Novel dealkoxyphenylation reaction

Abstract

[Abstract] [Problem] To provide a method for producing a dealkoxyphenylation product with high yield from a substrate, e.g., a sugar, which is bonded to an alkoxyphenyl group through an oxygen atom. [Solution] A substrate that is bonded to a phenyl group substituted by a C1 to C5 alkoxy group at a para- or ortho-position through an oxygen atom is reacted with a λ3-iodane in a fluorous alcohol and water, whereby a dealkoxyphenylation product can be obtained with high yield under mild conditions.

Description

[Technical Field]

[0001] The present invention relates to a novel dealkoxyphenylation reaction, and more specifically, to a method for obtaining a substrate having a hydroxyl group from a substrate such as a sugar bonded to a phenyl group substituted with an alkoxy at the para or ortho position via an oxygen atom. [Background technology]

[0002] In the chemical synthesis of oligosaccharide chains and other compounds having multiple hydroxyl groups, it is necessary to rationally utilize methods for selective protection and deprotection of such hydroxyl groups in order to efficiently obtain the desired compound. From this perspective, various protecting groups have been used, and methods for protection and deprotection have been developed in the chemical synthesis of sugars and other compounds. Among these, the paramethoxyphenyl group has been widely used, for example, as a general protecting group for sugar anomeric positions because it can be handled stably under both acidic and basic conditions and can be easily deprotected oxidatively (Non-Patent Literature 1).

[0003] A common and long-established method for deprotecting the above-mentioned paramethoxyphenyl group is the method using cerium(IV) ammonium nitrate (Non-Patent Literature 2). This method yields the desired deprotected product in moderate to high yields for a wide range of substrates. However, it generally requires the use of an excess amount of cerium(IV) ammonium nitrate, which necessitates the reduction of excess oxidizing agent during post-treatment. Furthermore, there have been reports that the desired deprotected product is not always obtained in satisfactory yields depending on the substrate applied (Non-Patent Literature 3). For these reasons, the development of a more efficient method has been desired.

[0004] As a means of achieving this objective, a method for deprotecting the anomeric paramethoxyphenyl group by electrolytic reaction has been reported (Non-Patent Literature 3). However, since this method requires special experimental equipment, it is considered difficult to scale up due to equipment limitations.

[0005] Furthermore, a method has been reported in which the anomeric hydroxyl group of a sugar is protected with a paramethoxyphenyl group, and then deprotected in the presence of zinc halide and acid halide to convert it to a halogenated sugar (Non-Patent Literature 4). However, during this deprotection, the benzyl group on the hydroxyl group is converted to an acetyl group, which makes it difficult to say that the reaction is carried out under mild conditions. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Matsuzaki,Y.;Ito,Y.;Nakahara,Y.;Ogawa,T.Tetrahedron Lett.1993,34,1061. [Non-Patent Document 2] Fukuyama,T.;Laird,AA;Hotchkiss,LMTetrahedron Lett.1985,26,6291. [Non-Patent Document 3] Iacobucci, S.; Filippova, N.; Alarcao, M. Carbohydrate Res.1995,277,321. [Non-Patent Document 4] Zhang, Z.; Magnusson, G. Carbohydrate Res.1996,925,41. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] Given the above background, there has been a need for the development of deparamethoxyphenylation reactions that can deprotect the protecting group of the paramethoxyphenyl group under milder conditions and obtain the deprotected product in high yield. [Means for solving the problem]

[0008] The inventors of the present invention have discovered that a dealkoxyphenylation product can be obtained in high yield under mild conditions by reacting (acting on) a substrate in which a phenyl group substituted with a C1-C5 alkoxy at the para or ortho position is bonded via an oxygen atom with λ3-iodane in fluorescein alcohol and water, thereby completing the present invention.

[0009] In other words, the present invention relates to the following: [1] A method for producing a compound represented by the formula R-OH, comprising the step of reacting a compound represented by the formula R-OX (wherein R is a substrate, and X is a phenyl group substituted with a C1-C5 alkoxy at the para or ortho position, the phenyl group may optionally be further substituted) with λ3-iodane in fluorescein alcohol and water. [2] The method according to [1], wherein the C1-C5 alkoxy in the X group is methoxy, ethoxy, propyroxy, or isopropyloxy. [3] The method according to [1], wherein the C1-C5 alkoxy in the X group is paramethoxy. [4] The aforementioned λ3-Yordan is given by equation R 1 -I(OR 2 It is a compound represented by )2, R 1 However, it is an unsubstituted or substituted phenyl group, R 2 The method according to any one of [1] to [3], wherein the selected element is from the group consisting of H, acetyl, trifluoroacetyl, tosyl, methanesulfonyl, and combinations thereof. [5] The above formula R 1 -I(OR 2The method according to [4], wherein the compound represented by )2 is selected from the group consisting of [bis(trifluoroacetoxy)iodo]benzene (PIFA), [hydroxy(tosyloxy)iodo]benzene (HTIB), (diacetoxyiodo)benzene (PIDA), [bis(trifluoroacetoxy)iodo]pentafluorobenzene, [hydroxy(methanesulfonyloxy)iodo]benzene, and combinations thereof. [6] The method according to any one of [1] to [5], wherein the amount of λ3-iodane is 0.1 to 10 equivalents relative to the substrate. [7] The method according to any one of [1] to [6], wherein the fluorescein alcohol is a fluorescein aliphatic alcohol. [8] The method according to [7], wherein the fluorous aliphatic alcohol is a fluorous C2-C8 aliphatic alcohol. [9] The method according to [8], wherein the fluorescein C2-C8 aliphatic 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.

[10] The method according to any one of [1] to [9], comprising adding a solvent selected from the group consisting of CH2Cl2, toluene, (trifluoromethyl)benzene, and combinations thereof.

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

[10] , wherein the amount of the fluorescein alcohol is 1.0 equivalent or more in molar ratio with respect to the substrate and 15 or less in volume ratio.

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

[11] , wherein the amount of water is 1.0 equivalent or more in molar ratio with respect to the substrate and 10 or less in volume ratio.

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

[12] , comprising adding an additive selected from the group consisting of sodium dihydrogen phosphate (NaH2PO4), potassium dihydrogen phosphate (KH2PO4), disodium hydrogen phosphate (Na2HPO4), and combinations thereof.

[14] The method according to any one of [5] to

[13] , comprising adding trifluoroacetic acid when (diacetoxyiodo)benzene (PIDA) is used as the λ3-iodane.

[15] A method described in any one of the following [1] to

[14] , performed at a temperature of -20°C to 60°C.

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

[15] , wherein the substrate R is a sugar having the OX group at the 1-position or anomeric position.

[17] The method according to

[16] , wherein the sugar is a monosaccharide or a polysaccharide.

[18] The method according to

[17] , wherein the monosaccharide has a cyclic structure of a 5-membered ring or a 6-membered ring.

[19] The method according to

[18] , wherein the monosaccharide is a pentasaccharide or a hexasaccharide.

[20] The method according to

[19] , wherein the hexose is glucose, mannose, galactose, or glucosamine. [twenty one] The method according to

[17] , wherein the polysaccharide is a disaccharide to a decasaccharide. [twenty two] The method according to

[17] , wherein the polysaccharide is (i) a disaccharide which is galactose-glucosamine, glucosamine-glucosamine, neuraminic acid-galactose, or mannose-glucosamine; (ii) a trisaccharide which is composed of two mannose molecules and one glucosamine molecule, or a trisaccharide which is composed of neuraminic acid, galactose, and glucosamine; or (iii) a tetrasaccharide which is composed of two mannose molecules and two glucosamine molecules, or a tetrasaccharide which is composed of three mannose molecules and one glucosamine molecule. [twenty three] The method according to any one of

[16] to

[22] , wherein the hydroxyl group of the carbon adjacent to the carbon at position 1 or anomeric in the sugar is protected with an acyl group, or the amino group of the carbon adjacent to the carbon at position 1 or anomeric in the sugar is protected with an imide group, an acyl group, or a carbamate group, or the carbon adjacent to the carbon at position 1 or anomeric in the sugar has an azide group (N3). [twenty four] The method according to

[23] , wherein the protecting group for the amino group is phthaloyl (Phth), the acyl group is acetyl (Ac), and the carbamate group is selected from the group consisting of (2,2,2-trichloroethoxy)carbonyl (Troc), allyloxycarbonyl (Alloc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), and benzyloxycarbonyl (Cbz). [twenty five] The method according to

[23] , wherein the acyl group is selected from the group consisting of acetyl (Ac) and benzoyl (Bz) as the protecting group for the hydroxyl group.

[26] A method for producing a sugar to which an addition is attached, comprising the step of attaching one or more additions selected from the group consisting of proteins, nucleic acid molecules, lipid molecules, eukaryotic cells, prokaryotic cells, tissues of biological origin, viruses, parasites, low molecular weight compounds and artificial materials to a sugar obtained by any one of the methods of

[16] to

[25] .

[27] The method according to

[26] , wherein the added portion is a protein.

[28] The method according to

[27] , wherein the protein is a receptor, and the receptor is a soluble receptor, fused to the Fc region of an antibody, or unmodified.

[29] The method according to

[27] , wherein the protein is an antibody or an antigen-binding fragment thereof, and the antibody or the antigen-binding fragment thereof is bound to a peptide, a nucleic acid molecule, a lipid molecule, a low molecular weight compound, an artificial product, another antibody or an antigen-binding fragment thereof, or a toxin, or forms a complex with a drug, or is not modified.

[30] The method according to

[27] , wherein the protein is a cytokine, and the cytokine is bound to an antibody or an antigen-binding fragment thereof, or is not modified.

[31] The method according to any one of

[26] to

[30] , further comprising a step of binding one or more additional moieties to the sugar, in addition to the moiety that is a protein.

[32] The substrate R is Ar-(CR 1 R 2 )n- (where n = 1 to 3, Ar is an aromatic ring, and R 1 and R 2 are each H, an aromatic ring, or an aliphatic group, and any of the aromatic rings and aliphatic groups may be optionally substituted), according to any one of [1] to

[15] .

[33] The aromatic ring is an optionally substituted C5-C 20 aryl group or a 5- to 20-membered heteroaryl group, and the aliphatic group is an optionally substituted C1-C 10 aliphatic hydrocarbon group, according to

[32] .

[34] The aromatic ring is selected from the group consisting of xylene, toluene, styrene, ethylbenzene, cumene, furan, thiophene, pyrrole, pyran, thiopyran, pyridine, thiazole, imidazole, pyrimidine, 1,3,5-triazine, naphthalene, indene, anthracene, phenanthrene, fluorene, biphenyl, triphenyl, terphenyl, binaphthyl, phenylnaphthalene, indole, quinoline, and purine, according to

[32] or

[33] . [Advantages of the Invention]

[0010] According to the present invention, a dealkoxyphenylation product can be obtained in high yield under mild conditions from a substrate such as a sugar bonded to a phenyl group substituted with a C1-C5 alkoxy at the para or ortho position via an oxygen atom. Therefore, it offers high operational safety, can be carried out with simple procedures, and the product can be easily purified, making it suitable for large-scale synthesis of such products. [Modes for carrying out the invention]

[0011] The present invention provides a method for obtaining a compound represented by the formula R-OH, comprising reacting (acting upon) a compound represented by the formula R-OX (wherein R is a substrate, and X is a phenyl group substituted with a C1-C5 alkoxy at the para or ortho position, and the phenyl group may optionally be further substituted) with λ3-iodane in fluorescein alcohol and water.

[0012] In this specification, the reaction in which a compound represented by formula R-OH is produced from a compound represented by formula R-OX is referred to as a "dealkoxyphenylation reaction." Although not bound by the reaction mechanism, the above reaction mechanism is understood to be as follows: λ3-iodane acts as a one-electron oxidizing agent for the compound represented by formula R-OX, the OX group is removed from the compound represented by formula R-OX, and then water (H2O) is added to it, resulting in the production of the compound represented by formula R-OH. It is well known to those skilled in the art that in the field of organic synthesis chemistry, including glycosylation, paramethoxyphenyl groups and the like are often used as "protecting groups" for highly reactive functional groups such as hydroxyl groups to achieve the desired reaction. However, the present invention is not limited to such deprotection purposes and applies to any case in which a compound represented by formula R-OH is produced from a compound represented by formula R-OX. However, in this specification, for the sake of ease of understanding, the compound represented by the above formula R-OX may be referred to as the "protected compound," the above alkoxyphenyl group (X group) may be referred to as the "protecting group," the above dealkoxyphenylation reaction may be referred to as the "deprotection reaction," and the resulting compound represented by the formula R-OH may be referred to as the "deprotected compound."

[0013] In the compound represented by the formula R-OX above, "R" refers to the substrate. A "substrate" refers to any organic compound that can bond to a phenyl group (X group) substituted with a C1-C5 alkoxy at the para or ortho position via an oxygen atom.

[0014] In one embodiment, the substrate R may be a "sugar." Sugars include monosaccharides and polysaccharides. The "monosaccharide" may be either a D-isomer or an L-isomer, and may be either an aldose or a ketose.

[0015] In one embodiment, the present invention preferably uses polyhydric alcohols having a 5-membered or 6-membered ring cyclic structure, in which one of the carbon atoms forming the cyclic structure is replaced by oxygen and contains two or more hydroxyl groups as the "monosaccharide". More specifically, monosaccharides such as pentoses, hexoses, heptoses, octuloses, and nonoses that form a 5-membered or 6-membered ring cyclic structure are preferably used, with pentoses and hexoses being more preferred, and hexoses being even more preferred. Specific examples of pentoses include ribose, xylose, aviose, arabinose, ribulose, and xylulose. Specific examples of hexoses include glucose, mannose, galactose, altrose, psicose, and fructose, with glucose, mannose, and galactose being preferably used.

[0016] In one embodiment, the present invention may use a "polysaccharide" as the substrate. A "polysaccharide" is a sugar in which two or more monosaccharides are linked by glycosidic bonds, and includes sugars generally called oligosaccharides. In the present invention, the polysaccharide is preferably a polysaccharide composed of monosaccharides that form a cyclic structure of a 5-membered ring or a 6-membered ring as described above, and disaccharides to decasaccharides are preferably used, but are not limited to these.

[0017] Furthermore, in the present invention, "sugar" also includes derivatives of monosaccharides or polysaccharides. Examples of monosaccharide derivatives include amino sugars (glucosamine, galactosamine, mannosamine, neuraminic acid, sialic acid, muramic acid, etc.), deoxy sugars (deoxyribose, deoxyglucose, rhamnose, fucose, etc.), uronic acids (glucuronic acid, guluronic acid, mannuronic acid, galacturonic acid, iduronic acid, etc.), etc., or their derivatives (e.g., acetylated derivatives). For example, the above amino sugars or their derivatives (e.g., N-acetylglucosamine, N-acetylgalactosamine, N-acetylneuraminic acid, etc.) are preferably used. Polysaccharide derivatives refer to sugars in which two or more monosaccharides are linked together and which contain at least one of the above monosaccharide derivatives.

[0018] Preferred examples of polysaccharides in the present invention include disaccharides, trisaccharides, or tetrasaccharides at any position constituting the human-type N-type sialyl glycopeptide (SGP), for example, (i) disaccharides such as galactose-glucosamine, glucosamine-glucosamine, neuraminic acid-galactose, and mannose-glucosamine; (ii) trisaccharides consisting of two mannose molecules and one glucosamine molecule, or trisaccharides consisting of neuraminic acid, galactose, and glucosamine; and (iii) tetrasaccharides consisting of two mannose molecules and two glucosamine molecules, or tetrasaccharides consisting of three mannose molecules and one glucosamine molecule. Another example of a polysaccharide in the present invention is a decasaccharide in which one N-acetylglucosamine (GlcNAc) molecule is missing from the reducing end of the sugar chain portion (SG) of the SGP.

[0019] In one embodiment, the sugar (monosaccharide, polysaccharide, or derivative thereof, etc.) used as the substrate in the present invention may have other parts (hereinafter referred to as "attaching parts") attached to it.

[0020] In another embodiment, a sugar represented by the formula R-OH (hereinafter referred to as "resulted sugar") can be produced from a sugar-containing compound represented by the formula R-OX, where the substrate R is a sugar, by the method of the present invention, and a sugar derivative (hereinafter referred to as "resulted sugar derivative" or "derivative of resulting sugar") can be produced by further reaction, either by adding another sugar to the resulting sugar or by modifying the resulting sugar by adding a protein or the like. The resulting sugar and the resulting sugar derivative may contain substances other than sugar, such as proteins, low molecular weight compounds, nucleic acid molecules, peptides, lipids, artificial materials, etc., as "additional parts." The present invention provides a method for producing a resulting sugar and a method for producing a resulting sugar derivative. Due to the presence of "additional parts" such as proteins, the resulting sugar and the resulting sugar derivative may possess activities or functions, such as catalytic activity, labeling function, enzyme substrate function, cytotoxic activity, immune cell activating activity, antioxidant activity, protective activity, receptor function, ligand function, pharmacokinetic regulatory function, drug delivery function, etc.

[0021] Examples of the "addition portion" to the sugar mentioned above include, but are not limited to, biomacromolecules such as proteins, nucleic acid molecules, and lipid molecules, cells (eukaryotic cells, prokaryotic cells), tissues of biological origin, parasites such as viruses, small molecule compounds, and artificial materials. The "addition portion" may possess activity or function, such as catalytic activity, labeling function, enzyme substrate function, cytotoxic activity, immune cell activating activity, antigen binding activity, protective effect, receptor function, ligand function, pharmacokinetic regulatory function, drug delivery function, infectivity, etc. Proteins as one embodiment of the "addition portion" can be derived from humans or non-human animals, are wild-type, modified, or artificially designed, and preferably include cytokines, receptors, immunoglobulins (antibodies), or fragments thereof. Suitable cytokines, but are not limited to, include wild-type human cytokines, immunocytokines, and fragments thereof. Suitable receptors, but are not limited to, include soluble receptors and nuclear receptors, and may be fusions of a receptor or fragment thereof with an immunoglobulin Fc region. The antibody may be an antigen-binding fragment of an antibody such as a full-body antibody or scFv, a complex of an antibody or its antigen-binding fragment with a drug (hereinafter referred to as "antibody-drug complex"), a multispecific antibody, an immunotoxin, a labeled antibody or its binding fragment, etc. In the present invention, these may also be referred to as "proteins". A "low molecular weight compound" as one aspect of the "additional portion" may be a platinum-based compound such as cisplatin or carboplatin. As stated above, the present invention also provides a method for producing a sugar to which an addition portion is attached, including a step of attaching the addition portion to the sugar, and a method for producing a sugar derivative to which an addition portion is attached, including a step of attaching the addition portion to the sugar derivative. However, the sugar and sugar derivative to which an addition portion is attached may be further modified or altered, and those that have been modified or altered in this way are also included in the scope of "sugar to which an addition portion is attached" and "sugar derivative to which an addition portion is attached".

[0022] Furthermore, the first addition portion and the second addition portion can be linked together via the generated sugar or generated sugar derivative of the present invention. For example, via the generated sugar or generated sugar derivative, immunocytokines formed by the binding of an antibody or its antigen-binding fragment to a cytokine, immunotoxins formed by the binding of an antibody or its binding fragment to a toxin, and antibody-drug conjugates formed by the binding of an antibody or its antigen-binding fragment to a drug can be produced. Therefore, the present invention also provides a method for producing a generated sugar formed by the linkage of the first addition portion and the second addition portion, and a method for producing a generated sugar derivative formed by the linkage of the first addition portion and the second addition portion. Examples of combinations of the first addition portion and the second addition portion include, but are not limited to, a first antibody and a second antibody, an antibody and a cytokine, an antibody and a toxin, an antibody and a drug, a receptor fragment and the Fc region of an antibody, etc. In another embodiment, the addition portion may be bound to or contained in a compound represented by the formula R-OX or a compound represented by the formula R-OH. Furthermore, a compound represented by the formula R-OH containing an adduct can be referred to as an "adducted-molecule-containing product." An adducted-molecule-containing product can be produced from a compound represented by the formula R-OX, in which R is a substrate containing an adduct, by the method provided in the present invention.

[0023] In the present invention, when a sugar is the substrate, the above-mentioned X group (a phenyl group substituted with a C1-C5 alkoxy at the para or ortho position) is covalently bonded to a hydroxyl group present at the 1st or anomeric carbon in the sugar, forming an "OX group".

[0024] In the present invention, in the substrate sugar, the hydroxyl group of the carbon adjacent to the carbon at position 1 or anomeric, which has an OX group, may be protected with an acyl group, for example, acetyl (Ac) or benzoyl (Bz), an ether protecting group, for example, benzyl (Bn), or a silyl protecting group, for example, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), or triisopropylsilyl (TIPS). Alternatively, in the substrate sugar, the amino group of the carbon adjacent to the carbon at position 1 or the anomeric position having an OX group (for example, if an amino group is present, such as in an amino sugar) may be protected with an imide group, such as phthaloyl (Phth), an acyl group, such as acetyl (Ac), or a carbamate group, such as (2,2,2-trichloroethoxy)carbonyl (Troc), allyloxycarbonyl (Alloc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), or benzyloxycarbonyl (Cbz). Alternatively, in the substrate sugar, the carbon adjacent to the carbon at position 1 or the anomeric position having an OX group may have an azide group (N3). In particular, it is preferable that in the substrate sugar, the hydroxyl group of the carbon adjacent to the carbon at position 1 or the anomeric position having the OX group is protected with an acyl group, or that the amino group of the carbon adjacent to the carbon at position 1 or the anomeric position having the OX group is protected with an imide group or a carbamate group. The presence of a protecting group having a carbonyl oxygen atom on the hydroxyl group or amino group on the carbon adjacent to the carbon at position 1 or the anomeric position having the OX group is very useful for increasing the yield of the dealkoxyphenylation reaction product. Other hydroxyl groups present in the sugar may be unsubstituted, or they may be protected with acyl groups (e.g., acetyl (Ac), benzoyl (Bz)), ether groups (e.g., benzyl (Bn), 2-naphthylmethyl (Nap), methoxymethyl (MOM), dihydropyran (DHP), allyl), silyl groups (e.g., trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), TBDPS (tert-butyldiphenylsilyl)), or trityl groups (e.g., triphenylmethyl).

[0025] In another embodiment, the substrate R is Ar-(CR 1 R 2 )n-(wherein n=1 to 3, preferably n=1 to 2, and especially preferably n=1, Ar is an aromatic ring, R 1 and R 2 Each of these is either H, an aromatic ring, or an aliphatic group, and any of the aromatic rings and aliphatic groups may be substituted at will.

[0026] The above Ar-(CR 1 R 2 )n- Ar, R 1 , and R 2The "aromatic ring" defined in this context can be a monocyclic aromatic ring or a polycyclic aromatic ring. Examples of a "monocyclic aromatic ring" include monocyclic aromatic hydrocarbons or monocyclic heteroaromatic rings (a heteroaromatic ring refers to a heterocyclic compound having aromatic properties). An example of a "monocyclic aromatic hydrocarbon" is unsubstituted benzene. As will be discussed later, this benzene may be substituted, and specific examples of benzene having hydrocarbon substituents include xylene, toluene, styrene, ethylbenzene, cumene, etc. Examples of "monocyclic heteroaromatic rings" include furan, thiophene, pyrrole, pyran, thiopyran, pyridine, thiazole, imidazole, pyrimidine, 1,3,5-triazine, etc. Examples of "polycyclic aromatic rings" include polycyclic aromatic hydrocarbons and polycyclic heteroaromatic rings. Examples of "polycyclic aromatic hydrocarbons" include ring-assembled aromatic hydrocarbons (i.e., aromatic compounds in which two or more aromatic rings, for example 2 to 5 aromatic rings, are directly linked) and condensed polycyclic aromatic hydrocarbons (in which two or more aromatic rings, for example 2 to 5 aromatic rings, are fused together), such as naphthalene, indene, anthracene, phenanthrene, fluorene, biphenyl, triphenyl, terphenyl, binaphthyl, and phenylnaphthalene. Examples of "polycyclic heteroaromatic rings" include ring-assembled heteroaromatic rings (in which at least one heteroaromatic ring is present and two or more, for example 2 to 5 aromatic rings or heteroaromatic rings, are directly linked) and condensed polycyclic heteroaromatic rings (in which at least one heteroaromatic ring is present and two or more, for example 2 to 5 aromatic rings or heteroaromatic rings, are fused together), such as indole, quinoline, and purine. The above aromatic ring can also be represented as an aryl group or a heteroaryl group, for example, C5~C 20 Aryl group, C5~C 14 Aryl group, or C5~C 10The aromatic ring may be an aryl group, or a 5-20 membered heteroaryl group, a 5-14 membered heteroaryl group, or a 5-10 membered heteroaryl group, but is not limited to these. The aromatic ring may be unsubstituted or may have one or more substituents. Examples of substituents include linear or branched saturated or unsaturated hydrocarbon groups, oxygen-containing groups (hydroxy, alkoxy, aldehyde, ketone, acetoxy, acetyl, carbonyl, oxy, carboxyl, ester, etc.), nitrogen-containing groups (amino, cyano, imide, azo, azide, etc.), sulfur-containing groups (sulfonyl, thiol, etc.), halogens (e.g., fluorine, chlorine, bromine, iodine), etc., but hydrocarbon groups, oxygen-containing groups, and halogens are more preferred. When these substituents contain carbon, for example, those having 1-10 carbon atoms, 1-5 carbon atoms, or 1-3 carbon atoms can be suitably used (e.g., C1-C 10 hydrocarbon group, C1-C5 hydrocarbon group, or C1-C3 hydrocarbon group, or C1-C 10 Alkyl alkoxy, C1-C5 alkoxy, or C1-C3 alkoxy can be preferably used.

[0027] The above Ar-(CR 1 R 2 )n-R in the middle 1 and R 2 The "aliphatic groups" defined for this are C1-C 10 Hydrocarbon groups, preferably C1-C5 hydrocarbon groups, more preferably C1-C3 hydrocarbon groups, may be saturated or unsaturated acyclic, or saturated or unsaturated cyclic. Furthermore, if the hydrocarbon group is acyclic, it may be linear or branched. 10 A hydrocarbon group is, for example, C1-C 10 Alkyl alkyl groups, C2-C 10 Alkenyl group, C2~C 10 Alkynyl group, C4~C 10 Alkyldienyl group, C4~C 10 Cycloalkyl groups, C4~C 10 It may contain cycloalkenyl groups, etc., and may also contain C1-C6 hydrocarbon groups or C1-C3 hydrocarbon groups.10 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, nonyl, and decyl. C2~C 10 Examples of alkenyl groups include vinyl, allyl, propenyl, isopropenyl, 2-methyl-1-propenyl, and 2-butenyl. C2~C 10 Examples of alkynyls include ethynyl, 2-propynyl, and 2-butynyl. C4~C 10 Examples of alkyldienyl groups include 1,3-butadienyl. C4~C 10 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. C4~C 10 Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, 2-cyclopenten-1-yl, and 2-cyclohexen-1-yl. The above examples of hydrocarbon groups are referenced throughout this specification. Furthermore, the above "aliphatic group" may be unsubstituted or may have one or more substituents, C1-C 10 At least one hydrogen atom in a hydrocarbon group or the like may be substituted with a non-hydrogen atom or group such as an oxygen-containing group (hydroxy, alkoxy, aldehyde, ketone, acetoxy, acetyl, carbonyl, oxy, carboxyl, ester, etc.), a nitrogen-containing group (amino, cyano, isosinate, imide, azo, azide, etc.), a sulfur-containing group (sulfonyl, thiol, etc.), or a halogen (e.g., fluorine, chlorine, bromine, iodine), or may have or contain such a group. Preferably, for example, an oxygen-containing group or a halogen. Furthermore, the above "aliphatic group" is C5~C 20 Aryl group (for example, C5~C 14 Aryl group, or C5~C 10 It may be substituted with an aryl group.

[0028] In the above formula R-OX, "OX" indicates that oxygen (O) and X are covalently bonded, and "X" represents a phenyl group substituted with a C1-C5 alkoxy (also called an alkyloxy group) at the para or ortho position. A compound represented by formula R-OX may contain one OX group or multiple OX groups. Specific examples of the above "C1-C5 alkoxy" include, for example, methoxy, ethoxy, propyroxy, 1-methylethoxy, butoxy, 2-methylpropyroxy, 1-methylpropyroxy, 1,1-dimethylethoxy, pentyloxy group, 3-methylbutoxy, 2-methylbutoxy, 2,2-dimethylpropyroxy, 1-ethylpropyroxy, 1,1-dimethylpropyroxy, etc. C1-C3 alkoxys, such as methoxy, ethoxy, propyroxy, and isopropyroxy, are preferred, methoxy and ethoxy are more preferred, and methoxy is even more preferred. The above examples of "C1-C5 alkoxy" are also referenced throughout this specification. Furthermore, the above "C1-C5 alkoxy" may be located at either the para or ortho position of the phenyl group, but the para position is preferred. The phenyl group in the above X group may be unsubstituted, or may be further substituted with one or more substituents of any choice. Examples of such substituents include linear or branched saturated or unsaturated hydrocarbon groups, oxygen-containing groups (hydroxy, alkoxy, aldehyde, ketone, acetoxy, acetyl, carboxyl, ester, etc.), nitrogen-containing groups (amino, cyano, imide, azo, azide, etc.), sulfur-containing groups (sulfonyl, thiol, etc.), halogens (e.g., fluorine, chlorine, bromine, iodine), etc., but more preferably hydrocarbon groups, oxygen-containing substituents, and halogens. When these substituents contain carbon, for example, those having 1 to 10 carbon atoms, 1 to 5 carbon atoms, or 1 to 3 carbon atoms can be suitably used (e.g., C1-C 10 hydrocarbon group, C1-C5 hydrocarbon group, or C1-C3 hydrocarbon group, or C1-C 10 Alkyl alkoxy, C1-C5 alkoxy, or C1-C3 alkoxy can be preferably used.

[0029] "λ3-iodane" refers to a trivalent hypervalent iodine compound. By using λ3-iodane, the yield of the dealkoxyphenylation reaction product is higher compared to conventional deprotection methods, and the reaction can be carried out under milder reaction conditions. Furthermore, since the reaction proceeds with a small excess of λ3-iodane, the purification of the deprotected product is easier and the operation is safer compared to conventional deprotection methods that use, for example, an excess of cerium(IV) ammonium nitrate.

[0030] In one embodiment, λ3-Yordan is given by formula R 1 -I(OR 2 The compound is represented by 2 (wherein R 1 R is an unsubstituted or substituted phenyl group, 2 (is selected from the group consisting of H, acetoxy, trifluoroacetoxy, tosyloxy, methanesulfonyloxy, and combinations thereof). As defined in the above formula, R 1 The substituent may be a "substituted phenyl group," and examples of such substituents include linear or branched saturated or unsaturated hydrocarbon groups, oxygen-containing groups (alkoxy, ester, etc.), nitrogen-containing groups (cyano, azide, etc.), halogens (e.g., fluorine, chlorine, bromine, iodine), etc., but more preferably hydrocarbon groups, oxygen-containing substituents, and halogens. When these substituents contain carbon, for example, those having 1 to 5 carbon atoms or 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.

[0031] The amount of λ3-iodane can be appropriately set depending on the type of substrate, from the viewpoint of achieving a high yield of the product, etc., but for example, it may be about 0.1 to 10 equivalents, about 0.5 to 7 equivalents, or about 1 to 5 equivalents relative to the substrate. These amounts are suitably applied to any substrate, but in particular, about 1 to 3 equivalents is more preferable when the substrate is a monosaccharide, and about 1 to 4.5 equivalents is more preferable when the substrate is a disaccharide, and the above Ar-(CR 1 R 2 If n-, approximately 1 to 3 equivalents are more preferable. Throughout this specification, the term "approximately" indicates a range of ±10% of the value mentioned.

[0032] "Fluorescent alcohol" refers to a fluorine-containing alcohol compound in which all carbon atoms except the carbon bonded to the alcohol are fluorine. Fluorescent alcohols are preferably those with more fluorine, as long as fluorine substitution is permitted. Fluorescent alcohols include, but are not limited to, fluorescent aliphatic alcohols. The hydrocarbon portion in a fluorescent aliphatic alcohol may be saturated or unsaturated, linear or branched, or cyclic. Examples of fluorescent aliphatic alcohols include fluorescent C2-C8 aliphatic alcohols, preferably fluorescent C2-C5 aliphatic alcohols, and more preferably fluorescent C2-C3 aliphatic alcohols. Specific examples of fluorescent alcohols include, but are not limited to, 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.

[0033] Furthermore, in preferred combinations thereof, fulcolas alcohol and λ3-iodane can yield deprotected products in higher yields. Such combinations can be appropriately selected by those skilled in the art, but for example, as shown in the examples below, PIFA is preferably used in combination with hexafluoro-2-propanol (HFIP), 2,2,2-trifluoroethanol (TFE), nonafluoro-tert-butyl alcohol, etc., HTIB is preferably used in combination with HFIP, TFE, 2,2,3,3,4,4,5,5-octafluoro-1-pentanol, etc., [bis(trifluoroacetoxy)iodo]pentafluorobenzene is preferably used in combination with hexafluoro-2-propanol (HFIP), etc., and [hydroxy(methanesulfonyloxy)iodo]benzene is preferably used in combination with hexafluoro-2-propanol (HFIP), etc., but the examples are not limited to these combinations.

[0034] The amount of fluorescein alcohol can be set appropriately from the viewpoint of achieving a high yield of the product, etc., but for example, it may be about 1.0 equivalent or more, about 1.5 equivalents or more, about 2.0 equivalents or more, or 2.5 equivalents or more in molar ratio relative to the substrate, and it may be about 15 or less, about 10 or less, about 8 or less, or about 5 or less in volume ratio relative to the substrate.

[0035] The dealkoxyphenylation reaction defined in the present invention is carried out in the presence of the above-mentioned fluorescein alcohol and "water". The amount of water can be appropriately set from the viewpoint of achieving a high yield of the product, etc., but for example, it may be about 1.0 equivalent or more, about 1.5 equivalents or more, about 2.0 equivalents or more, or about 2.5 equivalents or more in molar ratio with respect to the substrate, and it may be about 10 or less, about 8 or less, about 5 or less, or about 3 or less in volume ratio with respect to the substrate.

[0036] In the present invention, a solvent (also called a reaction solvent) may be added to the fluorescein alcohol and water. The solvent can be selected from the group consisting of dichloromethane (CH2Cl2), toluene, (trifluoromethyl)benzene, and combinations thereof, but is not limited to these. The type of solvent used can be appropriately selected depending on the solubility of the substrate and the λ3-iodane used, in order to achieve a high yield of the product. The amount of solvent can also be appropriately set to achieve a high yield of the product, for example, it may be about 0.5 to 50, about 1 to 20, or about 2 to 10 by volume relative to the substrate.

[0037] In the present invention, an "additive" may be added to the fluorescein alcohol and water. Preferably, the additive is selected from the group consisting of sodium dihydrogen phosphate (NaH2PO4), potassium dihydrogen phosphate (KH2PO4), disodium hydrogen phosphate (Na2HPO4), and combinations thereof. As the dealkoxyphenylation reaction proceeds, the acidity may increase. In particular, when using λ3-iodane (HTIB, etc.) which produces a strongly acidic by-product or substrates that are sensitive to acidic conditions, a higher product yield can be obtained by adding an additive such as sodium dihydrogen phosphate (NaH2PO4). The amount of the additive can also be appropriately set to achieve a high product yield, 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 substrate.

[0038] Furthermore, when using (diacetoxyiodo)benzene (PIDA) as λ3-iodane, it is preferable to add trifluoroacetic acid (TFA) to obtain the deprotected product in higher yield.

[0039] As explained above, in the present invention, it is believed that in the presence of fluorescein alcohol and water, λ3-iodane acts as a one-electron oxidizing agent on phenyl (X group) having an alkoxy at the ortho or para position in formula R-OX, causing the OX group to be removed from the compound represented by formula R-OX, followed by the addition of water (H2O), resulting in the easier removal of the alkoxyphenoxy group (OX group) from the compound represented by formula R-OX. This action of λ3-iodane is generally achieved by stirring, refluxing, etc., a solution containing the compound represented by formula R-OX and λ3-iodane in fluorescein alcohol and water. Therefore, the method of the present invention can be easily implemented and scaled up relatively easily. The dealkoxyphenylation product can be purified or isolated by any purification method known to those skilled in the art, such as crystallization or chromatography of the product.

[0040] The temperature at which the compound represented by formula R-OX reacts with λ3-iodan is preferably from about -20°C to below the boiling point of the fluorescein alcohol (for example, about 58°C for hexafluoro2-propanol (HFIP) and about 78°C for 2,2,2-trifluoroethanol (TFE)), and can be, for example, about -20 to 60°C, about 0°C to 60°C, or about 10°C to 30°C. Another advantage is that the dealkoxyphenylation reaction proceeds even at room temperature (15 to 30°C), eliminating the need for cooling or heating, and is also effective when using heat-sensitive substrates.

[0041] Furthermore, the reaction time can be appropriately set to obtain the product in high yield.

[0042] The present invention is illustrated more specifically in the following embodiments, but these embodiments do not limit the scope of the present invention in any way. [Examples]

[0043] <Example 1> (Example 1-1) Production and isolation of 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-D-glucopyranoside (2) by deparamethoxyphenylation reaction.

[0044] [ka] The deparamethoxyphenylation reaction was carried out by adding [bis(trifluoroacetoxy)iodo]benzene (PIFA) (8.82 g, 20.51 mmol, 1.4 equivalents) as λ3-iodan to a solution containing 4-methoxyphenyl 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-β-D-glucopyranoside (1) (10.0 g, 14.64 mmol), dichloromethane (80 mL, 8 volumes), hexafluoro-2-propanol (HFIP) (50 mL, 5 volumes), and water (5 mL, 0.5 volumes) at room temperature (below 25°C), and stirring at the same temperature for 4 hours. After confirming the completion of the reaction by HPLC, ethyl acetate (250 mL) was added, and the mixture was cooled on ice. Then, 100 mL of water containing 5 g of sodium bicarbonate and 5 g of sodium sulfite was added, and the mixture was separated to obtain the organic layer. The obtained organic layer was washed again with 100 mL of water containing 5 g of sodium bicarbonate and 5 g of sodium sulfite, and then washed again with 50 mL of 20% saline solution. The obtained organic layer was concentrated under reduced pressure to 100 mL (crystal precipitation was observed during concentration), and heptane (150 mL) was added dropwise. The resulting slurry was cooled to 0-5°C, 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 (8 / 24 mL) at 0-5°C, dried under reduced pressure at 40°C, and 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-D-glucopyranoside (2) (7.6 g, isolation yield 90%) was isolated as white crystals. As described above, the yield of the deprotected product obtained after isolation following the deparamethoxyphenylation reaction may be referred to as the "isolation yield."

[0045] 1 H-NMR (500 MHz, CDCl3) δ 7.38 - 7.21 (m, 10H), 5.17 (t, J = 3.5 Hz, 1H), 5.13 (d, J = 10.0 Hz, 1H), 4.98 (t, J = 10.0 Hz, 1H), 4.78 (d, J = 12.0 Hz, 1H), 4.65 - 4.55 (m, 3H), 4.50 (dd, J = 17.2, 12.0 Hz, 2H), 4.41 (d, J = 2.9 Hz, 1H), 4.13 - 4.09 (m, 1H), 3.97 (td, J = 10.2, 2.5 Hz, 1H), 3.72 (t, J = 10.0 Hz, 1H), 3.51 (dd, J = 10.6, 7.2 Hz, 1H), 3.44 (dd, J = 10.0, 2.5 Hz, 1H), 1.90 (3H, s). 13 C-NMR (125 MHz, CDCl3) δ 169.6, 154.1, 137.8, 137.2, 128.4, 128.1, 127.9, 127.7, 127.7, 95.3, 91.7, 77.3, 74.6, 73.7, 73.5, 70.9, 69.4, 68.8, 54.6, 20.7. HRMS (ESI - ) [M - H] - [C 25 H 27 Cl3NO8] ― Calculated value for [C

[0046] (There seems to be a missing word or phrase after "Calculated value for [C" in the original Japanese. I've translated as best as possible based on the context.) The measurement of the yield by HPLC analysis was carried out under the following analysis conditions. In addition, HPLC measurements were also performed according to the same analysis conditions in Example 1 and Examples 2 to 14 described later. <HPLC analysis conditions> Equipment used: SHIMAZU HPLC (2010A HT) Column: Xbrige C18 3.5μm, 4.6×150mm (Waters) Mobile phase A: 10 mM AcONH4 aqueous solution Mobile phase B: CH3CN Gradient conditions:

[0047]

Table 1

[0048] (Examples 1-2) Formation of 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-D-glucopyranoside (2) by deparamethoxyphenylation reaction

[0049] [ka] A deparamethoxyphenylation reaction was carried out by adding [bis(trifluoroacetoxy)iodo]benzene (PIFA) (0.09 g, 0.205 mmol, 1.4 equivalents) as λ3-iodan to a solution containing 4-methoxyphenyl 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-β-D-glucopyranoside (1) (100 mg, 0.146 mmol), dichloromethane (0.8 mL, 8 vols), hexafluoro-2-propanol (HFIP) (0.5 mL, 5 vols), and water (0.05 mL, 0.5 vols) at room temperature (below 25°C), and stirring at the same temperature for 2 hours. The solution was quantified by HPLC and the yield was calculated (HPLC quantification yield: 95%). As mentioned above, the yield obtained by quantifying the solution after the deparamethoxyphenylation reaction using HPLC can be referred to as the "HPLC quantitative yield."

[0050] (Examples 1-3) Using a method similar to that shown in Example 1-2, the deparamethoxyphenylation reaction was carried out on substrate 1 using the λ3-iodan, fluorescein alcohol, and reaction time shown in Table 1 below. The reaction solution was quantified by HPLC, and the yield of product 2 was calculated (entries 2-7 in Table 1) (Note that entry 1 in Table 1 relates to Example 1 (Example 1-1 (90%, isolated) and Example 1-2 (95%))).

[0051] (Examples 1-4) The deparamethoxyphenylation reaction was carried out by adding (diacetoxyiodo)benzene (PIDA) (72 mg, 0.222 mmol, 1.4 equivalents) as λ3-iodan to a solution containing 4-methoxyphenyl 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-β-D-glucopyranoside (1) (101 mg, 0.148 mmol), trifluoroacetic acid (57 μL, 0.740 mmol, 5 equivalents), dichloromethane (1.0 mL, 10 volumes), hexafluoro-2-propanol (HFIP) (0.6 mL, 6 volumes), and water (0.05 mL, 0.5 volumes) at room temperature (below 25°C), and stirring at the same temperature for 3 hours. This solution was quantified by HPLC, and the yield of 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-D-glucopyranoside (2) was calculated (HPLC quantification yield: 93%, entry 8 in Table 1).

[0052] [Table 2]

[0053] [ka]

[0054] <Example 2>

[0055] [ka] Using the same method as in Examples 1-2, the deparamethoxyphenylation reaction was carried out on 4-methoxyphenyl 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-β-D-glucopyranoside (1) using various solvents and reaction times shown in Table 2. However, in entry 4 shown in Table 2 below, HTIB was used instead of PIFA. The reaction solution was quantified by HPLC, and the yield of 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-D-glucopyranoside (2) was calculated. The results are shown in Table 2 below.

[0056] [Table 3]

[0057] <Example 3> Formation of 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-D-glucopyranoside (2) by deparamethoxyphenylation reaction using various amounts of λ3-iodan, fluorescein alcohol, and water.

[0058] [ka] To a solution containing 4-methoxyphenyl 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-β-D-glucopyranoside (1) (100 mg, 0.146 mmol), toluene (0.8 mL, 8 vols), hexafluoro-2-propanol (HFIP) (0.5 mL, 5 vols), and water (0.05 mL, 0.5 vols), [hydroxy(tosyloxy)iodo]benzene (HTIB) (0.08 g, 0.205 mmol, 1.4 equivalents) as λ3-iodanate was added at room temperature (below 25°C), and the mixture was stirred at the same temperature for 0.5 hours. This solution was quantified by HPLC, and the yield of the obtained 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-β-D-glucopyranoside (2) was calculated (Entry 1, HPLC quantification yield: >99%).

[0059] Using the same method as described above, the deparamethoxyphenylation reaction was carried out on substrate 1 using the λ3-iodan, fluorescein alcohol, water, temperature, and reaction time shown in Table 3 below. The reaction solution was quantified by HPLC, and the yield of product 2 was calculated (entries 2-7). Entry 7 in Table 3 is an example without water, but several impurities were clearly observed by HPLC, resulting in a significant decrease in yield. On the other hand, when water was present in relation to the substrate, the product (deprotected product) was obtained in high yield.

[0060] [Table 4]

[0061] <Example 4> Formation of 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-D-glucopyranoside (2) by deparamethoxyphenylation reaction using various additives

[0062] [ka] To a solution containing 4-methoxyphenyl 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-β-D-glucopyranoside (1) (100 mg, 0.146 mmol), toluene (0.8 mL, 8 vols), hexafluoro-2-propanol (HFIP) (0.5 mL, 5 vols), and water (0.05 mL, 0.5 vols), sodium dihydrogen phosphate (NaH2PO4) (0.05 g, 0.439 mmol, 3 equivalents) was added as an additive. Then, at room temperature (below 25°C), [hydroxy(tosyloxy)iodo]benzene (HTIB) (0.08 g, 0.205 mmol, 1.4 equivalents) was added and the mixture was stirred at the same temperature for 2 hours. This solution was quantified by HPLC, and the yield of 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-β-D-glucopyranoside (2) was calculated (HPLC quantification yield: >99%).

[0063] Using the same method as described above, the deparametric phenylation reaction was carried out on substrate 1 using the various additives shown in Table 4 below. However, in the reaction of entry 3, 1.8 equivalents of HTIB were used instead of 1.4 equivalents of HTIB, and 1 volume of water was used instead of 0.5 volume of water. The post-reaction solution was quantified by HPLC, and the yield of product 2 was calculated (entries 2 and 3).

[0064] [Table 5]

[0065] <Example 5> Production and isolation of 3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-D-glucopyranoside (7b) by deparamethoxyphenylation reaction.

[0066] [ka] The deparamethoxyphenylation reaction was carried out by adding [hydroxy(tosyloxy)iodo]benzene (HTIB) (0.86 g, 2.18 mmol, 1.4 equivalents) as λ3-iodan to a solution containing 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-β-D-glucopyranoside (7a) (1.00 g, 1.56 mmol), toluene (8 mL, 8 vols), hexafluoro-2-propanol (HFIP) (5 mL, 5 vols), and water (0.5 mL, 0.5 vols) at room temperature (below 25°C), and stirring at the same temperature for 2 hours. Subsequently, ethyl acetate (25 mL) and water (8 mL) in which sodium bicarbonate (0.5 g) and sodium sulfite (0.5 g) were dissolved were added, and the organic layer was obtained by liquid-liquid separation. The obtained organic layer was washed again with water (8 mL) in which sodium bicarbonate (0.5 g) and sodium sulfite (0.5 g) were dissolved, and then washed again with 20% saline solution (4 mL). The obtained organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0~97 / 3), and the selected fraction was concentrated under reduced pressure to isolate 3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-D-glucopyranoside (7b) (720 mg, isolation yield 87%) as a white solid.

[0067] Using 7a as the substrate, [bis(trifluoroacetoxy)iodo]benzene (PIFA) (1.4 equivalents) as the λ3-iodan, and dichloromethane as the reaction solvent, the deparametric phenylation reaction was carried out in the same manner as described above. Subsequently, the same treatment as described above was performed, and the isolation yield of 7b was 84%.

[0068] 1H-NMR (400MHz, CDCl3) δ7.37-7.27 (m, 10H), 5.22 (brs, 1H), 5.17 (d, J=10.0Hz, 1H), 4.8 0(d, J=11.6Hz, 1H), 4.79(d, J=12.0Hz, 1H), 4.72(d, J=11.6Hz, 1H), 4.64(d, J=12.0Hz, 1H), 4.59(d, J=12.4Hz, 1H), 4.54(d, J=12.4Hz, 1H), 4.01(ddd, J=7.6, 5.2, 4.0Hz, 1H), 3.92(ddd, J=10.4, 10.4, 4.0Hz, 1H), 3.80-3.58(m, 4H), 3.29(brs, 1H), 2.52(brs, 1H). 13 C-NMR (100MHz, CDCl3)δ154.3, 138.1, 137.6, 128.7, 128.5, 128.2, 128.0,128.0, 116.2, 95.4, 92.2, 79.7, 74.7, 74.6, 73.7, 71.9, 70.2, 54.7, 29.7. HRMS(ESI-)[MH] - [C 23 H 25 Cl3NO7] ― Calculated value: 532.0702; Measured value: 532.0701.

[0069] <Example 6> Production and isolation of 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-D-glucopyranoside (8b) by deparamethoxyphenylation reaction.

[0070] [ka] Using 4-methoxyphenyl 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-D-glucopyranoside (8a) as the substrate, and [hydroxy(tosyloxy)iodo]benzene (HTIB) (1.4 equivalents) as the λ3-iodan, and toluene as the reaction solvent, the deparamethoxyphenylation reaction was carried out in the same manner as in Example 5, and the isolation yield of 8b was 81%.

[0071] Using 8a as the substrate, [bis(trifluoroacetoxy)iodo]benzene (PIFA) (1.4 equivalents) as the λ3-iodan, and dichloromethane as the reaction solvent, the deparamethoxyphenylation reaction was carried out in the same manner as in Example 5, and the isolation yield of 8b was 94%.

[0072] 1 H-NMR (400MHz, CDCl3) δ7.71-7.65(m, 4H), 7.34-7.26(m, 5H), 7.01-6.87(m, 5H), 5.36( dd, J=8.0, 8.0Hz, 1H), 5.13(dd, J=8.4, 10.0Hz, 1H), 4.59(d, J=12.4Hz, 1H), 4.54(s, 2H) ), 4.50(dd, J=8.4, 10.4Hz, 1H), 4.33(d, J=12.4Hz, 1H), 4.17(dd, J=8.4, 10.4Hz,1H), 3 .79(ddd, J=8.4, 5.2, 4.8Hz, 1H), 3.61-3.53(m, 2H), 3.41(d, J=8.0Hz, 1H), 1.93(s, 3H). 13 C-NMR (100MHz, CDCl3)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 - )[MH] - [C 30 H 28 NO8] -Calculated value: 530.1820; Measured value: 530.1841.

[0073] <Example 7> Production and isolation of 2,4,6-tri-O-acetyl-3-O-benzyl-D-glucopyranoside (9b) by deparamethoxyphenylation reaction

[0074] [ka] Using 4-methoxyphenyl 2,4,6-tri-O-acetyl-3-O-benzyl-D-glucopyranoside (9a) as the substrate, [hydroxy(tosyloxy)iodo]benzene (HTIB) (1.4 equivalents) as the λ3-iodan, and toluene as the reaction solvent, the deparamethoxyphenylation reaction was carried out in the same manner as in Example 5, and the isolation yield of 9b was 97%.

[0075] Using 9a as the substrate, with [bis(trifluoroacetoxy)iodo]benzene (PIFA) (2.4 equivalents) as the λ3-iodan and dichloromethane as the reaction solvent, the deparamethoxyphenylation reaction was carried out in the same manner as in Example 5, and the isolation yield of 9b was 98%.

[0076] 1 H-NMR (400MHz, CDCl3) δ7.37-7.23(m, 5H), 5.47(dd, J=3.6, 3.6Hz, 1H), 5.10(dd, J=9.6, 9.6Hz, 1H), 4.90-4.84(m, 1H), 4.71(d, J=12 .0Hz,1H), 4.65-4.60(m, 1H), 4.24-4.01(m, 3H), 3.75-3.59(m, 1H), 2.93(brd, J=3.6Hz, 1H), 2.09(s, 3H), 2.07(s, 3H), 1.95(s, 3H). 13 C-NMR (100MHz, CDCl3)δ171.1, 170.3, 169.6, 138.2, 128.5, 127.8, 127.6, 90.3, 76.9, 75.0, 73.5, 69.8, 67.7, 62.3, 20.9, 20.8, 20.8. HRMS (ESI - ) [M-H] - [C 19 H 23 O9] - Calculated value for: 395.1349; measured value 395.1344.

[0077] <Example 8> Generation and isolation of 2,3,4,6-tetra-O-acetyl-D-mannopyranoside (10b) by deparamethoxyphenylation reaction

[0078] [[ID=2i2]]

Chemical Structure

[0079] 1 1H-NMR (400 MHz, CDCl3) δ 5.41 (dd, J = 3.6, 8.0 Hz, 1H), 5.33 - 5.01 (m, 3H), 4.43 (s, 1H), 4.29 - 4.22 (m, 2H), 4.17 - 4.11 (m, 1H), 2.16 (s, 3H), 2.11 (s, 3H),  2.06 (s, 3H), 2.00 (s, 3H). 13 13C-NMR (100 MHz, CDCl3) δ 171.0, 170.4, 170.2, 169.9, 92.0, 70.1, 68.9, 68.3, 66.1, 62.6, 20.9, 20.7, 20.7, 20.7. HRMS (ESI - ) [M-H] - [C 14 H 19 O 10 ― Calculated value for: 347.0984; measured value 347.0999.​

[0080] <Example 9> Production and isolation of 2-azido-3,6-di-O-benzyl-2-deoxy-D-glucopyranoside (11b) by deparamethoxyphenylation reaction

[0081] [ka] Using 4-methoxyphenyl 2-azido-3,6-di-O-benzyl-2-deoxy-D-glucopyranoside (11a) as the substrate, [hydroxy(tosyloxy)iodo]benzene (HTIB) (1.1 equivalents) as the λ3-iodane, dichloromethane as the reaction solvent, and potassium dihydrogen phosphate (3.0 equivalents) as an additive, the deparamethoxyphenylation reaction was carried out in the same manner as in Example 5, and the isolation yield of 11b was 88%.

[0082] Using 11a as the substrate, [bis(trifluoroacetoxy)iodo]benzene (PIFA) (1.4 equivalents) as the λ3-iodan, and dichloromethane as the reaction solvent, the deparamethoxyphenylation reaction was carried out in the same manner as in Example 5, and the isolation yield of 11b was 79%.

[0083] 11H-NMR (400 MHz, CDCl3) δ 7.40 (m, 10H), 5.20 (d, J = 2.8 Hz, 0.5H), 5.05 (brs, 0.5H), 4.88 (dd, J = 10.8, 2.8 Hz, 1H), 4.76 (d, J = 10.8 Hz, 0.5H), 4.70 (d, J = 10.8 Hz, 0.5H), 4.54 (d, J = 12.0 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 4.43 (brs, 0.5H), 4.37 (d, J = 8.0 Hz, 0.5H), 4.00 (ddd, J = 8.0, 5.2, 3.2 Hz, 0.5H), 3.81 (dd, J = 10.4, 8.8 Hz, 0.5H), 3.67 (ddd, J = 8.0, 6.0, 3.2 Hz, 1H), 3.58 (ddd, J = 6.0, 6.0, 1.2 Hz, 1H), 3.54 - 3.45 (m, 1H), 3.35 (ddd, J = 6.8, 6.0, 3.2 Hz, 0.5H), 3.27 (m, 1H), 3.15 (m, 0.5H), 2.74 (brd, J = 7.6 Hz, 1H).<H-NMR(400MHz、CDCl3)δ7.40(m、10H)、5.20(d、J=2.8Hz、0.5H)、5.05(brs、0.5H)、4.88(dd、J=10. 13 13C-NMR (100 MHz, CDCl3) δ 137.8, 137.8, 137.3, 137.2, 128.5, 128.4, 128.1, 128.0, 128.0, 127.8, 127.8, 95.9, 91.8, 82.4, 79.7, 77.2, 75.0, 74.9, 74.0, 73.5, 73.4, 71.6, 70.9, 69.9, 69.6, 66.5, 63.3. HRMS (ESI - ) [M + HCOO] - [C 21 H 24 N3O7] - Calculated value for: 430.1620; Observed value 430.1638.

[0084] <Example 10from Japanese Patent Application No. 2005-227401, filed on August 3, 2005, the entire contents of which are incorporated herein by reference. Production and Isolation of 6-O-{5-Acetamido-4,7,8,9-Tetra-O-acetyl-3,5-Dideoxy-1-Methyl-D-Glycero-α-D-Galacto-Non-2-Uropyranosyl}- <実施例10>

[0085]

Chemical Formula

[0086] 1 H-NMR (400MHz, CDCl3) δ8.14-8.09(m, 2H), 8.03-7.96(m, 2H), 7.63-7.12(m, 11H), 6.70( m, 1H), 5.99(brs, 1H), 5.66(m, 0.5H), 5.55-5.20(m, 3.5H), 4.84-4.75(m, 2H), 4.63-4.5 0(m, 2H), 4.34(brd, J=12.8Hz, 1H), 4.29(ddd, J=10.0, 7.6, 2.0Hz, 1H), 4.19-3.86(m, 4. 5H), 3.78(dd, J=9.6, 4.8Hz, 0.5H), 3.50-3.18(m, 4H), 2.55(m, 1H), 2.17-1.82(m, 16H). 13C-NMR (100MHz, CDCl3)δ171.7, 171.1, 170.5, 170.3, 170.2, 170.0, 168.0, 167.7, 167.4, 166.1, 165.5, 165.4, 165.2, 149.7, 137.8, 1 37.3, 137.2, 133.5, 133.3, 133.2, 133.1, 129.9, 129.8, 129.7, 129.5, 128.5, 128.4, 128.3, 128.2, 128.2, 128.0, 127.9, 127.6 ,127.5,116.1,98.7,98.7,98.4,96.0,90.9,77.2,76.2,76.0,72.9,72.8,72.7,72.5,71.8,71.5,71.3,71.1,69.9,69.3,68.9,67.7,67.4,67.3,67.3,67.1,66.2,63.3,62.8,62.2,61.8,52.6,52.4,49.1,37.9,29.6,23.0,21.0,20.9,20.8,20.7,20.7. HRMS (ESI - ) [M+HCOO] - [C 48 H 54 NO 22 ] ― Calculated value: 996.3143; Measured value: 996.3143.

[0087] <Example 11> Formation and isolation of 3-O-{5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-1-methyl-D-glycero-α-D-galactonone-2-uropyranosyl}-2,5,6-tri-O-benzoyl-D-galactopyranoside (13b)

[0088] [ka] Using 4-methoxyphenyl 3-O-{5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-1-methyl-D-glycero-α-D-galactonone-2-uropyranosyl}-2,5,6-tri-O-benzoyl-D-galactopyranoside (13a) as the substrate, and [bis(trifluoroacetoxy)iodo]benzene (PIFA) (2.4 equivalents) as the λ3-iodan, with dichloromethane as the reaction solvent and potassium dihydrogen phosphate (3.0 equivalents) as the additive, the deparamethoxyphenylation reaction was carried out in the same manner as in Example 5, and the isolation yield of 13b was 90%.

[0089] 1 H-NMR (400MHz, CDCl3) δ8.28-8.19(m, 2H), 8.09-7.93(m, 4H), 7.60-7.34(m, 9H), 5.70-5.54(m, 2H), 5.50(d , J=2.4Hz, 0.5H), 5.44(d, J=2.4Hz, 0.5H), 5.40-5.20(m, 2.5H), 5.15-5.05(m, 1H), 4.99(dd, J=10.0, 3.2Hz , 0.5H), 4.84(m, 1H), 4.63-4.55(m, 1H), 4.47(ddd, J=11.6, 11.2, 6.0Hz, 1H), 4.40-4.24(m, 3H), 4.09-3.91 (m, 2H), 3.82(s, 3H), 3.68(ddd, J=10.8, 4.8, 2.4Hz, 1H), 2.46(dd, J=12.8, 4.0Hz, 1H), 2.27-1.62(m, 15H). 13C-NMR (100MHz, CDCl3)δ171.5, 171.0, 170.9, 170.8, 170.6, 170.4, 170.3, 170.1, 17 0.1, 169.7, 169.6, 168.1, 168.1, 167.0, 165.9, 165.9, 165.7, 165.6, 165.4, 1 65.2, 133.5, 133.5, 133.3, 133.3, 133.3, 133.1, 133.1, 130.2, 130.1, 129.9, 129.8, 129.8, 129.7, 129.6, 129.5, 129.4, 129.3, 129.2, 128.5, 128.5, 128.2, 118.9, 114.3, 97.2, 97.0, 96.9, 96.8, 96.0, 92.1, 91.9, 77.2, 73.3, 72.5, 72.4, 72.1, 71.0, 70.9, 69.8, 69.4, 69.3, 68.8, 68.6, 68.4, 68.0, 67.6, 67.5, 67.2 , 67.0, 66.8, 66.7, 66.5, 62.6, 62.5, 62.4, 62.3, 61.5, 53.2, 53.1, 49.8, 48.9, 38.1, 37.4, 37.4, 23.1, 23.1, 21.4, 21.4, 21.1, 20.8, 20.7, 20.6, 20.6, 20.5. HRMS (ESI + ) [M+H] + [C 47 H 52 NO 21 ] + Calculated value: 966.3026; Measured value: 966.3024.

[0090] <Example 12> Formation and isolation of 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-4-O-{2,4,6-tri-O-acetyl-3-O-[(naphthalene-2-yl)methyl]-D-glucopyranosyl}-β-D-glucopyranosyl (14b)

[0091] [ka] Using 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-4-O-{2,4,6-tri-O-acetyl-3-O-[(naphthalene-2-yl)methyl]-D-glucopyranosyl}-β-D-glucopyranosyl (14a) as the substrate, [bis(trifluoroacetoxy)iodo]benzene (PIFA) (1.5 equivalents) as the λ3-iodan, dichloromethane as the reaction solvent, and potassium dihydrogen phosphate (3.0 equivalents) as an additive, the deparamethoxyphenylation reaction was carried out in the same manner as in Example 5, and the isolation yield of 14b was 95%.

[0092] 1 H-NMR (400MHz, CDCl3) δ7.82(m, 3H), 7.68-7.62(m, 5H), 7.48(m, 2H), 7.40 -7.27(m, 8H), 6.99(m, 2H), 6.80(m, 3H), 5.30(d, J=8.8Hz, 1H), 5.11(t, J= 9.6Hz, 1H), 5.06 (dd, J=9.6, 8.4Hz, 1H), 4.78 (dd, J=13.2, 7.2Hz, 2H), 4.7 4(d, J=11.6Hz, 1H), 4.70(d, J=11.6Hz, 1H), 4.52(d, J=8.4Hz, 1H), 4.42(d d, J=12.0, 15.6Hz, 2H), 4.26(dd, J=10.8, 8.4Hz, 1H), 4.18(dd, J=12.4, 4.8Hz, 1H), 4.03(dd, J=10.8, 8.8Hz, 2H), 3.96(dd, J=12.4, 2.4Hz, 1H), 3.78 (dd, J=11.2, 3.6Hz, 1H), 3.72(brd, J=11.2Hz, 1H), 3.54(t, J=9.6Hz, 1H), 3.39(ddd, J=7.6, 4.4, 2.0Hz, 1H), 1.96(s, 3H), 1.93(s, 3H), 1.91(s, 3H). 13C-NMR (100MHz, CDCl3)δ170.8, 169.3, 168.9, 167.9, 138.5, 137.8, 135.2, 133.7 , 133.1, 132.9, 131.5, 128.5, 128.2, 128.1, 127.9, 127.9, 127.8, 127.6, 12 7.0, 126.2, 126.2, 126.0, 125.5, 123.2, 100.3, 92.8, 80.3, 78.1, 76.3, 74 .7, 74.5, 73.8, 73.6, 72.8, 71.7, 69.6, 67.6, 61.9, 57.4, 20.8, 20.7, 20.6. HRMS (ESI - ) [MH] - [C 51 H 50 NO 15 ] - Calculated value: 916.3186; Measured value: 916.3204.

[0093] <Example 13> Formation and isolation of 3,6-di-O-benzyl-2-deoxy-4-O-{6-O-acetyl-2,4-di-O-benzyl-3-O-[(naphthalene-2-yl)methyl]-β-D-mannopyranosyl}-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-D-glucopyranoside (15b)

[0094] [ka] Using 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-4-O-{6-O-acetyl-2,4-di-O-benzyl-3-O-[(naphthalene-2-yl)methyl]-β-D-mannopyranosyl}-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-D-glucopyranoside (15a) as the substrate, [bis(trifluoroacetoxy)iodo]benzene (PIFA) (2.5 equivalents) as λ3-iodan, dichloromethane as the reaction solvent, and potassium dihydrogen phosphate (3.0 equivalents) as an additive, the deparamethoxyphenylation reaction was carried out in the same manner as in Example 5, and the isolation yield of 15b was 81%.

[0095] 1 H-NMR(400MHz, CDCl3)δ7.84-7.37(m、13H), 7.36-7.17(m、13H), 6.88-6.85(m, 2H), 6.77-6.71(m, 3H), 5.32(brd, J. Am =7.6Hz、1H)、4.93-4.85(m、4H)、4.64(d、J=12.4Hz、1H)4 .60(d、J=12.4Hz、1H)、4.56(d、J=7.2Hz、1H)、4.53(d、J=8 .4Hz、1H)、4.50(s、1H)、4.44(d、J=12.8Hz、1H)、4.35-4.2 1(m、4H)、4.05(dd、J=10.8、8.4Hz、1H)、3.99(dd、J=8.8、8 .8Hz、1H)、3.83(dd、J=10.0、10.0Hz、1H)、3.77(d、J=2.8H). z、1H)、3.65-3.51(m、4H)、3.41-3.35(m、2H)、1.88(s、3H). 13 C-NMR (100MHz、CDCl3)δ170.9、168.0、138.8、138.7、138.0、137.6、135.5、133.6、133. 2, 132.9, 131.5, 128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 127.7, 127.7, 127.4, 127.3, 126.8, 126.2, 125.9, 125.5, 123.2, 101.5, 92.9, 82.4, 79.2, 2, 76.9, 75.0, 74.7, 74.6, 74.4, 74.0, 73.5, 73.4, 71.7, 68.5, 63.4, 57.5, HRMS(ESI - ) [M+HCOO] - [C 62 H 60 WHEN 15 ] - Note: 1058.3968;

[0096] Table 5 below shows the conditions and results of the deparamethoxyphenylation reaction using the λ3-iodane-HFIP system with monosaccharides as substrates in Examples 5-9. Table 6 below shows the conditions and results of the deparamethoxyphenylation reaction using the λ3-iodane-HFIP system with disaccharides as substrates in Examples 10-13. In all cases, deprotected products were obtained in good yields. Furthermore, as shown in Table 6, deprotected products were obtained in high yields for disaccharides as well, similar to monosaccharides.

[0097] [Table 6]

[0098] [Table 7]

[0099] <Example 14> Deparamethoxyphenylation reaction of paramethoxyphenyl-protected benzyl alcohol

[0100] [ka] A solution containing 4-benzyloxyanisole (16) (100 mg, 0.467 mmol), toluene (0.8 mL), hexafluoro2-propanol (HFIP) (0.5 mL), and water (0.05 mL) was mixed with [hydroxy(tosyloxy)iodo]benzene (HTIB) (0.26 g, 0.653 mmol) as λ3-iodan at 5°C and stirred at the same temperature for 0.5 hours. The solution was quantified by HPLC, and the yield of p-benzoquinone obtained was calculated (HPLC quantification yield: benzyl alcohol (BnOH) > 99%, p-benzoquinone 67%).

[0101] A solution containing 4-benzyloxyanisole (16) (100 mg, 0.467 mmol), toluene (0.8 mL), dichloromethane (0.5 mL) and water (0.05 mL) was added with [bis(trifluoroacetoxy)iodo]benzene (PIFA) (1.4 equivalents) as λ3-iodane at 5 °C, and the mixture was stirred at the same temperature for 0.5 h. This solution was quantified by HPLC, and the yield of the obtained p-benzoquinone was calculated (HPLC quantitative yield: benzyl alcohol (BnOH) 99%, p-benzoquinone 75%).

[0102] Table 7 below summarizes the above-mentioned deparamethoxyphenylation reaction conditions and product yields. In each case, the deprotected product was obtained in good yield.

[0103]

Table 8

[0104] The yield measurement by HPLC analysis in Example 14 was carried out under the following analysis conditions. [[ID=第十七条]] <HPLC analysis conditions> Equipment used: SHIMAZU HPLC (2010A HT) Column: Xbrige C18 3.5 μm, 4.6 × 150 mm (Waters) Mobile phase A: 10 mM aqueous NH4OAc solution Mobile phase B: CH3CN Gradient conditions:

[0105]

Table 9

Claims

1. In fluorescein alcohol and water, a compound represented by the formula R-OX (wherein R is the substrate and X is C at the para or ortho position) is found. １ ~C ５ A method for producing a compound represented by the formula R-OH, comprising the step of reacting λ3-iodane with a phenyl group substituted with an alkoxy (the phenyl group may be further optionally substituted), The λ3-Yordan mentioned above is given by formula R １ -I(OR ２ ) ２ It is a compound represented by R １ However, it is an unsubstituted or substituted phenyl group, R ２ However, it is selected from the group consisting of H, acetyl, trifluoroacetyl, tosyl, methanesulfonyl, and combinations thereof. The substrate R is a sugar, and in the formula R-OX, the OX group is located at the 1-position or anomeric position of the sugar, or The substrate R is Ar-(CR3R4)n- (wherein n = 1 to 3, Ar is an aromatic ring, and R3 and R4 are each H, an aromatic ring, or an aliphatic group, and any of the aromatic rings and aliphatic groups may be optionally substituted). A method for producing the compound represented by the formula R-OH.

2. C in the X group １ ~C ５ The method according to claim 1, wherein the alkoxy is methoxy, ethoxy, propyloxy, or isopropyloxy.

3. C in the aforementioned X group １ ~C ５ The method according to claim 1, wherein the alkoxy is paramethoxy.

4. The above formula R １ -I(OR ２ ) ２ The method according to any one of claims 1 to 3, wherein the compound represented is selected from the group consisting of [bis(trifluoroacetoxy)iodo]benzene (PIFA), [hydroxy(tosyloxy)iodo]benzene (HTIB), (diacetoxyiodo)benzene (PIDA), [bis(trifluoroacetoxy)iodo]pentafluorobenzene, [hydroxy(methanesulfonyloxy)iodo]benzene, and combinations thereof.

5. The method according to any one of claims 1 to 4, wherein the amount of λ3-iodane is 0.1 to 10 equivalents relative to the substrate.

6. The method according to any one of claims 1 to 5, wherein the fluorescein alcohol is a fluorescein aliphatic alcohol.

7. The fluorescein aliphatic alcohol is fluorescein C ２ ~C ８ The method according to claim 6, wherein the alcohol is an aliphatic alcohol.

8. The aforementioned Fluorus C ２ ~C ８ The method according to claim 7, wherein the aliphatic 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. CH ２ Cl ２ The method according to any one of claims 1 to 8, comprising adding a solvent selected from the group consisting of toluene, (trifluoromethyl)benzene, and combinations thereof.

10. The method according to any one of claims 1 to 9, wherein the amount of the fluorescein alcohol is 1.0 equivalent or more in molar ratio and 15 or less in volume ratio relative to the substrate.

11. The method according to any one of claims 1 to 10, wherein the amount of water is 1.0 equivalent or more in molar ratio with respect to the substrate and 10 or less in volume ratio.

12. Sodium dihydrogen phosphate (NaH) ２ PO ４ ), potassium dihydrogen phosphate (KH ２ PO ４ ), disodium hydrogen phosphate (Na ２ HPO ４ The method according to any one of claims 1 to 11, comprising adding an additive selected from the group consisting of ), and combinations thereof.

13. The method according to any one of claims 1 to 12, wherein (diacetoxyiodine)benzene (PIDA) is used as the λ3-iodane, and the method comprises adding trifluoroacetic acid.

14. The method according to any one of claims 1 to 13, carried out at a temperature of -20°C to 60°C.

15. The method according to any one of claims 1 to 14, wherein the substrate R is a sugar, and in the formula R-OX, the OX group is located at the 1-position or anomeric position of the sugar.

16. The method according to claim 15, wherein the sugar is a monosaccharide or a polysaccharide.

17. The method according to claim 16, wherein the monosaccharide has a cyclic structure of a five-membered ring or a six-membered ring.

18. The method according to claim 17, wherein the monosaccharide is a pentose or a hexose.

19. The method according to claim 18, wherein the hexose is glucose, mannose, galactose, or glucosamine.

20. The method according to claim 16, wherein the polysaccharide is a disaccharide to a decasaccharide.

21. The method according to claim 16, wherein the polysaccharide is (i) a disaccharide which is galactose-glucosamine, glucosamine-glucosamine, neuraminic acid-galactose, or mannose-glucosamine; (ii) a trisaccharide which is composed of two mannose molecules and one glucosamine molecule, or a trisaccharide which is composed of neuraminic acid, galactose, and glucosamine; or (iii) a tetrasaccharide which is composed of two mannose molecules and two glucosamine molecules, or a tetrasaccharide which is composed of three mannose molecules and one glucosamine molecule.

22. The hydroxyl group of the carbon adjacent to the carbon at position 1 or anomeric in the sugar is protected by an acyl group, or the amino group of the carbon adjacent to the carbon at position 1 or anomeric in the sugar is protected by an imide group, an acyl group, or a carbamate group, or the carbon adjacent to the carbon at position 1 or anomeric in the sugar is protected by an azide group (N ３ The method according to any one of claims 1 to 21, having )

23. The method according to claim 22, wherein the protecting group for the amino group is phthaloyl (Phth), the acyl group is acetyl (Ac), and the carbamate group is selected from the group consisting of (2,2,2-trichloroethoxy)carbonyl (Troc), allyloxycarbonyl (Alloc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

24. The method according to claim 22, wherein the acyl group is selected from the group consisting of acetyl (Ac) and benzoyl (Bz) as the protecting group for the hydroxyl group.

25. A step of obtaining a sugar having an -OH group at the 1-position or anomeric position by the method of any one of claims 1 to 24, and A method for producing a sugar to which an addition is attached, comprising the step of attaching one or more additions selected from the group consisting of proteins, nucleic acid molecules, lipid molecules, eukaryotic cells, prokaryotic cells, and viruses to the sugar.

26. The method according to claim 25, wherein the added portion is a protein.

27. The method according to claim 26, wherein the protein is a receptor, and the receptor is a soluble receptor, fused to the Fc region of an antibody, or unmodified.

28. The method according to claim 26, wherein the protein is an antibody or an antigen-binding fragment thereof, and the antibody or antigen-binding fragment is bound to a peptide, nucleic acid molecule, lipid molecule, small molecule compound, artificial product, another antibody or antigen-binding fragment thereof, or toxin, or forms a complex with a drug, or is not modified.

29. The method according to claim 26, wherein the protein is a cytokine, and the cytokine is bound to an antibody or an antigen-binding fragment thereof, or is not modified.

30. The method according to any one of claims 25 to 29, further comprising the step of attaching one or more additional portions to the sugar in addition to the protein-containing addition portion.

31. The method according to any one of claims 1 to 14, wherein the substrate R is Ar-(CR3R4)n- (wherein n = 1 to 3, Ar is an aromatic ring, and R3 and R4 are each H, an aromatic ring, or an aliphatic group, and any of the aromatic rings and aliphatic groups may be optionally substituted).

32. The aforementioned aromatic ring may be optionally replaced with C ５ ~C ２０ C is an aryl group or a 5-20 membered ring heteroaryl group, and the aliphatic group may be optionally substituted. １ ~C １０ The method according to claim 31, wherein the group is an aliphatic hydrocarbon group.

33. The method according to claim 31 or 32, wherein the aromatic ring is selected from the group consisting of benzene, xylene, toluene, styrene, ethylbenzene, cumene, furan, thiophene, pyrrole, pyran, thiopyran, pyridine, thiazole, imidazole, pyrimidine, 1,3,5-triazine, naphthalene, indene, anthracene, phenanthrene, fluorene, biphenyl, triphenyl, terphenyl, binaphthyl, phenylnaphthalene, indole, quinoline, and purine.

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