group.
  • R 5 when R 5 is a methyl group, it is preferable that none of R 1 to R 4 is a methyl group. Thereby, in the reduction reaction of the C-aryl-hydroxyglycoside derivative, -OR 5 can be eliminated while maintaining -OR 1 , -OR 2 , -OR 3 and -OR 4 .
  • R 5 when R 5 is a trimethylsilyl group, it is preferable that none of R 1 to R 4 is a trimethylsilyl group. Thereby, in the reduction reaction of the C-aryl-hydroxyglycoside derivative, -OR 5 can be eliminated while maintaining -OR 1 , -OR 2 , -OR 3 and -OR 4 .
  • R 5 when R 5 is an acetyl group, it is preferable that none of R 1 to R 4 is an acetyl group. Thereby, in the reduction reaction of the C-aryl-hydroxyglycoside derivative, -OR 5 can be eliminated while maintaining -OR 1 , -OR 2 , -OR 3 and -OR 4 .
  • the C-aryl-hydroxyglycoside derivative can be obtained by a known method described in Patent Document 1, Non-Patent Document 1, Non-Patent Document 2, and the like.
  • the titanium compound acts as a Lewis acid.
  • a reduction reaction of a C-aryl-hydroxyglycoside derivative can be rapidly advanced at a low temperature, and a desired ⁇ -C-arylglycoside derivative can be obtained with high selectivity and high yield. Can be.
  • titanium compounds include, for example, those in which titanium is zero-valent, those in which titanium is divalent, those in which trivalent is tetravalent, those in which tetravalent is tetravalent, etc. Good.
  • examples of the titanium compound include triisopropoxy titanium monochloride (IV), diisopropoxy titanium dichloride (IV), monoisopropoxy titanium trichloride (IV), titanium chloride (IV), titanium bromide (IV), and 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; zero-valent titanium such as metallic Ti or solvates thereof.
  • the solvate include those in which a solvent such as water and tetrahydrofuran is coordinated.
  • 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. .
  • the titanium compound is preferably triisopropoxy titanium monochloride (IV), diisopropoxy titanium dichloride (IV), monoisopropoxy titanium trichloride (IV), titanium chloride (IV), titanium (III) chloride or the like. And more preferably titanium (IV) chloride. Titanium (IV) chloride has a low melting point and is a liquid at room temperature, and thus is preferable in that it is easy to handle and inexpensive.
  • the amount of the titanium compound used is not particularly limited, and can be appropriately adjusted.
  • the amount of the titanium compound to be used is preferably 0.05 to 10 mol, more preferably 0.1 to 7 mol, and still more preferably 1 mol of the C-aryl-hydroxyglycoside derivative represented by the formula (1). 1 to 5 mol.
  • the silane compound acts as a reducing agent.
  • silane compound examples include triethylsilane, triisopropylsilane, phenylsilane, dimethylphenylsilane, tert-butyldimethylsilane, triisobutylsilane, trichlorosilane, trimethoxyhydrosilane, triethoxyhydrosilane, and tetramethyldisiloxane.
  • the silane compound is preferably trimethoxyhydrosilane, triethoxyhydrosilane, tetramethyldisiloxane, or the like, and more preferably tetramethyldisiloxane.
  • the amount of the silane compound used is not particularly limited, and can be appropriately adjusted.
  • the amount of the silane compound to be used is preferably 1 to 10 mol, more preferably 1 to 5 mol, and still more preferably 1 to 3 mol, per mol of the C-aryl-hydroxyglycoside derivative, from the viewpoint of sufficiently proceeding the reaction. Is a mole.
  • the step of contacting the C-aryl-hydroxyglycoside derivative with the silane compound in the presence of the titanium compound it is preferable to stir and mix the C-aryl-hydroxyglycoside derivative, the titanium compound and the silane compound in the reaction solvent.
  • the reaction solvent is not particularly limited as long as it does not adversely affect the C-aryl-hydroxyglycoside derivative, the titanium compound and the silane compound and can smoothly reduce the C-aryl-hydroxyglycoside derivative.
  • the reaction solvent include aliphatic nitriles such as acetonitrile and propionitrile, tetrahydrofuran (THF), 2-methyl-THF, 1,4-dioxane, tert-butyl methyl ether, diisopropyl ether, dimethoxyethane, diglyme and the like.
  • Ethers ketones such as acetone, methyl ethyl ketone and diethyl ketone, acetates such as methyl acetate, ethyl acetate and butyl acetate, and halogenated carbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and chlorobenzene Examples thereof include hydrogens, aromatic hydrocarbons such as toluene and xylene, and aliphatic hydrocarbons such as hexane and heptane.
  • These reaction solvents can be used alone or as a mixed solvent.
  • the reaction solvent is preferably acetonitrile, methylene chloride or a mixed solvent thereof. These are aprotic polar solvents and are preferred because they are less susceptible to silane reduction.
  • the amount of the reaction solvent used is not particularly limited and can be appropriately adjusted.
  • the amount of the reaction solvent used is preferably 1 to 100 times, more preferably 1 to 50 times, even more preferably 2 to 20 times the volume of the C-aryl-hydroxyglycoside derivative.
  • the total amount of the mixed solvent should satisfy the above range.
  • the reduction reaction of the C-aryl-hydroxyglycoside derivative proceeds.
  • the reduction reaction can be advanced by mixing a C-aryl-hydroxyglycoside derivative, a titanium compound, a silane compound and, if necessary, a reaction solvent.
  • the method of mixing the components is not particularly limited, and can be carried out, for example, in a reaction vessel equipped with a stirring device.
  • the procedure for adding each component to the reaction vessel is not particularly limited, but a C-aryl-hydroxyglycoside derivative, a silane compound and, if necessary, a reaction solvent are charged in the reaction vessel in advance, and the titanium compound is added with stirring. And a method of mixing.
  • the temperature at the time of addition of the titanium compound and the reaction temperature after the addition are not particularly limited, and can be appropriately adjusted.
  • the temperature at the time of addition of the titanium compound and the reaction temperature after the addition are preferably in the range of ⁇ 100 ° C. to 100 ° C., more preferably ⁇ 78 ° C. to 50 ° C., and still more preferably ⁇ 60 ° C. to 10 ° C.
  • the reaction time is not particularly limited, and can be adjusted as appropriate, for example, while checking the conversion of the C-aryl-hydroxyglycoside derivative as a raw material.
  • the reaction time is generally from 10 minutes to 48 hours, preferably from 0.5 hours to 24 hours, more preferably from 1 hour to 17 hours.
  • the reaction atmosphere is not particularly limited, but is preferably under an inert gas atmosphere or an air atmosphere in order to suppress mixing of moisture.
  • the reaction system may be under atmospheric pressure, under pressure, or under reduced pressure, and among these, it is preferable to carry out the reaction under atmospheric pressure.
  • ⁇ A ⁇ -C-aryl glycoside derivative can be obtained by the reduction reaction.
  • the products obtained by the reduction reaction are a ⁇ -C-aryl glycoside derivative (hereinafter sometimes referred to as “ ⁇ -form”) and an ⁇ -C-aryl glycoside derivative (hereinafter sometimes referred to as “ ⁇ -form”).
  • ⁇ -form ⁇ -C-aryl glycoside derivative
  • ⁇ -form ⁇ -C-aryl glycoside derivative
  • the isomer ratio ( ⁇ -form / ⁇ -form) in the product is usually 73/27 or more, preferably 75/25 or more, more preferably 77/23 or more, still more preferably 80/20 or more, and even more preferably 85 or more. / 15 or more, more preferably 90/10 or more.
  • the isomer ratio is measured by the method described in the examples.
  • the ⁇ -C-aryl glycoside derivative obtained by the reduction reaction is preferably taken out of the reaction system.
  • the ⁇ -C-aryl glycoside derivative obtained by the reduction reaction is, for example, after adding water to the reaction solution, contacting with a poorly water-soluble organic solvent such as ethyl acetate, toluene, tert-butyl methyl ether, and methylene chloride,
  • a poorly water-soluble organic solvent such as ethyl acetate, toluene, tert-butyl methyl ether, and methylene chloride
  • ⁇ -C-arylglycoside derivative can be further purified by a known method such as column separation and recrystallization.
  • column separation and recrystallization it is difficult to separate ⁇ -form and ⁇ -form by column purification using a silica gel column or the like. Therefore, the usefulness of the present invention, in which a ⁇ -C-aryl glycoside derivative can be produced with high selectivity and high yield, is extremely high.
  • the resulting ⁇ -C-arylglycoside derivative may be used as it is when R 1 to R 4 are all hydrogen atoms, or as needed when at least one of R 1 to R 4 is a hydroxyl protecting group. After deprotection by a known method, it can be suitably used as an SGLT2 inhibitor useful as an antidiabetic drug or a synthetic intermediate thereof.
  • Production Example 1 Production of C-aryl-hydroxyglycoside derivative of alcohol derivative
  • the reaction represented by the following formula was carried out to obtain a C-aryl-hydroxyglycoside derivative of an alcohol derivative (in the formula (2), R 1 , R 2 , R 3 And R 4 is a benzyl group, R 5 is a hydrogen atom, and Ar is a phenyl group).
  • Bn represents a benzyl group. The same applies hereinafter.
  • Production Example 2 Production of methoxy C-aryl-hydroxyglycoside derivative The reaction represented by the following formula was carried out to obtain a methoxy C-aryl-hydroxyglycoside derivative (in the formula (2), R 1 , R 2 , R 3 And R 4 is a benzyl group, R 5 is a methyl group, and Ar is a phenyl group).
  • Production Example 3 Production of C-aryl-hydroxyglycoside derivative of alcohol derivative The reaction represented by the following formula was carried out to obtain a C-aryl-hydroxyglycoside derivative of an alcohol derivative (in the formula (2), R 1 , R 2 , R 3 And R 4 is a benzyl group, R 5 is a hydrogen atom, and Ar is an organic group represented by the above formula (Ar-1).
  • Example 1 Reduction with Titanium Compound (Production of ⁇ -C-Aryl Glycoside Derivative from Alcohol Form ) Using a titanium compound, a reaction represented by the following formula was carried out, and ⁇ -C was obtained from the alcohol form obtained in Production Example 1. -An aryl glycoside derivative was prepared.
  • Example 2 Reduction with Titanium Compound (Production of ⁇ -C-aryl Glycoside Derivative from Methoxy Form) A reaction represented by the following formula was carried out using a titanium compound, and ⁇ -C was obtained from the methoxy form obtained in Production Example 2. -An aryl glycoside derivative was prepared.
  • Example 3 Reduction with Titanium Compound (Production of ⁇ -C-aryl Glycoside Derivative from Alcohol Form) Using a titanium compound, a reaction represented by the following formula was carried out, and a ⁇ -C-arylglycoside derivative was produced from the alcohol obtained in Production Example 3.
  • Comparative Example 1 Reduction with aluminum chloride (production of ⁇ -C-aryl glycoside derivative from alcohol form) The reaction represented by the following formula was carried out using aluminum chloride, and a ⁇ -C-aryl glycoside derivative was produced from the alcohol obtained in Production Example 1.
  • the alcohol (10 mg, 0.02 mmol) obtained in Production Example 1 was dissolved in a mixed solution of methylene chloride (0.5 mL) and acetonitrile (1 mL), and then tetramethyldisiloxane (4.4 mg, 0.03 mmol) was dissolved. ) was added.
  • aluminum chloride 6.5 mg, 0.05 mmol was added at ⁇ 40 ° C., gradually raised to room temperature, and stirred at the same temperature for 18 hours.
  • Comparative Example 2 Reduction with aluminum chloride (Production of ⁇ -C-arylglycoside derivative from methoxy form) A reaction represented by the following formula was carried out using aluminum chloride, and ⁇ -C was obtained from the methoxy form obtained in Production Example 2. -An aryl glycoside derivative was prepared.
  • the methoxy compound (10 mg, 0.02 mmol) obtained in Production Example 2 was dissolved in a mixed solution of methylene chloride (0.5 mL) and an acetonitrile solution (1 mL), and then tetramethyldisiloxane (4.4 mg, 0.4 mL) was dissolved. 03 mmol) was added.
  • aluminum chloride 6.5 mg, 0.05 mmol was added at ⁇ 40 ° C., gradually raised to room temperature, and stirred at the same temperature for 17 hours.
  • the isomer ratios in Examples and Comparative Examples were evaluated by a method using high performance liquid chromatography (HPLC). HPLC was performed according to the following measurement conditions.
  • the isomer ratio of ⁇ -form and ⁇ -form is the ratio of the peak area value of each of the ⁇ -form and ⁇ -form measured by HPLC to the sum of the peak area values of ⁇ -form and ⁇ -form measured by HPLC. Ratio.
  • the yield in the examples was calculated from the amount of the raw material and the amount of the target substance after recovering the target substance.
  • the yield in the comparative example was calculated by a method using HPLC. HPLC was performed according to the following measurement conditions.
  • the yield of the target substance is a ratio of the peak area value of the target substance to the sum of the area values of all peaks (excluding the peak derived from the solvent).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention a pour objet de fournir un procédé destiné à fabriquer selon une haute sélectivité et un haut rendement un dérivé d'aryle β－C-glycoside représenté par la formule (1), selon lequel procédé, la réduction d'un dérivé d'aryle C-hydroxyglycoside représenté par la formule (2) est exécutée rapidement et à basse température. À cet effet, l'invention fournit un procédé qui inclut une étape au cours de laquelle le dérivé d'aryle C-hydroxyglycoside représenté par la formule (2) est mis en contact avec un composé silane en présence d'un composé titane, et le dérivé d'aryle β－C-glycoside représenté par la formule (1) est ainsi fabriqué.
PCT/JP2019/034981 2018-09-06 2019-09-05 PROCÉDÉ DE FABRICATION DE DÉRIVÉ D'ARYLE β－C-GLYCOSIDE WO2020050361A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092877A1 (fr) * 2004-03-16 2005-10-06 Boehringer Ingelheim International Gmbh Derives du benzol substitues par un glucopyranosyle,, medicaments renfermant ces composes, leur utilisation et leur procede de production
JP2007518683A (ja) * 2003-08-01 2007-07-12 田辺製薬株式会社 新規化合物
JP2008508213A (ja) * 2004-07-27 2008-03-21 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｄ−グルコピラノシル−フェニル置換環状体、そのような化合物を含有する医薬品、それらの使用及びその製造方法
JP2012505858A (ja) * 2008-10-17 2012-03-08 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Ｓｇｌｔの阻害物質として有用な化合物の調製方法
WO2017064679A1 (fr) * 2015-10-15 2017-04-20 Lupin Limited Procédé destiné à la préparation de canagliflozine amorphe

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007518683A (ja) * 2003-08-01 2007-07-12 田辺製薬株式会社 新規化合物
WO2005092877A1 (fr) * 2004-03-16 2005-10-06 Boehringer Ingelheim International Gmbh Derives du benzol substitues par un glucopyranosyle,, medicaments renfermant ces composes, leur utilisation et leur procede de production
JP2008508213A (ja) * 2004-07-27 2008-03-21 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｄ−グルコピラノシル−フェニル置換環状体、そのような化合物を含有する医薬品、それらの使用及びその製造方法
JP2012505858A (ja) * 2008-10-17 2012-03-08 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Ｓｇｌｔの阻害物質として有用な化合物の調製方法
WO2017064679A1 (fr) * 2015-10-15 2017-04-20 Lupin Limited Procédé destiné à la préparation de canagliflozine amorphe

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