Novel dealkoxyphenylation reactions

Abstract

The present invention provides a method for obtaining a dealkoxyphenylated product in high yield from a substrate such as a sugar bonded via an oxygen atom to an alkoxyphenyl group. By reacting a lambda 3 -iodide with a substrate bonded via an oxygen atom to a phenyl group substituted with a C1-C5 alkoxy group in the para or ortho position in a fluorine-containing alcohol and water, a dealkoxyphenylated product can be obtained in high yield under mild conditions.

Description

Technical Field

[0001] This 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 via an oxygen atom to a phenyl group substituted with an alkoxy group at the para or ortho position. Background Technology

[0002] In the chemical synthesis of oligosaccharide chains having (multiple) hydroxyl groups, it is necessary to rationally utilize methods for the selective protection and deprotection of these hydroxyl groups in order to efficiently obtain the target compound. From this perspective, various methods for utilizing, protecting, and deprotecting protecting groups have been developed to date in the chemical synthesis of sugars, etc. In particular, p-methoxyphenyl groups are widely used, for example, as general protecting groups for the anomeric positions of sugars because they are stable under both acidic and basic conditions and can be easily oxidized for deprotection (Non-Patent Literature 1).

[0003] As a deprotection method for the aforementioned p-methoxyphenyl groups, the commonly used and previously employed method is the method using cerium ammonium nitrate (IV) (Non-Patent Document 2). This method provides the target deprotected form for a wide range of substrates in medium to high yields, but it usually requires the use of excess cerium ammonium nitrate (IV). Consequently, the excess oxidant needs to be reduced in post-processing. Furthermore, there have been reports of cases where the target deprotected form could not be obtained in satisfactory yields for some applications (Non-Patent Document 3). Considering these factors, there is a desire to develop a more efficient method.

[0004] As a method to achieve this objective, a deprotection method for the angiomethyl p-methoxyphenyl group using an electrolytic reaction has been reported (Non-Patent Document 3). However, this method requires special experimental equipment and can therefore be considered a method that is difficult to scale up due to equipment limitations.

[0005] In addition, there is a method reported to convert halogenated sugars by protecting the anomeric hydroxyl group of a sugar with p-methoxyphenyl and then deprotecting it in the presence of zinc halide and acyl halide (non-patent document 4), but it is difficult to say that the conversion of the benzyl group on the hydroxyl group to an acetyl group or the like is carried out under mild reaction conditions during this deprotection.

[0006] Existing technical documents

[0007] Non-patent literature

[0008] Non-patent document 1: Matsuzaki, Y.; Ito, Y.; Nakahara, Y.; Ogawa, T. Tetrahedron Lett. 1993, 34, 1061.

[0009] Non-patent literature 2: Fukuyama, T.; Laird, AA; Hotchkiss, LMTetrahedron Lett. 1985, 26, 6291.

[0010] Non-patent literature 3: Iacobucci, S.; Filippova, N.; Alarcao, M. Carbohydrate Res. 1995, 277, 321.

[0011] Non-patent literature 4: Zhang, Z.; Magnusson, G. Carbohydrate Res. 1996, 925, 41. Summary of the Invention

[0012] The problem that the invention aims to solve

[0013] Based on the background described above, it is desirable to develop de-methoxyphenylation reactions that can deprotect the p-methoxyphenyl protecting group under milder conditions and obtain the deprotected product in high yield.

[0014] Solution for solving the problem

[0015] The inventors of this application discovered the following facts, thereby completing the invention of this application: by reacting λ3-iodane with a substrate in fluorous alcohol and water, a dealkoxyphenylized product can be obtained in high yield under mild conditions, wherein the substrate is bonded via an oxygen atom to a phenyl group substituted with a C1-C5 alkoxy group at the para or ortho position.

[0016] That is, the invention in this application relates to the following.

[0017] [1] A method for manufacturing a compound of formula R-OH, comprising the following steps: reacting a λ3-iodide with a compound of formula R-OX (where R is a substrate and X is a phenyl group substituted with a C1-C5 alkoxy group at the para or ortho position, wherein the phenyl group is optionally further substituted) in a fluorinated alcohol and water.

[0018] [2] According to the method described in [1], wherein the C1 to C5 alkoxy group of the X group is methoxy, ethoxy, propoxy or isopropoxy.

[0019] [3] According to the method described in [1], wherein the C1-C5 alkoxy group in the X group is a p-methoxy group.

[0020] [4] The method according to any one of [1] to [3], wherein the λ3-iodide is of formula R 1 -I (OR)2 The compound shown in 2, R 1 R is an unsubstituted or substituted phenyl group. 2 It is selected from the group consisting of H, acetyl, trifluoroacetyl, toluenesulfonyl, methanesulfonyl, and combinations thereof.

[0021] [5] According to the method described in [4], wherein the formula R 1 -I (OR) 2 The compound shown in 2 is selected from the group consisting of [bis(trifluoroacetoxy)iodide]benzene (PIFA), [hydroxy(toluenesulfonyl)iodide]benzene (HTIB), (diacetoxyiodide)benzene (PIDA), [bis(trifluoroacetoxy)iodide]pentafluorobenzene, [hydroxy(methanesulfonyl)iodide]benzene, and combinations thereof.

[0022] [6] The method according to any one of [1] to [5], wherein the amount of the λ3-iodide is 0.1 to 10 equivalents relative to the substrate.

[0023] [7] The method according to any one of [1] to [6], wherein the fluorinated alcohol is a fluorinated aliphatic alcohol.

[0024] [8] According to the method described in [7], wherein the fluorinated aliphatic alcohol is a fluorinated C2-C8 aliphatic alcohol.

[0025] [9] According to the method of [8], wherein the fluorinated 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, perfluoro-tert-butanol and combinations thereof.

[0026]

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

[0027]

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

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

[0028]

[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 to the substrate and 10 or less in volume ratio.

[0029]

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

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

[0030]

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

[13] includes the step of adding trifluoroacetic acid when using (diacetoxyiodine)benzene (PIDA) as the λ3-iodide.

[0031]

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

[14] , wherein the reaction is carried out at -20°C to 60°C.

[0032]

[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 the anodic position.

[0033]

[17] According to the method of

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

[0034]

[18] According to the method of

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

[0035]

[19] According to the method of

[18] , wherein the monosaccharide is a pentose or a hexose.

[0036]

[20] According to the method of

[19] , wherein the hexose is glucose, mannose, galactose or glucosamine.

[0037]

[21] According to the method described in

[17] , wherein the polysaccharide is a disaccharide to a decasaccharide.

[0038]

[22] According to the method of

[17] , wherein the polysaccharide is (i) a disaccharide, (ii) a trisaccharide or (iii) a tetrasaccharide, wherein the disaccharide is galactose-glucosamine, glucosamine-glucosamine, neuraminic acid-galactose or mannose-glucosamine, the trisaccharide is composed of two mannose and one glucosamine, or is composed of neuraminic acid, galactose and glucosamine, and the tetrasaccharide is composed of two mannose and two glucosamine, or is composed of three mannose and one glucosamine.

[0039]

[23] The method according to any one of

[16] to

[22] , wherein the hydroxyl group of the carbon adjacent to the carbon at the 1-position or the anterior position in the sugar is protected by an acyl group; or the amino group of the carbon adjacent to the carbon at the 1-position or the anterior position in the sugar is protected by an imide group, an acyl group or a carbamate group; or the carbon adjacent to the carbon at the 1-position or the anterior position in the sugar has an azide group (N3).

[0040]

[24] According to the method of

[23] , wherein, as the protecting group of the amino group, the imide 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-fluorenylmethoxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0041]

[25] According to the method of

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

[0042]

[26] A method for manufacturing a sugar with an attached portion, comprising the steps of: attaching one or more of the attached portions selected from the group consisting of proteins, nucleic acid molecules, lipid molecules, eukaryotic cells, prokaryotic cells, biologically derived tissues, viruses, parasites, low molecular weight compounds and artifacts to a sugar obtained by any one of the methods described in

[16] to

[25] .

[0043]

[27] According to the method of

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

[0044]

[28] According to the method of

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

[0045]

[29] According to the method of

[27] , wherein the protein is an antibody or an antigen-binding fragment thereof, which is bonded to a peptide, nucleic acid molecule, lipid molecule, low molecular weight compound, orthotopic, other antibody or antigen-binding fragment thereof, or toxin, or forms a conjugate with a drug, or is unmodified.

[0046]

[30] According to the method of

[27] , wherein the protein is a cytokine that is bonded to an antibody or its antigen-binding fragment, or is unmodified.

[0047]

[31] The method according to any one of

[26] to

[30] , wherein the method comprises the step of: in addition to the additional portion of the protein, binding one or more other additional portions to the sugar.

[0048]

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

[15] , wherein the substrate R is Ar-(CR) 3 R 4 )n-(where n=1~3, Ar is an aromatic ring, R 3 and R 4 These are H, an aromatic ring, or an aliphatic group, respectively, with any of the aromatic ring and aliphatic group optionally substituted.

[0049]

[33] According to the method of

[32] , wherein the aromatic ring is optionally substituted C5-C6. 20 Aryl or 5-20 membered heteroaryl, wherein the aliphatic group is optionally substituted C1-C2. 10 Aliphatic hydrocarbon groups.

[0050]

[34] According to the method of

[32] or

[33] , wherein the aromatic ring is selected from the group consisting of xylene, toluene, styrene, ethylbenzene, cumene, furan, thiophene, pyrrole, pyran, thiaran, pyridine, thiazole, imidazole, pyrimidine, 1,3,5-triazine, naphthalene, indene, anthracene, phenanthrene, fluorene, biphenyl, triphenyl, terphenyl, binatine, phenylnaphthalene, indole, quinoline, and purine.

[0051] Invention Effects

[0052] According to the invention of this application, dealkoxyphenylated products can be obtained in high yield from substrates such as sugars bonded via oxygen atoms to phenyl groups substituted with C1-C5 alkoxy groups at the para or ortho positions under mild conditions. Therefore, the operation is highly safe, can be performed with simple procedures, and the product is easy to purify, making it suitable for large-scale synthesis. Detailed Implementation

[0053] This invention provides a method for obtaining a compound of formula R-OH, comprising the following steps: reacting a λ3-iodide with a compound of formula R-OX (where R is a substrate and X is a phenyl group substituted with a C1-C5 alkoxy group at the para or ortho position, the phenyl group optionally being further substituted) in a fluorinated alcohol and water.

[0054] In this application, the reaction in which the compound represented by formula R-OX is converted into the compound represented by formula R-OH is referred to as a "dealkoxyphenylization reaction". While not limited to a specific reaction mechanism, the aforementioned reaction mechanism can be understood as follows: for the compound represented by formula R-OX, the λ3-iodide acts as a single-electron oxidant, the OX group is desorbed from the compound represented by formula R-OX, and then water (H2O) is added to it, resulting in the formation of the compound represented by formula R-OH. It should be noted that in the field of organic synthetic chemistry, including glycan synthesis, methoxyphenyl and similar compounds are often used as "protecting groups" for highly reactive functional groups such as hydroxyl groups to achieve the target reaction; this is well known to those skilled in the art. However, this invention is not limited to such use for deprotection purposes and can be applied to any situation where the compound represented by formula R-OX is converted into the compound represented by formula R-OH. In this application specification, for ease of understanding and convenience, the compound represented by the above formula R-OX is sometimes referred to as the "protecting body", the above alkoxyphenyl (X group) is sometimes referred to as the "protecting group", the above dealkoxyphenylization reaction is sometimes referred to as the "deprotection reaction", and the compound represented by the generated formula R-OH is sometimes referred to as the "deprotecting body".

[0055] In the compound represented by the formula R-OX above, "R" refers to the substrate. "Substrate" refers to any organic compound that can bond via an oxygen atom to a phenyl (X-group) substituted with a C1-C5 alkoxy group at the para or ortho position.

[0056] In one embodiment, the substrate R can also be a "sugar". Sugars include monosaccharides and polysaccharides. A "monosaccharide" can be any of the D-isomers and L-isomers, and can be any of the aldoses and ketoses.

[0057] In one embodiment of the present invention, the "monosaccharide" preferably used is a polyol having a five- or six-membered ring structure, wherein one of the carbon atoms forming the ring structure is replaced by an oxygen atom, and containing two or more hydroxyl groups. More specifically, monosaccharides such as pentoses, hexoses, heptoses, octoses, and nonoses that form a five- or six-membered ring structure are preferred, with pentoses and hexoses being more preferred, and hexoses being even more preferred. Specific examples of pentoses include ribose, xylose, apigenin, arabinose, ribulose, and xylulose. Specific examples of hexoses include glucose, mannose, galactose, arbutin, allulose, and fructose, with glucose, mannose, and galactose being preferred.

[0058] In one embodiment, "polysaccharide" may also be used as a substrate in this invention. "Polysaccharide" refers to a sugar formed by two or more monosaccharides linked by glycosidic bonds, and generally also includes sugars called oligosaccharides. In this invention, the preferred polysaccharide is one composed of monosaccharides forming a cyclic structure of a five- or six-membered ring as described above. Furthermore, disaccharides to decasaccharides are preferred, but not limited to these.

[0059] Furthermore, in this 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.), deoxysugars (deoxyribose, deoxyglucose, rhamnose, fucose, etc.), uronic acids (glucuronic acid, guluronic acid, mannouronic acid, galacturonic acid, iduronic acid, etc.), and their derivatives (e.g., acetylated derivatives). For example, the aforementioned amino sugars or their derivatives (e.g., N-acetylglucosamine, N-acetylgalactosamine, N-acetylneuraminic acid, etc.) are preferred. Furthermore, a polysaccharide derivative refers to a sugar formed by bonding two or more monosaccharides and containing at least one derivative of the aforementioned monosaccharides.

[0060] Preferred examples of polysaccharides in this invention include: disaccharides, trisaccharides, or tetrasaccharides constituting any position of human N-type sialic acid glycopeptide (SGP), such as: (i) disaccharides such as galactose-glucosamine, glucosamine-glucosamine, neuraminic acid-galactose, and mannose-glucosamine; (ii) trisaccharides composed of two mannoses and one glucosamine, or trisaccharides composed of neuraminic acid, galactose, and glucosamine; and (iii) tetrasaccharides composed of two mannoses and two glucosamines, or tetrasaccharides composed of three mannoses and one glucosamine. Other examples of polysaccharides in this invention include: decasaccharides of N-acetylglucosamine (GlcNAc) lacking the reduced terminus of a glycan portion (SG) of an SGP.

[0061] In one embodiment, the sugar (monosaccharide, polysaccharide or its derivatives, etc.) that is the substrate in this invention may also be bonded with other moiety (hereinafter referred to as "attaching moiety").

[0062] Furthermore, in another embodiment, a sugar derivative (hereinafter referred to as "resulted sugar derivative" or "derivative of resulted sugar") can be manufactured: A sugar with the formula R-OH (hereinafter referred to as "resulted sugar") is produced from a sugar-containing compound with the formula R-OX, where the substrate R is a sugar. Through further reaction, other sugars are added to the resulting sugar, or proteins or the like are added to modify the resulting sugar. The resulting sugar and its derivative may also include substances other than sugars, such as proteins, low-molecular-weight compounds, nucleic acid molecules, peptides, lipids, orthopedic substances, etc., as "additional components." This invention provides a method for manufacturing the resulting sugar and a method for manufacturing the resulting sugar derivative. The resulting sugar and its derivative may also possess activity or function due to the presence of "additional components" such as proteins, for example, catalytic activity, labeling function, enzyme substrate function, cytotoxic activity, immune cell activation activity, antioxidant effect, protective effect, receptor function, ligand function, in vivo dynamic regulation function, drug delivery function, etc.

[0063] Examples of the "additional component" for sugars mentioned above include: biological macromolecules such as proteins, nucleic acid molecules, and lipid molecules; cells (eukaryotic cells and prokaryotic cells); biologically derived tissues; parasites such as viruses; low-molecular-weight compounds; and orthopedic crops, but are not limited to these. The "additional component" may also possess activity or function, such as catalytic activity, labeling function, enzyme substrate function, cytotoxic activity, immune cell activation activity, antigen-binding activity, protective effect, receptor function, ligand function, in vivo dynamic regulation function, drug delivery function, and infectivity. Examples of proteins as an "additional component" include: proteins derived from humans or non-human animals, wild-type proteins, modified proteins, and artificially designed proteins. Preferably, examples include: cytokines, receptors, immunoglobulins (antibodies), or fragments thereof. Preferred cytokines are not limited, but examples include: wild-type human cytokines, immune cytokines, and fragments thereof. Preferred receptors are not limited, but examples include: soluble receptors, nuclear receptors, and fusions of receptors or fragments thereof with the Fc region of immunoglobulins. As antibodies, they can also be full-body antibodies, antigen-binding fragments of antibodies such as scFv, conjugates of antibodies or their antigen-binding fragments with drugs (hereinafter referred to as "antibody-drug conjugates"), multispecific antibodies, immunotoxins, tagged antibodies or their binding fragments, etc. In this invention, they are sometimes also referred to as "proteins". The "low molecular weight compound" as one embodiment of the "additional part" can also be platinum group compounds such as cisplatin and carboplatin. It should be noted that, as mentioned above, this invention also provides a method for manufacturing a sugar-forming compound with an additional part bonded thereto, which includes a step of bonding the additional part to the sugar-forming compound; and a method for manufacturing a sugar-forming derivative with an additional part bonded thereto, which includes a step of bonding the additional part to the sugar-forming derivative. The sugar-forming compound with an additional part bonded thereto and the sugar-forming derivative can also be further modified or altered, and the modified or altered substances are also included within the scope of "sugar-forming compounds with additional parts bonded thereto" and "sugar-forming derivatives with additional parts bonded thereto".

[0064] Furthermore, the first additional portion and the second additional portion can be combined (linked) via the sugar or sugar derivative of the present invention. For example, it is possible to manufacture immune cytokines formed by binding an antibody or its antigen-binding fragment to a cytokine via the sugar or sugar derivative, immunotoxins formed by binding an antibody or its binding fragment to a toxin, and antibody-drug conjugates formed by binding an antibody or its antigen-binding fragment to a drug. Therefore, the present invention also provides a method for manufacturing a sugar formed by combining the first additional portion and the second additional portion, and a method for manufacturing a sugar derivative formed by combining the first additional portion and the second additional portion. Examples of combinations of the first additional portion and the second additional portion include: 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., but are not limited thereto. In another embodiment, the additional portion may also be bonded to or contained in a compound represented by formula R-OX or a compound represented by formula R-OH. It should be noted that a compound represented by formula R-OH containing the additional portion can be referred to as a "product containing the additional portion". The method provided in this application enables the production of a product containing an additional portion from a compound of formula R-OX, where R is a substrate containing an additional portion.

[0065] In this invention, when sugar is the substrate, the aforementioned X group (a phenyl group substituted with C1 to C5 alkoxy groups at the para or ortho position) forms a covalent bond with a hydroxyl group present at the 1-position or anolyptic position of the sugar to form an "OX group".

[0066] In this invention, in the substrate sugar, the hydroxyl group of the carbon adjacent to the carbon at the 1-position or anomeric position having an OX group can also be protected by the following groups: acyl group, such as acetyl (Ac) or benzoyl (Bz); ether-based protecting group, such as benzyl (Bn); or silyl-based protecting group, such as 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 the 1-position or anodic position of the OX group (e.g., in the case of amino sugars) can also be protected by the following groups: 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-fluorenylmethoxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), or benzyloxycarbonyl (Cbz). Alternatively, in the substrate sugar, the carbon adjacent to the carbon at the 1-position or anodic position of the OX group can also have an azide group (N3). In particular, in the substrate sugar, it is preferable that the hydroxyl group of the carbon adjacent to the 1-position or anomeric carbon of the OX group is protected by an acyl group; or that the amino group of the carbon adjacent to the 1-position or anomeric carbon of the OX group is protected by an imide or carbamate group. Thus, the presence of a protecting group with a carbonyl oxygen atom on the hydroxyl or amino group of the carbon adjacent to the 1-position or anomeric carbon of the OX group is very useful for improving the yield of the dealkoxyphenylation reaction product. It should be noted that other hydroxyl groups present in the sugar may be unsubstituted or protected by the following groups: 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 triphenylmethyl (e.g., triphenylmethyl), etc.

[0067] In another embodiment, the substrate R can also be Ar-(CR) 3 R 4 )n-(where n=1~3, preferably n=1~2, particularly preferably n=1, Ar is an aromatic ring, R 3 and R 4 These can be H, an aromatic ring, or an aliphatic group, respectively, with any aromatic ring and aliphatic group optionally substituted.

[0068] As for the above Ar-(CR) 3 R 4 Ar and R in n- 3 and R 4The term "aromatic ring" as defined can be categorized as either monocyclic or polycyclic aromatic rings. As a "monocyclic aromatic ring," examples include monocyclic aromatic hydrocarbons or monocyclic heterocyclic aromatic rings (heterocyclic aromatic rings refer to heterocyclic compounds possessing aromatic properties). As a "monocyclic aromatic hydrocarbon," unsubstituted benzene can be listed. It should be noted that, as described later, the benzene may be optionally substituted. Specific examples of benzene having hydrocarbon substituents include: xylene, toluene, styrene, ethylbenzene, cumene, etc. As a "monocyclic heterocyclic aromatic ring," examples include: furan, thiophene, pyrrole, pyran, thiaran, pyridine, thiazole, imidazole, pyrimidine, 1,3,5-triazine, etc. As a "polycyclic aromatic ring," examples include polycyclic aromatic hydrocarbons and polycyclic heterocyclic aromatic rings. As for "polycyclic aromatic hydrocarbons," examples include cyclic aromatic hydrocarbons (i.e., aromatic compounds formed by the direct linkage of two or more aromatic rings, such as 2 to 5 aromatic rings) and condensed polycyclic aromatic hydrocarbons (substances formed by the condensation of two or more aromatic rings, such as 2 to 5 aromatic rings), such as naphthalene, indene, anthracene, phenanthrene, fluorene, biphenyl, triphenyl, terphenyl, binaphthalene, phenylnaphthalene, etc. As for "polycyclic heteroaromatic rings," examples include cyclic heteroaromatic rings (substances having at least one heteroaromatic ring, formed by the direct linkage of two or more aromatic rings, such as 2 to 5 aromatic rings) and condensed polycyclic heteroaromatic rings (substances having at least one heteroaromatic ring, formed by the condensation of two or more aromatic rings, such as 2 to 5 aromatic rings), such as indole, quinoline, purine, etc. The aromatic rings mentioned above are also represented as aryl or heteroaryl groups, for example, C5 to C6. 20 Aryl, C5~C 14 Aryl or C5~C 10 The aryl group can be a heteroaryl group with a 5-20 membered ring, a 5-14 membered ring, or a 5-10 membered ring, but is not limited thereto. The aforementioned "aromatic ring" may be unsubstituted or may have one or more substituents. Examples of such substituents include: straight-chain or branched saturated or unsaturated hydrocarbon groups, oxygen-containing groups (hydroxyl, alkoxy, aldehyde, ketone, acetoxy, acetyl, carbonyl, oxygen, carboxyl, ester, etc.), nitrogen-containing groups (amino, cyano, imide, azo, azido, etc.), sulfur-containing groups (sulfonyl, thiol, etc.), halogens (e.g., fluorine, chlorine, bromine, iodine), etc., more preferably hydrocarbon groups, oxygen-containing groups, or halogens. When these substituents contain carbon, for example, substituents having 1-10 carbons, substituents having 1-5 carbons, or substituents having 1-3 carbons (e.g., C1-C1 substituents are preferred) are preferred. 10 Hydrocarbon group, C1-C5 hydrocarbon group or C1-C3 hydrocarbon group; or C1-C 10 Alkoxy, C1-C5 alkoxy, or C1-C3 alkoxy, etc.

[0069] For the above Ar-(CR) 3 R4 R in n- 3 and R 4 The specified "aliphatic groups" can be listed as follows: C1~C 10 The hydrocarbon group, preferably a C1-C5 hydrocarbon group, more preferably a C1-C3 hydrocarbon group, can be saturated or unsaturated acyclic or saturated cyclic. Furthermore, when the hydrocarbon group is acyclic, it can be linear or branched. "C1-C5" 10 "Hydrocarbon group" includes, for example, C1 to C1. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C4~C 10 Alkyl diene group, C4-C 10 cycloalkyl, C4-C 10 Cycloalkenyl groups, etc., can also be C1-C6 hydrocarbon groups or C1-C3 hydrocarbon groups. As C1-C6 hydrocarbon groups... 10 Examples of alkyl groups include: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, nonyl, decyl, etc. As C2~C 10 Examples of alkenyl groups include: vinyl, allyl, propenyl, isopropenyl, 2-methyl-1-propenyl, 2-butenyl, etc. As C2~C 10 Examples of alkynyl groups include: ethynyl, 2-propynyl, 2-butynyl, etc. As C4~C 10 Examples of alkyl dienyl groups include 1,3-butadienyl, etc. As C4~C 10 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. These are C4-C6 groups. 10 Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, 2-cyclopenten-1-yl, and 2-cyclohexen-1-yl. It should be noted that the examples of the above-mentioned hydrocarbon groups can be referred to throughout this application specification. Furthermore, the above-mentioned "aliphatic group" may be unsubstituted or may have one or more substituents, C1 to C2. 10 At least one hydrogen atom in the hydrocarbon group or similar group may be replaced by, for example, non-hydrogen atoms or groups, or have or contain such groups: oxygen-containing groups (hydroxyl, alkoxy, aldehyde, ketone, acetoxy, acetyl, carbonyl, oxygen, carboxyl, ester, etc.), nitrogen-containing groups (amino, cyano, isocyanate, imide, azo, azido, etc.), sulfur-containing groups (sulfonyl, thiol, etc.), halogens (e.g., fluorine, chlorine, bromine, iodine), etc., preferably oxygen-containing groups or halogens. Furthermore, the aforementioned "aliphatic groups" are optionally replaced by C5 to C6 groups. 20 Aryl (e.g., C5-C5) 14 Aryl or C5~C 10 Aryl group substitution.

[0070] In the above formula R-OX, "OX" represents oxygen (O) covalently bonded to X, and "X" represents a phenyl group substituted at the para or ortho position with a C1-C5 alkoxy group (also called an alkyloxy group). A compound represented by formula R-OX may contain one or more OX groups. Specific examples of the aforementioned "C1-C5 alkoxy groups" include: methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, 1-methylpropoxy, 1,1-dimethylethoxy, pentooxy, 3-methylbutoxy, 2-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, etc., preferably C1-C3 alkoxy groups, such as methoxy, ethoxy, propoxy, and isopropoxy, more preferably methoxy and ethoxy, and even more preferably methoxy. Examples of the aforementioned "C1-C5 alkoxy groups" can be referenced throughout this application specification. Furthermore, the aforementioned "C1-C5 alkoxy" can be located anywhere in the para or ortho position of the phenyl group, preferably in the para position. Additionally, the phenyl group in the aforementioned X group can be unsubstituted or optionally further substituted with one or more substituents. Examples of such substituents include: straight-chain or branched saturated or unsaturated hydrocarbon groups, oxygen-containing groups (hydroxyl, alkoxy, aldehyde, ketone, acetoxy, acetyl, carboxyl, ester, etc.), nitrogen-containing groups (amino, cyano, imide, azo, azido, etc.), sulfur-containing groups (sulfonyl, thiol, etc.), halogens (e.g., fluorine, chlorine, bromine, iodine), etc., more preferably hydrocarbon groups, oxygen-containing substituents, and halogens. When these substituents contain carbon, for example, substituents having 1 to 10 carbons, substituents having 1 to 5 carbons, or substituents having 1 to 3 carbons (e.g., C1-C5 substituents are preferred) can be used. 10 Hydrocarbon group, C1-C5 hydrocarbon group or C1-C3 hydrocarbon group; or C1-C 10 Alkoxy, C1-C5 alkoxy, or C1-C3 alkoxy, etc.

[0071] "λ3-iodide" refers to trivalent supraatomic iodine compounds. By using λ3-iodide, compared to conventional deprotection methods, not only is the yield of the dealkoxyphenylation reaction product increased, but the reaction can also be carried out under mild reaction conditions. Furthermore, the reaction is carried out in a slight excess of λ3-iodide, thus, for example, compared to conventional deprotection methods using excess ammonium cerium(IV) nitrate, the purification of the deprotected product becomes easier and the operation is safer.

[0072] In one embodiment, the λ3-iodide is of formula R 1 -I (OR) 2 The compound shown in 2 (where R is a compound) 1 R is an unsubstituted or substituted phenyl group. 2Selected from the group consisting of H, acetoxy, trifluoroacetoxy, toluenesulfonyloxy, methanesulfonyloxy, and combinations thereof. As defined in the above formula, R 1 The substituent can be a "substituted phenyl group," and examples of substituents include: straight-chain 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., more preferably hydrocarbon groups, oxygen-containing substituents, and halogens. When these substituents contain carbon, for example, substituents having 1 to 5 carbons or substituents having 1 to 3 carbons are preferred. Specific examples of λ3-iodides include: [bis(trifluoroacetoxy)iodide]benzene (PIFA), [hydroxy(toluenesulfonyl)iodide]benzene (HTIB), (diacetoxy)iodide)benzene (PIDA), [bis(trifluoroacetoxy)iodide]pentafluorobenzene, and [hydroxy(methanesulfonyl)iodide]benzene, but are not limited to these.

[0073] The amount of λ3-iodide can be appropriately set according to the type of substrate and from the viewpoint of achieving a high yield of the product, for example, it can 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 preferably applicable to any substrate, and more preferably about 1 to 3 equivalents when the substrate is a monosaccharide, and more preferably about 1 to 4.5 equivalents when the substrate is a disaccharide, and more preferably about Ar-(CR) as described above. 3 R 4 In the case of n-, it is more preferable to be about 1 to 3 equivalents. It should be noted that throughout this specification, the term "about" indicates a range of ±10% of the mentioned value.

[0074] "Fluorohydrins" refer to fluorinated alcohol compounds in which all carbons except the carbon bonded to the alcohol are fluorinated. Fluorohydrins preferably have more fluorine, provided fluorine substitution is permitted. Fluorohydrins include, but are not limited to, fluorinated aliphatic alcohols. The hydrocarbon moiety in fluorinated aliphatic alcohols can be saturated or unsaturated, linear or branched, or cyclic. Fluorohydrins are, for example, fluorinated C2-C8 aliphatic alcohols, preferably fluorinated C2-C5 aliphatic alcohols, and more preferably fluorinated C2-C3 aliphatic alcohols. Specific examples of fluorinated 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, perfluorotert-butanol, and combinations thereof.

[0075] Furthermore, with regard to fluorinated alcohols and λ3-iodides, preferred combinations yield deprotected derivatives in higher yields. Such combinations can be appropriately selected by those skilled in the art; for example, as shown in the examples described later, PIFA is preferably used in combination with hexafluoro-2-propanol (HFIP), 2,2,2-trifluoroethanol (TFE), perfluorotert-butanol, etc.; HTIB is preferably used in combination with HFIP, TFE, 2,2,3,3,4,4,5,5-octafluoro-1-pentanol, etc.; [bis(trifluoroacetoxy)iodide]pentafluorobenzene is preferably used in combination with hexafluoro-2-propanol (HFIP), etc.; and [hydroxy(methanesulfonyloxy)iodide]benzene is preferably used in combination with hexafluoro-2-propanol (HFIP), etc., but these combinations are not limited to examples.

[0076] The amount of fluorinated alcohol can be appropriately set from the perspective of achieving a high yield of the product. For example, it can be 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 relative to the substrate in molar ratio. In addition, it can be about 15 or less, about 10 or less, about 8 or less, or about 5 or less relative to the substrate in volume ratio.

[0077] The dealkoxyphenylation reaction specified in this invention is carried out in the presence of the aforementioned fluorinated alcohol and "water". The amount of water can be appropriately set from the viewpoint of achieving a high yield of the product, for example, it can be 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 relative to the substrate in molar ratio, and it can be about 10 or less, about 8 or less, about 5 or less, or about 3 or less relative to the substrate in volume ratio.

[0078] In this invention, a "solvent" (also called a reaction solvent) may be further added to the fluorinated alcohol and water. The solvent may be selected from, but is not limited to, dichloromethane (CH₂Cl₂), toluene, (trifluoromethyl)benzene, and combinations thereof. The type of solvent used can be appropriately selected based on the solubility of the substrate and the λ₃-iodide used to achieve a high product yield. The amount of solvent can also be appropriately set to achieve a high product yield; for example, it may be about 0.5–50, about 1–20, or about 2–10 per volume relative to the substrate.

[0079] In this invention, "additives" may be further added to the fluorinated alcohol and water. The additives are preferably selected from the group consisting of sodium dihydrogen phosphate (NaH2PO4), potassium dihydrogen phosphate (KH2PO4), disodium hydrogen phosphate (Na2HPO4), and combinations thereof. As the dealkoxyphenylization reaction progresses, the acidity may increase; therefore, especially when using λ3-iodides (HTIB, etc.) that produce strongly acidic byproducts, or substrates sensitive to acidic conditions, higher product yields can be obtained by adding additives such as sodium dihydrogen phosphate (NaH2PO4). The amount of additive can also be appropriately set to achieve a high product yield, for example, it can be about 0.5 to 8 equivalents, about 1 to 6 equivalents, or about 1.5 to 5 equivalents relative to the substrate.

[0080] Furthermore, when using (diacetoxyiodine)benzene (PIDA) as the λ3-iodide, trifluoroacetic acid (TFA) is preferably added in order to obtain the deprotected product in higher yield.

[0081] As explained above, in this invention, it can be considered that in the coexistence of a fluorinated alcohol and water, the λ3-iodide acts as a single-electron oxidant for the phenyl group (X group) of formula R-OX with an alkoxy group at the ortho or para position, thereby desorbing the OX group from the compound represented by formula R-OX. Then, by adding water (H2O), the alkoxyphenoxy group (OX group) readily desorbs from the compound represented by formula R-OX, thus achieving a readily achievable result. Such action of the λ3-iodide is typically achieved by stirring, refluxing, or otherwise refluxing a solution containing the compound of formula R-OX and the λ3-iodide in the fluorinated alcohol and water. Therefore, the method of this invention is easy to implement and can be easily scaled up. The dealkoxyphenylized product can be purified or separated by any purification method known to those skilled in the art, such as crystallization or chromatography.

[0082] The preferred temperature for reacting the λ3-iodide with the compound represented by formula R-OX is about -20°C to below the boiling point of the fluorinated alcohol (e.g., about 58°C for hexafluoro-2-propanol (HFIP) and about 78°C for 2,2,2-trifluoroethanol (TFE)). For example, it can be about -20°C to 60°C, about 0°C to 60°C, or about 10°C to 30°C. Furthermore, the dealkoxyphenylization reaction can also be carried out at room temperature (15°C to 30°C), which is advantageous in that it eliminates the need for cooling or heating, and is also effective when using heat-sensitive substrates.

[0083] Furthermore, the reaction time can be appropriately set in order to obtain the product in high yield.

[0084] The invention described in this application is further illustrated in the following embodiments, but these embodiments do not limit the scope of the invention in any way.

[0085] Example

[0086] <Example 1>

[0087] (Example 1-1)

[0088] The formation and separation of 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-D-glucopyranoside (2) by de-methoxyphenylation reaction

[0089]

[0090] 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), bis(trifluoroacetoxy)iodobenzene) (PIFA) as the λ3-iodide (below 25 °C) was added, and the mixture was stirred at the same temperature for 4 hours to carry out the de-methoxyphenylization reaction. After the reaction was confirmed by HPLC, ethyl acetate (250 mL) was added, and after cooling, water (100 mL) containing sodium bicarbonate (5 g) and sodium sulfite (5 g) was added. The mixture was separated to obtain the organic layer. The obtained organic layer was washed again with 100 mL of water containing dissolved sodium bicarbonate (5 g) and sodium sulfite (5 g), and further washed with 50 mL of 20% saline solution. The obtained organic layer was concentrated under reduced pressure to 100 mL (crystal precipitation was confirmed during concentration), and heptane (150 mL) was added dropwise. The obtained slurry was cooled to 0–5 °C and stirred at the same temperature for 1 hour, and the precipitated crystals were filtered out. 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, 90% yield) was isolated as white crystals. It should be noted that the yield of the deprotected body obtained by separation after the above-mentioned de-methoxyphenylation reaction can be called the "separation yield".

[0091] 1H-NMR (500MHz, CDCl3) δ7.38-7.21 (m, 10H), 5.17 (t, J=3.5Hz, 1H), 5.13 (d, J=10.0Hz, 1H ), 4.98 (t, J=10.0Hz, 1H), 4.78 (d, J=12.0Hz, 1H), 4.65-4.55 (m, 3H), 4.50 (dd, J=17.2, 12 .0Hz, 2H), 4.41 (d, J=2.9Hz, 1H), 4.13-4.09 (m, 1H), 3.97 (td, J=10.2, 2.5Hz, 1H), 3.72 (t , J=10.0Hz, 1H), 3.51 (dd, J=10.6, 7.2Hz, 1H), 3.44 (dd, J=10.0, 2.5Hz, 1H), 1.90 (3H, s).

[0092] 13 C-NMR (125MHz, CDCl3) δ169.6, 154.1, 137.8, 137.2, 128.4, 128.1, 127.9, 12 7.7, 127.7, 95.3, 91.7, 77.3, 74.6, 73.7, 73.5, 70.9, 69.4, 68.8, 54.6, 20.7.

[0093] Regarding HRMS (ESI) － [M-H] － [C] 25 H 27 Cl3NO8] － Calculated value: 574.0808; Measured value: 574.0834.

[0094] The yield determination using HPLC analysis was performed under the following analytical conditions. It should be noted that the HPLC determinations were also performed under the same analytical conditions in Example 1 and Examples 2-14 described below.

[0095] <HPLC Analysis Conditions>

[0096] Equipment used: SHIMAZU HPLC (2010A HT).

[0097] Column: Xbrige C18 3.5μm, 4.6×150mm (Waters).

[0098] Mobile phase A: 10 mM AcONH4 aqueous solution.

[0099] Mobile phase B: CH3CN.

[0100] The gradient conditions are as follows.

[0101]

[0102] Flow rate: 1 mL / min.

[0103] Detection wavelength: 210nm.

[0104] Column temperature: 40℃.

[0105] Injection volume: 5μL.

[0106] Hold time: 18.3 minutes (1), 15.6 and 16.4 minutes (2), 14.7 minutes (iodobenzene).

[0107] (Examples 1-2)

[0108] The formation of 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-D-glucopyranoside (2) by de-methoxyphenylization.

[0109]

[0110] 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 volumes), hexafluoro-2-propanol (HFIP) (0.5 mL, 5 volumes), and water (0.05 mL, 0.5 volumes), bis(trifluoroacetoxy)iodobenzene (PIFA) as the λ3-iodide (0.09 g, 0.205 mmol, 1.4 equivalents) was added at room temperature (below 25 °C), and the mixture was stirred at the same temperature for 2 hours, thereby carrying out the de-methoxyphenylization reaction. The solution was quantified by HPLC, and the yield was calculated (HPLC quantitative yield: 95%). It should be noted that the yield calculated by HPLC after the de-methoxyphenylation reaction can be called "HPLC quantitative yield".

[0111] (Examples 1-3)

[0112] Using the same method as shown in Examples 1-2, substrate 1 was subjected to de-methoxyphenylization according to the λ3-iodide, fluorinated alcohol, and reaction time shown in Table 1 below. The yield of product 2 was calculated by quantifying the reaction solution by HPLC (entries 2-7 in Table 1) (Note that entry 1 in Table 1 pertains to Example 1 (Example 1-1 (90%, separation) and Example 1-2 (95%))).

[0113] (Examples 1-4)

[0114] 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), (diacetoxyiodide)benzene (PIDA) (72 mg, 0.222 mmol, 1.4 equivalents) as the λ3-iodide was added, and the mixture was stirred at the same temperature for 3 hours, thereby carrying out the de-methoxyphenylization reaction. The 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 quantitative yield: 93%, item 8 in Table 1).

[0115]

[0116]

[0117] <Example 2>

[0118]

[0119] Using the same method as shown in Examples 1-2, and with various solvents and reaction times as shown in Table 2, the de-methoxyphenylation of 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-β-D-glucopyranoside (1) was performed. HTIB was used instead of PIFA in item 4 of Table 2 below. 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 by quantifying the reaction solution by HPLC. The results are shown in Table 2 below.

[0120]

[0121] <Example 3>

[0122] The formation of 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-D-glucopyranoside (2) by de-p-methoxyphenylation reaction using various amounts of λ3-iodide, fluorinated alcohol, and water.

[0123]

[0124] 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 volumes), hexafluoro-2-propanol (HFIP) (0.5 mL, 5 volumes), and water (0.05 mL, 0.5 volumes), at room temperature (below 25 °C), [hydroxy(toluenesulfonyloxy)iodo]benzene (HTIB) as λ3-iodide (0.08 g, 0.205 mmol, 1.4 equivalents)) was added, and the mixture was stirred at the same temperature for 0.5 hours. The 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 (entry 1, HPLC quantitative yield: >99%).

[0125] Using the same method as described above, substrate 1 underwent de-methoxyphenylation according to the λ3-iodide, fluorinated alcohol, water, temperature, and reaction time shown in Table 3 below. The yield of product 2 was calculated by quantifying the reaction solution using HPLC (entries 2-7). Entry 7 in Table 3 is an example without water; several impurities were significantly observed by HPLC, resulting in a significant decrease in yield. On the other hand, when water was present in the substrate, the product (deprotected form) was obtained in a high yield.

[0126]

[0127] <Example 4>

[0128] The formation of 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-D-glucopyranoside (2) by de-methoxyphenylization reaction using various additives.

[0129]

[0130] Sodium dihydrogen phosphate (NaH2PO4) (0.05 g, 0.439 mmol, 3 equivalents) as an additive was added 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 volumes), hexafluoro-2-propanol (HFIP) (0.5 mL, 5 volumes), and water (0.05 mL, 0.5 volumes). Then, at room temperature (below 25 °C), [hydroxy(toluenesulfonyloxy)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. The 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 quantitative yield: >99%).

[0131] Using the same method as described above, substrate 1 was subjected to de-methoxyphenylation using the various additives shown in Table 4 below. In the reaction described in 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 volumes of water. The yield of product 2 (entries 2 and 3) was calculated by quantifying the reaction solution using HPLC.

[0132]

[0133] <Example 5>

[0134] The formation and separation of 3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-D-glucopyranoside (7b) by de-methoxyphenylation.

[0135]

[0136] 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 volumes), hexafluoro-2-propanol (HFIP) (5 mL, 5 volumes), and water (0.5 mL, 0.5 volumes), at room temperature (below 25 °C), [hydroxy(toluenesulfonyloxy)iodo]benzene (HTIB) as the λ3-iodide (0.86 g, 2.18 mmol, 1.4 equivalents)] was added, and the mixture was stirred at the same temperature for 2 hours, thereby carrying out the de-methoxyphenylization reaction. Then, ethyl acetate (25 mL) and water (8 mL) containing dissolved sodium bicarbonate (0.5 g) and sodium sulfite (0.5 g) were added, and the mixture was separated to obtain an organic layer. The obtained organic layer was washed again with water (8 mL) containing sodium bicarbonate (0.5 g) and sodium sulfite (0.5 g), and further washed with 20% saline (4 mL). The obtained organic layer was dried with 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, thereby separating 3,6-di-O-benzyl-2-deoxy-2-{[(2,2,2-trichloroethoxy)carbonyl]amino}-D-glucopyranoside (7b) (720 mg, 87% yield) as a white solid.

[0137] Using 7a as the substrate, [bis(trifluoroacetoxy)iodo]benzene (PIFA) (1.4 equivalents) as the λ3-iodide, and dichloromethane as the reaction solvent, the de-methoxyphenylization reaction was carried out in the same manner as described above. Then, the same treatment as described above was performed, resulting in a separation yield of 7b of 84%.

[0138] 1 H-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).

[0139] 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.

[0140] Regarding HRMS (ESI) － [M-H] － [C] 23 H 25 Cl3NO7] － Calculated value: 532.0702; Measured value: 532.0701.

[0141] <Example 6>

[0142] The formation and separation of 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-D-glucopyranoside (8b) by de-methoxyphenylization reaction.

[0143]

[0144] Using 4-methoxyphenyl 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-D-glucopyranoside (8a) as the substrate, [hydroxy(toluenesulfonyloxy)iodo]benzene (HTIB) (1.4 equivalents) as the λ3-iodide, and toluene as the reaction solvent, the de-methoxyphenylization reaction was carried out in the same manner as in Example 5, and the result was that the separation yield of 8b was 81%.

[0145] Using 8a as the substrate, [bis(trifluoroacetoxy)iodo]benzene (PIFA) (1.4 equivalents) as the λ3-iodide, and dichloromethane as the reaction solvent, the de-methoxyphenylization reaction was carried out in the same manner as in Example 5, and the result was that the separation yield of 8b was 94%.

[0146] 1H-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).

[0147] 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.

[0148] Regarding HRMS (ESI) － [M-H] － [C] 30 H 28 NO8] － Calculated value: 530.1820; Measured value: 530.1841.

[0149] <Example 7>

[0150] The formation and separation of 2,4,6-tri-O-acetyl-3-O-benzyl-D-glucopyranoside (9b) by de-methoxyphenylization reaction

[0151]

[0152] Using 4-methoxyphenyl 2,4,6-tri-O-acetyl-3-O-benzyl-D-glucopyranoside (9a) as the substrate, [hydroxy(toluenesulfonyloxy)iodo]benzene (HTIB) (1.4 equivalents) as the λ3-iodide, and toluene as the reaction solvent, the de-methoxyphenylization reaction was carried out in the same manner as in Example 5, and the result was that the separation yield of 9b was 97%.

[0153] Using 9a as the substrate, [bis(trifluoroacetoxy)iodo]benzene (PIFA) (2.4 equivalents) as the λ3-iodide, and dichloromethane as the reaction solvent, the de-methoxyphenylization reaction was carried out in the same manner as in Example 5, and the result was that the separation yield of 9b was 98%.

[0154] 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).

[0155] 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.

[0156] Regarding HRMS (ESI) － [M-H] － [C] 19 H 23 O9] － Calculated value: 395.1349; Measured value: 395.1344.

[0157] <Example 8>

[0158] The formation and separation of 2,3,4,6-tetra-O-acetyl-D-mannopyranoside (10b) by de-methoxyphenylation.

[0159]

[0160] Using 4-methoxyphenyl 2,3,4,6-tetra-O-acetyl-D-mannopyranoside (10a) as the substrate, [bis(trifluoroacetoxy)iodo]benzene (PIFA) (3.5 equivalents) as the λ3-iodide, dichloromethane as the reaction solvent, and potassium dihydrogen phosphate (3.0 equivalents) as the additive, the de-methoxyphenylization reaction was carried out in the same manner as in Example 5, and the result was that the separation yield of 10b was 88%.

[0161] 1 H-NMR (400MHz, CDCl3) δ5.41 (dd, J=3.6, 8.0Hz, 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).

[0162] 13 C-NMR (100MHz, CDCl3) δ171.0, 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.

[0163] Regarding HRMS (ESI) － [M-H] － [C] 14 H 19 O 10 ] － Calculated value: 347.0984; Measured value: 347.0999.

[0164] <Example 9>

[0165] The formation and separation of 2-azido-3,6-di-O-benzyl-2-deoxy-D-glucopyranoside (11b) by de-methoxyphenylation.

[0166]

[0167] Using 4-methoxyphenyl-2-azido-3,6-di-O-benzyl-2-deoxy-D-glucopyranoside (11a) as the substrate, [hydroxy(toluenesulfonyloxy)iodo]benzene (HTIB) (1.1 equivalents) as the λ3-iodide, dichloromethane as the reaction solvent, and potassium dihydrogen phosphate (3.0 equivalents) as the additive, the de-methoxyphenylization reaction was carried out in the same manner as in Example 5, and the result was that the separation yield of 11b was 88%.

[0168] Using 11a as the substrate, [bis(trifluoroacetoxy)iodo]benzene (PIFA) (1.4 equivalents) as the λ3-iodide, and dichloromethane as the reaction solvent, the de-methoxyphenylization reaction was carried out in the same manner as in Example 5, and the result was that the separation yield of 11b was 79%.

[0169] 1H-NMR (400MHz, CDCl3) δ7.40 (m, 10H), 5.20 (d, J=2.8Hz, 0.5H), 5.05 (brs, 0.5H), 4.88 (dd, J=10.8, 2.8Hz, 1H), 4.76 (d, J=10. 8Hz, 0.5H), 4.70 (d, J=10.8Hz, 0.5H), 4.54 (d, J=12.0Hz, 1H), 4.49 (d, J=12.0Hz, 1H), 4.43 (brs, 0.5H), 4.37 (d, J=8.0Hz, 0.5 H), 4.00 (ddd, J=8.0, 5.2, 3.2Hz, 0.5H), 3.81 (ddd, J=10.4, 8.8Hz, 0.5H), 3.67 (ddd, J=8.0, 6.0, 3.2Hz, 1H), 3.58 (ddd, J=6.0, 6.0, 1.2Hz, 1H), 3.54-3.45 (m, 1H), 3.35 (ddd, J=6.8, 6.0, 3.2Hz, 0.5H), 3.27 (m, 1H), 3.15 (m, 0.5H), 2.74 (brd, J=7.6Hz, 1H).

[0170] 13 C-NMR (100MHz, CDCl3) δ137.8, 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.

[0171] Regarding HRMS (ESI) － [M+HCOO] － [C] 21 H 24 N3O7] － Calculated value: 430.1620; Measured value: 430.1638.

[0172] <Example 10>

[0173] The formation and separation of 6-O-{5-acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-1-methyl-D-glycerol-α-D-galactose-non-2-ulopyranosyl}-2,4-di-O-benzoyl-3-O-benzyl-D-galactopyranoside (12b)

[0174]

[0175] Using 4-methoxyphenyl 6-O-{5-acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-1-methyl-D-glycerol-α-D-galactose-non-2-pyranulosyl}-2,4-di-O-benzoyl-3-O-benzyl-D-galactopyranoside (12a) as the substrate, [bis(trifluoroacetoxy)iodo]benzene (PIFA) (3.5 equivalents) as the λ3-iodide, dichloromethane as the reaction solvent, and potassium dihydrogen phosphate (3.0 equivalents) as the additive, the de-methoxyphenylization reaction was carried out in the same manner as in Example 5, and the result was a separation yield of 94% for 12b.

[0176] 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).

[0177] 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, 137.3, 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.

[0178] Regarding HRMS (ESI) － [M+HCOO] － [C] 48 H 54 NO 22 ] ― Calculated value: 996.3143; Measured value: 996.3143.

[0179] <Example 11>

[0180] The formation and separation of 3-O-{5-acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-1-methyl-D-glycerol-α-D-galactose-non-2-pyranulosyl}-2,5,6-tri-O-benzoyl-D-galactopyranoside (13b)

[0181]

[0182] Using 4-methoxyphenyl 3-O-{5-acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-1-methyl-D-glycerol-α-D-galactose-non-2-pyranulosyl}-2,5,6-tri-O-benzoyl-D-galactopyranoside (13a) as the substrate, [bis(trifluoroacetoxy)iodo]benzene (PIFA) (2.4 equivalents) as the λ3-iodide, dichloromethane as the reaction solvent, and potassium dihydrogen phosphate (3.0 equivalents) as the additive, the de-methoxyphenylization reaction was carried out in the same manner as in Example 5, and the result was a separation yield of 90% for 13b.

[0183] 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).

[0184] 13C-NMR (100MHz, CDCl3) δ171.5, 171.0, 170.9, 170.8, 170.6, 170.4, 170.3, 170. 1, 170.1, 169.7, 169.6, 168.1, 168.1, 167.0, 165.9, 165.9, 165.7, 165.6, 165. 4, 165.2, 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.

[0185] Regarding HRMS (ESI) ＋ [M+H] ＋ [C] 47 H 52 NO 21 ] ＋ Calculated value: 966.3026; Measured value: 966.3024.

[0186] <Example 12>

[0187] The formation and separation of 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-[(naphthyl-2-yl)methyl]-D-glucopyranosyl}-β-D-glucopyranoside (14b)

[0188]

[0189] Using 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-[(naphthyl-2-yl)methyl]-D-glucopyranosyl}-β-D-glucopyranoside (14a) as the substrate, [bis(trifluoroacetoxy)iodo]benzene (PIFA) (1.5 equivalents) as the λ3-iodide, dichloromethane as the reaction solvent, and potassium dihydrogen phosphate (3.0 equivalents) as the additive, the de-methoxyphenylization reaction was carried out in the same manner as in Example 5, and the result was a separation yield of 95% for 14b.

[0190] 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).

[0191] 13C-NMR (100MHz, CDCl3) δ170.8, 169.3, 168.9, 167.9, 138.5, 137.8, 135.2, 1 33.7, 133.1, 132.9, 131.5, 128.5, 128.2, 128.1, 127.9, 127.9, 127.8, 127.6 , 127.0, 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.

[0192] Regarding HRMS (ESI) － [M-H] － [C] 51 H 50 NO 15 ] － Calculated value: 916.3186; Measured value: 916.3204.

[0193] <Example 13>

[0194] The formation and separation of 3,6-di-O-benzyl-2-deoxy-4-O-{6-O-acetyl-2,4-di-O-benzyl-3-O-[(naphthyl-2-yl)methyl]-β-D-mannopyranosyl}-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-D-glucopyranoside (15b)

[0195]

[0196] Using 4-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-4-O-{6-O-acetyl-2,4-di-O-benzyl-3-O-[(naphthyl-2-yl)methyl]-β-D-mannopyranosyl}-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-D-glucopyranoside (15a) as the substrate, [bis(trifluoroacetoxy)iodo]benzene (PIFA) (2.5 equivalents) as the λ3-iodide, dichloromethane as the reaction solvent, and potassium dihydrogen phosphate (3.0 equivalents) as the additive, the de-methoxyphenylization reaction was carried out in the same manner as in Example 5, and the result was that the separation yield of 15b was 81%.

[0197] 1H-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 =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), 4.35-4.21 (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=2.8Hz, 1H), 3.65-3.51 (m, 4H), 3.41-3.35 (m, 2H), 1.88 (s, 3H).

[0198] 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, 12 7.7, 127.4, 127.3, 126.8, 126.2, 125.9, 125.5, 123.2, 101.5, 92.9, 82.4, 79.2, 77.2, 76.9, 75.0, 74.7, 74.6, 74.4, 74.0, 73.5, 73.4, 71.7, 68.5, 63.4, 57.5, 20.7.

[0199] Regarding HRMS (ESI) － [M+HCOO] － [C] 62 H 60 NO 15 ] － Calculated value: 1058.3968; Measured value: 1058.3933.

[0200] Table 5 below shows the de-p-methoxyphenylation reaction conditions and results achieved in Examples 5-9 using the λ3-iodide-HFIP system with monosaccharides as substrates. Furthermore, Table 6 below shows the de-p-methoxyphenylation reaction conditions and results achieved in Examples 10-13 using the λ3-iodide-HFIP system with disaccharides as substrates. All deprotected derivatives were obtained in good yields. Moreover, as shown in Table 6, the deprotected derivatives of the disaccharides were also obtained in high yields, similar to the monosaccharides.

[0201]

[0202]

[0203] <Example 14>

[0204] De-methoxyphenylization of protected benzyl alcohol

[0205]

[0206] To a solution containing 4-benzyloxyanisole (16) (100 mg, 0.467 mmol), toluene (0.8 mL), hexafluoro-2-propanol (HFIP) (0.5 mL), and water (0.05 mL), hydroxy(toluenesulfonyloxy)iodobenzene (HTIB) (0.26 g, 0.653 mmol) as the λ3-iodide was added at 5 °C, and the mixture was stirred at the same temperature for 0.5 h. The solution was quantified by HPLC, and the yield of p-benzoquinone was calculated (HPLC quantitative yield: benzyl alcohol (BnOH) > 99%, p-benzoquinone 67%).

[0207] To a solution containing 4-benzyloxyanisole (16) (100 mg, 0.467 mmol), toluene (0.8 mL), dichloromethane (0.5 mL), and water (0.05 mL), bis(trifluoroacetoxy)iodobenzene (PIFA) (1.4 equivalents) as the λ3-iodide was added at 5 °C, and the mixture was stirred at the same temperature for 0.5 h. The solution was quantified by HPLC, and the yield of p-benzoquinone was calculated (HPLC quantitative yield: benzyl alcohol (BnOH) 99%, p-benzoquinone 75%).

[0208] Table 7 below summarizes the reaction conditions and product yields for the above-mentioned de-methoxyphenylation. All deprotected products were obtained in good yields.

[0209]

[0210] The yield determination of Example 14 using HPLC analysis was carried out under the following analytical conditions.

[0211] <HPLC Analysis Conditions>

[0212] Equipment used: SHIMAZU HPLC (2010A HT).

[0213] Column: Xbrige C18 3.5μm, 4.6×150mm (Waters).

[0214] Mobile phase A: 10 mM AcONH4 aqueous solution.

[0215] Mobile phase B: CH3CN.

[0216] The gradient conditions are as follows.

[0217]

[0218] Flow rate: 1 mL / min.

[0219] Detection wavelength: 210nm.

[0220] Column temperature: 40℃.

[0221] Injection volume: 5μL.

[0222] Hold time: 19.4 minutes (16), 7.6 minutes (benzyl alcohol), 5.0 minutes (para-benzoquinone), 14.6 minutes (iodobenzene).

Claims

1. A method for manufacturing a compound represented by formula R-OH, comprising the following steps: In a fluorinated alcohol and water, the λ3-iodide is reacted with the compound represented by formula R-OX. In the formula R-OX, R is the substrate, and X is a phenyl group substituted with a methoxy group at the para position. The fluorinated alcohol is a fluorinated C2-C5 aliphatic alcohol. A fluorinated alcohol refers to a fluorinated alcohol compound in which all carbons except the carbon bonded to the alcohol are fluorinated. The λ3-iodide is of formula R 1 -I (OR) 2 The compound shown in 2, wherein the formula R 1 -I (OR) 2 The compound shown in 2 is selected from the group consisting of [bis(trifluoroacetoxy)iodide]benzene PIFA, [hydroxy(toluenesulfonyl)iodide]benzene HTIB, (diacetoxy)iodide)benzene PIDA, [bis(trifluoroacetoxy)iodide]pentafluorobenzene, [hydroxy(methanesulfonyl)iodide]benzene, and combinations thereof. The substrate R is a sugar, and in the formula R-OX, the OX group is present at the 1-position or anomeric position of the sugar, or the substrate R is Ar-(CR) 3 R 4 )n-,where n=1~3,Ar is an aromatic ring,R 3 and R 4 The aromatic ring and aliphatic group are H, aromatic ring, or aliphatic group, respectively, and any of the aromatic ring and aliphatic group may be substituted.

2. The method according to claim 1, wherein, The amount of the λ3-iodide is 0.1 to 10 equivalents relative to the substrate.

3. The method according to claim 1, wherein, The fluorinated C2-C5 aliphatic alcohols are 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, perfluoro-tert-butanol, and combinations thereof.

4. The method according to claim 1, wherein, The process includes the following steps: adding a solvent selected from the group consisting of CH2Cl2, toluene, (trifluoromethyl)benzene, and combinations thereof.

5. The method according to claim 1, wherein, The amount of the fluorinated alcohol relative to the substrate is more than 1.0 molar equivalent and less than 15 volume equivalent.

6. The method according to claim 1, wherein, The amount of water relative to the substrate is more than 1.0 molar equivalent and less than 10 volume equivalent.

7. The method according to claim 1, wherein, The process includes the following steps: adding additives selected from sodium dihydrogen phosphate (NaH2PO4), potassium dihydrogen phosphate (KH2PO4), disodium hydrogen phosphate (Na2HPO4), and combinations thereof.

8. The method according to claim 1, wherein, The process includes the following steps: when using (diacetoxyiodine)benzenePIDA as the λ3-iodide, trifluoroacetic acid is added.

9. The method according to claim 1, wherein, The reaction is carried out at temperatures ranging from -20°C to 60°C.

10. The method according to claim 1, wherein, The substrate R is a sugar, and in the formula R-OX, the OX group is present at the 1-position or the anomeric position of the sugar.

11. The method according to claim 10, wherein, The sugar is a monosaccharide or a polysaccharide.

12. The method according to claim 11, wherein, The monosaccharide has a cyclic structure of a five-membered or a six-membered ring.

13. The method according to claim 12, wherein, The monosaccharide is a pentose or hexose.

14. The method according to claim 13, wherein, The hexose is glucose, mannose, galactose, or glucosamine.

15. The method according to claim 11, wherein, The polysaccharide is a disaccharide to a decasaccharide.

16. The method according to claim 11, wherein, The polysaccharide is (i) a disaccharide, (ii) a trisaccharide, or (iii) a tetrasaccharide, wherein, The disaccharides are galactose-glucosamine, glucosamine-glucosamine, neuraminic acid-galactose, or mannose-glucosamine. The trisaccharide is composed of two mannoses and one glucosamine, or of neuraminic acid, galactose, and glucosamine. The tetrasaccharide consists of two mannoses and two glucosamines, or three mannoses and one glucosamine.

17. The method according to claim 1, wherein, The hydroxyl group of the carbon adjacent to the carbon at the 1-position or anodic position in the sugar is protected by an acyl group; or The amino group of the carbon adjacent to the carbon at the 1-position or anomeric position in the sugar is protected by an imide group, an acyl group, or a carbamate group; or The carbon in the sugar adjacent to the carbon at the 1-position or the anterior position has an azide group N3.

18. The method according to claim 17, wherein, As a protecting group of the amino group, the imide 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-fluorenylmethoxycarbonyl Fmoc, tert-butoxycarbonyl Boc, and benzyloxycarbonyl Cbz.

19. The method of claim 17, wherein, As a protecting group for the hydroxyl group, the acyl group is selected from the group consisting of acetyl Ac and benzoyl Bz.

20. The method according to claim 1, wherein, The substrate R is Ar-(CR) 3 R 4 )n-, In the formula, n = 1 to 3, Ar is an aromatic ring, and R 3 and R 4 The aromatic ring and aliphatic group are H, aromatic ring, or aliphatic group, respectively, and any of the aromatic ring and aliphatic group may be substituted.

21. The method according to claim 20, wherein, The aromatic ring is optionally substituted C5-C6. 20 Aryl or 5-20 membered heteroaryl, wherein the aliphatic group is optionally substituted C1-C2. 10 Aliphatic hydrocarbon groups.

22. The method according to claim 20, wherein, The aromatic ring, or optionally substituted aromatic ring, is selected from the group consisting of benzene, xylene, toluene, styrene, ethylbenzene, cumene, furan, thiophene, pyrrole, pyran, thiaran, pyridine, thiazole, imidazole, pyrimidine, 1,3,5-triazine, naphthalene, indene, anthracene, phenanthrene, fluorene, biphenyl, triphenyl, terphenyl, binaphthalene, phenylnaphthalene, indole, quinoline, and purine.

23. A method for manufacturing a sugar with an additional bonded portion, comprising the following steps: A process for obtaining a sugar having a -OH group at the 1-position or anterior position by any one of claims 1 to 22; and The process of attaching one or more additional components selected from the group consisting of proteins, nucleic acid molecules, lipid molecules, eukaryotic cells, prokaryotic cells, and viruses to the sugar.

24. The method according to claim 23, wherein, The additional component is protein.

25. The method according to claim 24, wherein, The protein is a receptor, which may be a soluble receptor, fused to the Fc region of an antibody, or unmodified.

26. The method according to claim 24, wherein, The protein is an antibody or its antigen-binding fragment, which is bonded to a peptide, nucleic acid molecule, lipid molecule, other antibody or its antigen-binding fragment, or toxin, or forms a conjugate with a drug, or is unmodified.

27. The method according to claim 24, wherein, The protein is a cytokine that is either bound to an antibody or its antigen-binding fragment, or is unmodified.

28. The method according to any one of claims 23 to 27, wherein, The process includes the following steps: in addition to the additional portion of the protein, binding one or more other additional portions to the sugar.

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