JP2980693B2 - Phosphoryl fluoroglucosamine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[Object of the invention]

[0002]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel phosphorylfluoroglucosamine derivative having an antitumor action based on macrophage activation and a salt thereof.

[0003]

2. Description of the Related Art The outermost layer of the cell wall of Gram-negative bacteria obtained from intestinal bacteria contains toxic components (endotoxins) that are not secreted outside the cells. In addition, immunoadjuvant activity related to the self defense of the living body,
It exhibits various biological activities such as macrophage activity, mitogen activity, pyrogenic action, tumor necrosis action, antibody production enhancement action, and TNF induction action. Such endotoxin is composed of lipopolysaccharide, and it has been confirmed that the so-called lipid A moiety is the active center of endotoxin activity (Imoto et al., Tetrahedron Letters, 26, 1545 (1985)). On the other hand, as a lipid A biosynthesis precursor, lipid X which is a monosaccharide,
Y was isolated from the E. coli mutant strain, and it was revealed that these also showed the same activity as lipid A.

[0004] Based on these results, lipid A, X
Or to synthesize a derivative of Y and examine its activity (for example, Imoto et al., Tetrahedron Letters, 26, 1545 (1985)) or Hasegawa, Kiso et al., Carbohydrate. Research, 162, 127 (1987)). However, since it is a bacterial endotoxin itself, problems such as lethal toxicity, pyrogenic action, leukopenia, and induction of autoimmune diseases remain.

[0005]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies over many years on the synthesis and pharmacological activity of phosphorylfluoroglucosamine derivatives belonging to lipid A monosaccharide derivatives, and as a result, have found that a known lipid A monosaccharide derivative is known. The present inventors have found that a novel phosphorylfluoroglucosamine derivative having a different structure from a saccharide derivative has an excellent macrophage activating effect and is useful as an immunostimulant or an antitumor agent, and thus completed the present invention.

[0006]

The novel phosphorylfluoroglucosamine derivatives of the present invention have the general formula

[0007]

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[In the formula, one of R1 and R4 represents a hydroxyl group or a protected hydroxyl group, and the other represents a fluorine atom.

R2 and R3 are the same or different and each represents an optionally substituted aliphatic acyl group having 6 to 20 carbon atoms (the substituent is a group selected from the following group A). . ] Or a general formula

[0010]

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[In the formula, one of R1 and R4 represents a hydroxyl group or a protected hydroxyl group, and the other represents a fluorine atom.

R2 and R3 are the same and may be an optionally substituted aliphatic acyl group having 6 to 20 carbon atoms (the substituent is a group selected from the following group A). ]. [Group A] A halogen atom, an aryl group, an aralkyl group, a hydroxyl group or an aliphatic acyloxy group having 6 to 20 carbon atoms.

In the above general formula (I), the “protecting group” of the “protected hydroxyl group” in the definition of R1 and R4 includes:
Shows a protecting group in the reaction and a protecting group when administered to a living body. Alkylcarbonyl groups, chloroacetyl, dichloroacetyl, trichloroacetyl, halogenated alkylcarbonyl groups such as trifluoroacetyl, lower alkoxyalkylcarbonyl groups such as methoxyacetyl, (E) -2-methyl-2-butenoyl Aliphatic acyl groups such as unsaturated alkylcarbonyl groups; benzoyl, α
Arylcarbonyl groups such as naphthoyl and β-naphthoyl, halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl, lower alkylated aryl groups such as 2,4,6-trimethylbenzoyl and 4-toluoyl Carbonyl group, lower alkoxylated arylcarbonyl group such as 4-anisoyl, 4-nitrobenzoyl, 2-
Aromatic acyl groups such as nitrated arylcarbonyl groups such as nitrobenzoyl, lower alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl, and arylated arylcarbonyl groups such as 4-phenylbenzoyl; vinyl, Lower alkenyl groups such as allyl; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran- Tetrahydropyranyl or tetrahydrothiopyranyl groups such as 4-yl; tetrahydrofuran-2-yl, tetrahydrothiofuran-2-
A tetrahydrofuranyl or tetrahydrothiofuranyl group such as yl; trimethylsilyl, triethylsilyl,
Tri-lower alkylsilyl groups such as isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, diphenylmethylsilyl, diphenyl-t
-Silyl groups such as tri-lower alkylsilyl groups substituted by one or two aryl groups such as butylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl; methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl , Propoxymethyl, isopropoxymethyl, butoxymethyl, lower alkoxymethyl groups such as t-butoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl, 2,2,
Alkoxymethyl groups such as halogenated lower alkoxymethyl such as 2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl; 1-ethoxyethyl, 1-methyl-1
-Lower alkoxylated ethyl groups such as methoxyethyl, 1- (isopropoxy) ethyl, halogenated ethyl groups such as 2,2,2-trichloroethyl, 2- (phenylzelenyl)
Substituted ethyl groups such as aryl-zellenylated ethyl groups such as ethyl; benzyl, phenethyl, 3-phenylpropyl,
lower alkyl group substituted with 1 to 3 aryl groups such as α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl , 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-
Aryl ring substituted with lower alkyl, lower alkoxy, nitro, halogen, cyano group such as chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl, piperonyl An aralkyl group such as a lower alkyl group substituted with 1 to 3 aryl groups; a lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, 2,2,2-trichloro Alkoxycarbonyl groups such as lower alkoxycarbonyl groups substituted with halogen or tri-lower alkylsilyl groups such as ethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; alkenyloxycarbonyl groups such as vinyloxycarbonyl and allyloxycarbonyl; Le oxycarbonyl, 4-
Such as methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
1 or 2 lower alkoxy or aralkyloxy carbonyl group aryl ring with a nitro group is substituted; protecting group in reaction such as allyl; Formula -COCH ₂ CH
_{2 COOH, -COCH 2 CH (OH} ) COOH or -COCH = terminal acyl groups having a carboxy group such as CH-COOH compound with; or when administered in vivo, such as pivaloyloxymethyl oxycarbonyl Protecting groups can be mentioned.

In the definition of R2 and R3, the "optionally substituted aliphatic acyl group having 6 to 20 carbon atoms", the "aliphatic acyl group having 6 to 20 carbon atoms" and the "carbon Examples of the “aliphatic acyl group having 6 to 20 carbon atoms” of the “aliphatic acyloxy group having 6 to 20 carbon atoms” include, for example, pentylcarbonyl, hexylcarbonyl, heptylcarbonyl, octylcarbonyl, nonylcarbonyl, decylcarbonyl, 3-methyl Nonylcarbonyl, 8-methylnonylcarbonyl, 3-ethyloctylcarbonyl, 3,7-dimethyloctylcarbonyl, undecylcarbonyl, dodecylcarbonyl, tridecylcarbonyl, tetradecylcarbonyl, pentadecylcarbonyl, hexadecylcarbonyl, 1-methylpenta Decylcarbonyl, 14-methylpentadecylcarbonyl, 13,13-dimethyltetradecylcarbonyl, heptadecylcarbonyl, 15-methylhexadecylcarbonyl, octadecylcarbonyl, 1-methylheptadecylcarbonyl and nonadecylcarbonyl, preferably 10 to 16 carbon atoms It is a linear or branched aliphatic acyl group.

The "halogen atom" in the definition of Group A represents fluorine, chlorine, bromine or iodine.

The “aryl group” in the definition of Group A is
For example, an aromatic hydrocarbon group having 6 to 14 carbon atoms such as phenyl and naphthyl can be mentioned, and a phenyl group is preferable. In addition, the group has 1 to 3 on the ring of the aryl group.
It may have four substituents, and such substituents include an amino group; a nitro group; a cyano group; a “lower alkyl” described below, a “halogeno lower alkyl” described below, or an “aralkyl” described below. A carbamoyl group which may be an ester type; a carbamoyl group; a lower alkyl-substituted carbamoyl group substituted with a linear or branched alkyl group having 1 to 6 carbon atoms (preferably a carbamoyl group having 1 to 4 carbon atoms) A carbamoyl group substituted with an alkyl group, more preferably methylcarbamoyl or dimethylcarbamoyl.); The halogen atom; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl , N-pentyl, isopentyl, 2-methylbutyl, neopentyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 3,3-dimethyl Straight or branched chain having 1 to 6 carbon atoms such as butyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, and 2,3-dimethylbutyl. A branched lower alkyl group;
Trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl A halogeno lower alkyl group such as 2,2-dibromoethyl; the above-mentioned "aliphatic acyl group"; and methylenedioxy,
Carbon number like ethylenedioxy, propylenedioxy
There may be mentioned 1 to 4 alkylenedioxy groups, preferably a lower alkyl group and a halogen atom.

The whole group is preferably an aryl group such as phenyl and naphthyl; 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-chlorophenyl Bromophenyl, 3-bromophenyl, 4-bromophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,5-dibromophenyl, 2, 5-dibromophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2,3,6-trifluorophenyl, 2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 2,5 , 6-trifluorophenyl, 2,4,6-trifluorophenyl, 2,3,6-tribromophenyl, 2,3,4-
Tribromophenyl, 3,4,5-tribromophenyl, 2,5,
6-trichlorophenyl, 2,4,6-trichlorophenyl, 1-
Fluoro-2-naphthyl, 2-fluoro-1-naphthyl, 3-fluoro-1-naphthyl, 1-chloro-2-naphthyl, 2-chloro
-1-naphthyl, 3-bromo-1-naphthyl, 3,8-difluoro
-1-naphthyl, 2,3-difluoro-1-naphthyl, 1,8-difluoro-1-naphthyl, 5,6-difluoro, -1-naphthyl, 3,8-dichloro-1-naphthyl, 2,3 dichloro -1-naphthyl, 4,8-dibromo-1-naphthyl, 5,6-dibromo-1-naphthyl, 2,3,6-trifluoro-1-naphthyl, 2,3,4-trifluoro-1-naphthyl Aryl groups substituted with halogen atoms such as 3,4,5-trifluoro-1-naphthyl, 4,5,6-trifluoro-1-naphthyl and 2,4,8-trifluoro-1-naphthyl 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl,
2-trichloromethylphenyl, 3-dichloromethylphenyl, 4-trichloromethylphenyl, 2-tribromomethylphenyl, 3-dibromomethylphenyl, 4-dibromomethylphenyl, 3,5-bistrifluoromethylphenyl, 2,
5-bistrifluoromethylphenyl, 2,6-bistrifluoromethylphenyl, 2,4-bistrifluoromethylphenyl, 3,5-bistribromomethylphenyl, 2,5-bisdibromomethylphenyl, 2,6-bisdichloromethyl Methylphenyl, 2,4-bisdichloromethylphenyl, 2,3,6-tristrifluoromethylphenyl, 2,3,4-tristrifluoromethylphenyl, 3,4,5-tristrifluoromethylphenyl, 2, 5,6-tristrifluoromethylphenyl, 2,4,6-tristrifluoromethylphenyl, 2,3,6-
Tristribromomethylphenyl, 2,3,4-trisdibromomethylphenyl, 3,4,5-tristribromomethylphenyl, 2,5,6-trisdichloromethylmethylphenyl, 2,
4,6-trisdichloromethylphenyl, 1-trifluoromethyl-2-naphthyl, 2-trifluoromethyl-1-naphthyl, 3-trifluoromethyl-1-naphthyl, 1-trichloromethyl-2-naphthyl, 2- Dichloromethyl-1-naphthyl,
3-tribromomethyl-1-naphthyl, 3,8-bistrifluoromethyl-1-naphthyl, 2,3-bistrifluoromethyl-
1-naphthyl, 4,8-bistrifluoromethyl-1-naphthyl, 5,6-bistrifluoromethyl-1-naphthyl, 3,8-bistrichloromethyl-1-naphthyl, 2,3-bisdichloromethyl-1- Naphthyl, 4,8-bisdibromomethyl-1-naphthyl, 5,6-bistribromomethyl-1-naphthyl, 2,3,6-tristrifluoromethyl-1-naphthyl, 2,3,4-tristrifluoro Methyl-1-naphthyl, 3,4,5-tristrifluoromethyl-1-naphthyl, 4,5,6-tristrifluoromethyl-1-naphthyl, 2,4,8-tristrifluoromethyl-
Aryl groups substituted with halogeno lower alkyl groups such as 1-naphthyl; 2-methylphenyl, 3-methylphenyl,
4-methylphenyl, 2-ethylphenyl, 3-propylphenyl, 4-ethylphenyl, 2-butylphenyl, 3-pentylphenyl, 4-pentylphenyl, 3,5-dimethylphenyl, 2,5-dimethylphenyl, 2 , 6-dimethylphenyl, 2,
4-dimethylphenyl, 3,5-dibutylphenyl, 2,5-dipentylphenyl, 2,6-dipropylmethylphenyl, 2,4-
Dipropylphenyl, 2,3,6-trimethylphenyl, 2,3,
4-trimethylphenyl, 3,4,5-trimethylphenyl, 2,
5,6-trimethylphenyl, 2,4,6-trimethylphenyl,
2,3,6-tributylphenyl, 2,3,4-tripentylphenyl, 3,4,5-tributylphenyl, 2,5,6-tripropylmethylphenyl, 2,4,6-tripropylphenyl, 1 -
Methyl-2-naphthyl, 2-methyl-1-naphthyl, 3-methyl
-1-naphthyl, 1-ethyl-2-naphthyl, 2-propyl-1-
Naphthyl, 3-butyl-1-naphthyl, 3,8-dimethyl-1-naphthyl, 2,3-dimethyl-1-naphthyl, 4,8-dimethyl-1-
Naphthyl, 5,6-dimethyl-1-naphthyl, 3,8-diethyl-1
-Naphthyl, 2,3-dipropyl-1-naphthyl, 4,8-dipentyl-1-naphthyl, 5,6-dibutyl-1-naphthyl, 2,3,6-
Trimethyl-1-naphthyl, 2,3,4-trimethyl-1-naphthyl, 3,4,5-trimethyl-1-naphthyl, 4,5,6-trimethyl
Aryl group substituted with a lower alkyl group such as -1-naphthyl, 2,4,8-trimethyl-1-naphthyl; 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 3,5-diaminophenyl , 2,5-diaminophenyl, 2,6-diaminophenyl, 2,4-diaminophenyl, 2,3,6-triaminophenyl, 2,3,4-triaminophenyl, 3,4,5-triamino Phenyl, 2,5,6-triaminophenyl, 2,4,6-triaminophenyl, 1-amino-2-naphthyl, 2-amino-1-naphthyl, 3-amino-1-naphthyl, 3,8- Diamino-1-naphthyl, 2,3-diamino-1-naphthyl, 4,8-diamino-1-naphthyl, 5,6-diamino-1-naphthyl, 2,3,6-triamino-
1-naphthyl, 2,3,4-triamino-1-naphthyl, 3,4,5-triamino-1-naphthyl, 4,5,6-triamino-1-naphthyl, 2,4,8-triamino-1- Aryl groups substituted with amino groups such as naphthyl; 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-dinitrophenyl, 2,
5-dinitrophenyl, 2,6-dinitrophenyl, 2,4-dinitrophenyl, 2,3,6-trinitrophenyl, 2,3,4-trinitrophenyl, 3,4,5-trinitrophenyl, 2 , 5,6-Trinitrophenyl, 2,4,6-trinitrophenyl, 1-nitro-2-naphthyl, 2-nitro-1-naphthyl, 3-nitro-1-
Naphthyl, 3,8-dinitro-1-naphthyl, 2,3-dinitro-
1-naphthyl, 4,8-dinitro-1-naphthyl, 5,6-dinitro
-1-naphthyl, 2,3,6-trinitro- 1-naphthyl, 2,3,4-
Substituted with a nitro group such as trinitro-1-naphthyl, 3,4,5-trinitro-1-naphthyl, 4,5,6-trinitro-1-naphthyl, 2,4,8-trinitro-1-naphthyl Aryl group; 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3,5-dicyanophenyl, 2,5-dicyanophenyl, 2,6-dicyanophenyl, 2,4-dicyanophenyl, 2,
3,6-tricyanophenyl, 2,3,4-tricyanophenyl,
3,4,5-tricyanophenyl, 2,5,6-tricyanophenyl, 2,4,6-tricyanophenyl, 1-cyano-2-naphthyl, 2-cyano-1-naphthyl, 3-cyano- 1-naphthyl, 3,
8-dicyano-1-naphthyl, 2,3-dicyano-1-naphthyl,
4,8-dicyano-1-naphthyl, 5,6-dicyano-1-naphthyl, 2,3,6-tricyano-1-naphthyl, 2,3,4-tricyano
-1-naphthyl, 3,4,5-tricyano-1-naphthyl, 4,5,6-
Aryl groups substituted by cyano groups such as tricyano-1-naphthyl and 2,4,8-tricyano-1-naphthyl; 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 3,5-diacetylphenyl , 2,5-diacetylphenyl, 2,6-diacetylphenyl, 2,4-diacetylphenyl, 2,3,6-tripropionylphenyl, 2,3,4-tripropionylphenyl, 3,4,5-tripropionyl Phenyl,
2,5,6-Tributyrylphenyl, 2,4,6-Tributyrylphenyl, 1-acetyl-2-naphthyl, 2-acetyl-1-naphthyl, 3-acetyl-1-naphthyl, 3,8- Diacetyl-1-naphthyl, 2,3-dipropionyl-1-naphthyl, 4,8-dibutyryl-1-naphthyl, 5,6-dibutyryl-1-naphthyl, 2,3,6-
Triacetyl-1-naphthyl, 2,3,4-triacetyl-1-naphthyl, 3,4,5-tripropionyl-1-naphthyl, 4,5,6-
Aryl groups substituted with aliphatic acyl groups such as tributyryl-1-naphthyl, 2,4,8-tributyryl-1-naphthyl; 2-carboxyphenyl, 3-carboxyphenyl,
Carboxyphenyl, 3,5-dicarboxyphenyl, 2,5-
Dicarboxyphenyl, 2,6-dicarboxyphenyl, 2,
Aryl groups substituted with a carboxy group such as 4-dicarboxyphenyl; 2-carbamoylphenyl, 3-carbamoylphenyl, 4-carbamoylphenyl, 3,5-dicarbamoylphenyl, 2,5-dicarbamoylphenyl, Aryl groups substituted with a carbamoyl group such as 6-dicarbamoylphenyl and 2,4-dicarbamoylphenyl; and aryl groups substituted with an alkylenedioxy group such as 3,4-methylenedioxyphenyl. it can.

The "aralkyl group" in the definition of Group A refers to a group in which the above "aryl group" is bonded to the above "lower alkyl group", for example, benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl , Triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, piperonyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl ,
1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl,
2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl, 2-naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyl, 6-naphthylhexyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3,5-difluorobenzyl, 2,5-di Fluorophenethyl, 2,6-difluorobenzyl, 2,4-difluorophenethyl, 3,5-dibromobenzyl, 2,5-dibromophenethyl, 2,6-dichlorobenzyl, 2,4-dichlorophenethyl, 2,3,6 -Trifluorobenzyl, 2,3,4-trifluorophenethyl, 3,4,5-trifluorobenzyl, 2,5,6-trifluorophenethyl, 2,4,6-trifluorobenzyl, 2,
3,6-tribromophenethyl, 2,3,4-tribromobenzyl, 3,4,5-tribromophenethyl, 2,5,6-trichlorobenzyl, 2,4,6-trichlorophenethyl, 1-fluoro- 2-
Naphthylmethyl, 2-fluoro-1-naphthylethyl, 3-fluoro-1-naphthylmethyl, 1-chloro-2-naphthylethyl, 2-
Chloro-1-naphthylmethyl, 3-bromo-1-naphthylethyl, 3,8-difluoro-1-naphthylmethyl, 2,3-difluoro-1-naphthylethyl, 4,8-difluoro-1-naphthylmethyl, 5 , 6-Difluoro-1-naphthylethyl, 3,8-dichloro-1-naphthylmethyl, 2,3-dichloro-1-naphthylethyl, 4,8-dibromo-1-naphthylmethyl, 5,6-dibromo-1
-Naphthylethyl, 2,3,6-trifluoro-1-naphthylmethyl, 2,3,4-trifluoro-1-naphthylethyl, 3,4,5-
Trifluoro-1-naphthylmethyl, 4,5,6-trifluoro
-1-naphthylethyl, 2,4,8-trifluoro-1-naphthylmethyl, bis (2-fluorophenyl) methyl, 3-fluorophenylphenylmethyl, bis (4-fluorophenyl) methyl, 4-fluorophenylphenyl Methyl, bis (2-chlorophenyl) methyl, bis (3-chlorophenyl) methyl, bis (4-chlorophenyl) methyl, 4-chlorophenylphenylmethyl, 2-bromophenylphenylmethyl, 3-bromophenylphenylmethyl, bis (4- Bromophenyl) methyl, bis (3,5-difluorophenyl) methyl, bis (2,5-difluorophenyl) methyl,
Bis (2,6-difluorophenyl) methyl, 2,4-difluorophenylphenylmethyl, bis (3,5-dibromophenyl) methyl, 2,5-dibromophenylphenylmethyl,
Aralkyl groups substituted with halogen atoms such as 6-dichlorophenylphenylmethyl, bis (2,4-dichlorophenyl) methyl, bis (2,3,6-trifluorophenyl) methyl; 2-trifluoromethylbenzyl, Trifluoromethylphenethyl, 4-trifluoromethylbenzyl, 2-
Trichloromethylphenethyl, 3-dichloromethylbenzyl, 4-trichloromethylphenethyl, 2-tribromomethylbenzyl, 3-dibromomethylphenethyl, 4-dibromomethylbenzyl, 3,5-bistrifluoromethylphenethyl, 2,5-bistrifluoro Methylbenzyl, 2,6-bistrifluoromethylphenethyl, 2,4-bistrifluoromethylbenzyl, 3,5-bistribromomethylphenethyl,
2,5-bisdibromomethylbenzyl, 2,6-bisdichloromethylmethylphenethyl, 2,4-bisdichloromethylbenzyl, 2,3,6-tristrifluoromethylphenethyl, 2,3,
4-tristrifluoromethylbenzyl, 3,4,5-tristrifluoromethylphenethyl, 2,5,6-tristrifluoromethylbenzyl, 2,4,6-tristrifluoromethylphenethyl, 2,3,6- Tristribromomethylbenzyl, 2,
3,4-trisdibromomethylphenethyl, 3,4,5-tristribromomethylbenzyl, 2,5,6-trisdichloromethylmethylphenethyl, 2,4,6-trisdichloromethylbenzyl, 1-trifluoromethyl- 2-naphthylethyl, 2-trifluoromethyl-1-naphthylmethyl, 3-trifluoromethyl-1-naphthylethyl, 1-trichloromethyl-2-naphthylmethyl, 2-dichloromethyl-1-naphthylethyl, 3-
Tribromomethyl-1-naphthylmethyl, 3,8-bistrifluoromethyl-1-naphthylethyl, 2,3-bistrifluoromethyl-1-naphthylmethyl, 4,8-bistrifluoromethyl-1-naphthylethyl, 5, 6-bistrifluoromethyl
-1-naphthylmethyl, 3,8-bistrichloromethyl-1-naphthylethyl, 2,3-bisdichloromethyl-1-naphthylmethyl, 4,8-bisdibromomethyl-1-naphthylethyl, 5,
6-bistribromomethyl-1-naphthylmethyl, 2,3,6-tristrifluoromethyl-1-naphthylethyl, 2,3,4-tristrifluoromethyl-1-naphthylmethyl, 3,4,5-tris Trifluoromethyl-1-naphthylethyl, 4,5,6-tristrifluoromethyl-1-naphthylmethyl, 2,4,8-tristrifluoromethyl-1-naphthylmethyl, bis (4-
Trifluoromethylphenyl) methyl, 4-trifluoromethylphenylphenylmethyl, bis (2-trichloromethylphenyl) methyl, bis (3-trichloromethylphenyl) methyl, bis (4-trichloromethylphenyl) methyl, 2-tribromo Methylphenylphenylmethyl, 3-
Tribromomethylphenylphenylmethyl, bis (4-tribromomethylphenyl) methyl, bis (3,5-bistrifluoromethylphenyl) methyl, bis (2,5-bistrifluoromethylphenyl) methyl, bis (2,6- Bis (trifluoromethylphenyl) methyl, 2,4-bistrifluoromethylphenylphenylmethyl, bis (3,5-bistribromomethylphenyl) methyl, 2,5-bistribromomethylphenylphenylmethyl, 2,6-bistrichloromethylphenyl Aralkyl groups substituted with halogeno lower alkyl groups such as phenylmethyl, bis (2,4-bistrichloromethylphenyl) methyl, bis (2,3,6-tristrifluoromethylphenyl) methyl; 2-methylbenzyl,
3-methylbenzyl, 4-methylbenzyl, 2-methylphenethyl, 4-methylphenethyl, 2-ethylbenzyl, 3-propylphenethyl, 4-ethylbenzyl, 2-butylphenethyl, 3-pentylbenzyl, 4-pentylphenethyl, 3,5-
Dimethylbenzyl, 2,5-dimethylphenethyl, 2,6-dimethylbenzyl, 2,4-dimethylphenethyl, 3,5-dibutylbenzyl, 2,5-dipentylphenethyl, 2,6-dipropylbenzyl, 2,4- Dipropylphenethyl, 2,3,6-trimethylbenzyl, 2,3,4-trimethylphenethyl, 3,4,5-trimethylbenzyl, 2,4,6-trimethylbenzyl, 2,5,6-trimethylphenethyl, 2 , 3,6-Tributylphenethyl, 2,
3,4-tripentylbenzyl, 3,4,5-tributylphenethyl, 2,5,6-tripropylbenzyl, 2,4,6-tripropylphenethyl, 1-methyl-2-naphthylmethyl, 2-methyl- 1
-Naphthylethyl, 3-methyl-1-naphthylmethyl, 1-ethyl-2-naphthylethyl, 2-propyl-1-naphthylmethyl, 3-butyl-1-naphthylethyl, 3,8-dimethyl-1-naphthylmethyl , 2,3-dimethyl-1-naphthylethyl, 4,8-
Dimethyl-1-naphthylmethyl, 5,6-dimethyl-1-naphthylethyl, 3,8-diethyl-1-naphthylmethyl, 2,3-dipropyl-1-naphthylmethyl, 4,8-dipentyl-1-naphthylethyl , 5,6-dibutyl-1-naphthylmethyl, 2,3,6-trimethyl-1-naphthylmethyl, 2,3,4-trimethyl-1-naphthylethyl, 3,4,5-trimethyl-1-naphthylmethyl ,
4,5,6-trimethyl-1-naphthylmethyl, 2,4,8-trimethyl-1-naphthylmethyl, bis (2-methylphenyl) methyl, 3-methylphenylphenylmethyl, bis (4-methylphenyl) methyl , 4-methylphenylphenylmethyl,
Bis (2-ethylphenyl) methyl, bis (3-ethylphenyl) methyl, bis (4-ethylphenyl) methyl, 2-propylphenylphenylmethyl, 3-propylphenylphenylmethyl, bis (4-propylphenyl) methyl, Bis (3,5-dimethylphenyl) methyl, bis (2,5-dimethylphenyl) methyl, bis (2,6-dimethylphenyl) methyl, 2,4-dimethylphenylphenylmethyl, bis (3,
5-dipropylphenyl) methyl, 2,5-dipropylphenylphenylmethyl, 2,6-diethylphenylphenylmethyl, bis (2,4-diethylphenyl) methyl, bis (2,3,
Aralkyl groups substituted with lower alkyl groups such as 6-trimethylphenyl) methyl; 2-aminophenethyl, 3-aminobenzyl, 4-aminophenethyl, 3,5-diaminobenzyl, 2,5-diaminophenethyl, 6-diaminobenzyl, 2,4-diaminophenethyl, 2,3,6-triaminobenzyl, 2,3,4-triaminophenethyl, 3,4,5-triaminobenzyl, 2,5,6-triamino Phenethyl, 2,4,6-triaminobenzyl, 1-amino-2-naphthylmethyl, 2-amino-1
-Naphthylethyl, 3-amino-1-naphthylmethyl, 3,8-
Diamino-1-naphthylmethyl, 2,3-diamino-1-naphthylethyl, 4,8-diamino-1-naphthylmethyl, 5,6-diamino-1-naphthylmethyl, 2,3,6-triamino-1- Naphthylethyl, 2,3,4-triamino-1-naphthylmethyl, 3,4,
5-triamino-1-naphthylmethyl, 4,5,6-triamino-1
-Naphthylethyl, 2,4,8-triamino-1-naphthylmethyl, bis (2-aminophenyl) methyl, 3-aminophenylphenylmethyl, bis (4-aminophenyl) methyl,
4-aminophenylphenylmethyl, bis (3,5-diaminophenyl) methyl, bis (2,5-diaminophenyl) methyl, bis (2,6-diaminophenyl) methyl, 2,4-diaminophenylphenylmethyl, bis An aralkyl group substituted with an amino group such as (2,3,6-triaminophenyl) methyl; 2-nitrophenethyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-nitrophenethyl, 3,5-dinitrobenzyl , 2,5-dinitrophenethyl, 2,6-dinitrobenzyl,
2,4-dinitrophenethyl, 2,3,6-trinitrobenzyl,
2,3,4-trinitrophenethyl, 3,4,5-trinitrobenzyl, 2,5,6-trinitrophenethyl, 2,4,6-trinitrobenzyl, 1-nitro-2-naphthylmethyl, 2 -Nitro-1-naphthylethyl, 3-nitro-1-naphthylmethyl, 3,8-dinitro-1-naphthylmethyl, 2,3-dinitro-1-naphthylethyl, 4,8-dinitro-1-naphthylmethyl, 5,6-dinitro
-1-naphthylmethyl, 2,3,6-trinitro-1-naphthylethyl, 2,3,4-trinitro-1-naphthylmethyl, 3,4,5-trinitro-1-naphthylmethyl, 4,5,6 -Trinitro-1-naphthylethyl, 2,4,8-trinitro-1-naphthylmethyl,
Bis (2-nitrophenyl) methyl, 3-nitrophenylphenylmethyl, bis (4-nitrophenyl) methyl, 4-nitrophenylphenylmethyl, bis (3,5-dinitrophenyl) methyl, bis (2,5-dinitro Phenyl) methyl,
Aralkyl groups substituted with nitro groups such as bis (2,6-dinitrophenyl) methyl, 2,4-dinitrophenylphenylmethyl, bis (2,3,6-trinitrophenyl) methyl; 2-cyanophenethyl, 3-cyanobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, 4-cyanophenethyl, 3,5-dicyanobenzyl, 2,5-dicyanophenethyl, 2,6-dicyanobenzyl, 2,4-dicyanophenethyl, 2,3,6-tricyanobenzyl, 2,3,4-tricyanophenethyl, 3,4,5-tricyanobenzyl, 2,5,6-tricyanophenethyl, 2,4,6-tricyanobenzyl, 1-cyano
2-naphthylmethyl, 3-cyano-1-naphthylmethyl, 3,8-
Dicyano-1-naphthylmethyl, 2,3-dicyano-1-naphthylethyl, 4,8-dicyano-1-naphthylmethyl, 5,6-dicyano-1-naphthylmethyl, 2,3,6-tricyano-1- Naphthylethyl, 2,3,4-tricyano-1-naphthylmethyl, 3,4,
5-tricyano-1-naphthylmethyl, 4,5,6-tricyano-1
-Naphthylethyl, 2,4,8-tricyano-1-naphthylmethyl, bis (2-cyanophenyl) methyl, 3-cyanophenylphenylmethyl, bis (4-cyanophenyl) methyl,
4-cyanophenylphenylmethyl, bis (3,5-dicyanophenyl) methyl, bis (2,5-dicyanophenyl) methyl, bis (2,6-dicyanophenyl) methyl, 2,4-dicyanophenylphenylmethyl, bis An aralkyl group substituted with a cyano group such as (2,3,6-tricyanophenyl) methyl; 2-acetylphenethyl, 3-acetylbenzyl, 4-
Acetylphenethyl, 3,5-diacetylbenzyl, 2,5-diacetylphenethyl, 2,6-diacetylbenzyl, 2,4-diacetylphenethyl, 2,3,6-tripropionylbenzyl, 2,3,4-tripropionylphenethyl 3,4,5-Tripropionylbenzyl, 2,5,6-Tributyrylphenethyl,
2,4,6-Tributyrylbenzyl, 1-acetyl-2-naphthylmethyl, 2-acetyl-1-naphthylethyl, 3-acetyl-1
-Naphthylmethyl, 3,8-diacetyl-1-naphthylmethyl, 2,3-dipropionyl-1-naphthylethyl, 4,8-dibutyryl-1-naphthylmethyl, 5,6-dibutyryl-1-naphthylmethyl, 2 , 3,6-Triacetyl-1-naphthylethyl, 2,
3,4-triacetyl-1-naphthylmethyl, 3,4,5-tripropionyl-1-naphthylmethyl, 4,5,6-tributyryl-1-
Naphthylethyl, 2,4,8-tributyryl-1-naphthylmethyl, bis (2-acetylphenyl) methyl, 3-acetylphenylphenylmethyl, bis (4-acetylphenyl) methyl, 4-acetylphenylphenylmethyl, bis ( 2-propionylphenyl) methyl, bis (3-propionylphenyl) methyl, bis (4-propionylphenyl) methyl, 2-butyrylphenylphenylmethyl, 3-butyrylphenylphenylmethyl, bis (4-butyrylphenyl) methyl , Bis (3,5-diacetylphenyl) methyl, bis (2,5-diacetylphenyl) methyl, bis (2,6-diacetylphenyl) methyl, 2,4-diacetylphenylphenylmethyl, bis (3,5-dibutyl Rylphenyl) methyl, 2,
Aliphatic acyl groups such as 5-dibutyrylphenylphenylmethyl, 2,6-dipropionylphenylphenylmethyl, bis (2,4-dipropionylphenyl) methyl, bis (2,3,6-triacetylphenyl) methyl An aralkyl group substituted with 2-carboxyphenethyl, 3-carboxybenzyl, 4-carboxyphenethyl, 3,5-dicarboxybenzyl, 2,5-dicarboxyphenethyl, 2,6-dicarboxybenzyl, 2,4- Dicarboxyphenethyl, bis (2-carboxyphenyl) methyl, 3-carboxyphenylphenylmethyl, bis (4-carboxyphenyl) methyl, 4-carboxyphenylphenylmethyl, bis (3,5-dicarboxyphenyl) methyl, bis ( 2,5-dicarboxyphenyl) methyl, bis (2,6-dicarboxyphenyl) methyl, 2,4-dicarboxyphenylphenylmethyl An aralkyl group substituted with a carboxy group such as bis (2,3,6-tricarboxyphenyl) methyl; 2-carbamoylbenzyl, 3-carbamoylphenethyl, 4-carbamoylbenzyl, 3,5-dicarbamoylphenethyl, 2 2,5-dicarbamoylbenzyl, 2,6-dicarbamoylphenethyl, 2,4-
Dicarbamoylbenzyl, bis (2-carbamoylphenyl) methyl, 3-carbamoylphenylphenylmethyl,
Bis (4-carbamoylphenyl) methyl, 4-carbamoylphenylphenylmethyl, bis (3,5-dicarbamoylphenyl) methyl, bis (2,5-dicarbamoylphenyl) methyl, bis (2,6-dicarbamoylphenyl) Aralkyl groups substituted with carbamoyl groups such as methyl, 2,4-dicarbamoylphenylphenylmethyl, bis (2,3,6-tricarbamoylphenyl) methyl; 3,4-methylenedioxybenzyl, 3,4- Methylenedioxyphenethyl,
Examples thereof include an aralkyl group substituted with an alkylenedioxy group such as bis (3,4-methylenedioxyphenyl) methyl and 3,4-methylenedioxyphenylphenylmethyl, and preferably an unsubstituted aralkyl group. Groups and lower alkoxy-substituted aralkyl groups, more preferably benzyl groups and lower alkoxy-substituted benzyl groups, most preferably benzyl and 4-methoxybenzyl.

The compound (I) of the present invention can be converted into a salt. The salt is preferably a salt of an alkali metal or an alkaline earth metal such as a sodium salt, a potassium salt or a calcium salt. A salt of an organic base such as a triethylamine salt or a trimethylamine salt.

The compound (I) of the present invention has an asymmetric carbon in the molecule, and there are stereoisomers each having S-coordination and R-coordination. Are also included in the present invention.

Representative compounds of the present invention include, for example,
The compounds described in Table 1 can be mentioned, but the present invention is not limited to these compounds.

Table 1

[0023]

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[0024]

Among the above exemplified compounds, preferred compounds are 1,2,3,4,5,6,7,8,9,10,1
1,12,13,14,15,16,17,18,1
9, 20, 37, 38, 39, 40, 41, 42, 4
3,44,45,46,47,48,49,50,5
1,52,53,54,55,56,57,58,5
9,60,67,68,69,70,71,72,7
3, 74, 75, 76, 77, 78, 79 and 80 compounds.

The osphorylfluoroglucosamine derivative of the present invention can be produced as a starting material of a known compound, glucosamine (1), by the method described below.

[Method A]

[0028]

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[Method B]

[0030]

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[Method A] is a method for producing the compound (I) of the present invention in which a fluorine atom is bonded to the 1-position. [Method B] is a method for producing the compound (I) of the present invention in which a fluorine atom is bonded to the 6-position.

In the above formula, R 2 ′ and R 3 ′ represent an optionally substituted aliphatic acyl group having 6 to 20 carbon atoms (the substituent is a group selected from the following group B). Show. [Group B] Halogen atom, aryl group, aralkyl group, hydroxyl group, protected hydroxyl group (indicating the same group as "protected hydroxyl group" in the definition of R1 and R4) and aliphatic having 6 to 20 carbon atoms. Acyloxy group.

R6 is, for example, the aforementioned “aliphatic acyl group”;
The “aromatic acyl group”; the “alkoxycarbonyl group”; the “alkenyloxycarbonyl group”; the “aralkyloxycarbonyl group”; the “silyl group”
Or an amine protecting group such as the aforementioned “aralkyl group”.

R7 and R9 are the same or different and represent the same groups as the "protected hydroxyl group" in the definition of R1 and R4.

R8 represents a protecting group for the diol, preferably a lower alkylidene group such as methylidene, ethylidene and isopropylidene; an aralkylidene group such as benzylidene or an alkoxyethylidene group such as methoxyethylidene and ethoxyethylidene. be able to.

R10 is the same or different and represents a phosphate-protecting group such as the above-mentioned "aryl group" or the above-mentioned "aralkyl group".

In the first step, glucosamine hydrochloride (1) is
Trifluoroacetic acid and dicyclohexylcarbodiimide (D
CC), trifluoroacetic anhydride and triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, 1,5-diazabicyclo [ 4.3.
0] nona-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene (DB
In this step, an amide derivative (2) is produced by reacting an organic base such as U) or a trifluoroacetate such as ethyl trifluoroacetate with the above organic base.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but is preferably a halogenated hydrocarbon such as methylene chloride or chloroform; , Tetrahydrofuran, dioxane, ethers such as dimethoxyethane; methanol, ethanol, n-propanol, isopropanol, alcohols such as n-butanol, isobutanol, isoamyl alcohol; dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide Examples of such amides include sulfoxides such as dimethyl sulfoxide. The reaction is carried out at a temperature of from 0 ° C. to 100 ° C., preferably at room temperature.
24 hours.

In the second step, the amid form (2) is converted into an
In this step, a compound (3) is produced by forming a glycosidic bond with an alcohol having the general formula R7-OH (eg, methanol, ethanol, benzyl alcohol, allyl alcohol, 2- (trimethylsilyl) ethanol).

As the solvent, a large excess of an alcohol having the general formula R7-OH as a reaction reagent is used. The acid used is
In general, there is no particular limitation as long as it functions as an acid, but preferred examples include mineral acids such as hydrochloric acid and sulfuric acid and organic acids such as p-toluenesulfonic acid, and the above-mentioned hydrous acids can also be used. . The reaction is carried out at a temperature of 0 ° C. to 2000 ° C., preferably at a reflux temperature, and the reaction time varies depending mainly on the reaction temperature, the type of the starting compound and the type of the solvent used, but is usually 0.1 hour to 24 hours. Time.

In the third step, the alcohols at the 4- and 6-positions of the compound (3) are converted to isopropylidene in a solvent under an acid catalyst,
This is a step of producing a compound (4) by protecting a diol such as benzylidene or ethylidene.

The reagent used for protecting the diol is not particularly limited as long as it is usually used for protecting the diol, but is preferably an aldehyde derivative such as benzaldehyde, or an acetone such as acetone. Ketone derivatives,
Examples thereof include dimethoxy compounds such as 2,2-dimethoxypropane and dimethoxybenzyl. The solvent is not particularly limited as long as it does not inhibit the reaction. Examples include hydrogens, aromatic hydrocarbons such as benzene and toluene, esters such as ethyl acetate, and polar solvents such as dimethylformamide and acetone.
The acid catalyst to be used is not particularly limited as long as it is usually used as an acid.Preferably, an organic acid such as paratoluenesulfonic acid, camphorsulfonic acid, or pyridium paratoluenesulfonate or an inorganic acid such as hydrochloric acid is used. Can be mentioned. The reaction temperature varies depending on the acid catalyst used, the starting compound, etc., but is usually carried out at 0 to 100 ° C. The reaction time varies mainly depending on the reaction temperature, the starting compound and the type of the solvent used. , Usually 0.1 to 24 hours.

In the fourth step, the R6 group of the compound (4) is removed,
This is a step of producing compound (5).

When a silyl group is used as the R6 group, the silyl group is usually removed by treating with a compound which generates a fluorine anion such as tetrabutylammonium fluoride. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferable. The reaction temperature and reaction time are not particularly limited, but the reaction is usually performed at room temperature for 10 minutes to 18 hours.

When the R6 group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it can be removed by treating with a base in the presence of an aqueous solvent or by reduction. The base is not particularly limited as long as it does not affect the other parts of the compound, but is preferably sodium carbonate, an alkali metal carbonate such as potassium carbonate, sodium hydroxide, or potassium hydroxide. It is carried out using an alkali metal hydroxide or concentrated aqueous ammonia-methanol. The solvent used is not particularly limited as long as it is one used in a usual hydrolysis reaction, and water or water and methanol, ethanol, alcohols such as n-propanol or tetrahydrofuran,
A mixed solvent with an organic solvent such as ethers such as dioxane is preferable. The reaction temperature and reaction time vary depending on the starting material and the base to be used, and are not particularly limited. The removal by reduction is performed using a reducing agent such as sodium borohydride according to a conventional method.

When the R6 group is an aralkyl group or an aralkyloxycarbonyl group, a method of performing catalytic reduction at room temperature using a catalyst such as platinum or palladium carbon is preferable. The solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in the reaction, but alcohols such as methanol, ethanol and isopropanol, diethyl ether, tetrahydrofuran, ethers such as dioxane, toluene Benzene, aromatic hydrocarbons such as xylene, hexane, aliphatic hydrocarbons such as cyclohexane, esters such as ethyl acetate and propyl acetate, fatty acids such as acetic acid, or an organic solvent thereof and water. Are preferred. The catalyst used is not particularly limited as long as it is generally used for a catalytic reduction reaction, but is preferably palladium carbon, Raney nickel,
Platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride, and palladium-barium sulfate are used. The pressure is not particularly limited, but it is usually 1 to 10 atm. The reaction temperature and reaction time are
Although it depends on the type of starting material and catalyst, etc., it is usually 0 ° C.
Performed at 乃至 100 ° C. for 5 minutes to 24 hours.

When the R6 group is an alkenyloxycarbonyl group, the removal reaction is usually carried out in the same manner as in the case where the amino-protecting group is an aliphatic acyl group, an aromatic acyl group or a lower alkoxycarbonyl group. It can be eliminated by treating with a base. In the case of allyloxycarbonyl, the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is particularly simple and can be carried out with few side reactions.

The fifth step is a step of acylating the 2-position amino group of compound (5) to produce compound (6).

As a method for acylation, the general formula R2'-OH
A carboxylic acid having the formula: wherein R2 'is as defined above. Is reacted in the presence of a condensing agent such as dicyclohexylcarbimide (DCC), carbonyldiimidazole, or an activated acylating agent R2′-X (where R
2 'is as defined above, X is a group having a set of OR2'; a halogen atom such as base, bromine and iodine; an alkylcarbonyloxy group such as acetoxy and propionyloxy; chloroacetyloxy and dichloroacetyloxy. , Trichloroacetyloxy, halogenated alkylcarbonyloxy groups such as trifluoroacetyloxy, lower alkoxyalkylcarbonyloxy groups such as methoxyacetyloxy, and unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyloxy Aliphatic acyloxy groups such as oxy groups; arylcarbonyloxy groups such as benzoyloxy, halogenated arylcarbonyloxy groups such as 2-bromobenzoyloxy and 4-chlorobenzoyloxy, 2,4,6-trimethylbenzoyloxy, 4-Toluoyloxy Aromatic acyloxy such as lower alkylated arylcarbonyloxy group, lower alkoxylated arylcarbonyloxy group such as 4-anisoyloxy, nitrated arylcarbonyloxy group such as 4-nitrobenzoyloxy and 2-nitrobenzoyloxy Trihalogenomethyloxy groups such as trichloromethyloxy; lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; halogeno lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; It represents a leaving group such as an arylsulfonyloxy group such as benzenesulfonyloxy and p-toluenesulfonyloxy. ) With a solvent in the presence of a base. The solvent is not particularly limited as long as it does not inhibit the reaction, but preferably, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, ethers, dioxane, ethers such as terahydrofuran are preferable. , Hydrocarbons such as hexane, aromatic hydrocarbons such as benzene and toluene, esters such as ethyl acetate, and polar solvents such as dimethylsulfoxide and dimethylformamide.
As the base used, preferably, an organic base can be mentioned, for example, triethylamine, pyridine, DBU
, DBN, N, N-dimethylaniline, N, N-diethylaniline and N, N-dimethylaminopyridine. Reaction temperature is 0
C. to 100.degree. C., preferably 20 to 50.degree.
The reaction time varies depending mainly on the reaction temperature, the starting compound and the type of the solvent used, but is usually 0.1 hour to 24 hours.

In the sixth step, the 3-position hydroxyl group of compound (6) is
In the same manner as in the acylation of the amino group in the fifth step, R3 ′
This is a step of producing compound (7) by modification with a group.

The seventh step is a step of producing the compound (8) by removing the protecting group R8 of the diol of the compound (7).

For example, aqueous acetic acid, tetrahydrofuran,
In a solvent such as ethers such as dioxane or alcohols such as ethanol and methanol, 0 to 10
The reaction is carried out at 0 ° C. to remove, or at −78 ° C. to room temperature by catalytic reduction under a palladium carbon catalyst, and, if desired, by further performing catalytic reduction under a platinum oxide catalyst.

In the eighth step, the hydroxyl group at the 6-position of compound (8) is
This is the step of producing compound (9) by protecting with a group.

The R9 group must be a protecting group that can be removed separately from the R7 group. Examples of such a combination include the compound (I) of the present invention in which the 1-position is a fluorine atom.
In the case of preparing, it is preferred that the R7 group be a lower alkenyl group such as allyl, the R9 group be an aralkyloxycarbonyl group such as benzyloxycarbonyl, and the 6-position is a fluorine atom. When producing the compound (I) of the present invention, it is preferred that the R7 group be a lower alkenyl group such as allyl and the R9 group be a silyl group such as trimethylsilyl and t-butyldimethylsilyl. .

The primary hydroxyl group at the 6-position is converted to a compound having the general formula R9-X (wherein R9 and X have the same meanings as described above, and in this step, benzyloxycarbonyl chloride, t- Butyldimethylsilyl chloride) in a solvent at −50 to 50 ° C. (for example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, ethers, dioxane, tetrahydrofuran, etc.). Ethers, hydrocarbons such as hexane, benzene, aromatic hydrocarbons such as toluene, esters such as ethyl acetate, dimethyl sulfoxide,
Polar solvents such as dimethylformamide, acetone),
Bases (eg, DBU, DBN, DMAP, DABCO, pyridine,
Triethylamine, aniline, N, N-dimethylaniline,
Manufactured using an aqueous solution of a base (eg, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate) in a solvent (eg, acetone, tetrahydrofuran, dioxane) or in a solvent (eg, acetone, tetrahydrofuran, dioxane). can do.

The ninth step is a step of preparing the compound (10) by phosphorylating the 4-position hydroxyl group of the compound (9).

Phosphorylation is carried out by forming an anion with a base in a solvent and then reacting with a phosphorylating agent. The solvent is not particularly limited as long as it does not inhibit the reaction, but is preferably ether, dioxane, ethers such as tetrahydrofuran or chloroform,
Halogenated hydrocarbons such as methylene chloride can be mentioned. The base used is not particularly limited as long as it normally forms an anion, but is preferably a lithium compound such as normal butyl lithium or phenyl lithium or an organic base such as DBU, DBN, DMAP, triethylamine, or pyridine. And the like. As the phosphorylating agent, a reagent usually used for phosphorylation such as dibenzylchlorophosphate and diphenylchlorophosphate is used. The reaction is carried out at a temperature of -78 ° C to 50 ° C, preferably at -78 ° C to room temperature, and the reaction time varies mainly depending on the reaction temperature, the type of the starting compound or the solvent used, but is usually 10 minutes. Up to 24 hours.

The tenth step is a step of selectively removing the protecting group R7 at the 1-position hydroxyl group of the compound (10) to produce the compound (11).

When the R7 group is a silyl group, an aralkyloxycarbonyl group, an aralkyl group, an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group, an alkoxymethyl group or a substituted ethyl group, According to the method for removing when the R6 group is a corresponding group. When the R7 group is a tetrahydropyranyl group, a tetrahydrofuranyl group, a vinyl group, or the like, it can be usually removed by treating with an acid in a solvent. The acid used is preferably hydrochloric acid, acetic acid, sulfuric acid or p-toluenesulfonic acid. The solvent to be used is not particularly limited as long as it does not participate in the present reaction, but includes alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane, or a mixed solvent of these organic solvents and water. It is suitable. The reaction temperature and the reaction time vary depending on the starting material and the kind of the acid used, but are usually 0 ° C. to 50 ° C. and 10 minutes to 18 hours.

When the R7 group is an alkenyloxycarbonyl group, it is usually treated with a base in the same manner as the removal reaction when the R7 group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group. Can be desorbed. In addition, in the case of allyloxycarbonyl, the removal method using palladium and triphenylphenylphosphine or nickel tetracarbonyl is particularly simple and can be carried out with few side reactions.

When the R7 group is a lower alkenyl group such as allyl, the reaction is preferably carried out in a solvent in the presence of a catalyst, and the double bond is transferred to form an enol ether type. It can be removed by adding water or dilute hydrochloric acid. The solvent is not particularly limited as long as it does not inhibit the reaction.
Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, ethers such as ether, dioxane and tetrahydrofuran, hydrocarbons such as hexane, aromatic hydrocarbons such as benzene and toluene, and ethyl acetate And polar solvents such as dimethylsulfoxide and dimethylformamide. Examples of the catalyst used include a palladium catalyst such as palladium chloride and palladium acetate, a rhodium catalyst such as 1,5-cyclooctadiene-bis [methyldiphenylphosphine] rhodium hexafluorophosphate, and rhodium acetate; Cyclooctadiene-
A double bond transfer agent such as an iridium catalyst such as bis [methyldiphenylphosphine] iridium hexafluorophosphate may be used. The reaction temperature varies depending on the catalyst, solvent and the like to be used, but is usually from 0 to 100 ° C. The reaction time varies depending on the reaction temperature in addition to the above, but is usually 1 to 5 hours.

In the eleventh step, the 1-hydroxyl group of the compound (11) is replaced with a fluorine atom using a fluorinating reagent in a solvent,
This is a step of producing compound (12).

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably an aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether. Hydrogens; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate; Esters such as butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexane It can be mentioned ketones such as cyclohexanone. The fluorination reagent to be used is not particularly limited as long as it is a reagent usually used for fluorination of alcohol, and preferably, a compound represented by the general formula (R11) (R12) NSF ₃
(Wherein R11 and R12 are the same or different and each represents the above-mentioned "lower alkyl group" (preferably a methyl or ethyl group), or may be taken together and interrupted by an oxygen atom. Here, the term "lower alkylene group" refers to, for example, methylene, methylmethylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene,
Examples thereof include an alkylene group having 1 to 6 carbon atoms such as 3-methyltrimethylene, pentamethylene, and hexamethylene, preferably tetramethylene or pentamethylene. The dialkylaminosulfur trifluoride compound represented by) is used. The reaction temperature is from -20 ° C to 120 ° C, preferably from 0 ° C to 100 ° C. The reaction time depends mainly on the reaction temperature, the starting compound, the fluorinating reagent used or the type of the solvent used, but is usually 0.1 hour to 5 days.

The twelfth step is a step of producing the compound (13) by removing the protecting group R9 at the 6-position hydroxyl group of the compound (12), and is carried out according to the tenth step.

In the thirteenth step, the protecting group for the phosphoric acid residue of the compound (13) is removed, and if necessary, the protecting group for the hydroxyl group present in the R2 'and / or R3' groups is removed.
This is a step of manufacturing (14).

In principle, the reaction for removing the protecting group for the phosphoric acid residue and the reaction for removing the protecting group for the hydroxyl group vary depending on the type of the protecting group, but the desired removal reaction can be carried out in any order and in order. In some cases, the protecting group of the phosphoric acid residue may be removed at the same time by the operation of removing the protecting group of the hydroxyl group.
The 0 group is preferably removed last. The reaction for removing the protecting group of the phosphoric acid residue is usually achieved by catalytic reduction at −78 ° C. to 0 ° C. in the presence of a palladium carbon catalyst.
In some cases, after the catalytic reduction under a palladium carbon catalyst, the catalytic reduction is further performed under a platinum oxide catalyst.

When a protecting group for a hydroxyl group is present on R2 'and / or R3', the removal of the protecting group is carried out according to the tenth step.

In order to obtain a water-soluble salt of phosphoric acid, for example, the salt is dissolved in a solvent of a halogenated hydrocarbon such as chloroform, washed once with an inorganic acid diluted with water such as dilute hydrochloric acid, and then washed with a base. Can be obtained by adding water containing

The fourteenth step is a step of selectively removing the protecting group R9 at the 6-position hydroxyl group of the compound (10) to produce the compound (15), and is carried out according to the tenth step.

The fifteenth step is a step of converting the hydroxyl group at the 6-position of compound (15) to a fluorine atom to produce compound (16), and is carried out according to the eleventh step.

The sixteenth step is a step of producing the compound (17) by removing the protecting group R7 at the 1-position hydroxyl group of the compound (16), and is carried out according to the twelfth step.

In the seventeenth step, the protecting group for the phosphoric acid residue of the compound (17) is removed, and if necessary, the protecting group for the hydroxyl group present in the R2 'group and / or the R3' group is removed.
This is a step of manufacturing (18), which is performed according to the thirteenth step.

[0073]

Industrial Applicability The novel phosphorylfluoroglucosamine analog of the present invention has an excellent macrophage activating activity and low toxicity, and is therefore useful as an immunostimulant or an antitumor agent.

The administration form of the compound (I) of the present invention includes
For example, oral administration using tablets, capsules, granules, powders, syrups and the like, or parenteral administration using injections, suppositories and the like can be mentioned. These formulations are:
It is manufactured by a known method using additives such as excipients, binders, disintegrants, lubricants, stabilizers, and flavoring agents. The amount used varies depending on symptoms, age, etc., but it can be usually administered to adults at a dose of 0.01-50 mg / kg body weight once or several times a day.

Hereinafter, the present invention will be described more specifically with reference to examples.

[0076]

Example 1 (a) N-trifluoroacetylglucosamine Hydrochloride D-(+)-Glucosamine 160 g (0.742 mol) was dissolved in methanol (99.6%) 2200 ml, and triethylamine 187.9 g
(1.86 mol) was added. Further, 115.9 g of ethyl trifluoroacetate was added dropwise under ice-cooling, and the mixture was stirred at room temperature overnight. Concentrate under reduced pressure, benzene 250 ml x 2, ethyl acetate 250 ml
, And concentrated under reduced pressure, and further dried sufficiently with a vacuum pump. The process proceeded to (b) without purification of the crude trifluoroacetyl form obtained here.

(B) To the crude trifluoroacetyl compound obtained from allyl 2-deoxy-2-trifluoroacetamido-D-glucopyranoside (a), 1850 ml of a 2% hydrochloric acid-allyl alcohol solution was added. Heated to reflux for minutes. The mixture was cooled to about 50 ° C. with ice water and filtered through celite. The filtrate was concentrated and further dried sufficiently with a vacuum pump. Without purifying the crude allyl ether obtained here,
Proceed to (c).

(C) Allyl 2-deoxy-2-trifluoroacetamide-4,6-O-isopropylidene-D-glucopyranoside The crude allyl ether obtained from (b) was converted to N, N- The residue was dissolved in 740 ml of dimethylformamide, 370 ml of 2,2-dimethoxypropane was added, and 7.5 g of pyridinium p-toluenesulfonate was further added. The mixture was stirred at room temperature overnight. It concentrated under reduced pressure and diluted with ethyl acetate. The precipitate was removed by filtration, and the filtrate was washed with aqueous sodium hydrogen carbonate, water, and brine. The extract was dried over anhydrous magnesium sulfate, filtered using celite and activated carbon, and concentrated. The residue was applied to a silica gel column, and cyclohexane: ethyl acetate = 3: 2 was used to obtain 80.5 g, 7 and 8 each having α- and β-ether bonds at the 1-position.
7.3 g separated. Both α-form and β-form can be used for the subsequent reaction. [Α-allyl form] Mass spectrum m / z: 356 (M ⁺ +1), 340, 298, 282, 25
6, 240, 222, 211, 193, 168, 126, 109, 101. [β-allyl form] Mass spectrum m / z: 356 (M ⁺ +1), 340, 298, 280, 25
6, 240, 222, 211, 193, 168, 155, 145,126, 114, 101
.

(D) Allyl 2-deoxy-2-amino-4,6-
10 g of the trifluoroacetyl compound obtained with O-isopropylidene-α-D-glucopyranoside (c) was dissolved in 200 ml of ethanol (99.5%). The mixture was heated and refluxed for 4 hours. It concentrated under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtration, ethyl acetate was distilled off under reduced pressure, and the residue oily substance was applied to a silica gel column and purified with ethyl acetate to obtain 6.6 g (90.5%) of the desired compound. NMR spectrum (60 MHz) (CDCl ₃ ) δ ppm 1.42 (3H, s); 1.50 (3H, s); 2.98 (2H, broad); 3.5-4.4 (5
H, m); 4.6-6.3 (7H, m). Elemental analysis (as C ₁₂ H ₂₁ NO ₅ = 259.302)

(E) Allyl 2-deoxy-2-[(3'R) -3'-
Benzyloxytetradecanoylamino] -4,6-O-isopropylidene-α-D-glucopyranoside and allyl 2-deoxy-2-[(3 ′S) -3′-benzyloxytetradecanoylamino] -4,6-O-isopropylidene-α-
5 g (19.3 mmol) of the compound obtained in D-glucopyranoside (d) was dissolved in 100 ml of methylene chloride, and 6.8 g of (±) -3-benzyloxytetradecanoic acid was added. Then, 4.78 g of N, -dicyclohexylcarbodiimide was added, and the mixture was stirred at room temperature for 1 hour. After filtration, the mixture was concentrated under reduced pressure, and diluted with ethyl acetate.
The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was distilled off under reduced pressure. The residue was applied to a silica gel column and purified with cyclohexane: ethyl acetate 9:11 to obtain the desired 3′-R form (Rf = 0.289) 4.1 g, 3 ′ -S form (Rf = 0.196)
4.2 g were obtained. [3′R form] Infrared absorption spectrum ν max (KBr) cm ^-1 : 3510, 328
0, 1643. NMR spectrum (270MHz) (CDCl ₃ ) δ ppm: 0.88 (3H, t, J = 6.9 Hz); 1.20-1.41 (18H, m); 1.45 (3H, s);
1.52 (3H, s); 1.56-1.70 (2H, m); 2.43 (1H, dd, J = 6.9,15.
4 Hz); 2.56 (1H, dd, J = 3.7,15.0 Hz); 3.19-3.29 (1H, m);
3.46-3.63 (2H, m); 3.75-3.94 (5H, m); 4.18-4.24 (1H,
m); 4.36 (1H, d, J = 2.6 Hz); 4.45-4.62 (3H, m); 5.12-5.2
6 (2H, m); 5.70-5.88 (1H, m); 6.72 (1H, d, J = 5.9 Hz); 7.3
0- 7.37 (5H, m). [3'S form] Infrared absorption spectrum ν max (KBr) cm ^-1 : 3510, 328
0, 1643. NMR spectrum (270MHz) (CDCl ₃ ) δ ppm: 0.88 (3H, t, J = 6.6 Hz); 1.15-1.73 (20H, m); 1.45 (3H, s);
1.53 (3H, s); 2.35-2.62 (2H, m); 3.02 (1H, d, J = 2.6 Hz);
3.55-4.25 (9H, m); 4.54,4.59 (2H, ABq, J = 11.4 Hz); 4.7
8 (1H, d, J = 3.7 Hz); 5.10-5.28 (2H, m); 5.66-5.84 (1H,
m); 6.77 (1H, d, J = 8.8 Hz); 7.25-7.37 (5H, m).

(F) Allyl 2-[(R) -3'-benzyloxytetradecanoylamino] -2-deoxy-3-O-[(R)-
3 ″ -tetradecanoyloxytetradecanoyl] -4.6-
O-isopropylidene-α-D-glucopyranoside and allyl 2-[(S) -3′-benzyloxytetradecanoylamino] -2-deoxy-3-O-[(R) -3 ″ -tetra Decanoyloxytetradecanoyl] -4.6-O-isolopylidene-α-D-glucopyranoside (e), 1 g of the compound (3′R or 3 ′S) obtained was dissolved in tetrahydrofuran, 0.869 g of 3 (R) tetradecanoyloxytetradecanoic acid was added, and further, N, N'-
0.466 g of dimethylcyclohexylcarbodiimide and 0.233 g of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 4 hours. After filtration, the filtrate was concentrated under reduced pressure, diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: cyclohexane: ethyl acetate 85:15) to obtain 1.23 g (70%) of the target product 3'R form, 3'S form 1.27 g (73%)
was gotten. [3'R form] Infrared absorption spectrum ν max (liquid film) cm ^-1 : 3350, 17
30, 1650, 1530, 1470, 1370. NMR spectrum (270MHz) (CDCl ₃ ) δ ppm: 0.80-1.00 (9H, m); 1.00-1.80 (68H, m); 2.10-2.70 (6H,
m); 3.60-4.40 (8H, m); 4.49,4.54 (2H, d, J = 11.7 Hz); 4.
65-4.90 (1H, m); 5.03-5.35 (4H, m); 5.60-5.95 (1H, m);
6.25 (1H, d, J = 9.5 Hz); 7.25-7.65 (5H, m). [3'S form] Infrared absorption spectrum ν max (liquid film) cm ^-1 : 3400, 17
30, 1670, 1650. NMR spectrum (270MHz) (CDCl ₃ ) δ ppm: 0.80-0.97 (9H, m); 1.10-1.70 (68H, m); 2.12-2.64 (6H,
m); 3.63-3.90 (6H, m); 3.95-4.05 (1H, m); 4.22-4.34 (1
H, m); 4.49,4.60 (2H, d, J = 11.4 Hz); 4.78 (1H, d, J = 3.7 H
z); 5.05-5.23 (4H, m); 5.60-5.77 (1H, m); 6.85 (1H, d, J =
9.2 Hz); 7.25-7.40 (5H, m).

(G) Allyl 2-[(R) -3'-benzyloxytetradecanoylamino] -2-deoxy-3-O-[(R)-
3 ″ -tetradecanoyloxytetradecanoyl] -α-
D-glucopyranoside and allyl 2-[(S) -3'-benzyloxytetradecanoylamino] -2-deoxy-3-O-[(R) -3 ″ -tetradecanoyloxytetradecanoyl] 3′R form or 3 ′S form obtained from -α-D-glucopyranoside (f), 1 g each
Was dissolved in 20 ml of 90% acetic acid and stirred at 55-60 ° C. for 1 hour. Acetic acid was concentrated under reduced pressure and diluted with ethyl acetate.
The diluted product was washed with an aqueous solution of sodium hydrogen carbonate and a saline solution, and then subjected to silica gel chromatography (developing solvent: cyclohexane:
Ethyl acetate = 3.2). The desired product was obtained in an amount of 0.6 g (57%) from the 3'R form and 0.66 g (69%) from the 3'S form. [3'R] Infrared absorption spectrum ν max (nujol) cm ^-1 : 34
80, 3400, 3300, 1735, 1720, 1700, 1650, 1550, 146
5, 1380, 1310.NMR spectrum (270MHz) (CDCl ₃ ) δ ppm: 0.82-0.95 (9H, m); 1.15-1.70 (64H, m); 2.24-2.58 (6H,
m); 3.62-3.92 (6H, m); 4.00-4.10 (1H, m); 4.20-4.30 (1
H, m); 4.50,4.55 (2H, d); 4.79 (1H, d, J = 3.3 Hz); 5.03-
5.24 (4H, m); 5.65-5.82 (1H, m); 6.33 (1H, d, J = 9.5 Hz);
7.22-7.36 (5H, m). [3 ′ S-isomer] Infrared absorption spectrum ν max (nujol) cm ^-1 : 32
80, 1737, 1722, 1643, 1550, 1466, 1177, 1103, 105
3. NMR spectrum (270MHz) (CDCl ₃ ) δ ppm: 0.80-0.95 (9H, m); 1.15-1.72 (62H, m); 2.24-2.50 (6H,
m); 3.62-3.92 (6H, m); 4.00-4.10 (1H, m); 4.18-4.30 (1
H, m); 4.50,4.57 (2H, dd, J = 11.4 Hz); 4.86 (1H, d, J = 3.3 H
z); 5.02-5.27 (4H, m); 5.64-5.81 (1H, m); 6.80 (1H, d, J =
8.8 Hz); 7.25-7.40 (5H, m).

(H) Allyl 6-O-benzyloxycarbonyl-2-[(R) -3'-benzyloxytetradecanoylamino] -2-deoxy-3-O-[(R) -3 ″ -tetra Decanoyloxytetradecanoyl] -α-D-glucopyranoside and allyl 6-O-benzyloxycarbonyl-2-[(S) -3′-
Benzyloxytetradecanoylamino] -2-deoxy-3-O-[(R) -3 ″ -tetradecanoyloxytetradecanoyl] -α-D-glycopyranoside (g) The 3 '(R) or 3' (S) form was dissolved in 0.645 g of each and 10 ml of dichloromethane, and 0.136 g of benzyloxycarbonyl chloride and 4-
After adding 0.122 g of dimethylaminopyridine, the mixture was stirred at room temperature for 2 hours. The dichloromethane was concentrated under reduced pressure, diluted with ethyl acetate, and washed with an aqueous sodium hydrogen carbonate solution and brine. After drying over anhydrous magnesium sulfate and filtration, ethyl acetate was distilled off under reduced pressure and the residue was purified by silica gel chromatography (developing solvent: cyclohexane: ethyl acetate = 4:
1), 0.46 g each of the desired product (3'R form, 3'S form)
(63%). [3 'R form] Infrared absorption spectrum ν max (nujol) cm ^-1 : 350
0, 3310, 1730, 1650, 1545, 1465, 1380, 1305, 1280. NMR spectrum (270MHz) (CDCl ₃ ) δ ppm: 0.80-0.96 (9H, m); 1.10-1.70 (62H, m); 2.22- 2.60 (6H,
m); 3.34 (1H, d, J = 4.0 Hz); 3.53-3.66 (1H, m); 3.72-3.9
0 (3H, m); 3.95-4.05 (1H, m); 4.20-4.32 (1H, m); 4.35-4.
52 (2H, m); 4.49,4.56 (2H, dd, J = 11.7 Hz); 4.77 (1H, d, J =
3.7 Hz); 5.00-5.25 (6H, m); 5.62-5.78 (1H, m); 6.29 (1
H, m); 7.22-7.43 (10H, m). [3 ′ S form] Infrared absorption spectrum ν max (nujol) cm ^-1 : 350
0, 3290, 1737, 1720, 1647, 1546, 1466, 1282. NMR spectrum (270MHz) (CDCl ₃ ) δ ppm: 0.82-0.93 (9H, m); 1.15-1.65 (62H, m); 2.22-2.50 ( 6H,
m); 3.33 (1H, d, J = 4.0 Hz); 3.55-3.67 (1H, m); 3.67-3.9
0 (3H, m); 3.96-4.05 (1H, m); 4.18-4.30 (1H, m); 4.37-4.
52 (2H, m); 4.49,4.57 (2H, dd, J = 11.4 Hz); 4.83 (1H, d, J =
3.3 Hz); 5.00-5.22 (6H, m); 5.60-5.77 (1H, m); 6.76 (1
H, d, J = 8.8Hz); 7.25-7.42 (10H, m).

(I) Allyl 2-deoxy-6-O-benzyloxycarbonyl-2-[(R) -3'-benzyloxytetradecanoylamino] -4-O- (diphenylphosphoryl-3-
O-[(R) -3 ″ -tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside and allyl 2-deoxy-6-O-benzyloxycarbonyl
-2-[(S) -3'-benzyloxytetradecanoylamino] -4-O-diphenylphosphoryl-3-O-[(R) -3 "-
Tetradecanoyloxytetradecanoyl] -α-D-
The compound 3 ′ (R) or 3 ′ (S) form obtained with glucopyranoside (h) was dissolved in 11.3 g and 230 ml of dichloromethane, respectively, and 8.22 g of diphenylchlorophosphate, 4-dimethylaminopyridine 7.48 g was added, and the mixture was stirred at room temperature for 1 hour. The dichloromethane was concentrated under reduced pressure and diluted with ethyl acetate. The diluted product was washed with an aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was distilled off under reduced pressure.
Compound, 6.12 g (45%) and 11.34 g (83%) of the 3'S compound were obtained. [3 'R form] Infrared absorption spectrum ν max (nujol) cm ^-1 : 173
5, 1720, 1665, 1590, 1485, 1255, 1066, 965. NMR spectrum (270MHz) (CDCl ₃ ) δ ppm: 0.82-0.94 (9H, m); 1.10-1.60 (62H, m); 2.10-2.20 ( 2H,
m); 2.30-2.46 (4H, m); 3.67-3.78 (1H, m); 3.78-3.90 (1
H, m); 3.90-4.03 (1H, m); 4.15-4.37 (3H, m); 4.48-4.54
(2H, ABq, J = 11.4 Hz); 4.72 (1H, dd, J = 9.2,19.1 Hz); 4.8
0 (1H, d, J = 3.3 Hz); 5.00-5.20 (5H, m); 5.40 (1H, dd, J = 9.
2,10.6 Hz); 5.65-5.77 (1H, m); 6.22 (1H, d, J = 8.8 Hz);
7.10-7.38 (20H, m). [3 ′ S-isomer] Infrared absorption spectrum ν max (nujol) cm ^-1 : 33
50, 1745, 1650, 1590, 1490, 960. NMR spectrum (270MHz) (CDCl ₃ ) δ ppm: 0.80-0.93 (9H, m); 1.10-1.65 (62H, m); 2.08-2.20 (2H,
m); 2.30-2.52 (4H, m); 3.65-3.87 (2H, m); 3.93-4.05 (2
H, m); 4.16-4.35 (3H, m); 4.49,4.61 (2H, d, J = 11.4 Hz);
4.72 (1H, dd, J = 9.2,4.7 Hz); 4.85 (1H, d, J = 3.3 Hz); 5.0
1-5.20 (5H, m); 5.39 (1H, dd, J = 9.2,10.6 Hz); 5.59-5.74
(1H, m); 6.86 (1H, d, J = 8.8 Hz); 7.10-7.20 (20H, m).

(J) 2-deoxy-6-O-benzyloxycarbonyl-2-[(R) -3'-benzyloxytetradecanoylamino] -4-O-diphenylphosphoryl-3-O-[(R )
-3 "-tetradecanoyloxytetradecanoyl] -D
-Glucopyranoside and 2-deoxy-6-O-benzyloxycarbonyl-2-[(S)
-3'-Benzyloxytetradecanoylamino] -4-O
-Compound 3 '(R) or 3' (S) obtained with diphenylphosphoryl-3-O-[(R) -3 "-tetradecanoyloxytetradecanoyl] -D-glucopyranoside (i) ) Isomers were dissolved in 0.28 g of each and 5 ml of tetrahydrofuran, and 8.9 mg of bis (methyldiphenylphosphine) cyclooctadieneiridium was added, followed by nitrogen replacement, hydrogen replacement, activation of the iridium complex, and nitrogen replacement again. The mixture was stirred at room temperature for 3 hours, added with 0.5 ml of water, 0.1 g of iodine, and 0.066 g of pyridine, stirred at room temperature for 30 minutes, concentrated under reduced pressure, and diluted with ethyl acetate. Washed with sodium aqueous solution and saline,
Ethyl acetate was distilled off under reduced pressure. Purification by silica gel chromatography (cyclohexane: ethyl acetate = 7: 3)
0.23 g (84%) of the 3'R form and 0.24 g (88%) of the 3'S form were obtained. [3 'R form] Infrared absorption spectrum ν max (nujol) cm ^-1 : 33
20, 1735, 1650, 1590, 1535, 1490, 1455. NMR spectrum (270MHz) (CDCl ₃ ) δ ppm: 0.82-0.93 (9H, m); 1.08-1.70 (62H, m); 2.10-2.22 (2H,
m); 2.27-2.35 (2H, m); 2.38-2.44 (2H, m); 2.50 (1H, dd, J
= 1.1,4.4 Hz); 3.82-3.93 (1H, m); 4.10-4.39 (4H, m); 4.
39,4.60 (2H, ABg, J = 11.0 Hz); 4.68 (1H, dd, J = 9.2,18.3 H
z); 5.00-5.13 (4H, m); 5.39 (1H, dd, J = 9.2,11.6 Hz); 6.
22 (1H, d, J = 8.8 Hz); 7.09-7.39 (20H, m). [3 ′ S form] Infrared absorption spectrum ν max (liquid film) cm ^-1 : 3600-320
0, 1748, 1640, 1540, 1490, 961. NMR spectrum (270 MHz) (CDCl ₃ ) δ ppm: 0.82-0.96 (9H, m); 1.07-1.65 (62H, m); 2.12-2.22 (2H,
m); 2.32-2.46 (4H, m); 2.99 (1H, dd, J = 1.5,4.0 Hz); 3.7
0-3.82 (1H, m); 4.13-4.38 (4H, m); 4.52,4.57 (2H, d, J = 1
1.01); 4.71 (1H, dd, J = 9.2,18.7 Hz); 4.97-5.25 (4H,
m); 5.46 (1H, dd, J = 9.2,10.6 Hz); 6.86 (1H, d, J = 8.4H
z); 7.08-7.40 (20H, m).

(K) 6-O-benzyloxycarbonyl-2-
[(R) -3'-benzyloxytetradecanoylamino]-
1,2-dideoxy-4O-diphenylphosphoryl-1fluoro-3-O-[(R) -3 ″ -tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside and 6-O-benzyl Oxycarbonyl-2-[(R) -3'-benzyloxytetradecanoylamino] -1,2-dideoxy-4-
O-diphenylphosphoryl-1-fluoro-3O-[(R) -3 ″
-Tetradecanoyloxytetradecanoyl] -β-D-
Glucopyranoside diethylaminosulfur trifluoride (DAST) 1.36
g (8.44 mmol) was dissolved in 30 ml of dry methylene chloride, and the solution of 2-deoxy-6O-benzyloxycarbonyl-2-[(R) -3'-benzyloxy Myristoylamide] -4-O- (diphenylphosphoryl) -3-O
A solution of 2.74 g (2.11 mmol) of-[(R) -3 ″ -myristoyloxymyristoyl] -D-glucopyranoside in 25 ml of dry methylene chloride is gradually added, and the mixture is stirred under ice cooling for 1 hour. Was added to 130 ml of ice water, the methylene chloride layer was separated, the aqueous layer was extracted with methylene chloride, washed with aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification with (cyclohexane: ethyl acetate = 8: 2) gave 1.10 g (40%) of the indicated α-fluoride compound, β-fluoride compound.
1.14 g (42%) of the fluoride compound was obtained as a white solid. [Α-fluoride compound] Infrared absorption spectrum ν max (nujol) cm ^-1 : 33
80, 1740, 1660, 1590. Elemental analysis value (as C75H111NO14FP) [Β-fluoride compound] Infrared absorption spectrum ν max (nujol) cm ^-1 : 33
20, 1745, 1725, 1662,1590. Elemental analysis value (as C75H111NO14FP)

(1) 1,2-dideoxy-4-O-diphenylphosphoryl-1-fluoro-2-[(R) -3'-hydroxytetradecanoylamino] -3-O-[(R) -3 0.4 g of glycopyranosyl fluoride obtained from ″ -tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside (k) was dissolved in 6 ml of tetrahydrofuran, and 10% palladium carbon was added to the solution. Then, 24 ml of methanol and 50 mg of formic acid were added, and the mixture was stirred in a hydrogen stream at room temperature for 4 hours. Chromatography (cyclohexane: ethyl acetate = 6: 4)
Purification gave 0.1 g (30%) of the title compound as a solid. Infrared absorption spectrum ν max (nujol) cm ^-1 : 35
50, 3420, 1732, 1646, 1590.

(M) 1,2-dideoxy-1-fluoro-2-[(R)-
3'-hydroxytetradecanoylamino] -3-O-[(R)-
3 ″ -tetradecanoyloxytetradecanoyl] -α-
85 mg of the compound obtained in D-glucopyranosyl-4-phosphate (l) was dried in tetrahydrofuran.
After dissolving in 5 ml, 17 mg of platinum oxide was added, and the mixture was stirred in a hydrogen stream at room temperature for 4 hours. The reaction solution was heated to 45 ° C. to dissolve insolubles, and filtered through celite. The solvent was distilled off under reduced pressure to give the title compound as a solid, 72 mg (97%)
Obtained. NMR spectrum (270 MHz) (d5-pyridine) δ ppm: 0.82-0.95 (9H, m), 1.15-1.90 (62H, m), 2.48 (2H, t, J = 7.3
Hz), 2.80-2.90 (2H, m), 3.06-3.30 (2H, m), 4.01-4.60
(7H, m), 5.00-5.50 (2H, m), 5.71 (1H, t, J = 5.9 Hz), 5.97
(1H, dd, J = 2.4,52.5 Hz), 6.06 (1H, t, J = 10.3 Hz), 9.56
(1H, d, J = 9.3 Hz). Infrared absorption spectrum ν max (nujol) cm-1: 325
0, 1722, 1645, 1550.

[0089]

Example 2 (a) 6-O-benzyloxycarbonyl-2-
[(S) -3'-benzyloxytetradecanoylamino] -1,2
Dideoxy-4-O-diphenylphosphoryl-1-fluoro
-3-O-[(R) -3 ″ -tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside diethylamino sulfur trifluoride (DAST) 1.49 g
(9.2 mmol) was dissolved in 30 ml of dry methylene chloride, and 2-deoxy-6-O-benzyloxycarbonyl-2-[(S) -3′-benzyl Oxytetradecanoylamino] -4-O- (diphenylphosphoryl) -3-
A solution of 3.0 g (2.31 mmol) of O-[(R) -3 ″ -tetradecanoyloxytetradecanoyl] -D-glucopyranoside in 30 ml of dry methylene chloride was slowly added.
The mixture was stirred for 1 hour on ice and for 30 minutes at room temperature. Ice water
The mixture was poured into 150 ml, the methylene chloride layer was separated, the aqueous layer was extracted with methylene chloride, washed with aqueous sodium chloride, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 5 g of silica gel (No.9385 manufactured by Merck) and 100 ml of methylene chloride were added to the residue.
And stirred at room temperature overnight to convert the α, β-fluoro compound into an α-fluoro compound. The silica gel was removed by filtration, the methylene chloride was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (cyclohexane: ethyl acetate = 85: 15) to obtain 2.4 g (80%) of the title compound. Infrared absorption spectrum ν max (Nujol) cm-1: 339
0, 1740, 1650, 1590.

(B) 1,2-dideoxy-4-O-diphenylphosphoryl-1-fluoro-2-[(S) -3'-hydroxytetradecanoylamino] -3-O-[(R) -3 1.82 g of the compound obtained with "-tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside 2 (a) was treated with 12 m of tetrahydrofuran.
l, and 1.8 g of 10% palladium-carbon was added thereto, followed by 45 ml of methanol and 70 mg of formic acid,
The mixture was stirred at room temperature for 5 hours in a hydrogen stream. Palladium carbon was removed from the reaction solution by celite filtration, and the filtrate was dried under reduced pressure. The residue was purified by silica gel flash chromatography (cyclohexane: ethyl acetate = 6: 4) to give 0.38 g (25%) of the title compound as a solid. Infrared absorption spectrum ν max (Nujol) cm-1:
3600-3100, 1740, 1720, 1645,1590. Elemental analysis value (as C60H99NO12FP)

(C) 1,2-dideoxy-1-fluoro-2-[(S)-
3'-hydroxytetradecanoylamino] -3-O-[(R)-
3 ″ -tetradecanoyloxytetradecanoyl] -α-
80 mg of the compound obtained with D-glucopyranosyl-4 phosphate 2 (b) was dissolved in 3 ml of dry tetrahydrofuran, 16 mg of platinum oxide was added, and the mixture was stirred in a hydrogen stream at room temperature for 4 hours. The reaction solution was heated to 45 ° C. to dissolve insolubles, and filtered through celite. The solvent was distilled off under reduced pressure to obtain 60 mg (87%) of the title compound as a solid. NMR spectrum (270 MHz) (d5-pyridine) δ ppm: 0.80-0.97 (9H, m), 1.10-1.90 (62H, m), 2.46 (2H, t, J = 7.3
Hz), 2.82 (2H, d, J = 5.9 Hz), 3.04-3.25 (2H, m), 3.60-
3.70 (1H, m), 3.80-3.70 (1H, m); 3.80-4.55 (6H, m), 5.65
-7.77 (1H, m), 6.00-6.10 (1H, m), 6.10 (1H, dd, J = 2.9,53.
7 Hz), 9.47 (1H, d, J = 9.3 Hz) .Infrared absorption spectrum ν max (nujol) cm-1: 355
0, 3300, 1730, 1650.

[0092]

Example 3 (a) Allyl 2-[(R) -3'-benzyloxytetradecanoylamino] -2-deoxy-6-O-t-butyldimethylsilyl-3O-[(R) -3 Allyl 2-[(R) -2'-benzyloxytetradecanoylamino] -2-deoxy obtained from 1 "-tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside -3-O-[(R) -3 '
-Tetradecanoyloxytetradecanoyl] -α-D-
Dissolve 0.49 g (0.5 mmol) of glucopyranoside in 10 ml of dry methylene chloride and add dimethylaminopyridine
0.15 g (1.25 mmol) and 0.11 g (0.75 mmol) of t-butyldimethylsilyl chloride were added. After stirring at room temperature for 4 hours, methylene chloride was distilled off under reduced pressure. The residue was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate, aqueous sodium chloride, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by flash chromatography on silica gel (ethyl cyclohexane = 85: 15) to give 0.53 g (97%) of the title compound as a colorless oil. NMR spectrum (270 MHz) (deuterated chloroform) δ ppm: 0.08 (6H, s), 0.82-0.94 (18H, m), 1.16-1.67 (62H, m), 2.
28 (2H, t, J = 7.6 Hz), 2.35 (2H, d, J = 5.9 Hz), 2.42-2.63
(2H, m), 3.30 (1H, br.s),; 3.60-4.10 (7H, m), 4.18-4.30
(1H, m), 4.49,4.54 (2H, ABq, J = 12.0 Hz), 4.77 (1H, d, J =
3.9 Hz), 5.04-5.22 (4H, m), 5.65-5.82 (1H, m), 6.27 (1H, m
d, J = 9.3 Hz), 7.22-7.35 (5H, m). Infrared absorption spectrum ν max (nujol) cm-1: 3550
-3150, 1730, 1650.

(B) Allyl 2-[(R) -3'-benzyloxytetradecanoylamino] -2-deoxy-4-O-diphenylphosphoryl-6O-t-butyldimethylsilyl-3-O
[(R) -3 ″ -tetradecanoyloxytetradecanoyl]-
100 mg (0.09 mmol) of the compound obtained as α-D-glucopyranoside 3 (a) and 34 mg (0.27 mmol) of dimethylaminopyridine were dissolved in 2 ml of dry methylene chloride, and 70 mg of diphenylchlorophosphate was added thereto. (0.27 mmol) in 1 ml of dry methylene chloride was added slowly and stirred at room temperature for 1 hour. The methylene chloride was evaporated under reduced pressure, the residue was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and aqueous sodium chloride, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel flash chromatography (cyclohexane:
Purification with ethyl acetate (9: 1) yielded 110 mg (94%) of the title compound as a colorless oil. NMR spectrum (270 MHz) (deuterated chloroform) δ ppm: 0.013 (6H, s), 0.82-0.95 (18H, m), 1.10-2.66 (62H, m),
2.14 (2H, t, J = 6.3-8.3 Hz), 2.35 (2H, d, J = 5.9 Hz), 2.44
(2H, d, J = 6.8 Hz), 3.65-4.12 (7H, m),, 4.23-4.35 (1H,
m), 4.53,4.57 (2H, ABq, J = 11.5 Hz), 4.67 (1H, dd, J = 9.3,
18.6 Hz), 4.80 (1H, d, J = 3.4 Hz), 5.05-5.25 (3H, m), 5.43
(1H, dd, J = 9.3,10.7 Hz), 5.67-5.85 (1H, m), 6.23 (1H, d, J
= 9.3 Hz) 7.12-7.40 (15H, m) .Infrared absorption spectrum ν max (liquid film) cm-1: 3350, 17
40, 1675, 1590.

(C) Allyl 2-[(R) -3'benzyloxytetradecanoylamino] -2-deoxy-4-O-diphenylphosphoryl-3-O-[(R) -3 ″ -tetradecanoyl [Oxytetradecanoyl] -α-D-glucopyranoside 100 mg of the compound obtained in 3 (b) was added to 2 m of tetrahydrofuran.
Then, 0.4 ml of 3N hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 3 hours. The tetrahydrofuran is evaporated under reduced pressure,
The residue was dissolved in ethyl acetate, aqueous sodium hydrogen carbonate,
The extract was washed with aqueous sodium chloride and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel flash cross chromatography (cyclohexane: ethyl acetate = 7:
Purification in 3) yielded 90 mg (95%) of the title compound as a solid. Infrared absorption spectrum ν max (Nujol) cm-1: 34
70, 3330, 1735, 1720, 1650, 1590. Elemental analysis (as C70H110O13NP)

(D) Allyl 2-[(R) -3'-benzyloxytetradecanoylamino] -2,6-dideoxy-4-O-diphenylphosphoryl-6-fluoro-3O-[(R)- 3 ″ -tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside 70 mg (0.06 mmol) of the compound obtained in 3 (c) in a solution of 40 mg (0.23 mmol) of DAST in 0.8 ml of dry methylene chloride Was added slowly under ice-cooling, stirred for 3 hours under ice-cooling, and further stirred at room temperature for 30 minutes.The reaction solution was poured into 40 ml of ice-water and the methylene chloride layer was separated The aqueous layer was extracted with methylene chloride, washed with aqueous sodium chloride, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel flash chromatography (cyclohexane: ethyl acetate = 8: 2). Purification gave 60 mg (87%) of the title compound as a solid. (270 MHz) (deuterated chloroform) δ ppm: 0.88 (9H, t, J = 7.3-7.8 Hz), 1.10-1.65 (62H, m), 2.15 (2
H, t, J = 7.6 Hz), 2.34 (2H, d, J = 5.9 Hz), 2.42 (2H, d, J = 6.
3 Hz), 3.70-4.07 (4H, m), 4.27-4.55 (3H, m), 4.49,4.55
(2H, ABq, J = 11.5 Hz), 4.69 (1H, dd, J = 9.3,19.0 Hz), 4.8
4 (1H, d, J = 3.9 Hz), 5.30-5.24 (3H, m), 5.43 (1H, dd, J = 9.
3,10.7 Hz), 5.63-5.80 (1H, m), 6.25 (1H, d, J = 8.8 Hz), 7.
12-7.38 (15H, m). Infrared absorption spectrum ν max (Nujol) cm-1: 33
30, 1740, 1730, 1660, 1600.

(E) 2-[(R) -3'-benzyloxytetradecanoylamino] -2,6-dideoxy-4-O-diphenylphosphoryl-6-fluoro-3O-[(R) -3 To a solution of 460 mg (0.37 mmol) of ″ -tetradecanoyloxytetradecanoyl] -D-glucopyranose 3 (d) in 10 ml of dry tetrahydrofuran was added bis (methyldiphenylphosphine) cyclooctadiene iridium (I). Hexafluorophosphate (16 mg, 0.019 mmol) was added, the iridium complex was activated with hydrogen, and the mixture was stirred for 3 hours in a stream of nitrogen, and then 0.19 g (0.74 mmol) of iodine, 1 ml of water, 0.12 g (1.48 mmol) of pyridine was added, and the mixture was stirred at room temperature for 30 minutes, concentrated under reduced pressure, and the residue was dissolved in 80 ml of ethyl acetate. Wash and dry magnesium sulfate After concentration, the residue was purified by silica gel flash chromatography (cyclohexane: ethyl acetate = 75: 25) to obtain 370 mg (85%) of the title compound as a pale yellow solid NMR spectrum (270 MHz) (Deuterated chloroform) δ ppm: 1.07-1.72 (62H, m), 2.15 (2H, t, J = 7.6 Hz), 2.25-2.45 (5
H, m), 3.82-4.25 (3H, m), 4.39,4.62 (2H, ABq, J = 11.2 H
z), 4.42 (2H, dd, J = 2.4,46.9 Hz), 4.67 (1H, dd, J = 9.3,1
9.1 Hz),, 5.04 (1H, d, J = 3.4 Hz), 5.04-5.15 (1H, m,),
5.41 (1H, dd, J = 9.3,10.7 Hz), 6.22 (1H, d, J = 8.8 Hz), 7.1
2-7.40 (15H, md). Infrared absorption spectrum ν max (Nujol) cm-1: 34
40, 1740, 1720, 1665, 1590.

(F) 2,6-dideoxy-4 O-diphenylsulfolyl-6-fluoro-2-[(R) -3'-hydroxytetradecanoylamino] -3-O-[(R) -3 370 mg of the compound obtained from "-tetradecanoyloxytetradecanoyl] -D-glucopyranose 3 (e) was added to 4 ml of tetrahydrofuran.
, And 0.37 g of 10% palladium carbon was added thereto.
Next, 24 ml of methanol and 2 drops of formic acid were added, and the mixture was stirred for 3 hours while heating to 35 ° C. in a hydrogen stream. The reaction solution was diluted with tetrahydrofuran, filtered through celite to remove palladium carbon, and the filtrate was dried under reduced pressure. The residue was purified by silica gel flash chromatography (cyclohexane: ethyl acetate = 65: 35) to give 220 mg of the title compound as a solid.
(65%) obtained. Infrared absorption spectrum ν max (Nujol) cm-1: 34
50-3200, 1740, 1642, 1595. Elemental analysis value (as C60H99N12FP)

(G) 2,6-dideoxy-6-fluoro-2-[(R)-
3'-hydroxytetradecanoylamino] -3-O-[(R)-
3 "-tetradecanoyloxytetradecanoyl] -D-
0.135 g of the compound obtained with glucopyranosyl-4-phosphate 3 (f) was dissolved in 8 ml of dry tetrahydrofuran, 27 mg of platinum oxide was added thereto, and the mixture was stirred at room temperature for 1 hour in a stream of hydrogen. The reaction solution was diluted with tetrahydrofuran to dissolve insolubles, and the platinum was removed by filtration. The filtrate was dried under reduced pressure to give 107 mg of the title compound as a solid.
(92%). NMR spectrum (270 MHz) (d5-pyridine) δ ppm: 0.80-0.98 (9H, m), 1.12-1.95 (62H, m), 2.47 (2H, t, J = 7.3
Hz), 2.77-2.92 (2H, m), 2.97-3.36 (2H, m), 3.62-3.70
(1H, m), 4.45-5.80 (7H, m),, 6.24 (1H, dd, J = 8.8,10.7 H
z), 8.88 (1H, d, J = 9.8 Hz). Infrared absorption spectrum ν max (Nujol) cm-1: 36
00-3200, 1730, 1640, 1380. Elemental analysis (as C48H91NO12FP)

[0099]

Example 4 (a) Allyl 2-[(S) -3'-benzyloxytetradecanoylamino] -2-deoxy-6-O-t-butyldimethylsilyl-3-O-[(R)- Allyl 2-[(S) -3'-benzyloxytetradecanoylamino]-obtained from 3 "-tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside 1 (g) 2-deoxy-3-O-[(R) -3 ″-
Tetradecanoyloxytetradecanoyl] -α-D-
Dissolve 0.5 g (0.51 mmol) of glucopyranoside in 10 ml of dry methylene chloride and add dimethylaminopyridine (DMAP)
0.16 g (1.29 mmol) and 0.12 g (0.78 mmol) of t-butyldimethylsilyl chloride were added, and the mixture was stirred at room temperature for 4 hours. Methyl chloride was distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate and aqueous sodium chloride, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography (cyclohexane: ethyl acetate = 9: 1),
0.56 (99%) of the title compound was obtained as a colorless oil. Infrared absorption spectrum ν max (liquid film) cm-1: 3600-3150,
1730, 1650. Elemental analysis value (as C64H115NO10Si)

(B) Allyl 2-[(S) -3'-benzyloxytetradecanoylamino] -2-deoxy-4-O-diphenylphosphoryl-6-O-t-butyldimethylsilyl-3-O-
[(R) -3 ″ -tetradecanoyloxytetradecanoyl]-
0.56 g (0.51 mmol) of the compound obtained from α-D-glucopyranoside 4 (a) and 0.19 g (1.54 mmol) of dimethylaminopyridine were dissolved in 12 ml of dry methylene chloride, and diphenylchlorophosphate was dissolved.
A solution of 0.41 g (1.53 mmol) in 4 ml of dry methylene chloride was slowly added and stirred at room temperature for 4 hours. The methylene chloride was evaporated under reduced pressure, the residue was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and aqueous sodium chloride, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography (cyclohexane: ethyl acetate = 9: 1) to obtain 0.63 g (93%) of the title compound as a colorless oil. Infrared absorption spectrum ν max (liquid film) cm-1: 3350, 173
5, 1670, 1590. Elemental analysis (as C76H124NO13PSi)

(C) Allyl 2-[(S) -3'-benzyloxytetradecanoylamino] -2-deoxy-4-O-diphenylphosphoryl-3-O-[(R) -3 ″ -tetradeca Noyloxytetradecanoyl] -α-D-glucopyranoside 0.56 g (0.42 mmol) of the compound obtained in 4 (b) was dissolved in 10 ml of tetrahydrofuran, and 2 ml of 3N acid salt was added thereto. The mixture was stirred at room temperature for 4 hours, the tetrahydrofuran was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, washed with aqueous sodium carbonate and sodium chloride, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel flash chromatography. Purification by chromatography (cyclohexane: ethyl acetate = 7: 3) gave 0.45 g (89%) of the title compound as a solid.
%) was gotten. Infrared absorption spectrum ν max (Nujol) cm-1: 34
50, 3320, 1730, 1650, 1585. Elemental analysis (as C70H110NO13p)

(D) Allyl 2-[(S) -3'-benzyloxytetradecanoylamino] -2,6-dideoxy-4-O-diphenylphosphoryl-6 fluoro-3O-[(R) -3 "-Tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside diethylaminosulfur trifluoride (DAST) 0.21
g (1.3 mmol) in 4 ml of dry methylene chloride, 4 (c)
A solution of 0.39 g (0.32 mmol) of the compound obtained in the above in 4 ml of dry methylene chloride was gradually added under cooling with water, and the mixture was stirred with water cooling for 3 hours, and further stirred at room temperature for 30 minutes. 40 ml of ice water
, The methylene chloride layer was separated, and the aqueous layer was extracted with methylene chloride. Then, it was washed with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography (cyclohexane: ethyl acetate = 8: 2) to obtain 0.36 g (91%) of the title compound as a solid. Infrared absorption spectrum ν max (liquid film) cm-1: 3350, 174
0, 1675, 1590. Elemental analysis value (as C70H109O12NPF)

(E) 2-[(s) -3'-benzyloxytetradecanoylamino] -2,6-dideoxy-4-O-diphenylphosphoryl-6-fluoro-3-O-[(R)- 3 "-tetradecanoyloxytetradecanoyl] -D-glucopyranose In a 2 ml solution of 100 mg (0.08 mmol) of the compound obtained in 4 (d) in dry tetrahydrofuran, bis (methyldiphenylphosphine) cyclooctadieneiridium ( I) 3.6 mg (0.004 mmol) of hexafluorophosphate was added, the iridium complex was activated with hydrogen, and the mixture was stirred in a nitrogen stream at room temperature for 3 hours.
g (0.17 mmol), 0.2 ml of water and 30 mg (0.33 mmol) of pyridine were added, and the mixture was stirred at room temperature for 30 minutes. Concentrate under reduced pressure,
The residue was dissolved in 20 ml of ethyl acetate, washed with 5% aqueous sodium thiosulfate, aqueous sodium hydrogen carbonate, and aqueous sodium chloride, and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel flash chromatography (cyclohexane: ethyl acetate = 75: 25) to obtain 90 mg (90%) of the title compound as a pale yellow solid. Infrared absorption spectrum ν max (Nujol) cm-1: 34
00, 1735, 1720, 1665, 1590. Elemental analysis (as C67H105NO12PF)

(F) 2,6-dideoxy-4-O-diphenylphosphoryl-6-fluoro-2-[(S) -3'-hydroxytetradecanoylamino] -3-O-[(R) -3 "-Tetradecanoyloxytetradecanoyl-D-glucopyranose 0.20 g of the compound obtained in 4 (e) was added to 2 ml of tetrahydrofuran.
And 0.2 g of 10% palladium on carbon was added thereto.
Next, 12 ml of methanol and one drop of formic acid were added, and the mixture was stirred for 5 hours while heating at 35 ° C. in a hydrogen stream. The reaction solution was diluted with tetrahydrofuran, filtered through celite to remove palladium carbon, and the filtrate was dried under reduced pressure. The residue was purified by silica gel flash chromatography (cyclohexane: ethyl acetate = 7: 3) to give 0.15 g (81%) of the title compound as a solid.
%) was gotten. Infrared absorption spectrum ν max (Nujol) cm-1: 3
600-3100, 1730, 1660, 1590. Elemental analysis value (as C60H99NO12PF)

(G) 2-deoxy-6-fluoro-2-[(S) -3'-
[Hydroxytetradecanoylamino] -4-O-phosphono-
3-O-[(R) -3 ″ -tetradecanoyloxytetradecanoyl] -D-glucopyranose 72 mg of the compound obtained in 4 (f) was dried in tetrahydrofuran.
The mixture was dissolved in 4 ml, 15 mg of platinum oxide was added thereto, and the mixture was stirred in a hydrogen stream at room temperature for 30 minutes. The reaction was diluted with tetrahydrofuran and heated to 45 ° C. to dissolve the agar.
Then, the platinum was removed by filtration, and the filtrate was dried under reduced pressure to obtain 62 mg (quantitative) of the title compound as a solid. NMR spectrum (270 MHz) (d5-pyridine) δ ppm: 0.80-0.97 (9H, m), 1.10-1.90 (62H, m), 2.45 (2H, t, J = 7.3
Hz), 2.84 (2H, d, J = 5.9 Hz), 3.11 (1H, dd, J = 6.4,16.3 H
z), 3.27 (1H, dd, J = 6.4,16.3 Hz), 3.62-3.70 (1H, m),,
4.38-5.50 (7H, m), 6.25 (1H, dd, J = 9.3,10.9 Hz) .Infrared absorption spectrum ν max (nujol) cm-1:
3600-3200, 1730, 1700, 1650. Elemental analysis value (as C48H91NO12FP)

[0106]

Example 5 Triethylamine Salt of Phosphoric Acid Compound When it is necessary to obtain a water-soluble triethylamine salt of a phosphoric acid compound obtained in 1 (m), 2 (c), 3 (g) and 4 (g), Perform the above operations. Suspend 30 mg of the phosphoric acid compound in 8 ml of 0.1 N hydrochloric acid, then add 30 ml of chloroform-methanol (1: 2).
And ultrasonic waves were applied for dissolution. When 10 ml of chloroform and 10 ml of 0.1 N hydrochloric acid were added to this solution, the solution was separated into two layers, and the chloroform layer was separated. Chloroform was removed under reduced pressure and dissolved in 0.1% triethylamine water, and this aqueous solution was used as a sample for activity measurement.

────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Tetsuo Hiraoka 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Tomoo Kobayashi 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Minoru Akamatsu 1-26-21 Shimizu, Suginami-ku, Tokyo (72) Inventor Masahiro Nishijima 1-4-29, Miyamaidaira, Miyamae-ku, Kawasaki-shi, Kanagawa Prefecture A-101 (56) References JP 62-108895 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07H 13/06 A61K 31/70 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula [Wherein, R1 represents a hydroxyl group or a protected hydroxyl group, and R4 represents a fluorine atom. R2 and R3 are the same or different and each may be an optionally substituted aliphatic acyl group having 6 to 20 carbon atoms (the substituent is
Shows a group selected from the group. ). And a salt thereof. [Group A] A halogen atom, an aryl group, an aralkyl group, a hydroxyl group and an aliphatic acyloxy group having 6 to 20 carbon atoms. 2. The method according to claim 1, wherein R2 and R3 are the same,
An optionally substituted aliphatic acyl group having 6 to 20 carbon atoms (the substituent is a group selected from Group A below)
And a salt thereof. [Group A] A halogen atom, an aryl group, an aralkyl group, a hydroxyl group and an aliphatic acyloxy group having 6 to 20 carbon atoms.