Novel oligosaccharide, manufacturing intermediate for novel oligosaccharide, and method for manufacturing these

Abstract

[Problem] The problem of the present invention is to provide: a novel oligosaccharide that can be used in order to manufacture a 2-branched glycan having an α2,6-sialic acid structure at a non-reducing end; a method for manufacturing the same; a manufacturing intermediate for the novel oligosaccharide; a method for manufacturing the intermediate; a novel oligosaccharide that is a 2-branched glycan having an α2,6-sialic acid structure at a non-reducing end; a method for manufacturing that oligosaccharide; an intermediate of that oligosaccharide; and a method for manufacturing that intermediate. [Solution] Provided are: novel oligosaccharides shown in formulas A-13 and D-13; a method for manufacturing the oligosaccharides shown in formula A-13 and formula D-13, as shown in fig. 1, fig. 3, etc.; an intermediate of those novel oligosaccharides; and a method for manufacturing the intermediate.

Description

Novel oligosaccharides, intermediates for the production of said oligosaccharides, and methods for producing them

[0001] The present invention relates to a novel oligosaccharide, which is a biantennary glycan having an α2,6-sialic acid structure at the non-reducing end, a method for producing said oligosaccharide, an intermediate thereof, and a method for producing said intermediate.

[0002] Glycosylation of proteins is known to have a significant impact on their function and structure. N-linked glycans, in particular, are deeply involved in the physiological activity of proteins, and it has been reported that biantennary N-glycans with an α2,6-sialic acid structure at the non-reducing end are optimal structures for enhancing antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) (Non-Patent Document 1).

[0003] In order to develop and commercialize pharmaceuticals that utilize glycans, it is desirable to be able to produce high-purity glycans stably in large quantities at an industrially affordable price. The synthesis of α2,6-sialylglycans that has been reported so far can be broadly divided into two methods: 1) semi-chemical synthesis, which combines separation and purification of natural extracts or chemical synthesis of the main skeleton precursor with enzymatic conversion, and 2) pure chemical synthesis.

[0004] For example, it has been reported that N-linked glycans can be obtained from chicken egg yolk by combining an enzymatic method and a chemical method (Non-Patent Document 2). While these methods can synthesize the target glycans with fewer steps than pure chemical synthesis, they often require the procurement of large amounts of egg yolk, and special techniques and purification equipment are often required for subsequent isolation and purification from the egg yolk and purification of the water-soluble unprotected glycans after chemical conversion (Patent Documents 1 to 4).

[0005] On the other hand, the following reports have been published regarding purely chemical synthesis of α2,6-sialyl oligosaccharides: (1) Total synthesis of a complex-type 11-saccharide glycan having an α2,6-sialyl moiety (Non-Patent Document 3); (2) Total synthesis of immunoglobin G13 glycopeptide having an α2,6-sialyl moiety (Non-Patent Document 4); (3) Total synthesis of an α2,6-sialyl 12-saccharide N-linked oligosaccharide containing core fucose (Non-Patent Document 5); (4) Total synthesis of an α2,6-sialyl 10-saccharide oligosaccharide chain fluorinated at the 3-position (Non-Patent Document 6); (5) Total synthesis of an asymmetrically deuterated α2,6-sialyl biantennary 11-saccharide oligosaccharide chain and a tetraantennary 17-saccharide oligosaccharide chain (Non-Patent Document 7).

[0006] Pure chemical synthesis of glycans, once a robust production method is established, is expected to offer a high degree of freedom in the amount of sugars produced, as they are derived from monosaccharides, just like conventional low-molecular-weight compounds. Furthermore, because the conversion involves the conversion of sugars modified with protecting groups, most purification procedures involve handling water-insoluble compounds, which is expected to significantly reduce the complexity and labor required compared to semi-chemical synthesis. Furthermore, by applying established chemical synthesis methods, a wide variety of unnatural glycans can be easily synthesized.

[0007] On the other hand, the previously reported examples mentioned above have two major synthetic challenges: 1) the highly difficult conversion of sugar parts, such as the construction of β-mannoside parts and α-sialyl parts, and the linking process thereof, involve low-selectivity, low-yield steps; and 2) in both the sugar part conversion and linking processes, silica gel column chromatographic purification, which is not suitable for scale-up, is frequently used in each step, and precise preparative chromatographic purification procedures are essential in many steps to remove isomers and impurities generated as by-products in the reaction.

[0008] As described above, purely chemical synthesis of glycans has potential advantages over semi-chemical synthesis in terms of large-scale synthesis, but technological development is not yet sufficiently advanced in terms of yield, selectivity, efficiency, and cost, and there are very few examples of its adoption as an actual large-scale synthesis method.Furthermore, with regard to biantennary glycans (α2,6-sialyl glycans), in which different glycan units are linked to the 3- and 6-positions of the mannose branch point, their large-scale synthesis is structurally extremely difficult, whether by derivation from natural extracts, semi-chemical synthesis, or total chemical synthesis.

[0009] In addition, in sugar derivatives protected by phthalimide groups, it may be necessary to simultaneously benzylate multiple hydroxyl groups. In this case, it is necessary to proceed with the reaction while suppressing ring-opening of the phthalimide group. However, since the ring-opening reaction of the phthalimide group readily proceeds under strongly basic conditions in the presence of trace amounts of hydroxide ions, the yield varies greatly depending on the amount of sodium hydroxide in NaH under the NaH / DMAc conditions used in conventional benzylation reactions. Furthermore, NaH / DMAc is not easily applicable as a large-scale synthesis method due to the risk of mixing and explosion. Therefore, a method for simultaneously benzylating multiple hydroxyl groups under milder conditions while suppressing ring-opening of the phthalimide group is desired.

[0010] In addition, sugar derivatives protected by phthalimide groups may require deacylation. However, when trace amounts of water are present in the system, the phthalimide group readily undergoes a ring-opening reaction under basic conditions, making it necessary to strictly control the amount of water in the system. Even at water levels on the order of ppm, it is difficult to completely suppress ring-opening. Therefore, there is a need for a method that can suppress ring-opening of the phthalimide group while promoting deacylation in high yield.

[0011] Furthermore, in the chemical synthesis of oligosaccharide chains and the like having hydroxyl groups, in order to efficiently obtain the target compound, it is necessary to rationally utilize methods for selective protection and deprotection of such hydroxyl groups, and in particular, the 2-naphthylmethyl group has been widely used as a general protecting group for hydroxyl groups. On the other hand, a method using 2,3-dichloro-5,6-dicyano-p-benzoquinone in dichloromethane-water is known as a method for deprotecting the 2-naphthylmethyl group, and this method gives the target deprotected product in moderate to high yields for a wide range of substrates. However, dichloromethane and water are generally immiscible, and 2,3-dichloro-5,6-dicyano-p-benzoquinone and its by-product, 2,3-dichloro-5,6-dicyano-p-benzohydroquinone, are almost insoluble in dichloromethane-water, which affects the stirring properties and makes it difficult to apply to large-scale synthesis. Furthermore, it has been reported that, depending on the substrate used, the desired deprotected product may not be obtained in a satisfactory yield (Non-Patent Document 8). Furthermore, the reaction yield tends to decrease with an increase in the number of benzyl groups in the substrate (Non-Patent Document 9). Therefore, the development of a milder, more efficient method applicable to complex substrates is desired. As a means to achieve this goal, improved conditions using β-pinene as an additive have been reported (Non-Patent Document 10). However, even with this method, the yield remains moderate for complex substrates containing multiple benzyl groups (Non-Patent Document 11). Given the above background, there is a need for the development of a 2-naphthylmethylation deprotection reaction under milder conditions that can remove the 2-naphthylmethyl protecting group and obtain the deprotected product in high yield.

[0012] Furthermore, liquid-phase synthesis and solid-phase synthesis are known methods for chemically synthesizing oligosaccharide chains. However, while liquid-phase synthesis can utilize conventional organic synthesis techniques, making it easy to track and scale up the reaction, it has the drawback of requiring time and labor, due to the need for post-treatment and purification at each step. Solid-phase synthesis is advantageous in that it can be automated and allows for rapid production, but it is limited in its scale-up due to equipment limitations. Furthermore, its low reactivity requires the use of an excess of glycosyl donors in the glycosyl elongation reaction, making it unsuitable for industrial large-scale synthesis. Furthermore, it is difficult to monitor the progress of the reaction at intermediate stages (Patent Document 5). To address these issues, several methods for producing oligosaccharides using substrates tagged with molecular structures (tags) that specifically precipitate, partition, adsorb, or otherwise react to certain environments have been developed (Patent Document 6; Non-Patent Documents 12, 13, and 14). These methods combine the advantages of both liquid-phase and solid-phase synthesis, i.e., the reaction can be performed in a homogeneous system, facilitating analysis, and utilizing the characteristics of the tags to enable separation from reagent residues, etc. For example, a method is known in which a branched long-chain alkane is used as a hydrophobic tag and the post-reaction solution is adsorbed with octadecyl-modified silica gel to separate untagged compounds (Non-Patent Document 14). However, both methods require the use of a tag, which requires a desorption step. Furthermore, as oligomerization proceeds, the substrate portion becomes larger than the tag, gradually overcoming the physical properties of the substrate and weakening the function of the tag. Therefore, there is a need for a method for more efficiently purifying oligosaccharides in oligosaccharide chain production methods.

[0013] In glycosylation reactions, the presence of -NHAc groups in the reaction substrate significantly reduces the reactivity of the target glycosylation reaction due to interactions with Lewis acids, often requiring an excess of glycosyl donors to complete the reaction. For this reason, in the synthesis of acetylglucosamine-containing oligosaccharide chains, a Troc group (Non-Patent Documents 5, 6, and 7), a phthalimide group, or a sulfonyl group (Non-Patent Document 4) has been used as a temporary protecting group on the glucosamine nitrogen during the glycosylation reaction, followed by deprotection and subsequent N-Ac conversion. However, the Troc group requires deprotection conditions using zinc / AcOH or prolonged reaction with excess lithium hydroxide, and in complex glycans, deprotection conditions can lead to substrate decomposition. Furthermore, the use of excess ethylenediamine in deprotection of phthalimide groups can lead to the problem of amidation of the sialic acid ester moiety as a side reaction. To avoid this, a two-step process is required: selective hydrolysis of the ester moiety followed by deprotection. Furthermore, the sulfonyl group is deprotected using sodium metal under reaction conditions that make it difficult to scale up. Therefore, in the production of acetylglucosamine-containing oligosaccharide chains, there is a need to develop a protecting group that can be easily converted to an acetyl group without reducing the reactivity of the glycosylation reaction.

[0014] In addition, polyethylene glycol has been widely used in the development of pharmaceuticals in recent years as a biocompatible water-soluble moiety. In the development of pharmaceuticals, it is desirable for these polyethylene glycol structures to be more uniform and highly pure. However, many impurities are present in commercially available reagents, and their purification requires strict distillation or complicated column purification. Furthermore, if a compound having a polyethylene glycol structure contains an azide structure, distillation procedures requiring heating cannot be applied due to concerns about explosion. Recently, MgCl ２ A purification method using a metal complex with MgCl has been reported (Non-Patent Document 15). ２However, since this method involves adsorbing the target substance onto a polyethylene glycol structure, there is a large loss of the target substance into the filtrate, and it is predicted that the purification effect will be smaller than that of isolation by crystallization. Therefore, a method for purifying the above-mentioned compound having a polyethylene glycol structure is desired.

[0015] In oligosaccharide synthesis, isolation and purification of intermediates as crystals becomes increasingly difficult as the molecular weight increases. In particular, there have been no reports of crystallization of intermediates consisting of protected trisaccharides or more, with molecular weights exceeding 1,000. Therefore, a major challenge is how to remove structurally similar analogs, such as isomers produced as by-products in trace amounts during the reaction and impurities derived from the remaining raw materials, from the target product. Conventionally, silica gel column purification has been employed at each step of the synthesis to remove these analogs, but this has been a major obstacle to achieving efficient large-scale synthesis. Given this background, there is a need for crystallization and purification methods that can efficiently remove structurally similar impurities from oligosaccharide synthesis intermediates.

[0016] International Publication No. 2011 / 027868, International Publication No. 96 / 02255, International Publication No. 2014 / 208742, International Publication No. 2017 / 110984, International Publication No. 2002 / 16384, Japanese Patent No. 6001267

[0017] Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 10611-10616 Beilstein J. Org. Chem. 2018, 14, 416-429 Tetrahedron Lett. 1986, 27, 5739-5742J. Am. Chem. Soc. 2009, 131, 16669-16671J. Org. Chem. 2016, 81, 10600-10616J. Am. Chem. Soc. 2019, 141, 6484-6488 Angew. Chem. Int. Ed. 2021, 60, 24686-24693 Org. Lett. 2002, 4, 4551-4554 J. Am. Chem. Soc. 2018, 140, 4632-4638 J. Org. Chem. , 2017, 82, 3926-3934 Angew. Chem. Int. Ed. 2021, 60, 19287-19296 Journal of the Organic Synthesis Society, 2002, Vol. 60, No. 5, pp. 494-495 Org. Biomol. Chem. 2018, 16, 4720-4727 J. AM. CHEM. SOC. 2005, 127, 7296-7297Org. Process. Res. Dev. 2021, 25, 10, 2270-2276

[0018] One object of the present invention is to provide a novel oligosaccharide that can be used to produce a biantennary glycan having an α2,6-sialic acid structure at the non-reducing end, a method for producing the oligosaccharide, an intermediate thereof, and a method for producing the intermediate. Another object of the present invention is to provide a novel oligosaccharide that is a biantennary glycan having an α2,6-sialic acid structure at the non-reducing end, a method for producing the oligosaccharide, an intermediate thereof, and a method for producing the intermediate.

[0019] The present inventors have conducted extensive research to solve the above-mentioned problems, and as a result have discovered a novel oligosaccharide represented by A-13 below, a novel method for efficiently producing the oligosaccharide, an intermediate thereof, and a method for producing the intermediate, as well as a novel oligosaccharide represented by D-13 below, which is a biantennary glycan having an α2,6-sialic acid structure at the non-reducing end, a novel method for efficiently producing the oligosaccharide, and an intermediate thereof and a method for producing the intermediate, thereby completing the present invention.

[0020] That is, the present invention relates to, but is not limited to, the following:

[0021] [1] Formula A-13 below: (Step I-1) a method for producing an oligosaccharide represented by formula A-3: The compound represented by the following formula A-4: to form a compound represented by the following formula A-5: The method of the present invention includes a step of producing a compound represented by the following formula A-7: (Step I-2) reacting the compound represented by formula A-7 with a compound represented by the following formula A-8: to form a compound represented by the following formula A-9: The method of claim 1, further comprising the step of producing a compound represented by formula A-10: (Step I-3) reacting the compound represented by formula A-10 with a compound represented by formula A-11: to form a compound represented by the following formula A-12: [2] The method according to [1], wherein in step I-2, the compound represented by formula A-9 is reacted with a strong base in the presence of an alkyl ester of a perfluorocarboxylic acid to produce the compound represented by formula A-10. [3] The method according to [2], wherein the alkyl ester of a perfluorocarboxylic acid is methyl trifluoroacetate, ethyl trifluoroacetate, propyl trifluoroacetate, isopropyl trifluoroacetate, butyl trifluoroacetate, methyl pentafluoropropionate, ethyl pentafluoropropionate, propyl pentafluoropropionate, isopropyl pentafluoropropionate, methyl heptafluorobutyrate, ethyl heptafluorobutyrate, propyl heptafluorobutyrate, isopropyl heptafluorobutyrate, butyl heptafluorobutyrate, methyl nonafluorovalerate, ethyl nonafluorovalerate, propyl nonafluorovalerate, isopropyl nonafluorovalerate, butyl nonafluorovalerate, methyl undecafluorocaproate, ethyl undecafluorocaproate, propyl undecafluorocaproate, isopropyl undecafluorocaproate, or butyl undecafluorocaproate. [4] The method according to [2] or [3], wherein the strong base is selected from the group consisting of sodium, lithium, and potassium salts of metal amides; sodium, lithium, potassium, cesium, and barium salts of C1 to C20 alkoxides; sodium hydride, potassium hydride, lithium hydride, butyllithium, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, cesium phosphate, lithium phosphate, diazabicycloundecene (DBU), diazabicyclononene (DBN), and 1,1,3,3-tetramethylguanidine (TMG); and combinations thereof. [5] The method according to [2] or [3], wherein the strong base is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, or LHMDS (lithium hexamethyldisilazide).[6] The method according to any one of [2] to [5], wherein the reaction in the step I-2 is carried out in a C1 to C10 alcohol solvent alone or in a mixed solvent of a C1 to C10 alcohol solvent with an amide solvent, an ether solvent, an ester solvent, an aromatic solvent, a halogenated solvent, a hydrocarbon solvent, or a nitrile solvent. [7] The method according to any one of [1] to [6], wherein the step I-3 comprises reacting the compound represented by formula A-12 with DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone) in a mixed solvent of a fluorous alcohol and water to eliminate the 2-naphthylmethyl group in the compound represented by formula A-12, thereby producing the oligosaccharide represented by formula A-13. [8] The method according to [7], wherein the fluorous alcohol is selected from the group consisting of hexafluoro-2-propanol (HFIP), 2,2,2-trifluoroethanol (TFE), 2,2,3,3,4,4,5,5-octafluoro-1-pentanol, nonafluoro-tert-butyl alcohol, and combinations thereof. [9] The method according to [7] or [8], wherein the reaction in step I-3 is carried out at -35°C to 70°C.

[10] The method according to [7] or [8], wherein the reaction in step I-3 is carried out at -30°C to -10°C.

[11] The method according to any one of [1] to

[10] , comprising: in the step I-1, after terminating the reaction between the compound represented by formula A-4 and the compound represented by formula A-3, adding a hydrophobic carrier and water to a water-soluble organic solvent containing the produced compound represented by formula A-5 and impurities, thereby adsorbing the compound represented by formula A-5 onto the hydrophobic carrier; subsequently, filtering and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and the water to remove the impurities; and subsequently eluting the compound represented by formula A-5 from the hydrophobic carrier using an organic solvent, thereby purifying the compound represented by formula A-5.

[12] The method according to any one of [1] to

[11] , comprising: in the step I-2, after terminating the reaction between the compound represented by formula A-7 and the compound represented by formula A-8, adding a hydrophobic carrier and water to a water-soluble organic solvent containing the produced compound represented by formula A-9 and impurities, thereby adsorbing the compound represented by formula A-9 onto the hydrophobic carrier; subsequently filtering and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and the water to remove the impurities; and subsequently eluting the compound represented by formula A-9 from the hydrophobic carrier using an organic solvent, thereby purifying the compound represented by formula A-9.

[13] The method according to any one of [1] to

[12] , comprising, in Step 1-3, terminating the reaction between the compound represented by Formula A-10 and the compound represented by Formula A-11, adding a hydrophobic carrier and water to a water-soluble organic solvent containing the compound represented by Formula A-12 thus produced and contaminants, thereby adsorbing the compound represented by Formula A-12 onto the hydrophobic carrier, filtering the mixture and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and the water to remove the contaminants, and then eluting the compound represented by Formula A-12 from the hydrophobic carrier with an organic solvent, thereby purifying the compound represented by Formula A-12.

[14] The method according to

[11] , wherein the contaminants include a sugar compound other than the compound represented by Formula A-5 and / or a compound derived from a reaction reagent used to obtain the purified compound.

[15] The method according to

[12] , wherein the contaminants include sugar compounds other than the compound represented by formula A-9 and / or compounds derived from a reaction reagent used to obtain the compound to be purified.

[16] The method according to

[13] , wherein the contaminants include sugar compounds other than the compound represented by formula A-12 and / or compounds derived from a reaction reagent used to obtain the compound to be purified.

[17] The method according to any one of

[11] to

[16] , wherein the hydrophobic support is a reversed-phase partition chromatography packing resin.

[18] The method according to

[17] , wherein the reversed-phase partition chromatography packing resin is selected from the group consisting of poly(styrene / divinylbenzene) polymer gel resin, polystyrene-divinylbenzene resin, polyhydroxymethacrylate resin, styrene-vinylbenzene copolymer resin, polyvinyl alcohol resin, polystyrene resin, polymethacrylate resin, chemically bonded silica gel resin, and combinations thereof.

[19] The method according to

[18] , wherein the chemically bonded silica gel resin is selected from the group consisting of (1) a resin obtained by reacting silica gel with a silane coupling agent, (2) a resin obtained by chemically bonding dimethyloctadecyl, octadecyl, trimethyloctadecyl, dimethyloctyl, octyl, butyl, ethyl, methyl, phenyl, cyanopropyl, or aminopropyl groups to silica gel, (3) a resin obtained by chemically bonding docosyl or triacontyl groups to silica gel, and (4) a combination of the above (1) to (3).

[20] The method according to

[18] , wherein the chemically bonded silica gel resin is an octadecyl group-bonded silica gel resin (ODS resin).

[21] The method according to any one of

[11] to

[20] , wherein the water-soluble organic solvent is a water-soluble alcohol solvent, a water-soluble nitrile solvent, a water-soluble ether solvent, a water-soluble ketone solvent, a water-soluble amide solvent, or a water-soluble sulfoxide solvent, or a mixed solvent containing at least one of the above-mentioned water-soluble organic solvents.

[22] The method according to

[21] , wherein the water-soluble nitrile solvent is acetonitrile.

[23] The method according to any one of

[11] to

[22] , wherein the organic solvent used in the step of eluting the target substance from the hydrophobic carrier is a nitrile solvent, an ether solvent, an ester solvent, a ketone solvent, a halogenated solvent, an aromatic solvent, or a mixed solvent containing at least one of the above-mentioned solvents.

[24] The compound represented by formula A-11 is (Step Y-1) a compound represented by the following formula B-1: The compound represented by the following formula B-2: to form a compound represented by the following formula B-3: The method of the present invention includes a step of producing a compound represented by the following formula B-4: (Step Y-2) adding lithium tert-butoxide or lithium tert-amoxide to a solvent containing the compound represented by formula B-4 and benzyl halide or benzyl sulfonate to protect the hydroxyl group present in the compound represented by formula B-4 with a benzyl group, thereby producing a compound represented by formula B-5:

[25] The method according to any one of [1] to

[23] , wherein the compound represented by formula B-4 is produced by a process comprising the steps of:

[0023] forming a compound represented by formula B-5:

[0024]

[25] The method according to

[24] , wherein the solvent containing the compound represented by formula B-4 and a benzyl halide or benzyl sulfonate is an amide solvent, an ether solvent, an aromatic solvent, a hydrocarbon solvent, a urea solvent, or a mixed solvent containing at least one of the above solvents.

[26] The compound represented by formula B-5 is produced by ring-opening the phthalimide group in the compound represented by formula B-5 and then forming a salt with cinchonidine, thereby obtaining a crystalline compound represented by the following formula B-6: The crystalline compound represented by formula B-6 is separated from the amorphous substance, and then an acidic aqueous solution and a solvent are added to remove cinchonidine from the compound represented by formula B-6, to obtain a compound represented by formula B-7: The method according to

[24] or

[25] , further comprising a step of purifying the compound represented by formula A-13 by ring-opening the phthalimide group in the compound represented by formula A-13 and then forming a salt with (R)-(+)-1-(1-naphthyl)ethylamine to obtain a crystalline compound represented by formula A-14: The crystalline compound represented by formula A-14 is separated from the amorphous substance, and then, by adding an acidic aqueous solution and a solvent, (R)-(+)-1-(1-naphthyl)ethylamine in the compound represented by formula A-14 is removed to obtain a compound represented by formula A-15:

[28] The method according to any one of [1] to

[26] , further comprising a step of producing a compound represented by the following formula D-13, and then purifying the compound represented by the formula A-15 by ring-closing the opened phthalimide group: (Step II-1) a method for producing an oligosaccharide represented by the following formula A-13: The oligosaccharide represented by the following formula A-3: to form a compound represented by the following formula D-1: The method includes the step of producing a compound represented by the following formula D-2: (Step II-2) reacting the compound represented by formula D-2 with a compound represented by the following formula D-3: to form a β-1,2-glycosidic bond with a compound represented by the following formula D-4: The method of claim 1, further comprising the step of producing a compound represented by formula D-5: After producing a compound represented by formula D-5, the amino group in the compound represented by formula D-5 is protected with a protecting group selected from an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, a 2,2,2-trichloroethoxycarbonyl (Troc) group, and a phthalimide (Pht) group to produce a compound represented by formula D-6: (wherein R ５ is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R ６ is a hydrogen atom, or R ５ and R ６ form a phthalimido group together with the nitrogen atom to which they are attached), or by removing the acetyl (Ac) group on the compound of formula D-4, a compound of formula D-6 (wherein R ５ and R ６ form a phthalimide group together with the nitrogen atom to which they are bonded), (Step II-3) treating the compound represented by formula D-6 with a compound represented by the following formula D-7: to form a β-1,4-glycosidic bond with a compound represented by the following formula D-8: (wherein R ５ is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R ６ is a hydrogen atom, or R ５ and R ６ form a phthalimide group together with the nitrogen atom to which they are attached), and then the protecting groups of the amino group and the acyl protecting group of the alcohol on the compound represented by formula D-8 are removed to produce a compound represented by formula D-9 below: (wherein M ＋ is a sodium ion, a lithium ion, a potassium ion, or a protonated triethylamine cation), (wherein M ＋ is a sodium ion, a lithium ion, a potassium ion, or a protonated triethylamine cation), (Step II-4) reacting the compound represented by formula D-11 with a compound represented by the following formula D-12:

[29] The method according to

[28] , comprising, in Step II-1, reacting the compound represented by formula D-1 with a strong base in the presence of an alkyl ester of a perfluorocarboxylic acid to produce the compound represented by formula D-2.

[30] The method according to

[29] , wherein the alkyl ester of a perfluorocarboxylic acid is methyl trifluoroacetate, ethyl trifluoroacetate, propyl trifluoroacetate, isopropyl trifluoroacetate, butyl trifluoroacetate, methyl pentafluoropropionate, ethyl pentafluoropropionate, propyl pentafluoropropionate, isopropyl pentafluoropropionate, methyl heptafluorobutyrate, ethyl heptafluorobutyrate, propyl heptafluorobutyrate, isopropyl heptafluorobutyrate, butyl heptafluorobutyrate, methyl nonafluorovalerate, ethyl nonafluorovalerate, propyl nonafluorovalerate, isopropyl nonafluorovalerate, butyl nonafluorovalerate, methyl undecafluorocaproate, ethyl undecafluorocaproate, propyl undecafluorocaproate, isopropyl undecafluorocaproate, or butyl undecafluorocaproate.

[31] The method according to

[29] or

[30] , wherein the strong base is selected from the group consisting of sodium, lithium, and potassium salts of metal amides; sodium, lithium, potassium, cesium, and barium salts of C1 to C20 alkoxides; sodium hydride, potassium hydride, lithium hydride, butyllithium, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, cesium phosphate, lithium phosphate, diazabicycloundecene (DBU), diazabicyclononene (DBN), and 1,1,3,3-tetramethylguanidine (TMG); and combinations thereof.

[32] The method according to

[29] or

[30] , wherein the strong base is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, or LHMDS (lithium hexamethyldisilazide).

[33] The method according to any one of

[29] to

[32] , wherein the step of producing the compound represented by formula D-2 by reacting the compound represented by formula D-1 with a strong base in the presence of trifluoroacetic acid ester is carried out in a C1-C10 alcohol solvent alone or a mixed solvent of a C1-C10 alcohol solvent with an amide solvent, an ether solvent, an ester solvent, an aromatic solvent, a halogenated solvent, a hydrocarbon solvent, or a nitrile solvent.

[34] The method according to any one of

[28] to

[33] , wherein the step II-3 of producing the compound represented by formula D-6 by protecting the amino group in the compound represented by formula D-5 with an aryloxycarbonyl (COOAr) group.

[35] The method according to any one of

[28] to

[34] , wherein the step of producing the compound represented by formula D-6 from the compound represented by formula D-5 in the step II-3 is carried out in an aqueous solution of sodium hydrogen carbonate, potassium hydrogen carbonate, disodium hydrogen phosphate, or dipotassium hydrogen phosphate.

[36] The compound represented by the formula D-12 can be obtained by the following steps: To a solution containing the crude compound represented by the formula D-12, a compound represented by the following formula E-1: (wherein R ７ is a hydrogen atom, a methyl group, or a methoxy group) to form a compound of the following formula E-2: A crystalline compound represented by the formula: ７is a hydrogen atom, a methyl group, or a methoxy group), isolating the crystalline compound, and then extracting the compound represented by formula D-12 from the isolated crystalline compound.

[37] The method according to

[36] , wherein the purified compound represented by formula D-12 has a purity of 95% or more as measured by HPLC.

[38] The method according to

[37] , wherein the purity is 98% or more.

[39] The method according to any one of

[28] to

[38] , comprising: in the step II-1, after terminating the reaction between the compound represented by formula A-13 and the compound represented by formula A-3, adding a hydrophobic carrier and water to a water-soluble organic solvent containing the produced compound represented by formula D-1 and impurities, thereby adsorbing the compound represented by formula D-1 onto the hydrophobic carrier; subsequently, filtering and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and the water to remove the impurities; and subsequently eluting the compound represented by formula D-1 from the hydrophobic carrier using an organic solvent, thereby purifying the compound represented by formula D-1.

[40] The method according to any one of

[28] to

[39] , comprising: in the step II-2, after terminating the reaction between the compound represented by formula D-3 and the compound represented by formula D-4, adding a hydrophobic carrier and water to a water-soluble organic solvent containing the produced compound represented by formula D-5 and impurities, thereby adsorbing the compound represented by formula D-5 onto the hydrophobic carrier; subsequently, filtering and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and the water to remove the impurities; and subsequently eluting the compound represented by formula D-5 from the hydrophobic carrier using an organic solvent, thereby purifying the compound represented by formula D-5.

[41] The method according to any one of

[28] to

[40] , comprising: in Step II-3, after terminating the reaction between the compound represented by Formula D-6 and the compound represented by Formula D-7, adding a hydrophobic carrier and water to a water-soluble organic solvent containing the resulting compound represented by Formula D-8 and impurities, thereby adsorbing the compound represented by Formula D-8 onto the hydrophobic carrier; then filtering and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and the water to remove the impurities; and then eluting the compound represented by Formula D-8 from the hydrophobic carrier using an organic solvent to purify the compound represented by Formula D-8.

[42] In Step II-3, protecting the amino group on Formula D-9 with acetyl to obtain a compound represented by Formula D-10:

[43] The method according to any one of

[39] to

[44] , wherein the contaminants include a sugar compound other than the compound represented by formula D-1 and / or a compound derived from a reaction reagent used to obtain the compound to be purified.

[44] The method according to

[40] , wherein the contaminants include a sugar compound other than the compound represented by formula D-5 and / or a compound derived from a reaction reagent used to obtain the compound to be purified.

[45] The method according to

[41] , wherein the contaminants include sugar compounds other than the compound represented by formula D-8 and / or compounds derived from a reaction reagent used to obtain the compound to be purified.

[46] The method according to

[42] , wherein the contaminants include sugar compounds other than the compound represented by formula C-10 and / or compounds derived from a reaction reagent used to obtain the compound to be purified.

[47] The method according to any one of

[39] to

[46] , wherein the hydrophobic support is a reversed-phase partition chromatography resin.

[48] The method according to

[47] , wherein the reversed-phase partition chromatography resin is selected from the group consisting of poly(styrene / divinylbenzene) polymer gel resin, polystyrene-divinylbenzene resin, polyhydroxymethacrylate resin, styrene-vinylbenzene copolymer resin, polyvinyl alcohol resin, polystyrene resin, polymethacrylate resin, chemically bonded silica gel resin, and combinations thereof.

[49] The method according to

[48] , wherein the chemically bonded silica gel resin is selected from the group consisting of (1) a resin obtained by reacting silica gel with a silane coupling agent, (2) a resin obtained by chemically bonding dimethyloctadecyl, octadecyl, trimethyloctadecyl, dimethyloctyl, octyl, butyl, ethyl, methyl, phenyl, cyanopropyl, or aminopropyl groups to silica gel, (3) a resin obtained by chemically bonding docosyl or triacontyl groups to silica gel, and (4) a combination of the above (1) to (3).

[50] The method according to

[48] , wherein the chemically bonded silica gel resin is an octadecyl group-bonded silica gel resin (ODS resin).

[51] The method according to any one of

[39] to

[50] , wherein the water-soluble organic solvent is a water-soluble alcohol solvent, a water-soluble nitrile solvent, a water-soluble ether solvent, a water-soluble ketone solvent, a water-soluble amide solvent, a water-soluble sulfoxide solvent, or a mixed solvent containing at least one of the above water-soluble organic solvents.

[52] The method according to

[51] , wherein the water-soluble nitrile solvent is acetonitrile.

[53] The method according to any one of

[39] to

[52] , wherein the organic solvent used in the step of eluting the target substance from the hydrophobic carrier is a nitrile solvent, an ether solvent, an ester solvent, a ketone solvent, a halogenated solvent, an aromatic solvent, or a mixed solvent containing at least one of the above solvents.

[54] A crystalline compound of the following formula D-5-FMA is obtained by forming a salt with fumaric acid of the compound represented by formula D-5:

[55] The method according to any one of

[28] to

[53] , further comprising the step of producing a compound represented by the formula B-5: The method for producing a compound represented by the following formula B-4:

[56] The method according to

[55] , wherein the solvent is an amide solvent, an ether solvent, an aromatic solvent, a urea solvent, a hydrocarbon solvent, or a mixed solvent containing at least one of the above solvents.

[57] A compound represented by the following formula A-10: The method for producing a compound represented by the following formula A-9: with a strong base in the presence of an alkyl ester of a perfluorocarboxylic acid.

[58] The method according to

[57] , wherein the alkyl ester of a perfluorocarboxylic acid is methyl trifluoroacetate, ethyl trifluoroacetate, propyl trifluoroacetate, isopropyl trifluoroacetate, butyl trifluoroacetate, methyl pentafluoropropionate, ethyl pentafluoropropionate, propyl pentafluoropropionate, isopropyl pentafluoropropionate, methyl heptafluorobutyrate, ethyl heptafluorobutyrate, propyl heptafluorobutyrate, isopropyl heptafluorobutyrate, butyl heptafluorobutyrate, methyl nonafluorovalerate, ethyl nonafluorovalerate, propyl nonafluorovalerate, isopropyl nonafluorovalerate, butyl nonafluorovalerate, methyl undecafluorocaproate, ethyl undecafluorocaproate, propyl undecafluorocaproate, isopropyl undecafluorocaproate, or butyl undecafluorocaproate.

[59] The method according to

[57] or

[58] , wherein the strong base is selected from the group consisting of sodium, lithium, and potassium salts of metal amides, sodium, lithium, potassium, cesium, and barium salts of C1 to C20 alkoxides, sodium hydride, potassium hydride, lithium hydride, butyllithium, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, cesium phosphate, lithium phosphate, diazabicycloundecene (DBU), diazabicyclononene (DBN), and 1,1,3,3-tetramethylguanidine (TMG), and combinations thereof.

[60] The method according to

[57] or

[58] , wherein the strong base is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, or LHMDS (lithium hexamethyldisilazide).

[61] The method according to any one of

[57] to

[60] , wherein the reaction is carried out in a C1 to C10 alcohol solvent alone or in a mixed solvent of a C1 to C10 alcohol solvent with an amide solvent, an ether solvent, an ester solvent, an aromatic solvent, a halogenated solvent, a hydrocarbon solvent, or a nitrile solvent.

[62] Formula A-13 below: A method for producing an oligosaccharide represented by the following formula A-12: with DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone) in a mixed solvent of a fluorous alcohol and water to eliminate the 2-naphthylmethyl group in the compound represented by formula A-12.

[63] The method according to

[62] , wherein the fluorous alcohol is selected from the group consisting of hexafluoro-2-propanol (HFIP), 2,2,2-trifluoroethanol (TFE), 2,2,3,3,4,4,5,5-octafluoro-1-pentanol, nonafluoro-tert-butyl alcohol, and combinations thereof.

[64] The method according to

[62] or

[63] , which is carried out at -35°C to 70°C.

[65] The method according to

[62] or

[63] , which is carried out at -30°C to -10°C.

[66] A compound represented by the following formula A-5:

[67] A method for purifying a compound represented by the following formula A-9:

[68] A method for purifying a compound represented by the following formula A-12:

[69] A method for purifying a compound represented by the following formula D-1:

[70] A method for purifying a compound represented by the following formula D-5:

[71] A method for purifying a compound represented by the following formula D-8: (wherein R ５ is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R ６ is a hydrogen atom, or R ５ and R ６

[72] A method for purifying a compound represented by the following formula D-10:

[73] The method according to

[69] , wherein the contaminants include sugar compounds other than the compound represented by formula D-1 and / or compounds derived from a reaction reagent used to obtain the compound to be purified.

[74] The method according to

[70] , wherein the contaminants include sugar compounds other than the compound represented by formula D-5 and / or compounds derived from a reaction reagent used to obtain the compound to be purified.

[75] The method according to

[71] , wherein the contaminants include sugar compounds other than the compound represented by formula D-8 and / or compounds derived from a reaction reagent used to obtain the compound to be purified.

[76] The method according to

[72] , wherein the contaminants include sugar compounds other than the compound represented by formula D-10 and / or compounds derived from a reaction reagent used to obtain the compound to be purified.

[77] The method according to any one of

[69] to

[76] , wherein the hydrophobic support is a reversed-phase partition chromatography resin.

[78] The method according to

[77] , wherein the reversed-phase partition chromatography resin is selected from the group consisting of poly(styrene / divinylbenzene) polymer gel resin, polystyrene-divinylbenzene resin, polyhydroxymethacrylate resin, styrene-vinylbenzene copolymer resin, polyvinyl alcohol resin, polystyrene resin, polymethacrylate resin, chemically bonded silica gel resin, and combinations thereof.

[79] The method according to

[78] , wherein the chemically bonded silica gel resin is selected from the group consisting of (1) a resin obtained by reacting silica gel with a silane coupling agent, (2) a resin obtained by chemically bonding dimethyloctadecyl, octadecyl, trimethyloctadecyl, dimethyloctyl, octyl, butyl, ethyl, methyl, phenyl, cyanopropyl, or aminopropyl groups to silica gel, (3) a resin obtained by chemically bonding docosyl or triacontyl groups to silica gel, and (4) a combination of the above (1) to (3).

[80] The method according to

[79] , wherein the chemically bonded silica gel resin is an octadecyl group-bonded silica gel resin (ODS resin).

[81] The method according to any one of

[69] to

[80] , wherein the water-soluble organic solvent is a water-soluble alcohol solvent, a water-soluble nitrile solvent, a water-soluble ether solvent, a water-soluble ketone solvent, a water-soluble amide solvent, a water-soluble sulfoxide solvent, or a mixed solvent containing at least one of the above water-soluble organic solvents.

[82] The method according to

[81] , wherein the water-soluble nitrile solvent is acetonitrile.

[83] The method according to any one of

[69] to

[82] , wherein the organic solvent used in the step of eluting the target substance from the hydrophobic carrier is a nitrile solvent, an ether solvent, an ester solvent, a ketone solvent, a halogenated solvent, an aromatic solvent, or a mixed solvent containing at least one of the above solvents.

[84] The method according to the following formula D-8: (wherein R ５ is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R ６ is a hydrogen atom, or R ５ and R ６ form a phthalimide group together with the nitrogen atom to which they are attached, the method comprising producing a compound of the following formula D-6: (wherein R ５ is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R ６ is a hydrogen atom, or R５ and R ６ form a phthalimido group together with the nitrogen atom to which they are attached), and then the compound represented by formula D-6 is treated with the following compound D-7:

[85] A method for producing a compound represented by formula D-8 by forming a β-1,4-glycosidic bond with a compound represented by formula R ５ is an aryloxycarbonyl (COOAr) group.

[86] The method according to

[84] , wherein the protecting group of the amino group and the acyl protecting group of the alcohol in the compound represented by formula D-8 are removed to obtain a compound represented by formula D-9: (wherein M ＋

[87] The method according to

[84] or

[85] , comprising generating a compound represented by the following formula D-12: The method for purifying a compound represented by the formula E-1 is carried out by adding a compound represented by the formula E-1 to a solution containing the crude compound represented by the formula D-12: (wherein R ７ is a hydrogen atom, a methyl group, or a methoxy group) to form a compound of the following formula E-2: A crystalline compound represented by the formula: ７ is a hydrogen atom, a methyl group, or a methoxy group), isolating the crystalline compound, and then extracting the compound represented by formula D-12 from the isolated crystalline compound.

[88] A method for producing a compound represented by formula A-13:

[89] An oligosaccharide represented by the following formula A-5:

[90] A compound represented by the following formula A-6:

[91] A compound represented by the following formula A-7:

[92] A compound represented by the following formula A-9:

[93] A compound represented by the following formula A-10:

[94] A compound represented by the following formula A-11:

[95] A compound represented by the following formula A-12:

[96] A compound represented by the following formula A-14:

[97] A compound represented by the following formula A-15:

[98] A compound represented by the following formula B-4:

[99] A compound represented by the following formula B-5:

[100] A compound represented by the following formula B-6:

[101] A compound represented by the following formula B-7:

[102] A compound represented by the following formula B-8:

[103] A compound represented by the following formula D-1:

[104] A compound represented by the following formula D-2:

[105] A compound represented by the following formula D-4:

[106] A compound represented by the following formula D-5:

[107] A compound represented by the following formula D-5-FMA:

[108] A compound represented by the following formula D-6: (wherein R ５ is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R ６ is a hydrogen atom, or R ５ and R ６ form a phthalimido group together with the nitrogen atom to which they are attached).

[109] The following formula D-8: (wherein R ５ is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R ６ is a hydrogen atom, or R ５ and R ６ form a phthalimido group together with the nitrogen atom to which they are attached).

[110] Formula D-9 below: (wherein M ＋is a sodium ion, a lithium ion, a potassium ion, or a protonated triethylamine cation).

[111] A compound represented by the following formula D-10: (wherein M ＋ is a sodium ion, a lithium ion, a potassium ion, or a protonated triethylamine cation).

[112] The following formula D-11: (wherein M ＋ is a sodium ion, a lithium ion, a potassium ion, or a protonated triethylamine cation).

[113] Formula E-2 below: A crystalline compound represented by the formula: ７ is a hydrogen atom, a methyl group, or a methoxy group.)

[114] A compound of the following formula D-12:

[115] The compound according to claim 109, wherein the purity is 95% or more.

[116] A compound of the following formula D-13: An oligosaccharide represented by the formula:

[0022] The present invention provides an oligosaccharide represented by the above formula A-13 and a novel method for producing the same, a production intermediate of the oligosaccharide and a method for producing the same, an oligosaccharide represented by the above formula D-13 and a novel method for producing the same, and a production intermediate of the oligosaccharide and a method for producing the same.

[0023]

[0023] Figure 1 shows a simplified example of a novel method for producing an oligosaccharide represented by the above formula A-13, provided by the present invention.

[0024] Figure 1 shows a simplified example of a novel method for producing a compound represented by the above formula A-11, provided by the present invention.

[0025] Figure 1 shows a simplified example of a novel method for producing an oligosaccharide represented by the above formula D-13, provided by the present invention.

[0024] Preferred embodiments for carrying out the present invention will be described below. Note that the embodiment described below shows one example of a typical embodiment of the present invention, and the scope of the present invention should not be construed as being narrow.

[0025] 1. Method for Producing Oligosaccharide Represented by Formula A-13 In one aspect of the present invention, a novel oligosaccharide represented by formula A-13 and a novel method for producing the same are provided. In the present invention, the oligosaccharide represented by formula A-13 refers to the following oligosaccharide:

[0026] The novel synthesis scheme for the oligosaccharide represented by the above formula A-13 includes the following steps I-1 to I-3.

[0027] <Step I-1> Step I-1 is a step of reacting a compound of formula A-3: The compound represented by the following formula A-4: to form a compound represented by the following formula A-5: The method of the present invention includes a step of producing a compound represented by the following formula A-7: Step I-1 includes the following steps I-1-1 to I-1-3.

[0028] <Step I-1-1> Step I-1-1 is a step of producing a compound represented by formula A-5 by forming an α-1,6-glycosidic bond between a compound represented by formula A-3 and a compound represented by formula A-4. This step can be carried out by utilizing or adapting a known method, but is preferably carried out, for example, by the method shown in Example 22. For example, the compound represented by formula A-3 can be subjected to an α-1,6-glycosidic bond with the compound represented by formula A-4 by sequentially adding molecular sieve 4A powder and trimethylsilyl trifluoromethanesulfonate (TMSOTf) in an organic solvent (e.g., toluene), thereby producing the compound represented by formula A-5. The starting compounds represented by formula A-3 and formula A-4 can also be produced as follows.

[0029] <Production of Compound Represented by Formula A-3> In one embodiment of the present invention, the compound represented by Formula A-3 can be produced by the following steps, but the present invention is not limited to this production method.

[0030] First, the following formula A-1: (3,4,6-tri-O-benzyl-1,2-O-(1-methoxyethylidene)-β-D-mannopyranose) is reacted with, for example, water and p-TsOH.H ２ O, followed by reaction with triethylamine to give the compound of formula A-2: This step can be preferably carried out by the method shown in Example 1, for example.

[0031] Next, for example, trichloroacetonitrile and diazabicycloundecene (DBU) are added to the compound of formula A-2 to produce a compound of formula A-3. This step can be preferably carried out by, for example, the method shown in Example 2.

[0032] <Production of Compound Represented by Formula A-4> In one embodiment of the present invention, the compound represented by Formula A-4 is produced by the following steps X-1 to X-14, or the following steps X-1 to X-8 + X-15 to X-16. Details of each step are exemplified below, but each step can also be carried out using a conventional method for producing monosaccharides or oligosaccharides, or by applying such a conventional method.

[0033] <Step X-1> Step X-1 is a step of reacting a compound represented by the following formula C-1: The hydroxyl group bonded to the carbon atom at position 3 of the compound represented by the following formula C-2: The compound of formula C-1, which is the starting material of this step, can be produced by known methods, or a commercially available product can be used. An example of a commercially available product of the compound of formula C-1 is 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose manufactured by Sigma-Aldrich. This step can be carried out by utilizing or adapting known methods, but is preferably carried out by, for example, the method shown in Example 10.

[0034] <Step X-2> In step X-2, the compound represented by formula C-2 is converted into a compound represented by formula C-3 by acid hydrolysis of two isopropylidenes and pyranose ring formation. This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 11.

[0035] <Step X-3> In step X-3, the hydroxyl group on the compound represented by formula C-3 is protected with an acetyl group to give a compound represented by formula C-4: This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 12.

[0036] <Step X-4> In step X-4, only the acetyl group in the acetyloxy group bonded to the carbon atom at position 1 of the compound represented by formula C-4 is selectively removed to give a compound represented by formula C-5: This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 12.

[0037] The process for producing the compound of formula C-5 from the compound of formula C-3 above may be carried out in one pot, for example, as shown in Example 12.

[0038] <Step X-5> In step X-5, a compound of formula C-5 is reacted with trichloroacetonitrile to give a compound of formula C-6: This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 13.

[0039] <Step X-6> Step X-6 is a step of reacting a compound represented by formula C-6 with a compound represented by formula C-7: by reacting with a compound of formula C-8: The compound of formula C-7 can be produced by known methods, or a commercially available product can be used. An example of a commercially available product of the compound of formula C-7 is 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-phthalimido-β-D-glucopyranoside manufactured by Tokyo Chemical Industry Co., Ltd. This step can be carried out by utilizing or adapting known methods, but is preferably carried out by, for example, the method shown in Example 14.

[0040] <Step X-7> In step X-7, an acetyl group is removed from a compound of formula C-8 to give a compound of formula C-9: This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 15.

[0041] In one embodiment of the present invention, step X-7 is a step in which a compound represented by formula C-8 is reacted with a strong base in the presence of a trifluoroacetic acid ester to eliminate the acetyl group, thereby producing a compound represented by formula C-9. It has been reported that the acetyl group elimination reaction is carried out using sodium methoxide in methanol ( Org. Biomol. Chem., 2018, 16, 4720-4727 ). However, in this case, an undesired side reaction, namely, ring-opening of the phthalimide group, may also occur. On the other hand, by using a method in which the compound is reacted with a strong alkoxide base in the presence of an alkyl ester of a perfluorocarboxylic acid, it is possible to eliminate the acetyl group while suppressing ring-opening of the phthalimide group.

[0042] The "alkyl ester of perfluorocarboxylic acid" used in the above step is not limited as long as the reaction proceeds, but includes methyl trifluoroacetate, ethyl trifluoroacetate, propyl trifluoroacetate, isopropyl trifluoroacetate, butyl trifluoroacetate, methyl pentafluoropropionate, ethyl pentafluoropropionate, propyl pentafluoropropionate, isopropyl pentafluoropropionate, methyl heptafluorobutyrate, ethyl heptafluorobutyrate, propyl heptafluorobutyrate, isopropyl heptafluorobutyrate, butyl heptafluorobutyrate, methyl nonafluorovalerate, ethyl nonafluorovalerate, propyl nonafluorovalerate, isopropyl nonafluorovalerate, butyl nonafluorovalerate, methyl undecafluorocaproate, ethyl undecafluorocaproate, propyl undecafluorocaproate, isopropyl undecafluorocaproate, and butyl undecafluorocaproate, and preferably methyl trifluoroacetate is used.

[0043] The "strong base" is not limited as long as the reaction proceeds, and may be selected from the group consisting of, for example, sodium salts, lithium salts, and potassium salts of metal amides; sodium salts, lithium salts, potassium salts, cesium salts, and barium salts of C1 to C20 alkoxides; sodium hydride, potassium hydride, lithium hydride, butyllithium, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, cesium phosphate, lithium phosphate, diazabicycloundecene (DBU), diazabicyclononene (DBN), and 1,1,3,3-tetramethylguanidine (TMG); and combinations thereof, for example, sodium salts of C1 to C20 alkoxides. Examples of the lithium salt and potassium salt include lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-pentoxide, sodium tert-pentoxide, and potassium tert-pentoxide, and particularly preferred are sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, and LHMDS (lithium hexamethyldisilazide).

[0044] The solvent used in this step is not limited as long as the reaction proceeds, and for example, a C1-C10 alcohol solvent alone or a mixed solvent of a C1-C10 alcohol solvent with an amide solvent (dimethylformamide, dimethylacetamide, etc.), an ether solvent (tetrahydrofuran, dimethoxyethane, cyclopentyl methyl ether, etc.), an ester solvent (ethyl acetate, etc.), an aromatic solvent (toluene, etc.), a halogenated solvent (dichloromethane, etc.), a hydrocarbon solvent (hexane, etc.), or a nitrile solvent (acetonitrile, etc.) can be used. Methanol or a mixed solvent of methanol and tetrahydrofuran is preferably used, but the solvent is not limited to these. Note that while alcohols having a larger number of carbon atoms can also be used as the above-mentioned "C1-C10 alcohol solvent," C1-C5 alcohols (methanol, ethanol, propanol, butanol, etc.) are preferably used due to their ease of availability and convenience.

[0045] The reaction temperature in this step is not limited as long as the reaction proceeds, but examples thereof include −20° C. to 80° C., preferably 0° C. to 70° C., more preferably 20° C. to 65° C., and particularly preferably 40° C. to 60° C.

[0046] <Step X-8> In step X-8, the hydroxyl groups bonded to the carbon atoms at the 4- and 6-positions of the D-glucopyranoside in the compound of formula C-9 are selectively protected with benzaldehyde dimethyl acetal to obtain a compound of formula C-10: This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 16.

[0047] <Step X-9> In step X-9, a compound represented by formula C-10 is reacted with a compound imparting a leaving group selected from the group consisting of a trifluoromethanesulfonyloxy group, a nonafluorobutanesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, and a 4-nitrobenzenesulfonyloxy group to obtain a compound represented by formula C-11: (wherein X １represents a substituent selected from the group consisting of a trifluoromethanesulfonyl group, a nonafluorobutanesulfonyl group, a 2-nitrobenzenesulfonyl group, and a 4-nitrobenzenesulfonyl group). This step can be carried out by utilizing or applying a known method for providing a leaving group, but is preferably carried out by, for example, the method shown in Example 17.

[0048] In this step, examples of the "compound that imparts a leaving group selected from the group consisting of a trifluoromethanesulfonyloxy group, a nonafluorobutanesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, and a 4-nitrobenzenesulfonyloxy group" include trifluoromethanesulfonic anhydride, nonafluoro-1-butanesulfonyl fluoride, bis(nonafluoro-1-butanesulfonic) anhydride, 2-nitrobenzenesulfonyl chloride, and 4-nitrobenzenesulfonyl chloride, and preferably trifluoromethanesulfonic anhydride.

[0049] The solvent used in this step is not limited as long as the reaction proceeds, but examples thereof include ethyl acetate, toluene, dichloromethane, acetonitrile, cyclopentyl methyl ether, and tert-butyl methyl ether, and preferred examples include ethyl acetate, toluene, and dichloromethane.

[0050] The reaction temperature in this step is not limited as long as the reaction proceeds, but examples thereof include -40°C to 60°C, preferably -30°C to 40°C, and more preferably -20°C to 10°C.

[0051] This step is preferably carried out in the presence of a base. The base used in this step is not particularly limited as long as the reaction proceeds, but examples thereof include 1-methylimidazole, pyridine, 4-dimethylaminopyridine, picoline, lutidine, and collidine, and preferred examples include 1-methylimidazole.

[0052] <Step X-10> In step X-10, a compound of formula C-11 is reacted with cesium acetate or tetrabutylammonium acetate to give a compound of formula C-12: (wherein X ２ is an acetyl group), or by reacting the compound of formula C-11 with tetrabutylammonium benzoate, a compound of formula C-12: (wherein X ２ is a benzoyl group). Stereoinversion from glucose to mannose is a known conversion reaction, but no conversion has been reported in which the protecting group for the hydroxyl group attached to the carbon at the 3-position of the D-glucopyranoside of a glucose-glucosamine disaccharide linked by a β-glycosidic bond is a 2-naphthylmethyl (Nap) group. By employing this method, stereoinversion from glucose to mannose can be achieved, and a mannose-glucosamine disaccharide skeleton linked by a β-glycosidic bond can be constructed with high yield and high selectivity.

[0053] The solvent used in this step is not limited as long as the reaction proceeds, and examples thereof include dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, N,N-dimethylimidazolidinone, sulfolane, tetrahydrofuran, and acetonitrile, and preferred examples include dimethyl sulfoxide.

[0054] The reaction temperature in this step is not limited as long as the reaction proceeds, but examples thereof include 20°C to 80°C, preferably 23°C to 70°C, more preferably 26°C to 60°C, and particularly preferably 30°C to 50°C.

[0055] <Step X-11> Step X-11 is a step of reacting a compound represented by formula C-12 with X ２ The group is removed and the phthalimide group is opened to give the compound of the following formula C-13: This step can be carried out by utilizing or applying a known hydrolysis method, but is preferably carried out by, for example, the method shown in Example 18.

[0056] The compound of formula C-13 produced in this step may be dissolved in a solvent and used as is in the next step, or it may be isolated and purified by recrystallization. The compound of formula C-13 has the great advantage of being able to be isolated and purified by crystallization, which allows for almost complete removal of impurities with similar structures that are difficult to remove by column purification. In this case, the compound of formula C-13 can be obtained with an HPLC purity of 99% or more.

[0057] Examples of the isolation and purification by recrystallization in this step include a method in which the solvent is completely removed from a state in which the compound is dissolved in a solvent by a drying operation under reduced pressure, or a method in which tetrahydrofuran is used as a good solvent and isopropanol is added dropwise as a poor solvent in the presence of a trace amount of water.

[0058] The recrystallization in this step can also be carried out using seed crystals of the compound represented by formula C-13. When seed crystals are used, for example, crystallization can be carried out by a method in which tetrahydrofuran is used as a good solvent, a portion of isopropanol is added dropwise as a poor solvent in the presence of a trace amount of water, the seed crystals are added, crystal precipitation is confirmed, and then the remaining isopropanol is added dropwise.

[0059] The process for producing the compound of formula C-13 from the compound of formula C-11 above may be carried out in one pot, for example, as shown in Example 18.

[0060] <Step X-12> In step X-12, the ring-opened phthalimide group in the compound represented by formula C-13 is closed by dehydration condensation to give a compound represented by formula C-14: This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 19.

[0061] <Step X-13> Step X-13 is to protect the hydroxyl group bonded to the carbon atom at the 2-position of D-mannopyranoside in the compound of formula C-14 with a benzyl group to obtain the compound of formula C-15 below: This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 20.

[0062] In one embodiment of the present invention, Step X-13 comprises protecting the hydroxyl group bonded to the carbon atom at position 2 of the D-mannopyranoside in a compound of Formula C-14 with a benzyl group in the presence of lithium tert-butoxide or lithium tert-amoxide to produce a compound of Formula C-15. By carrying out Step X-15 in the presence of lithium tert-butoxide or lithium tert-amoxide, ring-opening of the phthalimide can be suppressed. Furthermore, compared to general conditions using sodium hydride, this method can be carried out safely and is easily scaled up.

[0063] The solvent used in this step is not limited as long as the reaction proceeds, but examples thereof include dimethylacetamide, dimethylformamide, N-methylpyrrolidone, and N,N-dimethylimidazolidinone, and preferably dimethylacetamide.

[0064] The reaction temperature in this step is not limited as long as the reaction proceeds, but examples thereof include -20°C to 100°C, preferably -15°C to 70°C, and particularly preferably -10°C to 50°C.

[0065] <Step X-14> Step X-14 is a step of selectively reducing the benzylidene protecting group in a compound of formula C-15 (see Angew. Chem. Int. Ed. 2005, 44, 1665-1668 for more details), thereby obtaining a compound of formula A-4 below, in which only the hydroxyl group bonded to the carbon at position 6 of D-mannopyranoside is deprotected. This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 21.

[0066] In this step, the compound represented by formula A-4 produced in the form of a solution in a solvent may be used as is in the next step, or it may be isolated and purified by column purification or the like.

[0067] In one embodiment of the present invention, the stereoinversion of glucose → mannose is Ｎ Instead of steps X-9 to X-12, which include steps for carrying out the reaction utilizing the two reactions, steps X-15 and X-16 shown below, which are carried out using an oxidation-reduction reaction, are included.

[0068] <Step X-15> Step X-15 is to oxidize the 2-position of D-glucopyranoside in the compound of formula C-10 to obtain a compound of formula C-16: This step can be carried out by utilizing or applying a known method.

[0069] <Step X-16> Step X-16 is a step of reducing the ketone group bonded to the carbon atom at the 2-position of 2-keto-D-glucopyranoside in a compound of formula C-16 to obtain a compound of formula C-14: This step can be carried out by utilizing or applying a known method.

[0070] The solvent used in this step is not limited as long as the reaction proceeds, and examples thereof include diethyl ether, cyclopentyl methyl ether, tert-butyl methyl ether, diisopropyl ether, dipropyl ether, dibutyl ether, and 1,4-dioxane, and preferably tetrahydrofuran.

[0071] The reaction temperature in this step is not limited as long as the reaction proceeds, but may be, for example, −80° C. to 20° C. As described below, the optimal reaction temperature varies depending on the reducing agent used.

[0072] In one embodiment of the present invention, the oxo group bonded to the carbon atom at the 2-position of 2-keto-D-glucopyranoside in the compound represented by formula C-16 can be substituted with L-selectride, LS-selectride, lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), or a compound represented by the following formula W: (wherein R ３ is the following formula: and di-tert-butylmethylphenoxide or hydride represented by the formula: ３ is di-tert-butylmethylphenoxide), and combinations thereof. ４ When using the reducing agent NaBH, the stereoselectivity was low (about 7:3), and it was difficult to efficiently achieve the desired stereoinversion from Gln to Man (Org. Biomol. Chem., 2018, 16, 4720-4727). ４ Compared with the case where Benzylamine was used, the selectivity of the stereoinversion from Gln to Man was greatly improved (93.6:6.4 to 98.1:1.9).

[0073] Of the compounds represented by formula W, three R ３ The compound in which R is di-tert-butylmethylphenoxide can be obtained, for example, by adding dibutylhydroxytoluene (885.41 mg, 4.02 mmol) to a tetrahydrofuran suspension (2 mL) of lithium aluminum hydride (50.0 mg, 1.32 mmol) at 0° C., followed by stirring at 25° C. Among the compounds represented by formula W, ３ The compound in which is di-tert-butylmethylphenoxide can be obtained in a similar manner by using 2 molar equivalents of dibutylhydroxytoluene for 1 molar equivalent of lithium aluminum hydride.

[0074] As described above, the reaction temperature in this step is not limited as long as the reaction proceeds, but when L-selectride, LS-selectride, or LDBBA is used as the reducing agent, the reaction temperature is preferably −80° C. to −20° C., more preferably −80° C. to −30° C., even more preferably −80° C. to −40° C., and particularly preferably −80° C. to −50° C. When a compound represented by formula A is used as the reducing agent, the reaction temperature is preferably −20° C. to 20° C., more preferably −15° C. to 15° C., and particularly preferably −10° C. to 10° C. Therefore, a compound represented by formula W is particularly preferred as the reducing agent to be used in this step, in that the reaction proceeds at a temperature that is easier to handle.

[0075] <Purification of Compound A-5> In Step I-1-1, the compound represented by Formula A-5 can be obtained in a purified form by the following purification method. This purification method includes terminating the reaction between the compound represented by Formula A-4 and the compound represented by Formula A-3, adding a hydrophobic carrier and water to a water-soluble organic solvent containing the resulting compound represented by Formula A-5 and impurities, allowing the compound represented by Formula A-5 to be adsorbed onto the hydrophobic carrier, filtering the mixture, and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and water to remove the impurities, and then eluting the compound represented by Formula A-5 from the hydrophobic carrier using an organic solvent, thereby purifying the compound represented by Formula A-5. This purification method allows for easy removal of residual reagents and impurities derived from glycosyl donors and glycosyl acceptors remaining after glycosylation in liquid-phase synthesis of oligosaccharide chains by washing with a small amount of hydrophobic support. This prevents reaction inhibition and side reactions caused by these impurities, enabling the efficient mass production of high-quality oligosaccharides. Furthermore, compared to previously developed methods, the present invention utilizes the hydrophobic nature of the substrate itself, thereby reducing the number of tag removal steps and preventing loss of tag functionality during oligosaccharide synthesis, thereby enabling more efficient oligosaccharide production. In particular, in this process, the above purification method allows for easy separation and purification of the compound represented by Formula A-5 from degradation products derived from the compound represented by Formula A-3.

[0076] The purification of the compound represented by Formula A-5 is not limited to the purification in Step I-1-1. Accordingly, in one embodiment of the present invention, a method is also provided, which includes adding a hydrophobic carrier and water to a water-soluble organic solvent containing the compound represented by Formula A-5 and impurities to adsorb the compound represented by Formula A-5 onto the hydrophobic carrier, filtering the mixture and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and water to remove the impurities, and then eluting the compound represented by Formula A-5 from the hydrophobic carrier using an organic solvent, thereby purifying the compound represented by Formula A-5. Furthermore, the above purification method can also be applied to the purification of organic compounds other than sugar compounds. Furthermore, when the organic compound to be purified is a sugar compound, protected oligosaccharides having a sugar chain structure consisting of 3 to 15 sugar residues in which one or all of the hydroxyl groups in the sugar are protected can be suitably purified. Protecting groups for the sugar chain in this case include, but are not limited to, alkyl ethers, benzyl ethers, silyl ethers, esters, and carbonate esters.

[0077] The above-mentioned "impurities" refer to compounds or reagents other than the protected oligosaccharides (in this step, the compounds represented by the above formula A-5), and mainly refer to reagents or their residues used in the synthesis reaction of the protected oligosaccharides, sugars other than the protected oligosaccharides such as monosaccharides or disaccharide compounds used in the elongation reaction of the protected oligosaccharides, or by-products generated by the deprotection reaction of the protected oligosaccharides.

[0078] The above-mentioned "hydrophobic carrier" refers to a hydrophobic adsorbent material that adsorbs specific compounds, including sugar compounds, and examples thereof include a packing resin for reversed-phase partition chromatography. The "packing resin for reversed-phase partition chromatography" is selected from the group consisting of poly(styrene / divinylbenzene) polymer gel resin, polystyrene-divinylbenzene resin, polyhydroxymethacrylate resin, styrene-vinylbenzene copolymer resin, polyvinyl alcohol resin, polystyrene resin, polymethacrylate resin, chemically bonded silica gel resin, and combinations thereof, but is not limited to these.

[0079] The "chemically bonded silica gel resin" is selected from the group consisting of (1) a resin obtained by reacting silica gel with a silane coupling agent, (2) a resin obtained by chemically bonding dimethyloctadecyl, octadecyl, trimethyloctadecyl, dimethyloctyl, octyl, butyl, ethyl, methyl, phenyl, cyanopropyl, or aminopropyl groups to silica gel, (3) a resin obtained by chemically bonding docosyl or triacontyl groups to silica gel, and (4) a combination of the above (1) to (3). Octadecyl group-bonded silica gel resin (ODS resin) is preferably used, but is not limited to these.

[0080] The "water-soluble organic solvent" is not particularly limited, but may be a water-soluble alcohol solvent (preferably C1 to C4), a water-soluble nitrile solvent (acetonitrile, etc.), a water-soluble ether solvent (tetrahydrofuran, etc.), a water-soluble ketone solvent (acetone, etc.), a water-soluble amide solvent (dimethylformamide, etc.), or a water-soluble sulfoxide solvent (dimethyl sulfoxide, etc.), and acetonitrile is preferably used.

[0081] The "organic solvent" used in the step of eluting the target substance from the hydrophobic carrier is not particularly limited, but may be a nitrile solvent (e.g., acetonitrile), an ether solvent (e.g., tetrahydrofuran), an ester solvent (e.g., ethyl acetate), a ketone solvent (e.g., acetone), a halogen-based solvent (e.g., dichloromethane), an aromatic solvent (e.g., toluene), or a mixed solvent containing at least one of the above-mentioned solvents, and acetonitrile, ethyl acetate, tetrahydrofuran, or toluene can be preferably used.

[0082] The above purification step can be carried out at a temperature of 0°C to 50°C, although this is not particularly limited.

[0083] After the above step I-1-1, the compound represented by formula A-7 can be produced from the compound represented by formula A-5 by the following steps I-1-2 to I-1-3, but the production steps are not limited to these.

[0084] <Step I-1-2> Step I-1-2 is to obtain a compound represented by the above formula A-6 by deprotecting the 4-methoxyphenyl group from the compound represented by the above formula A-5. This is a process for producing a compound represented by the formula:

[0085] In one embodiment of the present invention, this step is a step of reacting the compound represented by the above formula A-5 with λ3-iodane in a fluorous alcohol and water to deprotect the 4-methoxyphenyl group, thereby producing the compound represented by the above formula A-6. This step can be preferably carried out, for example, by the method shown in Example 23.

[0086] The term "λ3-iodane" refers to a trivalent hypervalent iodine compound. In one embodiment, the compound of formula R ４ -I (OR ５ ) ２ (wherein R ４ is an unsubstituted or substituted phenyl group, R ５ is selected from the group consisting of H, acetoxy, trifluoroacetoxy, tosyloxy, methanesulfonyloxy, and combinations thereof. As defined in the formula above, R ４ may be a "substituted phenyl group", and examples of the substituent include a linear or branched saturated or unsaturated hydrocarbon group, an oxygen-containing group (alkoxy, ester, etc.), a nitrogen-containing group (cyano, azide, etc.), a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), etc., with a hydrocarbon group, an oxygen-containing substituent, or a halogen atom being more preferred. When these substituents contain carbon, for example, those having 1 to 5 carbon atoms or those having 1 to 3 carbon atoms can be suitably used. Specific examples of λ3-iodane include, but are not limited to, [bis(trifluoroacetoxy)iodo]benzene (PIFA), [hydroxy(tosyloxy)iodo]benzene (HTIB), (diacetoxyiodo)benzene (PIDA), [bis(trifluoroacetoxy)iodo]pentafluorobenzene, and [hydroxy(methanesulfonyloxy)iodo]benzene.

[0087] The term "fluorous alcohol" used in the above process refers to a fluorine-containing alcohol compound in which all carbons except the carbon bonded to the alcohol have fluorine. As long as fluorine substitution is allowed, it is preferable that the fluorous alcohol has more fluorine. Fluorous alcohols include, but are not limited to, fluorous aliphatic alcohols. The hydrocarbon moiety in the fluorous aliphatic alcohol may be saturated or unsaturated, linear or branched, or cyclic. Fluorous aliphatic alcohols include, for example, fluorous C ２ ~C ８ aliphatic alcohols, preferably fluorous C ２ ~C ５ aliphatic alcohols, more preferably fluorous C ２ ~C ３ Specific examples of fluorous alcohols include, but are not limited to, the group consisting of hexafluoro-2-propanol (HFIP), 2,2,2-trifluoroethanol (TFE), 2,2,3,3,4,4,5,5-octafluoro-1-pentanol, nonafluoro-tert-butyl alcohol, and combinations thereof.

[0088] This step is carried out in the coexistence of the fluorous alcohol and water. The amount of water can be appropriately determined from the viewpoint of achieving a high yield of the product, and may be, for example, about 1.0 equivalents or more, about 1.5 equivalents or more, about 2.0 equivalents or more, or about 2.5 equivalents or more in molar ratio relative to the compound represented by Formula A-5, and may be about 10 or less, about 8 or less, about 5 or less, or about 3 or less in volume ratio relative to the compound represented by Formula A-5.

[0089] In this step, an "additive" may be further added to the fluorous alcohol and water. The additive is preferably selected from the group consisting of sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, trifluoroacetic acid, and combinations thereof. The amount of the additive can be appropriately set and may be, for example, about 0.5 to 8 equivalents, about 1 to 6 equivalents, or about 1.5 to 5 equivalents relative to the compound represented by Formula A-5.

[0090] <Step I-1-3> Step I-1-3 is a step of producing the compound represented by formula A-7 from the compound represented by formula A-6. This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 24.

[0091] In one embodiment of the present invention, this step is a step of producing a compound represented by formula A-7 by reacting a compound represented by formula A-6 with 2,2,2-trifluoro-N-phenylacetimidoyl chloride (TFPC) in the presence of DBU. By using DBU as the base, it is possible to reduce the equivalent amount of TFPC compared to when potassium carbonate is used, for example, and the target product can be obtained in high yield. Since TFPC is an expensive reagent, improving the yield of this step is extremely beneficial for commercial production.

[0092] The solvent used in this step is not limited as long as the reaction proceeds, but examples thereof include dichloromethane, toluene, ethyl acetate, acetonitrile, and tetrahydrofuran, and preferably dichloromethane.

[0093] The reaction temperature in this step is not limited as long as the reaction proceeds, but is preferably −20° C. to 40° C., more preferably −10° C. to 35° C., and particularly preferably 0° C. to 30° C.

[0094] This step is preferably carried out in the presence of a dehydrating agent. The dehydrating agent used in this step is not limited as long as the reaction proceeds, but examples thereof include molecular sieves, and preferably molecular sieves 4A powder having a powder particle size of 10 μm or less.

[0095] In this step, the compound represented by A-7 produced may be dissolved in a solvent and used in the next step as is, provided that the base used in the reaction has been removed, or it may be isolated and purified by column purification, etc. Examples of isolation and purification using a column include isolation and purification using silica gel as the stationary phase and dichloromethane or a toluene-ethyl acetate mixed solvent system as the mobile phase.

[0096] <Step I-2> Step I-2 is a step of reacting the compound represented by the above formula A-7 with the compound represented by the following formula A-8: to form a compound represented by the following formula A-9: The method of claim 1, further comprising the step of producing a compound represented by formula A-10: Step I-2 includes the following steps I-2-1 to I-2-2.

[0097] <Step I-2-1> Step I-2-1 is a step in which a compound represented by formula A-7 is bonded to a compound represented by formula A-8 via a β-1,4-glycosidic bond to produce a compound represented by formula A-9. The compound represented by formula A-8 can be produced by a known method, or a commercially available product can be used. An example of a commercially available product of the compound represented by formula A-8 is 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-phthalimido-β-D-glucopyranoside manufactured by Tokyo Chemical Industry Co., Ltd. This step can be carried out by utilizing or adapting a known method, but is preferably carried out by, for example, the method shown in Example 25.

[0098] <Purification of the Compound of Formula A-9> In this step I-2-1, the compound of Formula A-9 can be obtained in a purified form by the following purification method. This purification method involves terminating the reaction between the compound of Formula A-7 and the compound of Formula A-8, adding a hydrophobic carrier and water to a water-soluble organic solvent containing the resulting compound of Formula A-9 and impurities, thereby adsorbing the compound of Formula A-9 onto the hydrophobic carrier, filtering the mixture, and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and water to remove impurities, and then eluting the compound of Formula A-9 from the hydrophobic carrier using an organic solvent to purify the compound of Formula A-9. As described for the purification method for the compound of Formula A-5, this purification method enables the efficient mass production of high-quality oligosaccharides by liquid-phase synthesis of oligosaccharide chains using a small amount of hydrophobic carrier. In particular, the monosaccharide compound represented by formula A-8 and the tetrasaccharide compound represented by formula A-9 have very similar polarities in normal phase silica gel column chromatography, and have the same Rf value under conditions of, for example, a typical column solvent system of hexane-ethyl acetate, making separation difficult. However, by utilizing the purification method of the present invention, it has become possible to easily separate the monosaccharide and tetrasaccharide, which have very similar polarities.

[0099] It should be noted that the purification of the compound represented by formula A-9 is not limited to the purification in step I-2-1. Accordingly, one embodiment of the present invention also provides a method comprising adding a hydrophobic carrier and water to a water-soluble organic solvent containing the compound represented by formula A-9 and impurities to adsorb the compound represented by formula A-9 onto the hydrophobic carrier, then filtering and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and water to remove the impurities, and then eluting the compound represented by formula A-9 from the hydrophobic carrier using an organic solvent, thereby purifying the compound represented by formula A-9.

[0100] The term "impurities" refers to compounds and reagents other than the protected oligosaccharide (in this step, the compound represented by formula A-9), and mainly refers to reagents and their residues used in the synthesis reaction of the protected oligosaccharide, sugars other than the protected oligosaccharide, such as monosaccharide or disaccharide compounds used in the elongation reaction of the protected oligosaccharide, or by-products generated by the deprotection reaction of the protected oligosaccharide. Note that the "hydrophobic carrier" (e.g., a resin for packing reversed-phase partition chromatography), "water-soluble organic solvent," "organic solvent," and purification temperature used in this step are the same as those described in the purification method for the compound represented by formula A-5 above.

[0101] <Step I-2-2> Step I-2-2 is a step of producing a compound represented by formula A-10 from a compound represented by formula A-9.

[0102] In one embodiment of the present invention, Step I-2-2 is a step of reacting a compound of Formula A-9 with a strong base in a solvent in the presence of an alkyl ester of perfluorocarboxylic acid to eliminate the acetyl group (deacetylation reaction) to produce a compound of Formula A-10, and can be preferably carried out, for example, by the method shown in Example 26. This deacetylation reaction can be carried out in the same manner as the deacetylation reaction described in Step X-7, except for the use of a different substrate. By using a technique of reacting with a strong base in the presence of an alkyl ester of perfluorocarboxylic acid, it is possible to carry out the deacetylation reaction while suppressing ring-opening of the phthalimide group.

[0103] The deacetylation reaction described above is not limited to use in Step I-2-2. Accordingly, one aspect of the present invention also provides a method for producing a compound represented by Formula A-10, which comprises reacting a compound represented by Formula A-9 with a strong base in the presence of an alkyl ester of a perfluorocarboxylic acid.

[0104] The alkyl ester of perfluorocarboxylic acid, the strong base, the solvent, and the reaction temperature used in this step are as described in the above step X-7.

[0105] <Step I-3> Step I-3 is a step of reacting the compound represented by the above formula A-10 with the compound represented by the following formula A-11: to form a compound represented by the following formula A-12: In one embodiment of the present invention, step I-3 comprises the following steps I-3-1 to I-3-2:

[0106] <Step I-3-1> Step I-3-1 is a step in which the compound represented by formula A-10 is bonded to the compound represented by formula A-11 via a β-1,2-glycosidic bond to produce the compound represented by formula A-12. The glycosidic bond step can be carried out by utilizing or adapting a known method, but is preferably carried out by, for example, the method shown in Example 27. The compound represented by formula A-11 can also be produced as follows. Furthermore, the compound represented by formula A-12 may be purified as described below.

[0107] <Production of Compound Represented by Formula A-11> In one embodiment, the compound represented by formula A-11 can be produced by (Step Y-1) reacting a compound represented by the following formula B-1: The compound represented by the following formula B-2: to form a compound represented by the following formula B-3: The method of the present invention includes a step of producing a compound represented by the following formula B-4: (Step Y-2) adding lithium tert-butoxide or lithium tert-amoxide to a solvent containing the compound represented by formula B-4 and benzyl halide or benzyl sulfonate to protect the hydroxyl group present in the compound represented by formula B-4 with a benzyl group, thereby producing a compound represented by formula B-5: The above-mentioned step Y-1 includes steps Y-1-1 and Y-1-2, and the above-mentioned step Y-2 includes steps Y-2-1 to Y-2-3.

[0108] <Step Y-1-1> Step Y-1-1 is a step in which the compound represented by formula B-1 is bonded to the compound represented by formula B-2 via a β1,4-glycosidic bond to produce the compound represented by formula B-3. A commercially available product of the compound represented by formula B-1 is 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl 2,2,2-trichloroacetimidate (86520-63-0) manufactured by Tokyo Chemical Industry Co., Ltd. Furthermore, a commercially available product of the compound represented by formula B-2 is 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-phthalimido-β-D-glucopyranoside manufactured by Tokyo Chemical Industry Co., Ltd. This step can be carried out by utilizing or adapting a known method. Preferably, for example, this step can be carried out by the method shown in Example 3. For example, a solution containing the compound represented by formula B-1, molecular sieve 4A powder, and trimethylsilyl trifluoromethanesulfonate (TMSOTf) can be sequentially added to a solution containing the compound represented by formula B-2 to produce a compound represented by formula B-3.

[0109] <Step Y-1-2> In step Y-1-2, an acetyl group is removed from a compound represented by B-3 to obtain a compound represented by the following formula B-4: The deprotection of the acetyl group (AcO) can be carried out by utilizing a known method, but is preferably carried out by, for example, the method shown in Example 4. For example, the compound represented by formula B-3 can be reacted with a strong base in a solvent such as toluene in the presence of a trifluoroacetic acid ester to remove the acetyl group, thereby producing a compound represented by formula B-4.

[0110] <Step Y-2-1> Step Y-2-1 is a step of protecting the multiple hydroxyl groups present in the compound represented by the above formula B-4 with benzyl groups to produce the compound represented by the above formula B-5.

[0111] In one embodiment, Step Y-2-1 is a step of adding lithium tert-butoxide or lithium tert-amoxide to a solvent containing the compound represented by Formula B-4 above and a benzyl halide (benzyl bromide, benzyl chloride, benzyl fluoride, or benzyl iodide) or benzyl sulfonate to protect multiple hydroxyl groups present in the compound represented by Formula B-4 above with benzyl groups, thereby producing a compound represented by Formula B-5 above. When it is necessary to simultaneously benzylate multiple hydroxyl groups in a sugar derivative protected with phthalimide groups, such as Compound N-2) represented by B-4 above, the reaction must be carried out while suppressing ring-opening of the phthalimide groups. However, because the ring-opening reaction of phthalimide groups readily proceeds under strongly basic conditions in the presence of trace amounts of hydroxide ions, the yield varies greatly depending on the amount of sodium hydroxide in NaH under the NaH / DMAc conditions used in conventional benzylation reactions, and furthermore, NaH / DMAc has the drawback of being difficult to apply as a mass synthesis method due to the risk of mixing and explosion.The present inventors have discovered a method for simultaneously benzylating multiple hydroxyl groups under milder conditions by performing the above benzylation reaction while suppressing the ring-opening of phthalimide groups.

[0112] It should be noted that the benzylation reaction described above is not limited to use in Step Y-2-1. Accordingly, one aspect of the present invention also provides a method for producing a compound represented by Formula B-5, which comprises the step of adding lithium tert-butoxide or lithium tert-amoxide to a solution containing a compound represented by Formula B-4 and a solvent containing a benzyl halide (benzyl bromide, benzyl chloride, benzyl fluoride, or benzyl iodide) or benzyl sulfonate, thereby protecting the hydroxyl group present in the compound represented by Formula B-4 with a benzyl group.

[0113] The solvent used in this step is not particularly limited as long as the reaction proceeds. However, it is possible to use an amide solvent (dimethylformamide, dimethylacetamide, etc.), an ether solvent (tetrahydrofuran, dimethoxyethane, etc.), an aromatic solvent (toluene, etc.), a hydrocarbon solvent (hexane, etc.), a urea solvent, or a mixed solvent containing at least one of the above-mentioned solvents, and it is more preferable to use an amide solvent (dimethylformamide, dimethylacetamide, etc.).

[0114] The reaction in this step is preferably carried out at a temperature of 0°C to 60°C, more preferably 30°C to 50°C.

[0115] <Purification of the Compound Represented by Formula B-5> The compound represented by formula B-5 can be purified by the following process: opening the phthalimide group in the compound represented by formula B-5, and then forming a salt with cinchonidine to obtain a crystalline cinchonidine salt, represented by the following formula B-6: The crystalline compound of formula B-6 is separated from the amorphous material, and then a solvent is added to remove cinchonidine from the compound of formula B-6 to obtain a compound of formula B-7: The compound represented by formula B-5 can be regenerated by first ring-opening the phthalimide group in the compound represented by formula B-7, and then ring-closing the opened phthalimide group in the compound represented by formula B-7. While the compound represented by formula B-6 (cinchonidine salt of the compound represented by formula B-7) is crystalline, the compounds represented by formulas B-3, B-4, and B-5 do not crystallize. Therefore, the phthalimide in the compound represented by formula B-5 can be crystallized by first ring-opening the phthalimide, and then forming a salt with the carboxylic acid moiety in the phthalimide group produced thereby. After separating the crystalline substance from the amorphous substance, the cinchonidine in the compound represented by formula B-6 can be removed, for example, by adding an acidic aqueous solution and a solvent, and then ring-closing the phthalimide again to obtain a highly purified compound represented by formula B-5. The ring-opening and ring-closure of phthalimide can be carried out by using known methods, for example, by adding sodium hydroxide in methanol-tetrahydrofuran, and the ring-closure of phthalimide can be carried out by adding carbonyldiimidazole (CDI) in tetrahydrofuran. This step can be preferably carried out by the methods shown in Examples 6 and 7.

[0116] <Step Y-2-2> In Step Y-2-2, a compound represented by the formula B-5 is subjected to elimination of the 4-methoxyphenyl group to give a compound represented by the formula B-8: This is a process for producing a compound represented by the formula:

[0117] In one embodiment, Step Y-2-2 is a step of reacting a compound represented by Formula B-5 with λ3-iodane in a fluorous alcohol and water to eliminate the 4-methoxyphenyl group, thereby producing a compound represented by Formula B-8 above, and can be preferably carried out, for example, by the method shown in Example 8. This step can be carried out in accordance with Step I-1-2 above, and the fluorous alcohol and λ3-iodane used in this step can be the same as those used in Step I-1-2 above.

[0118] <Step Y-2-3> Step Y-2-3 is a step of producing the compound represented by the above formula A-11 from the compound represented by the above formula B-8.

[0119] In one embodiment of the present invention, Step Y-2-3 is a step in which the compound represented by Formula B-8 is reacted with 2,2,2-trifluoro-N-phenylacetimidoyl chloride (TFPC) in the presence of N-methylimidazole to produce the compound represented by Formula A-11. This step can be preferably carried out, for example, by the method shown in Example 9. As described for the similar reaction in Step I-1-3, the use of N-methylimidazole as the base makes it possible to reduce the equivalent amount of TFPC compared to the case where potassium carbonate is used, and the target product can be obtained in high yield. The solvent and reaction temperature used, the fact that the reaction is preferably carried out in the presence of a dehydrating agent, and the fact that isolation and purification by column purification or the like may be performed are similar to those in Step I-1-3.

[0120] <Purification of Compound A-12> In step I-3-1, the compound represented by formula A-12 can be obtained in a purified form by the following purification method. This purification method includes terminating the reaction between the compound represented by formula A-10 and the compound represented by formula A-11, adding a hydrophobic carrier and water to a water-soluble organic solvent containing the resulting compound represented by formula A-12 and impurities, thereby adsorbing the compound represented by formula A-12 onto the hydrophobic carrier, filtering the mixture, and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and water to remove impurities, and then eluting the compound represented by formula A-12 from the hydrophobic carrier using an organic solvent, thereby purifying the compound represented by formula A-12. As described for the purification method for the compound represented by formula A-5, this purification method enables efficient mass production of high-quality oligosaccharides by liquid-phase synthesis of oligosaccharide chains using a small amount of hydrophobic carrier.

[0121] It should be noted that the purification of the compound represented by formula A-12 is not limited to the purification in step I-3-1. Accordingly, one embodiment of the present invention also provides a method comprising adding a hydrophobic carrier and water to a water-soluble organic solvent containing the compound represented by formula A-12 and impurities to adsorb the compound represented by formula A-12 onto the hydrophobic carrier, then filtering and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and water to remove the impurities, and then eluting the compound represented by formula A-12 from the hydrophobic carrier using an organic solvent, thereby purifying the compound represented by formula A-12.

[0122] The above-mentioned "impurities" refer to compounds or reagents other than the protected oligosaccharide (in this step, the compound represented by formula A-12), and mainly refer to reagents or their residues used in the synthesis reaction of the protected oligosaccharide, sugars other than the protected oligosaccharide such as monosaccharide or disaccharide compounds used in the elongation reaction of the protected oligosaccharide, or by-products generated by the deprotection reaction of the protected oligosaccharide.

[0123] The "hydrophobic support" (e.g., a resin for packing reversed-phase partition chromatography), "water-soluble organic solvent," "organic solvent," and purification temperature used in the above steps are the same as those described in the purification method for the compound represented by formula A-5 above.

[0124] <Step I-3-2> Step I-3-2 is a step of producing an oligosaccharide represented by formula A-13 from a compound represented by formula A-12.

[0125] In one embodiment of the present invention, Step I-3-2 is a step of reacting a compound represented by Formula A-12 with DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone) in a mixed solvent of fluorous alcohol and water to eliminate the 2-naphthylmethyl group in the compound represented by Formula A-12 (2-naphthylmethyl removal reaction), thereby producing an oligosaccharide represented by Formula A-13, and this step can be preferably carried out, for example, by the method shown in Example 28-1.

[0126] Regarding the above-mentioned 2-naphthylmethylation reaction, the present inventors have discovered that by reacting (acting) 2,3-dichloro-5,6-dicyano-p-benzoquinone with a substrate having a 2-naphthylmethyl group bound via an oxygen atom in a fluorous alcohol and water, the reaction can be carried out under mild conditions with good stirring properties, and a 2-naphthylmethylated product can be obtained in high yield. The advantages of the 2-naphthylmethylation reaction are explained in more detail below. In the above-mentioned 2-naphthylmethylation reaction of the present invention, a 2-naphthylmethylated product can be obtained in high yield under mild conditions from a substrate such as a sugar having a 2-naphthylmethyl group bound via an oxygen atom. The by-product 2,3-dichloro-5,6-dicyano-p-benzohydroquinone does not cause deterioration in stirring properties or adhesion to the vessel wall, and the reaction can be carried out with good reproducibility, making it suitable for mass synthesis of such a product. Furthermore, HFIP-H ２ Due to the abnormal freezing point depression of O, the solvent does not freeze even when the reaction temperature is lowered to -30°C, and a wide temperature range can be applied depending on the reactivity of the reaction substrate (melting point HFIP: -3.3°C, H ２ 0:0°C). In addition, when carrying out the denaphthylmethylation reaction of the compound represented by formula A-12 having many benzyl groups, DDQ was used as the oxidizing agent and HFIP-H was used as the solvent. ２We found that the use of O allows the reaction to proceed with superior selectivity compared to conventional conditions. Many reports of this conversion reaction use two-phase dichloromethane-water reaction conditions, but in this case, debenzylation of multiple benzyl groups proceeds at a constant rate, resulting in only moderate yields. Although improved conditions using β-pinene as an additive have been reported (see, for example, J. Org. Chem., 2017, 82, 3926), the yields for compounds with multiple Bn groups are only moderate (see, for example, Angew. Chem. Int. Ed. 2021, 60, 19287). Furthermore, the selectivity for substrates with 10 or more benzyl groups, such as the compound represented by formula A-12, is not fully understood. Furthermore, in dichloromethane-water systems, DDQ and DDQ-derived by-products cause deterioration of the stirring properties, making these reaction conditions unsuitable for large-scale synthesis. On the other hand, DDQ / HFIP-H of this method ２ In the O system, a high selectivity of 85% or more was achieved for the compound represented by formula A-12, which has 15 benzyl groups. This method does not show the deterioration of stirring properties caused by DDQ as mentioned above. Furthermore, HFIP-H ２ Due to the abnormal freezing point depression of O, the solvent does not freeze even when the reaction temperature is lowered to -30°C, and a wide temperature range can be applied depending on the reactivity of the reaction substrate (melting point HFIP: -3.3°C, H ２ O: 0°C).

[0127] The above-mentioned 2-naphthylmethylation reaction is not limited to the reaction in Step I-3-1. Accordingly, one aspect of the present invention also provides a method for producing an oligosaccharide represented by the above formula A-13, which comprises the step of reacting a compound represented by formula A-12 with DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone) in a mixed solvent of a fluorous alcohol and water to remove the 2-naphthylmethyl group in the compound represented by formula A-12.

[0128] The "fluorous alcohol" is not limited as long as the reaction proceeds, but is preferably selected from the group consisting of hexafluoro-2-propanol (HFIP), 2,2,2-trifluoroethanol (TFE), 2,2,3,3,4,4,5,5-octafluoro-1-pentanol, nonafluoro-tert-butyl alcohol, and combinations thereof.

[0129] The temperature at which the 2-naphthyl methyl removal reaction proceeds is not particularly limited, as long as the reaction proceeds, but it is preferably carried out at -35°C to 70°C, more preferably -30°C to -10°C.

[0130] By the above production method, the following formula A-13: The oligosaccharide of formula A-13 also includes modifications thereof, such as those having a similar protecting group such as a chlorobenzyl group instead of the benzyl group in the oligosaccharide of formula A-13, as long as they have the same function or activity as the oligosaccharide of formula A-13.

[0131] <Purification of the Compound Represented by Formula A-13> The compound represented by formula A-13 may be purified by the following process, which involves ring-opening the phthalimide group in the compound represented by formula A-13, followed by forming a salt with (R)-(+)-1-(1-naphthyl)ethylamine to obtain a crystalline compound represented by formula A-14: The crystalline compound represented by formula A-14 is separated from the amorphous material, and then (R)-(+)-1-(1-naphthyl)ethylamine in the compound represented by formula A-14 is removed by adding an acidic aqueous solution and a solvent to obtain a compound represented by formula A-15: The compound represented by Formula A-13 can be regenerated by first ring-opening the phthalimide group in the compound represented by Formula A-14, and then closing the ring-opened phthalimide group in the compound represented by Formula A-15. While the compound represented by Formula A-14 (the (R)-(+)-1-(1-naphthyl)ethylamine salt of the compound represented by Formula A-15) is crystalline, the compound represented by Formula A-13 does not crystallize. Therefore, the phthalimide in the compound represented by Formula A-13 is first ring-opened, and the carboxylic acid moiety in the resulting phthalimide group forms a salt with (R)-(+)-1-(1-naphthyl)ethylamine. The resulting crystalline substance is then separated from the amorphous substance. An acidic aqueous solution and a solvent are then added to remove the (R)-(+)-1-(1-naphthyl)ethylamine from the compound represented by Formula A-14 to obtain the compound represented by Formula A-15. The phthalimide is then again ring-closed, yielding a highly purified compound represented by Formula A-13. The ring-opening and ring-closure of phthalimide can be carried out by using known methods, for example, by adding sodium hydroxide in methanol-tetrahydrofuran, and the ring-closure of phthalimide can be carried out by adding carbonyldiimidazole (CDI) in tetrahydrofuran. This step can be preferably carried out by, for example, the method shown in Example 28-2.

[0132] 2. Method for Producing Oligosaccharide Represented by Formula D-13 In one aspect of the present invention, a novel oligosaccharide represented by formula D-13 and a novel method for producing the same are provided. In the present invention, the oligosaccharide represented by formula D-13 refers to the following oligosaccharide:

[0133] The novel synthesis scheme for the oligosaccharide represented by the above formula D-13 includes the following steps II-1 to II-4.

[0134] <Step II-1> Step II-1 is a step of reacting a compound of the following formula A-13: The oligosaccharide represented by the following formula A-3: to form a compound represented by the following formula D-1: The method includes the step of producing a compound represented by the following formula D-2: In one embodiment of the present invention, Step II-1 includes the following Steps II-1-1 to II-1-2.

[0135] <Step II-1-1> Step II-1-1 is a step of producing a compound represented by formula D-1 by forming an α-1,3-glycosidic bond between a compound represented by formula A-13 and a compound represented by formula A-3. This step can be carried out by utilizing or adapting a known method, but is preferably carried out, for example, by the method shown in Example 52. For example, the compound represented by formula A-13 can be subjected to an α-1,3-glycosidic bond with the compound represented by formula A-3 in an organic solvent (e.g., toluene) by sequentially adding molecular sieve 4A powder and trimethylsilyl trifluoromethanesulfonate (TMSOTf). This allows the compound represented by formula D-1 to be produced.

[0136] <Purification of the Compound of Formula D-1> In this step II-1-1, the compound of Formula D-1 can be obtained in a purified form by the following purification method. This purification method includes terminating the reaction between the compound of Formula A-13 and the compound of Formula A-3, adding a hydrophobic carrier and water to a water-soluble organic solvent containing the resulting compound of Formula D-1 and impurities, thereby adsorbing the compound of Formula D-1 onto the hydrophobic carrier, filtering and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and water to remove impurities, and then eluting the compound of Formula D-1 from the hydrophobic carrier using an organic solvent, thereby purifying the compound of Formula D-1. As described in the purification method for the compound of Formula A-5 in step I-1-1, this purification method enables the efficient mass production of high-quality oligosaccharides by using a small amount of hydrophobic carrier in liquid-phase synthesis of oligosaccharide chains.

[0137] It should be noted that the purification of the compound represented by formula D-1 is not limited to the purification in this step. Thus, in one embodiment of the present invention, there is also provided a method comprising adding a hydrophobic carrier and water to a water-soluble organic solvent containing the compound represented by formula D-1 and impurities to adsorb the compound represented by formula D-1 onto the hydrophobic carrier, then filtering and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and water to remove the impurities, and then eluting the compound represented by formula D-1 from the hydrophobic carrier using an organic solvent, thereby purifying the compound represented by formula D-1.

[0138] The term "impurities" refers to compounds and reagents other than the protected oligosaccharide (in this step, the compound represented by Formula D-1), and mainly refers to reagents and their residues used in the synthesis reaction of the protected oligosaccharide, sugars other than the protected oligosaccharide, such as monosaccharide or disaccharide compounds used in the elongation reaction of the protected oligosaccharide, or by-products generated by the deprotection reaction of the protected oligosaccharide. Note that the "hydrophobic carrier" (e.g., a resin for packing reversed-phase partition chromatography), "water-soluble organic solvent," "organic solvent," and purification temperature used in this step are the same as those described in the method for purifying the compound represented by Formula A-5 in Step I-1-1 above.

[0139] <Step II-1-2> Step II-1-2 is a step of producing a compound represented by formula D-2 by removing the acetyl group from the compound represented by formula D-1. This step can be performed by utilizing or adapting a known method, but is preferably performed by, for example, the method shown in Example 53.

[0140] In one embodiment of the present invention, Step II-1-2 is a step of reacting the compound represented by Formula D-1 with a strong base in the presence of an alkyl ester of perfluorocarboxylic acid to eliminate the acetyl group, thereby producing a compound represented by Formula D-2. This deacetylation reaction can be carried out in the same manner as the deacetylation reaction described in Step X-7, except for the use of a different substrate. This method, in which a compound is reacted with a strong base in the presence of an alkyl ester of perfluorocarboxylic acid, makes it possible to carry out the deacetylation reaction while suppressing ring-opening of the phthalimide group.

[0141] The deacetylation reaction described above is not limited to use in Step II-1-2. Accordingly, one aspect of the present invention also provides a method for producing a compound represented by Formula D-2, which comprises reacting a compound represented by Formula D-1 with a strong base in the presence of an alkyl ester of a perfluorocarboxylic acid.

[0142] <Step II-2> In Step II-2, the compound represented by the above formula D-2 is reacted with the compound represented by the following formula D-3: to form a β-1,2-glycosidic bond with a compound represented by the following formula D-4: The method of claim 1, further comprising the step of producing a compound represented by formula D-5: After producing a compound represented by formula D-5, the amino group in the compound represented by formula D-5 is protected with a protecting group selected from an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, a 2,2,2-trichloroethoxycarbonyl (Troc) group, and a phthalimide (Pht) group to produce a compound represented by formula D-6: (wherein R ５ is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R ６ is a hydrogen atom, or R ５ and R ６form a phthalimido group together with the nitrogen atom to which they are attached), or by removing the acetyl (Ac) group from the compound represented by formula D-4, a compound represented by formula D-6 (wherein R ５ and R ６ and (b) form a phthalimide group together with the nitrogen atom to which they are bonded. In one embodiment of the present invention, Step II-2 includes the following Steps II-2-1 to II-2-3.

[0143] <Step II-2-1> Step II-2-1 is a step of forming a β-1,2-glycosidic bond between the compound represented by formula D-2 and the compound represented by formula D-3 to produce a compound represented by formula D-4. The glycosidic bond step can be carried out by utilizing or adapting a known method, but is preferably carried out by, for example, the method shown in Example 54. For example, the compound represented by formula D-2 can be formed into a β-1,2-glycosidic bond with the compound represented by formula D-3 in an organic solvent (e.g., toluene) by sequentially adding molecular sieve 4A powder and trimethylsilyl trifluoromethanesulfonate (TMSOTf). This allows the compound represented by formula D-4 to be produced.

[0144] <Preparation of Compound Represented by Formula D-3> The compound represented by formula D-3 can be prepared by the following substeps Z-1 to Z-3.

[0145] <Sub-step Z-1> First, the compound represented by formula A-8, which was also used in the above-mentioned step Y-1: By protecting the hydroxyl group on the compound represented by the following formula F-1: This step can be carried out by utilizing or applying a known method, and is preferably carried out, for example, by the method shown in Example 34, in which triethylamine, dimethylaminopyridine, and acetic anhydride are added to an ethyl acetate solution of the compound represented by formula A-8, but is not limited to this method.

[0146] <Substep Z-2> Next, the 4-methoxyphenyl group is removed from the compound of formula F-1 to obtain a compound of formula F-2: This produces a compound represented by the formula:

[0147] In one embodiment of the present invention, substep Z-2 is a step of producing a compound of formula F-2 by reacting a compound of formula F-1 with λ3-iodane in a fluorous alcohol and water to eliminate the 4-methoxyphenyl group, and can be preferably carried out, for example, by the method shown in Example 35. This step can be carried out in accordance with the above-mentioned step I-1-2, and the fluorous alcohol and λ3-iodane used in this step can be the same as those used in the above-mentioned step I-1-2.

[0148] <Substep Z-3> Next, the compound represented by formula F-2 is reacted with 2,2,2-trifluoro-N-phenylacetimidoyl chloride (TFPC) to give a compound represented by formula D-3: This step can be carried out by utilizing or applying a known method.

[0149] In one embodiment of the present invention, substep Z-3 is a step of producing a compound represented by formula D-3 by reacting with 2,2,2-trifluoro-N-phenylacetimidoyl chloride (TFPC) in the presence of N-methylimidazole, and can be preferably carried out by, for example, the method shown in Example 36. As described for the similar reaction in step I-1-3, by using N-methylimidazole as the base, it is possible to reduce the equivalent amount of TFPC compared to when potassium carbonate is used, and the target product can be obtained in high yield. The solvent and reaction temperature used, the fact that the reaction is preferably carried out in the presence of a dehydrating agent, and the fact that isolation and purification by column purification or the like may be performed are similar to those in step I-1-3.

[0150] <Step II-2-2> Step II-2-2 is a step of removing the phthalimide group, which is a protecting group for the amino group on the compound represented by formula D-4, to produce a compound represented by formula D-5. This step can be preferably performed by, for example, the method shown in Example 55-1, for example, by adding n-butanol and ethylenediamine to a solution containing the compound represented by formula D-4, but is not limited thereto.

[0151] <Purification of Compound of Formula D-5 (1)> In this step II-2-2, the compound of Formula D-5 can be obtained in a purified form by the following purification method. This purification method includes terminating the reaction between the compound of Formula D-3 and the compound of Formula D-4, adding a hydrophobic carrier and water to a water-soluble organic solvent containing the resulting compound of Formula D-5 and impurities, adsorbing the compound of Formula D-5 onto the hydrophobic carrier, filtering and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and water to remove impurities, and then eluting the compound of Formula D-5 from the hydrophobic carrier using an organic solvent to purify the compound of Formula D-5. As described in the purification method for the compound of Formula A-5 in step I-1-1, this purification method enables the efficient mass production of high-quality oligosaccharides by using a small amount of hydrophobic carrier in liquid-phase synthesis of oligosaccharide chains.

[0152] It should be noted that the purification of the compound represented by formula D-5 is not limited to the purification in this step. Accordingly, one embodiment of the present invention also provides a method comprising adding a hydrophobic carrier and water to a water-soluble organic solvent containing the compound represented by formula D-5 and impurities to adsorb the compound represented by formula D-5 onto the hydrophobic carrier, then filtering and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and water to remove the impurities, and then eluting the compound represented by formula D-5 from the hydrophobic carrier using an organic solvent, thereby purifying the compound represented by formula D-5.

[0153] The term "impurities" refers to compounds and reagents other than the protected oligosaccharide (in this step, the compound represented by Formula D-5), and mainly refers to reagents and their residues used in the synthesis reaction of the protected oligosaccharide, sugars other than the protected oligosaccharide, such as monosaccharide or disaccharide compounds used in the elongation reaction of the protected oligosaccharide, or by-products generated by the deprotection reaction of the protected oligosaccharide. Note that the "hydrophobic carrier" (e.g., a resin for packing reversed-phase partition chromatography), "water-soluble organic solvent," "organic solvent," and purification temperature used in this step are the same as those described in the method for purifying the compound represented by Formula A-5 in Step I-1-1 above.

[0154] <Purification (2) of the Compound Represented by Formula D-5> The compound represented by formula D-5 can also be purified by the following process. This purification may be carried out separately from or in addition to the purification (1) of the compound represented by formula D-5. In this process, the compound represented by formula D-5 is first reacted with fumaric acid to obtain a crystalline fumarate salt of the following formula D-5-FMA: The crystalline compound represented by formula D-5-FMA can be separated from the amorphous material. The compound represented by formula D-5-FMA dissolved in a solvent can be used directly in the next step II-2-3, or it can be converted to the compound represented by formula D-5. Conversion to the compound represented by formula D-5 can be carried out by removing the fumaric acid in the compound represented by formula D-5-FMA into the aqueous layer, for example, by adding a basic aqueous solution and a solvent, and then concentrating the organic layer, resulting in a highly purified compound represented by formula D-5. This procedure can easily remove structurally similar impurities, such as stereoisomers, which are difficult to remove even by column purification. This step can be preferably carried out, for example, by the method shown in Example 55-2.

[0155] <Step II-2-3> Step II-2-3 is a step of protecting the amino group in the compound represented by the formula D-5 with a protecting group selected from an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, a 2,2,2-trichloroethoxycarbonyl (Troc) group, and a phthalimide (Pht) group to obtain a compound represented by the formula D-6 (wherein R ５ is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R ６ is a hydrogen atom, or R ５ and R ６form a phthalimide group together with the nitrogen atom to which they are bound. The purpose of introducing the above-mentioned amino-protecting group is that, although using an acetyl group as the protecting group for the amino group provides a more direct route and is more efficient for the production of the target compound (compound represented by formula D-13), if an amino group protected with an acetyl group (-NHAc group) is present in the reaction substrate in the glycosylation reaction between the compound represented by formula D-6 and the compound represented by formula D-7 in the next step II-3, the reactivity of the target glycosylation reaction is significantly reduced due to interaction with the Lewis acid, and an excess amount of glycosyl donor is required to complete the reaction. Therefore, the above disadvantages can be avoided by temporarily protecting the nitrogen atom of glucosamine during the glycosylation reaction with a protecting group selected from the group consisting of an aryloxycarbonyl (COOAr) group, a 2,2,2-trichloroethoxycarbonyl (Troc) group, and a phthalimide (Pht) group, and then deprotecting the nitrogen atom to form an -NHAc group after the glycosylation reaction. Furthermore, it is most preferable to use an aryloxycarbonyl (COOAr) group as the protecting group. The "aryl (Ar) group" in aryloxycarbonyl refers to a group generated by removing one hydrogen atom from the aromatic ring of an aromatic hydrocarbon. Examples include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, 2-pyridyl, 3-pyridyl, nitrophenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, methoxyphenyl, and C1-C4 alkylphenyl groups, with phenyl being preferred. It has been found that the aryloxycarbonyl (COOAr) group undergoes glycosylation more favorably than other protecting groups, and furthermore, the subsequent deprotection reaction can be carried out under suitable conditions, such as general hydrolysis conditions at room temperature within one hour.

[0156] The above step can be suitably carried out by, for example, the method shown in Examples 56 to 59, for example, by adding an aqueous solution of tetrahydrofuran and sodium hydrogen carbonate, potassium hydrogen carbonate, disodium hydrogen phosphate, or dipotassium hydrogen phosphate in water to a solution of the compound represented by Formula D-5 in tetrahydrofuran, but is not limited thereto.

[0157] Instead of the above-mentioned Step II-2-2 and Step II-2-3, the acetyl (Ac) group on the compound represented by the above-mentioned formula D-4 can be selectively removed to obtain the compound represented by the above-mentioned formula D-6 (wherein R ５ and R ６ may form a phthalimide group together with the nitrogen atom to which they are bound. The selective removal of the acetyl group can be carried out under, but is not limited to, methyl trifluoroacetate conditions. This step produces the same results as when a phthalimide (Pht) group is selected as the protecting group for the amino group in the compound represented by formula D-5 in Steps II-2-2 and II-2-3.

[0158] <Step II-3> Step II-3 is a step of reacting the compound represented by the formula D-6 with a compound represented by the following formula D-7: to form a β-1,4-glycosidic bond with a compound represented by the following formula D-8: (wherein R ５ is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R ６ is a hydrogen atom, or R ５ and R ６ form a phthalimide group together with the nitrogen atom to which they are attached), and then the protecting group of the amino group in the compound of formula D-8 is removed to give a compound of formula D-9: (wherein M ＋ is a sodium ion, a lithium ion, a potassium ion, or a protonated triethylamine cation), (wherein M＋ is a sodium ion, a lithium ion, a potassium ion, or a protonated triethylamine cation). In one embodiment of the present invention, Step II-3 includes the following Steps II-3-1 to II-3-4.

[0159] <Step II-3-1> This step is a step of forming a compound represented by formula D-8 by forming a β-1,4-glycosidic bond between the compound represented by formula D-6 above and the compound represented by formula D-7 below. The glycosidic bond step can be carried out by utilizing or adapting a known method, but is preferably carried out by, for example, the methods shown in Examples 60 to 63.

[0160] <Production of Compound Represented by Formula D-7> In one embodiment of the present invention, the compound represented by formula D-7 can be produced by the following substeps V-1 to V-11. These steps include, as an essential substep, substep V-7, which synthesizes a disaccharide block by linking two monosaccharide molecules via an α-2,6-glycosidic bond, as described below. However, the remaining steps can be carried out using or by applying conventional methods for producing monosaccharides or oligosaccharides.

[0161] In one embodiment of the present invention, step V comprises the following substeps:

[0162] <Substep V-1> Substep V-1 is a reaction of a compound represented by the following formula G-1: With a benzoyl group, the hydroxyl group on the compound represented by the following formula G-2: The compound represented by formula G-1, which is the starting material of this step, is a compound identified as CAS No. 100759-10-2, and can be produced by known methods, for example, by the methods shown in Examples 37 and 38. This step can be carried out by utilizing or applying known methods, but is preferably carried out by, for example, the method shown in Example 39.

[0163] <Substep V-2> Substep V-2 is a step of removing the benzylidene protecting group from a compound of formula G-2 to obtain a compound of formula G-3: This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 40.

[0164] In one embodiment of the present invention, this step includes a step of contacting a solvent in which the produced compound represented by formula G-3 is dissolved with silica gel to perform solid-phase extraction of the compound represented by formula G-3. Since the unreacted compound represented by formula G-2 and the eliminated benzaldehyde are not adsorbed to silica gel, this step allows the compound represented by formula G-3 to be efficiently purified.

[0165] Examples of the solvent for dissolving the compound represented by Formula G-3 include toluene, heptane, dichloromethane, chloroform, and a combination thereof. Preferred examples include toluene, dichloromethane, chloroform, and a combination thereof. Particularly preferred examples include, but are not limited to, toluene.

[0166] The amount of silica gel used in this step can be, for example, 2 to 5 times the amount of the raw materials, preferably 2 to 4 times the amount of the raw materials, and more preferably about 3 times the amount of the raw materials.

[0167] In this step, the solvent for eluting the compound represented by Formula G-3 adsorbed on the silica gel is not particularly limited as long as it does not dissolve the silica gel and can elute the target compound. Examples of the solvent include cyclopentyl methyl ether, ethyl acetate, and tert-butyl methyl ether.

[0168] <Substep V-3> Substep V-3 is a reaction of a compound represented by the following formula G-4: and then adding water to obtain a compound of the following formula G-5: The compound of formula G-4, which is the starting material of this step, can be produced by known methods, or a commercially available product can be used. An example of a commercially available product of the compound of formula G-4 is N-acetylneuraminic acid manufactured by Tokyo Chemical Industry Co., Ltd. This step can be carried out by utilizing or adapting known methods, but is preferably carried out by, for example, the method shown in Example 41.

[0169] <Substep V-4> Substep V-4 is to selectively protect hydroxyl groups other than the hydroxyl group bonded to the carbon atom at position 1 in the compound represented by formula G-5 with acetyl groups to obtain a compound represented by formula G-6: This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 42.

[0170] <Substep V-5> Substep V-5 is a reaction of a compound of formula G-6 with 2,2,2-trifluoro-N-phenylacetimidoyl chloride (TFPC) to give a compound of formula G-7: This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 43.

[0171] In one embodiment of the present invention, this step is a step of producing a compound represented by formula G-7 by reacting a compound represented by formula G-6 with TFPC in the presence of N-methylimidazole. ２ CO ３ Compared with the case where N-methylimidazole is used, the amount of TFPC can be reduced and the target product can still be obtained in high yield. Since TFPC is an expensive reagent, improving the yield of this step is very beneficial for commercial production.

[0172] The solvent used in this step is not limited as long as the reaction proceeds, but examples thereof include dichloromethane, toluene, ethyl acetate, acetonitrile, and tetrahydrofuran, and preferably dichloromethane.

[0173] The reaction temperature in this step is not limited as long as the reaction proceeds, but is preferably 20°C to 40°C, more preferably 10°C to 35°C, and particularly preferably 0°C to 30°C.

[0174] This step is preferably carried out in the presence of a dehydrating agent. The dehydrating agent used in this step is not limited as long as the reaction proceeds, but examples thereof include molecular sieves, and preferably molecular sieves 4A powder having a powder particle size of 10 μm or less.

[0175] <Substep V-6> Substep V-6 is to protect the nitrogen atom in the acetamide group of the compound of formula G-7 with a tert-butoxycarbonyl group to obtain a compound of formula G-8: This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 44.

[0176] In this step, the compound of formula G-8 produced in the solvent may be used as is in the next step, or it may be isolated and purified by recrystallization. The compound of formula G-8 has the great advantage of being able to be isolated and purified by crystallization; crystallization allows the compound of formula G-8 to be obtained with an HPLC purity of 99% or more, and since it contains no impurities, it becomes possible to stably carry out the glycosylation reaction in the next step. Isolation and purification by recrystallization can be carried out, for example, by adding heptane to a solution of cyclopentyl methyl ether to cause crystallization.

[0177] <Substep V-7> Substep V-7 is a step of combining a compound represented by formula G-8 and a compound represented by formula G-3 via an α-2,6-glycosidic bond to obtain a compound represented by formula G-9: This process involves the production of a compound represented by the formula: (Figure 1). It is difficult to selectively bond an N-acetylneuraminic acid derivative and a galactose derivative via an α-2,6-glycosidic bond. For example, a method for synthesizing a disaccharide by reacting a compound represented by formula G-7 with a compound represented by formula G-3 has been reported (J. Org. Chem., 2016, 81, 10600-10616). However, the reaction is difficult to reproduce, and the desired yield and selectivity could not be achieved. Furthermore, this reaction also had issues such as a decrease in selectivity as the scale increased, a narrow tolerance for reaction temperature, and a significant effect of reaction heat. Because the compound represented by formula G-7, one of the raw materials for this reaction, is very expensive, the low reproducibility, yield, and selectivity of this reaction pose a major problem, particularly for commercial production, which requires scale-up. On the other hand, when the compound represented by formula G-8, which has a tert-butoxycarbonyl group added thereto, is used as the starting compound instead of the compound represented by formula G-7, high selectivity for α-2,6-glycosidic bonds (α:β=93:7) can be achieved with good reproducibility, and the yield can also be improved. In addition, the temperature tolerance range is widened, and high reproducibility, yield, and selectivity can be achieved even when scaled up. This is an extremely beneficial effect for commercial production.

[0178] This step is preferably carried out in the presence of a Lewis acid. The Lewis acid used in this step is not limited as long as the reaction proceeds, but examples thereof include trimethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, and tert-butyldimethylsilyl trifluoromethanesulfonate, and preferably trimethylsilyl trifluoromethanesulfonate.

[0179] The solvent used in this step is not limited as long as the reaction proceeds, and examples thereof include diisopropyl ether, tert-butyl methyl ether, diethyl ether, dibutyl ether, dipropyl ether, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, toluene, chlorobenzene, trifluoromethylbenzene, propionitrile, and acetonitrile, and preferred examples include cyclopentyl methyl ether.

[0180] The reaction temperature in this step is not limited as long as the reaction proceeds, but examples thereof include −78° C. to 0° C., preferably −78° C. to −20° C., more preferably −78° C. to −30° C., and particularly preferably −78° C. to −40° C.

[0181] In this step, it is preferable to add 1 to 3 equivalents of the compound represented by formula G-3 relative to 1 equivalent of the compound represented by formula G-8, and it is more preferable to add 1.4 to 2 equivalents of the compound represented by formula G-3 relative to 1 equivalent of the compound represented by formula G-8.

[0182] This step is not limited as long as the reaction proceeds, but can be carried out, for example, by adding a mixed solution of the compound represented by Formula G-8 and the compound represented by Formula G-3 (preferably a cyclopentyl methyl ether mixed solution) dropwise to a solution containing a Lewis acid (preferably a cyclopentyl methyl ether solution) for an extended period of time, or by adding a solution of the compound represented by Formula G-8 (preferably a cyclopentyl methyl ether solution) dropwise to a solution containing a Lewis acid and the compound represented by Formula G-3 (preferably a cyclopentyl methyl ether solution) for an extended period of time, or preferably by adding a solution of the compound represented by Formula G-8 (preferably a cyclopentyl methyl ether solution) dropwise to a solution containing a Lewis acid and the compound represented by Formula G-3 (preferably a cyclopentyl methyl ether solution) for an extended period of time. The dropwise addition time is not limited as long as the reaction proceeds, but can be, for example, 30 minutes to 5 hours, preferably 1 hour to 4 hours, more preferably 2 hours to 3.5 hours, and particularly preferably about 3 hours.

[0183] In one embodiment of the present invention, this step includes a step of contacting a solvent in which the compound of formula G-9 is dissolved with silica gel to perform solid-phase extraction of the compound of formula G-9. Since N-phenyltrifluoroacetamide, a by-product of the glycosylation reaction, and other trace impurities in the toluene solvent that are not adsorbed by silica gel are not adsorbed by silica gel, the compound of formula G-9 can be efficiently purified by this step.

[0184] Examples of the solvent for dissolving the compound represented by formula G-9 include toluene, heptane, dichloromethane, chloroform, and a combination thereof. Preferred examples include toluene, dichloromethane, chloroform, and a combination thereof. Particularly preferred examples include, but are not limited to, toluene.

[0185] The amount of silica gel used in this step can be, for example, 2 to 5 times the amount of the raw materials, preferably 2 to 4 times the amount of the raw materials, and more preferably about 3.5 times the amount of the raw materials.

[0186] In this step, the solvent for eluting the compound represented by Formula G-9 adsorbed on the silica gel is not particularly limited as long as it does not dissolve the silica gel and can elute the target compound. Examples of the solvent include ethyl acetate, cyclopentyl methyl ether, and tert-butyl methyl ether, and preferred is ethyl acetate.

[0187] This step can be carried out, for example, by the method shown in Example 45.

[0188] <Substep V-8> Substep V-8 is a step of removing the tert-butoxycarbonyl group from a compound of formula G-9 to give a compound of formula G-10: This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 46.

[0189] <Substep V-9> Substep V-9 is to further protect the hydroxyl group and the nitrogen atom in the acetamide group of the compound of formula G-10 with an acetyl group to obtain a compound of formula G-11: This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 47.

[0190] In one embodiment of the present invention, this step includes a step of solid-phase extraction of the compound of formula G-11 by contacting a solvent in which the compound of formula G-11 is dissolved with silica gel. Because by-products such as the diacetyl form of the compound of formula G-3, which is produced by acetylation of the compound of formula G-3 used in excess in the upstream glycosylation reaction, are not adsorbed to silica gel, the compound of formula G-11 can be efficiently purified by this step.

[0191] Examples of the solvent for dissolving the compound represented by formula G-11 include toluene, heptane, dichloromethane, chloroform, and a combination thereof. Preferred examples include toluene, dichloromethane, chloroform, and a combination thereof. Particularly preferred examples include, but are not limited to, toluene.

[0192] The amount of silica gel used in this step can be, for example, 2 to 5 times the amount of the raw materials, preferably 2 to 4 times the amount of the raw materials, and more preferably about 3.5 times the amount of the raw materials.

[0193] In this step, the solvent for eluting the compound represented by Formula G-11 adsorbed on the silica gel is not particularly limited as long as it does not dissolve the silica gel and can elute the target compound. Examples of the solvent include ethyl acetate, cyclopentyl methyl ether, and tert-butyl methyl ether, and preferred is ethyl acetate.

[0194] <Substep V-10> Substep V-10 is a step of removing the allyl group bonded to the carbon atom at position 1 of the D-galactopyranoside in a compound of formula G-11 to obtain a compound of formula G-12: This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 48.

[0195] In this step, the compound of formula G-12 produced in the solvent may be used as is in the next step, or it may be isolated and purified by recrystallization. The compound of formula G-12 has the great advantage of being able to be isolated and purified by crystallization. Crystallization allows the compound of formula G-12 to be obtained with an HPLC purity of 99% or more, and since it is free of impurities, it becomes possible to stably carry out the reaction in the next step. Isolation and purification by recrystallization can be carried out, for example, by adding 2-propanol to a solution of the compound of formula G-12 dissolved in ethyl acetate to cause crystallization, and is preferably carried out, for example, by the method shown in Example 48.

[0196] <Substep V-11> Substep V-11 is a step of reacting a compound of formula G-12 with 2,2,2-trifluoro-N-phenylacetimidoyl chloride (TFPC) to give a compound of formula D-7: This step can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 49.

[0197] <Purification of the Compound of Formula D-8> In this step II-3-1, the compound of Formula D-8 can be obtained in a purified form by the following purification method. This purification method includes terminating the reaction between the compound of Formula D-6 and the compound of Formula D-7, adding a hydrophobic carrier and water to a water-soluble organic solvent containing the resulting compound of Formula D-8 and impurities, adsorbing the compound of Formula D-8 onto the hydrophobic carrier, filtering and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and water to remove impurities, and then eluting the compound of Formula D-8 from the hydrophobic carrier using an organic solvent to purify the compound of Formula D-8. As described in the purification method for the compound of Formula A-5 in step I-1-1, this purification method enables the efficient mass production of high-quality oligosaccharides by using a small amount of hydrophobic carrier in liquid-phase synthesis of oligosaccharide chains.

[0198] It should be noted that the purification of the compound represented by formula D-8 is not limited to the purification in this step. Accordingly, one embodiment of the present invention also provides a method comprising adding a hydrophobic carrier and water to a water-soluble organic solvent containing the compound represented by formula D-8 and impurities to adsorb the compound represented by formula D-8 onto the hydrophobic carrier, then filtering and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and water to remove the impurities, and then eluting the compound represented by formula D-8 from the hydrophobic carrier using an organic solvent, thereby purifying the compound represented by formula D-8.

[0199] The term "impurities" refers to compounds and reagents other than the protected oligosaccharide (in this step, the compound represented by Formula D-8), and mainly refers to reagents and their residues used in the synthesis reaction of the protected oligosaccharide, sugars other than the protected oligosaccharide, such as monosaccharide or disaccharide compounds used in the elongation reaction of the protected oligosaccharide, or by-products generated by the deprotection reaction of the protected oligosaccharide. Note that the "hydrophobic carrier" (e.g., a resin for packing reversed-phase partition chromatography), "water-soluble organic solvent," "organic solvent," and purification temperature used in this step are the same as those described in the method for purifying the compound represented by Formula A-5 in Step I-1-1 above.

[0200] <Step II-3-2> This step is a step of removing the protecting group of the amino group and the acyl-based protecting group of the alcohol on the compound of formula D-8 to produce a compound of formula D-9. The removal (deprotection) of the protecting group of the amino group can be carried out by utilizing or applying a known method, and is preferably carried out by, for example, the method shown in Example 64, for example, by sequentially adding 1,2-dimethoxyethane and an aqueous solution of potassium hydroxide, sodium hydroxide, or lithium hydroxide, but is not limited thereto.

[0201] The following Steps II-3-3 and II-3-4 are illustrative embodiments for producing a compound represented by formula D-11 from a compound represented by formula D-9, but the present invention is not limited to these production steps.

[0202] <Step II-3-3> In this step, the amino group on the compound represented by formula D-9 is protected with an acetyl group to give a compound represented by formula D-10: The protection of the amino group with an acetyl group can be carried out by utilizing or applying a known method, but is preferably carried out by, for example, the method shown in Example 65.

[0203] <Purification of the Compound of Formula D-10> In this step II-3-3, the compound of Formula D-10 can be obtained in a purified form by the following purification method. This purification method includes adding a hydrophobic carrier and water to a water-soluble organic solvent containing the produced compound of Formula D-10 and impurities, adsorbing the compound of Formula D-10 onto the hydrophobic carrier, filtering and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and water to remove impurities, and then eluting the compound of Formula D-10 from the hydrophobic carrier using an organic solvent, thereby purifying the compound of Formula D-10. As described in the purification method for the compound of Formula A-5 in step I-1-1 above, this purification method makes it possible to efficiently produce high-quality oligosaccharides in large quantities by using a small amount of hydrophobic carrier in liquid-phase synthesis of oligosaccharide chains.

[0204] It should be noted that the purification of the compound represented by formula D-10 is not limited to the purification in this step. Thus, in one embodiment of the present invention, there is also provided a method comprising adding a hydrophobic carrier and water to a water-soluble organic solvent containing the compound represented by formula D-10 and impurities to adsorb the compound represented by formula D-10 onto the hydrophobic carrier, then filtering and washing the hydrophobic carrier with a mixed solution of the water-soluble organic solvent and water to remove the impurities, and then eluting the compound represented by formula D-10 from the hydrophobic carrier using an organic solvent, thereby purifying the compound represented by formula D-10.

[0205] The term "impurities" refers to compounds and reagents other than the protected oligosaccharide (in this step, the compound represented by Formula D-10), and mainly refers to reagents and their residues used in the synthesis reaction of the protected oligosaccharide, sugars other than the protected oligosaccharide, such as monosaccharide or disaccharide compounds used in the elongation reaction of the protected oligosaccharide, or by-products generated by the deprotection reaction of the protected oligosaccharide. Note that the "hydrophobic carrier" (e.g., a resin for packing reversed-phase partition chromatography), "water-soluble organic solvent," "organic solvent," and purification temperature used in this step are the same as those described in the method for purifying the compound represented by Formula A-5 in Step I-1-1 above.

[0206] <Step II-3-4> This step is a step of removing the benzyl group from the benzyloxy group on the compound represented by formula D-10 to produce the compound represented by formula D-11. The removal of the benzyl group can be carried out by utilizing or applying a known method, and is preferably carried out, for example, by the method shown in Example 66, for example, by adding N-methylpyrrolidone and Pd / C to the compound represented by formula D-10, reducing the pressure, replacing with nitrogen, and pressurizing with hydrogen, and then releasing the pressure, but is not limited to this.

[0207] <Step II-4> Step II-4 is a step of reacting the compound represented by the above formula D-11 with an azide PEG linker represented by the following formula D-12: The coupling of the compound represented by formula D-11 with the compound represented by formula D-12 can be carried out by utilizing or adapting a known method, but is preferably carried out by, for example, the method shown in Example 72, for example, by sequentially adding the compound represented by formula D-12, N-ethyldiisopropylamine, and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, bromotripyrrolidinophosphonium hexafluorophosphate, or 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride to a solution containing the compound represented by formula D-11, followed by stirring.

[0208] <Purification of the Compound Represented by Formula D-12> In one embodiment of the present invention, the compound represented by formula D-12 can be purified by adding a compound represented by formula E-1 below to a solution containing the crude compound represented by formula D-12: (wherein R ７ is a hydrogen atom, a methyl group, or a methoxy group) to form a compound of the following formula E-2: A crystalline compound represented by the formula: ７is a hydrogen atom, a methyl group, or a methoxy group), isolating the crystalline compound, and then extracting the compound represented by formula D-12 from the isolated crystalline compound. This purification method can produce a highly pure compound represented by formula D-12, and the compound represented by formula D-12 has a purity measured by HPLC (also referred to herein as "HPLC purity") of preferably 95% or more, more preferably 96% or more or 97% or more, and even more preferably 98% or more or 99% or more. The purpose of purifying the compound represented by formula D-12 is that commercially available reagents of this compound contain a dimer and several other impurities. Furthermore, conventional techniques have required strict distillation purification or complicated column purification for their purification. Furthermore, when the compound contains an azide structure, distillation procedures requiring heating cannot be applied due to concerns about explosion. The present inventors have investigated purification methods for obtaining the compound represented by formula D-12 with high purity, and have found that three types of tartaric acid derivatives represented by formula E-1 (wherein R ７ is a hydrogen atom, a methyl group, or a methoxy group), the compound represented by formula D-12 forms a one-to-one salt with the tartaric acid derivative thereof and can be isolated as a crystal. The resulting compound represented by formula E-2 is a novel crystalline compound, and after isolation, it is possible to obtain the compound represented by formula D-12 having a higher HPLC purity (preferably 95% or more HPLC purity) than before purification by separating the compound with an ethyl acetate / hydrochloric acid aqueous solution or the like, followed by freezing and extraction.

[0209] An exemplary purification method is as follows. First, a compound represented by Formula E-1 is added to a solution of a compound represented by Formula D-12 in a solvent such as acetonitrile and water, and the mixture is stirred. After dissolution is confirmed, a solvent such as acetonitrile is added. The resulting slurry is concentrated under reduced pressure, and the resulting crystals are filtered by stirring the slurry. The filtered crystals are washed with acetonitrile and dried under reduced pressure to obtain crystals of a compound represented by Formula E-2 (crystallization step). Next, concentrated hydrochloric acid is added to a solution of the resulting crystalline compound in ethyl acetate and water, and the mixture is stirred and then separated. The resulting aqueous layer is washed with ethyl acetate or the like, adjusted to basicity with an aqueous sodium hydroxide solution or the like, and then sodium chloride or the like is added and dissolved. A solvent such as dichloromethane is added, and the mixture is stirred and then separated. The resulting organic layer is concentrated under reduced pressure. A solvent such as acetonitrile is added and concentrated under reduced pressure. The resulting solution is filtered, washed with a solvent such as acetonitrile, and concentrated under reduced pressure (extraction step), thereby obtaining a compound represented by Formula D-12 with high HPLC purity. More preferably, this can be performed, for example, by the methods shown in Examples 67 to 71.

[0210] The purification of the compound represented by formula D-12 is not limited to the purification in this step. Therefore, in one embodiment of the present invention, a solution containing the crude compound represented by formula D-12 is added with a compound represented by formula E-1 (wherein R ７ is a hydrogen atom, a methyl group, or a methoxy group) to obtain a crystalline compound represented by the above formula E-2 (wherein R ７ is a hydrogen atom, a methyl group, or a methoxy group), isolating the crystalline compound, and then extracting the compound of formula D-12 from the isolated crystalline compound.

[0211] <New Compounds> The intermediates for the oligosaccharides represented by the above formula A-13 are useful in the production of the oligosaccharides, but are not limited to the production of the oligosaccharides and can be applied to a variety of uses. Thus, the present invention provides the oligosaccharides represented by the above formula A-13 and their intermediates.

[0212] In one embodiment of the present invention, a compound of formula A-13: The oligosaccharide is represented by the formula:

[0213] In one embodiment of the present invention, a compound of formula A-5: The compound is provided as follows:

[0214] In one embodiment of the present invention, a compound of formula A-6: The compound is provided as follows:

[0215] In one embodiment of the present invention, a compound of formula A-7: The compound is provided as follows:

[0216] In one embodiment of the present invention, a compound of formula A-9: The compound is provided as follows:

[0217] In one embodiment of the present invention, a compound of formula A-10: The compound is provided as follows:

[0218] In one embodiment of the present invention, a compound of formula A-11: The compound is provided as follows:

[0219] In one embodiment of the present invention, a compound of formula A-12: The compound is provided as follows:

[0220] In one embodiment of the present invention, a compound of formula A-14: The compound is provided as follows:

[0221] In one embodiment of the present invention, a compound of formula A-15: The compound is provided as follows:

[0222] Furthermore, the intermediate of the compound represented by the formula A-11 is useful in the production of the compound, but is not limited to the production of the compound and can be applied to any purpose. Thus, the present invention also provides an intermediate of the compound represented by the formula A-11.

[0223] In one embodiment of the present invention, the compound of formula B-4: The compound is provided as follows:

[0224] In one embodiment of the present invention, the compound of formula B-5: The compound is provided as follows:

[0225] In one embodiment of the present invention, the compound of formula B-6: The compound is provided as follows:

[0226] In one embodiment of the present invention, a compound of formula B-7: The compound is provided as follows:

[0227] In one embodiment of the present invention, a compound of formula B-8: The compound is provided as follows:

[0228] Furthermore, the intermediate for the oligosaccharide represented by the above formula D-13 is useful in the production of the oligosaccharide, but is not limited to the production of the oligosaccharide and can be applied to a variety of uses. As described below, the present invention provides the oligosaccharide represented by the above formula D-13 and its intermediate (including the compound represented by the above formula A-13 and its intermediate).

[0229] In one embodiment of the present invention, a compound of formula D-13: The oligosaccharide is represented by the formula:

[0230] In one embodiment of the present invention, a compound of formula D-1: The compound is provided as follows:

[0231] Formula D-2 below: The compound is provided as follows:

[0232] In one embodiment of the present invention, a compound of formula D-4: The compound is provided as follows:

[0233] In one embodiment of the present invention, a compound of formula D-5: The compound is provided as follows:

[0234] In one embodiment of the present invention, a compound of formula D-5-FMA: The compound is provided as follows:

[0235] In one embodiment of the present invention, a compound of formula D-6: (wherein R５ is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R ６ is a hydrogen atom, or R ５ and R ６ together with the nitrogen atom to which they are attached form a phthalimido group).

[0236] In one embodiment of the present invention, a compound of formula D-8: (wherein R ５ is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R ６ is a hydrogen atom, or R ５ and R ６ together with the nitrogen atom to which they are attached form a phthalimido group).

[0237] In one embodiment of the present invention, a compound of formula D-9: (wherein M ＋ is a sodium ion, a lithium ion, a potassium ion, or a protonated triethylamine cation).

[0238] In one embodiment of the present invention, a compound of formula D-10: (wherein M ＋ is a sodium ion, a lithium ion, a potassium ion, or a protonated triethylamine cation).

[0239] In one embodiment of the present invention, a compound of formula D-11: (wherein M ＋ is a sodium ion, a lithium ion, a potassium ion, or a protonated triethylamine cation).

[0240] In one embodiment of the present invention, a compound of formula E-2: A crystalline compound represented by the formula: ７ is a hydrogen atom, a methyl group, or a methoxy group).

[0241] In one embodiment of the present invention, a compound of the following formula D-12: In one embodiment of the present invention, there is provided a compound represented by the above formula D-12, which has a purity of 95% or more as determined by HPLC.

[0242] <Glycoproteins, etc. and Production Methods Thereof> In one aspect of the present invention, a novel glycoprotein, etc. and a novel production method therefor are provided, which utilize a biantennary glycan having an α2,6-sialic acid structure at the non-reducing end (i.e., an oligosaccharide represented by formula D-13) as a donor molecule in the synthesis of a glycoprotein, etc. (particularly, a glycochain-remodeling antibody or an Fc-region-containing molecule thereof, or an antibody-drug conjugate). As described in detail below, the oligosaccharide represented by formula D-13 obtained by the production method of the present invention can be used for the production of glycoproteins (particularly, a glycochain-remodeling antibody or an Fc-region-containing molecule, or an antibody-drug conjugate) (WO 2019 / 065964, WO 2020 / 050406, etc.), but the use is not limited thereto and can also be for other purposes.

[0243] Recently, a method has been reported in which heterogeneous antibody sugar chains are remodeled by enzymatic reaction to uniformly introduce sugar chains having functional groups (ACS Chem. Biol. 2012, 7, 110-122, ACS Med. Chem. Lett. 2016, 7, 1005-1008). Attempts have also been made to use this sugar chain remodeling technique to site-specifically introduce drugs and synthesize homogeneous antibody-drug conjugates (ADCs) (Bioconjugate Chem. 2015, 26, 2233-2242, Angew. Chem. Int. Ed. 2016, 55, 2361-2367, US2016361436).

[0244] In glycan remodeling, first, a hydrolase is used to remove heterogeneous glycans attached to a protein (such as an antibody), leaving only the terminal N-acetylglucosamine (GlcNAc) to prepare a homogeneous protein portion with GlcNAc attached (hereinafter referred to as the "acceptor molecule"). Next, a separately prepared glycan of your choice (hereinafter referred to as the "donor molecule") is prepared, and this acceptor molecule and donor molecule are linked using a glycosyltransferase. This allows the synthesis of a homogeneous glycoprotein with a desired glycan structure.

[0245] In one embodiment of the present invention, the oligosaccharide represented by formula D-13 produced by the novel production method of the present invention can be used as a donor molecule in synthesizing the above-mentioned homogeneous glycoprotein (particularly, a glycosylated antibody or its Fc region-containing molecule) by activating its terminal structure.

[0246] In the following examples, room temperature refers to 15°C to 35°C. Silica gel chromatography was performed using a Biotage Sfar HC D (20 μm, manufactured by Biotage). Reverse-phase column chromatography was performed using a Universal Column ODS Premium 30 μm L size (manufactured by Yamazen Corporation) and an Inject column ODS L size (manufactured by Yamazen Corporation). Preparative HPLC was performed using an Agilent Preparative HPLC System (manufactured by Agilent Technology). The preparative column used was an XBridge Prep OBD (5 μm, C18, 130 Å, 250 × 30 mm, manufactured by Waters).

[0247] The following instruments were used to measure various spectral data. １ H-NMR and １３ C-NMR spectra were measured using JEOL ECZ500R and ECX400P instruments. Mass spectra were measured using Shimadzu LCMS-2010 and LCMS-2020 (Shimadzu Corporation), XEVO Q-Tof MS (Waters), and Q-Exactive (Thermo Fisher).

[0248] <Synthesis of Compound Represented by Formula A-3> The compound represented by Formula A-3 was synthesized according to the following synthesis scheme 1. [Synthesis Scheme 1]

[0249] Example 1 2-O-acetyl-3,4,6-tri-O-benzyl-D-mannopyranose (compound represented by formula A-2) 3,4,6-Tri-O-benzyl-1,2-O-(1-methoxyethylidene)-β-D-mannopyranose (compound represented by formula A-1) (40.0 g, 78.9 mmol) was added to a 1 L four-neck flask, followed by the addition of ethyl acetate (400 mL). Under a nitrogen atmosphere, water (2 mL) and p-TsOH.H ２ 0 (45 mg, 0.237 mmol) was added and stirred at the same temperature for 6 hours. After confirming the completion of the reaction by HPLC, triethylamine (7.99 g, 78.9 mmol) was added and stirred at the same temperature overnight. After confirming the completion of the acetyl group rearrangement by HPLC, 5% aqueous sodium bicarbonate (400 mL) was added to the reaction solution and the mixture was separated. 20% brine (200 mL) was added to the organic layer and the mixture was separated. The organic layer was concentrated under reduced pressure to 80 mL, and toluene (400 mL) was added and the mixture was concentrated under reduced pressure to 80 mL. Toluene (400 mL) was added again and the mixture was concentrated under reduced pressure to 80 mL. Anhydrous toluene (120 mL) was added to obtain a toluene solution of 2-O-acetyl-3,4,6-tri-O-benzyl-D-mannopyranose (compound represented by Formula A-2) as a colorless solution.

[0250] Example 2 2-O-acetyl-3,4,6-tri-O-benzyl-1-O-(2,2,2-trichloroethanimidoyl)-D-mannopyranose (compound represented by formula A-3)

[0251] A toluene solution (78.9 mmol) of 2-O-acetyl-3,4,6-tri-O-benzyl-D-mannopyranose (compound represented by Formula A-2) was added to a 1 L flask, followed by the addition of trichloroacetonitrile (12 mL, 118 mmol) and DBU (119 μL, 0.789 mmol). The mixture was stirred under nitrogen at 0°C for 2 hours. After confirming the completion of the reaction by HPLC, acetic acid (45 μL, 0.789 mmol) was added to the reaction solution at 0°C to obtain a toluene solution (78.9 mmol) of 2-O-acetyl-3,4,6-tri-O-benzyl-1-O-(2,2,2-trichloroethanimidoyl)-D-mannopyranose as a brown solution. This solution was used directly in the next step.

[0252] <Synthesis of Compound Represented by Formula A-11> The compound represented by Formula A-11 was synthesized according to the following Synthesis Scheme 2. [Synthesis Scheme 2]

[0253] Example 3 4-Methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-β-D-glucopyranoside (Compound represented by Formula B-3)

[0254] To a solution of 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-phthalimido-β-D-glucopyranoside (compound represented by formula B-2) (2.508 kg, 4.211 mol) in dichloromethane (17.5 L) were added 2,3,4,6-tetra-O-acetyl-1-O(2,2,2-trichloroethanimidoyl)-α-D-galactopyranose (compound represented by formula B-1) (2.275 kg, 4.618 mol) and molecular sieve 4A powder (10 μm or less, 375 g). The mixture was stirred at 20 to 30°C for 20 minutes, then cooled to -20 to -10°C, and trimethylsilyl trifluoromethanesulfonate (140 g, 0.630 mol) was added dropwise over 3 minutes. After stirring at -5°C to -10°C for 3 hours, triethylamine (106 g, 1.05 mol) was added, the temperature was raised to 0°C to 5°C, and the mixture was filtered through molecular sieves 4A and washed with toluene (5 L). The resulting solution was concentrated under reduced pressure to 12.5 L, and then toluene (12.5 L) was added. Separation washing with a mixed solution of methanol (6.5 L) and water (18.5 L) was carried out four times. The obtained organic layer was concentrated under reduced pressure to 9 L, toluene (25 L) was added, and then the mixture was concentrated under reduced pressure to 7.5 L, thereby obtaining a toluene solution (7.5 L) of 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-β-D-glucopyranoside (compound represented by Formula B-3).

[0255] Example 4 4-Methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-β-D-galactopyranosyl-β-D-glucopyranoside (Compound represented by formula B-4)

[0256] To a toluene solution (7.5 L) of 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-β-D-glucopyranoside (the compound represented by Formula B-3), tetrahydrofuran (10 L), methanol (5 L), and methyl trifluoroacetate (538 g, 4.20 mol) were added, followed by addition of a potassium t-butoxide-tetrahydrofuran solution (1 M, 2.1 L, 2.1 mol), and the mixture was stirred at 40°C to 45°C for 2 hours. After cooling to 20°C to 25°C, acetic acid (151 g) and ethyl acetate (25 L) were added, and separation washing was performed three times with a solution of sodium hydrogen carbonate (750 g)-sodium chloride (750 g)-water (20 L) and once with a solution of sodium chloride (2.5 kg)-water (10 L). The resulting organic layer was concentrated under reduced pressure to 7.5 L, and N,N-dimethylacetamide (25 L) and cyclopentyl methyl ether (37.5 L) were added thereto, followed by concentration under reduced pressure to 27.5 L. After that, cyclopentyl methyl ether (12.5 L) was added thereto, and the mixture was concentrated under reduced pressure to 27.5 L, thereby obtaining an N,N-dimethylacetamide solution (27.5 L) of 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-β-D-galactopyranosyl-β-D-glucopyranoside (compound represented by Formula B-4).

[0257] Example 5 4-Methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-β-D-glucopyranoside (Compound represented by Formula B-5)

[0258] To a solution of t-butyl alcohol (1.56 kg, 21.0 mol) in hexane (3.28 kg) was added dropwise over 4 hours at −15° C. to 0° C. Methyl trifluoroacetate (26.9 g, 0.170 mol) was added to obtain a lithium t-butoxide hexane solution. To a solution of 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-β-D-galactopyranosyl-β-D-glucopyranoside (compound represented by formula B-4) in N,N-dimethylacetamide (27.5 L) were added benzyl bromide (5.03 kg, 29.4 mol) and molecular sieve 4A powder (10 μm or less, 750 g), and a lithium t-butoxide-hexane solution (12.1 kg) was added dropwise over 3 hours at 35 to 45° C. After cooling to 20 to 25° C., acetic acid (378 g, 6.29 mol) was added, and the molecular sieves 4A were filtered and washed with N,N-dimethylacetamide (7.5 L). Heptane (12.5 L) was added and the mixture was separated and washed. To the resulting N,N-dimethylacetamide layer, t-butyl methyl ether (25 L) was added, and the mixture was separated and washed with water (20 L) three times. The resulting organic layer was concentrated under reduced pressure to 7.5 L to give a t-butyl methyl ether solution (7.5 L) of 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-β-D-glucopyranoside (compound represented by Formula B-5).

[0259] Example 6 4-Methoxyphenyl 3,6-di-O-benzyl-2-(2-carboxybenzamido)-2-deoxy-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-β-D-glucopyranoside cinchonidine salt (Compound represented by formula B-6)

[0260] Tetrahydrofuran (12.5 L), methanol (5 L), and water (1 L) were added to a t-butyl methyl ether solution (7.5 L) of 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-β-D-glucopyranoside (compound represented by Formula B-5). The mixture was cooled to 0°C to 10°C, and then 4N aqueous sodium hydroxide solution (2.6 L, 10.4 mol) was added dropwise over 5 minutes. The mixture was stirred at 0°C to 10°C for 6 hours, followed by addition of triethylamine (1.70 kg, 16.8 mol), and the mixture was stirred at 20°C to 30°C for 16 hours. After cooling to 0°C to 10°C, 6M hydrochloric acid (3.0 L, 18.0 mol) was added dropwise over 20 minutes, and the temperature was raised to 20°C to 25°C. Ethyl acetate (20 L) was added, and after separation and washing with water (17.5 L), separation and washing were carried out with a sodium chloride (2.5 kg)-water (10 L) solution. The resulting organic layer was concentrated under reduced pressure to 7.5 L, and then ethyl acetate (17.5 L) was added and concentrated under reduced pressure to 7.5 L. Ethyl acetate (30 L) and cinchonidine (1.36 kg, 4.62 mol) were added to the resulting solution, and the mixture was stirred at 20°C to 25°C for 18 hours. The mixture was then cooled to 0°C to 5°C over 1 hour, and heptane (20 L) was added dropwise over 1 hour. After stirring at that temperature for 1.5 hours, the resulting crystals were filtered and washed with a mixed solvent of ethyl acetate (7.5 L) and heptane (5.6 L) cooled to 0° C. to 5° C. The resulting crystals were dried under reduced pressure at 40° C. to give 4-methoxyphenyl 3,6-di-O-benzyl-2-(2-carboxybenzamido)-2-deoxy-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-β-D-glucopyranoside cinchonidine salt (compound represented by formula B-6) (5.10 kg, total yield for four steps: 85.0%).

[0261] １ H-NMR (500MHz, CDCl ３ ​)δ8.78(d,4.6Hz,1H),8.75(d,J=8.0Hz,1H),8.07(d,J=8.5Hz,1H),8.06(d,J=8.0Hz,2H),7.65-7.68(m,3H),7.61(dd,3.9,7.7Hz,1H),7.55(d,J=4.6Hz,1H),7.43(dd,3.7,7.4Hz,2H),7.19-7.33(m,28H),6.98-7.04(m,5H),6.68-6.70(m,2H),6.32(brd,1H),5.39-5.46(m,1H),5.35(d,J=6.9Hz,1H),4.97(d,J=11Hz,1H),4.83-4.91(m,3H),4.66-4.73(m,5H),4.55(d,J=12Hz,1H),4.46(s,1H),4.43(d,J=4.0Hz,1H),4.35(dd,J=5.7,12Hz,2H),4.26(d,J=12Hz,1H),4.22(dd,J=4.2,8.4Hz,1H),4.03-4.09(m,3H),3.92(d,J=2.6Hz,1H),3.74(d,J=3.7Hz,2H),3.67-3.70(m,4H),3.57-3.60(m,1H),3.54(t,J=7.9Hz,1H),3.36-3.44(m,3H),3.31(t,J=9.2Hz,1H),3.12(dd,10,14Hz,1H),3.02(d,J=13Hz,1H),2.93(m,1H),2.36(s,1H),1.86-1.89(m,2H),1.81(dd,J=9.0,13Hz,1H),1.53(dd,J=4.7,9.5Hz,1H),1.09(dd,J=5.7,11Hz,1H). 　１３ C-NMR(125MHz,CDCl ３) δ176.2, 169.5, 155.3, 151.6, 150.1, 148.0, 146.4, 138.88, 138.7, 138.53, 138.48, 138.39, 138.35, 138.26, 137.8, 133.4 , 130.15, 130.07, 129.11, 128.73, 128.70, 128.51, 128.4, 128.34, 128.22, 128.2, 128.16, 127.95, 127.92, 127.83, 127.75 , 127.57, 127.55, 127.43, 127.41, 127.19, 127.12, 124.9, 122.8, 119.5, 118.7, 116.2, 114.3, 103.2, 100.3, 82.4, 79.8, 78 7, 76.2, 75.2, 75.1, 74.8, 73.7, 73.4, 73.03, 72.99, 72.7, 68.7, 68.1, 59.8, 55.5, 55.3, 54.1, 43.4, 37.6, 27.0, 25.0, 19.1 HRMS (ESI ＋ ) [M + HNEt ３ ] ＋ calcd for C ７５ H ８５ N ２ O １４ :1237.5995;found 1237.5977. [α] Ｄ ２０ =-21.889 (c 1.003, CDCl ３ ).

[0262] Example 7 4-Methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-β-D-glucopyranoside (Compound represented by Formula B-5)

[0263] To a suspension of 4-methoxyphenyl 3,6-di-O-benzyl-2-(2-carboxybenzamido)-2-deoxy-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-β-D-glucopyranoside cinchonidine salt (compound represented by formula B-6) (4.50 kg, 3.15 mol) in ethyl acetate (33.8 L), 0.5 M hydrochloric acid (33.8 L, 16.9 mol) was added at 15°C to 25°C, and the mixture was stirred to dissolve. After removing the aqueous layer, the mixture was separated and washed with a sodium chloride (4.5 kg)-water (18 L) solution, and the resulting organic layer was concentrated under reduced pressure to 6.8 L. After adding ethyl acetate (33.8 L), the mixture was concentrated under reduced pressure to 6.8 L to obtain the compound represented by formula B-7: was obtained as an ethyl acetate solution. Next, tetrahydrofuran (18 L) was added to the obtained solution. After cooling to 0°C to 5°C, 1,1'-carbonyldiimidazole (765 g, 4.12 mol) was added and stirred for 17 hours. Ethyl acetate (22.5 L), water (22.5 L), and 6 M hydrochloric acid (1.57 L, 9.42 mol) were added, and the aqueous layer was then removed. The obtained organic layer was washed sequentially with water (22.5 L) and a solution of sodium chloride (4.5 kg) in water (18 L). The resulting organic layer was concentrated under reduced pressure to 4.5 L, and then toluene (22.5 L) was added and the mixture was concentrated under reduced pressure to 4.5 L, yielding a toluene solution (4.5 L) of 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-β-D-glucopyranoside (compound represented by Formula B-5).

[0264] Example 8 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-β-D-glucopyranose (Compound represented by formula B-8)

[0265] To a toluene solution (4.5 L) of 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-β-D-glucopyranoside (compound represented by Formula B-5), dichloromethane (6.75 L), 1,1,1,3,3,3-hexafluoro-2-propanol (6.75 L), and water (675 mL) were added at 15 to 25° C. A suspension of bis(trifluoroacetoxy)iodobenzene (2.16 kg, 5.02 mol) in dichloromethane (6.75 L) was added in 10 portions, and the mixture was stirred at 15 to 25° C. for 20 hours. The mixture was cooled to 0°C to 5°C, toluene (31.5 L) was added, and then separation washing with a sodium bicarbonate (900 g)-sodium sulfite (900 g)-water (22.5 L) solution was performed twice at 0°C to 20°C. The obtained organic layer was separated and washed with a sodium chloride (4.5 kg)-water (18 L) solution, then concentrated under reduced pressure to 9 L, and toluene (22.5 L) was added and further concentrated under reduced pressure to 9 L. Toluene (36 L) was added to the obtained solution, and the mixture was divided into two portions. Silica gel (4.5 kg) was added to each divided solution, and the mixture was stirred at 20°C to 25°C for 3 hours. The silica gel was then filtered and washed with toluene (45 L). The obtained silica gel was desorbed from the silica gel by washing with a mixed solution of ethyl acetate (7.5 L) and toluene (22.5 L). The resulting organic layers were combined and concentrated under reduced pressure to 9 L, yielding a toluene solution (9 L) of 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-β-D-glucopyranose (compound represented by formula B-8).

[0266] １ H-NMR (500MHz, CDCl ３)δ7.60-7.87(m,4H),7.18-7.36(m,25H),6.96(d,J=6.9Hz,2H),6.89(m,1H),6.83(dd,J=7.4,10Hz,2H),5.33(dd,J=1.9,3.7Hz,0.2H),5.30(dd,J=4.3,8.6Hz,0.8H),4.92(dd,J=9.9,12Hz,2H),4.78-4.86(m,2H),4.71(d,J=2.3Hz,2H),4.44-4.61(m,3H),4.36-4.14(m,3H),4.34(d,J=4.6Hz,1H),4.26(d,J=12Hz,1H),4.03-4.12(m,2H),3.89(d,J=2.8Hz,1H),3.85(dd,J=4.0,11Hz,1H),3.77(dd,J=7.7,9.7Hz,1H),3.67(dd,J=1.6,11Hz,1H),3.56-3.60(m,1H),3.35-3.49(m,4H),2.88(d,J=8.6Hz,1H). 　１３ C-NMR(125MHz,CDCl ３ )δ168.2,139.06,139.04,138.98,138.91,138.7,138.6,138.5,138.10,138.06,133.8,131.7,128.40,128.38,128.32,128.27,128.24,128.10,127.99,127.96,127.90,127.84,127.78,127.76,127.72,127.68,127.65,127.63,127.55,127.51,127.49,127.44,127.42,127.3,126.8,123.6,123.3,102.9,102.8,93.1,92.8,82.34,82.32,80.02,79.99,77.8,77.7,76.6,75.43,75.39,75.31,74.53,74.49,74.33,73.98,73.72,73.63,73.41,73.24,73.20,73.07,72.63,72.59,70.6,68.3,68.0,67.8,57.7,55.8, HRMS(ESI ＋ )[M+Na] ＋ calcd for C ６２ H ６１ NNaO １２:1034.4092;found 1034.4071. [α] Ｄ ２０ =+33.243(c 1.002, CDCl ３ ).

[0267] Example 9 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-1-O-(2,2,2-trifluoro-N-phenylethanimidoyl)-β-D-glucopyranose (Compound represented by Formula A-11)

[0268] To a toluene solution (total amount: 1002 g) of 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-β-D-glucopyranose (compound represented by formula B-8) (the solution obtained in Examples 7 and 8 derived from 500 g, 0.349 mol of compound represented by formula B-6), dichloromethane (2.0 L), molecular sieve 4A powder (10 μm or less, 250 g), and N-methylimidazole (34.4 g, 0.419 mol) were added at 20° C. to 30° C. Thereafter, 2,2,2-trifluoro-N-phenylacetimidoyl chloride (79.8 g, 0.384 mol) was added, and the mixture was stirred at 20°C to 30°C for 17 hours. After filtering through molecular sieves 4A and washing with toluene (500 mL), the resulting solution was cooled to 0°C to 10°C. The solution was passed through a column packed with silica gel (1.5 kg) wetted with dichloromethane cooled to 0°C to 5°C, and washed with dichloromethane (15 L) cooled to 0°C to 5°C, and fractions were obtained by fractionating in 2.5 L to 3 L increments. Next, the column was washed with a mixture of dichloromethane (10 L) containing 3% ethyl acetate, and fractions were obtained by fractionating in 2.5 L to 3 L increments. The first to seventh fractions obtained were combined and concentrated under reduced pressure to 1 L to give a solution of 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-1-O-(2,2,2-trifluoro-N-phenylethanimidoyl)-β-D-glucopyranose (compound of formula A-11) in a toluene-dichloromethane mixture. This solution was used as is in Example 27.

[0269] １ H-NMR (500MHz, CDCl ３ ​)δ7.62-7.82(m,4H),7.01-7.53(m,31H),6.98-7.01(m,1H),6.95(d,J=7.2Hz,2H),6.80-6.88(m,3H),6.64(brd,2H),4.93(d,J=12Hz,1H),4.89(d,J=12Hz,1H),4.83(d,J=11Hz,1H),4.77(d,J=11Hz,1H),4.67-4.72(m,2H),4.56(d,J=12Hz,1H),4.53(d,J=12Hz,1H),4.36-4.48(m,5H),4.28(d,J=12Hz,1H),4.14(t,J=8.7Hz,1H),3.89(d,J=2.6Hz,1H),3.85(d,J=7.7Hz,1H),3.76(t,J=8.4Hz,1H),3.38-3.50(m,4H). 　１３ C-NMR(125MHz,CDCl ３ )δ167.6,143.4,143.1,139.0,138.68,138.66,138.5,137.08,137.06,135.2,133.92,131.5,129.3,129.1,129.0,128.5,128.41,128.37,128.31,128.27,128.22,128.90,127.86,127.69,127.56,127.45,127.44,127.2,126.9,126.2,124.3,123.4,120.6,120.5,119.3,116.3(q,J=148.5Hz),102.9,93.5,82.3,79.9,76.6,76.0,75.4,74.5,73.61,73.41,73.08,73.05,72.6,68.3,67.2,54.8. HRMS(ESI ＋ ) [M+Na] ＋ calcd for C ７０ H ６５ F ３ N ２ NaO １２ :1205.4387;found 1205.43835. [α] Ｄ ２０ =+66.645(c 1.099,CDCl ３ ).

[0270] <Synthesis of Compound Represented by Formula A-13> The compound represented by Formula A-13 was synthesized according to the following Synthesis Scheme 3. [Synthesis Scheme 3]

[0271] Example 10 1,2:5,6-bis-O-(1-methylethylidene)-3-O-(2-naphthylmethyl)-α-D-glucofuranose (compound represented by formula C-2)

[0272] A solution of sodium hydride (55.32 g, 1.38 mol, content: 50-72%) in tetrahydrofuran (900 mL) was cooled to 0°C, and a solution of 1,2:5,6-bis-O-(1-methylethylidene)-α-D-glucofuranose (compound represented by formula C-1) (300.00 g, 1.15 mol) in tetrahydrofuran (1.05 L) was added dropwise over 1 hour. The mixture was then heated to 25°C, and 1,3-dimethyl-2-imidazolidinone (150 mL) and 2-bromomethylnaphthalene (280.31 g, 1.27 mol) were added. After stirring at 25°C for 6 hours, the completion of the reaction was confirmed by HPLC, and ethylenediamine (anhydrous) (13.85 g, 230.52 mmol) was added, followed by stirring for an additional 1 hour. This solution was cooled to 0°C, and 10% aqueous citric acid solution (1.2 L) was added over 1 hour. The reaction solution was diluted with heptane (3 L) and separated into an organic layer and an aqueous layer. The organic layer was washed with water (900 mL) and then concentrated under reduced pressure until the liquid volume reached 900 mL. Further acetonitrile (3 L) was added, and the solution was again concentrated until the liquid volume reached 900 mL, yielding crude 1,2:5,6-bis-O-(1-methylethylidene)-3-O-(2-naphthylmethyl)-α-D-glucofuranose (compound represented by formula C-2) as an acetonitrile solution. This product was used as is in the next step.

[0273] Example 11 3-O-(2-naphthylmethyl)-D-glucopyranose (compound represented by formula C-3)

[0274] Acetonitrile (1.5 L), water (600 mL), and concentrated hydrochloric acid (17.51 ​​g, 172.89 mmol) were added to a solution (900 mL) of the crude compound represented by formula C-2 obtained in Example 10, and the mixture was stirred at 55°C for 18.5 hours. After confirming the completion of the reaction by HPLC, the reaction solution was cooled to 0°C, and the pH of the system was adjusted to 6.25 with 4 N aqueous sodium hydroxide solution (43.22 mL). The reaction solution was diluted with heptane (900 mL), and the mixture was separated into an acetonitrile layer and a heptane layer. Ethyl acetate (2.4 L) and water (600 mL) were added to the acetonitrile layer and the mixture was separated to obtain an organic layer A and an aqueous layer. A mixed solution of ethyl acetate (1.5 L) and tetrahydrofuran (1.5 L) was added to the aqueous layer again, and the mixture was separated to obtain an organic layer B and an aqueous layer. The organic layers A and B were mixed, washed with saturated saline (600 mL), and concentrated under reduced pressure until the liquid volume reached 1.5 L (crystal precipitation was confirmed during the concentration stage). Ethyl acetate (4.5 L) was added, and the mixture was concentrated again until the liquid volume reached 3 L. Ethyl acetate (1.5 L) and cyclopentyl methyl ether (1.5 L) were added to this suspension, and the mixture was stirred at 55°C for 1 hour. Heptane (3 L) was added dropwise over 1.5 hours, and the mixture was stirred for 1 hour and then cooled to 0°C. The precipitated crystals were then filtered and washed with a mixed solution of ethyl acetate (1.2 L) and heptane (600 mL) cooled to 0°C. The resulting crystals were dried under reduced pressure at 40°C to obtain 3-O-(2-naphthylmethyl)-D-glucopyranose (compound represented by formula C-3) (356.95 g, yield 96.7%).

[0275] １ H-NMR (500MHz, DMSO-d ６ ) δ7.85-7.90 (m, 4H), 7.59 (dd, J=8.0, 1.5Hz, 1H), 7.46-7.51 (m, 2H), 6 .69 (d, J=6.0Hz, 1H), 5.12 (dd, J=5.0, 3.0Hz, 2H), 4.94-5.00 (m, 2H), 4. 53 (t, J=6.0Hz, 1H), 4.35 (dd, J=8.0, 6.5Hz, 1H), 3.70 (ddd, J=11.5, 5. 0, 2.0Hz, 1H), 3.45-3.50 (m, 1H), 3.25-3.31 (m, 2H), 3.11-3.16 (m, 2H). 　１３ C-NMR (125MHz, DMSO-d ６) δ137.3, 132.8, 132.3, 127.6, 127.5, 127.4, 126.1, 126.0, 125.6, 125.5, 96.9, 85.4, 76.7, 74.8, 73.7, 69.9, 61.1. HRMS (ESI － ) [M-H] － calcd for C １７ H ２０ O ６ :320.1260;found 319.1175.

[0276] Example 12 2,4,6-tri-O-acetyl-3-O-(2-naphthylmethyl)-D-glucopyranose (compound represented by formula C-5)

[0277] To a solution of 3-O-(2-naphthylmethyl)-D-glucopyranose (compound represented by formula C-3) (150.00 g, 468.25 mmol) in tetrahydrofuran (675 mL), triethylamine (236.92 g, 2.34 mol) and 4-dimethylaminopyridine (0.29 g, 2.34 mmol) were added and cooled to 0°C. Then, acetic anhydride (195.99 g, 1.92 mol) was added dropwise over 30 minutes. The mixture was then heated to 25°C and stirred for 3 hours, after which the completion of the reaction was confirmed by HPLC. The reaction solution was cooled to 10°C, and 1-methylpiperazine (60.97 g, 608.73 mmol) was added. After stirring at 35°C for 18 hours, the completion of the reaction was confirmed by HPLC, and the mixture was cooled to 0°C. The pH was adjusted to 6.36 with 6 N hydrochloric acid (480 mL), then diluted with heptane (375 mL), and the organic and aqueous layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate (450 mL) and water (450 mL) and then concentrated under reduced pressure to a volume of 450 mL. Ethyl acetate (2.25 L) was added, and the mixture was concentrated again to a volume of 450 mL. The same procedure was repeated once more. Dichloromethane (2.25 L) was added to this solution, and the mixture was concentrated to a volume of 450 mL. The same procedure was repeated once more to obtain crude 2,4,6-tri-O-acetyl-3-O-(2-naphthylmethyl)-D-glucopyranose (compound represented by formula C-5) as a dichloromethane solution. This product was used directly in the next step. The process from the compound represented by formula C-3 to the compound represented by formula C-5 was carried out in one pot.

[0278] Example 13 2,4,6-tri-O-acetyl-3-O-[(naphthalen-2-yl)methyl]-1-O-(2,2,2-trichloroethanimidoyl)-D-glycero-hexopyranose (compound represented by formula C-6)

[0279] To a solution (450 mL) of crude 2,4,6-tri-O-acetyl-3-O-(2-naphthylmethyl)-D-glucopyranose (compound represented by formula C-5) obtained in Example 12, dichloromethane (450 mL) and trichloroacetonitrile (338.03 g, 2.34 mol) were added and cooled to 0°C. 1,8-diazabicyclo[5.4.0]-7-undecene (5.70 g, 37.46 mmol) was then added dropwise. After stirring at 0°C for 14.5 hours, the completion of the reaction was confirmed by HPLC, and acetic acid (2.25 g, 37.46 mmol) was added. Silica gel 60N (Kanto Chemical, particle size: 40-50 μm, 150 g) was added to this solution, followed by stirring for 1.5 hours and filtration. The silica gel was washed with dichloromethane (1.5 L), and the filtrate was concentrated under reduced pressure to a volume of 450 mL. Further, dichloromethane (1.5 L) was added and the mixture was concentrated to a volume of 450 mL to obtain 2,4,6-tri-O-acetyl-3-O-[(naphthalen-2-yl)methyl]-1-O-(2,2,2-trichloroethanimidoyl)-D-glycero-hexopyranose (compound represented by formula C-6) as a dichloromethane solution, which was used as is in the next step.

[0280] Example 14 4-Methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-{2,4,6-tri-O-acetyl-3-O-[(naphthalen-2-yl)methyl]-β-D-glucopyranosyl}-β-D-glucopyranoside (Compound represented by formula C-8)

[0281] To a solution (450 mL) of 2,4,6-tri-O-acetyl-3-O-[(naphthalen-2-yl)methyl]-1-O-(2,2,2-trichloroethanimidoyl)-D-glycero-hexopyranose (compound represented by formula C-6) obtained in Example 13, 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula C-7) (276.66 g, 468.25 mmol), dichloromethane (4.2 L), and molecular sieve 4A powder (10 μm or less, 83.00 g) were added, and the mixture was cooled to −5° C. Trimethylsilyl trifluoromethanesulfonate (10.41 g, 46.83 mmol) was added dropwise to this suspension over 20 minutes, followed by stirring for 3 hours. After confirming the completion of the reaction by HPLC, triethylamine (23.69 g, 234.13 mmol) was added. The suspension was filtered and washed with ethyl acetate (2.8 L), and the filtrate was concentrated under reduced pressure to a liquid volume of 1.4 L. Further ethyl acetate (4.2 L) was added, and the mixture was concentrated to a liquid volume of 1.4 L, and the same procedure was repeated once more. Ethyl acetate (2.8 L) was added to this solution, and the mixture was washed with saturated aqueous sodium bicarbonate (830 mL) and water (830 mL), and the organic layer was concentrated under reduced pressure to a liquid volume of 830 mL. Further 2-propanol (4.2 L) was added, and the mixture was concentrated to a liquid volume of 1.4 L, after which the suspension was kept at 65°C. Ethyl acetate (830 mL) was added and the mixture was stirred at 65°C for 2 hours, after which 2-propanol (5.53 L) was added dropwise over 2 hours. The suspension was cooled to 0°C, and the crystals were filtered and washed with 2-propanol (1.4 L) cooled to 0°C. The resulting crystals were dried under reduced pressure at 40°C to give crude 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-{2,4,6-tri-O-acetyl-3-O-[(naphthalen-2-yl)methyl]-β-D-glucopyranosyl}-β-D-glucopyranoside (compound represented by formula C-8) (355.34 g, yield 90.5%, based on the compound represented by formula C-3).To the resulting crude compound of formula C-8 (350.00 g), methyl isobutyl ketone (2.1 L) was added and the mixture was dissolved at 50° C., followed by dropwise addition of ethylcyclohexane (1.4 L) over 1 hour. 4-Methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-{2,4,6-tri-O-acetyl-3-O-[(naphthalen-2-yl)methyl]-β-D-glucopyranosyl}-β-D-glucopyranoside (compound of formula C-8) (70.00 mg) was added and stirred for 1 hour. After confirming the precipitation of crystals, ethylcyclohexane (4.9 L) was added dropwise over 2 hours. The suspension was cooled to room temperature and stirred for 14.5 hours. The precipitated crystals were filtered and washed with a mixed solution of methyl isobutyl ketone (350 mL) and ethylcyclohexane (1.4 L). The obtained crystals were dried under reduced pressure at 40°C to give 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-{2,4,6-tri-O-acetyl-3-O-[(naphthalen-2-yl)methyl]-β-D-glucopyranosyl}-β-D-glucopyranoside (compound represented by formula C-8) (331.74 g, yield 94.8%).

[0282] １ H-NMR (500MHz, CDCl ３ ​) δ7.81-7.84 (m, 4H), 7.69 (br, 1H), 7 .65(br,3H),7.46-7.51(m,2H),7.28- 7.36 (m, 6H), 7.00 (dd, J=7.0, 1.5Hz, 2 H), 6.77-6.84 (m, 5H), 6.66-6.69 (m, 2 H), 5.59, (d, J=9.0Hz, 1H), 5.09-5.15 (m, 2H), 4.82 (d, J=12.5Hz, 1H), 4.77 ( d, J=12.0Hz, 1H), 4.71-4.77 (m, 2H), 4 .60 (d, J=8.0Hz, 1H), 4.50 (d, J=12.5H z, 1H), 4.45 (d, J=13.0Hz, 1H), 4.36 ( dd, J=11.0, 8.5Hz, 1H), 4.28 (dd, J=11 .0, 8.5Hz, 1H), 4.20 (dd, J=12.5, 5.0Hz, 1H), 4.10 (dd, J=10.0, 8.5Hz, 1H), 3 . 99 (dd, J=12.0, 2.0Hz, 1H), 3.80 (br, 2H), 3.69 (s, 3H), 3.58-3.62 (m, 2H), 3 .44 (ddd, J=10.0, 4.5, 2.5Hz, 1H), 1.9 8 (s, 3H), 1.938 (s, 3H), 1.937 (s, 3H). 　１３ C-NMR (125MHz, CDCl ３ ) δ171.0, 169.5, 169.1, 155.6, 151.0, 138.7, 138.2, 135.5, 133.9, 133.4, 13 3.2, 128.7, 128.4, 128.23, 128.20, 128.06, 128.05, 127.9, 127.2, 126.5, 12 6.2, 125.7, 123.5, 118.9, 114.5, 100. 7, 97.8, 80.6, 78.5, 76.8, 75.2, 74.8, 74.1, 73.8, 73.1, 72.1, 69.9, 67.8, 62 .2, 55.78, 55.75, 21.1, 20.94, 20.85. HRMS(ESI ＋ )[M+H] ＋ calcd for C ５８ H ５8 NO １６ : 1024.3750; found 1024.3706. The following documents are consistent and confirmed: Oｽg. Biomol. Chem. , 2018, 16, 4720-4727.

[0283] Example 15 4-Methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-{3-O-[(naphthalen-2-yl)methyl]-β-D-glucopyranosyl}-β-D-glucopyranoside (Compound represented by formula C-9)

[0284] To a solution of 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-{2,4,6-tri-O-acetyl-3-O-[(naphthalen-2-yl)methyl]-β-D-glucopyranosyl}-β-D-glucopyranoside (compound represented by formula C-8) (30.00 g, 29.29 mmol) in tetrahydrofuran (150 mL), methanol (90 mL) and methyl trifluoroacetate (3.75 g, 29.29 mmol) were added, and the mixture was stirred at 25°C for 10 minutes, followed by the addition of potassium tert-butoxide (1 mol / L tetrahydrofuran solution) (14.7 mL, 14.65 mmol). The mixture was then heated to 55°C and stirred for 2 hours, after which completion of the reaction was confirmed by HPLC. The reaction mixture was cooled to 25°C, and acetic acid (1.76 g, 29.29 mmol) and ethyl acetate (300 mL) were added, in that order. This solution was washed twice with 1% aqueous sodium chloride solution (300 mL) and then concentrated under reduced pressure to 90 mL. Ethyl acetate (450 mL) was added, and the mixture was again concentrated to 90 mL. Acetonitrile (450 mL) was then added, and the mixture was concentrated to 90 mL to obtain 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-{3-O-[(naphthalen-2-yl)methyl]-β-D-glucopyranosyl}-β-D-glucopyranoside (compound represented by formula C-9) as an acetonitrile solution. This product was used directly in the next step.

[0285] Example 16 4-Methoxyphenyl 3,6-di-O-benzyl-4-O-{4,6-O-benzylidene-3-O-[(naphthalen-2-yl)methyl]-β-D-glucopyranosyl}-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (Compound represented by Formula C-10)

[0286] Acetonitrile (210 mL), benzaldehyde dimethyl acetal (5.13 g, 33.69 mmol), and p-toluenesulfonic acid monohydrate (0.17 g, 0.88 mmol) were added to a solution (90 mL) of 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-{3-O-[(naphthalen-2-yl)methyl]-β-D-glucopyranosyl}-β-D-glucopyranoside (compound represented by formula C-9), and the mixture was stirred for 30 minutes at 25° C. Toluene (600 mL) was added and the mixture was concentrated to a volume of 300 mL, at which point completion of the reaction was confirmed by HPLC. Further, 1-methylimidazole (12.03 g, 146.47 mmol) was added, and the solution was concentrated to 90 mL to give 4-methoxyphenyl 3,6-di-O-benzyl-4-O-{4,6-O-benzylidene-3-O-[(naphthalen-2-yl)methyl]-β-D-glucopyranosyl}-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula C-10) as a toluene solution containing 1-methylimidazole, which was used as is in the next step.

[0287] Example 17 4-Methoxyphenyl 3,6-di-O-benzyl-4-O-{4,6-O-benzylidene-3-O-[(naphthalen-2-yl)methyl]-2-O-(trifluoromethanesulfonyl)-β-D-glucopyranosyl}-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula C-11 (wherein X １ is a Tf group)

[0288] Ethyl acetate (210 mL) was added to a solution (90 mL, containing 1-methylimidazole) of 4-methoxyphenyl 3,6-di-O-benzyl-4-O-{4,6-O-benzylidene-3-O-[(naphthalen-2-yl)methyl]-β-D-glucopyranosyl}-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula C-10) obtained in Example 16, and the mixture was cooled to 0°C. Trifluoromethanesulfonic anhydride (16.53 g, 58.59 mmol) was added dropwise to this solution over 1 hour, followed by stirring for 30 minutes. After confirming the completion of the reaction by HPLC, water (300 mL) was added and the mixture was separated into an organic layer and an aqueous layer. The organic layer was washed twice with water (300 mL) and once with saturated aqueous sodium chloride solution (150 mL), and then concentrated under reduced pressure until the liquid volume was 90 mL. Ethyl acetate (300 mL) was added, and the liquid was concentrated again until the liquid volume was 90 mL to obtain 4-methoxyphenyl 3,6-di-O-benzyl-4-O-{4,6-O-benzylidene-3-O-[(naphthalen-2-yl)methyl]-2-O-(trifluoromethanesulfonyl)-β-D-glucopyranosyl}-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula C-11 (wherein, X １ is a Tf group) was obtained as an ethyl acetate solution, which was used as is in the next step.

[0289] Example 18 4-Methoxyphenyl 3,6-di-O-benzyl-4-O-{4,6-O-benzylidene-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl}-2-(2-carboxybenzamido)-2-deoxy-β-D-glucopyranoside (Compound represented by formula C-13)

[0290] 4-Methoxyphenyl 3,6-di-O-benzyl-4-O-{4,6-O-benzylidene-3-O-[(naphthalen-2-yl)methyl]-2-O-(trifluoromethanesulfonyl)-β-D-glucopyranosyl}-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula C-11 (wherein, X １Dimethyl sulfoxide (150 mL) and tetrabutylammonium acetate (17.67 g, 58.59 mmol) were added to a solution (90 mL) of the compound (Tf group), and the mixture was heated to 30°C. After stirring for 17 hours, the completion of the reaction was confirmed by HPLC. Toluene (150 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to a volume of 165 mL. Methanol (45 mL) and 50% aqueous sodium hydroxide solution (3.52 g, 87.88 mmol) were added, and the mixture was stirred at 25°C for 1.5 hours. After the completion of the reaction was confirmed by HPLC, ethyl acetate (450 mL) and water (300 mL) were added and the mixture was separated. Water (300 mL) was added to the organic layer, the mixture was cooled to 0°C, and the pH was adjusted to 2.73 with 6 N hydrochloric acid under vigorously stirring. Tetrahydrofuran (300 mL) was added to the separated organic layer, and the mixture was concentrated under reduced pressure to a volume of 150 mL. Tetrahydrofuran (300 mL) was added, and the mixture was concentrated again until the liquid volume reached 90 mL, and the internal temperature was adjusted to 45°C. After adding tetrahydrofuran (60 mL), the mixture was cooled to 25°C, and 2-propanol (150 mL) and water (15 mL) were added. 4-Methoxyphenyl 3,6-di-O-benzyl-4-O-{4,6-O-benzylidene-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl}-2-(2-carboxybenzamido)-2-deoxy-β-D-glucopyranoside (compound represented by formula C-13) (30 mg) was added. The mixture was stirred at 25°C for 14 hours, and after confirming the precipitation of crystals, 2-propanol (210 mL) was added dropwise over 1 hour, and the mixture was cooled to 0°C. After stirring for 2 hours, the precipitated crystals were filtered and washed with 2-propanol (150 mL) cooled to 0°C. The obtained crystals were dried under reduced pressure at 40°C to give 4-methoxyphenyl 3,6-di-O-benzyl-4-O-{4,6-O-benzylidene-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl}-2-(2-carboxybenzamido)-2-deoxy-β-D-glucopyranoside (compound represented by formula C-13) (27.74 g, yield 94.3%, based on the compound represented by formula C-8). *The process from the compound represented by formula C-12 to the compound represented by formula C-13 was carried out in one pot. *The seed crystals were prepared by dividing the reaction mixture into small portions, concentrating the mixture, and precipitating the solid.This reaction proceeds smoothly using tetrabutylammonium acetate manufactured by Tokyo Chemical Industry Co., Ltd. (product code: T2694, purity: >90.0%) and Sigma-Aldrich (product code: 86849, purity: >90%). Tetrabutylammonium acetate from other manufacturers may contain excess acetic acid, which tends to significantly slow the reaction. Alternatively, a similar conversion reaction can be performed using cesium acetate (details below). The conversion of compound C-11 to compound C-12 was also possible using cesium acetate (3 equivalents), dimethyl sulfoxide, at 50°C, for 24 hours. The compound C-13 was then obtained by the same reaction (compound C-12 to compound C-13) and post-treatment.

[0291] １ H-NMR (500MHz, CDCl ３ ) δ8.02 (dd, J=6.0, 2.0Hz, 1H), 7.69-7.83 (m, 4H), 7.38-7.49 (m, 12H), 7 .32-7.34 (m, 2H), 7.16-7.29 (m, 8H), 6.97 (ddd, J=9.0, 4.0, 2.5Hz, 2H), 6.76 (ddd, J=9.5, 3.5, 2.5Hz, 2H), 5.51 (s, 1H), 5.40 (d, J=6.0Hz, 1H), 4 .83-4.91 (m, 3H), 4.76 (d, J = 11.5Hz, 1H), 4.55 (d, J = 0.5Hz, 1H), 4.49 (d , J=12.0Hz, 1H), 4.36 (d, J=12.0Hz, 1H), 4.26-4.30 (m, 1H), 4.16 (t, J=6 .5Hz, 1H), 4.05-4.09 (m, 2H), 3.99 (dd, J=3.0, 0.5Hz, 1H), 3.93 (t, J=9. 5Hz, 1H), 3.80-3.86 (m, 2H), 3.71 (s, 3H), 3.65-3.69 (m, 1H), 3.56 (t, J= 10.0Hz, 1H), 3.51 (dd, J=10.0, 3.5Hz, 1H), 3.13 (td, J=9.5, 5.0Hz, 1H). 　１３ C-NMR (125MHz, CDCl ３ ​) δ170.9, 168.4, 155.3, 151.4, 138.7, 138.0, 137.6, 136.2, 135.4, 133.4, 133.3. , 132.2, 132.1, 130.7, 130.3, 129.2, 128.6, 128.49, 128.45, 128.11, 128.07, 128.0, 127.89, 127.87, 127.8, 126.8, 126.4, 126. 3,126.2, 125.8, 118.6, 114.7, 101.7, 100.4, 99.1, 78.3, 76.7, 76.4, 75.1, 73.7, 73.3, 72.5, 69.9, 69.4, 68.5, 67.0, 55.8, 54.4. HRMS (ESI ＋ ) [M+H] ＋ calcd for C ５９ H ５８ NO １４ :1004.3852;found 1004.3873.

[0292] Example 19 4-Methoxyphenyl 3,6-di-O-benzyl-4-O-{4,6-O-benzylidene-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl}-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (Compound represented by Formula C-14)

[0293] To a solution of 4-methoxyphenyl 3,6-di-O-benzyl-4-O-{4,6-O-benzylidene-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl}-2-(2-carboxybenzamido)-2-deoxy-β-D-glucopyranoside (compound represented by formula C-13) (6.00 g, 5.98 mmol) in dichloromethane (30 mL), 1-hydroxybenzotriazole monohydrate (0.18 g, 1.20 mmol), N,N-diisopropylethylamine (0.85 g, 6.57 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.26 g, 6.57 mmol) were added, and the mixture was heated to 40°C and stirred for 31 hours. After confirming the completion of the reaction by HPLC, the reaction solution was cooled to 0°C, ethyl acetate (90 mL) and water (60 mL) were added, and 6 N hydrochloric acid was added under vigorously stirring until the pH reached 7. The organic and aqueous layers were separated, and the organic layer was washed with water (60 mL) and saturated brine (30 mL). This solution was concentrated under reduced pressure to a volume of 12 mL. Tetrahydrofuran (60 mL) was added, and the solution was again concentrated to a volume of 9 mL to obtain a tetrahydrofuran solution of crude 4-methoxyphenyl 3,6-di-O-benzyl-4-O-{4,6-O-benzylidene-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl}-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula C-14). This product was used directly in the next step.

[0294] Example 20 4-Methoxyphenyl 3,6-di-O-benzyl-4-O-{2-O-benzyl-4,6-O-benzylidene-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl}-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (Compound represented by Formula C-15)

[0295] To a solution of crude 4-methoxyphenyl 3,6-di-O-benzyl-4-O-{4,6-O-benzylidene-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl}-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound of formula C-14) was added N,N-dimethylacetamide (60 mL), benzyl bromide (1.53 g, 8.96 mmol), methyl trifluoroacetate (0.15 g, 1. To the reaction mixture, 20 mmol) and molecular sieves 4A (1.8 g) were added and cooled to 0°C. A solution of lithium tert-butoxide in tetrahydrofuran (Note: This solution was prepared by cooling a mixed solution of 2-methyl-2-propanol (0.66 g, 8.96 mmol) and tetrahydrofuran (2.4 mL) to 0°C, adding a solution of n-butyllithium in hexane (1.55 mol / L) (5.78 mL, 8.96 mmol) and stirring for 30 minutes.) was added and stirred for 3 hours. After confirming the completion of the reaction by HPLC, ethylenediamine (anhydrous) (0.18 g, 2.99 mmol) was added and stirred for an additional 1 hour. To this solution, acetic acid (0.72 g, 11.95 mmol) was added and the mixture was filtered. The molecular sieves 4A were washed with ethyl acetate (90 mL), and then water (60 mL) was added and the mixture was separated. The organic layer was washed twice with water (60 mL) and then concentrated under reduced pressure until the liquid volume reached 12 mL. Toluene (30 mL) was added, and the mixture was concentrated again until the liquid volume reached 12 mL. Toluene (18 mL) and silica gel 60N (spherical, manufactured by Kanto Chemical, particle size: 40-50 μm) (9 g) were added, and the mixture was stirred at 25°C for 30 minutes. The suspension was filtered, and the silica gel was washed with a mixed solution of toluene (191 mL) and ethyl acetate (19 mL). The filtrate was concentrated under reduced pressure until the liquid volume reached 9 mL, thereby obtaining a toluene solution of crude 4-methoxyphenyl 3,6-di-O-benzyl-4-O-{2-O-benzyl-4,6-O-benzylidene-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl}-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula C-15).

[0296] Example 21 4-Methoxyphenyl 3,6-di-O-benzyl-2-deoxy-4-O-{2,4-di-O-benzyl-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl}-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (Compound represented by Formula A-4)

[0297] The crude 4-methoxyphenyl Dichloromethane (16.5 mL) and molecular sieves 4A (550 mg) were added to a solution of 3,6-di-O-benzyl-4-O-{2-O-benzyl-4,6-O-benzylidene-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl}-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound of formula C-15) (5.50 g (5.48 mmol) based on the compound of formula C-14) and the mixture was cooled to 0°C. Borane-tetrahydrofuran complex (0.91 mol / L tetrahydrofuran solution) (18.06 mL, 16.43 mmol) and copper(II) trifluoroacetate (0.59 g, 1.64 mmol) were added and the mixture was stirred for 3 hours. After confirming the completion of the reaction by HPLC, methanol (5.5 mL) was added and the mixture was stirred for an additional 30 minutes. The solution was filtered, and the molecular sieves 4A were washed with ethyl acetate (110 mL). 0.5 N hydrochloric acid (55 mL) was added and the mixture was stirred for 30 minutes. The organic and aqueous layers were separated, and the organic layer was washed with 0.5 N hydrochloric acid (55 mL) and saturated brine (27.5 mL). The solution was concentrated to dryness under reduced pressure. This product was purified by silica gel column chromatography (silica gel 300 g, hexane:ethyl acetate=55:45→30:70) to give 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-4-O-{2,4-di-O-benzyl-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl}-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula A-4) (4.94 g, yield 83.6%, HPLC area: 98.54%).

[0298] １ H-NMR(500MHz,CDCl ３ )δ7.67-7.84(m,8H),7.44-7.49(m,4H),7.40(dd,J=8.0,1.5Hz,1H),7.21-7.33(m,13H),6.87-6.93(m,5H),6.82(ddd,J=9.5,4.0,2.5Hz,2H),6.70(ddd,J=9.0,4.0,2.0Hz,2H),5.64(d,J=8.5Hz,1H),4.94(d,J=12.5Hz,1H),4.91(d,J=10.0Hz,1H),4.90(s,2H),4.66(s,2H),4.60(d,J=11.0Hz,1H),4.59(d,J=12.0Hz,1H),4.55(s,1H),4.40-4.46(m,3H),4.33(dd,J=11.0,9.0Hz,1H),4.06(dd,J=9.5,8.5Hz,1H),3.80-3.85(m,2H),3.70-3.76(m,2H),3.71(s,3H),3.61-3.68(m,2H),3.45-3.48(m,1H),3.44(dd,J=9.5,3.0Hz,1H),3.23(ddd,J=9.5,5.5,2.5Hz,1H),1.97(br-t,1H). １３ C-NMR(125MHz,CDCl ３ )δ155.6,151.1,138.9,138.64,138.56,138.0,135.9,134.0,133.5,133.2,131.8,128.7,128.6,128.4,128.3,128.20,128.19,128.15,128.1,120.04,128.01,127.9,127.7,127.6,127.3,126.4,126.3,126.1,125.8,123.6,119.0,114.6,101.2,98.0,82.6,79.0,77.2,75.9,75.4,75.3,75.2,75.1,74.8,74.7,73.8,72.1,68.7,62.6,55.82,55.78,34.4,30.5. HRMS(ESI － )[M+HCO ２ ] － calcd for C ６７ H ６４ NO １５:1122.4281;found 1122.4285.

[0299] Example 22

[0300] A toluene solution (equivalent to 78.4 mmol) of 4-methoxyphenyl-3,6-di-O-benzyl-2-deoxy-4-O-{2,4-di-O-benzyl-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl}-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula A-4) (65.0 g, 60.3 mmol) and 2-O-acetyl-3,4,6-tri-O-benzyl-1-O-(2,2,2-trichloroethanimidoyl)-D-mannopyranose (compound represented by formula A-3) was added to a 1 L 4-neck flask and dissolved in 650 mL of toluene. Molecular sieve 4A powder (10 μm or less, 13.0 g) was added. Under nitrogen, trimethylsilyl trifluoromethanesulfonate (2.7 mL, 15.1 mmol) was added dropwise over 15 minutes at -15°C, and the mixture was stirred at the same temperature for 30 minutes. After confirming the completion of the reaction by HPLC, triethylamine (4.2 mL, 30.2 mmol) was added and the temperature was raised to room temperature. The reaction solution was filtered through Celite and washed with acetonitrile (195 mL). The filtrate was concentrated under reduced pressure, and acetonitrile (650 mL) was added to the concentrated residue, followed by the addition of reverse-phase silica gel 120RP-18 (Kanto Chemical, particle size: 40-50 μm, 97.5 g). Water (130 mL) was added dropwise over 30 minutes to adsorb the target substance onto the solid phase, followed by filtration. The solid phase was washed with acetonitrile / water (3 / 1, 326 mL) (the filtrate was discarded), and the target substance was desorbed with an acetonitrile (585 mL)-ethyl acetate (65 mL) solution. The filtrate was concentrated under reduced pressure to give 4-methoxyphenyl 2-O-acetyl-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula A-5) (70.5 g, isolated yield 94%) as a white amorphous substance.

[0301] １ H-NMR (CDCl ３ ​)σ 7.85-7.80(m,1H),7.78(d,J =8.6Hz,1H),7.74-7.58(m,5H),7.50-7.43(m,5H),7.39(dd,J=8.6,1.7Hz,1H),7.32-7.02(m,30H),6.92-6.89(m,2H),6.78-6.76(m,2H),6.71-6.62(m,5H),5.59(d,J=8.6Hz,1H),5.36(dd,J=2.9,2.3Hz,1H),5.00-4.90(m,4H),4.87(d,J=12.6Hz,1H),4.79(d,J=11.5Hz,1H),4.66-4.50(m,7H),4.43(dd,J=11.5,2.3Hz,1H),4.40-4.34(m,3H),4.28(dd,J=10.3,8.6Hz,1H),4.22(d,J=11.5Hz,1H),4.08(dd,J=9.7,9.2Hz,1H),3.94(dd,J=9.2,9.2Hz,1H),3.89-3.83(m,3H),3.83-3.58(m,10H),3.55-3.50(m,1H),3.42(dd,J=9.2,2.9Hz,1H),3.37-3.31(m,1H),1.90(s,3H). 　１３ C-NMR(CDCl ３ )σ 167.0,155.3,150.8,138.8,138.7,138.51,138.49,138.4,138.0,137.9,135.6,133.6,133.2,132.9,131.6,128.44,128.41,128.32,128.26,128.22,128.19,128.12,127.86,127.81,127.75,127.71,127.69,127.63,127.56,127.44,127.37,127.27,127.0,126.3,126.2,125.9,125.7,123.2,118.7,114.3,101.9,98.3,97.6,82.7,79.6,77.8,76.6,75.04,74.98,74.91,74.89,74.75,74.4,74.3,74.1,74.0,73.4,73.3,71.70,71.65,71.3,68.8,68.6,68.3,67.1,55.6,55.5,20.9. HRMS(ESI ＋ )[M+HNEt ３ ]＋　 calcd for C １０１ H １０９ N ２ O １９ ＋ : 1654.7653; found 1654.7618. [α] Ｄ ２０ =+31.589 (c 1.002, CDCl ３ ).

[0302] Example 23

[0303] 4-Methoxyphenyl 2-O-acetyl-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound of formula A-5) (44.0 g, 28.3 mmol) was added to a 1 L 4-neck flask, followed by the addition of dichloromethane (228 mL), 1,1,1,3,3,3-hexafluoro-2-propanol (163 mL), and water (14 mL). Under nitrogen, a solution of [bis(trifluoroacetoxy)iodo]benzene (25.9 g, 56.6 mmol) in dichloromethane (80 mL) and trifluoroacetic acid (6.9 mL, 84.9 mmol) were added at 2°C, and the mixture was stirred at the same temperature for 8 hours. After confirming the completion of the reaction by HPLC, a solution of sodium bicarbonate (18.7 g) in water (228 mL) was added, followed by stirring for 5 minutes, and a solution of sodium sulfite (11.7 g) in water (228 mL) was added. After stirring for 5 minutes, the mixture was allowed to stand, and the dichloromethane layer was separated. The resulting organic layer was concentrated under reduced pressure to 97.5 mL, and then ethyl acetate (325 mL) and a solution of sodium chloride (23.4 g) in water (211 mL) were added. After stirring for 5 minutes, the mixture was allowed to stand, and the organic layer was separated. The resulting organic layer was concentrated under reduced pressure to 97.5 mL, and then toluene (890 mL) was added, and the mixture was again concentrated under reduced pressure to 97.5 mL. Toluene (164 mL) and dichloromethane (65 mL) were added, and silica gel 60N (Kanto Chemical, particle size: 40-50 μm, 130 g) was added to adsorb the target substance onto the silica gel, followed by filtration. The product was washed with a dichloromethane (130 mL)-toluene (520 mL) solution (the filtrate was discarded), and the target substance was desorbed from the solid phase with an ethyl acetate (220 mL)-dichloromethane (455 mL) solution.The filtrate was concentrated under reduced pressure, and then toluene (228 mL) was added and the mixture was concentrated under reduced pressure to 97.5 mL to give a toluene solution of 2-O-acetyl-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-D-glucopyranose (compound represented by formula A-6). This solution was used directly in the next step.

[0304] １ H-NMR (CDCl ３ ) σ 7.85-7.80 (m, 1H), 7.78 (d, J =8.6Hz, 1H), 7.72 (s, 1H), 7.70-7.64 (m, 1H), 7.63 (brs, 2H), 7.48-7.43 (m, 4H), 7.3 9 (dd, J=8.6, 1.7Hz, 1H), 7.33-7.10 (m, 30H), 6.92-6.87 (m, 2H), 6.77-6.66 (m, 3H), 5 .. 38 (dd, J=3.4, 1.7Hz, 1H), 5.23 (dd, J=8.6, 8.6Hz, 1H), 4.97-4.86 (m, 4H), 4.84 (d, J = 12.6Hz, 1H), 4.79 (d, J = 10.9Hz, 1H), 4.63 (d, J = 11.5Hz, 1H), 4.60-4.48 (m, 7H), 4.4 6 (d, J=11.5Hz, 1H), 4.37 (dd, J=12.0, 3.4Hz, 1H), 4.32 (dd, J=10.9, 8.6Hz, 1H), 4.23 (d, J=10.9Hz, 1H), 4.06 (dd, J=9.2, 9.2Hz, 1H), 4.01 (dd, J=10.9, 9.2Hz, 1H), 3.92 (d d, J = 9.2, 3.4Hz, 1H), 3.89-3.74 (m, 6H), 3.72-3.65 (m, 2H), 3.64-3.57 (m, 2H), 3.48 ( dd, J=10.9, 1.1Hz, 1H), 3.42-3.34 (m, 2H), 2.68 (dd, J=9.2, 1.1Hz, 1H), 1.95 (s, 3H). １３ C-NMR (CDCl ３ ​) σ 170.2, 167.9, 138.85, 138.79, 138.6, 138.5, 138.4, 138.0, 137.8, 135.6, 133.6, 133.2, 132.9, 131.6, 128.55, 128.50, 128.33, 128.24, 128.20, 128.16, 127.9, 127.80, 127.75, 127.69, 127.66, 127.62, 127.54, 127.45, 127.36, 127.33, 126.97, 126.22, 126.17, 125.9, 125.6, 123.2, 101.1, 97.9, 92.9, 82.6, 78.6, 78.0, 76.1, 74.9, 74.8, 74.4, 74.15, 74.13, 74.0, 73.5, 73.2, 71.7, 71.6, 71.3, 68.8, 68.7, 68.4, 67.0, 57.6, 20.9. HRMS (ESI ＋ ) [M + HNEt ３ ＋　 calcd for C ９４ H １０３ N ２ O １８ ＋ : 1548.7234; found 1548.7237. [α Ｄ ２０ = +32.528 (c 1.006, CDCl ３ ).

[0305] Example 24

[0306] A toluene solution of 2-O-acetyl-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-D-glucopyranose obtained in Example 23 (compound represented by formula A-6) was added to a 1 L four-neck flask, and dichloromethane (260 mL) and molecular sieve 4A powder (10 μm or less, 21.8 g) were added, followed by cooling to 0°C. Under nitrogen, 1,8-diazabicyclo[5.4.0]undec-7-ene (5.08 mL, 34.0 mmol) and 2,2,2-trifluoro-N-phenylacetimidoyl chloride (5.25 mL, 31.1 mmol) were added at the same temperature, and the mixture was stirred for 5 hours. The reaction solution was filtered through a neutral silica gel pad (silica gel 60N, Kanto Chemical, particle size: 40-50 μm, 130 g) filled with dichloromethane. The silica gel pad was washed with 10% ethyl acetate / dichloromethane (1760 mL, 220 mL fractions), and the main fraction was concentrated under reduced pressure. Toluene (228 mL) was added and the mixture was concentrated under reduced pressure to 97.5 mL to give a toluene solution of 2-O-acetyl-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-O-(2,2,2-trifluoro-N-phenylethanimidoyl)-D-glucopyranose (compound of formula A-7). This solution was used directly in the next step.

[0307] １ H-NMR (CDCl ３ ​)σ 7.85-7.80(m,1H),7.78(d,J =8.6Hz,1H),7.72(s,1H),7.70-7.64(m,3H),7.50-7.43(m,4H),7.39(dd,J=8.6,1.7Hz,1H),7.33-7.08(m,30H),7.06-7.01(m,1H),6.88(d,J=6.9Hz,2H),6.70-6.60(m,4H),5.35(dd,J=2.9,1.7Hz,1H),4.97-4.88(m,4H),4.84(d,J=13.2Hz,1H),4.79(d,J=10.9Hz,1H),4.65-4.49(m,7H),4.43(dd,J=11.5,4.0Hz,1H),4.36(dd,J=12.0,7.4Hz,1H),4.22(d,J=11.5Hz,1H),4.11-4.04(m,1H),3.93(dd,J=9.7,9.7Hz,1H),3.89-3.83(m,2H),3.82-3.69(m,4H),3.64(dd,J=10.9,4.0Hz,1H),3.52(dd,J=10.9,1.1Hz,1H),3.39(dd,J=9.7,2.9Hz,1H),3.33-3.28(m,1H),1.89(s,3H). 　１３ C-NMR(CDCl ３ )σ 170.0,167.4,143.0,138.8,138.7,138.5,138.4,138.0,137.6,135.6,133.7,133.2,133.0,131.5,128.56,128.53,128.4,128.32.128.30,128.26,128.22,128.19,128.14,128.12,127.90,127.86,127.81,127.74,127.72,127.69,127.54,127.46,127.38,127.28,127.0,126.3,126.2,126.0,125.6,124.3,123.3,119.3,101.8,98.2,82.6,79.0,77.8,76.2,75.5,75.0,74.91,74.89,74.7,74.5,74.3,74.1,74.0,73.4,73.3,71.7,71.7,71.3,68.8,68.3,68.0,67.0,54.7,20.8. HRMS(ESI ＋ )[M+HNH ３ ]＋　 calcd for C ９６ H ９１ F ３ N ３ O １８ ＋ : 1635.6591; found 1635.6549. [α] Ｄ ２０ =+62.169 (c 1.002, CDCl ３ ).

[0308] Example 25

[0309] A toluene solution of 2-O-acetyl-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-O-(2,2,2-trifluoro-N-phenylethanimidoyl)-D-glucopyranose obtained in Example 24 (compound represented by formula A-7), toluene (488 mL) and 4-methoxyphenyl 3,6-Di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula A-8) (21.55 g, 36.2 mmol) was placed in a 1 L 4-neck flask, and molecular sieves 4A powder (14.6 g) was added. Trimethylsilyl trifluoromethanesulfonate (545 μL, 2.83 mmol) was added dropwise over 5 minutes at −15°C under nitrogen, and the mixture was stirred at the same temperature for 1 hour. After confirming the completion of the reaction by HPLC, triethylamine (1.67 mL, 11.32 mmol) was added, and the mixture was warmed to room temperature. The reaction solution was filtered and washed with acetonitrile (160 mL). The filtrate was concentrated under reduced pressure to 97.5 mL, acetonitrile (650 mL) was added, and the mixture was again concentrated under reduced pressure to 97.5 mL. Acetonitrile (488 mL) and reverse-phase silica gel 120RP-18 (Kanto Chemical, particle size 40-50 μm, 130 g) were added. Water (146 mL) was added dropwise over 30 minutes to adsorb the target substance onto the solid phase, followed by filtration. The mixture was washed with acetonitrile (536 mL) and water (146 mL) (the filtrate was discarded), and the target substance was desorbed with acetonitrile (975 mL) and ethyl acetate (244 mL).The filtrate was concentrated under reduced pressure and subjected to azeotropic distillation twice with toluene (325 mL) to a final volume of 97.5 mL to obtain 4-methoxyphenyl The compound of formula A-9 was obtained as a toluene solution of 2-O-acetyl-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound of formula A-9). A portion of this solution (90 mL, based on the compound of formula A-4: 26.1 mmol) was used in the next step.

[0310] １ H-NMR (CDCl ３ )σ 7.86-7.81 (m, 1H), 7.81-7.75 (m, 2H), 7.74-7.60 (m, 7H), 7.56-7.44 (m, 5H), 7.40 (dd, J=8.6, 1.1Hz, 1H), 7.28-7.05 (m, 35H), 6.95-6.91 (m, 2H), 6.91-6.88 (m, 2H) , 6.78-6.62 (m, 8H), 6.61-6.55 (m, 2H), 5.42 (d, J=8.6Hz, 1H), 5.33 (dd, J=2.9, 1. 7Hz, 1H), 5.23 (d, J = 8.0Hz, 1H), 4.98 (d, J = 12.6Hz, 1H), 4.94-4.85 (m, 4H), 4.82 (d , J=13.2Hz, 1H), 4.76 (d, J=10.9Hz, 1H), 4.65-4.29 (m, 16H), 4.25-4.12 (m, 5H), 4 .04 (dd, J=10.3, 8.0Hz, 1H), 3.95 (dd, J=9.2, 9.2Hz, 1H), 3.89-3.80 (m, 3H), 3.77 (d, J=9.2Hz, 1H), 3.73 (d, J=10.9Hz, 1H), 3.70-3.65 (m, 1H), 3.64 (s, 3H), 3.63-3 .57 (m, 2H), 3.53-3.46 (m, 2H), 3.44-3.35 (m, 4H), 3.30-3.23 (m, 2H), 1.83 (s, 3H).​　１３ C-NMR (CDCl ３ ), σ 169.8, 168.1, 167.4, 155.2, 150.8, 138.9, 138.71, 138.68, 138.55, 138.48, 138.36, 137.9, 135.6, 133.8, 133.6, 133.2, 133.0, 131.8, 131.6, 131.5, 128.5, 128.34, 128.32, 128.29, 128.26, 1..28.20, 128.17, 128.12, 128.10, 127.89, 127.85, 127.80, 127.77, 127.69, 127.65, 127.52, 127.47, 127.44, 127.36, 127.29, 127.28, 126.90, 126.87, 126.3, 126.2, 126.0, 125.7, 123.5, 123.2, 123.1, 118.5, 114.2, 102.1, 98.2, 97.4, 97.1, 82.7, 80.0, 77.8, 76.6, 75.9, 74.9, 74.8, 74.63, 74.61, 74.56, 74.49, 74.3, 74.06, 74.03, 73.3, 73.2, 72.6, 71.7, 71.6, 71.2, 68.7, 68.3, 68.11, 68.06, 68.8, 56.5, 55.6, 55.5, 20.8. HRMS (ESI ＋ ), [M + HNet ３ , ＋　 calcd for C １２９ H １３４ N ３ O ２５ ＋ : 2125.9334; found 2125.9267. [α] Ｄ ２０ = +30.098 (c 1.008, CDCl ３ ).

[0311] Example 26

[0312] The 4-methoxyphenyl 2-O-acetyl-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→4)-3,6-di-O-benzyl obtained in Example 25 A toluene solution of 1,3-dioxo-2-(1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by Formula A-9) (90 mL, 26.1 mmol based on the compound represented by Formula A-4) was added to a 1 L 4-neck flask, and tetrahydrofuran (165 mL), methanol (75 mL), and methyl trifluoroacetate (2.76 mL, 27.8 mmol) were added. After stirring at room temperature under nitrogen for 5 minutes, a 1 M solution of potassium t-butoxide in tetrahydrofuran (13.9 mL, 13.9 mmol) was added and the mixture was stirred at 40°C for 1 hour. After confirming the completion of the reaction by HPLC, the mixture was cooled to room temperature. Acetic acid (1.11 mL, 19.4 mmol) was added, followed by ethyl acetate (330 mL) and water (270 mL). Triethylamine was added until the pH reached 7, and then sodium chloride (2.7 g) was added and the mixture was stirred for 5 minutes. After standing, the mixture was separated and the resulting organic layer was washed twice with water (270 mL). The organic layer was concentrated under reduced pressure to 90 mL, toluene (300 mL) was added, and the mixture was concentrated under reduced pressure to 90 mL. Toluene (300 mL) was added, and the mixture was concentrated under reduced pressure again to 90 mL to obtain 4-methoxyphenyl 4-methyl-2-propanol. The compound of formula A-10 was obtained as a toluene solution of 3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside. The solution was used directly in the next step.

[0313] １ H-NMR(CDCl ３ )σ 7.85-7.81(m,1H),7.79(d,J=8.6Hz,1H),7.78-7.72(m,2H),7.72-7.60(m,6H),7.59-7.54(m,1H),7.50-7.44(m,4H),7.41(dd,J=8.6,1.1Hz,1H),7.31-7.13(m,32H),7.10-7.05(m,2H),6.97-6.93(m,2H),6.90-6.86(m,2H),6.78-6.67(m,8H),6.61-6.56(m,2H),5.43(d,J=8.6Hz,1H),5.25(d,J=8.0Hz,1H),4.99-4.86(m,4H),4.83(d,J=12.6Hz,1H),4.71(d,J=10.9Hz,1H),4.64(d,J=12.0Hz,1H),4.61(d,J=12.0Hz,1H),4.56(d,J=6.9Hz,1H),4.53-4.39(m,7H),4.39-4.31(m,5H),4.30(d,J=11.5Hz,1H),4.25-4.14(m,4H),4.05(dd,J=9.7,8.6Hz,1H),3.94-3.88(m,2H),3.86-3.80(m,2H),3.76-3.68(m,3H),3.68-3.59(m,5H),3.57-3.35(m,7H),3.31-3.25(m,2H),2.15(d,J=4.0Hz,1H). １３ C-NMR(CDCl ３)σ 168.2, 167.5, 155.2, 150.8, 138.91, 138.88, 138.6, 138.52, 138.47, 138.38, 128.32, 128.0, 137.9, 135.7, 133.9, 133.6, 133.3, 133.0, 131.8, 131.6, 131.4, 128.5, 128.29, 128.23, 128.19, 128.13, 128.0, 127.92, 127.87, 127.82, 127.79, 127.76, 127.70, 127.56, 127.53, 127.46, 127.36, 127.31, 127.28, 126.9, 126.3, 126.2, 126.0, 125.7, 123.5, 123.2, 123.1, 118.6, 114.2, 101.9, 99.7, 97.4, 97.1, 82.7, 79.7, 79.6, 76.7, 75.9, 75.3, 74.9, 74.8, 74.73, 74.68, 74.63, 74.5, 74.4, 74.2, 74.1, 73.2, 73.2, 72.6, 71.8, 71.3, 71.2, 68.9, 68.13, 68.07, 67.8, 66.6, 56.5, 55.6, 55.5. HRMS (ESI ＋ )[M + HNEt ３ ＋　 ＋　 calcd for C １２７ １２７ H １３２ １３２ N ３ ３ O ２４ ２４ [[ID=I4]] ＋ : 2083.9229; found 2083.9150. [α] Ｄ Ｄ ２０ = +27.776 (c 1.007, CDCl ３ ３ ３

[0314] [[ID=I23]] Example 27

[0315] 4-Methoxyphenyl 3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside obtained in Example 26 (compound represented by formula A-10) To the toluene solution of the above, dichloromethane (450 mL) and a toluene solution of 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-1-O-(2,2,2-trifluoro-N-phenylethanimidoyl)-β-D-glucopyranose (compound of formula A-11) (118.2 g, 36.2 mmol) were added to a 1 L 4-neck flask, and molecular sieves 4A powder (10 μm or less, 15.0 g) was added. t-Butyldimethylsilyl trifluoromethanesulfonate (2.4 mL, 10.4 mmol) was added dropwise over 5 minutes at −78°C under nitrogen, and the mixture was stirred at the same temperature for 10 hours. Triethylamine (4.6 mL, 33.2 mmol) was added, and the mixture was warmed to room temperature. The reaction solution was filtered through Celite and washed with acetonitrile (150 mL). The filtrate was concentrated under reduced pressure to 150 mL, and acetonitrile (600 mL) was added, followed by further concentration under reduced pressure to 150 mL. Acetonitrile (600 mL) and reverse-phase silica gel 120RP-18 (Kanto Chemical, particle size: 40-50 μm, 135 g) were added. Water (120 mL) was added dropwise over 30 minutes to adsorb the target substance onto the solid phase, followed by filtration. The solid phase was washed with acetonitrile (900 mL) and water (135 mL) (the washings were discarded), and the target substance was desorbed from the solid phase using an acetonitrile (840 mL)-ethyl acetate (210 mL) solution.The desorbed liquid was concentrated under reduced pressure, and then toluene (300 mL) was added and concentrated under reduced pressure to 90 mL to obtain 4-methoxyphenyl 2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→2)-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-3-O-[(naphthalen-2-yl)methyl]-β-D- Mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound of formula A-12) was obtained as a toluene solution. The solution was used directly in the next step.

[0316] １ H-NMR (CDCl ３ )σ 7.84-7.73 (m, 4H), 7.70-7.57 (7H), 7.55-7.03 (m, 68H), 6.99-6.89 (m, 11H), 6.88-6.83 (m, 1H), 6.82-6.67 (m, 7 H), 6.67-6.62 (m, 2H), 6.62-6.56 (m, 3H), 5.42 (d, J = 8.6Hz, 1H), 5.23 (d, J = 8.6Hz, 1H), 5.02 (d, J = 8.6Hz, 1H), 4 .. 95-4.89 (m, 3H), 4.86-4.79 (m, 5H), 4.77-4.66 (m, 4H), 4.64-4.08 (m, 30H), 4.06-3.98 (m, 3H), 3.91-3.68 (m, 9H) ), 3.65 (s, 3H), 3.58 (d, J = Hz, 1H), 3.54-3.32 (m, 13H), 3.32-3.27 (m, 1H), 3.22-3.16 (m, 3H), 2.84 (dd, J = 10.9, 5.7Hz, 1H). １３ C-NMR (CDCl ３ ​)σ 168.4, 168.2, 167.4, 155.2, 150.8, 139.1, 139.02, 139.99, 138.93, 138.8, 138.7, 138.52, 138.48, 138.38, 138.32, 138.06, 138.01, 135.6, 133.7, 133.61, 133.56, 133.3, 133.2, 132.9, 131.8, 131.6, 131.4, 128.54, 128.50, 128.39, 128.34, 128.17, 128.13, 128.10, 128.00, 127.96, 127.89, 127.82, 127.78, 127.67, 127.64, 127.62, 127.59, 127.51, 127.48, 127.46, 127.41, 127.39, 127.29, 127.20, 127.05, 127.01, 126.9, 126.7, 126.3, 126.2, 125.9, 125.7, 123.5, 123.2, 123.1, 123.0, 118.6, 114.2, 102.9, 102.7, 97.8, 97.4, 97.0, 96.9, 83.1, 82.5, 80.4, 79.9, 77.7, 77.4, 76.9, 76.6, 75.7, 75.3, 75.1, 75.0, 74.8, 74.7, 74.6, 74.52, 74.46, 74.0, 73.95, 73.85, 73.7, 73.4, 73.2, 73.0, 72.9, 72.58, 72.55, 72.52, 72.48, 72.0, 71.9, 69.8, 69.7, 68.2, 3, 68.20, 68.06, 68.03, 67.0, 56.6, 55.6, 55.5 HRMS (ESI ＋ ) [M + HNEt ３ ＋　 calcd for C １９１ H １７５ N ４ O ３５ ＋ : 3078.3350; found 3078.3200. [α] Ｄ ２０ = +9.276 (c 1.002, CDCl ３ ).

[0317] Example 28-1

[0318] The 4-methoxyphenyl 2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→2)-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-3-O-[(naphthalen-2-yl)methyl]-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(2-methyl-4-phenylpropan-2-yl)-2H-isoindol-2-yl)-2H-glucopyranosyl obtained in Example 27 A toluene solution (equivalent to 64.2 mmol) of -(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by Formula A-12) was added to a 3 L, 4-neck flask, followed by the addition of 1,1,1,3,3,3-hexafluoro-2-propanol (1337 mL) and water (133.7 mL). The reaction solution was cooled to approximately -30°C, and then 2,3-dichloro-5,6-dicyano-p-benzoquinone (17.48 g, 77.0 mmol) was added and the mixture was stirred for 38 hours. After confirming that the reaction had progressed sufficiently, a solution of sodium sulfite (4.04 g, 32.1 mmol) in water (95.6 mL) was added to terminate the reaction, and the mixture was allowed to warm to room temperature over one hour. Dichloromethane (1910 mL) and a solution of sodium bicarbonate (38.2 g) - sodium sulfite (38.2 g) - water (1910 mL) were added, and the mixture was stirred for five minutes. After allowing to stand, the mixture was separated, and the organic layer was concentrated under reduced pressure to 573 mL. Toluene (955 mL) was added to the residue, and the mixture was concentrated under reduced pressure to 573 mL. Ethyl acetate (955 mL) and a solution of sodium chloride (95.5 g) in water (860 mL) were added, and the mixture was stirred for five minutes. After allowing to stand, the mixture was separated, and the organic layer was concentrated under reduced pressure to 382 mL, after which acetonitrile (1910 mL) was added and the mixture was again concentrated under reduced pressure to 382 mL. Acetonitrile (1528 mL) and reverse-phase silica gel 120RP-18 (Kanto Chemical, particle size 40-50 μm, 573 g) were added to the residue. Water (1242 mL) was added dropwise over 30 minutes to adsorb the target substance onto the solid phase, followed by filtration.The solid phase was washed with acetonitrile (1337 mL)-water (573 mL) (the washings were discarded) and then with methanol (955 mL). The target substance was then desorbed from the solid phase with a solution of acetonitrile (6876 mL)-tetrahydrofuran (764 mL). The desorbed solution was concentrated under reduced pressure and dried to obtain a crude product: 4-methoxyphenyl 2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→2)-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-β-D-mannopyranosyl. 167 g of -(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula A-13) was obtained. The obtained crude product was purified by preparative HPLC to obtain 4-methoxyphenyl methyl acrylate as a purified product. 2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→2)-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-β-D-mannopyranosyl-(1→4)-3,6-di-O- 96 g of benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula A-13) was obtained (overall yield from compound represented by formula C-13: 36.1%).

[0319] １ H-NMR (CDCl ３ ​)σ 7.75(d,J=8.0Hz,1H),7.69-7.40(10H),7.55-7.10(m,54H),7.06-6.97(5H),6.97-6.89(m,8H),6.88-6.84(m,1H),6.82-6.73(m,5H),6。72-6.67(m,2H),6.62-6.56(m,5H),5.42(d,J=8.6Hz,1H),5.22(d,J=8.0Hz,1H),5.03(d,J=12.0Hz,1H),4.99(d,J=8.6Hz,1H),4.92(d,J=10.9Hz,1H),4.87-4.79(m,5H),4.75(d,J=11.5Hz,1H),4.70(d,J=12.0Hz,1H),4.67(d,J=12.0Hz,1H),4.63(d,J=6.3Hz,1H),4.61(d,J=6.9Hz,1H),4.60-3.97(m,30H),3.88(d,J=2.9Hz,1H),3.84(d,J=12.0Hz,1H),3.82-3.67(m,5H),3.66-3.60(m,5H),3.54-3.33(m,14H),3.27-3.23(m,1H),3.20(d,J=10.9Hz,1H),3.15-3.09(m,2H),2.83-2.78(m,1H),2.27-2.21(m,1H). １３ C-NMR(CDCl ３)σ 168.4,168.2,167.4,167.3,155.2,150.8,139.1,139.0,138.9,138.8,138.7,138.51,138.49,138.44,138.38,138.37,138.35,138.26,138.0,137.7,133.8,133.6,122.49,133.41,133.36,131.8,131.4,128.6,128.52,128.49,128.39,128.34,128.30,128.2,128.14,128.10,128.06,128.0,127.85,127.82,127.7,127.69,127.65,127.56,127.53,127.48,127.38,127.33,127.26,127.1,127.0,126.9,126.7,123.5,123.2,123.09,123.05,122.98,118.5,114.2,102.9,102.6,97.8,97.4,97.0,96.9,82.5,80.5,79.9,78.5,77.8,77.4,76.9,76.7,75.87,75.80,75.2,75.0,74.79,74.77,74.62,74.59,74.48,74.41,74.2,74.0,73.9,73.6,73.4,73.0,72.9,72.7,72.62,72.56,72.0,69.8,68.24,68.20,68.1,67.8,67.2,56.6,55.6,55.5,53.4. HRMS(ESI ＋ )[M+HNEt ３ ] ＋　 calcd for C １７２ H １８３ N ４ O ３５ ＋ :2938.2725;found 2938.2516. [α] Ｄ ２０ =+14.385(c 1.005,CDCl ３ ).

[0320] Example 28-2 The compound represented by formula A-13 was purified by the method according to the following scheme. As shown below, this purification method enabled the production of a highly pure compound represented by formula A-13 without HPLC preparative purification.

[0321] Methoxyphenyl 2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(2-carboxybenzamido)-β-D-glucopyranosyl-(1→2)-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(2-carboxybenzamido)-β-D-glucopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(2-carboxybenzamido)-β-D-glucopyranoside Synthesis of tri(R)-(+)-1-(1-naphthyl)ethylamine salt (compound represented by formula A-14)

[0322] 4-Methoxyphenyl 2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→2)-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1 ,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula A-13) (25.00 g, 8.82 mmol, purity 72.2% PA) was dissolved in dichloromethane (250 mL), and the solution was then passed through silica gel (62.5 g, Chromatorex SMB100-20 / 45, manufactured by Fuji Silysia Chemical Industries) and eluted with a diisopropyl ether / dichloromethane mixed solvent (7 / 93, 1000 mL) (125 mL fractions were collected during the pass-through and elution procedures). Purity was measured by HPLC to select fractions. The selected fractions were mixed and concentrated to 38 mL. Tetrahydrofuran (125 mL) was added to the concentrated solution, and the mixture was concentrated to 38 mL. Tetrahydrofuran (100 mL), methanol (38 mL), and aqueous sodium hydroxide (4 M, 16.5 mL, 7.5 equivalents) were then added dropwise, and the mixture was heated to 45 °C and stirred for 1 hour. After confirming the completion of the reaction, the mixture was cooled to 0 °C and neutralized by adding hydrochloric acid (6 M, 11 mL, 7.5 equivalents) dropwise at 10 °C or below. Ethyl acetate (250 mL) and 3% saline (250 mL) were added, and the pH of the aqueous layer was adjusted to 2.0 or less with hydrochloric acid (6 M) under stirring. The aqueous layer was removed by separation, and the resulting organic layer was washed with 3% saline (250 mL). The organic layer was concentrated to 38 mL, and ethyl acetate (250 mL) was added, followed by further concentration to 38 mL. To the concentrate were added ethyl acetate (138 mL), (R)-(+)-1-(1-naphthyl)ethylamine (5.28 g, 3.5 equivalents) and seed crystals (0.03 g), and the mixture was stirred at 25°C for 12 hours or more and then cooled to 0°C.Heptane (88 mL) was added dropwise over 1 hour, and after stirring for 2 hours, the precipitated crystals were filtered to obtain wet crystals (purity 92.9 PA%). Ethyl acetate (125 mL) was added to the resulting wet crystals, and the mixture was stirred at 35°C for 30 minutes, then cooled to 25°C and stirred for 12 hours. The slurry was cooled to 0°C over 1 hour, and heptane (75 mL) was added dropwise over 1 hour. After stirring at 0°C for 2 hours, the precipitated crystals were filtered and dried under reduced pressure to give 4-methoxyphenyl 2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(2-carboxybenzamido)-β-D-glucopyranosyl-(1→2)-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(2-carboxybenzamido)-β-D-glucopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(2-carboxybenzamido)-β-D-glucopyranoside Tri(R)-(+)-1-(1-naphthyl)ethylamine salt (compound represented by formula A-14) (18.93 g, yield 63.1%, purity 97.2% PA) was obtained as white crystals. The powder X-ray crystallography of the obtained crystals is shown below.

[0323] <Measurement equipment> Powder X-ray crystallography measurement device: Rigaku <Measurement conditions> Wavelength: Cuka / 1.541862 Å Goniometer: MiniFlex 300 / 600 Scan speed: CONTINUOUS Scan speed / counting time: 10.00 Step width: 0.02 deg Scan axis: 2θ / θ Scan range: 3.00 to 40.00 deg Filter: K-beta (x1) Rotation: Yes <Powder X-ray crystallography measurement chart for compound of formula A-14>

[0324] Conversion of a compound of formula A-14 to a compound of formula A-13

[0325] 4-Methoxyphenyl 2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(2-carboxybenzamido)-β-D-glucopyranosyl-(1→2)-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(2-carboxybenzamido)-β-D-glucopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(2-carboxybenzamido)-β-D-glucopyranoside Cyclopentyl methyl ether (90 mL) was added to tri(R)-(+)-1-(1-naphthyl)ethylamine salt (compound represented by Formula A-14) (18.00 g, purity 97.2%), and the mixture was washed three times with 1M aqueous hydrochloric acid (180 mL) and then with 5% brine (90 mL). The resulting organic layer was concentrated to 18 mL, to which cyclopentyl methyl ether (90 mL) was added, and the mixture was concentrated under reduced pressure to 18 mL. Tetrahydrofuran (90 mL) was added to the concentrated solution, and carbonyldiimidazole (6.86 g, 8 equivalents) was added. The mixture was stirred at 35°C for 1 hour, and after confirming the completion of the reaction (not only was the phthalimide ring-closure reaction confirmed, but also the product of imidazole carbonylation of the hydroxyl group), water (9 mL) and trifluoroacetic acid (12.1 g, 20 equivalents) were added. The mixture was heated to 60°C and stirred for 20 hours. After confirming the progress of the imidazole carbonylation, it was cooled to room temperature. Ethyl acetate (90 mL) and water (90 mL) were added and the organic layer was separated. The organic layer was washed sequentially with 5% aqueous sodium bicarbonate (90 mL) and water (90 mL). The resulting organic layer was concentrated under reduced pressure to 18 mL. Toluene (90 mL) was added and the mixture was concentrated to 18 mL, followed by the addition of dichloromethane (162 mL). This dichloromethane solution was passed through silica gel (36 g, Fuji Silysia Chromatorex SMB100-20 / 45) and eluted with a diisopropyl ether / dichloromethane mixed solvent (7 / 93, 720 mL) (90 mL fractions were collected during the pass-through and elution procedures). Purity measurements were performed using HPLC to select fractions. The selected fractions were mixed and concentrated to 18 mL.Cyclopentyl methyl ether (90 mL) was added to the concentrate and concentrated to 36 mL, and the resulting solution was added dropwise to isopropanol (630 mL) cooled to 0° C. over 30 minutes with stirring. After stirring at 0° C. for 2 hours, the slurry was filtered and washed with isopropanol (180 mL) at 0° C. The resulting powder was dried under reduced pressure to give 4-methoxyphenyl-2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→2)-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4- Di-O-benzyl-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula A-13) (14.1 g, yield 93%, purity 97.0 PA%) was obtained as a white powder.

[0326] [Analysis conditions] Column: Xbridge Phenyl 3.5 μm, 4.6φ×150 mm (Waters) Wavelength: 220 nm Oven: 40°C Eluent: (A) 10 mM AcONH ４ Aqueous solution, (B) acetonitrile Gradient: 0 min (B) concentration 85% 30 min (B) concentration 100% 30.01 min (B) concentration 85% 35 min (B) concentration 85% Flow rate: 1 mL / min Injection: 5 μL

[0327] HRMS (ESI ＋ ) [M + NH ４ ] ＋ calcd for C １７２ H １６８ N ３ O ３５ :2852.1718;found:2852.1694 1H-NMR (500MHz, CDCl ３)δσ7.75(d,J=8.0Hz,1H),7.69-7.40(10H),7.55-7.10(m,54H),7.06-6.97(5H),6.97-6.89(m,8H),6.88-6.84(m,1H),6.82-6.73(m,5H),6。72-6.67(m,2H),6.62-6.56(m,5H),5.42(d,J=8.6Hz,1H),5.22(d,J=8.0Hz,1H),5.03(d,J=12.0Hz,1H),4.99(d,J=8.6Hz,1H),4.92(d,J=10.9Hz,1H),4.87-4.79(m,5H),4.75(d,J=11.5Hz,1H),4.70(d,J=12.0Hz,1H),4.67(d,J=12.0Hz,1H),4.63(d,J=6.3Hz,1H),4.61(d,J=6.9Hz,1H),4.60-3.97(m,30H),3.88(d,J=2.9Hz,1H),3.84(d,J=12.0Hz,1H),3.82-3.67(m,5H),3.66-3.60(m,5H),3.54-3.33(m,14H),3.27-3.23(m,1H),3.20(d,J=10.9Hz,1H),3.15-3.09(m,2H),2.83-2.78(m,1H),2.27-2.21(m,1H) 13C-NMR(125MHz,CDCl ３) δ168.4, 168.2, 167.4, 167.3, 155.2, 150.8, 139.1, 139.0, 138.9, 138.8, 138.7, 138.51, 138 .49,138.44,138.38,138.37,138.35,138.26,138.0,137.7,133.8,133.6,122.49,133.41,13 3.36, 131.8, 131.4, 128.6, 128.52, 128.49, 128.39, 128.34, 128.30, 128.2, 128.14, 128.10, 128.06, 128.0, 127.85, 127.82, 127.7, 127.69, 127.65, 127.56, 127.53, 127.48, 127.38, 127.3 3, 127.26, 127.1, 127.0, 126.9, 126.7, 123.5, 123.2, 123.09, 123.05, 122.98, 118.5, 114.2, 102.9, 102.6, 97.8, 97.4, 97.0, 96.9, 82.5, 80.5, 79.9, 78.5, 77.8, 77.4, 76.9, 76.7, 75.87, 75.8 . 80, 75.2, 75.0, 74.79, 74.77, 74.62, 74.59, 74.48, 74.41, 74.2, 74.0, 73.9, 73.6, 73.4, 73.0, 72.9, 72.7, 72.62, 72.56, 72.0, 69.8, 68.24, 68.20, 68.1, 67.8, 67.2, 56.6, 55.6, 55.5, 53.4

[0328] Example 29: A comparative experiment on the deacylation reaction of producing a compound represented by formula C-9 from a compound represented by formula C-8 in Example 15 above was carried out using the reaction conditions shown in the table below. Entries 1 to 3 are comparative examples, and Entries 4 and 5 are examples of the present invention.

[0329] - With NaOMe, the ring-opening reaction proceeded completely due to the influence of moisture in the reagent (Entry 1). - Under acidic conditions, the ring-opening of the phthalimide group could be suppressed, but the reaction rate was slow and decomposition proceeded (Entry 2). - When t-BuOK was used, the target product was produced in about 85%, but the ring-opened product was produced as a by-product in about 8% due to the influence of moisture in the reagent and solvent (Entry 3). - CF ３ CO ２ When Me was added, the ring-opened product was almost completely suppressed and the reaction was completed. Using t-BuOK and LHMDS as bases gave equivalent results (Entries 4 and 5).

[0330] Example 30: The compound of formula A-12 containing 15 benzyl groups and one 2-naphthylmethyl group was subjected to de-2-naphthylmethylation under conventional conditions (CH ２ Cl ２ -H ２ O) (Entry 1) and the method of the present invention (HFIP-H ２ The reaction was carried out with Entries 2 and 3, and analyzed by HPLC to calculate the peak area ratio of the target product (the compound represented by formula A-13) and the debenzylated product, which is the excess reactant. The results are shown in the table below.

[0331] Entry 1: Under the conditions of the conventional method, the selectivity to the debenzylated product was moderate. Entry 2: Selectivity was improved by using HFIP. Entry 3: The best results were obtained by using HFIP and carrying out the reaction at an even lower temperature.

[0332] Example 31 The compound of formula A-4 containing four benzyl groups and one 2-naphthylmethyl group was subjected to de-2-naphthylmethylation under conventional conditions (CH ２ Cl ２ -H ２ O) (Entry 1), the method of the present invention (HFIP-H ２ Reactions were carried out under acidic conditions (Entry 2), acidic conditions (Entry 3), and hydrogenation conditions (Entry 4), and the area peak ratio of the target product (compound represented by the following formula A-4') was calculated by HPLC analysis. The results are shown in the table below.

[0333] ・Entry 1: The reaction proceeded with moderate to high yields even under conventional conditions. ・Entry 2: The reaction was further improved by using HFIP. ・Entry 3: The HCl / HFIP conditions reported in the paper (J. Org. Chem. 2015, 80, 8796-8806) were applied, but the reaction became complicated and resulted in a low yield. ・Entry 4: When hydrogenation conditions were used, elimination of the benzyl group was also observed, resulting in a low yield.

[0334] Example 32 The compound of formula A-10 containing nine benzyl groups and one 2-naphthylmethyl group was subjected to de-2-naphthylmethylation under conventional conditions (CH ２ Cl ２ -H ２ O) (Entry 1) and the method of the present invention (HFIP-H ２ A reaction was carried out for Entry 2), and the peak area ratio of the target product (a compound represented by the following formula A-10') was calculated by HPLC analysis. The results are shown in the table below.

[0335]

[0336] Example 33 <Separation and Purification of Compounds Represented by Formula A-8 and A-9> An example of the separation and purification of the compound represented by Formula A-8, which is a glycosyl acceptor used in the synthesis of a tetrasaccharide, and the compound represented by Formula A-9 is shown below. The glycosyl acceptor compound represented by Formula A-8 and the tetrasaccharide compound represented by Formula A-9 have very similar polarities in normal-phase silica gel column chromatography; for example, they have the same Rf value under conditions of a typical column solvent system of hexane-ethyl acetate, making separation difficult. Utilizing the present invention, it has become possible to easily separate a monosaccharide and a tetrasaccharide, which have very similar polarities, on silica gel.

[0337] The experimental procedure was as follows. First, triethylamine was added to the reaction solution to terminate the reaction, followed by molecular sieve filtration and concentration, followed by addition of acetonitrile. Octadecyl-modified silica gel was added to the solution, and water was then added to adsorb the tetrasaccharide compound represented by formula A-9. Analysis of the filtrate by HPLC revealed that the tetrasaccharide compound represented by formula A-9 had been adsorbed, while the monosaccharide compound represented by formula A-8 was present in the filtrate. After washing the monosaccharide compound represented by formula A-8 with an optional addition of acetonitrile-water, the tetrasaccharide compound represented by formula A-9 was extracted with acetonitrile and toluene. The purification results for the compound represented by formula A-8 are shown in Tables 1 and 2 below.

[0338]

[0339] <Synthesis of Compound Represented by Formula D-3> The compound represented by Formula D-3 was synthesized according to the following synthesis scheme Z. [Synthesis Scheme Z]

[0340] Example 34 4-Methoxyphenyl 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (Compound represented by Formula F-1)

[0341] (Substep Z-1) Triethylamine (11.04 g, 109.12 mmol), dimethylaminopyridine (0.31 g, 2.52 mmol), and acetic anhydride (11.10 g, 109.12 mmol) were added to a solution of 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by Formula A-8) (50.0 g, 83.94 mmol) in ethyl acetate (200 mL), and the mixture was stirred at 20° C. for 4 hours. After confirming the completion of the reaction by HPLC, ethanol (500 mL) and water (150 mL) were added dropwise. The slurry was stirred for 1 hour, and the precipitated crystals were filtered. The filtered crystals were washed with a mixed solution of ethanol and water (150 / 50 mL) and dried under reduced pressure at 40°C to obtain 4-methoxyphenyl 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula F-1) (49.0 g, yield 91%) as white crystals.

[0342] １ H-NMR (500MHz, CDCl ３ ) δ7.85-7.60 (m, 4H), 7.24-7.34 (m, 5H), 7.04-7.00 (m, 2H), 6.96-6.87 (m, 3H ), 6.84 (dt, J=9.0, 3.0Hz, 2H), 6.67 (dt, J=8.5, 2.5Hz, 2H), 5.66 (t, J=4.0Hz, 1H), 5.22-5.18 (m, 1H), 4.64 (d, J = 12.0Hz, 1H), 4.55-4.48 (m, 4H), 4.36 (d, J = 12.0Hz, 1H), 3.90-3.84 (m, 1H), 3.68 (s, 3H), 3.68-3.64 (m, 2H), 1.98 (s, 3H). １３ C-NMR (125MHz, CDCl ３ ) δ169.6, 155.3, 150.6, 137.8, 137.5, 133.9, 128.2, 128.0, 127.7, 127.7, 127.5, 127 .4,123.3,118.4,114.3,97.4,76.8,73.9,73.7,73.5,72.2,69.4,55.4,55.3,20.8. HRMS (ESI＋ ) [M+H] ＋ calcd for C ３７ H ３６ NO ９ :638.2385;found 638.2401.

[0343] Example 35 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-D-glucopyranoside (compound represented by formula F-2)

[0344] (Substep Z-2) To a solution of 4-methoxyphenyl 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranoside (compound represented by formula F-1) (49.0 g, 76.84 mmol) in dichloromethane (392 mL), hexafluoro-2-propanol (245 mL), and water (25 mL), [bis(trifluoroacetoxy)iodo]benzene (46.3 g, 107.58 mmol) was added at 25°C or below, and the mixture was stirred at the same temperature for 4 hours. After confirming the completion of the reaction by HPLC, ethyl acetate (1225 mL) was added, the mixture was ice-cooled, and then water (490 mL) containing sodium bicarbonate (24.5 g) and sodium sulfite (24.5 g) was added, and the mixture was separated to obtain an organic layer. The resulting organic layer was washed again with water (490 mL) containing sodium bicarbonate (24.5 g) and sodium sulfite (24.5 g), and further washed with 20% brine (245 g). The resulting organic layer was concentrated under reduced pressure to 490 mL (precipitation of crystals was confirmed during concentration), and heptane (735 mL) was added dropwise. The resulting slurry was cooled to 0°C to 5°C and stirred at the same temperature for 1 hour, and the precipitated crystals were filtered. The filtered crystals were washed with a mixture of ethyl acetate and heptane (39 / 118 mL) at 0°C to 5°C and dried under reduced pressure at 40°C to obtain 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-D-glucopyranoside (compound represented by formula F-2) (37.5 g, yield 92%) as white crystals.

[0345] １ H-NMR (400MHz, CDCl ３ ) δ7.71-7.65 (m, 4H), 7.34-7.26 (m, 5H), 7.01-6.87 (m, 5H), 5.36 (dd, J=8.0, 8.0 Hz, 1H), 5.13 (dd, J=8.4, 10.0 Hz, 1H ), 4.59 (d, J = 12.4 Hz, 1H), 4.54 (s, 2H), 4.50 (dd, J = 8.4, 10.4 Hz, 1H), 4.33 (d, J = 12.4 Hz, 1H), 4.17 (dd, J = 8.4, 10.4 Hz, 1H), 3.79 (ddd, J=8.4, 5.2, 4.8 Hz, 1H ), 3.61-3.53 (m, 2H), 3.41 (d, J=8.0 Hz, 1H), 1.93 (s, 3H). 　１３ C-NMR (100MHz, CDCl ３ ) δ169.8, 168.1, 137.7, 137.7, 134.0, 131.6, 128.4, 128.2, 128.0, 127.8. 127.7, 127.5, 123.4, 116.2, 92.9, 73.9, 73.7, 73.5, 72.2, 69.3, 57.1, 20.9. HRMS (ESI － ) [M-H] － calcd for C ３０ H ２８ NO ８ :530.1820;found 530.1841.

[0346] Example 36 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-O-[2,2,2-trifluoro-N-phenylethanimidoyl]-β-D-glucopyranoside (Compound represented by formula D-3)

[0347] (Substep Z-3) 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-D-glucopyranoside (compound represented by formula F-2) (20.0 g, 37.63 mmol) was added to a 500 mL recovery flask, followed by the addition of dichloromethane (200 mL) and molecular sieve 4A powder (10 μm or less, 10.0 g). Under nitrogen, N-methylimidazole (3.40 g, 41.39 mmol) and 2,2,2-trifluoro-N-phenylacetimidoyl chloride (8.20 g, 39.51 mmol) were added sequentially at 0°C, and the mixture was stirred at the same temperature for 18 hours. After confirming the completion of the reaction by HPLC, the reaction solution was filtered and washed with dichloromethane (100 mL). The filtrate was filtered through a neutral silica gel pad (Silica Gel 60N, Kanto Chemical, particle size: 40-50 μm, 60 g) filled with dichloromethane, and 100 mL fractions were collected. The silica gel pad was washed with dichloromethane (400 mL, 100 mL fractions) and ethyl acetate / dichloromethane (1:4, 400 mL, 100 mL fractions), and the selected fractions were concentrated until the liquid volume reached 40 mL. Toluene (200 mL) was added, and the mixture was concentrated again until the liquid volume reached 40 mL. Further toluene (200 mL) was added, and the mixture was concentrated until the liquid volume reached 40 mL to obtain crude 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-O-[2,2,2-trifluoro-N-phenylethanimidoyl]-β-D-glucopyranoside (compound represented by formula D-3) as a toluene solution. This product was used directly in the next step.

[0348] <Synthesis of Compound Represented by Formula D-7> The compound represented by Formula D-7 was synthesized according to the following synthesis scheme V. [Synthesis scheme V]

[0349] First, the compound represented by formula G-1 was synthesized according to the following synthesis scheme W. [Synthesis scheme W]

[0350] Example 37 Allyl α-D-galactopyranoside (compound designated G-0)

[0351] D-Galactopyranose (20.00 g, 111.01 mmol) was added to a 500 mL four-neck flask, followed by the addition of allyl alcohol (200.0 mL). ２ 0 (2.11 g, 11.10 mmol) was added, the mixture was heated to 70°C, and stirred for 24 hours. The reaction solution was cooled to 40°C, triethylamine (1.69 g, 16.65 mmol) was added, and the mixture was stirred for 5 minutes. The reaction solution was then concentrated under reduced pressure to a volume of 100 mL. nBuOH (200 mL) was added dropwise to the concentrated solution over 30 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction solution was then concentrated under reduced pressure to a volume of 80 mL and stirred overnight at room temperature. The suspension was filtered, and the crystals were washed with nBuOH (40 mL) at 0°C and dried under reduced pressure at 40°C to obtain allyl α-D-galactopyranoside (compound designated G-0) (8.41 g, yield 34.4%) as white crystals.

[0352] １ H-NMR (500MHz, METHANOL-D4) δ5.97 (qd, J=11.2, 5.7Hz, 1H), 5.33 (dd, J=17.2, 1.7Hz, 1H), 5.17 (dd, J=10.6, 1. 4Hz, 1H), 4.22 (dd, J=13.2, 5.2Hz, 1H), 4.04 (dd, J=13.0, 6.0Hz, 1H), 3.88 (d, J=1.7Hz, 1H), 3.82-3.66 (m, 5H). 　１３ C-NMR (125 MHz, METHANOL-D4) δ62.74, 69.36, 70.21, 71.08, 71.51, 72.49, 99.46, 117.47, 135.69. MS (ESI) m / z: 221 (M+H) ＋ , 219 (M-H) － .

[0353] Example 38 Prop-2-en-1-yl 4,6-O-benzylidene-α-D-galactopyranoside (Compound represented by formula G-1)

[0354] Under a nitrogen atmosphere, acetonitrile (5.0 mL), benzaldehyde dimethyl acetal (5.18 g, 34.1 mmol) and p-TsOH·H ２ After adding 431.9 mg (2.27 mmol) of 4,6-O-benzylidene-α-D-galactopyranoside (4.6 mg, 2.27 mmol) to a 100 mL recovery flask, allyl α-D-galactopyranoside (5.00 g, 22.7 mmol) was added portionwise. The solution was heated to 40°C and stirred for 30 minutes. Subsequently, triethylamine (344.6 mg, 3.41 mmol) was added and stirred for 5 minutes, after which isopropyl alcohol (75 mL) was added dropwise at 40°C. The reaction solution was concentrated under reduced pressure to a volume of 25 mL and stirred overnight at 0°C. Subsequently, the suspension was filtered, and the resulting crystals were washed with isopropyl alcohol (5 mL) cooled to 0°C and dried under reduced pressure at 40°C to obtain prop-2-en-1-yl 4,6-O-benzylidene-α-D-galactopyranoside (compound represented by formula G-1) (5.35 g, yield 76.3%) as white crystals.

[0355] １ H-NMR (500MHz, METHANOL-D4) δ7.53-7.52 (dd, J=7.5, 2.0Hz, 2H), 7.34 (m, 3H), 5.9 8 (qd, J=11.1, 5.4Hz, 1H), 5.59 (s, 1H), 5.35 (d, J=18.9Hz, 1H), 5.19 (d, J=10.3Hz, 1H), 4.95 (d, J=4.0Hz, 1H), 4.26 (d, J=3.4Hz, 1H), 4.22 (dd, J=13.2, 5.2Hz, 1H), 4. 13 (s, 2H), 4.08 (q, J=6.5Hz, 1H), 3.92 (ddd, J=24.1, 10.3, 3.4Hz, 2H), 3.74 (s, 1H). 　１３ C-NMR (125 MHz, METHANOL-D4) δ64.60, 69.70, 70.03, 70.08, 70.34, 78. 07, 100.22, 102.28, 117.58, 127.54, 129.02, 129.86, 135.59, 139.77. MS (ESI) m / z: 309 (M+H) ＋ , 307 (M-H) － .

[0356] Example 39 Prop-2-en-1-yl 2,3-di-O-benzoyl-4,6-O-benzylidene-α-D-galactopyranoside (Compound represented by formula G-2)

[0357] (Substep V-1) To a solution of prop-2-en-1-yl 4,6-O-benzylidene-α-D-galactopyranoside (compound represented by formula G-1) (30.0 g, 97.30 mmol) in pyridine (150 mL), benzoyl chloride (47.87 g, 340.54 mmol) was added dropwise at 40°C or lower, and the mixture was stirred at the same temperature for 2 hours. After confirming the completion of the reaction by HPLC, the mixture was cooled to 20°C-30°C, and ethanol (450 mL) was added, followed by the dropwise addition of water (300 mL) over 30 minutes. The slurry was stirred at 20°C to 30°C for 1 hour, and then the precipitated crystals were filtered. The filtered crystals were washed with a mixed solution of ethanol and water (75 / 75 mL) and dried under reduced pressure at 40°C to obtain prop-2-en-1-yl 2,3-di-O-benzoyl-4,6-O-benzylidene-α-D-galactopyranoside (compound represented by formula G-2) (47.9 g, yield 95%) as white crystals.

[0358] １ H-NMR (500MHz, CDCl ３ ) δ8.03-7.98 (m, 4H), 7.55-7.46 (m, 4H), 7.40-7.30 (m, 7H), 5.90-5.78 (m, 2H), 5. 82 (s, 1H), 5.57 (s, 1H), 5.42 (d, J = 1.7Hz, 1H), 5.31 (dd, J = 17.2, 1.7Hz, 1H), 5.15 ( dd, J=1.7, 10.5Hz, 1H), 4.66 (s, 2H), 4.33 (d, J=12.5Hz, 1H), 4.26 (dd, J=12.5, 4. 5Hz, 1H), 4.12 (dd, J=12.5, 1.0Hz, 1H), 4.08 (dd, J=6.5, 13.5Hz, 1H), 3.95 (s, 1H). １３ C-NMR (125MHz, CDCl ３) δ166.1, 165.8, 137.5, 133.4, 133.2, 133.1, 129.8, 129.7, 129.5, 129.4, 128. 8, 128.3, 128.1, 126.1, 117.5, 100.6, 96.2, 74.2, 69.3, 69.1, 68.7, 68.6, 62.4. HRMS (ESI ＋ ) [M+H] ＋ calcd for C ３０ H ２９ O ８ :517.1857;found 517.1880.

[0359] Example 40 Prop-2-en-1-yl 2,3-di-O-benzoyl-α-D-galactopyranoside (compound represented by formula G-3)

[0360] (Substep V-2) A solution of prop-2-en-1-yl 2,3-di-O-benzoyl-4,6-O-benzylidene-α-D-galactopyranoside (compound represented by Formula G-2) (47.1 g, 91.18 mmol) in acetonitrile (377 mL) was heated to 45°C, and water (24 mL) and concentrated hydrochloric acid (9.2 g, 91.18 mmol) were added, followed by stirring at the same temperature for 30 minutes. Water (353 mL) was added dropwise at 45°C to 50°C over 3 hours, followed by stirring for an additional 30 minutes. After confirming the completion of the reaction by HPLC, sodium acetate (11.22 g, 136.78 mmol) was added, and ethyl acetate (942 mL) and water (471 mL) were added. The mixture was cooled to below 25°C, and the organic layer was separated. The resulting organic layer was washed twice with water (471 mL) and then further washed with 20% brine (236 mL). The organic layer was concentrated under reduced pressure to 141 mL, toluene (707 mL) was added, and the mixture was again concentrated under reduced pressure to 141 mL. Toluene (236 mL) was added to the resulting concentrate, and the mixture was concentrated under reduced pressure to 141 mL. The concentrate was cooled to 0°C to 5°C, and then a toluene (330 mL) slurry containing neutral silica gel (silica gel 60N, Kanto Chemical, particle size: 40-50 μm, 141 g) cooled to 0°C to 5°C was poured into the mixture. The mixture was stirred at the same temperature for 15 minutes to adsorb the product onto the silica gel, followed by filtration. The silica gel solid phase containing the product was washed with toluene (942 mL) at 0°C to 5°C (the filtrate from the toluene wash was discarded), and the target product was desorbed from the silica gel with cyclopentyl methyl ether (707 mL) to give a cyclopentyl methyl ether solution of prop-2-en-1-yl 2,3-di-O-benzoyl-α-D-galactopyranoside (compound represented by formula G-3) (quantitative value 36.2 g, quantitative yield 93%). This solution was used in the next step.

[0361] Example 41 Methyl 5-acetamido-3,5-dideoxy-D-glycero-D-galacto-non-2-ulopyranosonate monohydrate (compound represented by formula G-5)

[0362] (Substep V-3) To a solution of 5-acetamido-3,5-dideoxy-D-glycero-D-galacto-non-2-ulopyranosonic acid (compound represented by formula G-4) (40.1 g, 129.66 mmol) and methyl orthoformate (15.60 mL, 142.59 mmol) in methanol (321 mL), sulfuric acid (1.0 g, 10.20 mmol) was added, heated to 40°C, and stirred for 3 hours. After confirming the completion of the reaction by HPLC, the mixture was cooled to 25°C, dimethylacetamide (40 mL) was added, and the mixture was concentrated under reduced pressure to 160 mL. The temperature of the resulting concentrate was adjusted to 15°C, and water (20 mL) and ethyl acetate (722 mL) were added. After stirring at 25°C for 1 hour, the slurry was cooled to 0°C to 5°C and stirred at the same temperature for 2 hours. The precipitated crystals were filtered, washed with ethyl acetate (80 mL) at 0°C to 5°C, and dried under reduced pressure at 40°C to obtain methyl 5-acetamido-3,5-dideoxy-D-glycero-D-galacto-non-2-ulopyranosonate monohydrate (compound represented by formula G-5) (41.1 g, yield 93%) as white crystals.

[0363] １ H-NMR (500MHz, CD ３ OD) δ4.07-3.98 (m, 2H), 3.85-3.77 (m, 2H), 3.78 (s, 3H), 3.72-3.68 (m, 1H), 3.62 (dd, J = 10.9, 5.7Hz, 1H) , 3.48 (dd, J=9.2, 1.1Hz, 1H), 2.22 (dd, J=12.9, 4.9Hz, 1H), 2.02 (s, 3H), 1.89 (dd, J=12.6, 11.5Hz, 1H). １３ C-NMR (125MHz, CD ３ OD) δ175.2, 175.1, 171.8, 96.6, 72.1, 72.0, 71.6, 70.1, 67.9, 64.8, 54.4, 54.3, 53.2, 40.7, 22.7, 22.7. HRMS (ESI ＋ ) [M+H] ＋ calcd for C １２ H ２２ NO ９ :324.1289;found 324.1288.

[0364] Example 42 Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-D-galacto-non-2-ulopyranosonate (Compound represented by formula G-6)

[0365] (Substep V-4) A slurry of methyl 5-acetamido-3,5-dideoxy-D-glycero-D-galacto-non-2-ulopyranosonate monohydrate (compound represented by formula G-5) (40.3 g, 118.07 mmol) in acetonitrile (403 mL) was adjusted to 25°C, and acetic anhydride (60.27 g, 590.36 mmol) and paratoluenesulfonic acid monohydrate (1.12 g, 5.89 mmol) were added, followed by stirring at 25°C for 24 hours. Thereafter, the reaction solution was cooled to 15°C, and acetic anhydride (12.05 g, 118.03 mmol) was added, followed by stirring at the same temperature for 47 hours. After confirming the completion of the reaction by HPLC, methanol (40 mL) was added, the temperature was adjusted to 25°C, and the mixture was stirred at the same temperature for 2 hours. Next, sodium acetate (0.97 g, 11.82 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to 120 mL and cooled to 0 to 5°C. Ethyl acetate (403 mL) and water (161 mL) were then poured into the mixture, and triethylamine was added to the mixture while stirring at 0 to 5°C to adjust the pH to 7.0. The organic layer obtained by separation was washed twice with 10% brine (121 mL) and concentrated under reduced pressure to 200 mL. Ethyl acetate (605 mL) was added to the concentrate, and the mixture was again concentrated under reduced pressure to 200 mL. Ethyl acetate (40 mL) was added to the concentrate, seed crystals were added, and the mixture was stirred at 25°C for 4 hours. Heptane (302 mL) was then added dropwise over 30 minutes. The slurry was stirred at 25°C for 2 hours, and then the precipitated crystals were filtered. The filtered crystals were washed with a mixture of ethyl acetate and heptane (67 / 135 mL) and dried under reduced pressure at 35°C to obtain methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-D-galacto-non-2-ulopyranosonate (compound represented by formula G-6) (44.1 g, yield 76%) as white crystals.

[0366] １ H-NMR (500MHz, CDCl ３) δ6.28 (d, J=10.3Hz, 1H), 5.41 (dd, J=4.6, 2.3Hz, 1H), 5.28-5.23 (m, 1H), 5.2 1-5.14 (m, 1H), 5.09 (s, 1H), 4.62 (dd, J=12.3, 2.6Hz, 1H), 4.28 (dd, J=10.3, 2. 3Hz, 1H), 4.21-4.11 (m, 1H), 4.04 (dd, J=12.3, 8.3Hz, 1H), 3.85 (s, 3H), 2.24- 2.20 (m, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H), 1.91 (s, 3H). １３ C-NMR (125MHz, CDCl ３ ) δ171.5, 171.1, 170.8, 170.3, 170.2, 168.9, 94.9, 72.1, 71.4, 69.1, 68.3, 62.5, 53.2, 49.1, 36.1, 23.0, 21.0, 20.8, 20.7, 20.7. HRMS (ESI ＋ ) [M+H] ＋ calcd for C ２０ H ３０ NO １３ :492.1712;found 492.1712.

[0367] Example 43 Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-O-(2,2,2-trifluoro-N-phenylethanimidoyl)-D-glycero-β-D-galacto-non-2-ulopyranosonate (Compound represented by formula G-7)

[0368] (Substep V-5) A slurry of methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-D-galacto-non-2-ulopyranosonate (compound represented by formula G-6) (44.0 g, 89.53 mmol) and molecular sieves 4A powder (powder particle size 10 μm or less) (22 g) in dichloromethane (352 mL) was adjusted to 20°C and stirred at the same temperature for 30 minutes, after which 2,2,2-trifluoro-N-phenylacetimidoyl chloride (26.02 g, 125.35 mmol) was added. Subsequently, N-methylimidazole (11.03 g, 134.33 mmol) was added dropwise, and the mixture was stirred at 20°C for 7.5 hours. After confirming the completion of the reaction by HPLC, the reaction solution was filtered and washed with dichloromethane (88 mL) to obtain a filtrate. The obtained filtrate was cooled to 0°C, and cold water (440 mL) was added. Triethylamine was added with stirring at 0°C to 5°C to adjust the pH to 7.5. After stirring at 0°C to 5°C for 30 minutes, the layers were separated, and the obtained organic layer was washed twice with cold water (440 mL) and with cooled 20% brine (220 mL) and concentrated under reduced pressure to 88 mL. Ethyl acetate (440 mL) was added to the concentrated solution, and the solution was again concentrated under reduced pressure to 88 mL. t-Butyl methyl ether (308 mL) was added to the concentrated solution, seed crystals were added, and the solution was stirred at 20°C for 4 hours. To the resulting slurry, heptane (264 mL) was added dropwise over 1 hour, and the mixture was stirred at the same temperature for 2 hours. The precipitated crystals were then filtered, washed with a mixture of t-butyl methyl ether and heptane (132 / 88 mL), and dried under reduced pressure at 35°C to obtain methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-O-(2,2,2-trifluoro-N-phenylethanimidoyl)-D-glycero-β-D-galacto-non-2-ulopyranosonate (compound represented by formula G-7) (39.5 g, yield 67%) as white crystals.

[0369] １ H-NMR (500MHz, CDCl ３) δ7.30-7.24 (m, 2H), 7.09 (t, J = 7.4Hz, 1H), 6.72 (d, J = 8.0Hz, 2H), 5.76 (d, J = 9.7Hz, 1H), 5.48-5.45 (m, 1H), 5.30 (td, J=10.9, 4.8Hz, 1H), 5.15-5.10 (m, 1H), 4.60 (dd, J=12.6, 2.3Hz, 1H), 4.30 (q, J=10 .. 3Hz, 1H), 4.23 (dd, J = 10.3, 2.3Hz, 1H), 4.11 (dd, J = 12.3Hz, 7.7Hz, 1H), 3.81 (s, 3H), 2.79 (dd, J = 13 .5, 4.9Hz, 1H), 2.21-2.15 (m, 1H), 2.16 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H), 1.90 (s, 3H), 1.75 (s, 3H). 　１３ C-NMR (125MHz, CDCl ３ ) δ171.0, 170.7, 170.4, 170.2, 170.1, 165.3, 142.6, 141.0 (q, ２ J Ｃ－Ｆ =36.0Hz), 128.8, 124.6, 119.0, 115.1(q, １ J Ｃ－Ｆ =284.4Hz), 99.7, 73.6, 71.9, 68.3, 68.0, 62.4, 53.1, 48.6, 35.6, 23.0, 20.8, 20.8, 20.7, 20.3. HRMS (ESI ＋ ) [M + NH ４ ] ＋ calcd for C ２８ H ３７ F ３ N ３ O １３ :680.2273;found 680.2314.

[0370] Example 44 Methyl 4,7,8,9-tetra-O-acetyl-5-[acetyl(tert-butoxycarbonyl)amino]-3,5-dideoxy-2-O-(2,2,2-trifluoro-N-phenylethanimidoyl)-D-glycero-β-D-galacto-non-2-ulopyranosonate (Compound represented by formula G-8)

[0371] (Substep V-6) Di-tert-butyl dicarbonate (27.05 g, 123.94 mmol) and dimethylaminopyridine (1.80 g, 14.73 mmol) were added to a solution of methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-O-(2,2,2-trifluoro-N-phenylethanimidoyl)-D-glycero-β-D-galacto-non-2-ulopyranosonate (compound represented by formula G-7) (39.0 g, 58.86 mmol) in tetrahydrofuran (390 mL), and the mixture was heated to reflux. After stirring under reflux for 30 minutes, completion of the reaction was confirmed by HPLC, and the reaction solution was concentrated under reduced pressure to 117 mL. Toluene (195 mL) was added to the concentrated solution, and the mixture was again concentrated under reduced pressure to 117 mL. The concentrated solution was filtered using a funnel packed with silica gel (Silica Gel 60N, Kanto Chemical, particle size: 40-50 μm, 117 g, wet-filled with toluene) and washed with a toluene / ethyl acetate mixture (8 / 2) (975 mL) to obtain a filtrate. The obtained filtrate was concentrated under reduced pressure (to a weight of 59 g), and cyclopentyl methyl ether (23 mL) was added. The solution was adjusted to a temperature of 20°C, and heptane (156 mL) was added dropwise over 15 minutes, followed by stirring at the same temperature for 1 hour. After confirming the precipitation of crystals, heptane (312 mL) was added dropwise over 1 hour, and the precipitated crystals were filtered. The filtered crystals were washed with heptane (78 mL) and dried under reduced pressure at 35°C to obtain methyl 4,7,8,9-tetra-O-acetyl-5-[acetyl(tert-butoxycarbonyl)amino]-3,5-dideoxy-2-O-(2,2,2-trifluoro-N-phenylethanimidoyl)-D-glycero-β-D-galacto-non-2-ulopyranosonate (compound represented by formula G-8) (37.0 g, yield 82%) as white crystals.

[0372] １ H-NMR (500MHz, CDCl ３) Note) ca. 1 / 4 mixture of opposite sexes. Major isomer: δ 7.27 (t, J = 8.9 Hz, 2H), 7.09 (t, J = 7.2 Hz, 1H), 6.73 (d, J=8.0Hz, 2H), 5.75-5.65 (m, 1 H), 5.31 (d, J=4.6Hz, 1H), 5.18-5.14 (m, 1H), 5 .15 (d, J=6.0Hz, 2H), 4.54 (dd, J=12.0, 2.0Hz, 1H), 4.08 (dd, J=12.6, 6.9Hz, 1H), 3.84 (s, 3H) , 2.90 (dd, J=13.7, 5.2Hz, 1H), 2.39 (s, 3H), 2. 25 (dd, J=13.7, 11.2Hz, 1H), 2.09 (s, 3H), 2.07 (s, 3H), 1.99 (s, 3H), 1.77 (s, 3H), 1.62 (s, 9H). Minor isomer:δ 6.76 (d, J=8.0Hz, 2H), 5.85-5.80 (m, 1H), 5.29-5.25 (m, 1 H), 5.22-5.19 (m, 1H), 4.44 (d, J=11.0Hz, 1H), 4.15-4.11 ( m, 1H), 3.03 (dd, J=14.0, 5.0Hz, 1H), 2.41 (s, 3H), 2.12 (s , 3H), 2.00 (s, 3H), 1.88 (s, 3H), 1.74 (s, 3H), 1.54 (s, 9H). １３ C-NMR (125MHz, CDCl ３ ) Mixture: δ173.7, 170.4, 170.2, 170.0, 169.9, 1 65.4, 151.7, 142.8, 128.7, 124.5, 119.1, 100.6 ,85.2,72.8,71.3,67.7,65.9,62.0,53.1,52.0 ,36.7,27.9,27.7,26.6,20.8,20.7,20.6,20.3. HRMS(ESI ＋ )[M+NH ４ ] ＋ calcd for C ３３ H ４５ F ３ N ３ O １５ : 780.2797; found 780.2801.

[0373] Example 45 Prop-2-en-1-yl 2,3-di-O-benzoyl-6-O-{4,7,8,9-tetra-O-acetyl-5-[acetyl(tert-butoxycarbonyl)amino]-3,5-dideoxy-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl}-α-D-galactopyranoside (Compound represented by Formula G-9)

[0374] (Substep V-7) A cyclopentyl methyl ether solution (quantitative value 31.46 g, 73.43 mmol) of prop-2-en-1-yl 2,3-di-O-benzoyl-α-D-galactopyranoside (compound represented by Formula G-3) was concentrated under reduced pressure to 105 mL, and then added to a cyclopentyl methyl ether (175 mL) solution of methyl 4,7,8,9-tetra-O-acetyl-5-[acetyl(tert-butoxycarbonyl)amino]-3,5-dideoxy-2-O-(2,2,2-trifluoro-N-phenylethanimidoyl)-D-glycero-β-D-galacto-non-2-ulopyranosonate (compound represented by Formula G-8) (35.0 g, 45.89 mmol). Next, cyclopentyl methyl ether was added to the resulting mixed solution, and the total volume was adjusted to 350 mL (a cyclopentyl methyl ether mixed solution of the compound represented by Formula G-3 and the compound represented by Formula G-8). Cyclopentyl methyl ether (525 mL) and molecular sieves 4A powder (powder particle size 10 μm or less) (17.5 g) were added to a separate container, and the mixture was cooled to −60°C. After that, trimethylsilyl trifluoromethanesulfonate (4.2 mL, 23.24 mmol) was added. To this solution, the cyclopentyl methyl ether mixed solution of the compound represented by Formula G-3 and the compound represented by Formula G-8 was added dropwise over 4.5 hours at −60°C with vigorous stirring, and the mixture was stirred at the same temperature for 2 hours. After confirming the completion of the reaction by HPLC, triethylamine (4.5 mL, 32.12 mmol) was added, and the reaction solution was warmed to 0°C. Celite 545 (35.00 g) was then added, and the reaction solution was filtered and washed with cyclopentyl methyl ether (175 mL). Water (350 mL) was added to the filtrate, and the layers were separated. Next, 0.5 N aqueous hydrochloric acid (350 mL) was added to the organic layer, and the mixture was stirred at 20°C for 2 hours. After confirming the decomposition of by-products by HPLC, the organic layer was separated to obtain the organic layer. The organic layer was washed with water (350 mL) and 20% brine (175 mL), and then concentrated under reduced pressure to 70 mL. Toluene (700 mL) was added to the concentrated solution, and the mixture was concentrated under reduced pressure to 70 mL. Toluene (700 mL) and neutral silica gel (silica gel 60N, Kanto Chemical, particle size: 40-50 μm, 158 g) were added to the concentrated solution again, and the mixture was stirred at 20°C for 30 minutes.The product was adsorbed onto silica gel, filtered, and the silica gel solid phase containing the product was washed with toluene (1575 mL) (the filtrate from the toluene wash was discarded). The target product was then desorbed from the silica gel with ethyl acetate (875 mL). The resulting ethyl acetate solution was concentrated under reduced pressure to 70 mL, to which toluene (175 mL) was added. The mixture was again concentrated under reduced pressure to 70 mL to give a toluene solution of prop-2-en-1-yl 2,3-di-O-benzoyl-6-O-{4,7,8,9-tetra-O-acetyl-5-[acetyl(tert-butoxycarbonyl)amino]-3,5-dideoxy-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl}-α-D-galactopyranoside (compound represented by formula G-9). This solution was used in the next step.

[0375] Example 46 Prop-2-en-1-yl 6-O-{5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl}-2,3-di-O-benzoyl-α-D-galactopyranoside (Compound represented by formula G-10)

[0376] (Substep V-8) Dichloromethane (525 mL) and copper(II) trifluoromethanesulfonate (8.30 g, 22.95 mmol) were added to a toluene solution of prop-2-en-1-yl 2,3-di-O-benzoyl-6-O-{4,7,8,9-tetra-O-acetyl-5-[acetyl(tert-butoxycarbonyl)amino]-3,5-dideoxy-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl}-α-D-galactopyranoside (compound represented by formula G-9) obtained in Example 45, and the mixture was heated to 40°C and stirred at the same temperature for 2 hours. After confirming the completion of the reaction by HPLC, the mixture was cooled to 25°C and concentrated under reduced pressure to 70 mL. Ethyl acetate (525 mL) was added to the concentrated solution, which was then washed three times with 5% brine (350 mL). Heptane (263 mL) was then added to the organic layer, which was then washed four times with 20% aqueous methanol (525 mL). After confirming by HPLC that impurities derived from the β-eliminated form of compound 8, a by-product of the glycosylation reaction, had been removed from the aqueous layer, the organic layer was concentrated under reduced pressure to 70 mL. Isopropenyl acetate (525 mL) was added to the concentrated solution, which was then concentrated under reduced pressure to 350 mL to obtain a solution of prop-2-en-1-yl 6-O-{5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl}-2,3-di-O-benzoyl-α-D-galactopyranoside (compound represented by formula G-10) in isopropenyl acetate. This solution was used in the next step.

[0377] Example 47 Prop-2-en-1-yl 4-O-acetyl-2,3-di-O-benzoyl-6-O-[4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-(diacetylamino)-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl]-α-D-galactopyranoside (Compound represented by formula G-11)

[0378] (Substep V-9) To a solution of prop-2-en-1-yl 6-O-{5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl}-2,3-di-O-benzoyl-α-D-galactopyranoside (compound represented by formula G-10) obtained in Example 46 in isopropenyl acetate, paratoluenesulfonic acid monohydrate (0.88 g, 4.62 mmol) was added, and the mixture was heated to reflux (internal temperature around 90°C) and stirred at the same temperature for 3 hours. After confirming the completion of the reaction by HPLC, the mixture was cooled to 25°C, triethylamine (0.95 mL, 6.85 mmol) was added, and the mixture was concentrated under reduced pressure to 70 mL. Toluene (350 mL) was added to the concentrated solution, and the mixture was again concentrated under reduced pressure to 70 mL. Toluene (630 mL) was added to the concentrated solution, and neutral silica gel (Silica Gel 60N, manufactured by Kanto Chemical, particle size: 40-50 μm, 123 g) was added. The mixture was stirred at the same temperature for 30 minutes to adsorb the product onto the silica gel, and then filtered. The silica gel solid phase containing the product was washed with toluene (1925 mL) and a toluene / ethyl acetate mixture (97 / 3, 1400 mL) (the filtrate from the washing was discarded), and the target substance was desorbed from the silica gel solid phase containing the product with ethyl acetate (1050 mL). The resulting ethyl acetate solution was concentrated under reduced pressure to give prop-2-en-1-yl 4-O-acetyl-2,3-di-O-benzoyl-6-O-[4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-(diacetylamino)-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl]-α-D-galactopyranoside (compound represented by formula G-11) (30.1 g, yield 67% (based on compound represented by formula G-8)) as a white foamy solid (containing 0.42 equivalents of toluene (approximately 4% by weight)).

[0379] １ H-NMR (500MHz, CDCl ３) δ7.99 (d, J=8.4 Hz, 2H), 7.88 (dd, J=8.4, 1.4 Hz, 2H), 7.53-7.47 (m, 2H), 7.37 (dt, J=14.7, 6.9 Hz, 4H), 5.90-5.82 (m, 1H), 5.82 (dd, J = 10.9, 3.4 Hz, 1H), 5.73 (d, J = 2.9 Hz, 1H), 5.58 (dd, J=10.9, 4.0 Hz, 1H), 5.51 (td, J=10.6, 5.0 Hz, 1H), 5.35-5.30 (m, 3H), 5.17-5.15 (m, 2H), 4.94 (dd, J=10.3, 1.7 Hz, 1H), 4.38-4.27 (m, 3H), 4.20-4.13 (m, 2H), 4.08 (dd, J=13.2, 5.7 Hz, 1H), 3.94 (dd, J=10.3, 6.3 Hz, 1H), 3.82 (s, 3H), 3.50 (dd, J=9.7, 7.4 Hz, 1H), 2.73 (dd, J=13.2, 5.2 Hz, 1H), 2.37 (s, 3H), 2.31 (s, 3H), 2.19 (s, 3H), 2.15 (s, 3H), 2.14 (s, 3H), 2.03 (s, 3H), 1.97 (s, 3H), 1.86 (dd, J=13.2, 10.9 Hz, 1H). １３ C-NMR (125MHz, CDCl ３ ) δ174.5, 173.6, 170.5, 170.1, 169.9, 169.8, 169.6, 167.3, 166.0, 165 .5,133.5,133.3,133.1,129.8,129.5,129.4,128.4,128.3,117.5,98 .6,95.5,77.2,69.8,68.9,68.6,6 8.6, 68.3, 68.3, 67.5, 67.0, 66.7, 6 2.4, 61.8, 57.0, 52.9, 38.7, 27.9, 25.9, 21.0, 20.9, 20.7, 20.7, 20.6. HRMS (ESI ＋ )[M+H] ＋ calcd for C ４７ H ５６ NO ２２ : 986.3288; found 986.3277. Obtained the られた compound について, and the following documents とスペクトルの are consistent and confirmed: J. Org. Chem. 2016, 81, 10600-10616.

[0380] Example 48 4-O-acetyl-2,3-di-O-benzoyl-6-O-[4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-(diacetylamino)-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl]-D-galactopyranose (Compound represented by formula G-12)

[0381] (Substep V-10) A methanol solution (290 mL) of prop-2-en-1-yl 4-O-acetyl-2,3-di-O-benzoyl-6-O-[4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-(diacetylamino)-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl]-α-D-galactopyranoside (compound of formula G-11) (29.00 g, 29.41 mmol), 1,3-dimethylbarbituric acid (9.19 g, 58.86 mmol), and triphenylphosphine (2.31 g, 8.81 mmol) was degassed by reducing the pressure and replacing the atmosphere with nitrogen five times, followed by the addition of palladium(II) acetate (0.66 g, 2.94 mmol) and stirring at 40° C. for 12 hours. After confirming the completion of the reaction by HPLC, toluene (580 mL) and water (1015 mL) were added, and the layers were separated to obtain an organic layer. The organic layer was washed four times with 20% aqueous methanol (580 mL). After removing the 1,3-dimethylbarbituric acid into the aqueous layer, the mixture was concentrated under reduced pressure to 58 mL. Toluene (435 mL) was added, and the mixture was again concentrated under reduced pressure to 58 mL. Toluene (383 mL), chloroform (197 mL), and neutral silica gel (Silica gel 60N, Kanto Chemical, particle size: 40-50 μm, 145 g) were added to the concentrated solution, and the mixture was stirred for 30 minutes to adsorb the product onto the silica gel, followed by filtration. The silica gel solid phase containing the product was washed with a toluene / chloroform mixture (2 / 1, 4350 mL) (the filtrate from the washing was discarded), and the target compound was desorbed from the silica gel solid phase containing the product with ethyl acetate (870 mL). To the resulting ethyl acetate solution, SH silica gel (29.00 g) was added, stirred for 30 minutes, filtered, and washed with ethyl acetate (145 mL) to obtain an ethyl acetate solution containing the target compound. The resulting solution was concentrated under reduced pressure to 58 mL, to which toluene (145 mL) was added, and concentrated again under reduced pressure to 58 mL. The concentrated solution was purified using a silica gel column (silica gel 60N, Kanto Chemical, particle size: 40-50 μm, 290 g, mobile phase: hexane / ethyl acetate 50 / 50-30 / 70), and selected fractions were concentrated under reduced pressure to 29 mL. Ethyl acetate (290 mL) and activated carbon (Shirasagi A, 14.5 g) were added to the concentrated solution, stirred for 30 minutes, filtered, and washed with ethyl acetate (87 mL) to obtain a purified ethyl acetate solution containing the target compound.The resulting solution was concentrated under reduced pressure to give 4-O-acetyl-2,3-di-O-benzoyl-6-O-[4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-(diacetylamino)-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl]-D-galactopyranose (compound represented by formula G-12) (18.70 g, yield 67%) as a white foamy solid.

[0382] １ H-NMR (500MHz, CDCl ３ ) Major isomer: δ7.98-8.03 (m, 2H), 7.89 (t, 2H, J = 8.9 Hz), 7.52-7.48 (m, 2H), 7.39-7.34 (m, 4H), 5.92 (dd, 1H, J = 10.3, 2.9 Hz), 5.82 (d, 1H, J = 3.4Hz), 5.68 (t, 1H, J = 2.3 Hz), 5.59-5.48 (m, 2H), 5.37 (td, 1H, J = 7.5, 2.5 Hz), 5.17 (d, 1H, J = 7.5 Hz), 5.02 (d, 1H, J=10.5 Hz), 4.74-4.71 (m, 1H), 4.44-4.38 (m, 1H), 4.16-4.08 (m, 2H), 3.85 (s, 3H), 3.80 (m, 1H), 3.60-3.54 (m, 1H), 2.76 (dd, 1H, J=13.0, 6.0 Hz), 2.38 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H), 2.15 (s, 3H), 2.12 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H), 1.93-1.87 (m, 1H). １３ C-NMR (125MHz, CDCl ３)α / β mixture: 174.5, 173.8, 173.6, 171.7, 171.0, 170.5, 170.3, 170.3, 169.9, 169.8, 169.8, 169.6, 167.6, 167.3, 166.3, 166.0, 165.6, 165.4, 133.3, 133.2, 133.2, 133.1, 129.8, 129.7, 129.5, 129.4, 129.4, 129.3, 129.0, 128.4, 128.3, 99. 1,98.8,95.9,91.0,72.2,71.6,71.5,69.9,69.9,69.3,69.3,68.8,68.5,68.1,67.5,67.5,67.3,67.0,66.6,62.9,6 2.6, 62.4, 60.3, 57.2, 56.8, 53.0, 52.9, 38.6, 38.3, 27.9, 27.8, 26.1, 25.7, 21.0, 20.9, 20.8, 20.7, 20.7, 20.6, 20.5. HRMS (ESI － ) [M + HCOO] － calcd for C ４５ H ５２ NO ２４ :990.2885;found 990.2873.

[0383] Purification method by crystallization of 4-O-acetyl-2,3-di-O-benzoyl-6-O-[4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-(diacetylamino)-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl]-D-galactopyranose (compound represented by formula G-12)

[0384] 4-O-acetyl-2,3-di-O-benzoyl-6-O-[4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-(diacetylamino)-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl]-D-galactopyranose (compound represented by formula G-12) (3.00 g, 3.17 mmol, sialyl moiety α / β ratio=95.7 / 4.3) was dissolved in ethyl acetate (4 mL), and then 2-propanol (60 mL) was added. The mixture was stirred at 25°C and then concentrated under reduced pressure to 18 mL. The slurry was stirred at 0°C for 3 hours, and the precipitated crystals were filtered. The filtered crystals were washed with cold 2-propanol (9 mL) and dried under reduced pressure at 40°C to give 4-O-acetyl-2,3-di-O-benzoyl-6-O-[4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-(diacetylamino)-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl]-D-galactopyranose (compound represented by formula G-12) (2.66 g, yield 88.7%, sialyl moiety α / β ratio=>99.9 / N.D.) as white crystals.

[0385] [Analysis conditions] Column: CAPCELL PAK ADME φ4.6 × 150 mm, film thickness 3 μm Wavelength: 220 nm Oven: 40°C Eluent: (A) 0.1% trifluoroacetic acid aqueous solution, (B) acetonitrile Gradient: 0-150 min (B) concentration 40% 150.1 min (B) concentration 95% 155 min (B) concentration 95% 155.1 min (B) concentration 40% 160 min (B) concentration 40% Flow rate: 1 mL / min Injection: 5 μL

[0386] Example 49: 4-O-acetyl-2,3-di-O-benzoyl-6-O-[4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-(diacetylamino)-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl]-1-O-(2,2,2-trifluoro-N-phenylethanimidoyl)-D-galactopyranose (Compound represented by Formula D-7)

[0387] (Substep V-11) 4-O-acetyl-2,3-di-O-benzoyl-6-O-[4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-(diacetylamino)-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl]-D-galactopyranose (compound represented by formula G-12) (20.0 g, 21.1 mmol) was added to a 500 mL recovery flask, and dichloromethane (200 mL) and molecular sieve 4A powder (10 μm or less, 10.0 g) were added, followed by cooling to 0 ° C. Under nitrogen, N-methylimidazole (1.91 g, 23.3 mmol) and 2,2,2-trifluoro-N-phenylacetimidoyl chloride (4.39 g, 21.1 mmol) were added at the same temperature, and the mixture was warmed to room temperature and stirred for 24 hours. After confirming the completion of the reaction by HPLC, the reaction solution was filtered and washed with dichloromethane (100 mL). The filtrate was filtered through a neutral silica gel pad (silica gel 60N, Kanto Chemical, particle size: 40-50 μm, 60 g) filled with dichloromethane, and 100 mL aliquots were collected. The silica gel pad was washed with ethyl acetate / dichloromethane (1:9, 1000 mL, 200 mL aliquots), and selected fractions were concentrated under reduced pressure to give 4-O-acetyl-2,3-di-O-benzoyl-6-O-[4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-(diacetylamino)-1-methyl-D-glycero-α-D-galacto-non-2-ulopyranosyl]-1-O-(2,2,2-trifluoro-N-phenylethanimidoyl)-D-galactopyranose (compound represented by formula D-7) (20.1 g, yield 85%) as a white amorphous solid.

[0388] １ H-NMR (500MHz, CDCl ３)δ7.99(dd,2H,J=8.3,1.4Hz),7.91-7.88(m,2H),7.59-7.56(m,1H),7.51(tt,1H,J=9.7,2.4Hz),7.44-7.34(m,4H),7.12(t,2H,J=7.7Hz),7.01(t,1H,J=7.4Hz),6.82(brs,1H),6.43(brs,2H),5.87-5.77(m,3H),5.52(td,1H,J=11.0,5.0Hz),5.38-5.34(m,1H),5.18(dd,1H,J=8.6,1.7Hz),4.95(dd,1H,J=10.0,2.0Hz),4.53(brs,1H),4.29(dd,1H,J=12.6,2.9Hz),4.21-4.09(m,3H),4.04(dd,1H,J=10.0,6.0Hz),3.84(s,3H),3.53(dd,1H,J=10.3,7.4Hz),2.76(dd,1H,J=12.9,5.4Hz),2.39(s,3H),2.31(s,3H),2.18(s,3H),2.17(s,3H),2.14(s,3H),2.02(s,3H),1.98(s,3H),1.86(dd,1H,J=13.0,11.0Hz). 　１３ C-NMR(125MHz,CDCl ３ )δ174.5,173.5,170.5,170.1,169.8,169.7,169.6,167.2,165.5,165.4,165.3,142.9,133.6,133.3,129.8,129.7,129.6,129.5,129.0,128.7,128.6,128.5,128.4,124.2,119.0,98.7,98.5,70.4,69.8,68.3,68.2,67.5,67.5,66.9,66.7,62.0,61.7,60.3,56.9,53.7,52.9,38.7,31.7,29.2,27.9,26.0,25.8,21.0,21.0,20.9,20.8,20.7,20.6,20.5. HRMS(ESI ＋ )[M+NH ４ ] ＋ calcd for C ５２ H ５９ F ３ N ３ O ２２: 1134.3537; found 1134.3564. The spectrum was confirmed to match the following literature: J. Org. Chem. 2016, 81, 10600-10616.

[0389] <Synthesis of Compound Represented by Formula D-13> The compound represented by Formula D-13 was synthesized according to the following synthesis scheme 4. [Synthesis Scheme 4]

[0390] Example 50

[0391] 3,4,6-tri-O-benzyl-1,2-O-(1-methoxyethylidene)-β-D-mannopyranose (compound represented by formula A-1) (4.56 g, 9.00 mmol) was added to a 200 mL recovery flask, followed by the addition of ethyl acetate (45.6 mL). Under a nitrogen atmosphere, the mixture was stirred at room temperature with water (0.23 mL) and p-TsOH.H ２ 0 (5.1 mg, 0.027 mmol) was added and stirred at the same temperature for 8 hours. After confirming the completion of the reaction by HPLC, triethylamine (1.25 mL, 9.00 mmol) was added and stirred at the same temperature overnight. After confirming the completion of the acetyl group transfer by HPLC, 5% aqueous sodium bicarbonate (45 mL) was added to the reaction solution and the mixture was separated. 20% brine (22.8 mL) was added to the organic layer and the mixture was separated. The organic layer was concentrated under reduced pressure to 9 mL, and toluene (45.6 mL) was added and the mixture was concentrated under reduced pressure to 9 mL. Toluene (45.6 mL) was added again and the mixture was concentrated under reduced pressure to 9 mL. Anhydrous toluene (13.7 mL) was added to obtain a toluene solution of 2-O-acetyl-3,4,6-tri-O-benzyl-D-mannopyranose (compound represented by Formula A-2) as a colorless solution.

[0392] Example 51

[0393] A toluene solution (9.00 mmol) of 2-O-acetyl-3,4,6-tri-O-benzyl-D-mannopyranose (compound represented by Formula A-2) was added to a 100 mL recovery flask and cooled to 0°C. Trichloroacetonitrile (1.95 g, 13.5 mmol) and DBU (13.5 μL, 8.96 μmol) were then added. The mixture was stirred under nitrogen at 0°C for 4 hours. After confirming the completion of the reaction by HPLC, acetic acid (5.2 μL, 8.96 μmol) was added to the reaction solution at 0°C to obtain a toluene solution (9.00 mmol) of 2-O-acetyl-3,4,6-tri-O-benzyl-1-O-(2,2,2-trichloroethanimidoyl)-D-mannopyranose (compound represented by Formula A-3) as a brown solution. This solution was used directly in the next step.

[0394] Example 52

[0395] 4-Methoxyphenyl 2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→2)-3,4,6-tri-O-benzyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzyl-β-D-mannopyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-β-D-glucopyranosyl-(1→4 A toluene solution (equivalent to 1.27 mmol) of 2-O-acetyl-3,4,6-tri-O-benzyl-1-O-(2,2,2-trichloroethanimidoyl)-D-mannopyranose (compound represented by Formula A-3) (3.0 g, 1.06 mmol) was added to a 100 mL recovery flask, and toluene (30 mL) and molecular sieve 4A powder (10 μm or less, 600 mg) were added. Trimethylsilyl trifluoromethanesulfonate (38.5 μL, 0.212 mmol) was added dropwise over 15 minutes at −15°C under nitrogen, followed by stirring at the same temperature for 1 hour. After confirming the completion of the reaction by HPLC, triethylamine (0.19 mL, 1.06 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered and washed with acetonitrile (30 mL). The resulting filtrate was concentrated under reduced pressure to a volume of 6 mL. Acetonitrile (30 mL) was added again, and the mixture was concentrated under reduced pressure to a volume of 6 mL. To this concentrated mixture, acetonitrile (30 mL) was added, and reverse-phase silica gel 120RP-18 (Kanto Chemical, particle size 40-50 μm, 9.0 g) was added. Water (20 mL) was added dropwise over 30 minutes to adsorb the target substance onto the solid phase, followed by filtration. The solid phase was washed with acetonitrile / water (5:4, 90 mL) (the filtrate was dis...

Claims

1. Formula A-13 below: 【Chemical 1】 A method for producing an oligosaccharide represented by the formula: (Step I-1) Formula A-3: 【Chemistry 2】 The compound represented by the following formula A-4: 【Chemistry 3】 to form a compound represented by the following formula A-5: 【Chemistry 4】 The method of the present invention includes a step of producing a compound represented by the following formula A-7: 【Chemistry 5】 a step of producing a compound represented by (Step I-2) The compound represented by formula A-7 is reacted with a compound represented by formula A-8 below: 【Chemistry 6】 to form a compound represented by the following formula A-9: 【Chemistry 7】 The method of claim 1, further comprising the step of producing a compound represented by formula A-10: 【Chemistry 8】 a step of producing a compound represented by (Step I-3) The compound represented by formula A-10 is reacted with the compound represented by formula A-11 below: 【Chemistry 9】 to form a compound represented by the following formula A-12: 【Chemistry 10】 a step of producing an oligosaccharide represented by the formula A-13, comprising a step of producing a compound represented by the formula A-13; A method comprising:

2. The method according to claim 1, wherein in step I-2, the compound represented by formula A-9 is reacted with a strong base in the presence of an alkyl ester of a perfluorocarboxylic acid to produce the compound represented by formula A-10.

3. 3. The method of claim 2, wherein the alkyl ester of a perfluorocarboxylic acid is methyl trifluoroacetate, ethyl trifluoroacetate, propyl trifluoroacetate, isopropyl trifluoroacetate, butyl trifluoroacetate, methyl pentafluoropropionate, ethyl pentafluoropropionate, propyl pentafluoropropionate, isopropyl pentafluoropropionate, methyl heptafluorobutyrate, ethyl heptafluorobutyrate, propyl heptafluorobutyrate, isopropyl heptafluorobutyrate, butyl heptafluorobutyrate, methyl nonafluorovalerate, ethyl nonafluorovalerate, propyl nonafluorovalerate, isopropyl nonafluorovalerate, butyl nonafluorovalerate, methyl undecafluorocaproate, ethyl undecafluorocaproate, propyl undecafluorocaproate, isopropyl undecafluorocaproate, or butyl undecafluorocaproate.

4. 3. The method of claim 2, wherein the strong base is selected from the group consisting of sodium, lithium, and potassium salts of metal amides; sodium, lithium, potassium, cesium, and barium salts of C1-C20 alkoxides; sodium hydride, potassium hydride, lithium hydride, butyllithium, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, cesium phosphate, lithium phosphate, diazabicycloundecene (DBU), diazabicyclononene (DBN), and 1,1,3,3-tetramethylguanidine (TMG); and combinations thereof.

5. 3. The method of claim 2, wherein the strong base is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, or LHMDS (lithium hexamethyldisilazide).

6. The method according to claim 1, wherein in the step I-3, the compound represented by formula A-12 is reacted with DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone) in a mixed solvent of a fluorous alcohol and water to eliminate the 2-naphthylmethyl group in the compound represented by formula A-12, thereby producing the oligosaccharide represented by formula A-13.

7. The compound represented by the formula A-11 is (Step Y-1) A compound of the following formula B-1: 【Chemistry 11】 The compound represented by the following formula B-2: 【Chemistry 12】 to form a compound represented by the following formula B-3: 【Chemistry 13】 The method of the present invention includes a step of producing a compound represented by the following formula B-4: 【Chemistry 14】 a step of producing a compound represented by (Step Y-2) To a solvent containing the compound represented by formula B-4 and benzyl halide or benzyl sulfonate, lithium tert-butoxide or lithium tert-amoxide is added to protect the hydroxyl group present in the compound represented by formula B-4 with a benzyl group, thereby obtaining a compound represented by formula B-5: 【Chemistry 15】 a step of producing a compound represented by The method of claim 1 , wherein the polymer is produced by a process comprising:

8. The compound represented by formula B-5 can be obtained by ring-opening the phthalimide group in the compound represented by formula B-5 and then reacting it with cinchonidine to obtain a crystalline compound represented by formula B-6: 【Chemistry 16】 The crystalline compound represented by formula B-6 is separated from the amorphous substance, and then an acidic aqueous solution and a solvent are added to remove cinchonidine from the compound represented by formula B-6, to obtain a compound represented by formula B-7: 【Chemistry 17】 and then purifying the compound represented by formula B-7 by ring-closing the opened phthalimide group.

9. The compound represented by formula A-13 is subjected to ring-opening of the phthalimide group in the compound represented by formula A-13, followed by forming a salt with (R)-(+)-1-(1-naphthyl)ethylamine to obtain a crystalline compound represented by formula A-14 below: 【Chemistry 18】 The crystalline compound represented by formula A-14 is separated from the amorphous substance, and then, by adding an acidic aqueous solution and a solvent, (R)-(+)-1-(1-naphthyl)ethylamine in the compound represented by formula A-14 is removed to obtain a compound represented by formula A-15: 【Chemistry 19】 and then purifying the compound of formula A-15 by ring closure of the opened phthalimide group.

10. Formula D-13 below 【Chemistry 20】 A method for producing an oligosaccharide represented by the formula: (Step II-1) Compound of Formula A-13 below: 【Chemical Formula 21】 The oligosaccharide represented by the following formula A-3: 【Chemical 22】 to form a compound represented by the following formula D-1: 【Chemical 23】 The method includes the step of producing a compound represented by the following formula D-2: 【Chemistry 24】 a step of producing a compound represented by (Step II-2) The compound represented by formula D-2 is reacted with the compound represented by formula D-3 below: 【Chemistry 25】 to form a β-1,2-glycosidic bond with a compound represented by the following formula D-4: 【Chemical 26】 The method of claim 1, further comprising the step of producing a compound represented by formula D-5: 【Chemical 27】 After producing a compound represented by formula D-5, the amino group in the compound represented by formula D-5 is protected with a protecting group selected from an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, a 2,2,2-trichloroethoxycarbonyl (Troc) group, and a phthalimide (Pht) group to produce a compound represented by formula D-6: 【Chemical 28】 (wherein R ５ is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R ６ is a hydrogen atom, or R ５ and R ６ form a phthalimido group together with the nitrogen atom to which they are attached), or by removing the acetyl (Ac) group on the compound of formula D-4, a compound of formula D-6 (wherein R ５ and R ６ together with the nitrogen atom to which they are attached form a phthalimide group; (Step II-3) The compound represented by formula D-6 is reacted with the compound represented by formula D-7 below: 【Chemical formula 29】 to form a β-1,4-glycosidic bond with a compound represented by the following formula D-8: 【Chemistry 30】 (wherein R ５ is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R ６ is a hydrogen atom, or R ５ and R ６ form a phthalimide group together with the nitrogen atom to which they are attached), and then the protecting groups of the amino group and the acyl protecting group of the alcohol on the compound represented by formula D-8 are removed to produce a compound represented by formula D-9 below: 【Chemical 31】 A compound represented by the formula: ＋ is a sodium ion, a lithium ion, a potassium ion, or a protonated triethylamine cation), 【Chemical 32】 A compound represented by the formula: ＋ is a sodium ion, a lithium ion, a potassium ion, or a protonated triethylamine cation; (Step II-4) The compound represented by the formula D-11 is reacted with the compound represented by the following formula D-12: 【Chemical 33】 with a compound represented by formula D-13 to produce the oligosaccharide represented by formula D-13.

11. The method according to claim 10, wherein in step II-1, the compound represented by formula D-1 is reacted with a strong base in the presence of an alkyl ester of a perfluorocarboxylic acid to produce the compound represented by formula D-2.

12. 12. The method of claim 11, wherein the alkyl ester of a perfluorocarboxylic acid is methyl trifluoroacetate, ethyl trifluoroacetate, propyl trifluoroacetate, isopropyl trifluoroacetate, butyl trifluoroacetate, methyl pentafluoropropionate, ethyl pentafluoropropionate, propyl pentafluoropropionate, isopropyl pentafluoropropionate, methyl heptafluorobutyrate, ethyl heptafluorobutyrate, propyl heptafluorobutyrate, isopropyl heptafluorobutyrate, butyl heptafluorobutyrate, methyl nonafluorovalerate, ethyl nonafluorovalerate, propyl nonafluorovalerate, isopropyl nonafluorovalerate, butyl nonafluorovalerate, methyl undecafluorocaproate, ethyl undecafluorocaproate, propyl undecafluorocaproate, isopropyl undecafluorocaproate, or butyl undecafluorocaproate.

13. 12. The method of claim 11, wherein the strong base is selected from the group consisting of sodium, lithium, and potassium salts of metal amides; sodium, lithium, potassium, cesium, and barium salts of C1-C20 alkoxides; sodium hydride, potassium hydride, lithium hydride, butyllithium, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, cesium phosphate, lithium phosphate, diazabicycloundecene (DBU), diazabicyclononene (DBN), and 1,1,3,3-tetramethylguanidine (TMG); and combinations thereof.

14. 12. The method of claim 11, wherein the strong base is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, or LHMDS (lithium hexamethyldisilazide).

15. The method according to claim 10, wherein in step II-3, the amino group in the compound represented by formula D-5 is protected with an aryloxycarbonyl (COOAr) group to produce the compound represented by formula D-6.

16. The compound represented by formula D-12 can be prepared by the following process: To a solution containing the crude compound represented by formula D-12, a compound represented by formula E-1: 【Chemical 34】 (wherein R ７ is a hydrogen atom, a methyl group, or a methoxy group) to form a compound of the following formula E-2: 【Chemistry 35】 A crystalline compound represented by the formula: ７ is a hydrogen atom, a methyl group, or a methoxy group), isolating the crystalline compound, and then extracting the compound represented by formula D-12 from the isolated crystalline compound; The method according to claim 10, obtained by a purification method comprising:

17. The compound represented by formula D-5 is salted with fumaric acid to obtain a crystalline compound represented by the following formula: D-5-FMA: 【Chemical 36】 and then isolating and purifying the crystalline compound of formula D-5-FMA from non-crystalline material.

18. Formula A-10 below: 【Chemical 37】 The method for producing a compound represented by the following formula A-9: 【Chemical 38】 with a strong base in the presence of an alkyl ester of a perfluorocarboxylic acid.

19. 19. The method of claim 18, wherein the alkyl ester of a perfluorocarboxylic acid is methyl trifluoroacetate, ethyl trifluoroacetate, propyl trifluoroacetate, isopropyl trifluoroacetate, butyl trifluoroacetate, methyl pentafluoropropionate, ethyl pentafluoropropionate, propyl pentafluoropropionate, isopropyl pentafluoropropionate, methyl heptafluorobutyrate, ethyl heptafluorobutyrate, propyl heptafluorobutyrate, isopropyl heptafluorobutyrate, butyl heptafluorobutyrate, methyl nonafluorovalerate, ethyl nonafluorovalerate, propyl nonafluorovalerate, isopropyl nonafluorovalerate, butyl nonafluorovalerate, methyl undecafluorocaproate, ethyl undecafluorocaproate, propyl undecafluorocaproate, isopropyl undecafluorocaproate, or butyl undecafluorocaproate.

20. 19. The method of claim 18, wherein the strong base is selected from sodium, lithium, and potassium salts of metal amides; sodium, lithium, potassium, cesium, and barium salts of C1-C20 alkoxides; sodium hydride, potassium hydride, lithium hydride, butyllithium, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, cesium phosphate, lithium phosphate, diazabicycloundecene (DBU), diazabicyclononene (DBN), and 1,1,3,3-tetramethylguanidine (TMG); and combinations thereof.

21. 19. The method of claim 18, wherein the strong base is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, or LHMDS (lithium hexamethyldisilazide).

22. Formula A-13 below: 【Chemical 39】 A method for producing an oligosaccharide represented by the following formula A-12: 【Chemistry 40】 with DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone) in a mixed solvent of a fluorous alcohol and water to eliminate the 2-naphthylmethyl group in the compound represented by formula A-12.

23. Formula D-8 below: 【Chemistry 41】 (wherein R ５ is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R ６ is a hydrogen atom, or R ５ and R ６ form a phthalimide group together with the nitrogen atom to which they are attached, the method comprising producing a compound of the following formula D-6: 【Chemistry 42】 (wherein R ５ is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R ６ is a hydrogen atom, or R ５ and R ６ form a phthalimido group together with the nitrogen atom to which they are attached), and then the compound represented by formula D-6 is treated with the following compound D-7: 【Chemistry 43】 to a compound represented by formula D-8 via a β-1,4-glycosidic bond.

24. R ５ 24. The method of claim 23, wherein is an aryloxycarbonyl (COOAr) group.

25. The protecting group of the amino group and the acyl protecting group of the alcohol in the compound represented by formula D-8 are removed to give a compound represented by formula D-9: 【Chemical 44】 A compound represented by the formula: ＋ is a sodium ion, a lithium ion, a potassium ion, or a protonated triethylamine cation.

26. Formula A-13 or D-13 below: 【Chemistry 45】 、 【Chemistry 46】 An oligosaccharide represented by the formula:

27. A compound selected from the group consisting of compounds represented by the following formulae A-5, A-6, A-7, A-9, A-10, A-11, A-12, A-14, A-15, D-1, D-2, D-4, D-5, D-5-FMA, D-6, D-8, D-9, D-10, and D-11: 【Chemistry 47】 、 【Chemistry 48】 、 【Chemistry 49】 、 【Chemistry 50】 、 【Chemistry 51】 、 【Chemistry 52】 、 【Chemistry 53】 、 【Chemical 54】 、 【Chemistry 55】 、 【Chemical 56】 、 【Chemical 57】 、 【Chemistry 58】 、 【Chemical Formula 59】 、 【Chemistry 60】 、 【Hua 61】 、 【Hua 62】 、 【Chemistry 63】 、 【Hua 64】 、 【Chemistry 65】 (In the compounds represented by formula D-6 and formula D-7, R 5 is an aryloxycarbonyl (COOAr) group, an acetyl (Ac) group, or a 2,2,2-trichloroethoxycarbonyl (Troc) group, and R 6 is a hydrogen atom, or R 5 and R 6 together with the nitrogen atom to which they are bonded form a phthalimido group; In the compounds represented by formula D-9, formula D-10, and formula D-11, M + is a sodium ion, a lithium ion, a potassium ion, or a protonated triethylamine cation.

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