JPWO2013141350A1 - Oligosaccharide compound, production method thereof and intermediate thereof - Google Patents

Abstract

An object of the present invention is to provide a highly versatile oligosaccharide capable of producing a protected sulfated oligosaccharide that can be a production intermediate of polysulfated hyaluronic acid, a production method thereof, and an intermediate thereof. Reaction to sugar acceptors with electron-withdrawing groups, such as glucuronic acid and protected sulfate groups, by using a sugar donor in which the amino group at position 2 in glucosamine, galactosamine, etc. is protected with a specific protecting group Can be made.

Description

  The present invention relates to a method for producing an oligosaccharide compound.

  Polysulfated oligosaccharides are known to have pharmacological activity. For example, polysulfated hyaluronic acid having excellent antiallergic and antiinflammatory effects has been reported (Patent Document 1). ). According to Patent Document 1, the polysulfated hyaluronic acid is produced by preparing biologically-derived hyaluronic acid by an enzyme treatment or the like and then sulfating it. However, in this production method, when the sugar chain becomes long like hyaluronic acid, the number of sites to be sulfated increases, so it is difficult to obtain a sulfated sugar in which all sites to be sulfated are reliably sulfated. Tended to be.

  On the other hand, as a method for producing an O-glycoside-linked oligosaccharide, a sugar having a leaving group at the anomeric position (sugar donor) and a sugar having a free hydroxyl group (sugar acceptor) are subjected to a condensation reaction (glycosylation). Is known (Non-Patent Document 1). Also known is a method of producing a hyaluronic acid type oligosaccharide by glucosylation of a glucosamine derivative (sugar donor) having an imidate group as a leaving group at the anomeric position and a glucuronic acid derivative (sugar acceptor). (Non-patent document 2).

  In view of these conventional production methods, after introducing a sulfate group protected with a substituent that can be easily converted into a sulfate group (hereinafter referred to as a protected sulfate group) into a sugar donor and a sugar acceptor in advance, It is considered that polysulfated hyaluronic acid can be obtained by performing the glycosylation reaction.

  However, contrary to the above expectation, the desired oligosaccharide cannot be obtained by reacting a glucosamine derivative (sugar donor) introduced with a protected sulfate group and a glucuronic acid derivative (sugar acceptor) introduced with a protected sulfate group. .

  Therefore, at present, a highly versatile method for producing polysulfated hyaluronic acid using a glycosylation reaction has not yet been established.

WO2010 / 087207

Angew. Chem. Int. Ed. 2009, 48, 1900-1934 J. Org. Chem., 2009, 74, 4208-4216

  An object of the present invention is to provide a highly versatile oligosaccharide production method capable of producing a protected sulfated oligosaccharide that can be a production intermediate of polysulfated hyaluronic acid.

  Another object of the present invention is to provide a sugar donor and a sugar acceptor that can be applied to the production method.

  Furthermore, this invention makes it a subject to provide the manufacturing intermediate of polysulfated hyaluronic acid which introduce | transduced the protective sulfate group.

  As a result of intensive studies to achieve the above-mentioned problems, the present inventors have used glucuronic acid and protected sulfuric acid by using a sugar donor in which the 2-position amino group in glucosamine, galactosamine and the like is protected with a specific protecting group. It has been found that the reaction can be carried out also on a sugar acceptor having an electron-withdrawing group such as a group, and the present invention has been completed. That is, the present invention provides the production method, sugar donor, sugar acceptor, and oligosaccharide compound described in Items 1 to 5 below.

  Item 1. A method for producing an oligosaccharide compound represented by the general formula (1), wherein a sugar donor represented by the general formula (2) and a sugar acceptor represented by the general formula (3) Reacting in the presence.

[Wherein R ¹ , R ² , R ³ and R ⁴ represent a hydroxyl-protecting group or a group —SO ₃ R ⁶ . Here, R ⁶ is a C _1-8 alkyl group, a C _1-6 haloalkyl group, a benzyl group (on the phenyl ring of the benzyl group, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, C One or more substituents selected from the group consisting of _1-4 alkoxy groups, C _1-4 haloalkoxy groups, C _1-4 alkoxycarbonyl groups, nitro groups and cyano groups may be substituted) Or a phenyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, 1 or more of at least one substituent selected from the group consisting of a nitro group and a cyano group may be substituted). R ⁵ represents a C _1-4 alkoxycarbonyl group or a benzyloxycarbonyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4). One or more substituents selected from the group consisting of a haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group and a cyano group may be substituted), a benzhydryloxycarbonyl group (phenyl ring) Above, from halogen atom, C _1-4 alkyl group, C _1-4 haloalkyl group, C _1-4 alkoxy group, C _1-4 haloalkoxy group, C _1-4 alkoxycarbonyl group, nitro group and cyano group One or more substituents selected from the group consisting of one or more may be substituted) or a group —CH ₂ OR ⁷ . Here, R ⁷ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ .
R ^a and R ^b are the same or different and each represents a C _1-4 alkyl group, a C _1-4 haloalkyl group or a C _1-4 haloalkoxy group, or bonded to each other to form a C _1-4 alkylene group, C _{2- 4 represents an} alkenylene group or a phenylene group. Q ¹ and Q ^{2 each} represent a hydroxyl protecting group, a group —SO ₃ R ⁶ or a sugar residue. ]

[Wherein R ³ , R ⁴ , R ^a , R ^b and Q ² are the same as described above. X represents a leaving group. ]

[Wherein, R ¹ , R ² , R ⁵ and Q ¹ are the same as described above. ]
Item 2. A sugar compound represented by the general formula (2a).

[Wherein, R ⁴ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ . R ⁶ represents a C _1-8 alkyl group, a C _1-6 haloalkyl group, a benzyl group (on the phenyl ring of the benzyl group, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _{1- At} least one substituent selected from the group consisting of ₄ alkoxy groups, C _1-4 haloalkoxy groups, C _1-4 alkoxycarbonyl groups, nitro groups and cyano groups may be substituted) or phenyl Group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group) And at least one substituent selected from the group consisting of cyano group may be substituted one or more). R ⁵ represents a C _1-4 alkoxycarbonyl group or a benzyloxycarbonyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4). One or more substituents selected from the group consisting of a haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group and a cyano group may be substituted), a benzhydryloxycarbonyl group (phenyl ring) Above, from halogen atom, C _1-4 alkyl group, C _1-4 haloalkyl group, C _1-4 alkoxy group, C _1-4 haloalkoxy group, C _1-4 alkoxycarbonyl group, nitro group and cyano group One or more substituents selected from the group consisting of one or more may be substituted) or a group —CH ₂ OR ⁷ . Here, R ⁷ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ . R ⁸ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ . R ^a and R ^b are the same or different and each represents a C _1-4 alkyl group, a C _1-4 haloalkyl group or a C _1-4 haloalkoxy group, or bonded to each other to form a C _1-4 alkylene group, C _{2- 4 represents an} alkenylene group or a phenylene group. X ^a represents a halogen atom, a C _1-5 alkylcarbonyloxy group, a C _2-6 alkenylcarbonyloxy group, a trihaloacetimidoyloxy group or a thioformimidoyloxy group. ]
Item 3. A sugar compound represented by the general formula (3a).

[Wherein, R ⁵ represents a C _1-4 alkoxycarbonyl group, a benzyloxycarbonyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, At least one substituent selected from the group consisting of a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group, and a cyano group may be substituted), benzhydryloxycarbonyl Group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group) And at least one substituent selected from the group consisting of a cyano group and one or more substituents may be substituted) or a group —CH ₂ OR ⁷ . Here, R ⁷ represents a hydroxyl-protecting group, a group —SO ₃ R ⁶ . R ⁶ represents a C _1-8 alkyl group, a C _1-6 haloalkyl group, a benzyl group (on the phenyl ring of the benzyl group, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _{1- At} least one substituent selected from the group consisting of ₄ alkoxy groups, C _1-4 haloalkoxy groups, C _1-4 alkoxycarbonyl groups, nitro groups and cyano groups may be substituted), phenyl Group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group) And at least one substituent selected from the group consisting of cyano group may be substituted one or more). Q ³ represents the following formula (Q ^3a ) or (Q ^3b ):

Indicates. R ⁹ and R ^{10 each} represent a hydroxyl protecting group, a group —SO ₃ R ⁶ . A is a group —OSO ₃ R ⁶ , an azide group,

Indicates. Here, R ^c and R ^d are the same or different and each represents a hydrogen atom, a C _1-4 alkylcarbonyl group, a C _1-4 haloalkylcarbonyl group or a C _1-4 haloalkoxycarbonyl group, and R ^e and R ^f Are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group or a phenyl group, and R ^g , R ^h , R ⁱ and R ^j are the same or different and represent a hydrogen atom, a halogen atom or a C _1-4 alkyl. A group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group or a cyano group; ]
Item 4. An oligosaccharide compound represented by the general formula (1).

[Wherein R ¹ , R ² , R ³ and R ⁴ represent a hydroxyl-protecting group or a group —SO ₃ R ⁶ . Here, R ⁶ is a C _1-8 alkyl group, a C _1-6 haloalkyl group, a benzyl group (on the phenyl ring of the benzyl group, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, C One or more substituents selected from the group consisting of _1-4 alkoxy groups, C _1-4 haloalkoxy groups, C _1-4 alkoxycarbonyl groups, nitro groups and cyano groups may be substituted) Or a phenyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, 1 or more of at least one substituent selected from the group consisting of a nitro group and a cyano group may be substituted). R ⁵ represents a C _1-4 alkoxycarbonyl group or a benzyloxycarbonyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4). One or more substituents selected from the group consisting of a haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group and a cyano group may be substituted), a benzhydryloxycarbonyl group (phenyl ring) Above, from halogen atom, C _1-4 alkyl group, C _1-4 haloalkyl group, C _1-4 alkoxy group, C _1-4 haloalkoxy group, C _1-4 alkoxycarbonyl group, nitro group and cyano group One or more substituents selected from the group consisting of one or more may be substituted) or a group —CH ₂ OR ⁷ . Here, R ⁷ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ .
R ^a and R ^b are the same or different and each represents a C _1-4 alkyl group, a C _1-4 haloalkyl group or a C _1-4 haloalkoxy group, or bonded to each other to form a C _1-4 alkylene group, C _{2- 4 represents an} alkenylene group or a phenylene group. Q ¹ and Q ^{2 each} represent a hydroxyl protecting group, a group —SO ₃ R ⁶ or a sugar residue. ]
Item 5. An oligosaccharide compound represented by the general formula (1a).

[Wherein, R ³ and R ^{4 each} represent a hydroxyl-protecting group or a group —SO ₃ R ⁶ . R ⁶ represents a C _1-8 alkyl group, a C _1-6 haloalkyl group, a benzyl group (on the phenyl ring of the benzyl group, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4). At least one substituent selected from the group consisting of an alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group and a cyano group may be substituted) or a phenyl group (On the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group, and 1 or more of at least one substituent selected from the group consisting of cyano groups may be substituted). R ⁵ represents a C _1-4 alkoxycarbonyl group or a benzyloxycarbonyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4). One or more substituents selected from the group consisting of a haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group and a cyano group may be substituted), a benzhydryloxycarbonyl group (phenyl ring) Above, from halogen atom, C _1-4 alkyl group, C _1-4 haloalkyl group, C _1-4 alkoxy group, C _1-4 haloalkoxy group, C _1-4 alkoxycarbonyl group, nitro group and cyano group One or more substituents selected from the group consisting of one or more may be substituted) or a group —CH ₂ OR ⁷ . Here, R ⁷ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ .
R ^a and R ^b are the same or different and each represents a C _1-4 alkyl group, a C _1-4 haloalkyl group or a C _1-4 haloalkoxy group, or bonded to each other to form a C _1-4 alkylene group, C _{2- 4 represents an} alkenylene group or a phenylene group. Q ⁴ is a hydroxyl group protected by a protecting group, the following formula (Q ^4a ) or (Q ^4b ):

Alternatively, it represents a hydroxyl group protected by a protecting group, and R ⁹ and R ¹⁰ represent a hydroxyl protecting group or a group —SO ₃ R ⁶ . A is a group —OSO ₃ R ⁶ , an azide group,

Indicates. Here, R ^c and R ^d are the same or different and each represents a hydrogen atom, a C _1-4 alkylcarbonyl group, a C _1-4 haloalkylcarbonyl group or a C _1-4 haloalkoxycarbonyl group, and R ^e and R ^f Are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group or a phenyl group, and R ^g , R ^h , R ⁱ and R ^j are the same or different and represent a hydrogen atom, a halogen atom or a C _1-4 alkyl. A group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group or a cyano group; Q ⁵ is the following formula (Q ^5a ):

Alternatively, it represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ . R ⁸ represents a hydrogen atom, a hydroxyl-protecting group, or a group —SO ₃ R ⁶ . m represents an integer of 0 or 1, and n represents an integer of 0 to 4. ]

  According to the present invention, it is possible to synthesize hyaluronic acid, sulfated hyaluronic acid, chondroitin, chondroitin sulfate and other sulfated polysaccharides, etc., oligosaccharides controlled to have a target sugar chain length and sulfation degree. .

1 is a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar donor (2a-1). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar donor (2a-2). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar donor (2a-3). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar donor (2a-4). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar donor (2a-5). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of the compound (8-3). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of the compound (7-3). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar donor (2a-6). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar donor (2a-7). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar donor (2a-8). 1 is a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar receptor (3a-1). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar receptor (3a-2). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar receptor (3a-3). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar receptor (3a-4). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar receptor (3a-5). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar receptor (3a-6). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar receptor (3a-7). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar receptor (3a-8). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-1). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-2). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-3). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-4). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-5). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-6). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-7). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-8). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-9). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-10). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-11). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-12). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-13). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar receptor (3a-9). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-14). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar receptor (3a-10). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-15). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-16). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-17). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-18). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar donor (2a-9). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar donor (2a-10). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-19). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-20). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar receptor (3a-11). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-21). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-22). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-23). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of an oligosaccharide compound (1-24). ^{1 is} a ¹ H-NMR (500 MHz, CDCl ₃ ) chart of a sugar receptor (3a-12).

  In the present invention, a sugar donor represented by the general formula (2) is reacted with a sugar acceptor represented by the general formula (3) in the presence of an acid, and the sugar donor is represented by the general formula (1). An oligosaccharide compound is produced.

[Wherein R ¹ , R ² , R ³ and R ⁴ represent a hydroxyl-protecting group or a group —SO ₃ R ⁶ . Here, R ⁶ is a C _1-8 alkyl group, a C _1-6 haloalkyl group, a benzyl group (on the phenyl ring of the benzyl group, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, C One or more substituents selected from the group consisting of _1-4 alkoxy groups, C _1-4 haloalkoxy groups, C _1-4 alkoxycarbonyl groups, nitro groups and cyano groups may be substituted) Or a phenyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, 1 or more of at least one substituent selected from the group consisting of a nitro group and a cyano group may be substituted). R ⁵ represents a C _1-4 alkoxycarbonyl group or a benzyloxycarbonyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4). One or more substituents selected from the group consisting of a haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group and a cyano group may be substituted), a benzhydryloxycarbonyl group (phenyl ring) Above, from halogen atom, C _1-4 alkyl group, C _1-4 haloalkyl group, C _1-4 alkoxy group, C _1-4 haloalkoxy group, C _1-4 alkoxycarbonyl group, nitro group and cyano group One or more substituents selected from the group consisting of one or more may be substituted) or a group —CH ₂ OR ⁷ . Here, R ⁷ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ .
R ^a and R ^b are the same or different and each represents a C _1-4 alkyl group, a C _1-4 haloalkyl group or a C _1-4 haloalkoxy group, or bonded to each other to form a C _1-4 alkylene group, C _{2- 4 represents an} alkenylene group or a phenylene group. Q ¹ and Q ^{2 each} represent a hydroxyl protecting group, a group —SO ₃ R ⁶ or a sugar residue. ]

[Wherein R ³ , R ⁴ , R ^a , R ^b and Q ² are the same as described above. X represents a leaving group. ]

[Wherein, R ¹ , R ² , R ⁵ and Q ¹ are the same as described above. ]

  The oligosaccharide compound represented by the general formula (1) is a novel compound not described in any literature, and can be a production intermediate of various physiologically active substances. In particular, the oligosaccharide compound represented by the following general formula (1a) is a useful substance that can be a production intermediate of polysulfated hyaluronic acid.

[Wherein, R ³ and R ^{4 each} represent a hydroxyl-protecting group or a group —SO ₃ R ⁶ . R ⁶ represents a C _1-8 alkyl group, a C _1-6 haloalkyl group, a benzyl group (on the phenyl ring of the benzyl group, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4). At least one substituent selected from the group consisting of an alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group and a cyano group may be substituted) or a phenyl group (On the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group, and 1 or more of at least one substituent selected from the group consisting of cyano groups may be substituted). R ⁵ represents a C _1-4 alkoxycarbonyl group or a benzyloxycarbonyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4). One or more substituents selected from the group consisting of a haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group and a cyano group may be substituted), a benzhydryloxycarbonyl group (phenyl ring) Above, from halogen atom, C _1-4 alkyl group, C _1-4 haloalkyl group, C _1-4 alkoxy group, C _1-4 haloalkoxy group, C _1-4 alkoxycarbonyl group, nitro group and cyano group One or more substituents selected from the group consisting of one or more may be substituted) or a group —CH ₂ OR ⁷ . Here, R ⁷ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ .
R ^a and R ^b are the same or different and each represents a C _1-4 alkyl group, a C _1-4 haloalkyl group or a C _1-4 haloalkoxy group, or bonded to each other to form a C _1-4 alkylene group, C _{2- 4 represents an} alkenylene group or a phenylene group. Q ⁴ is a hydroxyl group protected by a protecting group, the following formula (Q ^4a ) or (Q ^4b ):

Alternatively, it represents a hydroxyl group protected by a protecting group, and R ⁹ and R ¹⁰ represent a hydroxyl protecting group or a group —SO ₃ R ⁶ . A is a group —OSO ₃ R ⁶ , an azide group,

Indicates. Here, R ^c and R ^d are the same or different and each represents a hydrogen atom, a C _1-4 alkylcarbonyl group, a C _1-4 haloalkylcarbonyl group or a C _1-4 haloalkoxycarbonyl group, and R ^e and R ^f Are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group or a phenyl group, and R ^g , R ^h , R ⁱ and R ^j are the same or different and represent a hydrogen atom, a halogen atom or a C _1-4 alkyl. A group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group or a cyano group; Q ⁵ is the following formula (Q ^5a ):

Alternatively, it represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ . R ⁸ represents a hydrogen atom, a hydroxyl-protecting group, or a group —SO ₃ R ⁶ . m represents an integer of 0 or 1, and n represents an integer of 0 to 4. ]

  The sugar donor represented by the general formula (2) is also a novel compound not described in any literature. In particular, the saccharide compound represented by the following general formula (2a) is a useful substance that can be a raw material for producing polysulfated hyaluronic acid.

[Wherein, R ⁴ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ . R ⁶ represents a C _1-8 alkyl group, a C _1-6 haloalkyl group, a benzyl group (on the phenyl ring of the benzyl group, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _{1- At} least one substituent selected from the group consisting of ₄ alkoxy groups, C _1-4 haloalkoxy groups, C _1-4 alkoxycarbonyl groups, nitro groups and cyano groups may be substituted) or phenyl Group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group) And at least one substituent selected from the group consisting of cyano group may be substituted one or more). R ⁵ represents a C _1-4 alkoxycarbonyl group or a benzyloxycarbonyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4). One or more substituents selected from the group consisting of a haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group and a cyano group may be substituted), a benzhydryloxycarbonyl group (phenyl ring) Above, from halogen atom, C _1-4 alkyl group, C _1-4 haloalkyl group, C _1-4 alkoxy group, C _1-4 haloalkoxy group, C _1-4 alkoxycarbonyl group, nitro group and cyano group One or more substituents selected from the group consisting of one or more may be substituted) or a group —CH ₂ OR ⁷ . Here, R ⁷ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ . R ⁸ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ . R ^a and R ^b are the same or different and each represents a C _1-4 alkyl group, a C _1-4 haloalkyl group or a C _1-4 haloalkoxy group, or bonded to each other to form a C _1-4 alkylene group, C _{2- 4 represents an} alkenylene group or a phenylene group. X ^a represents a halogen atom, a C _1-5 alkylcarbonyloxy group, a C _2-6 alkenylcarbonyloxy group, a trihaloacetimidoyloxy group or a thioformimidoyloxy group. ]

  In addition, among the sugar receptors represented by the general formula (3), in particular, the sugar compound represented by the following general formula (3a) is a novel compound that has not been described in the literature, and production of polysulfated hyaluronic acid. It is a useful substance that can be used as a raw material.

[Wherein, R ⁵ represents a C _1-4 alkoxycarbonyl group, a benzyloxycarbonyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, At least one substituent selected from the group consisting of a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group, and a cyano group may be substituted), benzhydryloxycarbonyl Group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group) And at least one substituent selected from the group consisting of a cyano group and one or more substituents may be substituted) or a group —CH ₂ OR ⁷ . Here, R ⁷ represents a hydroxyl-protecting group, a group —SO ₃ R ⁶ . R ⁶ represents a C _1-8 alkyl group, a C _1-6 haloalkyl group, a benzyl group (on the phenyl ring of the benzyl group, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _{1- At} least one substituent selected from the group consisting of ₄ alkoxy groups, C _1-4 haloalkoxy groups, C _1-4 alkoxycarbonyl groups, nitro groups and cyano groups may be substituted), phenyl Group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group) And at least one substituent selected from the group consisting of cyano group may be substituted one or more). Q ³ represents the following formula (Q ^3a ) or (Q ^3b ):

Indicates. R ⁹ and R ^{10 each} represent a hydroxyl protecting group, a group —SO ₃ R ⁶ . A is a group —OSO ₃ R ⁶ , an azide group,

Indicates. Here, R ^c and R ^d are the same or different and each represents a hydrogen atom, a C _1-4 alkylcarbonyl group, a C _1-4 haloalkylcarbonyl group or a C _1-4 haloalkoxycarbonyl group, and R ^e and R ^f Are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group or a phenyl group, and R ^g , R ^h , R ⁱ and R ^j are the same or different and represent a hydrogen atom, a halogen atom or a C _1-4 alkyl. A group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group or a cyano group; ]

1. Oligosaccharide compounds and sugar compounds
1-1. Oligosaccharide compound represented by general formula (1) The groups in general formula (1) are as follows.

  As a halogen atom, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom are mentioned, for example.

Examples of the _C1-4 alkyl group include C1-C4 such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and tert-butyl group. A linear or branched alkyl group is mentioned.

Examples of the C _1-8 alkyl group include, in addition to the groups exemplified for the C _1-4 alkyl group, an n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, an n-hexyl group, an isohexyl group, C1-C8 linear or branched alkyl groups, such as n-heptyl group and n-octyl group, are mentioned.

Examples of the C _1-4 haloalkyl group include a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a trifluoromethyl group, a chlorodifluoromethyl group, a bromodifluoromethyl group, a dichlorofluoromethyl group, 1 -Fluoroethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2-iodoethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, pentafluoroethyl 1-9, preferably 1-5, such as a group, 1-fluoroisopropyl group, 3-fluoropropyl group, 3-chloropropyl group, 3-bromopropyl group, 4-fluorobutyl group, 4-chlorobutyl group, etc. And a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a halogen atom. The

Examples of the C _1-6 haloalkyl group include 5-chloropentyl group, 5-fluoropentyl group, 6-chlorohexyl group, 6-fluorohexyl group, etc., in addition to the groups exemplified for the C _1-4 haloalkyl group. 1-13, preferably 1-7, straight-chain or branched alkyl groups substituted with 1-7 carbon atoms.

Examples of the C _1-4 alkoxy group include carbon number 1 such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, cyclopropyloxy group, n-butoxy group, sec-butoxy group, and tert-butoxy group. -4 linear or branched alkoxy groups.

Examples of the C _1-4 haloalkoxy group include a fluoromethoxy group, a chloromethoxy group, a bromomethoxy group, an iodomethoxy group, a dichloromethoxy group, a trichloromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a chlorodifluoromethoxy group, Bromodifluoromethoxy group, dichlorofluoromethoxy group, 1-fluoroethoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, 2-bromoethoxy group, 2-iodoethoxy group, 2,2,2-trifluoroethoxy group 2,2,2-trichloroethoxy group, pentafluoroethoxy group, 1-fluoroisopropoxy group, 3-fluoropropoxy group, 3-chloropropoxy group, 3-bromopropoxy group, 4-fluorobutoxy group, 4-chloro 1-9 such as butoxy groups, preferred Or a linear or branched alkoxy group having 1 to 4 carbon atoms substituted with 1 to 5 halogen atoms.

Examples of the C _1-4 alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, a sec-butoxycarbonyl group, and a tert-butoxycarbonyl group. Examples thereof include a linear or branched alkoxycarbonyl group having 1 to 4 carbon atoms.

Examples of the C _1-4 alkylene group include a methylene group, an ethylene group, a trimethylene group, and a tetramethylene group. These alkylene groups may contain an oxygen atom or a sulfur atom, and may be via a phenylene group. Examples of such an alkylene group include —CH ₂ OCH ₂ —, —CH ₂ OCH ₂ CH ₂ —, —CH ₂ SCH ₂ —, —CH ₂ SCH ₂ CH ₂ —,

And may have a substituent such as a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group, a phenyl group, or a halogen atom at an arbitrary position. .

Examples of the C _2-4 alkenylene group include a vinylene group, a propenylene group, a 2-butenylene group, and a 1,4-butadienylene group, and have a substituent such as a C _1-4 alkyl group or a phenyl group at an arbitrary position. You may do it.

Examples of the phenylene group include a 1,2-phenylene group, a 1,3-phenylene group, and a 1,4-phenylene group, and a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _{1- 4} You may have substituents, such as an alkoxycarbonyl group, a nitro group, a phenyl group, and a halogen atom.

The hydroxyl protecting group is not particularly limited as long as it is usually used as a hydroxyl protecting group of a sugar compound. For example, Protective Group in Organic Synthesis, Chapter 2, pp. 10-142, Theodora W. Greene and Peter the GM Wuts, 2 ^nd ed. hydroxyl protecting groups are described in exemplified. More specifically, for example, benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, methoxymethyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, benzoyl group, acetyl group, pivaloyl group, levulyl group An allyl group, etc., and the number of carbon atoms that may be substituted with a phenyl group that may have a C _1-4 alkyl group, a C _2-6 alkenyl group, or a substituent with respect to two adjacent hydroxyl groups You may form a ring with the bivalent group of ~ 3.

Examples of the C _2-6 alkenyl group include a vinyl group, 1-propenyl group, allyl group, isopropenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-2-propenyl group, 1,3- Butadienyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1,1-dimethyl-2-propenyl group, 1-ethyl-2-propenyl group, 1-methyl-2-butenyl Group, 1-methyl-3-butenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 1,1-dimethyl-2-butenyl group, 1,1 -A C2-C6 linear or branched alkenyl group having at least one double bond at an arbitrary position such as a dimethyl-3-butenyl group.

  Examples of the divalent group having 1 to 3 carbon atoms include methylene group, ethylene group, trimethylene, propylene group, isopropylidene group, ethylethylene group, allylmethylene group, benzylidene group, and p-methoxybenzylidene group. .

Examples of sugar residues include glucose, galactose, mannose, glucosamine, N-acetylglucosamine, galactosamine, N-acetylgalactosamine, mannosamine, N-acetylmannosamine, fructose, glucuronic acid, iduronic acid and other monosaccharides, maltose Disaccharides such as isomaltose, lactose, lactosamine, N-acetyllactosamine, cellobiose, melibiose, maltooligosaccharide, isomaltoligosaccharide, lactoligosaccharide, lactosamine oligosaccharide, N-acetyllactosamine oligosaccharide, cellooligosaccharide, meliviooligosaccharide Oligosaccharides such as hyaluronic acid oligosaccharide, chondroitin sulfate oligosaccharide, keratan sulfate oligosaccharide, heparin oligosaccharide, heparan sulfate oligosaccharide, sialo-complex type sugar chain, N-linked sugar chain, O-linked sugar chain, Examples thereof include saccharide residues derived from polysaccharides such as lycosaminoglycan, starch, amylose, amylopectin, cellulose, chitin, glycogen, agarose, alginic acid, hyaluronic acid, inulin, and glucomannan. These sugar residues may have their hydroxyl groups protected by an arbitrary protecting group or group —SO ₃ R ⁶ , or may be sugar derivatives derived from these reducing sugars.

  The oligosaccharide compound represented by the general formula (1) of the present invention is a method of deprotecting the imide protecting group of the amino group at the 2-position of the glycosamine or galactosamine unit constituting the compound and the generally known imide protecting group. Since it can be deprotected, it can be a production intermediate of various physiologically active substances as described above. In particular, the oligosaccharide compound represented by the general formula (1a) can be deprotected without removal of the sulfate group even under basic conditions that are deprotection conditions (see Reference Example 13). It can be used as an intermediate for the production of sulfated hyaluronic acid.

1-2. Sugar donor represented by the general formula (2) The groups in the general formula (2) are as follows.

Formula ^{(2) R 3, R 4} , R a, each group in ^{R b} and ^{Q 2} in is the same as each group in the general formula (1).

The leaving group includes a halogen atom, a C _1-4 alkylthio group such as a methylthio group, an arylthio group such as a phenylthio group, a C _1-5 alkylcarbonyloxy group, a C _2-6 alkenylcarbonyloxy group, a trihaloacetimidoyloxy group. A thioformimidoyloxy group, and among these leaving groups, a C _2-6 alkenylcarbonyloxy group or a trihaloacetimidoyloxy group is preferable.

1-3. Each group in R ¹ , R ² , R ⁵ and Q ¹ in the sugar receptor general formula (3) represented by the general formula (3) is the same as each group in the general formula (1).

1-4. Each group in R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^a , R ^b and X ^a in the saccharide compound represented by the general formula (2a) is represented by the general formula (1) ) The same as each group in

Examples of the C _1-5 alkylcarbonyloxy group include an acetoxy group, propionyloxy group, n-butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, sec-butylcarbonyloxy group, tert-butyl. Examples include carbonyloxy group and pivaloyloxy.

Examples of the C _2-6 alkenylcarbonyloxy group include an acryloyloxy group, a methacryloyloxy group, a crotonoyloxy group, an isocrotonoyloxy group, and a 4-pentenoyloxy group.

Examples of the trihaloacetimidoyloxy group include imide nitrogen atoms such as a trifluoroacetimidoyloxy group, a trichloroacetimidoyloxy group, an N-methyltrichloroacetimidoyloxy group, and an N-phenyltrichloroacetimidoyloxy group. , An acetimidoyloxy group substituted with 3 halogen atoms, which may be substituted by a C _1-4 alkyl group or a phenyl group.

  Examples of the thioformimidoyloxy group include p-trifluoromethylbenzylthio-p-trifluoromethylphenylformimidoyloxy group, p-trifluoromethylbenzylthio-p-nitrophenylformimidoyloxy group, and the like. be able to.

Further, when R ⁸ is a hydroxyl protecting group, R ⁵ is a group —CH ₂ OR ⁷ , and R ⁷ is a hydroxyl protecting group, R ⁸ and R ⁷ are combined together to form a carbon number. 1 to 3 divalent groups may be formed, and a C _1-4 alkyl group, a C _2-6 alkenyl group or a phenyl group which may have a substituent is substituted at any position of the divalent group. It may be.

Among the sugar compounds represented by the general formula (2a), a sugar compound in which X ^a is a C _2-6 alkenylcarbonyloxy group or a trihaloacetimidoyloxy group is preferable, and X ^a is a 4-pentenoyloxy group, trichloro A sugar compound which is an acetimidoyloxy group or an N-phenyltrichloroamidoyloxy group is more preferable.

Among the sugar compounds represented by the general formula (2a), R ^a and R ^b are the same or different and are a C _1-4 alkyl group, a C _1-4 haloalkoxy group, or a C _2-4 alkenylene bonded to each other. Or a phenylene group is preferred, and R ^a and R ^b are the same or different and are a methyl group, a 2,2,2-trichloroethoxy group, or a vinylene group or a 1,2-dimethylvinylene group bonded to each other. , A sugar compound which is a 1,2-diphenylvinylene group or a 1,2-phenylene group is more preferable.

Among the sugar compounds represented by the general formula (2a), R ⁵ is an alkoxycarbonyl group, and is a methoxycarbonyl group, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, or benzhydryloxycarbonyl group. Sugar compounds are preferred.

Among the sugar compounds represented by the general formula (2a), a sugar compound in which R ⁵ is a group —CH ₂ OR ⁷ and R ⁷ and R ⁸ are each an acetyl group is preferable.

Among the sugar compounds represented by the general formula (2a), R ⁵ is a group —CH ₂ OR ⁷ , and R ⁷ and R ⁸ are bonded to each other to form an isopropylidene group, a benzylidene group, or a p-methoxybenzylidene group. A sugar compound is preferred.

Among the sugar compounds represented by the general formula (2a), a sugar compound in which R ⁶ is a 2,2,2-trichloroethyl group is preferable.

1-5. R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , A, R ^c , R ^d , R ^e , R ^f , R ^g in the saccharide compound represented by the general formula (3a) Each group in R ^h , R ⁱ and R ^j is the same as each group in the general formula (1).

The C _1-4 alkylcarbonyl group is a group in which a linear or branched alkyl group having 1 to 4 carbon atoms and a carbonyl group are bonded, for example, a methylcarbonyl group (acetyl group), an ethylcarbonyl group (Propionyl group), n-propylcarbonyl group (butyryl group), isopropylcarbonyl group (isobutyryl group), n-butylcarbonyl group (valeryl group), isobutylcarbonyl group (isovaleryl group), sec-butylcarbonyl group, tert-butyl A carbonyl group and the like are included.

The C _1-4 haloalkylcarbonyl group is a group in which a linear or branched haloalkyl group having 1 to 4 carbon atoms and a carbonyl group are bonded, and examples thereof include a chloroacetyl group, a bromoacetyl group, and an iodoacetyl group. , Difluoroacetyl group, trifluoroacetyl group, trichloroacetyl group, chlorodifluoroacetyl group, 2,2,2-trifluoropropionyl group, 2,2,2-trichloropropionyl group, pentafluoropropionyl group, 4-fluorobutanoyl Groups and the like are included.

Examples of the C _1-4 haloalkoxycarbonyl group include a 2,2,2-trichloroethoxycarbonyl group.

Among the sugar compounds represented by the general formula (3a), a sugar compound in which R ⁵ is a benzyloxymethyl group, a p-methoxybenzyloxymethyl group or a methoxycarbonyl group is preferable, and a sugar compound in which a methoxycarbonyl group is more preferable. .

Among the general formula (3a) a sugar compound represented by the, ^{Q 3} is a sugar compound is a ^{Q 3a} or ^{Q 3b,} A on ^{Q 3a} or ^{Q 3b} is an azide group, dimethyl maleimide group or a phthalimido group A sugar compound is preferable, and a sugar compound in which A is a dimethylmaleimide group or a phthalimide group is more preferable.

Among the sugar compounds represented by the general formula (3a), a sugar compound in which R ⁶ is a 2,2,2-trichloroethyl group is preferable.

Among the sugar compounds represented by the general formula (3a), a sugar compound in which Q ³ is Q ^3a is preferable.

Among the sugar compounds represented by the general formula (3a), in the sugar compound in which Q ³ is Q ^3a , a sugar compound in which R ⁹ is a methyl group, a benzyl group or a p-methoxybenzyl group is preferable, and p-methoxybenzyl is preferred. A sugar compound as a group is more preferred.

Among the sugar compounds represented by the general formula (3a), in the sugar compound in which Q ³ is Q ^3a , a sugar compound in which R ¹⁰ is an acetyl group, a benzyl group, a p-methoxybenzyl group, or a levnyl group is preferable. A sugar compound as a group is more preferred.

1-6. R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , A, R ^c , R ^{d in the} oligosaccharide compound represented by the general formula (1a) , R ^e , R ^f , R ^g , R ^h , R ⁱ , R ^j , Q ⁴ and Q ⁵ are the same as the groups in the general formulas (1), (2a) and (2b).

When R ³ and R ⁴ are hydroxyl protecting groups, Q ⁵ of the oligosaccharide compound represented by the general formula (1a) is Q ^5a , and R ⁸ in Q ^5a is a hydroxyl protecting group. And R ⁵ is a group —CH ₂ OR ⁷ and R ⁷ is a protecting group for a hydroxyl group, R ³ and R ⁴ , or R ⁷ and R ⁸ are combined together to form a carbon number. 1 to 3 divalent groups may be formed, and the divalent group is substituted with a C _1-4 alkyl group, a C _2-6 alkenyl group or a phenyl group which may have a substituent at any position. May be.

Among the oligosaccharide compounds represented by the general formula (1a), an oligosaccharide compound in which Q ⁴ is the formula (Q ^4a ) or (Q ^4b ) is preferable.

Among the oligosaccharide compounds represented by the general formula (1a), an oligosaccharide compound in which Q ⁵ is the formula (Q ^5a ) is preferable.

Among the oligosaccharide compounds represented by the general formula (1a), Q ⁴ is the formula (Q ^4a ) or (Q ^4b ), Q ⁵ is the formula (Q ^5a ), and m is an integer of 0 or 1 An oligosaccharide compound in which n is an integer of 0 to 4 is preferred.

Among the oligosaccharide compounds represented by the general formula (1a), Q ⁴ is the formula (Q ^4a ) or (Q ^4b ), Q ⁵ is the formula (Q ^5a ), and m and n are 0. Oligosaccharide compounds are preferred.

Among the oligosaccharide compounds represented by the general formula (1a), Q ⁴ is the formula (Q ^4a ) or (Q ^4b ), Q ⁵ is the formula (Q ^5a ), and R ³ is a group —SO _3. An oligosaccharide compound which is R ⁶ and m and n are 0 is preferable.

Among the oligosaccharide compounds represented by the general formula (1a), Q ⁴ is the formula (Q ^4a ) or (Q ^4b ), and Q ⁵ is the following formula (Q ^5b ):

[Wherein, R ⁶ is the same as defined above. R ^11a and R ^11b are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group, a C _2-6 alkenyl group or a phenyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, C _{1 -4} haloalkyl group, C _1-4 alkoxy group, C _1-4 haloalkoxy group, C _1-4 alkoxycarbonyl group, at least one substituent selected from the group consisting of nitro group and cyano group May be substituted). Are preferred.

Among the oligosaccharide compounds represented by the general formula (1a), Q ⁴ is the formula (Q ^4a ) or (Q ^4b ), Q ⁵ is the formula (Q ^5a ), and R ³ is a group —SO _3. An oligosaccharide compound which is R ⁶ and the sum of m and n is 2 or 3 is preferred.

2. Production method
2-1. Method for Producing Oligosaccharide A method for producing an oligosaccharide compound represented by the general formula (1) of the present invention comprises a sugar donor represented by the general formula (2) and a general formula as shown in the following reaction formula-1. The sugar receptor represented by (3) is reacted in the presence of an acid.

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^a , R ^b , Q ¹ , Q ² and X are the same as described above. ]

Examples of the acid used in this reaction include inorganic acids such as sulfuric acid, boron trifluoride diethyl ether (BF ₃ · OEt ₂ ), trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, tripropylsilyl trifluoromethanesulfonate, Dimethylethylsilyl trifluoromethanesulfonate, tribenzylsilyl trifluoromethanesulfonate, trinaphthylsilyl trifluoromethanesulfonate or tribenzylmethylsilyl trifluoromethanesulfonate, silver trifluoromethanesulfonate, hafnium cyclopentadienyl chloride, cyclopentadienyl Examples include Lewis acids such as zirconium chloride and tin chloride, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, trifluoroacetic anhydride, and trifluoromethanesulfonic acid. . Among these, Lewis acid is preferable, and trimethylsilyl trifluoromethanesulfonate is particularly preferable.

  These acids can be used alone or in combination of two or more, and the amount used is 0.1 to 5 equivalents, preferably 0.2 to the sugar donor represented by the general formula (2). It is good to set it as 1.5 equivalent. The use ratio of the sugar donor represented by the general formula (2) and the sugar acceptor represented by the general formula (3) can be used at an arbitrary ratio, but with respect to 1 mol of the sugar donor, Preferably, the sugar receptor is 0.2 to 10 mol, more preferably 0.7 to 4 mol.

  In this reaction, when X of the sugar donor represented by the general formula (2) is an alkenylcarbonyl group, a Lewis acid such as silver trifluoromethanesulfonate and an activator such as phenyl selenium bromide and tritert- The reaction is preferably carried out in combination with a base such as butylpyridine or in combination with an Lewis acid such as trimethylsilyl trifluoromethanesulfonate and an activator such as N-iodosuccinimide. The use ratio when the activator and the base are used in combination with the Lewis acid is, for example, about 1 to 5 equivalents of the Lewis acid and 1 to 1 of the activator with respect to the sugar donor represented by the general formula (2). About 5 equivalents, the base may be about 1 to 5 equivalents, and the use ratio when the activator is used in combination with the Lewis acid is, for example, Lewis with respect to the sugar donor represented by the general formula (2) The acid may be about 0.1 to 2 equivalents and the activator may be about 1 to 5 equivalents.

  This reaction is usually performed in a solvent. The solvent to be used is not particularly limited as long as it is inert to the reaction. For example, aliphatic hydrocarbons such as hexane, heptane and pentane, alicyclic hydrocarbons such as cyclohexane, benzene, toluene, Aromatic hydrocarbons such as xylene, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, 1,1,1-trichloroethane, tetrachloroethylene, trichloroethylene, carbon tetrachloride, chlorobenzene, o-dichlorobenzene, Ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, monoglyme, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethylimidazolidinone, sulfoxides such as dimethyl sulfoxide, Acetonite Le, nitriles or a mixture of these solvents, such as propane nitriles. Among these, aromatic hydrocarbons, nitriles and halogenated hydrocarbons are preferable, and halogenated hydrocarbons are particularly preferable. Specifically, dichloromethane, chloroform, 1,2-dichloroethane, 1,1,1-trichloroethane, tetrachloroethylene, trichloroethylene, carbon tetrachloride, chlorobenzene, and o-dichlorobenzene are preferable.

  The amount of these solvents used may be about 1 to 100 liters, preferably about 1 to 40 liters per kg of the sugar donor represented by the general formula (2).

  This reaction is usually performed at a temperature of -100 ° C to 40 ° C, more preferably -40 ° C to 25 ° C. The reaction time is not particularly limited, but usually proceeds in 1 to 24 hours.

  In this reaction, it is preferable to remove water, hydrohalic acid and the like in the system, and it is preferable to use a trapping body such as molecular sieve.

  According to the production method of the present invention, an oligosaccharide compound having a β-glycosyl bond represented by the general formula (1) can be selectively and efficiently produced.

2-2. Production Method of Sugar Donor The sugar donor represented by the general formula (2) used in this reaction can be produced, for example, by the method of the following reaction formula-2.

[Wherein R ³ , R ⁴ , R ^a , R ^b , Q ² and X are the same as above. R ¹² represents a hydroxyl-protecting group. Here, the hydroxyl-protecting group has the same definition as in the general formula (1). ]

  As shown in the above reaction formula-2, the amino group at the 2-position of the 2-amino sugar compound represented by the general formula (4) is imidized (Process 1) and represented by the general formula (5). A 2-imide sugar compound is produced and then converted to a 2-imide sugar compound represented by the general formula (6) (Process 2), followed by deprotection of the hydroxyl protecting group at position 1 (Process 3). Thus, a 2-imide sugar compound represented by the general formula (7) is produced. The free hydroxyl group of the obtained sugar compound represented by the general formula (7) is substituted with a predetermined leaving group (Process 4) to obtain the intended sugar donor represented by the general formula (2). be able to.

In the general formula (2), when a C _2-6 alkenylcarbonyloxy group is present as the leaving group, the leaving group X is first introduced, and then the 2-position amino group is imidized, whereby the general formula ( The sugar donor represented by 2) can also be obtained (see Reference Example 10 and Examples 5 and 6 described later).

  Further, as a leaving group, a thioformimidoyl group such as a p-trifluoromethylbenzylthio-p-trifluoromethylphenylformimidoyl group, a p-trifluoromethylbenzylthio-p-nitrophenylformimidoyl group, and the like. In the case of introduction, the 2-imide sugar compound represented by the general formula (5) is reacted with p-trifluoromethylphenyl isothiocyanate or p-nitrophenyl isothiocyanate, and then p-trifluoromethylbenzyl bromide or the like. The sugar donor represented by the general formula (2) can be produced by treating with

( Process 1 )
The reaction (Process 1) for producing the 2-imide sugar compound represented by the general formula (5) by imidizing the amino group at the 2-position of the 2-amino sugar compound represented by the general formula (4), The reaction is usually performed in a solvent using a reactant.

  Examples of the reactant used in this reaction include acyl halides such as acetyl chloride, acetyl bromide and trichloroacetyl chloride, acid anhydrides such as acetic anhydride and trifluoroacetic anhydride, p-nitrophenyl acetate, and ethyl trifluoroacetate. Amidating agents such as esters such as isopropenyl acetate, carbamates such as 2,2,2-trichloroethoxycarbonyl chloride, phthalic anhydride, N-ethoxycarbonylphthalimide, o-methoxycarbonyl benzoic acid chloride, maleic anhydride Examples thereof include imidizing agents such as acid, 2-methylmaleic anhydride, 2,3-dimethylmaleic anhydride, and 2,3-diphenylmaleic anhydride.

  When an amidating agent is used, the 2-position amino group may be imidized at a time using 2 mol or more of the amidating agent with respect to 1 mol of the 2-aminosugar compound represented by the general formula (4). However, it is possible to form a mono-substituted product (amide compound) once by carrying out a reaction control such as using about 1 mol, and then further react with an amidating agent to imidize. A method of imidizing in stages is preferable from the viewpoint of reaction efficiency, and it is preferable because different amide groups can be introduced.

  As the solvent used in this reaction, known solvents can be widely used as long as they are inert to the reaction. For example, aliphatic or alicyclic carbonization such as hexane, cyclohexane, heptane, etc. Hydrogen solvents, aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, xylene, halogenated hydrocarbon solvents such as methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1, Ether solvents such as 4-dioxane, ester solvents such as methyl acetate and ethyl acetate, ketone solvents such as acetone and methyl ethyl ketone, amide solvents such as N, N-dimethylformamide, nitriles such as acetonitrile and propionitrile Solvent, dimethyl sulfoxide, N-methylpyrrolidone, N, N′-dimethyl Examples thereof include aprotic polar solvents such as tilimidazolinone. These solvents can be used alone or in combination of two or more as required.

  The amount of these solvents used may be appropriately set depending on the type of reactant used and the type of reaction, etc., but is usually 1 part by weight of the 2-aminosaccharide compound represented by the general formula (4). About 1 to 500 parts by weight, preferably about 5 to 100 parts by weight, more preferably about 1 to 20 parts by weight may be used.

In addition, this reaction is usually preferably carried out in the presence of a base, and known inorganic bases and organic bases can be used as the base to be used. Examples of the inorganic base include alkali metals such as sodium and potassium, alkali metal carbonates such as sodium carbonate, potassium carbonate and sodium bicarbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride, Examples thereof include alkali metal hydrides such as potassium hydride. Examples of the organic base include alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, amines such as triethylamine, diisopropylethylamine and pyridine. These bases are used individually by 1 type or in mixture of 2 or more types.

  The amount of such a base used is appropriately set according to the type and amount of the reactant used, but is usually relative to the 2-amino sugar compound represented by the general formula (2). 0.1 to 100 equivalents, preferably 0.5 to 5 equivalents, more preferably about 1 to 2.0 equivalents.

  This reaction can usually be performed within a range from −100 ° C. to the boiling temperature of the solvent used. The reaction is preferably performed at 0 ° C. to the boiling point of the solvent to be used, and more preferably the reaction is performed under heating and reflux.

  The reaction time varies depending on the type of reaction agent used, reaction temperature, and the like, and cannot be generally specified, but the reaction is usually completed in about 0.5 to 24 hours.

( Process 2 )
The method (Process 2) for deriving from the 2-imide sugar compound represented by the general formula (5) to the 2-imide sugar compound represented by the general formula (6) usually uses a reactant in a solvent. Done in

  Examples of the reactant used in this reaction include acetic acid-acetic anhydride.

  The amount of the reactant used may be appropriately set depending on the type of reactant used, the type of reaction, and the like. However, when acetic acid-acetic anhydride is used as the reactant, it is usually represented by the general formula (5) 2 -About 5 to 30 equivalents of acetic acid, preferably about 10 to 20 with respect to the amino sugar compound, and acetic anhydride is about 10 to 500 parts by weight with respect to 1 part by weight of 2-amino sugar compound, preferably What is necessary is just to use about 10-200 weight part.

  As the solvent used in this reaction, a known solvent can be widely used as long as it is an inert solvent for the reaction. For example, aliphatic or alicyclic carbonization such as hexane, cyclohexane, heptane, etc. Hydrogen solvents, aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, xylene, halogenated hydrocarbon solvents such as methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1, Ether solvents such as 4-dioxane, ester solvents such as methyl acetate and ethyl acetate, ketone solvents such as acetone and methyl ethyl ketone, amide solvents such as N, N-dimethylformamide, nitriles such as acetonitrile and propionitrile Solvent, dimethyl sulfoxide, N-methylpyrrolidone, N, N′-di Examples include aprotic polar solvents such as methylimidazolinone. These solvents can be used alone or in combination of two or more as required.

  The amount of these solvents used may be appropriately set depending on the type of reactant used and the type of reaction, etc., but is usually 1 part by weight of the 2-aminosaccharide compound represented by the general formula (5). About 0 to 500 parts by weight, preferably about 0 to 100 parts by weight may be used.

  In addition, this reaction is usually preferably carried out in the presence of an acid, and a known inorganic acid or organic acid can be used as the acid used. Examples of the inorganic acid include acid anhydrides such as sulfuric acid and nitric acid, and examples of the organic acid include trifluoroacetic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, and the like. These acids are used individually by 1 type or in mixture of 2 or more types.

  The amount of such an acid used is appropriately set according to the type and amount of the reactant used, but is usually relative to the 2-amino sugar compound represented by the general formula (5). 1 to 200 equivalents, preferably 10 to 100 equivalents, more preferably about 20 to 60 equivalents.

  This reaction can usually be performed within a range from −100 ° C. to the boiling temperature of the solvent used. The reaction is preferably performed at 0 ° C to 60 ° C, preferably room temperature to 40 ° C.

  The reaction time varies depending on the type of reaction agent used, reaction temperature, and the like, and cannot be generally specified, but the reaction is usually completed in about 0.5 to 24 hours.

( Process 3 )
The deprotection reaction (Process 3) of the hydroxyl group at the 1-position of the 2-imide sugar compound represented by the general formula (6) is performed by a conventionally known method according to the type of the protective group to be deprotected. Apply.

  For example, when the protecting group is an acetyl group, it is usually carried out in a solvent in the presence of a base.

  Examples of the base to be used include hydrazine acetic acid and benzylamine.

  The amount of such a base used is appropriately set according to the type and amount of the reactant used, but is generally normal to the 2-aminosaccharide compound represented by the general formula (6). 1 to 100 equivalents, preferably 1 to 5 equivalents, more preferably about 1 to 2.0 equivalents.

  As a solvent to be used, a known solvent can be widely used as long as it is an inert solvent for the reaction. For example, an aliphatic or alicyclic hydrocarbon solvent such as hexane, cyclohexane, heptane, etc. , Aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, xylene, halogenated hydrocarbon solvents such as methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4-dioxane Ether solvents such as methyl acetate and ethyl acetate, ketone solvents such as acetone and methyl ethyl ketone, amide solvents such as N, N-dimethylformamide, nitrile solvents such as acetonitrile and propionitrile, dimethyl Sulfoxide, N-methylpyrrolidone, N, N′-dimethyli Examples include aprotic polar solvents such as midazolinone. These solvents can be used alone or in combination of two or more as required.

  The amount of these solvents to be used may be appropriately set depending on the type of reactant used, the type of reaction, and the like, but is usually based on 1 part by weight of the 2-aminosaccharide compound represented by the general formula (6). About 1 to 500 parts by weight, preferably about 5 to 100 parts by weight may be used.

  This reaction can usually be performed within a range from −100 ° C. to the boiling temperature of the solvent used. The reaction is preferably performed at −30 ° C. to room temperature, and more preferably at −15 ° C. to room temperature.

  The reaction time varies depending on the type of reaction agent used, reaction temperature, and the like, and cannot be generally specified, but the reaction is usually completed in about 0.5 to 24 hours.

( Process 4 )
The reaction (Process 4) for substituting a predetermined leaving group at the 1-position of the 2-imide sugar compound represented by the general formula (7) selects a reaction corresponding to the reactant corresponding to the leaving group to be introduced. And do it.

  When a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom is introduced as a leaving group, a conventionally known halogenating agent can be allowed to act, for example, in a solvent that does not adversely influence the reaction. That's fine.

  Examples of the halogenating agent include chlorine, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, and hydrogen bromide. The amount of such a halogenating agent to be used is appropriately set according to the type of the halogenating agent to be used, but is usually at least equimolar or more with respect to the compound represented by the general formula (7). Use it.

  Examples of the solvent used include halogenated hydrocarbon solvents such as methylene chloride, 1,2-dichloroethane, chloroform and carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane, acetic acid. , Water and the like. These solvents can be used alone or in combination of two or more as required.

When a C _1-4 alkylthio group such as a methylthio group or an arylthio group such as a phenylthio group is introduced as a leaving group, an acid anhydride is usually used in a solvent that does not adversely influence the reaction in the presence of an acid or a base. And a predetermined thiol compound may be allowed to act.

  Examples of the acid anhydride include acetic anhydride. The amount of the acid anhydride used is usually at least equimolar or more with respect to the compound represented by the general formula (7).

  Examples of the thiol compound include methyl thiol, isopropyl thiol, and thiophenol. The amount of the thiol compound used is appropriately set according to the type of the thiol compound to be used, but is usually at least equimolar or more with respect to the compound represented by the general formula (7). Good.

  Examples of the acid include Lewis acids such as boron fluoride diethyl ether.

  Examples of the base include 1,3-dimethylimidazolium chloride, triethylamine and the like. The amount of the acid or base used is appropriately set according to the type and amount of the thiol compound to be used. For example, at least 0 with respect to the compound represented by the general formula (7). .1 mol or more, preferably equimolar or more.

  Moreover, as a solvent to be used, single or 2 types or more of mixed solvents, such as a dichloromethane, acetonitrile, toluene, water, can be mentioned.

When a C _1-5 alkylcarbonyloxy group is introduced as a leaving group, usually in a solvent that does not adversely influence the reaction, in the presence of a base, a reaction accelerator is used in combination with the reaction agent as necessary. May be used.

  Examples of the reactant include acetic anhydride and propionic anhydride. The amount of such a reactive agent used is appropriately set according to the type of the reactive agent to be used, but is usually at least equimolar or more with respect to the compound represented by the general formula (7). Good.

  Examples of the base include pyridine, triethylamine, diisopropylethylamine, diazabicycloundecene and the like. The amount of such base used is appropriately set according to the type and amount of reactant used, but is usually at least equimolar or more with respect to the compound represented by the general formula (7). Use it.

  Examples of the reaction accelerator include dimethylaminopyridine.

  Examples of the solvent used include halogenated hydrocarbon solvents such as methylene chloride, 1,2-dichloroethane, chloroform and carbon tetrachloride, amide solvents such as N, N-dimethylformamide, and the like. These solvents can be used alone or in combination of two or more as required.

  Alternatively, the desired compound can be obtained by reacting an acyl halide such as acetyl chloride in a solvent that does not adversely affect the reaction.

When a C _2-6 alkenylcarbonyloxy group is introduced as a leaving group, usually in a solvent that does not adversely influence the reaction, in the presence of a base, a reaction accelerator is used in combination with the reaction agent as necessary. May be used.

  Examples of the reactant include anhydrous 4-pentenyl acid, anhydrous 3-butenyl acid, and the like. The amount of such a reactive agent used is appropriately set according to the type of the reactive agent to be used, but is usually at least equimolar or more with respect to the compound represented by the general formula (7). Good.

  Examples of the base include pyridine, triethylamine, diisopropylethylamine, diazabicycloundecene base, etc. The amount of such a base used is appropriately set according to the type and amount of the reactant used. In general, the compound represented by the general formula (7) may be used at least in an equimolar amount or more.

  Examples of the reaction accelerator include dimethylaminopyridine.

  Examples of the solvent used include halogenated hydrocarbon solvents such as methylene chloride, 1,2-dichloroethane, chloroform and carbon tetrachloride, amide solvents such as N, N-dimethylformamide, and the like. These solvents can be used alone or in combination of two or more as required.

  When a trihaloacetimidoyloxy group such as a trifluoroacetimidoyloxy group, trichloroacetimidoyloxy group, or N-phenyltrichloroacetimidoyloxy group is introduced as a leaving group, the reaction is usually adversely affected. The reaction agent may be allowed to act in the presence of a base in a non-solvent.

  Examples of the base include triethylamine, diisopropylethylamine, diazabicycloundecene and the like. The amount of these bases to be used is appropriately set according to the type and amount of the reactants to be used, but is usually 0.1 with respect to the 2-amino sugar compound represented by the general formula (7). -10 equivalents, preferably 0.1-5 equivalents, more preferably about 0.2-1.0 equivalents.

  As the reactant, trichloroacetonitrile, trifluoroacetonitrile, or the like may be allowed to act. Although the usage-amount of these reactants is set suitably according to the kind of reactant used, it is 1-200 equivalent normally with respect to the 2-amino sugar compound represented by General formula (7). More preferably, it may be about 5 to 100 equivalents.

  Examples of the solvent used include aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene and xylene, halogenated hydrocarbon solvents such as methylene chloride, 1,2-dichloroethane, chloroform and carbon tetrachloride, acetone. And ketone solvents such as methyl ethyl ketone. These solvents can be used alone or in combination of two or more as required. The amount of these solvents used is usually about 10 to 100 parts by weight, preferably about 10 to 50 parts by weight per 1 part by weight of the 2-aminosaccharide compound represented by the general formula (7). .

  This reaction can usually be performed within a range from -100 ° C to the boiling point of the solvent used, and is preferably performed at -50 ° C to room temperature, and is performed at -40 ° C to 0 ° C. Is more preferable. The reaction time varies depending on the type of reaction agent used, reaction temperature, and the like, and cannot be generally specified, but the reaction is usually completed in about 0.5 to 24 hours.

  As a leaving group, a thioformimidoyl group such as p-trifluoromethylbenzylthio-p-trifluoromethylphenylformimidoyl group, p-trifluoromethylbenzylthio-p-nitrophenylformimidoyl group is introduced. In the case, the 2-imide sugar compound represented by the general formula (5) is reacted with p-trifluoromethylphenyl isothiocyanate or p-nitrophenyl isothiocyanate, and then treated with p-trifluoromethylbenzyl bromide or the like. By doing so, the sugar donor represented by the general formula (2) can be produced.

  This reaction proceeds in the presence of a base in a solvent.

  Examples of the base used include n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium hydride, potassium hydride and the like. The amount of such a base used is appropriately set according to the type and amount of the reactant used, but is usually a catalyst amount, for example, relative to the compound represented by the general formula (7). , At least 0.1 mol may be used.

  Examples of the solvent used include aliphatic or alicyclic hydrocarbon solvents such as hexane, cyclohexane, and heptane, aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, and xylene, methylene chloride, and 1,2-dichloroethane. , Halogenated hydrocarbon solvents such as chloroform and carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane, ester solvents such as methyl acetate and ethyl acetate, ketone solvents such as acetone and methyl ethyl ketone Amide solvents such as N, N-dimethylformamide, nitrile solvents such as acetonitrile and propionitrile, aprotic polar solvents such as dimethyl sulfoxide, N-methylpyrrolidone and N, N′-dimethylimidazolinone be able to. These solvents can be used alone or in combination of two or more as required.

  The reaction temperature is selected between room temperature and -100 ° C, but the first step is preferably -78 ° C, and the second step is preferably 0 ° C. This reaction can be carried out usually within a range from −100 ° C. to room temperature. In the reaction using phenyl isothiocyanate, about −78 ° C. is preferable, and in the case of benzylation treatment, around 0 ° C. is preferable.

2-3. Production Method of Sugar Receptor The sugar receptor represented by the general formula (3) used as a raw material of Reaction Formula-1 can be produced, for example, by the method shown in the following Reaction Formula-3.

[Wherein, R ¹ , R ² , R ⁵ and Q ¹ are the same as described above. R ^13a and R ^13b are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group, a C _2-6 alkenyl group or a phenyl group. Here, the C _1-4 alkyl group and the C _2-6 alkenyl group are the same as defined in the general formula (1). ]

As shown in Reaction Formula-3, the 4- and 6-position hydroxyl protecting groups of the saccharide compound represented by the general formula (8) were deprotected and converted to the saccharide compound represented by the general formula (9). After (Process 5), (a) selectively protecting the hydroxyl group at the 6-position, or (b) oxidizing the -CH ₂ OH at the 5-position and then introducing the protecting group, the general formula (3) Can be produced (Process 6).

Alternatively, by selectively deprotecting the hydroxyl-protecting group at the 4-position of the sugar compound represented by the general formula (8), R ⁵ is a group —CH ₂ OCHR ^13a R ^13b. ) Can be induced in one step (Process 7).

( Process 5 )
The reaction (Process 5) for deprotecting the 4- and 6-position hydroxyl protecting groups of the saccharide compound represented by the general formula (8) and converting it into the saccharide compound represented by the general formula (9) is usually performed. By hydrolysis in the presence of an acid in a solvent.

  As the acid used in this reaction, a known inorganic acid or organic acid can be used. Examples of the inorganic acid include acid anhydrides such as sulfuric acid and nitric acid, and examples of the organic acid include trifluoroacetic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, and the like. These acids are used individually by 1 type or in mixture of 2 or more types.

  The amount of these acids used is appropriately set according to the type and amount of the reactant used, but is usually 1 to 100 equivalents relative to the saccharide compound represented by the general formula (8), Preferably, it may be about 10 to 50 equivalents.

  As the solvent to be used, known solvents can be widely used as long as they are inert to the reaction. For example, aliphatic or alicyclic hydrocarbons such as hexane, cyclohexane, heptane, etc. Solvents, aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, xylene, halogenated hydrocarbon solvents such as methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4 -Ether solvents such as dioxane, ester solvents such as methyl acetate and ethyl acetate, ketone solvents such as acetone and methyl ethyl ketone, amide solvents such as N, N-dimethylformamide, and nitrile solvents such as acetonitrile and propionitrile. , Dimethyl sulfoxide, N-methylpyrrolidone, N, N′-dimethyl Examples thereof include aprotic polar solvents such as tilimidazolinone. These solvents can be used alone or in combination of two or more as required.

  The amount of these solvents to be used may be appropriately set depending on the type of reactant used, the type of reaction, and the like, but is usually 1 to 1 part by weight of the disaccharide compound represented by the general formula (8). About 100 parts by weight, preferably about 1 to 50 parts by weight may be used.

  This reaction can be carried out usually within a range from -20 ° C to the boiling point of the solvent used. The reaction is preferably performed at −10 ° C. to 30 ° C., and preferably 0 to 30 ° C.

  The reaction time varies depending on the type of reaction agent used, the reaction temperature, and the like, and cannot be generally stated, but the reaction is usually completed in about 0.5 to 24 hours.

( Process 6 )
For the sugar compound represented by the general formula (9), (a) selectively protecting the hydroxyl group at the 6-position, or (b) introducing a protecting group after oxidizing -CH ₂ OH at the 5-position. Thus, the reaction (Process 6) for obtaining the sugar receptor represented by the general formula (3) is performed by selecting a reaction corresponding to the reactant corresponding to the group to be introduced.

  (A) The reaction for selectively protecting the hydroxyl group at the 6-position is usually carried out by reacting a reactant in a solvent.

  Examples of the reactive agent include those in which the corresponding protecting group is activated with a trichloroimidoyloxy group or the like, and halogen compounds of the corresponding protecting group. The amount of these reactants to be used is appropriately set according to the type and amount of the reactant to be used, but is usually 1 to 100 equivalents relative to the sugar compound represented by the general formula (9). Preferably, it may be about 1.5 to 10 equivalents.

  As the solvent used in the present invention, known solvents can be widely used as long as they are inert to the reaction. For example, aliphatic or alicyclic such as hexane, cyclohexane, heptane, etc. Hydrocarbon solvents, aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, xylene, halogenated hydrocarbon solvents such as methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1 Ether solvents such as 1,4-dioxane, ester solvents such as methyl acetate and ethyl acetate, ketone solvents such as acetone and methyl ethyl ketone, amide solvents such as N, N-dimethylformamide, nitriles such as acetonitrile and propionitrile Solvents, dimethyl sulfoxide, N-methylpyrrolidone, N, N ′ -Aprotic polar solvents such as dimethylimidazolinone. These solvents can be used alone or in combination of two or more as required.

  The amount of these solvents to be used may be appropriately set depending on the type of reactant used, the type of reaction, and the like, but is usually 1-100 parts per 1 part by weight of the sugar compound represented by the general formula (9). About 1 part by weight, preferably about 1 to 50 parts by weight may be used.

  In addition, this reaction is usually preferably carried out in the presence of an acid, and a known inorganic acid or organic acid can be used as the acid used. Examples of the inorganic acid include acid anhydrides such as sulfuric acid and nitric acid, and examples of the organic acid include trifluoroacetic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, and the like. These acids are used individually by 1 type or in mixture of 2 or more types.

  The amount of these acids used is appropriately set according to the type and amount of the reactants to be used, but is usually from 0.05 to the sugar compound represented by the general formula (9). It may be 10 equivalents, preferably about 0.1 to 2 equivalents.

  This reaction can usually be performed within a range from −20 ° C. to the boiling temperature of the solvent used. The reaction is preferably performed at −10 ° C. to 30 ° C., and preferably 0 to 30 ° C.

  The reaction time varies depending on the type of reaction agent used, reaction temperature, etc., and cannot be generally specified, but the reaction is usually completed in about 0.5 to 24 hours.

(B) The oxidation reaction of —CH ₂ OH at the 5-position is usually performed in a solvent by combining a catalyst necessary for oxidation and a reoxidant.

  As the catalyst, TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) is used, and as the reoxidant, hypochlorous acid, BAIB ((Diacetoxyiodo) benzene), hydrogen peroxide, potassium permanganate, etc. are used. It is done.

  The usage-amount of these catalysts is 0.05-10 equivalent normally with respect to the saccharide compound represented by General formula (9), Preferably what is necessary is just to be about 0.1-2 equivalent. Moreover, what is necessary is just to make the usage-amount of a reoxidant into 1-50 equivalent normally with respect to the saccharide | sugar compound represented by General formula (9), Preferably it is about 1.5-3 equivalent.

  As a solvent to be used, a known solvent can be widely used as long as it is an inert solvent for the reaction. For example, an aliphatic or alicyclic hydrocarbon solvent such as hexane, cyclohexane, heptane, etc. , Aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, xylene, halogenated hydrocarbon solvents such as methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4-dioxane Ether solvents such as methyl acetate, ester solvents such as methyl acetate and ethyl acetate, ketone solvents such as methyl ethyl ketone, and these solvents can be used alone or in admixture of two or more. A two-phase reaction solvent with water added thereto can be used.

  The amount of these solvents to be used may be appropriately set depending on the type of reactant used, the type of reaction, and the like, but is usually 1-100 parts per 1 part by weight of the sugar compound represented by the general formula (9). About 1 part by weight, preferably about 1 to 50 parts by weight may be used.

  The reaction time varies depending on the type of reaction agent used, reaction temperature, and the like, and cannot be generally specified, but the reaction is usually completed in about 0.5 to 24 hours.

  After the oxidation reaction, the protecting group introduction reaction is usually performed by reacting a reactant in a solvent.

  As the reactant, trimethylsilyldiazomethane, a mixture of alcohol / hydrochloric acid, or the like is used. The amount of these reactants to be used is usually about 1 to 50 equivalents, preferably about 1.5 to 5 equivalents, relative to the sugar compound represented by the general formula (9).

  As a solvent to be used, a known solvent can be widely used as long as it is an inert solvent for the reaction. For example, an aliphatic or alicyclic hydrocarbon solvent such as hexane, cyclohexane, heptane, etc. , Aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, xylene, halogenated hydrocarbon solvents such as methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4-dioxane Ether solvents such as methyl acetate, ester solvents such as methyl acetate, ketone solvents such as methyl ethyl ketone, alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol and butanol, and these solvents are one kind. Can be used alone, or two or more types can be mixed and used as necessary Rukoto can, or can be used by mixing two or more kinds as necessary.

  The amount of these solvents to be used may be appropriately set depending on the type of reactant used, the type of reaction, and the like, but is usually 1-100 parts per 1 part by weight of the sugar compound represented by the general formula (9). About 1 part by weight, preferably about 1 to 50 parts by weight may be used.

  This reaction can usually be performed within a range from −40 ° C. to the boiling temperature of the solvent used. The reaction is preferably performed at -20 ° C to 30 ° C, and preferably -10 to 25 ° C.

  The reaction time varies depending on the type of reaction agent used, the reaction temperature, etc., and cannot be generally specified, but the reaction is usually completed in about 0.5 to 248 hours.

( Process 7 )
In the general formula (3), R ⁵ is a group —CH ₂ OCH ₂ R ^13a R ^13b by selectively deprotecting the protecting group of the hydroxyl group at the 4-position of the sugar compound represented by the general formula (8). The reaction (Process 7) induced to the sugar acceptor represented in one step is usually performed by selectively performing a reduction reaction with a combination of a Lewis acid and a reducing agent in a solvent.

Examples of the Lewis acid used include BF ₃ .OEt ₂ , AlCl ₃ , AlMeCl ₂ , AlMe ₂ Cl, AgCl, CuCl _{2, and the} like. Examples of the reducing agent include triethylsilane, NaCNBH ₃ , BH ₃ .NMe _{3, and the} like. Can be mentioned. The amount of these Lewis acids used is usually 0.1 to 100 equivalents, preferably about 0.2 to 20 equivalents, relative to the saccharide compound represented by the general formula (8). Moreover, the usage-amount of a reducing agent is 1-30 equivalent normally with respect to the saccharide | sugar compound represented by General formula (8), Preferably what is necessary is just to be about 1.5-20 equivalent.

  As a solvent to be used, a known solvent can be widely used as long as it is an inert solvent for the reaction. For example, an aliphatic or alicyclic hydrocarbon solvent such as hexane, cyclohexane, heptane, etc. , Aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, xylene, halogenated hydrocarbon solvents such as methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4-dioxane Ether solvents such as methyl acetate, ester solvents such as methyl acetate and ethyl acetate, ketone solvents such as methyl ethyl ketone, and these solvents can be used alone or in admixture of two or more. It can be used, or two or more can be mixed and used as necessary.

  The amount of these solvents to be used may be appropriately set depending on the type of reactant used, the type of reaction, and the like, but is usually 1-100 parts per 1 part by weight of the sugar compound represented by the general formula (8). About 1 part by weight, preferably about 1 to 50 parts by weight may be used.

  This reaction can usually be performed within a range from -70 ° C to the boiling point of the solvent used. The reaction is preferably performed at -40 ° C to 30 ° C, and preferably -20 to 25 ° C.

  The reaction time varies depending on the type of reaction agent used, reaction temperature, and the like, and cannot be generally specified, but the reaction is usually completed in about 0.5 to 24 hours.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Examples, but the present invention is not limited to the following Examples.

In addition, abbreviations described in each reaction formula in the following reference examples and examples are as follows.
Ac: acetyl group, All: allyl group, Bn: benzyl group, Me: methyl group, NDMM: dimethylmaleimide group, NPhth: phthalimide group, OMP: p-methoxyphenoxy group, Ph: phenyl group, TCA: trichloroacetyl group, Tf: trifluoromethanesulfonyl group, Z: group —SO ₃ CH ₂ CCl ₃ .

Reference Example 1 (Preparation of sugar acceptor / donor raw material 1-1)

  Glucose (90 g) and N, N-dimethylformamide (DMF) (600 ml) are stirred at room temperature, Benzaldehyde dimethyl acetal (90 ml) and camphorsulfonic acid (CSA) (6.18 g) are added in this order, and 25 at room temperature under reduced pressure. Stir for hours. After completion of the reaction, DMF was distilled off under reduced pressure, and triethylamine (4.5 ml) and pyridine (450 ml) were added and dissolved in the resulting concentrated residue. The solution was cooled to 0-5 ° C., acetic anhydride (450 ml) was added, and the mixture was warmed to room temperature and stirred for 15 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and toluene was added to the residue for azeotropy to distill off pyridine. Dichloromethane (600 ml) was added to the resulting concentrated residue to dissolve it, washed with saturated aqueous sodium hydrogen carbonate (450 ml) and saturated brine (450 ml), and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrated residue was crystallized from hot methanol to obtain compound (11) (90.75 g, yield 45.9%).

  Tetrahydrofuran (THF) (900 ml) was added and dissolved in compound (11) (90 g), benzylamine (31.2 ml) was added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, dichloromethane (1500 ml) was added, washed with 1N hydrochloric acid (300 ml), saturated aqueous sodium hydrogen carbonate (600 ml) and saturated brine (600 ml), and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrated residue was purified with a silica gel column to obtain compound (12) (62.3 g, yield 77.6%).

  Dichloromethane (2100 ml) was added to compound (12) (82.8 g) and dissolved, and the mixture was cooled to an internal temperature of −10 ° C. under a nitrogen atmosphere. Trichloroacetonitrile (117.8 ml) was added to this, and DBU (1,8-diazabicyclo [5.4.0] undec-7-ene) (10.4 ml) was slowly added dropwise while maintaining the range of −10 to −3 ° C. . After stirring at −8 to −5 ° C. for 3 hours, the reaction solution was concentrated under reduced pressure, and the resulting concentrated residue was purified by a silica gel column to obtain compound (13) (104.1 g, yield 90.0%). .

Reference Example 2 (Preparation of sugar acceptor / donor raw material 1-2)

  A solution of p-toluenesulfonyl chloride (16.93 g) / pyridine (34.3 ml) was added dropwise to mannose (10.0 g) and pyridine (40.3 ml) under an argon atmosphere, and the mixture was stirred at room temperature for 4.5 hours. (29.3 ml) was added and stirred at room temperature for 16.5 hours. The reaction solution was poured into ice and extracted with chloroform. The organic layer was washed with saturated brine, saturated aqueous sodium bicarbonate, and saturated brine in that order, and dried over magnesium sulfate. The organic layer was filtered, and the residue obtained by concentrating the filtrate was purified with a liqueur gel column. Alumina (316.89 g) was added to this and concentrated, followed by vacuum drying. The alumina after vacuum drying was irradiated with M.W. (high frequency output 500 W) for 2 minutes, and the powder was thoroughly mixed, and then heated for another 2 minutes. After filtration through celite, the mixture was washed with an ethanol / ethyl acetate (9/1) solution and concentrated. Methanol (110 ml), triethylamine (55 ml) and water (55 ml) were added to the concentrated residue, and the mixture was stirred for 16.5 hours. The reaction solution was concentrated and the concentrated residue after toluene azeotropy was purified with a silica gel column to obtain Compound (14) (4.0666 g, yield 48.4% (2 steps)).

  DMF (1168 ml) was added to sodium hydride (103.6 g) and cooled to 0-10 ° C. Compound (14) (70 g) / DMF (632 ml) was added dropwise to this suspension while maintaining the internal temperature at 0 to 10 ° C. After completion of the dropwise addition, the used container was washed with DMF (68 ml), stirred at this temperature for 1 hour, the internal temperature was adjusted to 15 to 20 ° C., and benzyl bromide (154 ml) was added dropwise over 30 minutes. added. After completion of dropping, the mixture was stirred for about 30 minutes, and benzyl bromide (154 ml) was added dropwise again over 30 minutes. The mixture was aged at this temperature for 30 minutes and then stirred at room temperature for 13 hours. The reaction solution was cooled to 0 to 5 ° C., and a solution in which methanol (210 ml) was added was added to a mixed solution of ethyl acetate (1720 ml) and 3% aqueous sodium hydrogen carbonate (1400 ml), followed by liquid separation. The aqueous layer was extracted with ethyl acetate, and the obtained organic layers were combined, washed with water and saturated brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrated residue was purified by a silica gel column to obtain compound (15) (172 g, yield 92%).

  Dichloromethane (4687 ml) was added to compound (15) (186 g) and dissolved, and after cooling under nitrogen atmosphere to an internal temperature of −10 to −5 ° C., tin (IV) chloride (55.4 ml) was slowly added. The mixture was stirred at the temperature of the lever for 1.5 hours. After completion of the reaction, the reaction solution was slowly poured into 1N hydrochloric acid (5125 ml) that had been ice-cooled in advance, followed by liquid separation, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed successively with water, 3% aqueous sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrated residue was purified by a silica gel column to obtain compound (16) (127 g, yield 86.7%).

  Dichloromethane (2000 ml) was added to compound (16) (131.2 g) and dissolved, and the mixture was cooled to −10 ° C. under a nitrogen atmosphere. Pyridine (77 ml) was added to this solution, and then trifluoromethanesulfonic anhydride (97 ml) was slowly added. The temperature was raised to 0 ° C. and stirred for 1 hour. After completion of the reaction, 3% aqueous sodium bicarbonate (3150 ml) was slowly poured into the reaction mixture, the phases were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and DMF (1725 ml) was added to the concentrated residue to dissolve it. Powdered molecular sieves (MS) 3A (220 g) and sodium azide (75 g) were added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, ethyl acetate and water were added to the filtrate for liquid separation, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with 10% brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrated residue was purified by a silica gel column to obtain compound (17) (123 g, yield 85.1%).

  Compound (17) (122 g) was dissolved in dichloromethane (6400 ml), titanium tetrachloride (44.9 ml) was slowly added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. Cold 1N hydrochloric acid (7600 ml) was slowly poured into the reaction mixture, the phases were separated, and the aqueous layer was extracted with dichloromethane (3400 ml). The organic layers were combined, washed successively with water, saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrated residue was purified by a silica gel column to obtain compound (18) (74.8 g, yield 80.0%).

  Compound (18) (74.5 g), MS3A (62.0 g) and dichloromethane (1170 ml) were stirred at room temperature, and the internal temperature was cooled to 0 to 5 ° C. under a nitrogen atmosphere, and then 1,2-dimethylimidazole (DMI) (51.7 g) was added followed by compound (19) (246 g). The reaction liquid was returned to room temperature and stirred as it was for 17 hours. After completion of the reaction, dichloromethane (2300 ml) was poured into the reaction solution, and the reaction solution was filtered through Celite. The filtrate was washed with water, 10% brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrated residue was purified with a silica gel column to obtain compound (20) (128.9 g, quantitative).

  Carbon tetrachloride (3520 ml) and water (1760 ml) were added to compound (20) (47.8 g), and the mixture was stirred at 30 to 32 ° C. N-bromosuccinimide (43.6 g) and calcium carbonate (42.8 g) were added to this, and nitrogen bubbling was performed for 30 minutes, followed by irradiation with an incandescent lamp (375 W, 10 minutes × 4 times). After completion of the reaction, the reaction solution was cooled to 10 to 15 ° C., and the reaction solution was filtered. Water was added to the filtrate for liquid separation, and the aqueous layer was extracted with dichloromethane. The obtained organic layers were combined, washed successively with 1% aqueous sodium sulfite solution, water and saturated brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrated residue was purified by a silica gel column to obtain compound (21) (33.2 g, yield 85%).

Reference Example 3 (Preparation of sugar acceptor / donor raw material 1-3)

  Dichloromethane (1180 ml) was added to the compound (13) (76.9 g) and the compound (21) (36.2 g) produced in Reference Example 2, and the mixture was stirred and dissolved at room temperature (20 to 25 ° C.). After replacing with nitrogen, MS4A (102 g) was added and stirred for 60 minutes. Trimethylsilyl trifluoromethanesulfonate (TMSOTf) (3.29 ml) was added to the reaction solution, and the mixture was stirred and stirred at room temperature for 1.5 hours. The reaction solution was filtered, and the filtrate was washed successively with 3% aqueous sodium hydrogen carbonate and saturated brine, Dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, chloroform (100 ml) was added to the resulting residue to dissolve it, and hexane (202 ml) was slowly added. The precipitate was removed by filtration, the obtained filtrate was concentrated under reduced pressure, and the concentrated residue was purified by a silica gel column to obtain compound (22) (53.6 g, yield 80%).

Reference Example 4 (Preparation of sugar acceptor / donor raw material 1-4)

  Dichloromethane (1425 ml) and methanol (1288 ml) were added to compound (22) (85.5 g) and dissolved. After purging with nitrogen and cooling the internal temperature to −10 ° C., 0.5 M sodium methoxide (200 ml) was added, and the mixture was stirred at −10 to −8 ° C. for 26 hours. 1N Hydrochloric acid (107 ml), saturated brine (800 ml), water (360 ml) and dichloromethane (1400 ml) were added to the reaction solution to separate the layers. The aqueous layer was extracted with dichloromethane (1400 ml), and the obtained organic layers were combined, washed with saturated brine and water, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrated residue was purified by a silica gel column to obtain compound (23) (48.5 g, yield 63%).

  Dichloromethane (310 ml) was added to and dissolved in the compound (23) (46.3 g), and the inside of the reaction system was purged with argon. DMI (25.8 g) and compound (19) (98.0 g) were added and reacted at an internal temperature of 37 ° C. One day and two days after the start of the reaction, DMI (25.8 g) and compound (19) (98.0 g) were additionally added, and the reaction was carried out for a total of 3 days. Then, the reaction solution was concentrated under reduced pressure. The concentrated residue was purified by a silica gel column to obtain compound (8-1) (48.2 g, yield 63%).

Reference Example 5 (Preparation 1 of sugar donor raw material)

  Compound (8-1) (300.0 mg) was dissolved in THF (11 ml) and water (1.2 ml), triphenylphosphine (147 mg) and silica gel (154 mg) were added thereto, and the mixture was stirred at room temperature for 3 hours. After confirming disappearance of the raw materials, water (5 ml) was added, and the mixture was stirred at 40 ° C. overnight. The reaction solution was filtered through Celite, and the filtrate was concentrated. The resulting residue was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, concentrated and the resulting residue was purified by column to give compound (4-1) (259.9 mg, 89% yield). .

  Compound (4-1) (50.0 mg) was dissolved in chloroform (1 ml), phthalic anhydride (10.6 mg) was added, and the mixture was heated to reflux. After confirming the formation spot of the carboxylic acid form by TLC, the temperature was returned to room temperature, acetic anhydride (45 μl) and pyridine (38 μl) were added, and the mixture was heated to reflux overnight. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed successively with 1N hydrochloric acid, aqueous sodium bicarbonate, and saturated brine, dried over magnesium sulfate, and concentrated to obtain a solid residue. This was crushed and washed with hexane / ethyl acetate (5/1 (V / V)) and collected by filtration to obtain compound (5-1) (43.4 mg, yield 77%).

  Compound (5-1) (4.20 g) was dissolved in acetic anhydride (500 ml) at 60 ° C., and acetic acid (2.1 ml) was added. The reaction solution was cooled to 40 ° C., trifluoroacetic acid (16 ml) was added, and the mixture was stirred at 40 ° C. for 8 hours, and then stirred at 30 ° C. overnight. The reaction solution was added with aqueous sodium bicarbonate to terminate the reaction, diluted with ethyl acetate, and further washed with aqueous sodium bicarbonate. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. After concentrating the filtrate, the residue obtained by azeotropic distillation with toluene was purified with a column to obtain compound (6-1) (3.15 g, yield 69%).

  Compound (6-1) (3.15 g) was dissolved in DMF (40 ml), cooled to −15 ° C., hydrazine acetic acid (295.4 mg) was added, and the mixture was stirred at −15 ° C. for 5 hours. The reaction mixture was diluted with ethyl acetate, and aqueous sodium bicarbonate was added to separate the layers. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained residue was purified with a column to obtain compound (7-1) (2.41 g, yield 79%).

Reference Example 6 (Preparation 2 of sugar donor raw material)

  Compound (4-1) (3.916 g) was dissolved in dichloromethane (20 ml), maleic anhydride (708.5 mg) and triethylamine (1.0 ml) were added, and the mixture was heated to reflux for 3 days. The precipitated target product was dissolved in dichloromethane, washed with 1N hydrochloric acid, and the aqueous hydrochloric acid used for washing was extracted with dichloromethane. The obtained organic layer was washed successively with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The organic layer was filtered, and the residue obtained by concentrating the filtrate was dissolved in chloroform (40 ml), and hexane (120 ml) was added dropwise over 20 minutes, followed by crystallization at room temperature. The crystals were collected by filtration and washed with chloroform / hexane (1/3 (v / v)) to obtain compound (5-2) (2.86 g, yield 66%).

  Compound (5-2) (651.6 mg) was dissolved in acetic anhydride (17 ml), acetic acid (330 μl) was added, and the mixture was ice-cooled. Trifluoroacetic acid (2.62 ml) was added to the reaction mixture, and the mixture was stirred at room temperature, heated to 40 ° C. to dissolve it, and stirred at 30 ° C. for 2 hours to return to room temperature. The reaction mixture diluted with ethyl acetate was poured into sodium bicarbonate water to terminate the reaction, and the phases were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined and washed with saturated brine. And dried over magnesium sulfate. The organic layer was filtered, the filtrate was concentrated and the residue obtained by further azeotroping with toluene was purified by column purification to obtain compound (6-2) (400.4 mg, yield 56%).

  Compound (6-2) (400.4 mg) was dissolved in DMF (5.3 ml), cooled to −15 ° C., hydrazine acetic acid (35.3 mg) was added, and the mixture was stirred at −15 ° C. for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by column purification to give compound (7- 2) (336.0 mg, 87% yield) was obtained.

Reference Example 7 (Preparation 2 of sugar acceptor raw material)

  Compound (8-1) (5.0 g) was dissolved in acetic anhydride (63 ml), acetic acid (2.75 ml) was added, cooled to −10 ° C., trifluoroacetic acid (20.3 ml) was added, and the mixture was stirred for 24 hours. . The reaction mixture was diluted with ethyl acetate, poured into aqueous sodium bicarbonate to terminate the reaction, and the phases were separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The organic layer was filtered, the filtrate was concentrated, and the residue obtained by toluene azeotropy was purified by column to obtain Compound (24) (3.63 g, 66% yield).

  Compound (24) (2.63 g) was dissolved in DMF (34 ml), cooled to 0 ° C., hydrazine acetic acid (371.5 mg) was added, and the mixture was stirred at 0 ° C. for 5 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The organic layer was filtered, and the residue obtained by concentrating the filtrate was purified by column to obtain Compound (25) (1.90 g).

  Compound (25) (336.0 mg) was dissolved in dichloromethane (5.6 ml), trichloroacetonitrile (2.8 ml) was added, and the mixture was cooled to −40 ° C. DBU (8.3 μl) was added to the reaction solution and stirred at −40 ° C. for 1 hour. The reaction mixture was concentrated, and the resulting residue was purified by column to obtain Compound (26) (324.1 mg, yield 86%).

  Compound (26) (1.64 g) and p-methoxyphenol (192 mg) are dissolved in toluene (16.4 ml), MS4A (1.8 g) is added and cooled to −40 ° C., boron trifluoride diethyl ether (32 μl) And stirred at the same temperature for 1.5 hours. The reaction solution was filtered through celite, washed successively with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The reaction solution was filtered, and the residue obtained by concentrating the filtrate was purified by column to obtain the compound (8-2) (1.36 g, yield 85%).

Reference Example 8 (Preparation 3 of sugar acceptor raw material)

Compound (13) (200.0 mg) and p-methoxyphenol (60 mg) were dissolved in dichloromethane (1 ml), MS4A (500 mg) was added, and the mixture was stirred at room temperature for 1 hour and cooled to -20 ° C.
TMSOTf (81 μl) was added to the reaction solution and stirred at the same temperature for 1 hour. The reaction solution was filtered through celite, washed successively with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The reaction solution was filtered, and the residue obtained by concentrating the filtrate was purified by column to obtain Compound (27) (164 mg, yield 89%).

  Dichloromethane (1.7 ml) and methanol (1.1 ml) were added to compound (27) (100 mg) and stirred at room temperature to dissolve. To this, 1M sodium methoxide (110 μl) was added and stirred for 3 hours. After completion of the reaction, 1N hydrochloric acid was added to the reaction solution to quench the reaction, and the reaction solution was diluted with dichloromethane and then separated. The aqueous layer was extracted with dichloromethane, and the obtained organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The organic layer was filtered, and the residue obtained by concentrating the filtrate was purified by a silica gel column to obtain compound (28) (67.8 mg, 83% yield).

  Compound (28) (67.6 mg), dichloromethane (730 μl) and MS4A (300 mg) were added and stirred at room temperature. After replacing the reaction system with argon gas, the reaction system was cooled to 0 ° C., DMI (43.5 mg) and compound (19) (166 mg) were added, and the mixture was reacted at 0 ° C. for 1 day. Thereafter, DMI (43.5 mg) and compound (19) (166 mg) were additionally added to the reaction solution, and the mixture was further reacted for 1 day, and then the reaction solution was concentrated under reduced pressure. The resulting concentrated residue was purified with a silica gel column to obtain compound (8-3) (110.2 mg, yield 76%).

Reference Example 9 (Preparation of sugar acceptor raw material 1-5)

  Compound (8-1) (4.0 g) was dissolved in dichloromethane (64 ml) and methanol (64 ml), CSA (6.07 g) was added, and the mixture was stirred at 35 ° C. for 3 hours. After the disappearance of the raw materials, dichloromethane was added to dilute, and the mixture was washed with multilayer water. The aqueous layer was extracted with dichloromethane, and the resulting organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The organic layer was filtered, and the residue obtained by concentrating the filtrate was purified by column to obtain compound (9-1) (3.62 g, yield 99%).

Reference Example 10 (Preparation 3 of sugar donor raw material)

  Compound (25) (1.0 g) was dissolved in dichloromethane (22 ml), 4-pentenoic anhydride (0.2 ml) was added, and the mixture was cooled to 0 ° C. Pyridine (85 μl) and 4- (dimethylamino) pyridine (32.4 mg) were added to the reaction solution and stirred at the same temperature for 1.5 hours. After completion of the reaction, the reaction mixture was quenched with 0.5N hydrochloric acid, extracted with dichloromethane, and the obtained organic layer was washed successively with 3% aqueous sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The reaction solution was filtered, and the residue obtained by concentrating the filtrate was purified by column to obtain Compound (29) (971 mg, yield 90%).

  Compound (29) (50.0 mg) was dissolved in chloroform (1 ml), pyridine (66 μl) and thioacetic acid (58.9 μl) were added, and the mixture was stirred at room temperature for 3.5 hours. Then, after heating up to 40 degreeC and reacting for 20 hours, ethyl acetate and 1N hydrochloric acid were added and extracted. The obtained aqueous layer was re-extracted with ethyl acetate, and the obtained organic layers were combined, washed successively with 3% aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The reaction mixture was filtered, and the residue obtained by concentrating the filtrate was purified by column to obtain compound (30) (35.4 mg, yield 70%).

Example 1 (Production of sugar donor 1)

Compound (7-1) (1.00 g, 0.809 mmol) was dissolved in dichloromethane (16 ml), trichloroacetonitrile (8.1 ml, 80.9 mmol) was added, and the mixture was cooled to −40 ° C. After adding DBU (24 μl, 0.162 mmol) and stirring at −40 ° C. for 1 hour, the reaction solution was directly charged on silica gel for purification, and the sugar donor (2a-1) (696.2 mg, 62% yield) and A sugar donor (2a-2) (223.4 mg, yield 20%) was obtained.
Mass: ESI calcd for C ₃₇ H ₃₄ Cl ₁₂ N ₂ O ₂₂ S ₃ , m / z = 1379.69, found; 1424.7 [M + HCO ₂ ] ^−
1 H-NMR (500 MHz, CDCl ₃ ) charts are shown in FIGS.

Example 2 (Production of sugar donor 2)

Compound (7-2) (336.0 mg, 0.277 mmol) was dissolved in dichloromethane (5.6 ml), trichloroacetonitrile (2.8 ml, 27.68 mmol) was added, and the mixture was cooled to −40 ° C. Then, DBU (8.3 μl, 0.0554 mmol) was added and stirred at −40 ° C. for 1 hour, followed by column purification to obtain a sugar donor (2a-3) (210.6 mg, yield 56%), a sugar donor (2a -4) (113.5 mg, yield 30%) was obtained.
Mass: ESI calcd for C ₃₅ H ₃₆ Cl ₁₂ N ₂ O ₂₂ S ₃ , m / z = 1357.71, found; 1358.6 [M + H] ⁺ 1356.7 [M−H] ^−
1 H-NMR (500 MHz, CDCl ₃ ) charts are shown in FIGS.

Example 3 (Production of sugar donor 3)

Compound (7-2) (544.4 mg, 0.448 mmol) was dissolved in dichloromethane (11 ml), pentenoyl anhydride (98 μl, 0.538 mmol) was added, and the mixture was ice-cooled. Then, pyridine (43 μl, 0.538 mmol) and DMAP (4-N, N-dimethylaminopyridine) were added and stirred overnight. The reaction was terminated by adding 1N hydrochloric acid, and extracted with dichloromethane. The obtained organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The organic layer was filtered, and the residue obtained by concentrating the filtrate was purified by column to obtain a sugar donor (2a-5) (502.2 mg, yield 86%).
Mass: ESI calcd for C ₃₈ H ₄₂ Cl ₉ NO ₂₃ S ₃ , m / z = 1294.84, 1312.8 [M + HH ₄ ] ⁺ , 1293.8 [M−H] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 4 (Production of sugar donor 4)

  Compound (7-1) (860 mg, 0.696 mmol) is dissolved in dichloromethane (46 ml) and methanol (46 ml), 10-camphorsulfonic acid (1.13 g, 4.872 mmol) is added to this, and the temperature is raised to 40 ° C. The reaction was carried out for 5 hours. After completion of the reaction, this was quenched with sodium bicarbonate water, and the aqueous layer was extracted with dichloromethane three times. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. To the resulting concentrated residue were added dichloromethane (7.0 ml) acetic anhydride (660 μl, 6.96 mmol), pyridine (560 μl, 6.96 mmol), and DMAP (85 mg, 0.696 mmol), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, it was quenched with 1N hydrochloric acid, and the aqueous layer was extracted twice with dichloromethane. The obtained organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The organic layer was filtered, and the residue obtained by concentrating the filtrate was purified by column to obtain the compound (8-3) (470 mg, yield 53%).

  Compound (8-3) (370 mg, 0.29 mmol) was dissolved in dimethylformamide (4.8 ml), and hydrazine acetic acid (48.1 mg, 0.523 mmol) was added thereto, followed by reaction at −15 ° C. for 5 hours. . After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate, and the resulting organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The organic layer was filtered, and the residue obtained by concentrating the filtrate was purified by column to obtain compound (7-3) (284 mg, yield 79%).

Compound (7-3) (351.7 mg, 0.285 mmol) was dissolved in dichloromethane (5.6 ml), trichloroacetonitrile (2.9 ml, 28.5 mmol) was added, and the mixture was cooled to −40 ° C. After adding DBU (8.5 μl, 0.057 mmol) and stirring at −40 ° C. for 1 hour, the reaction solution was directly charged on silica gel for purification, and sugar donor (2a-6) (321.5 mg, yield 82%) Got.
Compound (8-3)
^{A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.
Compound (7-3)
^{A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.
Compound (2a-6)
Mass: ESI calcd for C ₃₄ H ₃₄ Cl ₁₂ N ₂ O ₂₄ S ₃ , m / z = 1375.68, found; 1420.7 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 5 (Production of sugar donor 5)

Compound (30) (33.8 mg, 0.027 mmol), p-toluenesulfonic acid (1.3 mg, 0.0069 mmol) and isopropenyl acetate (0.6 ml, 5.51 mmol) were mixed, and the system was purged with argon. The temperature was raised to ° C. and the reaction was carried out for 2.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column to obtain a sugar donor (2a-7) (28.8 mg, yield 82.4%).
Mass: ESI calcd for C ₃₆ H ₄₂ Cl ₉ NO ₂₃ S ₃ , m / z = 1270.84, found; 1315.7 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 6 (Production of sugar donor 6)

Chloroform (12.8 ml) was added to compound (30) (550 mg, 0.447 mmol) in an argon atmosphere and the temperature was raised to 55 ° C., and pyridine (217 μl, 2.68 mmol), DMAP (16.4 mg, 0.1345 mmol) and chloroformic acid 2 , 2,2-trichloroethyl (184.7 μl, 1.341 mmol) was added, and after 1 hour, pyridine (217 μl, 2.68 mmol) and 2,2,2-trichloroethyl chloroformate (184.7 μl, 1.341 mmol) were further added. . After reacting for a total of 2 hours, dichloromethane (70 ml) and 1N hydrochloric acid (50 ml) were added for liquid separation, and dichloromethane (70 ml) was added to the aqueous layer for re-extraction.
The obtained organic layers were combined, washed successively with 3% aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The organic layer was filtered, and the residue obtained by concentrating the filtrate was purified by column to obtain a sugar donor (2a-8) (323.1 mg, yield 51.4%).
Mass: ESI calcd for C ₃₇ H ₄₁ Cl ₁₂ NO ₂₄ S ₃ , m / z = 1404.74, found; 1422.7 [M + NH ₄ ] ⁺ , 1449.6 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 7 (Production of sugar receptor 1)

Compound (9-1) (91.3 mg, 92.8 μmol) was dissolved in dichloromethane (1 ml), and 4-methoxybenzyl-2,2,2-trichloroacetimidate (43.1 mg, 152 μmol) and CSA (4.8 mg, 20.4 mol) were dissolved. μmol) was added, and the mixture was stirred at room temperature for 7 hours. 4-methoxybenzyl-2,2,2-trichloroacetimidate (25.0 mg, 88.5 μmol) was further added, and the reaction was further performed for 20 minutes. Thereafter, dichloromethane was added for dilution, followed by washing with aqueous sodium hydrogen carbonate, the aqueous layer was extracted with dichloromethane, and the resulting organic layers were combined, washed with saturated brine, and then dried over magnesium sulfate. The organic layer was filtered and the residue obtained by concentrating the filtrate was subjected to column purification to obtain sugar acceptor (3a-1) (92.2 mg, yield 90%).
Mass: ESI calcd for C ₂₆ H ₃₀ Cl ₉ N ₃ O ₁₉ S ₃ , m / z = 1102.78, found; 1120.7 [M + NH ₄ ] ⁺ , 1101.7 [M−H] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 8 (Production of sugar receptor 2)

Compound (9-1) (1.0 g, 1.02 mmol) is dissolved in dichloromethane (10 ml), allyl-2,2,2-trichloroacetimidate (768 μl, 5.08 mmol) and trifluoromethanesulfonic acid (27 μl, 305 μmol). Each was added and stirred at room temperature for 2 hours, and then allyl-2,2,2-trichloroacetimidate (768 μl, 5.08 mmol) and trifluoromethanesulfonic acid (27 μl, 305 μmol) were added and reacted for 6 hours. . Dichloromethane was added to the reaction solution for dilution, washed with aqueous sodium bicarbonate, the aqueous layer was extracted with dichloromethane, washed with saturated brine, and dried over magnesium sulfate. The organic layer was filtered, and the residue obtained by concentrating the filtrate was purified by column to obtain a sugar receptor (3a-2) (676 mg, 65%).
Mass: ESI calcd for C ₂₁ H ₂₆ Cl ₉ N ₃ O ₁₈ S ₃ , m / z = 1022.75, found; 1040.6 [M + NH ₄ ] ^{+
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 9 (Production of sugar receptor 3)

Compound (9-1) (2.00 g, 2.03 mmol) was dissolved in dichloromethane (34 ml), and water (17 ml) was added. Cool to 0 ° C and add TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) (63 mg, 40.6 μmol) and BAIB ([Diacetoxyiodo] benzene) (1.63 g, 5.08 mmol) at 0 ° C. Stir for 2 hours. After completion of the reaction, 2% aqueous sodium sulfite solution was added to terminate the reaction, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure to remove the solvent. Toluene (90 ml) and methanol (30 ml) were added to the residue and dissolved. After cooling to 0 ° C., trimethylsilyldiazomethane (3.0 ml, 6 mmol) was added and stirred at room temperature for 1.5 hours. The reaction solution was concentrated, and the resulting residue was purified by column to obtain a sugar acceptor (3a-3) (1.78 g, yield 87%).
Mass: ESI calcd for C ₁₉ H ₂₂ Cl ₉ N ₃ O ₁₉ S ₃ , m / z = 1010.71, found; 1028.7 [M + NH ₄ ] ⁺ 1009.7 [M−H] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Reference Example 11 (Preparation of sugar acceptor raw material 4-1)

  The sugar donor (2a-1) (500.0 mg) and p-methoxyphenol (90 mg) were dissolved in dichloromethane (3.6 ml), MS4A (100 mg) was added, and the mixture was stirred at room temperature for 1 hour. After cooling to −20 ° C., TMSOTf (19 μl) was added and stirred at about −20 ° C. for 1 hour. After confirming disappearance of the raw materials, the reaction solution was filtered through Celite. The filtrate was washed successively with aqueous sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The residue obtained by filtering and concentrating the filtrate was purified with a column to obtain compound (8-4) (418.7 mg, yield 86%).

Reference Example 12 (Preparation of sugar acceptor raw material 4-2)

Compound (8-4) (200.0 mg, 149.0 μmol) was dissolved in dichloromethane (4.6 ml), trifluoroacetic acid (460 μl) and water (46 μl) were added thereto, and the mixture was stirred at room temperature for 5 hours.
After confirming the disappearance of the raw materials, dichloromethane was added for dilution, and the mixture was washed with an aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane, and the resulting organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The residue obtained by filtering and concentrating the filtrate was purified with a column to give compound (9-2) (179.7 mg, 96%).

Example 10 (Production of sugar receptor 4)

Compound (9-2) (179.7 mg, 143.3 μmol) was dissolved in dichloromethane (1.4 ml), and 4-methoxybenzyl-2,2,2-trichloroacetimidate (25.4 mg) and CSA (6.7 mg, 28.66 μmol) were dissolved. And 4-methoxybenzyl-2,2,2-trichloroacetimidate (25.4 mg, 89.9 μmol) was added and reacted for 1 hour. After diluting with dichloromethane, the mixture was washed with aqueous sodium hydrogen carbonate, the aqueous layer was extracted with dichloromethane, and the resulting organic layer was washed with saturated brine and dried over magnesium sulfate. The organic layer was filtered, and the residue obtained by concentrating the filtrate was purified by column to obtain a sugar acceptor (3a-4) (166.7 mg, yield 85%).
Mass: ESI calcd for C ₄₃ H ₄₄ Cl ₉ NO ₂₄ S ₃ , m / z = 1372.86, found; 1390.8 [M + NH ₄ ] ⁺ , 1371.8 [M−H] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 11 (Production of sugar receptor 5)

Compound (9-2) (835.8 mg, 0.667 mmol) was dissolved in dichloromethane (15 ml), and water (7.5 ml) was added. After cooling to 10 ° C., TEMPO (31.3 mg, 0.200 mmol) and BAIB (537.1 mg, 1.668 mmol) were added, and the mixture was stirred at 10 ° C. for 1 hour. After confirming the disappearance of the raw materials, dichloromethane and water were separated, the aqueous layer was extracted with dichloromethane, combined with the reaction solution, and methanol (5 ml) was added thereto. After cooling to 0 ° C., trimethylsilyldiazomethane (1 ml, 2 mmol) was added and stirred at room temperature for 1 hour. Dichloromethane was added to the reaction solution for dilution, washed with a 10% sodium thiosulfate solution, the aqueous layer was extracted with dichloromethane, washed with saturated brine, and dried over magnesium sulfate. The organic layer was filtered, and the residue obtained by concentrating the filtrate was purified by column to obtain a sugar acceptor (3a-5) (411.7 mg, yield 48%).
Mass: ESI calcd for C ₃₆ H ₃₆ Cl ₉ NO ₂₄ S ₃ , m / z = 1280.79,
found; 1298.6 [M + NH ₄ ] ^{+
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 12 (Production of sugar receptor 6)

Compound (8-1) (1.06 g, 1.44 mmol) was dissolved in dichloromethane (10.5 ml) and cooled to 0 ° C. Triethylsilane (715 μl, 4.48 mmol) and boron trifluoride diethyl ether (92.1 μl, 0.74 mmol) were added to this, and then the mixture was returned to room temperature and stirred for 3 hours. After confirming the completion of the reaction, dichloromethane (60 ml) and 3% aqueous sodium bicarbonate solution (60 ml) were added for liquid separation, and the aqueous layer was re-extracted with dichloromethane. The obtained organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate was purified by a column to obtain a sugar acceptor (3a-6) (0.86 g, yield 81%).
Mass: ESI calcd for C ₂₅ H ₂₈ Cl ₉ N ₃ O ₁₈ S ₃ , m / z = 1072.77, found; 1090.6 [M + NH ₄ ] ^{+
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 13 (Production of sugar receptor 7)

Compound (8-2) (962.4 mg, 0.78 mmol) was dissolved in dichloromethane (31 ml) and cooled to 0 ° C. To this was added triethylsilane (1.5 ml, 9.32 mmol) and boron trifluoride diethyl ether (0.2 ml, 1.55 mmol), and the mixture was returned to room temperature and stirred for 3 hours. After confirming the completion of the reaction, dichloromethane and 3% aqueous sodium bicarbonate were added for liquid separation, and the aqueous layer was re-extracted with dichloromethane. The obtained organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate was purified by a column to obtain a sugar acceptor (3a-7) (0.72 g, yield 75%).
Mass: ESI calcd for C ₃₄ H ₃₈ Cl ₉ N ₃ O ₂₁ S ₃ , m / z = 1238.83, found; 1256.7 [M + NH ₄ ] ⁺ , 1237.7 [M−H] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 14 (Production of sugar receptor 8)

Compound (8-3) (1.62 g, 1.44 mmol) was dissolved in dichloromethane (20 ml) and cooled to 0 ° C. Triethylsilane (3.9 ml, 24.4 mmol) and boron trifluoride diethyl ether (513 μl, 4.07 mmol) were added to this, and then the mixture was returned to room temperature and stirred for 8 hours. After confirming the completion of the reaction, dichloromethane and 3% aqueous sodium bicarbonate were added for liquid separation, and the aqueous layer was re-extracted with dichloromethane. The obtained organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate was purified by a column to obtain sugar acceptor (3a-8) (966 mg, yield 59%).
Mass: ESI calcd for C ₂₄ H ₂₆ Cl ₆ O ₁₃ S ₂ , m / z = 79.89, found; 815.6 [M + NH ₄ ] ^{+
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 15 (Production 1 of oligosaccharide compound)

Sugar donor (2a-1) (51.8 mg, 37.53 μmol), sugar acceptor (3a-8) (20.0 mg, 25.02 μmol), MS4A (90 mg) and dichloromethane (0.4 ml) were stirred at room temperature for 1 hour. After cooling to −40 ° C., TMSOTf (1.3 μl, 7.506 μmol) was added, and the mixture was stirred at −40 ° C. for 1 hour and then gradually warmed to room temperature. The mixture was stirred overnight at room temperature, filtered through celite, and the filtrate was washed with sodium bicarbonate water and saturated brine in this order. After drying over magnesium sulfate, it was filtered. The residue obtained by concentrating the filtrate was purified by gel filtration column chromatography to obtain oligosaccharide compound (1-1) (19.6 mg, yield 39%).
Mass: ESI calcd for C ₅₉ H ₅₈ Cl ₁₅ NO ₃₄ S ₅ , m / z = 2014.67 found; 2032.4 [M + NH ₄ ] ⁺ , 2059.2 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 16 (Production of oligosaccharide compound 2)

The sugar donor (2a-1) was replaced with the sugar donor (2a-4) (51.8 mg, 37.53 μmol), and the same operation as in Example 15 was carried out to prepare the oligosaccharide compound (1-2) (8.8 mg, yield). 18%).
Mass: ESI calcd for C ₅₇ H ₆₀ Cl ₁₅ NO ₃₄ S ₅ , m / z = 1994.68, found; 2012.0 [M + NH ₄ ] ⁺ , 193.2 [M−H] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 17 (Production of oligosaccharide compound 3)

The sugar donor (2a-1) is converted into a sugar donor (2-1: product of Tokyo Chemical Industry Co., Ltd.) (24.3 mg, 41.9 μmol), and the sugar acceptor (3a-8) is converted into a sugar acceptor (3a-6). ) (30.0 mg, 27.9 μmol), MS4A (90 mg), dichloromethane (0.4 ml) and TMSOTf (1.5 μl, 8.38 μmol) were used in the same manner as in Example 15 to obtain the oligosaccharide compound (1-3 ) (24.0 mg, 58% yield).
Mass: ESI calcd for C ₄₅ H ₄₇ Cl ₉ N ₄ O ₂₇ S ₃ , m / z = 1488.87, found; 1507.5 [M + NH ₄ ] ⁺ , 1534.5 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 18 (Production of oligosaccharide compound 4)

The sugar donor (2a-1) is changed to the sugar donor (2-1) (21.0 mg, 36.3 μmol), and the sugar acceptor (3a-8) is changed to the sugar acceptor (3a-7 (β)) (30.0 mg, Instead of MS4A (90 mg), dichloromethane (0.4 ml) and TMSOTf (1.3 μl, 7.26 μmol), the oligosaccharide compound (1-4) (11.4 mg, Yield 19%) was obtained. The sugar receptor (3a-7 (β)) used in this reaction is a β-isomer obtained by further column purification of the sugar receptor (3a-7) produced according to Example 13.
Mass: ESI calcd for C ₅₄ H ₅₇ Cl ₉ N ₄ O ₃₀ S ₃ , m / z = 1655.94, found; 1673.6 [M + NH ₄ ] ⁺ , 1700.6 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 19 (Production 5 of oligosaccharide compound)

The sugar donor (2a-1) is changed to the sugar donor (2a-1,2) (100.0 mg, 72.45 μmol), and the sugar acceptor (3a-8) is changed to the sugar acceptor (3a-1) (320 mg, 289.8 μmol). ), And oligosaccharide compound (1-5) (26.7 mg, yield) was prepared in the same manner as in Example 15 using MS4A (300 mg), dichloromethane (1.3 ml) and TMSOTf (2.6 μl, 14.49 μmol). 16%). The sugar donor (2a-1, 2) is a mixture of about 3: 1 of the sugar donor (2a-1) and the sugar donor (2a-2) produced according to Example 1. It is.
Mass: ESI calcd for C ₆₁ H ₆₂ Cl ₁₈ N ₄ O ₄₀ S ₆ , m / z = 2319.55, found; 2337.5 [M + NH ₄ ] ⁺ , 2364.2 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 20 (Production of oligosaccharide compound 6)

The sugar acceptor (3a-8) was replaced with the sugar acceptor (3a-3) (30 mg, 36.3 μmol), and the sugar donor (2a-1) (74.8 mg, 54.4 μmol), MS4A (100 mg), dichloromethane (0.4 ml) and TMSOTf (1.9 μl, 10.9 μmol) in the same manner as in Example 15 to obtain oligosaccharide compound (1-6) (6.0 mg, yield 9%).
Mass: ESI calcd for C ₅₄ H ₅₄ Cl ₁₈ N ₄ O ₄₀ S ₆ , m / z = 2229.49, found; 2247.0 [M + NH ₄ ] ^{+
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 21 (Production of oligosaccharide compound 7)

The sugar donor (2a-1) is changed to the sugar donor (2a-1,2) (650 mg, 0.471 μmol), and the sugar acceptor (3a-8) is changed to the sugar acceptor (3a-4) (162 mg, 0.118 μmol). The oligosaccharide compound (1-7) (28.8 mg, yield 9.4) was prepared by operating in the same manner as in Example 15 using MS4A (600 mg), dichloromethane (2.1 ml) and TMSOTf (6.2 μl, 35.3 μmol). %).
Mass: ESI calcd for C ₇₈ H ₇₆ Cl ₁₈ N ₂ O ₄₅ S ₆ , m / z = 2591.63, found; 2609.4 [M + NH ₄ ] ⁺ , 2636.4 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 22 (Production of oligosaccharide compound 8)

The sugar donor (2a-1) is changed to the sugar donor (2a-1,2) (110.8 mg, 80.3 μmol), and the sugar acceptor (3a-8) is changed to the sugar acceptor (3a-5) (411.7 mg, 0.321). In the same manner as in Example 15 using MS4A (600 mg), dichloromethane (1.4 ml) and TMSOTf (4.2 μl, 24.09 μmol) instead of oligomol compound (1-8) (20.2 mg, yield). Rate 10%).
Mass: ESI calcd for C ₇₁ H ₆₈ Cl ₁₈ N ₂ O ₄₅ S ₆ , m / z = 2499.57, found; 2517.4 [M + NH ₄ ] ⁺ , 2544.2 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 23 (Production of oligosaccharide compound 9)

The sugar acceptor (3a-8) was replaced with the sugar acceptor (3a-6) (30.0 mg, 27.9 μmol), and the sugar donor (2a-1) (57.8 mg, 41.9 μmol), MS4A (90 mg), dichloromethane ( 0.4 ml) and TMSOTf (1.5 μl, 8.38 μmol) were used in the same manner as in Example 15 to obtain oligosaccharide compound (1-9) (7.2 mg, yield 11%).
Mass: ESI calcd for C ₆₀ H ₆₀ Cl ₁₈ N ₄ O ₃₉ S ₆ , m / z = 2229.54, found; 2307.0 [M + NH ₄ ] ⁺ , 2336.0 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 24 (Production of oligosaccharide compound 10)

The sugar acceptor (3a-8) is replaced with the sugar acceptor (3a-7 (β)) (50.1 mg, 36.4 μmol), and the sugar donor (2a-1) (30.0 mg, 24.3 μmol), MS4A (90 mg) , Dichloromethane (0.3 ml) and TMSOTf (1.3 μl, 7.3 μmol) were used in the same manner as in Example 15 to obtain oligosaccharide compound (1-10) (4.6 mg, yield 8%).
Mass: ESI calcd for C ₆₉ H ₇₀ Cl ₁₈ N ₄ O ₄₂ S ₆ , m / z = 2455.61, found; 2474.0 [M + NH ₄ ] ⁺ , 2501.0 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 25 (Production of oligosaccharide compound 11)

Sugar donor (2a-1) is sugar donor (2a-3) (56.9 mg, 41.9 μmol), and sugar acceptor (3a-8) is sugar acceptor (3a-6) (30.0 mg, 27.9 μmol). The oligosaccharide compound (1-11) (5.5 mg, yield 8.7) was prepared in the same manner as in Example 15 using MS4A (90 mg), dichloromethane (0.4 ml) and TMSOTf (1.5 μl, 8.38 μmol). %).
Mass: ESI calcd for C ₅₈ H ₆₂ Cl ₁₈ N ₄ O ₃₉ S ₆ , m / z = 2267.56, found; 2266.2 [M−H] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 26 (Production of oligosaccharide compound 12)

The sugar donor (2a-1) is changed to the sugar donor (2a-3) (56.9 mg, 41.9 μmol), and the sugar acceptor (3a-8) is changed to the sugar acceptor (3a-7 (β)) (30.0 mg, In place of 36.3 μmol), oligosaccharide compound (1-12) (4.1 mg, 4.1 mg, 4 mg (90 mg), dichloromethane (0.4 ml) and TMSOTf (1.9 μl, 10.9 μmol) were used in the same manner as in Example 15. Yield 7%).
Mass: ESI calcd for C ₆₇ H ₇₂ Cl ₁₈ N ₄ O ₄₂ S ₆ , m / z = 2435.62, found; 2453.2 [M + NH ₄ ] ⁺ , 2434.0 [M−H] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 27 (Production of oligosaccharide compound 13)

Sugar donor (2a-1) is sugar donor (2a-6) (27.0 mg, 36.7 μmol), and sugar acceptor (3a-8) is sugar acceptor (3a-6) (75.8 mg, 55.1 μmol). The oligosaccharide compound (1-13) (4.6 mg, yield 8) was prepared in the same manner as in Example 15 using MS4A (100 mg), dichloromethane (0.3 ml) and TMSOTf (1.9 μl, 10.9 μmol). %).
Mass: ESI calcd for C ₅₇ H ₆₀ Cl ₁₈ N ₄ O ₄₁ S ₆ , m / z = 2285.53, found; 2303.4 [M + NH ₄ ] ⁺ , 2330.3 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 28 (Sugar Receptor Preparation 9)

Oligosaccharide compound (1-9) (500.3 mg, 0.218 mmol) was dissolved in dichloromethane (8.3 ml) and ice-cooled. Triethylsilane (420 μl, 2.620 mmol) and boron trifluoride diethyl ether (55 μl, 0.437 mmol) were added to the solution, and the mixture was returned to room temperature and stirred for 3 hours. After confirming disappearance of the raw materials, sodium bicarbonate water was added to terminate the reaction. The reaction solution was separated, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over magnesium sulfate and filtered.
The residue obtained by concentrating the filtrate was purified by a column to obtain sugar acceptor (3a-9) (404.2 mg, yield 81%).
Mass: ESI calcd for C ₆₀ H ₆₂ Cl ₁₈ N ₄ O ₃₉ S ₆ , m / z = 2291.56, found; 2309.4 [M + NH ₄ ] ⁺ , 2290.3 [M−H] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 29 (Production of oligosaccharide compound 14)

The sugar acceptor (3a-8) was replaced with the sugar acceptor (3a-9) (60.0 mg, 26.16 μmol), and the sugar donor (2a-1) (162.5 mg, 117.71 μmol), MS4A (250 mg), dichloromethane ( 1.0 ml) and TMSOTf (1.4 μl, 7.85 μmol) were used in the same manner as in Example 15 to obtain oligosaccharide compound (1-14) (6.0 mg, yield 6.5%).
Mass: ESI calcd for C ₉₅ H ₉₄ Cl ₂₇ N ₅ O ₆₀ S ₉ , m / z = 3510.4, found; 3528.4 [M + NH ₄ ] ⁺ , 3555.4 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 30 (Sugar Receptor Preparation 10)

The oligosaccharide compound (1-14) (60.7 mg, 17.29 mmol) was dissolved in dichloromethane (1.3 ml) and ice-cooled. Triethylsilane (33 μl, 207.4 μmol) and boron trifluoride diethyl ether (4.4 μl, 34.58 μmol) were added to the solution, and the mixture was returned to room temperature and stirred for 1 hour. Dichloromethane was added to the reaction solution for dilution, and an aqueous sodium bicarbonate solution was added to terminate the reaction. The reaction solution was separated, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over magnesium sulfate and filtered. The residue obtained by concentrating the filtrate was purified with a column to give sugar acceptor (3a-10) (19.1 mg, yield 31%).
Mass: ESI calcd for C ₉₅ H ₉₆ Cl ₂₇ N ₅ O ₆₀ S ₉ , m / z = 3512.4, found; 3530.4 [M + NH ₄ ] ⁺ , 3511.4 [M−H] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 31 (Production of oligosaccharide compound 15)

The sugar donor (2a-1) is changed to the sugar donor (2a-1,2) (51.4 mg, 37.27 μmol), and the sugar acceptor (3a-8) is changed to the sugar acceptor (3a-10) (29.1 mg, 8.283). In the same manner as in Example 15 using MS4A (90 mg), dichloromethane (0.6 ml) and TMSOTf (0.9 μl, 4.97 μmol) instead of oligomol compound (1-15) (3.4 mg, yield). Rate 8.7%).
Mass: ESI calcd for C ₁₃₀ H ₁₂₈ Cl ₃₆ N ₆ O ₈₁ S ₁₂ , m / z = 4731.2, found; 4749.2 [M + NH ₄ ] ⁺ , 4776.3 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 32 (Production of oligosaccharide compound 16)

Compound (1-7) (52.4 mg, 20.2 μmol) is dissolved in dichloromethane (1 ml), water (50 μl), DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone) (6.9 mg, 30.3 μmol) ) And reacted at room temperature for 2.5 hours. Thereafter, DDQ (10.0 mg, 44.0 μmol) was further added and stirred for 2 hours. Thereafter, DDQ (23.0 mg, 101.3 μmol) was further added and stirred for 30 minutes, and then the reaction solution was diluted with ethyl acetate and washed with a sodium thiosulfate solution. Thereafter, the aqueous layer was extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate was purified by a column to obtain oligosaccharide compound (1-16) (36.4 mg, yield 73%).
Mass: ESI calcd for C ₇₀ H ₆₈ Cl ₁₈ N ₂ O ₄₄ S ₆ , m / z = 2469.57, found; 2487.4 [M + NH ₄ ] ⁺ , 2514, 2 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 33 (Production of oligosaccharide compound 17)

Compound (1-16) (165.8 mg, 67.1 μmol) is dissolved in dichloromethane (1.3 ml), levulinic acid (10.3 μl, 100.6 μmol) is added, and after ice cooling, DCC (dicyclohexylcarbodiimide) (20.8 mg, 100.6 μmol) , DMAP (2.5 mg, 20.1 μmol) was added, and the mixture was reacted at room temperature for 3 hours. After completion of the reaction, precipitated urea was removed by filtration, the filtrate was concentrated, and the resulting residue was purified with a column to obtain oligosaccharide compound (1-17) (162.6 mg, yield 94%).
Mass: ESI calcd for C ₇₅ H ₇₄ Cl ₁₈ N ₂ O ₄₆ S ₆ , m / z = 256.61, found; 2587.4 [M + NH ₄ ] ⁺ , 2614.2 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 34 (Production of oligosaccharide compound 18)

Compound (1-17) (30.0 mg, 11.7 μmol) was dissolved in toluene (0.25 ml), acetonitrile (375 μl) and water (0.25 ml), and CAN (ammonium hexanitratocerium (IV)) (68.1 mg, 124.2 μmol) was added and stirred at room temperature for 1.5 hours. Thereafter, CAN (32.0 mg, 58.4 μmol) was further added and reacted at room temperature for 30 minutes. After completion of the reaction, it was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, the resulting organic layer was washed with saturated brine, the organic layer was concentrated, and the resulting residue was purified with a column to obtain the oligosaccharide compound (1-18) (18.26 mg, 63%) was obtained.
Mass: ESI calcd for C ₆₈ H ₆₈ Cl ₁₈ N ₂ O ₄₅ S ₆ , m / z = 2463.57, found; 2481.4 [M + NH ₄ ] ⁺ , 2462.2 [M−H] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 35 (Production of sugar donor 7)

Compound (1-18) (18.2 mg, 7.39 μmol) was dissolved in dichloromethane (0.7 ml), trichloroacetonitrile (0.7 ml, 27.68 mmol) was added, and the mixture was cooled to −40 ° C. Then, DBU (0.1 M dichloromethane solution, 22 μl, 2.217 μmol) was added and stirred at −40 ° C. for 1 hour, followed by column purification to sugar donor (2a-9) (12.5 mg, yield 65%), sugar Donor (2a-10) (3.3 mg, 17% yield) was obtained.
Mass: ESI calcd for C ₇₀ H ₆₈ Cl ₂₁ N ₃ O ₄₅ S ₆ , m / z = 2606.48, found; 2651.0 [M + HCO ₂ ] ^−
1 H-NMR (500 MHz, CDCl ₃ ) charts are shown in FIGS.

Example 36 (Production of oligosaccharide compound 19)

Compound (1-16) (468.3 mg, 0.189 μmol) was dissolved in dichloromethane (3.8 ml), and water (0.95 ml) was added. After cooling to 10 ° C., TEMPO (17.7 mg, 0.113 μmol) and BAIB (152.2 mg, 0.473 μmol) were added respectively, followed by stirring at 10 ° C. for 12 hours. After completion of the reaction, water was removed by liquid separation. Dichloromethane (4 ml) and methanol (4 ml) were added to this solution, cooled to 0 ° C., trimethylsilyldiazomethane (189 μl, 378 μmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. did. Quench with acetic acid, dilute with dichloromethane, wash with aqueous sodium thiosulfate solution, extract the aqueous layer with dichloromethane, wash the combined organic layers with saturated brine, dry over magnesium sulfate, filter, reaction solution The residue was purified by column to give oligosaccharide compound (1-19) (360 mg, yield 76%).
Mass: ESI calcd for C ₇₁ H ₆₈ Cl ₁₈ N ₂ O ₄₅ S ₆ , m / z = 2499.57, found; 2517.4 [M + NH ₄ ] ⁺ , 2544.2 [M + HCO ₂ ] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 37 (Production of oligosaccharide compound 20)

Compound (1-19) (167.4 mg, 67.0 μmol) was dissolved in dichloromethane (1.3 ml), trifluoroacetic acid (134 μl) and water (13.4 μl) were added, and the mixture was stirred at room temperature for 1 hour. After confirming the disappearance of the raw materials, dichloromethane was added for dilution, and the mixture was washed with an aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane, and the resulting organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The residue obtained by filtering and concentrating the filtrate was purified by a column to obtain oligosaccharide compound (1-20) (123.8 mg, 77%).
Mass: ESI calcd for C ₆₄ H ₆₄ Cl ₁₈ N ₂ O ₄₅ S ₆ , m / z = 241.154, found; 2429.4 [M + NH ₄ ] ⁺ , 2410.1 [M−H] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 38 (Production of sugar receptor 11)

Compound (1-20) (123.8 mg, 51.3 μmol) was dissolved in dichloromethane (1.0 ml), and 4-methoxybenzyl-2,2,2-trichloroacetimidate (26.1 mg, 92.4 μmol) and CSA (4.3 mg 18.5 μmol) and stirred at room temperature for 2.5 hours. After completion of the reaction, dichloromethane was added for dilution, and the mixture was washed with aqueous sodium hydrogen carbonate. The aqueous layer was extracted with dichloromethane, and the obtained organic layer was washed with saturated brine and dried over magnesium sulfate. The organic layer was filtered, and the residue obtained by concentrating the filtrate was purified by column to obtain a sugar acceptor (3a-11) (110.5 mg, yield 85%).
Mass: ESI calcd for C ₇₂ H ₇₂ Cl ₁₈ N ₂ O ₄₆ S ₆ , m / z = 2531.59, found; 2549.4 [M + NH ₄ ] ⁺ , 2530.1 [M−H] ^{−
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 39 (Production of oligosaccharide compound 21)

The sugar donor (2a-1) is converted into the sugar donor (2a-1,2) (181.3 mg, 0.131 mmol), and the sugar acceptor (3a-8) is converted into the sugar acceptor (3a-11) (997.2 mg, 0.394). In the same manner as in Example 15 using MS4A (1.2 g), dichloromethane (2.2 ml) and TMSOTf (7.0 μl, 39.3 μmol) instead of mmol), oligosaccharide compound (1-21) (63.1 mg, Yield 13%) was obtained.
Mass: ESI calcd for C ₁₀₇ H ₁₀₄ Cl ₂₇ N ₃ O ₆₇ S ₉ , m / z = 3749.37, found; 1892.4 [M + 2NH ₄ ] ^{2+
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 40 (Production of oligosaccharide compound 22)

Compound (1-21) (133.9 mg, 35.7 μmol) was dissolved in dichloromethane (3.6 ml), water (360 μl) and DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone) (162.1 mg, 0.174 mmol) was added and allowed to react at room temperature for 5 hours. Thereafter, the reaction solution was diluted with ethyl acetate and washed with a 1% aqueous sodium sulfite solution. Thereafter, the aqueous layer was extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate was purified by a column to obtain oligosaccharide compound (1-22) (102.7 mg, yield 79%).
Mass: ESI calcd for C ₉₉ H ₉₆ Cl ₂₇ N ₃ O ₆₆ S ₉ , m / z = 362.32, found; 1831.8 [M + 2NH ₄ ] ^{2+
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 41 (Production of oligosaccharide compound 23)

Compound (1-22) (102.7 mg, 28.3 μmol) is dissolved in dichloromethane (2.8 ml), levulinic acid (8.7 μl, 84.9 μmol) is added, and after ice cooling, DCC (dicyclohexylcarbodiimide) (17.5 mg, 84.9 μmol) And DMAP (3.5 mg, 28.3 μmol) were added, respectively, and reacted at room temperature for 2 hours. After completion of the reaction, precipitated urea was removed by filtration, the filtrate was concentrated, and the resulting residue was purified with a column to obtain compound (1-23) (79.4 mg, yield 75%).
Mass: ESI calcd for C ₁₀₄ H ₁₀₂ Cl ₂₇ N ₃ O ₆₈ S ₉ , m / z = 372.35, found; 1881.3 [M + 2NH ₄ ] ^{2+
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 42 (Production of oligosaccharide compound 24)

Compound (1-23) (79.4 mg, 21.3 μmol) was dissolved in dichloromethane (2.1 ml), trifluoroacetic acid (105 μl) and water (21 μl) were added thereto, and the mixture was stirred at room temperature for 3 hours. After confirming the disappearance of the raw materials, dichloromethane was added for dilution, and the mixture was washed with an aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane, and the resulting organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The residue obtained by filtering and concentrating the filtrate was purified with a column to give compound (1-24) (56.6 mg, 73%).
Mass: ESI calcd for C ₉₇ H ₉₈ Cl ₂₇ N ₃ O ₆₈ S ₉ , m / z = 363.32, found; 1837.3 [M + 2NH ₄ ] ^{2+
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 43 (Production of sugar receptor 12)

Compound (1-24) (56.6 mg, 15.6 μmol) was dissolved in dichloromethane (2.7 ml), and 4-methoxybenzyl-2,2,2-trichloroacetimidate (8.6 mg, 31.1 μmol) and CSA (1.8 mg, 1.8 mg, 7.8 μmol) and stirred at room temperature for 1.5 hours. Furthermore, 4-methoxybenzyl-2,2,2-trichloroacetimidate (13.6 mg, 47.9 μmol) and CSA (3.3 mg, 14.3 μmol) were added and stirred at room temperature for 1 hour. Subsequently, 4-methoxybenzyl-2,2,2-trichloroacetimidate (13.6 mg, 47.9 μmol) and CSA (5.1 mg, 22.0 μmol) were added and stirred at room temperature for 30 minutes. After completion of the reaction, dichloromethane was added for dilution, washed with aqueous sodium bicarbonate, and the aqueous layer was extracted with dichloromethane. The obtained organic layer was washed with saturated brine, and dried over magnesium sulfate. The organic layer was filtered, and the residue obtained by concentrating the filtrate was purified by column to obtain a sugar acceptor (3a-12) (48.2 mg, yield 82%).
Mass: ESI calcd for C ₁₀₅ H ₁₀₆ Cl ₂₇ N ₃ O ₆₉ S ₉ , m / z = 3759.38, found; 1897.2 [M + 2NH ₄ ] ^{2+
A 1} H-NMR (500 MHz, CDCl ₃ ) chart is shown in FIG.

Example 44 (Production of oligosaccharide compound 25)

Sugar donor (2a-1) is sugar donor (2a-7) (16.7 mg, 6.4 μmol), and sugar acceptor (3a-8) is sugar acceptor (3a-12) (48.2 mg, 12.8 μmol). The oligosaccharide compound (1-25) was obtained in the same manner as in Example 15 except that MS4A (90 mg), dichloromethane (0.3 ml) and TMSOTf (0.34 μl, 1.9 μmol) were used.
Mass: ESI calcd for C ₁₇₃ H ₁₇₂ Cl ₄₅ N ₅ O ₁₁₃ S ₁₅ , m / z = 6203.94, found; 2086.2 [M + 3NH ₄ ] ³⁺

Reference Example 13

  Compound (5-1) (500 mg, 0.425 mmol) is dissolved in dichloromethane (28 ml) and methanol (14 ml), 10-camphorsulfonic acid (691.1 mg, 2.975 mmol) is added to this, and the temperature is raised to 40 ° C. The reaction was carried out for 14 hours, and after completion of the reaction, diluted with dichloromethane, washed with aqueous sodium bicarbonate, the aqueous layer was back extracted with dichloromethane, and the resulting organic layers were combined. The extract was washed with saturated brine, dried over magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate was purified with a column to give compound (31) (456 mg, yield 99%).

  Compound (31) (397.9 mg, 0.366 mmol) is dissolved in methanol (17.5 ml), ammonium formate (415 mg, 6.584 mmol) and zinc powder (502 mg, 7.682 mmol) are added, and the mixture is stirred at room temperature for 4.5 hours. did. Water (17.5 ml) was added and stirred overnight, then ammonium formate (277 mg, 4.392 mmol), zinc powder (360 mg, 5.490 mmol) and water (8.8 ml) were added and stirred overnight. The reaction mixture was filtered through Celite, washed with methanol / water (1/1 (V / V)), concentrated, and azeotroped with isopropyl alcohol, and the resulting residue was purified by gel filtration chromatography. Compound (32) (290.5 mg, quantitative) was obtained through the exchange resin.

  Compound (32) (50.0 mg, 65.83 μmol) was dissolved in ethanol (1.0 ml) and water (0.3 ml), 1,3-propanediamine (330 μl, 3.95 mmol) was added, and the mixture was heated to reflux for 5 hours. After returning to room temperature, water (0.2 ml) and acetic anhydride (922 μl, 9.773 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was purified by gel filtration chromatography to give compound (33) (15.5 mg, yield 35%) through an ion exchange resin.

Comparative Example 1

(1) Sugar donor (34) (19.6 mg, 14.2 μmol), sugar acceptor (35) (13.9 mg, 9.48 μmol), MS4A (100 mg), dichloromethane (0.5 ml) were added to perform nitrogen substitution, Stir at room temperature for 1 hour. Thereafter, the mixture was cooled to −40 ° C., TMSOTf (0.1 M solution, 28 μl, 2.84 μmol) was added, and the temperature was gradually raised from −40 ° C. to room temperature. After confirming the disappearance of the sugar donor (34), the mixture was filtered through Celite, washed with dichloromethane, washed with aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, purified through a silica gel column, and spotted. Although it fractionated, it was not the target oligosaccharide compound (36) but the by-product (37) derived from the sugar donor (34).

(2) Sugar donor (34) (17.8 mg, 12.9 μmol), MS4A (30 mg), sugar acceptor (35) (12.6 mg, 8.59 μmol) and toluene (0.43 ml) were added to perform nitrogen substitution. Stir at room temperature for 1 hour. Thereafter, TMSOTf (0.1 M solution, 26 μl, 2.58 μmol) was added at the same temperature, and the mixture was stirred for 30 minutes. After confirming the disappearance of the sugar donor (34), the solution was filtered through Celite, washed with dichloromethane, washed with multilayered water and saturated saline, dried over magnesium sulfate, and purified on a silica gel column to separate the spots. Although it took, it was not the target oligosaccharide compound (36) but the by-product (37) derived from the sugar donor (34).

(3) Sugar donor (34) (22.0 mg, 13.7 μmol), sugar acceptor (35) (13.4 mg, 9.14 μmol), MS4A (30 mg), dichloromethane (0.46 ml) were added to perform nitrogen substitution, Stir at room temperature for 1 hour. Then, add BF ₃ · OEt ₂ (0.1M solution, 27.4μl, 2.74μmol) at the same temperature, stir for 30 minutes, and add BF ₃ · OEt ₂ (0.1M solution, 27.4μl, 2.74μmol). In addition, the reaction was carried out for 1 hour. After confirming the disappearance of the sugar donor (34), the solution was filtered through Celite, washed with dichloromethane, washed with multilayered water and saturated saline, dried over magnesium sulfate, and purified on a silica gel column to separate the spots. The target oligosaccharide compound (36) was not obtained.

Comparative Example 2

  A sugar donor (38) (58.5 mg, 41.9 μmol), a sugar acceptor (3a-6) (30.0 mg, 27.9 μmol), MS4A (90 mg), and dichloromethane (0.4 ml) were added to each other, followed by nitrogen substitution. For 40 minutes. Then, it cooled to -25 degreeC, TMSOTf (1.5 microliters, 8.4 micromol) was added, reaction was performed at -25 degreeC for 1 hour, and it heated up gradually to room temperature. After reacting at room temperature for 2 hours and confirming the disappearance of the sugar donor (38), it was filtered through Celite, washed with dichloromethane, washed with aqueous sodium bicarbonate and saturated saline, dried over magnesium sulfate, and then on a silica gel column. Although the column was purified and the spots were collected, the by-product (40) derived from the sugar donor (38) (45.4 mg, conversion rate 88%) was obtained instead of the target oligosaccharide compound (39). . Regarding the sugar acceptor (3a-6), the raw material was recovered except that the hydroxyl group was changed to a trimethylsilylated one (4.6 mg (14%)).

Claims (5)

A method for producing an oligosaccharide compound represented by the general formula (1), wherein a sugar donor represented by the general formula (2) and a sugar acceptor represented by the general formula (3) Reacting in the presence.

[Wherein R ¹ , R ² , R ³ and R ⁴ represent a hydroxyl-protecting group or a group —SO ₃ R ⁶ . Here, R ⁶ is a C _1-8 alkyl group, a C _1-6 haloalkyl group, a benzyl group (on the phenyl ring of the benzyl group, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, C One or more substituents selected from the group consisting of _1-4 alkoxy groups, C _1-4 haloalkoxy groups, C _1-4 alkoxycarbonyl groups, nitro groups and cyano groups may be substituted) Or a phenyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, 1 or more of at least one substituent selected from the group consisting of a nitro group and a cyano group may be substituted). R ⁵ represents a C _1-4 alkoxycarbonyl group or a benzyloxycarbonyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4). One or more substituents selected from the group consisting of a haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group and a cyano group may be substituted), a benzhydryloxycarbonyl group (phenyl ring) Above, from halogen atom, C _1-4 alkyl group, C _1-4 haloalkyl group, C _1-4 alkoxy group, C _1-4 haloalkoxy group, C _1-4 alkoxycarbonyl group, nitro group and cyano group One or more substituents selected from the group consisting of one or more may be substituted) or a group —CH ₂ OR ⁷ . Here, R ⁷ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ .
R ^a and R ^b are the same or different and each represents a C _1-4 alkyl group, a C _1-4 haloalkyl group or a C _1-4 haloalkoxy group, or bonded to each other to form a C _1-4 alkylene group, C _{2- 4 represents an} alkenylene group or a phenylene group. Q ¹ and Q ^{2 each} represent a hydroxyl protecting group, a group —SO ₃ R ⁶ or a sugar residue. ]

[Wherein R ³ , R ⁴ , R ^a , R ^b and Q ² are the same as described above. X represents a leaving group. ]

[Wherein, R ¹ , R ² , R ⁵ and Q ¹ are the same as described above. ] A sugar compound represented by the general formula (2a).

[Wherein, R ⁴ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ . R ⁶ represents a C _1-8 alkyl group, a C _1-6 haloalkyl group, a benzyl group (on the phenyl ring of the benzyl group, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _{1- At} least one substituent selected from the group consisting of ₄ alkoxy groups, C _1-4 haloalkoxy groups, C _1-4 alkoxycarbonyl groups, nitro groups and cyano groups may be substituted) or phenyl Group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group) And at least one substituent selected from the group consisting of cyano group may be substituted one or more). R ⁵ represents a C _1-4 alkoxycarbonyl group or a benzyloxycarbonyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4). One or more substituents selected from the group consisting of a haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group and a cyano group may be substituted), a benzhydryloxycarbonyl group (phenyl ring) Above, from halogen atom, C _1-4 alkyl group, C _1-4 haloalkyl group, C _1-4 alkoxy group, C _1-4 haloalkoxy group, C _1-4 alkoxycarbonyl group, nitro group and cyano group One or more substituents selected from the group consisting of one or more may be substituted) or a group —CH ₂ OR ⁷ . Here, R ⁷ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ . R ⁸ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ . R ^a and R ^b are the same or different and each represents a C _1-4 alkyl group, a C _1-4 haloalkyl group or a C _1-4 haloalkoxy group, or bonded to each other to form a C _1-4 alkylene group, C _{2- 4 represents an} alkenylene group or a phenylene group. X ^a represents a halogen atom, a C _1-5 alkylcarbonyloxy group, a C _2-6 alkenylcarbonyloxy group, a trihaloacetimidoyloxy group or a thioformimidoyloxy group. ] A sugar compound represented by the general formula (3a).

[Wherein, R ⁵ represents a C _1-4 alkoxycarbonyl group, a benzyloxycarbonyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, At least one substituent selected from the group consisting of a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group, and a cyano group may be substituted), benzhydryloxycarbonyl Group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group) And at least one substituent selected from the group consisting of a cyano group and one or more substituents may be substituted) or a group —CH ₂ OR ⁷ . Here, R ⁷ represents a hydroxyl-protecting group, a group —SO ₃ R ⁶ . R ⁶ represents a C _1-8 alkyl group, a C _1-6 haloalkyl group, a benzyl group (on the phenyl ring of the benzyl group, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _{1- At} least one substituent selected from the group consisting of ₄ alkoxy groups, C _1-4 haloalkoxy groups, C _1-4 alkoxycarbonyl groups, nitro groups and cyano groups may be substituted), phenyl Group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group) And at least one substituent selected from the group consisting of cyano group may be substituted one or more). Q ³ represents the following formula (Q ^3a ) or (Q ^3b ):

Indicates. R ⁹ and R ^{10 each} represent a hydroxyl protecting group, a group —SO ₃ R ⁶ . A is a group —OSO ₃ R ⁶ , an azide group,

Indicates. Here, R ^c and R ^d are the same or different and each represents a hydrogen atom, a C _1-4 alkylcarbonyl group, a C _1-4 haloalkylcarbonyl group or a C _1-4 haloalkoxycarbonyl group, and R ^e and R ^f Are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group or a phenyl group, and R ^g , R ^h , R ⁱ and R ^j are the same or different and represent a hydrogen atom, a halogen atom or a C _1-4 alkyl. A group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group or a cyano group; ] An oligosaccharide compound represented by the general formula (1).

[Wherein R ¹ , R ² , R ³ and R ⁴ represent a hydroxyl-protecting group or a group —SO ₃ R ⁶ . Here, R ⁶ is a C _1-8 alkyl group, a C _1-6 haloalkyl group, a benzyl group (on the phenyl ring of the benzyl group, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, C One or more substituents selected from the group consisting of _1-4 alkoxy groups, C _1-4 haloalkoxy groups, C _1-4 alkoxycarbonyl groups, nitro groups and cyano groups may be substituted) Or a phenyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, 1 or more of at least one substituent selected from the group consisting of a nitro group and a cyano group may be substituted). R ⁵ represents a C _1-4 alkoxycarbonyl group or a benzyloxycarbonyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4). One or more substituents selected from the group consisting of a haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group and a cyano group may be substituted), a benzhydryloxycarbonyl group (phenyl ring) Above, from halogen atom, C _1-4 alkyl group, C _1-4 haloalkyl group, C _1-4 alkoxy group, C _1-4 haloalkoxy group, C _1-4 alkoxycarbonyl group, nitro group and cyano group One or more substituents selected from the group consisting of one or more may be substituted) or a group —CH ₂ OR ⁷ . Here, R ⁷ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ .
R ^a and R ^b are the same or different and each represents a C _1-4 alkyl group, a C _1-4 haloalkyl group or a C _1-4 haloalkoxy group, or bonded to each other to form a C _1-4 alkylene group, C _{2- 4 represents an} alkenylene group or a phenylene group. Q ¹ and Q ^{2 each} represent a hydroxyl protecting group, a group —SO ₃ R ⁶ or a sugar residue. ] An oligosaccharide compound represented by the general formula (1a).

[Wherein, R ³ and R ^{4 each} represent a hydroxyl-protecting group or a group —SO ₃ R ⁶ . R ⁶ represents a C _1-8 alkyl group, a C _1-6 haloalkyl group, a benzyl group (on the phenyl ring of the benzyl group, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4). At least one substituent selected from the group consisting of an alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group and a cyano group may be substituted) or a phenyl group (On the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group, and 1 or more of at least one substituent selected from the group consisting of cyano groups may be substituted). R ⁵ represents a C _1-4 alkoxycarbonyl group or a benzyloxycarbonyl group (on the phenyl ring, a halogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4). One or more substituents selected from the group consisting of a haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group and a cyano group may be substituted), a benzhydryloxycarbonyl group (phenyl ring) Above, a halogen atom, C _1-4
At least one substitution selected from the group consisting of an alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group and a cyano group One or more groups may be substituted) or a group —CH ₂ OR ⁷ . Here, R ⁷ represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ .
R ^a and R ^b are the same or different and each represents a C _1-4 alkyl group, a C _1-4 haloalkyl group or a C _1-4 haloalkoxy group, or bonded to each other to form a C _1-4 alkylene group, C _{2- 4 represents an} alkenylene group or a phenylene group. Q ⁴ is a hydroxyl group protected by a protecting group, the following formula (Q ^4a ) or (Q ^4b ):

Alternatively, it represents a hydroxyl group protected by a protecting group, and R ⁹ and R ¹⁰ represent a hydroxyl protecting group or a group —SO ₃ R ⁶ . A is a group —OSO ₃ R ⁶ , an azide group,

Indicates. Here, R ^c and R ^d are the same or different and each represents a hydrogen atom, a C _1-4 alkylcarbonyl group, a C _1-4 haloalkylcarbonyl group or a C _1-4 haloalkoxycarbonyl group, and R ^e and R ^f Are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group or a phenyl group, and R ^g , R ^h , R ⁱ and R ^j are the same or different and represent a hydrogen atom, a halogen atom or a C _1-4 alkyl. A group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a C _1-4 alkoxycarbonyl group, a nitro group or a cyano group; Q ⁵ is the following formula (Q ^5a ):

Alternatively, it represents a hydroxyl-protecting group or a group —SO ₃ R ⁶ . R ⁸ represents a hydrogen atom, a hydroxyl-protecting group, or a group —SO ₃ R ⁶ . m represents an integer of 0 or 1, and n represents an integer of 0 to 4. ]

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