Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/20—Carbocyclic rings
  • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
  • C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
• • 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
  • C07D309/04—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H1/00—Processes for the preparation of sugar derivatives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
  • C07H3/02—Monosaccharides

Definitions

• the present invention relates to a method for producing a sugar chain, a building block for sugar chain synthesis, and a compound.
• oligosaccharides In the fields related to dietary supplements (supplements), pharmaceuticals, agricultural chemicals, etc., the functionality of oligosaccharides (saccharides in which 2 to 10 or more monosaccharides are linked by glycoside bonds) has attracted attention.
• oligosaccharides for their intestinal regulating action (intestinal flora improving action), mineral absorption promoting action, pile caries action, antiallergic action and immunostimulating action. Is expected.
• oligosaccharides are expected as the active ingredient itself or the lead compound in the invention.
• oligosaccharides When utilizing oligosaccharides as such functional compounds, it is important to control stereoselectivity in oligosaccharide synthesis, that is, to form a glycoside bond with a desired stereochemistry. If stereoselectivity can be controlled, separation and purification of isomers will be unnecessary or simplified.
• oligosaccharide synthesis methods can be roughly divided into solid phase methods and liquid phase methods.
• the liquid phase methods are easy to scale up and do not need to be cut out from the carrier. There are many industrial advantages such as being present.
• Patent Document 1 Non-Patent Document 1 and Non-Patent Document 2 include a method of electrochemically oxidizing a sugar donor in an electrolytic solution to perform a glycosylation reaction. Manufacturing methods are described. Specifically, how described in these documents, tetrabutylammonium triflate (Snake 1_1 4 1 ⁇ 1_Rei Ding 1:) in the presence of Low temperature electrooxidation of a sugar donor to produce and accumulate glycosyl triflate as a key intermediate in the glycosylation reaction, followed by glycosylation of the intermediate and the sugar acceptor, and glycosylation. Deprotecting the resulting oligosaccharide precursor. Then, it is described that such a method can efficiently produce an oligosaccharide with high stereoselectivity and is also useful for automatic synthesis.
• tetrabutylammonium triflate Snake 1_1 4 1 ⁇ 1_Rei Ding 1:
• Patent Document 1 Japanese Patent Laid-Open No. 201 7 _ 1 65725
• Non-Patent Document 1 Toshiki Nokami, et a 1., Organic Letters, 2015, Vol. 17, No. 6, pp. 1525-1528.
• Non-Patent Document 2 Toshiki Nokami, et a 1., Organic Letters, 2013, Vol. 15, No. 17, pp. 4520-4523
• Patent Document 1 Non-Patent Document 1 and Non-Patent Document 2 improved the yield of stereocontrolled oligosaccharides in the synthesis of oligosaccharides by the liquid phase method. And further improvement of the yield is desired.
• the present invention has been made in view of the above problems, and an object of the present invention is to provide a method for producing a sugar chain having an excellent sterically controlled sugar chain yield.
• the present invention also aims to provide a building block for sugar chain synthesis used in the above production method. Furthermore, the present invention aims to provide novel compounds.
• building block represented by the following formula (1) and the sugar residue derived from the building block represented by the following formula (1) and the sugar residue derived from the building block represented by the following formula (2) Of the building blocks containing at least one building block, building block eight, is subjected to electrolytic oxidation in an aprotic organic solvent containing an electrolyte,
• a building block that is at least one type of building block represented by the following formula (2) and a building block containing a plurality of sugar residues derived from the building block represented by the following formula (2).
• a method for producing a sugar chain which comprises glycosylating Kusumi and an electrolytically oxidized building block 8;
• Eighty- one represents a ring structure having 4 to 8 carbon atoms
• 1 to 25 each independently represent a hydrogen atom or an electron-withdrawing group, and the total value of hammets from 1 to is greater than 0.12.
• the wavy lines each independently represent a bond in an equatorial or axial configuration
• 8 2 represents a ring structure having 4 to 8 carbon atoms
• 26 to 1 ⁇ are each independently a hydrogen atom or an electron-withdrawing group, and 6
• 8 4 represents a hydrogen atom or a monovalent organic group, at least one of the 4 is a hydrogen atom,
• 3 and 4 may be bonded to each other to form a ring, or represent an integer of 0 or more, represents an integer of 1 or more,
• + 9 is less than or equal to the number of carbon atoms in the ring structure
• Each wavy line independently represents a bond in an equatorial or axial configuration.
• Total 2 1 Hame' bets £ 7 value of 5 is not less 0.2 or more, and is the sum of 2 6-Hame' bets £ 7 value of 10 ⁇ . 2 or more,
• Total 2 1 Hame' bets £ 7 value of 5 is 1. 5 or less, and is the sum of Hame' bets £ 7 value of 6-10 1. 5 or less,
• At least one of the 2 1 to 1 ⁇ is a halogen atom
• At least one of 2 1 to 5 is a halogen atom, and at least one of 6 to 10 is a halogen atom,
• one is a halogen atom and the other is a hydrogen atom
• one is a halogen atom and the other is a hydrogen atom
• the halogen atom is at least one of a chlorine atom and a bromine atom, ⁇ 0 2020/175 440 6 ⁇ (: 17 2020 /007365
• the building block represented by the following equation (1 — 2) is used as the building block represented by the equation (1).
• 1 to 25 each independently represent a hydrogen atom or an electron-withdrawing group
• the wavy lines each independently represent a bond in an equatorial or axial configuration.
• 6 ⁇ 1 ⁇ are each independently hydrogen atom or an electron-withdrawing group, 6 More than 1 2
• V represents a monovalent organic group
• r i represents an integer of 0 to 4
• At least one of ( ⁇ ) is a hydroxyl group
• the wavy lines each independently represent a bond in an equatorial or axial configuration.
• At least one of building block 8 and building block M is a disaccharide, and as a result, a polysaccharide of trisaccharide or more is obtained,
• a building block in sugar chain synthesis containing a sugar residue derived from a block Formula (1)
• Eighty- one represents a ring structure having 4 to 8 carbon atoms
• 1 to 25 each independently represent a hydrogen atom or an electron-withdrawing group, and the total value of hammets from 1 to is greater than 0.12.
• n is equal to or less than the carbon number of the ring structure 1 ,
• Each wavy line independently represents a bond in an equatorial or axial configuration.
• 8 2 represents a ring structure having 4 to 8 carbon atoms
• 26 to 1 ⁇ are each independently a hydrogen atom or an electron-withdrawing group, and 6
• 8 4 represents a hydrogen atom or a monovalent organic group, at least one of the 4 is a hydrogen atom,
• 3 and 4 may be bonded to each other to form a ring, or represent an integer of 0 or more, represents an integer of 1 or more,
• + 9 is less than or equal to the number of carbon atoms in the ring structure / ⁇ 2 ,
• Each wavy line independently represents a bond in an equatorial or axial configuration.
• Eighty- one represents a ring structure having 4 to 8 carbon atoms
• 1 to 25 each independently represent a hydrogen atom or an electron-withdrawing group, and the total value of hammets from 1 to is greater than 0.12.
• ⁇ represents an integer of 1 to 10
• 1010 ( ⁇ ) (Where, 1 ⁇ is an integer from 1 to 1 0.)
• Ten (Rei_1 ⁇ 1 2) eight "(where ⁇ represents an integer of from 1 to 1 0, eight 'having a carbon number of 6 ⁇ Represents an aryl group of 10), _ _ _ ⁇ ( ⁇ ) _ 8 "(where, 8 "represents an aryl group having 6 to
• the wavy lines each independently represent a bond in an equatorial or axial configuration
• the bond between 1 and 3 is an equatorial configuration.
• 8 2 represents a ring structure having 4 to 8 carbon atoms
• 6 ⁇ 1 ⁇ are each independently hydrogen atom or an electron-withdrawing group
• !_ 2 represents a single bond or a divalent linking group
• ⁇ represents an integer of 1 to 10
• "" represents an integer of 1 to 5
• 1 ⁇ represents an integer of 1 to 10.
• 3 and 4 may be bonded to each other to form a ring, or represent an integer of 0 or more, represents an integer of 1 or more,
• + 9 is less than or equal to the number of carbon atoms in the ring structure / ⁇ 2 ,
• the wavy lines each independently represent a bond in an equatorial or axial configuration
• the bond between 2 and 3 is an equatorial configuration.
• 1- 3 1 and 1_ 3 2 each independently represent a single bond, a methylene group or an ethylene emissions group,
• Seo 1 and Seo 2 each independently represent an integer of 0 to 2
• 2 1 is each independently an integer of 2 or 3
• Each wavy line independently represents a bond in an equatorial or axial configuration.
• the yield of the sterically controlled sugar chain is improved as compared with the conventional method.
• the manufacturing method of the present invention can be carried out by the building block of the present invention. Further, the compounds of the present invention provide new materials.
• FIG. 1 is a graph showing a part of a synthesis sequence in an example of the present invention.
• a numerical range represented by using a symbol “to” means a range including numerical values described before and after “to” as a lower limit value and an upper limit value, respectively.
• process is not limited to an independent process, and is indistinguishable from other processes as long as the intended action of the process can be achieved. ⁇ 0 2020/175 440 14 ⁇ (: 170? 2020 /007365
• notation that does not indicate substituted or unsubstituted is meant to include not only those having no substituent but also those having a substituent.
• alkyl group when simply described as “alkyl group”, this includes both an alkyl group having no substituent (unsubstituted alkyl group) and an alkyl group having a substituent (substituted alkyl group). Is. In the present invention, it is preferable not to have a substituent unless otherwise specified.
• alkyl group this means that it may be linear or cyclic, and when linear, it may be linear or branched. The same applies to the "alkenyl group", “alkylene group” and "alkenylene group”.
• M is a butyl group, is a phenyl group, IV! 6 is a methyl group, and M 1 is an ethyl group, and 0 or 0.
• Dried is a triflate group
• N is a benzyl group
• 80 is an acetyl group
• 11 1: 11 is a phthaloyl group, Indicates a methoxymethyl group, respectively.
• ⁇ Bok 1 0 denotes the number of carbon atoms in the hydrocarbon chain can take.
• ⁇ Bok 1 0 alkyl group means 1 to 1 ⁇ alkyl group carbon atoms. The same applies to other hydrocarbon groups.
• the method for producing a sugar chain of the present invention is
• building block represented by the following formula (1) and the sugar residue derived from the building block represented by the following formula (1) and the sugar residue derived from the building block represented by the following formula (2) Of the building blocks containing at least one building block, building block VIII, is subjected to electrolytic oxidation in an aprotic organic solvent containing an electrolyte,
• Eighty- one represents a ring structure having 4 to 8 carbon atoms
• 1 to 25 each independently represent a hydrogen atom or an electron-withdrawing group, and the total value of hammets from 1 to is greater than 0.12.
• Each wavy line independently represents a bond in an equatorial or axial configuration.
• a ring atom is not formed and a sulfur atom 3
• a hydrogen atom is bonded to a bond that is not bonded to either of 1 and 1-1.
• 8 2 represents a ring structure having 4 to 8 carbon atoms
• 6 ⁇ 1 ⁇ are each independently hydrogen atom or an electron-withdrawing group, 6 More than 1 2
• !_ 2 represents a single bond or a divalent linking group
• 8 4 represents a hydrogen atom or a monovalent organic group, at least one of the 4 is a hydrogen atom,
• 3 and 4 may be bonded to each other to form a ring, or represent an integer of 0 or more, represents an integer of 1 or more,
• + 9 is less than or equal to the number of carbon atoms in the ring structure / ⁇ 2 ,
• Each wavy line independently represents a bond in an equatorial or axial configuration.
• the bond that is not bound to any of the _ 2 it is assumed that the water atom is bonded.
• the sugar chain according to the present invention can be obtained by glycosylating the building block 8 and the building block according to the present invention.
• the building block is also referred to as “sugar donor” in sugar chain synthesis, and the building block is also referred to as “sugar acceptor” in sugar chain synthesis.
• sucgar chain has a broad meaning with respect to the number of hydroxyl groups. ⁇ 0 2020/175 440 17 ⁇ (: 170? 2020/007365
• “sugar chain” means a chain compound of a sugar containing two or more hydroxyl groups (10!), and a compound that can be a chain compound of such a sugar by deprotection treatment. Is also meant to include. Therefore, the chain compound itself directly obtained by the production method of the present invention may not have a hydroxyl group like the compounds shown below.
• the chain compound having no hydroxyl group is separately subjected to deprotection treatment to be a sugar chain compound containing two or more hydroxyl groups (_ 0 to 1).
• the conditions for the deprotection reaction are appropriately determined depending on the type of protecting group, and known methods can be adopted.
• the presence of a functional group having a stronger electron-withdrawing property in the sulfur atom 3 at the glycoside terminal than in the conventional method allows stereocontrol in the synthesis of oligosaccharides by the liquid phase method as compared with the conventional method.
• the yield of the obtained sugar chain is improved. This is estimated to be as follows.
• the activated glycoside represented by the following reaction formula (31) (eg, glycosyl triflate in reaction formula (31)) is , Is recognized as an important reaction intermediate.
• reaction formula (31) eg, glycosyl triflate in reaction formula (31)
• triflate anion ⁇ 3 3_Rei 3 - in the presence of, if a sugar donor 1 1 at low temperature electrolytic oxidation, first, glycosyl riffs alert is generated and accumulated as an intermediate in the glycosylation reaction.
• the active site (eg, triflate site) of the intermediate reacts with the hydroxyl group of the sugar acceptor 2 I to glycosylate the sugar donor and the sugar acceptor, thereby stereoselectively controlling the sugar chain. 1 is obtained.
• the reaction represented by the reaction formula (31) is also referred to as a main reaction. ⁇ 0 2020/175 440 18 ⁇ (: 17 2020 /007365
• a functional group having a stronger electron-withdrawing property than before is linked to the sulfur atom.
• the electron density of the sulfur atom is relatively reduced, and the reactivity of the sulfur atom is reduced, so that side reactions are suppressed.
• the efficiency of the main reaction is improved, and the yield of sugar chains with high stereoselectivity (that is, a glycosidic bond is formed with a desired stereochemistry) is improved.
• the building block 8 may be a single building block represented by the formula (1), and a sugar residue derived from the building block represented by the formula (1) and a sugar residue derived from the building block represented by the formula (2). It may be a building block containing a group or a mixture thereof. A detailed explanation of the building block represented by equation (2) will be given together with the explanation of the building block.
• the structure of the ring structure is appropriately designed according to the structure of the target sugar chain to be produced, and there is no particular limitation in carrying out the production method of the present invention.
• Environment ⁇ 0 2020/175 440 20 (: 170? 2020 /007365
• the number of carbon atoms in Seizo 1 is preferably 7 or less, and more preferably 6 or less.
• the number of oxygen atoms contained in the ring structure is not particularly limited, but is usually 1.
• Ring eight 1, when using the building blocks (viii) in the sugar chain synthesis is an oxygen atom in the ring structure it is useful that only one.
• the ring structure eight 1, five pyranose ring carbon atoms and one oxygen atom constituting the six-membered ring vertices or a five-membered ring of four carbon atoms and one oxygen radicals as the vertex It is preferable to have a furanose ring constituting Note that the number of carbon atoms in the ring structure 1, means the number of carbon atoms constituting the ring of the ring structure 1.
• the monovalent organic group is not particularly limited as long as the glycosylation reaction is possible.
• the number of constituent atoms of this monovalent organic group is preferably 30 or less, and more preferably 20 or less from the viewpoint of forming a glycosidic bond at a desired specific site in the glycosylation reaction. It is more preferably 15 or less.
• the number of constituent atoms is 30 or less, the glycosylation reaction with the adjacent building block is less likely to be inhibited.
• the number of constituent atoms is preferably 3 or more, more preferably 4 or more, and further preferably 5 or more.
• the number of constituent atoms is 3 or more, it becomes easy to limit the bond form of glycoside bond to / 3 bond. Further, from the viewpoint of forming a glycosidic bond at a desired site, it is preferable that it is bonded to the 02 position adjacent to the anomeric (O 1) position.
• [0036] is, for example, a phthalimide group, an azido group, an amid group, an alkyl group,
• the amide group can have, as a substituent, a linear, branched or cyclic alkyl group or aryl group.
• the alkyl group as a substituent has preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and further preferably 1 to 3 carbon atoms.
• the aryl group as a substituent preferably has 6 to 10 carbon atoms.
• the amide group is, for example, a methyl amide group (acetylamino group), an ethyl amide group, a 1!!-propyl amide group, an isopropyl amide group, -Putylamide group or 1:-Putylamide group, or phenylamide group (benzoylamino group) or naphthylamide group is preferable, and acetylamino group, ethylamide group or benzoylamino group is more preferable. More preferably, it is an acetylamino group or a benzoylamino group.
• the alkyl group may have a linear, branched or cyclic structure, and preferably has 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms,
• the alkyl group is, for example, preferably a methyl group, an ethyl group, a _propyl group, an isopropyl group, a _butyl group or a __butyl group, preferably a methyl group or an ethyl group, and a methyl group. More preferably, it is a group.
• the integers and in these alkyl moieties are each preferably 1 to 6, more preferably 1 to 3, and even more preferably 1 or 2.
• the “integer” is preferably 3 or less, more preferably 2 or less, further preferably 1 or less, and may be 0. That is, this group is (1 ⁇ ⁇ 02020/175440 22 ⁇ (: 170? 2020 /007365
• this group is, for example, a methoxy group, an ethoxy group, an n-propyloxy group, 100 1 to 1 2 0 1 to 1 3 (methoxymethyloxy group), 100 2 1 ⁇ 1 4 ⁇ ⁇ 1 to 1 3 , _ ⁇ ⁇ 1 to 1 2 ⁇ ⁇ 2 1 to 1 5 , 1 ⁇ ⁇ 2 1 to 1 4 ⁇ ⁇ 2 1 to 1 5 , 1 ( ⁇ ⁇ 1 to 1 2 ) preferably 2_Rei_rei_1 ⁇ 1 3 or an (Rei_rei_1 ⁇ 1 2) 2 hundred 2 1 ⁇ 1 5, main butoxy group, an ethoxy group, n - propyl group, main butoxy methyl group, more that one hundred 2 1-1
• the “integer” is preferably 3 or less, more preferably 2 or less, further preferably 1 or less, and may be 0. That is, this group is particularly one of 3 0 3 1 to 1 5 or 1 0 (0 1 to 1 2 )
• this group is preferably, for example, a methylcarbonyloxy group (acetyloxy group), an ethylcarbonyloxy group or a propylpropylcarbonyloxy group, and more preferably an acetyloxy group.
• the number of carbon atoms of these substituents is preferably 1 to 6, more preferably 1 to 3, and even more preferably 1 or 2.
• this substituent is , A methyl group, an ethyl group, a methoxy group or an ethoxy group is preferable, and a methyl group or a methoxy group is more preferable.
• the number of the substituents is preferably 2 or 1.
• the position of the substituent may be any of the ortho (o) position, the meta () position and the para () position, but the para position is preferred.
• It is preferably a diloxy group, and more preferably a -methylbenzyloxy group or a -methoxybenzyloxy group.
• a 0 alkyl group or an alkyloxy group having 1 to 10 carbon atoms is also preferable to have a 0 alkyl group or an alkyloxy group having 1 to 10 carbon atoms as a substituent.
• the carbon number of these substituents is preferably 1 to 6, more preferably 1 to 3, and even more preferably 1 or 2.
• this substituent is preferably a methyl group, an ethyl group, a methoxy group or an ethoxy group, and more preferably a methyl group or a methoxy group.
• the number of substituents is preferably two or one, and more preferably one.
• the position of the substituent may be any of the ortho (o) position, the meta (111) position and the para () position, but the para position is preferable.
• it is a -methylbenzoyloxy group or a -methoxybenzoyloxy group.
• the alkylsiloxy group may be any of a monoalkylsiloxy group, a dialkylsiloxy group and a trialkylsiloxy group, and is preferably a trialkylsiloxy group.
• the alkyl group in the alkylsiloxy group may have a linear, branched or cyclic structure, preferably a linear structure.
• the alkyl group preferably has 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, and further preferably 1 or 2 carbon atoms.
• the alkylsiloxy group is, for example, a trimethylsiloxy group, a dimethylsiloxy group, an ethyldimethylsiloxy group, a triethylsiloxy group, a propyldimethylmethyloxy group or an I-butyldimethylsiloxy group, and a trimethylsiloxy group.
• a xy group is more preferred.
• the organic group of can have a substituent in addition to the substituent described above.
• substituents include a halogen atom, a cyano group, a nitro group, a hydrocarbon group, a heterocyclic group, _ ⁇ [3 ⁇ 4 1: 1 and 100 000 [3 ⁇ 4 1: 1 , _ ⁇ ⁇ [3 ⁇ 4
• [3 ⁇ 4 1: 1 and [3 ⁇ 4 1: 2 each independently represent a hydrogen atom, a hydrocarbon group or a heterocyclic group. These may combine with each other to form a ring.
• examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
• examples of the hydrocarbon group include an alkyl group, an alkenyl group, an alkynyl group, and an aryl group. 1-10 are preferable, as for carbon number of an alkyl group, 1-5 are more preferable, and 1-2 are further more preferable.
• the alkyl group may be linear, branched or cyclic, preferably linear or branched, and more preferably branched.
• the alkenyl group preferably has 2 to 10 carbon atoms, more preferably has 2 to 5 carbon atoms, and particularly preferably has 2 or 3 carbon atoms.
• the alkenyl group may be linear, branched or cyclic, preferably linear or branched.
• the carbon number of the alkynyl group is preferably 2 to 10, more preferably 2 to 5.
• the alkynyl group may be linear or branched, preferably linear or branched.
• the carbon number of the aryl group is preferably from 6 to 10, more preferably from 6 to 8, and even more preferably from 6 to 7.
• the heterocyclic group may be a monocyclic ring or a condensed ring.
• the heterocyclic group is preferably a single ring or a condensed ring having 2 to 4 condensed rings.
• the number of hetero atoms constituting the ring of the heterocyclic group is preferably 1 to 3.
• the hetero atom forming the ring of the heterocyclic group is preferably a nitrogen atom, an oxygen atom or a sulfur atom.
• the number of carbon atoms constituting the ring of the heterocyclic group is preferably 3-10, more preferably 3-8, and even more preferably 3-5.
• the hydrocarbon group and the heterocyclic group may further have a substituent, May be Examples of the substituent here include the above-mentioned substituents.
• R 1 preferably has no substituent, and in particular, phthalimide group, azido group, acetyloxy group, acetamido group, benzyloxy group. , P-methylbenzyloxy group,
• a phthalimide group, an azide group, an acetyloxy group, an acetamido group, a benzyloxy group or a benzoyloxy group is more preferable, and a phthalimide group, an azido group, an acetyloxy group, an acetamide group or More preferably, it is a benzyloxy group.
• m is preferably 1 to 3, more preferably 1 to 2, and even more preferably 1.
• the m R 1 s may independently be the above organic groups, and when m is 2 or more, they may be the same organic group or different organic groups.
• R 2 is preferably a hydroxyl-protecting group, and if it is a compound generally used as a hydroxyl-protecting group of a sugar compound, R 2 can be sufficiently protected in the production method of the present invention
• R 2 is preferably a hydroxyl-protecting group described in, for example, Protect ive Group m Organic Synthesis, Chapter 2, pp. 10-142, Theodora W. Greene and Peter GM Wuts, 2nd ed. .. More specifically, R 2 is, for example, each independently, an alkyl group, 1 [(CH 2 ), 0] ”C k H 2k+1 (where i represents an integer of 1 to 10).
• the alkyl group may have a linear, branched or cyclic structure, and ⁇ 02020/175 440 27 ⁇ (: 170? 2020 /007365
• the number is preferably 1 to 10, more preferably 1 to 6,
• the alkyl group is, for example, preferably a methyl group, an ethyl group, a _propyl group, an isopropyl group, a _butyl group or a __butyl group, preferably a methyl group or an ethyl group, and a methyl group. More preferably, it is a group.
• ” Represents an integer from 0 to 5, ) Is a linear, branched or cyclic alkyl moiety Having a linear, branched or cyclic Al Kill site (Rei_1 ⁇ 1 2)
• the integers and in these alkyl moieties are each preferably 1 to 6, more preferably 1 to 3, and even more preferably 1 or 2.
• the “integer” is preferably 3 or less, more preferably 2 or less, further preferably 1 or less, and may be 0. So this group is (1 ⁇ represents an integer of 1 or 2) or 1 ( ⁇ 1 ⁇ 1 2 ); -00 ⁇ +1 ( ⁇ represents an integer of 1 or 2; Or represents an integer of 2. ) Is especially preferred.
• this group is, for example, a methyl group, an ethyl group, an n-propyl group, _ ⁇ 1 to 1 2 ⁇ 0 1 to 1 3 (methoxymethyl group Ten 2 1 - 1 4 Rei_rei_1 to 1 3, One Rei_1 ⁇ 1 2_Rei_rei 2 1 ⁇ 1 5, ten 2 1 - 1 4 hundred 2 1 ⁇ 1 5, one (Rei_1 ⁇ 1 2 ⁇ ) 2 Rei_1 preferably to 1 3 or a (Rei_1 ⁇ 1 2 ⁇ ) 2_Rei a 2 1 ⁇ 1 5, a methyl group, an ethyl group, ⁇ -propyl group, main bets Kishimechiru group, ten 2 1 ⁇ 1 4 Rei_rei_1 to 1 3, one Rei_1 ⁇ 1 2 hundred 2 1 ⁇ 1 5 or more preferably ten 2 1 - 1 4 hundred 2 1 ⁇ 1 5, a methyl group or main Tokishimechir
• this group is preferably, for example, a methylcarbonyl group (acetyl group), an ethylcarbonyl group, or a _propylpropylcarbonyl group, and more preferably an acetyl group.
• ⁇ 02020/175 440 28 ⁇ (: 170? 2020 /007365
• this group can be linear, alkyl moiety branched or cyclic ( ⁇ 31 ⁇ 1 2)
• the integer number in the alkyl moiety is preferably 1 to 6, more preferably 1 to 3, and further preferably 1 or 2.
• this group is, for example, - ⁇ ⁇ 2 - 9 ⁇ (benzyl group), ten 2 1-1 4 - or ten 3 1-1 6 - Der Rukoto are preferred, with a benzyl group More preferably.
• Preferred content of the preferred substituent is Of ten (Rei_1 to 1 2) Is the same as the case of. Therefore, when having a substituent, one (Rei_1 ⁇ 1 2)
• the alkylsilyl group may be any of a monoalkylsilyl group, a dialkylsilyl group and a trialkylsilyl group, and is a trialkylsilyl group. ⁇ 0 2020/175 440 29 ⁇ (: 170? 2020 /007365
• the alkyl group in the alkylsilyl group can have a linear, branched or cyclic structure, preferably a linear structure.
• the alkyl group preferably has 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, and even more preferably 1 or 2 carbon atoms.
• the alkylsilyl group is, for example, a trimethylsilyl group, a dimethylsilyl group, an ethyldimethylsilyl group, a triethylsilyl group, a propyldimethylsilyl group or a 1:-butyldimethylsilyl group, and more preferably a trimethylsilyl group. I like it.
• [0060] preferably has no substituent from the viewpoint of glycosidic bond formation at a desired site and cost, and in particular, methyl group, ethyl group, acetyl group, trimethylacetyl group, benzyl group, _methylbenzyl group , _Methoxybenzyl group, benzoyl group, _methylbenzoyl group, _methoxybenzoyl group, trimethylsilyl group or I-butyldimethylsilyl group, preferably acetyl group, trimethylacetyl group, acetylamide group, benzyl group Alternatively, it is more preferably a benzoyl group.
• the organic group of 2 may have a substituent other than the above-described substituents, but preferably has no substituent.
• substituents include a halogen atom, a cyano group, a nitro group, a hydrocarbon group, a heterocyclic group, one
• [3 ⁇ 4 1: 1 and [3 ⁇ 4 1: 2 each independently represent a hydrogen atom, a hydrocarbon group or a heterocyclic group.
• I 2 is a hydrocarbon group, they may combine with each other to form a ring.
• Other content is the same as in the case of 8 1 substituent.
• a divalent linking group which may have a substituent straight or branched A alkylene group, an optionally substituted straight or branched alkenylene groups, ten ⁇ 0 2020/175 440 30 ⁇ (: 170? 2020 /007365
• a group composed of the above combination is preferable.
• the substituents are as described above, Is preferably a hydrogen atom.
• the alkylene group which may have a substituent preferably has 1 to 5 carbon atoms, more preferably 1 to 3 carbon atoms, and the alkylene group which may have a substituent is a methylene group or an ethylene group. Is more preferable.
• the alkenylene group which may have a substituent preferably has 2 to 5 carbon atoms, more preferably 2 or 3, and the alkenylene group which may have a substituent may be a vinyl group or a propylene group. More preferably, it is a benyl group. In particular, may have a single bond or a substituent. It is preferably an alkylene group, more preferably a single bond, a methylene group or an ethylene group.
• ⁇ ! + is appropriately set within a range in which it is equal to or less than the carbon number of the ring structure 1 .
• the number of hydroxyl groups in the sugar chain or the sugar chain after the deprotection treatment can be adjusted by the number of The door is preferably an integer from 2 to "the number of carbon atoms in the ring structure is 1", and more preferably 2 or 3.
• n It can independently be the above organic group, and when n is 2 or more, it may be the same organic group or different organic groups.
• a methylene group or an ethylene group having no substituent is preferable.
• eight 1 is a furanose ring, Are each independently a phthalimide group, an azido group, an acetyloxy group, an acetamido group, a benzyloxy group, a benzoyloxy group, which does not have a substituent, But independently, no substituent, a methyl group, an acetyl group, a benzyl group, a benzoyl group, 1_ 1 are each independently a methylene group having no single bond or a substituent.
• 1 to 25 are each independently a hydrogen atom or an electron-withdrawing group, and the sum of £7 values of the Hammets of 1 to 5 is more than 0.12.
• the wavy lines each independently represent a bond in an equatorial or axial configuration.
• the molecular weight of the building block represented by Formula (1) or Formula (1-2) is preferably 350 to 900, more preferably 400 to 800, and 450 to 750. More preferably, 500 to 700 is particularly preferable.
• sulfur atom 3 may be bonded to the site of the ring structure eight 1 throat, is preferably bonded to the carbon in contact next to an oxygen atom (so-called anomeric position). Also, the sulfur atom, to the ring structure eight 1 may be in either configuration of equatorial and axial, and more preferably equatorial arrangement
• the type and number of electron-withdrawing groups in 1 to 5 are not particularly limited as long as the sum of the values of each Hammet is more than 0.12.
• an “electron-withdrawing group” is a substituent having a positive Hammett substituent constant at each of the ortho, meta and para positions on the phenyl group with respect to the X atom.
• the Hammett “£7 value” means the Hammett substituent constant of £7.
• the Hammett's substituent constant of £7 is based on the dissociation reaction of benzoic acid and its derivatives in an aqueous solution at 25°.
• a negative Hammett substituent constant of £7 indicates that the substituent has an electron-donating property.
• the £7 values for the meta and para positions are 6111. 1991, ⁇ 91, ⁇ . 165-195, and the values described in this document are searched for. On the other hand, for substituents whose value is unknown, the value can be calculated by the method described in the above literature.
• the £7 value for the para position is generally similar to the £7 value for the para position, so the £7 value for the para position is used instead.
• the electron-withdrawing group is, for example, preferably at least one of a halogen atom, a nitro group, a cyano group, an azido group, a halogenated alkyl group and an acyl group, and is at least one of halogen atoms. More preferably, it is at least one of a chlorine atom and a bromine atom.
• Total Hame' Doo value between 5 ⁇ . 1 is preferably 5 or more, ⁇ . More preferably 2 or more, ⁇ . It is further favorable preferable is 2 2 or more.
• Preferred specific examples of the building block represented by the formula (1) are as follows.
• "3 3” represents a partial structure (including a sulfur atom) of the ring structure 81 in the formula (1)
• “3 ⁇ ” represents a partial structure on the phenyl group side in the formula (1) ( It does not contain a sulfur atom.)
• the symbols described in the column of “33” represent the respective symbols of the specific examples shown as the ring structure 1 and the preferred embodiments around it, and the symbols described in the column of “313” are 1 to 5
• the respective symbols of the specific examples shown as preferable combinations of are shown below.
• Each of the compounds in the table has a structure in which the partial structure described in the “3 3” column and the partial structure described in the “3 1 ⁇ ” column are bonded at the asterisk “” part.
• the building block 8 is a building block containing a sugar residue derived from the building block represented by formula (1) and a sugar residue derived from the building block represented by formula (2)
• a building block 8 can be obtained, for example, by glycosylating the building block represented by the formula (1) and the building block represented by the formula (2).
• building blocks of trisaccharides and tetrasaccharides can be prepared by performing such glycosylation multiple times.
• the linkage of sugar chains is It may be a bond (a bond in which the sulfur atom is in the equatorial configuration), or a ⁇ bond (a bond in which the sulfur atom is in the axial configuration), ⁇ 1 — 0 3 bond, 0 1 — 0 4 bond, 0 1 — 0 5 bond and Any of 0 1 — 0 6 bonds is acceptable.
• Preferred embodiments of the sugar residue derived from the building block represented by the formula (1) are, for example, as follows.
• a preferred specific example of the building block in which building block 8 contains a sugar residue derived from the building block represented by formula (1) and a sugar residue derived from the building block represented by formula (2) Is as follows.
• "3 NOTE” is table sugar residues from building blocks of the formula (1), "3 9", a sugar residue from building blocks of the formula (2)
• Represent The abbreviations described in the column “3 Ji” indicates the symbols of the specific example shown a preferred embodiment of the sugar residues from Birudin Guburokku of the formula (1), in the column of "3 9”
• the symbols described are the symbols of the specific examples described separately below as preferred embodiments of the sugar residue derived from the building block represented by the formula (2).
• Each of the compounds in the table has a partial structure described in the “3” column, a partial structure described in the “3 9” column, a sulfur atom (_ 3 _*), and a 3 1 ⁇ column.
• Partial structure ⁇ 0 2020/175 440 40 ⁇ (: 170? 2020 /007365
• the structure has a structure "3 to 1 3 9 — 3 — 3 13" that is connected in turn at the asterisk “e”. Between the partial structure described partial structure and "3 spoon” column in the "3 9” column, as described above, and a complement to a sulfur atom.
• the building block wall may be a single building block represented by formula (2), a building block containing a plurality of sugar residues derived from the building block represented by formula (2), or a mixture thereof.
• configuration of the ring structure eight 2 is appropriately designed in accordance with the configuration of the object of the carbohydrate to produce, in practicing the production method of the present invention, no particular restriction.
• the number of carbon atoms of the ring structure eight 2 is preferably 7 or less, more preferably 6 or less.
• the number of oxygen atoms contained in the ring structure is not particularly limited. It is preferable that only one oxygen atom is contained in the apex.
• the oxygen atom in the ring structure it is useful that only one, constitutes a six-membered ring with five carbon atoms and one oxygen atom as the vertex It is preferable to have a pyranose ring or a furanose ring having a five-membered ring with four carbon atoms and one oxygen atom as vertices.
• the monovalent organic group has the formula Similarly to, there is no particular limitation as long as the glycosylation reaction is possible.
• the number of constituent atoms of the monovalent organic group is preferably 30 or less, more preferably 20 or less, from the viewpoint of forming a glycosidic bond at a desired site in the glycosylation reaction. It is more preferably 15 or less. When the number of constituent atoms is 30 or less, it is difficult to inhibit the glycosylation reaction with the adjacent building block. From the viewpoint of forming a glycosidic bond at a desired site, the number of constituent atoms is preferably 3 or more, more preferably 4 or more, and further preferably 5 or more. The fact that the number of constituent atoms is 3 or more facilitates limiting the bond form of the glycosidic bond to the /3 bond.
• Alkyloxy "group (11 is an integer of 1-5.) ⁇ WINCH 1 0 Al kill carbonyl group, 0 WINCH] - For alkylcarbonyloxy group, ⁇ WINCH 1 0 alkylamine Mi de group or bird It is preferably an alkylsiloxy group.
• the organic group may have a substituent, and specific embodiments include formula (1) From the viewpoint of forming a glycosidic bond at a desired site, it is preferable that it has no substituents, and in particular, an unsubstituted phthalimide group, an azido group, an acetyloxy group, an acetamido group, a benzyloxy group, a benzoyloxy group.
• Zoyloxy group is more preferable, and unsubstituted phthalimide group, azido group, acetyloxy group, acetamide group or benzyloxy group is further preferable.
• hydroxyl-protecting group is not particularly limited as long as it is a group generally used as a hydroxyl-protecting group for sugar compounds.
• the number of hydrogen atoms therein is preferably 3 or less, more preferably 2 or less, and further preferably 1 from the viewpoint of glycosidic bond formation at a desired site. ..
• the compound does not have a substituent, and in particular, a methyl group, an ethyl group, an acetyl group, a trimethylacetyl group, a benzyl group (eg, -methoxybenzyl group, _methyl Benzyl group), benzoyl group, trimethylsilyl group or I-butyldimethylsilyl group, and more preferably acetyl group, trimethylacetyl group, acetylamide group, benzyl group or benzoyl group.
• a substituent e.g, a methyl group, an ethyl group, an acetyl group, a trimethylacetyl group, a benzyl group (eg, -methoxybenzyl group, _methyl Benzyl group), benzoyl group, trimethylsilyl group or I-butyldimethylsilyl group, and more preferably acetyl group, trimethylace
• the alkylene group which may have a substituent preferably has 1 to 3 carbon atoms, and the alkylene group which may have a substituent is more preferably a methylene group or an ethylene group.
• the substituents are as described above.
• 2 is preferably a single bond or an alkylen group which may have a substituent, and more preferably a single bond, a methylene group or an ethylene group.
• [0097] is appropriately set in the range where + is equal to or less than the carbon number of the ring structure 2 .
• the number of hydroxyl groups in the sugar chain or the sugar chain after the deprotection treatment can be adjusted by the number of It is good Mashiku an integer from 2 to "ring eight second number one 2 carbon atoms", more preferably 2 or 3. [3 ⁇ 4 4 ⁇ _ 1_ 2 pieces, it it independently can become the organic group, if but is 2 or more, may be made in the organic group of the same kind, is an organic group different Good.
• 6 ⁇ 1 ⁇ are each independently hydrogen atom or an electron-withdrawing group, 6 More than 1 2
• V represents a monovalent organic group
• [3 ⁇ 4 7 and [3 ⁇ 4 8 may be bonded to each other to form a ring, and r represents an integer of 0 to 4,
• At least one of ( ⁇ ) is a hydroxyl group
• the wavy lines each independently represent a bond in an equatorial or axial configuration.
• the molecular weight of the building block represented by formula (2) or formula (2-2) is preferably 200 to 600, more preferably 250 to 550, and more preferably 300 to 500. More preferable.
• Equation (2) ring structures eight 2 and preferred embodiments of its surroundings, for example, far-Ride follows.
• sulfur atom may be bonded to the site of the ring structure eight 2 throat, it is preferably bonded to a carbon (so-called anomeric position) adjacent to an oxygen atom. Further, sulfur atom, to the ring structure eight 2 may be in either configuration of equatorial and axial, and more preferably equatorial configuration.
• the type and number of the electron-withdrawing groups in 2 6 to 1 ° are not particularly limited as long as the sum of the 7 values of Hammet is more than 0.1 12.
• the total value of Hammett is calculated by the same method as in the case of 1 to 5 in Equation (1).
• the combination of formula (1)'to 7 ⁇ and the combination of 6 to 10 of formula (2) may be the same or different.
• the sum of the Hammett values of 2 6 to 10 is preferably not less than 0.15.
• the total of this £7 value is preferably 2 or less.
• the sum of the £7 values is 2 or less, activation of the sugar donor (formation of a reaction intermediate) is facilitated in the electrolytic oxidation step.
• the total of the £7 values is more preferably 1.5 or less, and further preferably 1.0 or less.
• Formula (1) 6 in equation (2) It may be the same or different.
• Preferred combinations of 6 to 1 ° are the same as the combinations exemplified for, for example, ⁇ 5 .
• at least one of the 2 1 to 1 ⁇ is a halogen atom.
• at least one of ⁇ 5 is a halogen atom and at least one of 6 ⁇ 10 is a halogen atom.
• 2020/007365 is preferable, for example, of 1 to 25 , two are halogen atoms and the other are hydrogen atoms, and of 2 6 to 1 ⁇ , An embodiment in which two are halogen atoms and the other are hydrogen atoms, or One embodiment is conceivable in which one is a halogen atom, the other is a hydrogen atom, and one of 26 to 1 ° is a halogen atom and the other is a hydrogen atom.
• Preferred specific examples of the building block represented by the formula (2) are as follows.
• "3_Rei” represents a ring structure eight 2 side of the partial structures in formula (2) (including the sulfur atom.).
• Symbols according to the column indicates the specific example shown as ring structures eight 2 and preferred aspects of the surrounding.
• "3 ⁇ ” represents a partial structure on the side of a phenyl group (containing no sulfur atom) as in the case of the formula (1).
• Each of the compounds in the table has a structure in which the partial structure described in the “30” column and the partial structure described in the “3” column are bonded at the asterisk “e” part.
• the building block structure is a building block containing a plurality of sugar residues derived from the building block represented by formula (2)
• a building block can be obtained, for example, by glycosylating the building blocks represented by the formula (2).
• building blocks of trisaccharides and tetrasaccharides can be prepared by performing such glycosylation multiple times.
• such a building block can also be prepared by partially deprotecting the sugar chain generated as the building block 8.
• the linkage of sugar chains is It may be a bond, a ⁇ bond, or a 01-01 bond, a 01-04 bond, a 01-05 bond, and a 0 1 _ 0 6 bond.
• Preferred embodiments of the sugar residue derived from the building block represented by the formula (2) are, for example, as follows. ⁇ 0 2020/175 440 50 ⁇ (: 17 2020 /007365
• Preferred specific examples of the building block in which the building block contains a plurality of sugar residues derived from the building block represented by the formula (2) are as follows.
• "3 9 1 " represents the first sugar residue derived from the building block represented by formula (2)
• "3 9 2 " represents the building block represented by formula (2).
• the symbols described in the columns of "3 9 1 " and “3 9 2 " represent specific examples shown as a preferred embodiment of the sugar residue group derived from the building block represented by the formula (2).
• the compounds in the table are ⁇ 0 2020/175 440 51 ⁇ (: 170? 2020 /007365
• Partial structure in column 3 9 1 and partial structure in column 3 9 2 and sulfur atom And the partial structure described in the "3 ⁇ " column are sequentially combined in the asterisk "*" part Have. Note that in the partial structure described in "3 column 9, replacing the asterisk hydrogen atoms not involved in binding, between a part component structure according to substructure and" 3 "column in the" 3 9 2 "column Shall supplement the sulfur atom as described above.
• the electrolyte used in the production method of the present invention is not particularly limited as long as the building block 8 can be activated as a reaction intermediate, but is not limited to sulfur-based anions (means anions containing a sulfur atom. The same applies hereinafter), phosphorus It is preferable that the electrolyte contains at least one of a system anion, a boron-based anion, and a chlorine oxide-based anion, and it is more preferable that the electrolyte contains a sulfur-based anion or a chloride-based anion. It is more preferable that the electrolyte contains an electrolyte.
• Sulfur-based anions include, for example, sulphate-based anions (3 0 4 -: X is any group), sulfonate-based anions ( 3 0 3 _) and fluorosulfonic acid-based anions (fluorine-containing sulfur oxide anions). Nion) etc.
• Phosphorus-based anion for example, phosphate based anionic (say yes ⁇ 4 _), Hosuhona _ Bok based anionic (say yes ⁇ 3 _), the Hosufina _ Bok system A anions (say yes ⁇ 2 _) and fluoro phosphate anions (fluorine Anions of the phosphorus oxide contained).
• the boron-based anions are, for example, boric acid-based anions ( ⁇ 3 _), boronic acid-based anions ( ⁇ 2 _), and fluorofuroic acid-based anions (fluorine-containing boron oxide anions). ..
• chlorinated anions include perchlorate anion (perchlorate anion) ( ⁇ I 0 4 _), chlorate anion ( ⁇ I 0 3 -), and chlorite anion ( ⁇ ⁇ ⁇ 2 -). ) Etc.
• electrolyte When the above-mentioned electrolyte is an electrolyte containing a sulfur-based anion or a phosphorus-based anion, these anions represent an alkyl group (straight chain, branched or cyclic structure bonded to a sulfur atom or a phosphorus atom). ), an aryl group, a fluorine atom or a chlorine atom is preferable, and a linear or branched alkyl group or a fluorine atom bonded to a sulfur atom or a phosphorus atom is more preferable. It is also preferable that the alkyl group is fluorinated.
• the carbon number of the alkyl group is preferably 1 to 6, more preferably 1 to 4, and even more preferably 1 or 2.
• the electrolyte contains an anion represented by the following formula (M1). ⁇ 02020/175 440 54 ⁇ (: 170? 2020 /007365
• X I represents a fluorine atom, a chlorine atom or a linear or branched alkyl group, and is preferably a fluorine atom or a linear or branched fluorinated alkyl group.
• the alkyl group has preferably 1 to 4 carbon atoms, more preferably 1 or 2, and even more preferably 1.
• the fluorinated alkyl group is a perfluoroalkyl group. It is preferable to be.
• X 1 is more preferably a fluorine atom or a straight-chain and C 1-4 perfluoroalkyl group, further preferably a fluorine atom or a trifluoromethyl group, and a trifluoromethyl group. Is particularly preferable.
• the anion represented by the formula (M1) is, specifically, a triflate anion ( ⁇ 3 3 0 3 _), a fluorosulfonate anion ( 3 0 3 _) and a nonaflatate anion ( ⁇ 4 93 0 3 _) and the like, preferably a triflate anion or a fluorosulfonate anion, and more preferably a triflate anion.
• the electrolyte used in the production method of the present invention may contain cations such as ammonium series, imidazolium series, pyridinium series, and phosphonium series cations, and may contain ammonium series or phosphonium series cations. It is particularly preferable to contain a quaternary ammonium-based or quaternary phosphonium-based cation represented by the following formula (M2).
• X 2 is a nitrogen atom or a phosphorus atom, and is a nitrogen atom. ⁇ 0 2020/175 440 55 ⁇ (: 170? 2020 /007365
• Min is 0. Hydrocarbon group or ⁇ 3! .. Is preferably a perfluorohydrocarbon group.
• the alkyl group is preferably a linear or branched alkyl group, and the alkyl group has preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and 1 to 6 carbon atoms. More preferably, it is 4.
• independent alkyl chain means an individual alkyl chain separated by an oxygen atom, and, for example, in the case of “ ⁇ 1 to 1 3 ⁇ 0 1 to 1 2 ”, The number of alkyl chains formed is 2. The number of independent alkyl chains is preferably from 1 to 10, 2 to
• the number of carbon atoms in each alkyl chain is preferably 1-5, more preferably 2 or 3. It is also preferably a perfluorinated group of the above hydrocarbon group or a polyalkylene glycol group having a repeating number of 2 or more.
• [0127] is specifically a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a cyclohexyl group, a methoxymethyl group, a 2-methoxyethoxymethyl group or a nonafluoroputyl group. Is preferred, and a butyl group is more preferred.
• cation represented by formula (Snake 2) specifically, tetramethylammonium Mukachion ((Rei_1 ⁇ 1 3) 4 +), tetrabutylammonium cation (( ⁇ 4 1 - 1 9) 4 +), dimethyl (dimethoxymethyl) ammonium cation (( ⁇ 1 ⁇ 1 3) 2 ( ⁇ 1 ⁇ 1 3 ⁇ ⁇ 1 ⁇ 1 2 ) 2 +), tetramethylphosphonium cation (( ⁇ 1 ⁇ 13) 4 + ), tetrabutylphosphonium cation (( ⁇ 4 1-1 9) 4 +), Oyo ⁇ 0 2020/175 440 56 ⁇ (: 170? 2020 /007365
• a tetraphenylphosphonium cation (114 4 +) and the like preferably a tetramethylammonium cation or a tetrabutylammonium cation, and particularly preferably a tetrabutylammonium cation.
• the electrolyte used in the production method of the present invention preferably contains the above-mentioned anion and the above-mentioned cation, which are each exemplified as a preferable embodiment.
• Preferred combinations of the above anions and cations are, for example, combinations of triflate anions and tetrabutylammonium cations, combinations of fluorosulfonate anions and tetrabutylammonium cations, and combinations of perchlorate anions and tetrabutylammonium cations.
• a combination of the triflate anion and the tetrabutylammonium cation is preferred.
• the above electrolytes may contain anions singly or in combination of two or more, and may also contain cations singly or in combination of two or more.
• the molar ratio of the sugar acceptor to the sugar donor is
• the molar ratio of the electrolyte to the sugar donor, which is administered to the reaction solution at the time of production is preferably in the range of...! 1 to 10, more preferably 2 to 5.
• An aprotic organic solvent is not particularly limited as long as it is an organic solvent that does not easily donate a proton (! !+) and can dissolve the electrolyte, but it is not limited to hydroxyl groups (10 to 1), amino 1 1 ⁇ 1 1 ⁇
• the aprotic organic solvent may be a non-polar solvent having a relatively small polarity or a polar solvent having a relatively large polarity.
• nonpolar solvents examples include hydrocarbons such as hexane, benzene, and toluene, ethers having a highly symmetrical structure (eg, diethyl ether having a point symmetric structure, etc.). ), chloroform and chloride ⁇ 0 2020/175 440 57 ⁇ (: 170? 2020 /007365
• Methylene or the like can be used.
• polar solvents include acetone, 1 ⁇ 1-methylpyrrolidone, ethyl acetate, acetonitrile, ethers other than the above (eg, tetrahydrofuran, etc.), dimethyl sulfoxide (mouth IV! Dimethylformamide (mouth 1 ⁇ /1) etc. can be used.
• the aprotic organic solvent preferably contains at least one of hexane, benzene, toluene, methylene chloride and acetonitrile, more preferably methylene chloride.
• the aprotic organic solvent may be used alone or in combination of two or more.
• the aprotic organic solvent may contain a solvent other than the aprotic organic solvent for the purpose of, for example, adjusting the current density at 1 to 1 of the reaction solution or the electrolytic oxidation.
• a solvent include a protic organic solvent.
• the protic organic solvent alcohol and ditromethane can be used, and alcohol is preferably used.
• the alcohol is preferably at least one of hexafluoroisopropanol and trifluoroethanol.
• the content of the solvent other than the aprotic organic solvent is preferably 0 to 50% by mass, more preferably 0 to 30% by mass, and 0 to 10% by mass with respect to the total amount of the solvent. It is more preferable that there is.
• the process of performing electrolytic oxidation and glycosylation is performed by energizing the building block 8 and the composition containing the electrolytic solution and the aprotic organic solvent (hereinafter also referred to as the “reaction solution”) 3.
• a sequence including the step of adding a composition containing a protic organic solvent (hereinafter also referred to as “addition liquid”) and the step of promoting glycosylation of these building blocks, and the sequence including these three steps By performing this as a cycle multiple times, the sugar chain can be scaled up.
• the number of repetitions of the cycle sequence is not particularly limited and may be appropriately determined according to the length of the target sugar chain.
• the type of the building block to be added may be changed.
• the kind of the protective group for the hydroxyl group can be changed, and the carbon position to which the hydroxyl group is bound can be changed. Changing the carbon position to which the hydroxyl group is attached is useful when it is desired to change the attachment method in the middle of the sugar chain.
• the usefulness of the production method of the present invention in which the yield of sugar chains is improved is remarkably exhibited when the sugar chains are extended, and even when a polysaccharide of 3 or more sugars is obtained as a product, it is still more useful than before. And a remarkably excellent yield can be secured.
• the number of sugar residues constituting the target sugar chain is not particularly limited because a simple operation of repeating a cycle sequence is required when extending the sugar chain.
• the number of sugar residues constituting the sugar chain is preferably 10 or less, more preferably 8 or less, and more preferably 6 or less. More preferably, and particularly preferably 5 or less.
• these steps may be carried out so as to be separated temporally, or may be carried out so as to partially overlap.
• the building block wall may be added while the reaction liquid is energized, or the temperature may be raised while adding the building block wall. From the viewpoint of improving the yield, it is preferable to perform these steps separately in time.
• the sugar donor building block VIII is activated by electrolytic oxidation, and a reaction intermediate is produced and accumulated.
• the energization strength is not particularly limited, but is preferably about 1 to 10018, more preferably 2 to 20018, and further preferably 4 to 128.
• the amount of electricity is appropriately determined according to the number of moles of the raw material, the oxidation potential, etc., but the lower limit is generally ⁇ .
• the temperature of the reaction liquid at the time of energization is preferably not more than 150 ° ⁇ , more preferably not more than 160 ° ⁇ , and even more preferably _ 70 ° ⁇ or less. ..
• the lower limit of this temperature is preferably, for example, 100°C or more, and may be 100°C or more. ⁇ 0 2020/175 440 59 ⁇ (: 170? 2020 /007365
• the building block which is a sugar acceptor, is added to the reaction solution.
• the concentration of building block in the reaction solution is 0.01 to 2.0.
• the addition rate of the addition liquid is, for example, preferably ⁇ .1 to 2.0 ⁇ 1 1_ /
• organic solvent an aprotic organic solvent that can be used in the reaction liquid can be used, and it is preferable that it is the same as the solvent actually used in the reaction liquid.
• the active site of the building block 8 activated by electrolytic oxidation and the hydroxyl group of the building block react to react with each other.
• the temperature at which the reaction solution is maintained at a high temperature is preferably, for example, 10 to 140 ° C, and more preferably 16.5 to 1450 ° .
• the rate of temperature rise and temperature decrease is not particularly limited, but is preferably 0.5 to 5 ° ⁇ / ⁇ 1 n, 1 to 3° ⁇ / ⁇ 1 n Is more preferable.
• the glycosylation reaction is carried out electrochemically, so that the safety at the time of operation is ensured, and there is almost no generation of hazardous waste such as metal oxidant residue.
• Safety ⁇ Environmentally preferable method.
• the production method of the present invention is an advantageous method in terms of cost, which is regarded as important as an industrial production method.
• the production method of the present invention is optimal for stereoselective one-pot synthesis of sugar chains using a liquid-phase electrolysis automatic synthesis system. It should be noted that it does not prevent manual execution of some steps such as isolation and purification of the product at each step in the sugar chain elongation. In addition, it is possible to manually execute all steps in sugar chain synthesis.
• a building block 8 Before carrying out sugar chain synthesis using the liquid-phase electrolysis automatic synthesis system, a building block 8, a composition containing an electrolytic solution and an aprotic organic solvent, and a building block are prepared in advance. ⁇ 0 2020/175 440 60 ⁇ (: 17 2020 /007365
• the first compound of the present invention is a compound represented by the following formula (3).
• Eighty- one represents a ring structure having 4 to 8 carbon atoms
• 1 to 25 are each independently a hydrogen atom or an electron-withdrawing group, and the sum of £7 values of the Hammets of 1 to 5 is more than 0.12.
• the wavy lines each independently represent a bond in an equatorial or axial configuration
• Coupling between eight 1 and sulfur atoms are equatorial configuration.
• the second compound of the present invention is a compound represented by the following formula (4).
• 8 2 represents a ring structure having 4 to 8 carbon atoms
• 6 ⁇ 1 ⁇ are each independently hydrogen atom or an electron-withdrawing group, 6 More than 1 2
• !_ 2 represents a single bond or a divalent linking group
• 3 and 4 may be bonded to each other to form a ring, or represent an integer of 0 or more, represents an integer of 1 or more, ⁇ 0 2020/175 440 62 ⁇ (: 170? 2020 /007365
• the wavy lines each independently represent a bond in an equatorial or axial configuration
• Coupling between eight 2 and sulfur atoms are equatorial configuration.
• the oxygen atom in the ring structure is only one
• For, for the preferred condition like is the same as 1 in formula (1). It preferably has no substituents, and in particular, a phthalimide group, an azido group, an acetyloxy group, an acetamide group, a benzyloxy group, a benzoyloxy group, a methoxy group, an ethoxy group, a methoxymethyloxy group or It is preferably a trimethylsiloxy group.
• [0146] 1 is a single bond or may have a substituent. It is preferably an alkylene group, and more preferably a single bond, a methylene group or an ethylene group. It is preferably 1 to 3, more preferably 1 to 2, and still more preferably 1. Each of which can be independently the above organic group, When is 2 or more, they may be the same kind of organic groups or different kinds of organic groups. In Equation (1) In the same manner as above, it is preferable that they have no substituents, especially methyl group, ethyl group, acetyl group, trimethylacetyl group, benzyl group (eg, _methoxybenzil group, _methylbenzyl group), benzoyl group, trimethylsilyl group.
• n is preferably an integer from 2 to “the number of carbon atoms in the ring structure 81 is 1 2 ”, and more preferably 2 or 3.
• a preferable combination of 1 to 5 is, for example, as in 21 to 5 in the formula (1),
• a preferable specific example of the building block represented by the formula (3) is also a preferable specific example of the building block represented by the formula (1) (compound 1 ⁇ ! ⁇ . ⁇ 3- 1 to ⁇ 3-80) And is shown in the table above.
• the oxygen atom in the ring structure is only one,
• For, for the preferred condition like is the same as 1 in formula (1). It preferably has no substituents, and in particular, a phthalimide group, an azido group, an acetyloxy group, an acetamide group, a benzyloxy group, a benzoyloxy group, a methoxy group, an ethoxy group, a methoxymethyloxy group or It is preferably a trimethylsiloxy group.
• !_ 2 may have a single bond or a substituent. It is preferably an alkylene group, and more preferably a single bond, a methylene group or an ethylene group. Is preferably 1 to 3, more preferably 1 to 2, and even more preferably 1. Each of them can independently be the above organic group, and when is 2 or more, they may be the same kind of organic groups or different kinds of organic groups.
• Equation (1) it is preferable that they have no substituents, especially methyl group, ethyl group, acetyl group, trimethylacetyl group, benzyl group (eg, _methoxybenzil group, _methylbenzyl group), benzoyl group, trimethylsilyl group. It is preferably a group or a 1:-butyldimethylsilyl group. 9 is preferably from 2 an integer from "ring structure eight 2 carbon atoms one 2", 2, or 3 Dearuko and is more preferable. Number of [3 ⁇ 4 4 ⁇ _! _ 2, each independently can be the above-mentioned organic group, in the case but is 2 or more, may be made in the organic group of the same type, different ⁇ 02020/175 440 64 ⁇ (: 170? 2020 /007365
• 1 ⁇ preferred combination is, for example, in the same manner as 2 1-5 in the formula (1),
• a preferable specific example of the building block represented by the formula (4) is also a preferable specific example of the building block represented by the formula (2) (Compound 1 ⁇ ! ⁇ . ⁇ 1 ⁇ -1 to ⁇ 13-80 ) And is shown in the table above.
• the third compound of the present invention is a compound represented by the following formula (5).
• 1_ 31 and 1_ 32 each independently represent a single bond, a methylene group or an ethylene emissions group
• Seo 1 and Seo 2 each independently represent an integer of 0 to 2
• 2 1 is each independently an integer of 2 or 3
• Each wavy line independently represents a bond in an equatorial or axial configuration.
• the third compound of the present invention can be produced by subjecting the first compound of the present invention and the second compound to a glycoside reaction.
• the father can adjust by increasing or decreasing the number of glycosylation of the building block, as described above.
• X is generally ⁇ to 10 and can be set to ⁇ to 7, and the lower limit can be 1 or more or 2 or more, and the upper limit is 5 or less, 4 or less. It can be less than or equal to 3 or less.
• the compound does not have a substituent, and in particular, a phthalimide group, an azido group, an acetyloxy group, an acetamide group, a benzyloxy group, a benzoyloxy group, It is preferably a methoxy group, an ethoxy group, a methoxymethyloxy group or a trimethylsiloxy group.
• V 1 and V 2 is preferably 1 to 3, more preferably 1 to 2, and even more preferably 1.
• 0, like the like 2 in the formula (1) preferably does not have a substituent, in particular, a methyl group, an ethyl group, an acetyl group, trimethylacetyl group, benzyl Le group (e.g., _ main Tokishibenjiru group, _ Methylbenzyl group), benzoyl group, trimethylsilyl group or I-butyldimethylsilyl group.
• 1 is preferably an integer up to 2 or 3, and more preferably 2.
• 2 is preferably an integer of 2 to 4,
• 1_3 1 can independently be the above organic groups, and when each of 1 and 2 is 2 or more, it may be the same organic group or different organic groups. May be.
• the bond between the sulfur atom and the carbon atom preferably has an equatorial configuration. ⁇ 0 2020/175 440 66 ⁇ (: 170? 2020 /007365
• the first compound of the present invention is a thioglycoside having a bond of "carbon 1-sulfur at position 1", for example, a monosaccharide having a desired ring structure such as glucose and a thiophenol having a desired phenyl group. It can be synthesized by reacting the thiol group with the 1st carbon of the monosaccharide.
• a monosaccharide and thiophenol are not particularly limited as long as they are compounds each having a desired ring structure and a desired phenyl group, and commercially available compounds can be used as such monosaccharide and thiophenol, respectively.
• the reaction between the monosaccharide and thiophenol is preferably carried out after protecting the hydroxyl group of the monosaccharide with a protective group such as an acetyl group.
• a protective group such as an acetyl group.
• a commercially available monosaccharide in which a hydroxyl group is protected in advance eg, penta_ ⁇ -acetyl-/3-0-glucopyranose, manufactured by Tokyo Chemical Industry Co., Ltd.
• the specific method for reacting the monosaccharide with thiophenol is not particularly limited and is appropriately selected from known methods.
• a method for example, there is a method of reacting a monosaccharide and thiophenol in the presence of a fluoric acid such as a trifluoroborane ether complex in an aprotic organic solvent.
• a fluoric acid such as a trifluoroborane ether complex
• the temperature at the time of this reaction is not particularly limited, but is preferably set to, for example, 0 to 50 degrees.
• the method for separating the thus obtained monosaccharide ⁇ body (where the sulfur atom is in the axial configuration) and /3 body (where the sulfur atom is in the equatorial configuration) is not particularly limited, and is well-known. The method is selected appropriately.
• the second compound of the present invention can be obtained by using the above-mentioned first compound of the present invention as a starting material and deprotecting all or some of the hydroxyl groups.
• the method for protecting the hydroxyl group and the method for deprotecting the hydroxyl group are not particularly limited, and include dehydration condensation reaction, hydrolysis reaction, oxidation reaction and reduction reaction.
• Known methods used eg Protective-Grooves-In-Genius-Synthesis 4th Edition) ⁇ 0 2020/175 440 67 ⁇ (: 170? 2020/007365
• Methods for selectively protecting and deprotecting some hydroxyl groups use bulky protecting groups, or use a combination of protecting groups that are added or removed under different acid/base conditions. It can be carried out by a method of protecting a plurality of hydroxyl groups with a polyvalent protecting group such as a diol and then deprotecting only a part thereof.
• the specific method of selective protection and deprotection varies depending on the type of sugar or protecting group, but may be appropriately selected from known methods.
• the protecting group of glucopyranose is deprotected.
• the deprotection treatment can be appropriately selected from known methods depending on the type of protecting group.
• the protecting group is an acetyl group
• the acetyl group can be deprotected by hydrolysis of the ester in an appropriate organic solvent (eg, methanol) under acidic conditions.
• the compound of the present invention can be used as a building block for sugar chain synthesis. ⁇ 0 2020/175 440 68 ⁇ (: 170? 2020/007365 Example
• the raw materials used are as follows.
• Glucose receptor Building block 2 3 shown below (the sum of ⁇ 7 values is 0.23.)
• Electrolyte Tetrabutylammonium triflate (Minori ⁇ Choho)
• the building block 1 3 was used as the starting material, through the second to fourth stage shown in the following reaction ⁇ (33) was synthesized building block 2 3.
• acetonitrile solvent 21 SmL
• benzaldehyde dimethyl acetal (22011_) was further added to this acetonitrile solution, which was stirred at room temperature for 4 days.
• FIG. 1 is a graph showing a part of the synthesis sequence in Example 1.
• the !-type glass separation membrane-equipped electrolytic cell (1600 !_ on one side) was heated and dried under reduced pressure, and then the inside of the electrolytic cell was replaced with argon.
• tetrabutylammonium triflate (1.60110 I, 626 ⁇ 19) and methyl chloride (1 61 _) were added to the anode and cathode, respectively, in the electrolytic cell.
• the Birudi anode ring block 1 8 ( ⁇ . 40.01111 million I, 225,019), trifluoroacetic methanesulfonic acid to the cathode ( ⁇ .
• Step a After the power was turned on, the total amount of the methylene chloride solution (1.0 mL) of building block 2a (0.40 mmol, 227 mg) was added to the reaction solution at a rate of 1. OmL/min using a syringe pump. (Step b in Figure 1).
• the temperature of the low temperature bath was raised to 50°C at a rate of 2°C/min, held at 50°C for 30 minutes, and then at a rate of 2°C/min. The temperature was once again lowered to 80 °C (step c in Fig. 1).
• the solvent at this time was a mixture of hexane (Hexane)/ethyl acetate (EtOAc), and the volume ratio of these was 2:1 at the beginning, and at the timing when the elution of the target substance could be confirmed. I switched to 1:1 from the middle.
• the solvent in the solution was distilled off with an evaporator, and vacuum drying was performed to obtain 450 mg of a crude product. Further, the crude product was again passed through a silica gel column for purification for the second time.
• the solvent at this time was also a mixture of hexane (Hexane)/ethyl acetate (EtOAc), and the volume ratio between them was 1:1 throughout.
• the solvent in the solution was distilled off with an evaporator and vacuum drying was performed to obtain the target trisaccharide (compound 3a shown below, 0.28mmol,
• reaction formula (S4) The above reaction is shown in reaction formula (S4).
• Glucose acceptor building block 2 shown below (“The total value of ⁇ 7 is 0.06.) ⁇ 0 2020/175 440 74 ⁇ (: 170? 2020 /007365
• the yield of the sterically controlled sugar chain is improved as compared with the conventional method.
• a long sugar chain is synthesized by repeating glycosylation of sugar addition, and thus the yield per cycle has a large effect on the yield when the sugar chain is scaled up. To do. Therefore, the present invention is particularly useful in achieving such scale-up.

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