JP2000297096A - Ether type lipid a-1-carboxylic acid analog - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having excellent suppressing actions on the macrophage activity and useful as an antiinflammatory agent, an anti- autoimmune disease agent or an antiseptic agent. SOLUTION: This compound is represented by formula I [R1 and R3 are each a (substituted)1-20C alkanoyl, a (substituted)3-20C alkenoyl or the like; R2 and R4 are each a (substituted)1-20C alkyl, a (substituted)2-20C alkenyl or the like; R5 is H, a halogen, OH or the like], e.g. 2,6-anhydro -7-O - 2 -acetamido-2-deoxy-3 -O -[(R)-3 -dodecyloxytetradecyl]-4 -O-phosphono -β-D- glucopyranosyl)}-3 -[(R)-3 -hydroxytetradecanamido]-4 -O-[(R) -3- hydroxytetradecyl]-3 -deoxy -D-glycero -D-ido -heptonic acid. For example, the compound represented by formula I can be produced by a method, etc., using, e.g. a compound represented by formula II (R6 and R7 are each H, a 1-6C alkyl or the like) and a compound represented by formula III as starting raw materials.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel lipid A analog having an excellent macrophage activity inhibitory activity and useful as an anti-inflammatory agent, an anti-autoimmune disease agent or an anti-sepsis agent.

[0002]

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. Also, immunoadjuvant activating action, macrophage activating action, mitogen activating action, pyrogenic action, tumor necrosis action, antibody production enhancing action, TN
Shows various biological activities such as F-inducing action.

[0003] Such endotoxins are composed of lipopolysaccharide, and it has been confirmed that the so-called lipid A is the active center of endotoxin activity (Imoto et al., Tetrahedron.
Letters, 26 , 1545 (1985)).

As precursors of lipid A biosynthesis, lipids X and Y, which are monosaccharides, are obtained from E. coli.
E. coli mutants, which have been shown to exhibit the same activity as lipid A.

[0005] From these results, attempts have been frequently made to synthesize derivatives of lipid A, X or Y having useful activities among the above various activities. For example, JP-A-10-324694 discloses The derivatives described are known.

[0006]

Problems to be solved by the present invention are as follows.
Has excellent macrophage activity inhibitory action,
It is to find a novel lipid A derivative useful as an anti-autoimmune disease drug or an anti-sepsis drug.

[0007]

Means for Solving the Problems The inventors of the present invention have made intensive efforts to solve the above-mentioned problems, and as a result, it has been found that a compound having an ether-type lipid A1-position carboxylic acid analogue has excellent macrophage activity inhibition. The present inventors have found an effect and completed the present invention.

The compound of the present invention has the following general formula: 1)

[0009]

Embedded image(Where R¹And R^ThreeAre the same or different and have the following (substitution
Substituted with one or more groups selected from group A)
Good C₁-C₂₀Alkanoyl group, the following (substituent group A)
C optionally substituted with one or more groups selected from
_Three-C₂₀Selected from an alkenoyl group or the following (substituent group A)
C optionally substituted with one or more selected groups _Three-C
₂₀R represents an alkinoyl group;^TwoAnd R^FourAre the same or different
Means one or more groups selected from the following (substituent group A)
C optionally substituted with₁-C₂₀Alkyl group, below
Substituted with one or more groups selected from (Substituent group A)
May be C_Two-C₂₀Alkenyl group, the following (substituent group
May be substituted with one or more groups selected from A)
C_Two-C₂₀An alkynyl group;^FiveIs a hydrogen atom,
C which may have a halogen atom, a hydroxyl group or an oxo group₁
-C₆C which may have an alkoxy group or an oxo group_Two−
C₆It may have an alkenyloxy group or an oxo group
C_Two-C₆An alkynyloxy group; (Substituent group A)
Has a halogen atom, a hydroxyl group, an oxo group, and an oxo group
May be C₁-C₂₀Has an alkoxy group and an oxo group
May be C_Two-C₂₀Alkenyloxy group, oxo group
C which may have_Two-C₂₀Alkynyloxy group,
C which may have a xo group₁-C₂₀Alkanoyl oki
C which may have a thio group or an oxo group_Three-C₂₀Arceno
C which may have an yloxy group and an oxo group_Three-C
₂₀A group consisting of alkinoyloxy groups. )
Or a pharmacologically acceptable salt or ester thereof.
is there.

Among the compounds of the present invention, preferred are 2) R¹Has a substituent selected from (Substituent group A)
C_Four-C₁₈A compound which is an alkanoyl group, 3) R¹Has a substituent selected from (Substituent group A)
C₈-C₁₆A compound which is an alkanoyl group, 4) R¹Is unsubstituted or selected from (Substituent group A)
C having a hydroxyl group as a substituent₁₂-C₁₄Alkanoyl group
5) R¹Is unsubstituted or selected from (Substituent group A)
Lauroyl group or myristo having hydroxyl group as a substituent
A compound which is an yl group, 6) R^TwoHas a substituent selected from (Substituent group A)
C_Four-C₁₈A compound which is an alkyl group, 7) R^TwoHas a substituent selected from (Substituent group A)
C₈-C₁₆A compound which is an alkyl group, 8) R^TwoIs unsubstituted or selected from (Substituent group A)
C having a hydroxyl group as a substituent₁₂-C₁₄An alkyl group
9) R^TwoIs unsubstituted or selected from (Substituent group A)
Dodecyl or tetradecyl group having a hydroxyl group as a substituent
10) R^ThreeIs an unsubstituted C₁-C₁₆Is an alkanoyl group
Compound, 11) R^ThreeIs an unsubstituted C₁-C₈Is an alkanoyl group
Compound, 12) R^ThreeIs an unsubstituted C₁-C_FourIs an alkanoyl group
Compound, 13) R^ThreeIs an acetyl group or a propionyl group
Compound, 14) R^ThreeIs an acetyl group, 15) R^FourIs a substituent selected from (Substituent group A)
C that you may have_Four-C₁₈A compound which is an alkyl group, 16) R^FourIs a substituent selected from (Substituent group A)
C that you may have₈-C₁₆A compound which is an alkyl group, 17) R^FourIs a fluorine atom selected from (Substituent group A)
, Hydroxyl group, unsubstituted C_{1 Two}-C₁₄Alkoxy or blank
Substitute C₁₂-C₁₄Alkanoyloxy group as a substituent
C₁₂-C₁₄A compound which is an alkyl group, 18) R^FourIs a dodecyl selected from (Substituent group A)
Having an oxy group or a tetradecyloxy group as a substituent
A compound which is a dodecyl group or a tetradecyl group;^FourIs a lauroyl selected from (Substituent group A)
Oxy group or myristoyloxy group as a substituent
A compound which is a dodecyl group or a tetradecyl group,^FiveIs a halogen atom, a hydroxyl group or an unsubstituted C₁−
C₆A compound which is an alkoxy group, or 21) R^FiveIs a fluorine atom, a hydroxyl group or a methoxy group
Compound. Of these, more preferred compounds are 2,6-anhydride
B-7-O- [2-acetamido-2-deoxy-6-O
-Methyl-4-O-phosphono-3-O-{(R) -3-
Tetradecanoyloxytetradecyl｝ -β-D-glu
Copyranosyl] -3-{(R) -3-hydroxytetra
Decanamide {-4-O-} (R) -3-hydroxytet
Radecyl} -3-deoxy-D-glycero-D-id-
Heptonic acid, 2,6-anhydro-7-O- [2-A
Cetamide-2-deoxy-4-O-phosphono-3-O-
{(R) -3-tetradecanoyloxytetradecyl}
-Β-D-glucopyranosyl] -3-{(R) -3-hi
Droxytetradecanamid {-4-O-} (R) -3-
Hydroxytetradecyl｝ -3-deoxy-D-glyce
R-D-id-heptonic acid, 2,6-anhydro-7
-O- [2-acetamide-2,6-dideoxy-6-fu
Fluoro-4-O-phosphono-3-O-{(R) -3-te
Tradecanoyloxytetradecyl｝ -β-D-gluco
Pyranosyl] -3-{(R) -3-hydroxytetrade
Canamide {-4-O-} (R) -3-hydroxytetra
Decyl} -3-deoxy-D-glycero-D-ido-f
Putnoic acid, 2,6-anhydro-7-O- [2-acetate
Tamide-2-deoxy-3-O-{(R) -3-dodeci
Ruoxytetradecyl {-6-O-methyl-4-O-e
Suphono-β-D-glucopyranosyl] -3-{(R)-
3-hydroxytetradecanamide {-4-O-} (R)
-3-Hydroxytetradecyl} -3-deoxy-D-
Glycero-D-id-heptonic acid, 2,6-anhydride
B-7-O- [2-acetamide-2-deoxy-3-O
-{(R) -3-dodecyloxytetradecyl} -4-
O-phosphono-β-D-glucopyranosyl] -3-
{(R) -3-hydroxytetradecanamide} -4-O
-{(R) -3-hydroxytetradecyl} -3-deo
Xy-D-glycero-D-ido-heptonic acid, or
2,6-anhydro-7-O- [2-acetamide-2,
6-dideoxy-3-O-{(R) -3-dodecyloxy
Citetradecyl} -6-fluoro-4-O-phosphono-
β-D-glucopyranosyl] -3-{(R) -3-hydride
Roxytetradecanamide {-4-O-} (R) -3-h
Droxytetradecyl｝ -3-deoxy-D-glycero
-D-id-heptonic acid.

The present invention also relates to a medicament containing the above compound (I) as an active ingredient, particularly a prophylactic or therapeutic agent for inflammation, a prophylactic or therapeutic agent for an autoimmune disease, or a prophylactic agent for sepsis. Or a therapeutic agent.

In the above formula (I), R¹And R^Three"Under
(Substituent group A)
C that may be₁-C₂₀Alkanoyl group ”₁-C
₂₀Alkanoyl group "and (substituent group A)
"C optionally having an oxo group₁-C₂₀Alkanoyl
"C" of "oxy group"₁-C₂₀As the "alkanoyl" part
Is, for example, formyl, acetyl, propionyl, iso
Propionyl, butyryl, isobutyryl, sec-butylyl
Tert-butyryl, valeryl, isovaleryl, pivalo
Yl, hexanoyl, isohexanoyl, heptanoy
, Isoheptanoyl, octanoyl, isooctanoy
, Nonanoyl, isononanoyl, decanoyl, isode
Canoyl, undecanoyl, isoundoundanoyl, lau
Royl, isolauroyl, tridecanoyl, isotride
Canoyl, myristoyl, pentadecanoyl, palmito
Il, heptadecanoyl, stearoyl, isostearo
Straight chain or yl, nonadecanoyl or icosanoyl groups
Is a branched C₁-C₂₀An alkanoyl group;¹Passing
And (Substituent group A)_Four-C₁₈A
Lucanoyl group, more preferably C₈-C₁₆Arca
A noyl group, more preferably C₁₂-C_{1 Four}Alkano
And particularly preferably a lauroyl group or myris.
A toyl group, R^ThreeIn, preferably, C₁-C₁₆
An alkanoyl group, more preferably C ₁-C₈Arca
A noyl group, more preferably C₁-C_FourArcanoy
And particularly preferably an acetyl group or a propioni group.
And most preferably an acetyl group.

In the above formula (I), “C ₃ -C ₂₀ alkenoyl group which may be substituted with one or more groups selected from the following (substituent group A)” for R ¹ and R ³ . _3- C
₂₀ alkenoyl group ", and, as the" C ₃ -C ₂₀ alkenoyl "moiety of the" optionally having an oxo group C ₃ -C ₂₀ alkenoyloxy group "in (Substituent group A), cited above Examples of the C ₁ -C ₂₀ alkanoyl groups include groups having 3 to 20 carbon atoms and having 1 to 3 double bonds. In R ¹ and (Substituent group A), Preferably, it is a C ₄ -C ₁₈ alkenoyl group,
More preferably, a C ₁₂ -C ₁₄ alkenoyl group (particularly, 9
-Tetradecenoyl group), and R ³ is preferably a C ₃ -C ₁₆ alkenoyl group, and more preferably a C ₃ -C ₄ alkenoyl group (particularly, a 3-butenoyl group).

In the above formula (I), the R ¹ and R ³ of the “C ₃ -C ₂₀ alkinoyl group optionally substituted by one or more groups selected from the following (substituent group A)”: _3- C
₂₀ alkynoyl group ", and, as the" C ₃ -C ₂₀ alkynoyl "moiety of the" optionally having an oxo group C ₃ -C ₂₀ alkyl alkanoyloxy group "in the (Substituent group A), cited above Examples of the C ₁ -C ₂₀ alkanoyl groups include groups having 3 to 20 carbon atoms and having 1 to 3 triple bonds. In R ¹ and (Substituent group A), preferred are Has a C ₄ -C ₁₈ alkinoyl group,
More preferably, a C ₁₂ -C ₁₄ alkinoyl group (particularly, 9
-Tetradecinoyl group), and R ³ is preferably a C ₃ -C ₁₆ alkinoyl group, and more preferably a C ₃ -C ₄ alkinoyl group (particularly, a 3-butinoyl group).

In the above formula (I), “C ₁ -C ₂₀ alkyl group which may be substituted with one or more groups selected from the following (substituent group A)” in R ² and R ⁴ the ₁ -C ₂₀ alkyl group ", for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s- butyl,
tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl,
Isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3
-Dimethylbutyl, 2,2-dimethylbutyl, 1,1-
Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-
Methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propyl Pentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl,
1-propylhexyl, 2-ethylheptyl, 6,6-
Dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl,
3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, dodecyl,
Tridecyl, tetradecyl, pentadecyl, 3,7,1
1-trimethyldodecyl, hexadecyl, 4,8,12
-Trimethyltridecyl, 1-methylpentadecyl, 1
Such as a 4-methylpentadecyl, 13,13-dimethyltetradecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, icosyl or 3,7,11,15-tetramethylhexadecyl group Examples thereof include a linear or branched alkyl group having 1 to 20 carbon atoms, preferably a C ₄ -C ₁₈ alkyl group, more preferably a C ₈ -C ₁₆ alkyl group,
More preferably, a C ₁₂ -C ₁₄ alkyl group, particularly preferably a dodecyl group or tetradecyl group.

In the above formula (I), the R ² and R ⁴ of “C ₂ -C ₂₀ alkenyl group optionally substituted by one or more groups selected from the following (substituent group A)”: ₂ -C ₂₀
The “alkenyl group” is a C ₁ -C ₂₀ alkyl group having 2 to 20 carbon atoms, and
Groups having from 3 to 3 double bonds, and preferably,
A C ₄ -C ₁₈ alkenyl group, more preferably a C ₁₂ -C ₁₈ alkenyl group.
—C ₁₄ alkenyl group (particularly, 9-tetradecenyl group).

In the above formula (I), the R ² and R ⁴ of the “C ₂ -C ₂₀ alkynyl group optionally substituted by one or more groups selected from the following (substituent group A)”: ₂ -C ₂₀
The “alkynyl group” is a C ₁ -C ₂₀ alkyl group having 2 to 20 carbon atoms, and
A group having from 3 to 3 triple bonds;
A C ₄ -C ₁₈ alkynyl group, more preferably a C ₁₂ -C ₁₈ alkynyl group;
—C ₁₄ alkynyl group (particularly, 9-tetradecynyl group).

In the above formula (I), R ⁵ and (Substituent group A)
As the "halogen atom" in, for example, fluorine,
Examples thereof include a chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom, and more preferably a fluorine atom.

In the above formula (I), the “C ₁ -C ₆ alkoxy group optionally having an oxo group” for R ⁵ , which is represented by “C _1-
Examples of the "C ₆ alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutyloxy, neopentyloxy, 1- Ethyl propyloxy, hexyloxy, isohexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutyloxy, 2,2-dimethylbutyloxy , 1,1
A straight or branched chain having 1 to 6 carbon atoms, such as -dimethylbutyloxy, 1,2-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2,3-dimethylbutyloxy or 2-ethylbutyloxy; Examples thereof include a chain alkoxy group, preferably a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms, and more preferably a methoxy group.

In the above formula (I), the “C ₂ -C ₆ alkenyloxy group” of the “C ₂ -C ₆ alkenyloxy group optionally having an oxo group” for R ⁵ is as described above. Among the C ₁ -C ₆ alkoxy groups, groups having 2 to 6 carbon atoms and having 1 to 3 double bonds can be mentioned. Preferably, a C ₂ -C ₄ alkenyloxy group ( In particular, 3
-Butenyloxy group).

In the above formula (I), the “C ₂ -C ₆ alkynyloxy group” of the “C ₂ -C ₆ alkynyloxy group optionally having an oxo group” for R ⁵ is as described above. Among the C ₁ -C ₆ alkoxy groups, mention may be made of those having 2 to 6 carbon atoms and having 1 to 3 triple bonds, preferably C ₂ -C ₄ alkynyloxy groups (especially , 3
-Butynyloxy group).

In the above formula (I), the “C ₁ -C ₂₀ alkoxy group optionally having an oxo group” in (Substituent group A) includes the above-mentioned “C ₁ -C ₂₀ alkyl group”. "
And a group in which an oxygen atom is bonded, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutyloxy, neomethyl Pentyloxy, 1-ethylpropyloxy, hexyloxy, isohexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3
-Dimethylbutyloxy, 2,2-dimethylbutyloxy, 1,1-dimethylbutyloxy, 1,2-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2,3
-Dimethylbutyloxy, 2-ethylbutyloxy, heptyloxy, 4-methylhexyloxy, 1-propylbutyloxy, 4,4-dimethylpentyloxy, octyloxy, 6-methylheptyloxy, 5,5-dimethylhexyloxy , Nonyloxy, decyloxy,
1-methylnonyloxy, 3-methylnonyloxy, 8
-Methylnonyloxy, 3-ethyloctyloxy,
3,7-dimethyloctyloxy, 7,7-dimethyloctyloxy, undecyloxy, 4,8-dimethylnonyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, 3,7,11-
Trimethyldodecyloxy, hexadecyloxy, 4,
8,12-trimethyltridecyloxy, 1-methylpentadecyloxy, 14-methylpentadecyloxy,
13,13-dimethyltetradecyloxy, heptadecyloxy, octadecyloxy, 1-methylheptadecyloxy, nonadecyloxy, icosyloxy or 3,
A straight-chain or branched-chain alkoxy group having 1 to 20 carbon atoms, such as a 7,11,15-tetramethylhexadecyloxy group, is preferred, and is preferably a C ₄ -C ₁₈ alkoxy group, more preferably Is a C ₈ -C ₁₆ alkoxy group, more preferably a C ₁₂ -C ₁₄ alkoxy group, and particularly preferably a dodecyloxy group or a tetradecyloxy group.

In the above formula (I), the “C ₂ -C ₂₀ alkenyloxy group optionally having an oxo group” in (Substituent group A) includes the above-mentioned “C ₁ -C ₂₀ alkoxy” A group having 2 to 20 carbon atoms,
Groups having from 3 to 3 double bonds, and preferably,
A C ₄ -C ₁₈ alkenyloxy group, more preferably, C ₁₂ -C ₁₄ alkenyloxy group (especially, 9-tetradecenyl oxy group).

In the above formula (I), the “C ₂ -C ₂₀ alkynyloxy group optionally having an oxo group” in (Substituent group A) includes the above-mentioned “C ₁ -C ₂₀ alkoxy” A group having 2 to 20 carbon atoms,
A group having from 3 to 3 triple bonds;
A C ₄ -C ₁₈ alkynyloxy group, more preferably a C ₁₂ -C ₁₄ alkynyloxy group (particularly, a 9-tetradecynyloxy group).

In the above formula (I), the substitution position of (Substituent group A) is preferably the 3-position.

In the above formula (I), preferred R ¹ is C ₄ -C ₁₈ which may have a substituent selected from (Substituent group A).
Alkanoyl group, more preferably (substituent group A)
A C ₈ -C ₁₆ alkanoyl group which may have a substituent selected from the group consisting of: unsubstituted or C ₁₂ -C having a hydroxyl group selected from (Substituent Group A) as a substituent;
A C ₁₄ alkanoyl group, particularly preferably an unsubstituted or lauroyl group or a myristoyl group having a hydroxyl group selected from (Substituent group A) as a substituent.

In the above formula (I), preferred R ² is C ₄ -C ₁₈ which may have a substituent selected from (Substituent group A).
An alkyl group, more preferably a C ₈ -C ₁₆ alkyl group which may have a substituent selected from (Substituent Group A), more preferably an unsubstituted or (Substituent Group A) A C ₁₂ -C ₁₄ alkyl group having a hydroxyl group selected from A) as a substituent, particularly preferably a non-substituted or a dodecyl group or a tetradecyl group having a hydroxyl group selected from (Substituent group A) as a substituent Group.

In the above formula (I), preferred R ³ is an unsubstituted C ₁ -C ₁₆ alkanoyl group, more preferably an unsubstituted C ₁ -C ₈ alkanoyl group, and further preferably Is
An unsubstituted C ₁ -C ₄ alkanoyl group, particularly preferably an acetyl group or a propionyl group, most preferably
Acetyl group.

In the above formula (I), preferred R^FourIs the (substituent
C optionally having substituents selected from group A)_Four-C₁₈
Alkyl group, more preferably from (substituent group A)
C optionally having selected substituents₈-C₁₆Alkyl group
And more preferably selected from (Substituent group A)
Fluorine atom, hydroxyl group, unsubstituted C₁₂-C₁₄Alkoxy group
Or unsubstituted C₁₂-C₁₄Substituting an alkanoyloxy group
C having as₁₂-C ₁₄An alkyl group, particularly preferably
Is a dodecyloxy group selected from (Substituent group A),
Tetradecyloxy group, lauroyloxy group or myris
Dodecyl or teryl having a toyloxy group as a substituent
It is a trdecyl group.

In the above formula (I), R ⁵ is preferably a halogen atom, a hydroxyl group or an unsubstituted C ₁ -C ₆ alkoxy group, and more preferably a fluorine atom, a hydroxyl group or a methoxy group.

The compound of formula (I) may be in the form of a salt, preferably such an alkali metal or alkaline earth salt as a sodium, potassium, magnesium or calcium salt. Salts of similar metals; salts of organic bases such as triethylamine salt and trimethylamine salt.

When the compound (I) of the present invention is left in the air, it may absorb water and may absorb adsorbed water or form hydrates. Included in the invention.

Further, the compound (I) of the present invention may absorb some other solvent to form a solvate, and such salts are also included in the present invention.

The compound of the above formula (I) can form an ester, and examples of the substituent forming the ester include those having the following formulas (a) to (f). , "Protective groups that can be cleaved in vivo by biological methods such as hydrolysis" and hydrogenolysis, hydrolysis,
"Protecting group in reaction" which can be cleaved by a chemical method such as electrolysis or photolysis is shown. ^{(A) -CHR a R b (} b) -CHR c R d (c) - (CHR e) n -OCOR f (d) - (CHR e) n -OR g (e) -SiR g R h R I (F) —CH ₂ —Ph—COOR ^{I In the} above formula, n represents 1 to 2, Ph represents a phenyl group, and ^Ra represents a hydrogen atom, a lower alkyl group, or an aryl-substituted lower alkyl group. , A halogeno lower alkyl group,
A lower alkenyl group, a lower alkynyl group, an aliphatic acyl group, or an aryl-substituted aliphatic acyl group;
It is preferably a hydrogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group or a lower alkynyl group, more preferably a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, and a halogeno carbon atom of 1 From 3 to 3 alkyl groups,
A lower alkenyl group having 2 to 3 carbon atoms, 2 to 3 carbon atoms
Lower alkynyl groups.

R ^b represents a hydrogen atom or a lower alkyl group, preferably a hydrogen atom.

R ^c represents an aryl group or a substituted aryl group (the substituent may be a lower alkyl group, a lower alkoxy group, a halogen atom or a nitro group), preferably a lower group. It is an alkoxylated aryl group, a halogenated aryl group or a nitrated aryl group, and more preferably a lower alkoxylated phenyl group, a halogenated phenyl group or a nitrated phenyl group.

R ^d represents a hydrogen atom or a group defined by R ^c .

[0038] R ^e is a hydrogen atom or a lower alkyl group, preferably having 1 to hydrogen atom or a carbon which is 3 alkyl groups.

R ^f represents a lower alkyl group, a lower alkoxy group or a group defined by R ^c , and is preferably a lower alkyl group or a lower alkoxy group, and more preferably a group having 1 to 3 carbon atoms. It is an alkyl group or an alkoxy group having 1 to 3 carbon atoms.

R ^e and R ^f together represent a phthalidyl group or a mono- or di-substituted phthalidyl group (the substituent may be a lower alkyl group or a lower alkoxy group). You may.

R ^g and R ^h are the same or different and each represents a lower alkyl group or a group defined by R ^c , preferably a lower alkyl group, and more preferably a ^C 1-3 alkyl group. It is an alkyl group.

R ⁱ represents a lower alkyl group, preferably an alkyl group having 1 to 3 carbon atoms.

The above-mentioned "protecting group which can be cleaved in vivo by a biological method such as hydrolysis" and "protecting group in the reaction" include the following groups.

That is, the "protecting group which can be cleaved in vivo by a biological method such as hydrolysis" is preferably methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, tert- -Butoxymethyl, phenoxymethyl, acetoxymethyl, pivaloyloxymethyl, cyclopentanoyloxymethyl, 1-cyclohexanoyloxybutyl, benzoyloxymethyl, methoxycarbonyloxymethyl, 2-propoxycarbonyloxyethyl, As the “protecting group”, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-
Butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl,
3,3-dimethylbutyl, 2,3-dimethylbutyl, 2
-Ethylbutyl; ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-1
-Propenyl, 2-ethyl-2-propenyl, 1-butenyl, 3-methyl-2-butenyl, 3-butenyl, 1-
Methyl-3-butenyl, 2-pentenyl, 1-methyl-
3-pentenyl, 2-hexenyl; ethynyl, 2-propynyl, 2-methyl-2-propynyl, 2-butynyl,
1-methyl-2-butynyl, 1-ethyl-2-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl; acetylmethyl; benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl,
β-naphthylmethyl, diphenylmethyl, triphenylmethyl, 6-phenylhexyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethyl Benzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl,
-Nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl,
-Methoxycarbonylbenzyl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-
Butyldimethylsilyl, methyldiisopropylsilyl,
Methyl di-tert-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, and phenyldiisopropylsilyl groups.

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

Examples of the compounds of the present invention include those listed in Table 1, but the present invention is not limited to these compounds.

In Table 1, abbreviations indicate the following groups or symbols.

Ac represents an acetyl group, Bu represents a butyl group, Byr represents a butyryl group, Dc represents a decyl group, and Dco represents
Indicates a decanoyl group, Ddc indicates a dodecyl group, Ei indicates an icosyl group, Eicn indicates an icosanoyl group, Fo indicates a formyl group, Hx indicates a hexyl group, Hdc indicates a hexadecyl group, and Hxn indicates a hexadecyl group. He represents a hexanoyl group, Lau represents a lauroyl group (dodecanoyl group), Me represents a methyl group, and Myr represents a myristoyl group (tetradecanoyl group)
Oc represents an octyl group, Odc represents an octadecyl group, Octo represents an octanoyl group, = O represents an oxo group (a carbonyl group together with carbon), and Pal represents a palmitoyl group (hexadecanoyl group). Prn represents a propionyl group, Ste represents a stearoyl group (octadecanoyl group), Tedc represents a tetradecyl group, and Va represents
l represents a valeryl group.

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[Table 1] ---------------------------------------------- ---------------------- Compound No R ¹ R ² R ³ R ⁴ R ⁵ ---------------- -------------------------------------------------- -1 3-OH-Lau 3-OH-Ddc Fo 3-OMyr-Tedc OMe 2 3-OH-Lau 3-OH-Ddc Ac 3-OMyr-Tedc OMe 3 3-OH-Lau 3-OH-Ddc Prn 3-OMyr-Tedc OMe 4 3-OH-Lau 3-OH-Ddc Byr 3-OMyr-Tedc OMe 53-OH-Lau 3-OH-Ddc Hxn 3-OMyr-Tedc OMe 63-OH-Lau 3- OH-Ddc Octo 3-OMyr-Tedc OMe 7 Myr Tedc Fo 3-OMyr-Tedc OMe 8 Myr Tedc Ac 3-OMyr-Tedc OMe 9 Myr Tedc Prn 3-OMyr-Tedc OMe 10 Myr Tedc Byr 3-OMyr-Tedc OMe 11 Myr Tedc Hxn 3-OMyr-Tedc OMe 12 3-OH-Myr 3-OH-Tedc Fo 3-OMyr-Tedc OMe 13 3-OH-Myr 3-OH-Tedc Ac 3-OMyr-Tedc OMe 14 3-OH -Myr 3-OH-Tedc Prn 3-OMyr-Tedc OMe 15 3-OH-Myr 3-OH-Tedc Byr 3-OMyr-Tedc OMe 16 3-OH-Myr 3-OH-Tedc Val 3-OMyr-Tedc OMe 17 3-OH-Myr 3-OH-Tedc Hxn 3-OMyr-Tedc OMe 18 3-OH-Myr 3-OH-Tedc Octo 3-OMyr-Tedc OMe 19 3-OH-Myr 3-OH-Tedc Dco 3- OMyr-Tedc OMe 20 3-OH-Myr 3-OH-Tedc Lau 3-OMyr-Tedc OMe 21 3-OH-Myr 3-OH-Tedc Myr 3-OMy r-Tedc OMe 22 3-OH-Myr 3-OH-Tedc Pal 3-OMyr-Tedc OMe 23 3-OH-Myr 3-OH-Tedc Ste 3-OMyr-Tedc OMe 24 3-OH-Myr 3-OH- Tedc Eicn 3-OMyr-Tedc OMe 25 3-OH-Myr 3-OH-Tedc 3-OAc-Byr 3-OByr-Bu OMe 26 3-OH-Myr 3-OH-Tedc 3-OByr-Hxn 3-OHxn- Hx OMe 27 3-OH-Myr 3-OH-Tedc 3-OHxn-Octo 3-OOcto-Oc OMe 28 3-OH-Myr 3-OH-Tedc 3-OOcto-Dco 3-ODco-Dc OMe 29 3-OH -Myr 3-OH-Tedc 3-ODco-Lau 3-OLau-Ddc OMe 30 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OMyr-Tedc OMe 31 3-OH-Myr 3-OH- Tedc 3-OH-Myr 3-OMyr-Tedc OMe 32 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OH-Tedc OMe 33 3-OH-Myr 3-OH-Tedc 3-OH-Myr 3-OH-Tedc OMe 34 3-OH-Myr 3-OH-Tedc 3-(= O) -Myr 3-OH-Tedc OMe 35 3-OH-Myr 3-OH-Tedc 3-OH-Myr 3- ( = O) -Tedc OMe 36 3-OH-Myr 3-OH-Tedc 2-F-3-OLau-Myr 2-F-3-OMyr-Tedc OMe 37 3-OH-Myr 3-OH-Tedc 2-F -3-OH-Dco 3-OMyr-Tedc OMe 38 3-OH-Myr 3-OH-Tedc 2-Cl-3-OLau-Myr 2-Cl-3-OMyr-Tedc OMe 39 3-OH-Myr 3- OH-Tedc 3-OLau-Myr 3-OMyr-Ddc OMe 40 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OMyr-Ddc OMe 41 3-OH-Myr 3-OH-Tedc 3-OLau -Lau 3-OMyr-Tedc OMe 42 3-OH-Myr 3-OH-Tedc 3-OMyr-P al 3-OPal-Hdc OMe 43 3-OH-Myr 3-OH-Tedc 3-OPal-Ste 3-OSte-Odc OMe 44 3-OH-Myr 3-OH-Tedc 3-OSte-Eicn 3-OEicn-Ei OMe 45 3-OH-Lau 3-OH-Ddc Fo 3-OMyr-Tedc OH 46 3-OH-Lau 3-OH-Ddc Ac 3-OMyr-Tedc OH 47 3-OH-Lau 3-OH-Ddc Prn 3 -OMyr-Tedc OH 48 3-OH-Lau 3-OH-Ddc Byr 3-OMyr-Tedc OH 49 3-OH-Lau 3-OH-Ddc Hxn 3-OMyr-Tedc OH 50 3-OH-Lau 3-OH -Ddc Octo 3-OMyr-Tedc OH 51 Myr Tedc Fo 3-OMyr-Tedc OH 52 Myr Tedc Ac 3-OMyr-Tedc OH 53 Myr Tedc Prn 3-OMyr-Tedc OH 54 Myr Tedc Byr 3-OMyr-Tedc OH 55 Myr Tedc Hxn 3-OMyr-Tedc OH 56 3-OH-Myr 3-OH-Tedc Fo 3-OMyr-Tedc OH 57 3-OH-Myr 3-OH-Tedc Ac 3-OMyr-Tedc OH 58 3-OH- Myr 3-OH-Tedc Prn 3-OMyr-Tedc OH 59 3-OH-Myr 3-OH-Tedc Byr 3-OMyr-Tedc OH 60 3-OH-Myr 3-OH-Tedc Val 3-OMyr-Tedc OH 61 3-OH-Myr 3-OH-Tedc Hxn 3-OMyr-Tedc OH 62 3-OH-Myr 3-OH-Tedc Octo 3-OMyr-Tedc OH 63 3-OH-Myr 3-OH-Tedc Dco 3-OMyr -Tedc OH 64 3-OH-Myr 3-OH-Tedc Lau 3-OMyr-Tedc OH 65 3-OH-Myr 3-OH-Tedc Myr 3-OMyr-Tedc OH 66 3-OH-Myr 3-OH-Tedc Pal 3-OMyr-Tedc OH 67 3-OH-Myr 3-OH-Tedc Ste 3-OMyr-Tedc OH 68 3-OH-Myr 3-OH-Tedc Eicn 3-OMyr-Tedc OH 69 3-OH-Myr 3-OH-Tedc 3-OAc-Byr 3-OByr-Bu OH 70 3-OH-Myr 3-OH-Tedc 3-OByr-Hxn 3-OHxn-Hx OH 71 3-OH-Myr 3-OH-Tedc 3-OHxn-Octo 3-OOcto-Oc OH 72 3-OH-Myr 3-OH-Tedc 3-OOcto-Dco 3 -ODco-Dc OH 73 3-OH-Myr 3-OH-Tedc 3-ODco-Lau 3-OLau-Ddc OH 74 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OMyr-Tedc OH 75 3-OH-Myr 3-OH-Tedc 3-OH-Myr 3-OMyr-Tedc OH 76 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OH-Tedc OH 77 3-OH-Myr 3 -OH-Tedc 3-OH-Myr 3-OH-Tedc OH 78 3-OH-Myr 3-OH-Tedc 3-(= O) -Myr 3-OH-Tedc OH 79 3-OH-Myr 3-OH- Tedc 3-OH-Myr 3-(= O) -Tedc OH 80 3-OH-Myr 3-OH-Tedc 2-F-3-OLau-Myr 2-F-3-OMyr-Tedc OH 81 3-OH- Myr 3-OH-Tedc 2-F-3-OH-Dco 3-OMyr-Tedc OH 82 3-OH-Myr 3-OH-Tedc 2-Cl-3-OLau-Myr 2-Cl-3-OMyr-Tedc OH 83 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OMyr-Ddc OH 84 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OMyr-Ddc OH 85 3-OH- Myr 3-OH-Tedc 3-OLau-Lau 3-OMyr-Tedc OH 86 3-OH-Myr 3-OH-Tedc 3-OMyr-Pal 3-OPal-Hdc OH 87 3-OH-Myr 3-OH-Tedc 3-OPal-Ste 3-OSte-Odc OH 88 3-OH-Myr 3-OH-Tedc 3-OSte-Eicn 3-OEicn-Ei OH 89 3-OH-Myr 3-OH-Tedc Fo 3-OH-Ddc OMe 90 3-OH-Myr 3-OH-Tedc Ac 3-OH-Ddc OMe 91 3-OH-Myr 3-OH-Tedc Prn 3-OH -Ddc OMe 92 3-OH-Myr 3-OH-Tedc Bry 3-OH-Ddc OMe 93 3-OH-Myr 3-OH-Tedc Val 3-OH-Ddc OMe 94 3-OH-Myr 3-OH-Tedc Hxn 3-OH-Ddc OMe 95 3-OH-Myr 3-OH-Tedc Octo 3-OH-Tedc OMe 96 3-OH-Myr 3-OH-Tedc Fo 3-OH-Tedc OMe 97 3-OH-Myr 3 -OH-Tedc Ac 3-OH-Tedc OMe 98 3-OH-Myr 3-OH-Tedc Prn 3-OH-Tedc OMe 99 3-OH-Myr 3-OH-Tedc Bry 3-OH-Tedc OMe 100 3- OH-Myr 3-OH-Tedc Val 3-OH-Tedc OMe 101 3-OH-Myr 3-OH-Tedc Hxn 3-OH-Tedc OMe 102 3-OH-Myr 3-OH-Tedc Fo 3-OLau-Tedc OMe 103 3-OH-Myr 3-OH-Tedc Ac 3-OLau-Tedc OMe 104 3-OH-Myr 3-OH-Tedc Prn 3-OLau-Tedc OMe 105 3-OH-Myr 3-OH-Tedc Bry 3 -OLau-Tedc OMe 106 3-OH-Myr 3-OH-Tedc Val 3-OLau-Tedc OMe 107 3-OH-Myr 3-OH-Tedc Hxn 3-OLau-Tedc OMe 108 3-OH-Myr 3-OH -Tedc Fo 3-OMyr-Ddc OMe 109 3-OH-Myr 3-OH-Tedc Ac 3-OMyr-Ddc OMe 110 3-OH-Myr 3-OH-Tedc Prn 3-OMyr-Ddc OMe 111 3-OH- Myr 3-OH-Tedc Bry 3-OMyr-Ddc OMe 112 3-OH-Myr 3-OH-Tedc Val 3-OMyr-Ddc OMe 113 3-OH-Myr 3-OH-Tedc Hxn 3-OMyr-Ddc OMe 114 3-OH-Myr 3-OH-Tedc Fo 3-OH-Ddc OH 115 3-OH-Myr 3-OH-Tedc Ac 3-OH-Ddc OH 116 3-OH-Myr 3- OH-Tedc Prn 3-OH-Ddc OH 117 3-OH-Myr 3-OH-Tedc Bry 3-OH-Ddc OH 118 3-OH-Myr 3-OH-Tedc Val 3-OH-Ddc OH 119 3-OH -Myr 3-OH-Tedc Hxn 3-OH-Ddc OH 120 3-OH-Myr 3-OH-Tedc Fo 3-OH-Tedc OH 121 3-OH-Myr 3-OH-Tedc Ac 3-OH-Tedc OH 122 3-OH-Myr 3-OH-Tedc Prn 3-OH-Tedc OH 123 3-OH-Myr 3-OH-Tedc Bry 3-OH-Tedc OH 124 3-OH-Myr 3-OH-Tedc Val 3- OH-Tedc OH 125 3-OH-Myr 3-OH-Tedc Hxn 3-OH-Tedc OH 126 3-OH-Myr 3-OH-Tedc Fo 3-OLau-Tedc OH 127 3-OH-Myr 3-OH- Tedc Ac 3-OLau-Tedc OH 128 3-OH-Myr 3-OH-Tedc Prn 3-OLau-Tedc OH 129 3-OH-Myr 3-OH-Tedc Bry 3-OLau-Tedc OH 130 3-OH-Myr 3-OH-Tedc Val 3-OLau-Tedc OH 131 3-OH-Myr 3-OH-Tedc Hxn 3-OLau-Tedc OH 132 3-OH-Myr 3-OH-Tedc Fo 3-OMyr-Ddc OH 133 3 -OH-Myr 3-OH-Tedc Ac 3-OMyr-Ddc OH 134 3-OH-Myr 3-OH-Tedc Prn 3-OMyr-Ddc OH 135 3-OH-Myr 3-OH-Tedc Bry 3-OMyr- Ddc OH 136 3-OH-Myr 3-OH-Tedc Val 3-OMyr-Ddc OH 137 3-OH-Myr 3-OH-Tedc Hxn 3-OMyr-Ddc OH 138 3-OH-Lau 3-OH-Dd c Fo 3-OMyr-Tedc F 139 3-OH-Lau 3-OH-Ddc Ac 3-OMyr-Tedc F 140 3-OH-Lau 3-OH-Ddc Prn 3-OMyr-Tedc F 141 3-OH-Lau 3-OH-Ddc Byr 3-OMyr-Tedc F 142 3-OH-Lau 3-OH-Ddc Hxn 3-OMyr-Tedc F 143 3-OH-Lau 3-OH-Ddc Octo 3-OMyr-Tedc F 144 Myr Tedc Fo 3-OMyr-Tedc F 145 Myr Tedc Ac 3-OMyr-Tedc F 146 Myr Tedc Prn 3-OMyr-Tedc F 147 Myr Tedc Byr 3-OMyr-Tedc F 148 Myr Tedc Hxn 3-OMyr-Tedc F 149 3 -OH-Myr 3-OH-Tedc Fo 3-OMyr-Tedc F 150 3-OH-Myr 3-OH-Tedc Ac 3-OMyr-Tedc F 151 3-OH-Myr 3-OH-Tedc Prn 3-OMyr- Tedc F 152 3-OH-Myr 3-OH-Tedc Byr 3-OMyr-Tedc F 153 3-OH-Myr 3-OH-Tedc Val 3-OMyr-Tedc F 154 3-OH-Myr 3-OH-Tedc Hxn 3-OMyr-Tedc F 155 3-OH-Myr 3-OH-Tedc Octo 3-OMyr-Tedc F 156 3-OH-Myr 3-OH-Tedc Dco 3-OMyr-Tedc F 157 3-OH-Myr 3- OH-Tedc Lau 3-OMyr-Tedc F 158 3-OH-Myr 3-OH-Tedc Myr 3-OMyr-Tedc F 159 3-OH-Myr 3-OH-Tedc Pal 3-OMyr-Tedc F 160 3-OH -Myr 3-OH-Tedc Ste 3-OMyr-Tedc F 161 3-OH-Myr 3-OH-Tedc Eicn 3-OMyr-Tedc F 162 3-OH-Myr 3-OH-Tedc 3-OAc-Byr 3- OByr-Bu F 163 3-OH-Myr 3-OH-Tedc 3-OByr-Hxn 3-OHxn-Hx F 164 3-OH-Myr 3-OH-Tedc 3-OHxn-Octo 3-OOcto-Oc F 165 3-OH-Myr 3-OH-Tedc 3-OOcto-Dco 3-ODco-Dc F 166 3-OH-Myr 3 -OH-Tedc 3-ODco-Lau 3-OLau-Ddc F 167 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OMyr-Tedc F 168 3-OH-Myr 3-OH-Tedc 3- OH-Myr 3-OMyr-Tedc F 169 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OH-Tedc F 170 3-OH-Myr 3-OH-Tedc 3-OH-Myr 3-OH -Tedc F 171 3-OH-Myr 3-OH-Tedc 3-(= O) -Myr 3-OH-Tedc F 172 3-OH-Myr 3-OH-Tedc 3-OH-Myr 3-(= O) -Tedc F 173 3-OH-Myr 3-OH-Tedc 2-F-3-OLau-Myr 2-F-3-OMyr-Tedc F 174 3-OH-Myr 3-OH-Tedc 2-F-3- OH-Dco 3-OMyr-Tedc F 175 3-OH-Myr 3-OH-Tedc 2-Cl-3-OLau-Myr 2-Cl-3-OMyr-Tedc F 176 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OMyr-Ddc F 177 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OMyr-Ddc F 178 3-OH-Myr 3-OH-Tedc 3-OLau-Lau 3 -OMyr-Tedc F 179 3-OH-Myr 3-OH-Tedc 3-OMyr-Pal 3-OPal-Hdc F 180 3-OH-Myr 3-OH-Tedc 3-OPal-Ste 3-OSte-Odc F 181 3-OH-Myr 3-OH-Tedc 3-OSte-Eicn 3-OEicn-Ei F 182 3-OH-Lau 3-OH-Ddc Fo 3-OMyr-Tedc H 183 3-OH-Lau 3-OH-Ddc Ac 3-OMyr-Tedc H 184 3-OH-Lau 3-OH-Ddc Prn 3-OMyr-Tedc H 185 3-OH-Lau 3-OH-Dd c Byr 3-OMyr-Tedc H 186 3-OH-Lau 3-OH-Ddc Hxn 3-OMyr-Tedc H 187 3-OH-Lau 3-OH-Ddc Octo 3-OMyr-Tedc H 188 Myr Tedc Fo 3- OMyr-Tedc H 189 Myr Tedc Ac 3-OMyr-Tedc H 190 Myr Tedc Prn 3-OMyr-Tedc H 191 Myr Tedc Byr 3-OMyr-Tedc H 192 Myr Tedc Hxn 3-OMyr-Tedc H 193 3-OH-Myr 3-OH-Tedc Fo 3-OMyr-Tedc H 194 3-OH-Myr 3-OH-Tedc Ac 3-OMyr-Tedc H 195 3-OH-Myr 3-OH-Tedc Prn 3-OMyr-Tedc H 196 3 -OH-Myr 3-OH-Tedc Byr 3-OMyr-Tedc H 197 3-OH-Myr 3-OH-Tedc Val 3-OMyr-Tedc H 198 3-OH-Myr 3-OH-Tedc Hxn 3-OMyr- Tedc H 199 3-OH-Myr 3-OH-Tedc Octo 3-OMyr-Tedc H 200 3-OH-Myr 3-OH-Tedc Dco 3-OMyr-Tedc H 201 3-OH-Myr 3-OH-Tedc Lau 3-OMyr-Tedc H 202 3-OH-Myr 3-OH-Tedc Myr 3-OMyr-Tedc H 203 3-OH-Myr 3-OH-Tedc Pal 3-OMyr-Tedc H 204 3-OH-Myr 3- OH-Tedc Ste 3-OMyr-Tedc H 205 3-OH-Myr 3-OH-Tedc Eicn 3-OMyr-Tedc H 206 3-OH-Myr 3-OH-Tedc 3-OAc-Byr 3-OByr-Bu H 207 3-OH-Myr 3-OH-Tedc 3-OByr-Hxn 3-OHxn-Hx H 208 3-OH-Myr 3-OH-Tedc 3-OHxn-Octo 3-OOcto-Oc H 209 3-OH-Myr 3-OH-Tedc 3-OOcto-Dco 3-ODco-Dc H 210 3-OH-Myr 3-OH-Tedc 3-OD co-Lau 3-OLau-Ddc H 211 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OMyr-Tedc H 212 3-OH-Myr 3-OH-Tedc 3-OH-Myr 3-OMyr -Tedc H 213 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OH-Tedc H 214 3-OH-Myr 3-OH-Tedc 3-OH-Myr 3-OH-Tedc H 215 3- OH-Myr 3-OH-Tedc 3-(= O) -Myr 3-OH-Tedc H 216 3-OH-Myr 3-OH-Tedc 3-OH-Myr 3-(= O) -Tedc H 217 3- OH-Myr 3-OH-Tedc 2-F-3-OLau-Myr 2-F-3-OMyr-Tedc H 218 3-OH-Myr 3-OH-Tedc 2-F-3-OH-Dco 3-OMyr -Tedc H 219 3-OH-Myr 3-OH-Tedc 2-Cl-3-OLau-Myr 2-Cl-3-OMyr-Tedc H 220 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3 -OMyr-Ddc H 221 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OMyr-Ddc H 222 3-OH-Myr 3-OH-Tedc 3-OLau-Lau 3-OMyr-Tedc H 223 3-OH-Myr 3-OH-Tedc 3-OMyr-Pal 3-OPal-Hdc H 224 3-OH-Myr 3-OH-Tedc 3-OPal-Ste 3-OSte-Odc H 225 3-OH-Myr 3 -OH-Tedc 3-OSte-Eicn 3-OEicn-Ei H 226 3-OH-Myr 3-OH-Tedc Fo 3-OH-Ddc H 227 3-OH-Myr 3-OH-Tedc Ac 3-OH-Ddc H 228 3-OH-Myr 3-OH-Tedc Prn 3-OH-Ddc H 229 3-OH-Myr 3-OH-Tedc Bry 3-OH-Ddc H 230 3-OH-Myr 3-OH-Tedc Val 3 -OH-Ddc H 231 3-OH-Myr 3-OH-Tedc Hxn 3-OH-Ddc H 232 3-OH-Myr 3-OH-Tedc Octo 3- OH-Tedc H 233 3-OH-Myr 3-OH-Tedc Fo 3-OH-Tedc H 234 3-OH-Myr 3-OH-Tedc Ac 3-OH-Tedc H 235 3-OH-Myr 3-OH- Tedc Prn 3-OH-Tedc H 236 3-OH-Myr 3-OH-Tedc Bry 3-OH-Tedc H 237 3-OH-Myr 3-OH-Tedc Val 3-OH-Tedc H 238 3-OH-Myr 3-OH-Tedc Hxn 3-OH-Tedc H 239 3-OH-Myr 3-OH-Tedc Fo 3-OLau-Tedc H 240 3-OH-Myr 3-OH-Tedc Ac 3-OLau-Tedc H 241 3 -OH-Myr 3-OH-Tedc Prn 3-OLau-Tedc H 242 3-OH-Myr 3-OH-Tedc Bry 3-OLau-Tedc H 243 3-OH-Myr 3-OH-Tedc Val 3-OLau- Tedc H 244 3-OH-Myr 3-OH-Tedc Hxn 3-OLau-Tedc H 245 3-OH-Myr 3-OH-Tedc Fo 3-OMyr-Ddc H 246 3-OH-Myr 3-OH-Tedc Ac 3-OMyr-Ddc H 247 3-OH-Myr 3-OH-Tedc Prn 3-OMyr-Ddc H 248 3-OH-Myr 3-OH-Tedc Bry 3-OMyr-Ddc H 249 3-OH-Myr 3- OH-Tedc Val 3-OMyr-Ddc H 250 3-OH-Myr 3-OH-Tedc Hxn 3-OMyr-Ddc H 251 3-OH-Myr 3-OH-Tedc Fo 3-OH-Ddc H 252 3-OH -Myr 3-OH-Tedc Ac 3-OH-Ddc H 253 3-OH-Myr 3-OH-Tedc Prn 3-OH-Ddc H 254 3-OH-Myr 3-OH-Tedc Bry 3-OH-Ddc H 255 3-OH-Myr 3-OH-Tedc Val 3-OH-Ddc H 256 3-OH-Myr 3-OH-Tedc Hxn 3-OH-Ddc H 257 3-OH-Myr 3-OH-Tedc Fo 3- OH-Tedc H258 3-OH-Myr 3-OH-Tedc Ac 3-OH-Tedc H259 3-OH-Myr 3-OH-Tedc Prn 3-OH-Tedc H260 3-OH-Myr 3-OH-Tedc Bry 3-OH-Tedc H261 3 -OH-Myr 3-OH-Tedc Val 3-OH-Tedc H 262 3-OH-Myr 3-OH-Tedc Hxn 3-OH-Tedc H 263 3-OH-Myr 3-OH-Tedc Fo 3-OLau- Ddc H 264 3-OH-Myr 3-OH-Tedc Ac 3-OLau-Ddc H 265 3-OH-Myr 3-OH-Tedc Prn 3-OLau-Ddc H 266 3-OH-Myr 3-OH-Tedc Bry 3-OLau-Ddc H 267 3-OH-Myr 3-OH-Tedc Val 3-OLau-Ddc H 268 3-OH-Myr 3-OH-Tedc Hxn 3-OLau-Ddc H 269 3-OH-Myr 3- OH-Tedc Fo 3-OMyr-Hdc H 270 3-OH-Myr 3-OH-Tedc Ac 3-OMyr-Hdc H 271 3-OH-Myr 3-OH-Tedc Prn 3-OMyr-Hdc H 272 3-OH -Myr 3-OH-Tedc Bry 3-OMyr-Hdc H 273 3-OH-Myr 3-OH-Tedc Val 3-OMyr-Hdc H 274 3-OH-Myr 3-OH-Tedc Hxn 3-OMyr-Hdc H 275 3-OH-Lau 3-OH-Ddc Fo 3-ODdc-Tedc OMe 276 3-OH-Lau 3-OH-Ddc Ac 3-ODdc-Tedc OMe 277 3-OH-Lau 3-OH-Ddc Prn 3- ODdc-Tedc OMe 278 3-OH-Lau 3-OH-Ddc Byr 3-ODdc-Tedc OMe 279 3-OH-Lau 3-OH-Ddc Hxn 3-ODdc-Tedc OMe 280 3-OH-Lau 3-OH- Ddc Octo 3-ODdc-Tedc OMe 281 Myr Tedc Fo 3-ODdc-Tedc OMe 282 Myr Tedc Ac 3-ODdc-Tedc OMe 283 Myr Tedc Prn 3-ODdc-Ted c OMe 284 Myr Tedc Byr 3-ODdc-Tedc OMe 285 Myr Tedc Hxn 3-ODdc-Tedc OMe 286 3-OH-Myr 3-OH-Tedc Fo 3-ODdc-Tedc OMe 287 3-OH-Myr 3-OH- Tedc Ac 3-ODdc-Tedc OMe 288 3-OH-Myr 3-OH-Tedc Prn 3-ODdc-Tedc OMe 289 3-OH-Myr 3-OH-Tedc Byr 3-ODdc-Tedc OMe 290 3-OH-Myr 3-OH-Tedc Val 3-ODdc-Tedc OMe 291 3-OH-Myr 3-OH-Tedc Hxn 3-ODdc-Tedc OMe 292 3-OH-Myr 3-OH-Tedc Octo 3-ODdc-Tedc OMe 293 3 -OH-Myr 3-OH-Tedc Dco 3-ODdc-Tedc OMe 294 3-OH-Myr 3-OH-Tedc Lau 3-ODdc-Tedc OMe 295 3-OH-Myr 3-OH-Tedc Myr 3-ODdc- Tedc OMe 296 3-OH-Myr 3-OH-Tedc Pal 3-ODdc-Tedc OMe 297 3-OH-Myr 3-OH-Tedc Ste 3-ODdc-Tedc OMe 298 3-OH-Myr 3-OH-Tedc Eicn 3-ODdc-Tedc OMe 299 3-OH-Myr 3-OH-Tedc 3-OAc-Byr 3-OBu-Bu OMe 300 3-OH-Myr 3-OH-Tedc 3-OByr-Hxn 3-OHx-Hx OMe 301 3-OH-Myr 3-OH-Tedc 3-OHxn-Octo 3-OOc-Oc OMe 302 3-OH-Myr 3-OH-Tedc 3-OOcto-Dco 3-ODc-Dc OMe 303 3-OH-Myr 3-OH-Tedc 3-ODco-Lau 3-ODdc-Ddc OMe 304 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-ODdc-Tedc OMe 305 3-OH-Myr 3-OH-Tedc 3 -OH-Myr 3-ODdc-Tedc OMe 306 3-OH-Myr 3-OH-Tedc 2-F-3-OLau -Myr 2-F-3-ODdc-Tedc OMe 307 3-OH-Myr 3-OH-Tedc 2-F-3-OH-Dco 3-ODdc-Tedc OMe 308 3-OH-Myr 3-OH-Tedc 2 -Cl-3-OLau-Myr 2-Cl-3-ODdc-Tedc OMe 309 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OTedc-Ddc OMe 310 3-OH-Myr 3-OH- Tedc 3-OLau-Myr 3-OTedc-Ddc OMe 311 3-OH-Myr 3-OH-Tedc 3-OLau-Lau 3-ODdc-Tedc OMe 312 3-OH-Myr 3-OH-Tedc 3-OMyr-Pal 3-OHdc-Hdc OMe 313 3-OH-Myr 3-OH-Tedc 3-OPal-Ste 3-OOdc-Odc OMe 314 3-OH-Myr 3-OH-Tedc 3-OSte-Eicn 3-OEi-Ei OMe 315 3-OH-Lau 3-OH-Ddc Fo 3-ODdc-Tedc OH 316 3-OH-Lau 3-OH-Ddc Ac 3-ODdc-Tedc OH 317 3-OH-Lau 3-OH-Ddc Prn 3- ODdc-Tedc OH 318 3-OH-Lau 3-OH-Ddc Byr 3-ODdc-Tedc OH 319 3-OH-Lau 3-OH-Ddc Hxn 3-ODdc-Tedc OH 320 3-OH-Lau 3-OH- Ddc Octo 3-ODdc-Tedc OH 321 Myr Tedc Fo 3-ODdc-Tedc OH 322 Myr Tedc Ac 3-ODdc-Tedc OH 323 Myr Tedc Prn 3-ODdc-Tedc OH 324 Myr Tedc Byr 3-ODdc-Tedc OH 325 Myr Tedc Hxn 3-ODdc-Tedc OH 326 3-OH-Myr 3-OH-Tedc Fo 3-ODdc-Tedc OH 327 3-OH-Myr 3-OH-Tedc Ac 3-ODdc-Tedc OH 328 3-OH-Myr 3-OH-Tedc Prn 3-ODdc-Tedc OH 329 3-OH-Myr 3-OH-Tedc Byr 3-ODdc-Tedc O H 330 3-OH-Myr 3-OH-Tedc Val 3-ODdc-Tedc OH 331 3-OH-Myr 3-OH-Tedc Hxn 3-ODdc-Tedc OH 332 3-OH-Myr 3-OH-Tedc Octo 3 -ODdc-Tedc OH 333 3-OH-Myr 3-OH-Tedc Dco 3-ODdc-Tedc OH 334 3-OH-Myr 3-OH-Tedc Lau 3-ODdc-Tedc OH 335 3-OH-Myr 3-OH -Tedc Myr 3-ODdc-Tedc OH 336 3-OH-Myr 3-OH-Tedc Pal 3-ODdc-Tedc OH 337 3-OH-Myr 3-OH-Tedc Ste 3-ODdc-Tedc OH 338 3-OH- Myr 3-OH-Tedc Eicn 3-ODdc-Tedc OH 339 3-OH-Myr 3-OH-Tedc 3-OAc-Byr 3-OBu-Bu OH 340 3-OH-Myr 3-OH-Tedc 3-OByr- Hxn 3-OHx-Hx OH 341 3-OH-Myr 3-OH-Tedc 3-OHxn-Octo 3-OOc-Oc OH 342 3-OH-Myr 3-OH-Tedc 3-OOcto-Dco 3-ODc-Dc OH 343 3-OH-Myr 3-OH-Tedc 3-ODco-Lau 3-ODdc-Ddc OH 344 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-ODdc-Tedc OH 345 3-OH- Myr 3-OH-Tedc 3-OH-Myr 3-ODdc-Tedc OH 346 3-OH-Myr 3-OH-Tedc 2-F-3-OLau-Myr 2-F-3-ODdc-Tedc OH 347 3- OH-Myr 3-OH-Tedc 2-F-3-OH-Dco 3-ODdc-Tedc OH 348 3-OH-Myr 3-OH-Tedc 2-Cl-3-OLau-Myr 2-Cl-3-ODdc -Tedc OH 349 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OTedc-Ddc OH 350 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OTedc-Ddc OH 351 3- OH-Myr 3-OH-Tedc 3 -OLau-Lau 3-ODdc-Tedc OH 352 3-OH-Myr 3-OH-Tedc 3-OMyr-Pal 3-OHdc-Hdc OH 353 3-OH-Myr 3-OH-Tedc 3-OPal-Ste 3- OOdc-Odc OH 354 3-OH-Myr 3-OH-Tedc 3-OSte-Eicn 3-OEi-Ei OH 355 3-OH-Myr 3-OH-Tedc Fo 3-OTdc-Tedc OMe 356 3-OH-Myr 3-OH-Tedc Ac 3-OTdc-Tedc OMe 357 3-OH-Myr 3-OH-Tedc Prn 3-OTdc-Tedc OMe 358 3-OH-Myr 3-OH-Tedc Bry 3-OTdc-Tedc OMe 359 3 -OH-Myr 3-OH-Tedc Val 3-OTdc-Tedc OMe 360 3-OH-Myr 3-OH-Tedc Hxn 3-OTdc-Tedc OMe 361 3-OH-Myr 3-OH-Tedc Fo 3-OTedc- Ddc OMe 362 3-OH-Myr 3-OH-Tedc Ac 3-OTedc-Ddc OMe 363 3-OH-Myr 3-OH-Tedc Prn 3-OTedc-Ddc OMe 364 3-OH-Myr 3-OH-Tedc Bry 3-OTedc-Ddc OMe 365 3-OH-Myr 3-OH-Tedc Val 3-OTedc-Ddc OMe 366 3-OH-Myr 3-OH-Tedc Hxn 3-OTedc-Ddc OMe 367 3-OH-Myr 3- OH-Tedc Fo 3-OTdc-Tedc OH 368 3-OH-Myr 3-OH-Tedc Ac 3-OTdc-Tedc OH 369 3-OH-Myr 3-OH-Tedc Prn 3-OTdc-Tedc OH 370 3-OH -Myr 3-OH-Tedc Bry 3-OTdc-Tedc OH 371 3-OH-Myr 3-OH-Tedc Val 3-OTdc-Tedc OH 372 3-OH-Myr 3-OH-Tedc Hxn 3-OTdc-Tedc OH 373 3-OH-Myr 3-OH-Tedc Fo 3-OTedc-Ddc OH 374 3-OH-Myr 3-OH-Tedc Ac 3-O Tedc-Ddc OH 375 3-OH-Myr 3-OH-Tedc Prn 3-OTedc-Ddc OH 376 3-OH-Myr 3-OH-Tedc Bry 3-OTedc-Ddc OH 377 3-OH-Myr 3-OH- Tedc Val 3-OTedc-Ddc OH 378 3-OH-Myr 3-OH-Tedc Hxn 3-OTedc-Ddc OH 379 3-OH-Lau 3-OH-Ddc Fo 3-OTedc-Tedc F 380 3-OH-Lau 3-OH-Ddc Ac 3-OTedc-Tedc F 381 3-OH-Lau 3-OH-Ddc Prn 3-OTedc-Tedc F 382 3-OH-Lau 3-OH-Ddc Byr 3-OTedc-Tedc F 383 3 -OH-Lau 3-OH-Ddc Hxn 3-OTedc-Tedc F 384 3-OH-Lau 3-OH-Ddc Octo 3-OTedc-Tedc F 385 Myr Tedc Fo 3-OTedc-Tedc F 386 Myr Tedc Ac 3- OTedc-Tedc F 387 Myr Tedc Prn 3-OTedc-Tedc F 388 Myr Tedc Byr 3-OTedc-Tedc F 389 Myr Tedc Hxn 3-OTedc-Tedc F 390 3-OH-Myr 3-OH-Tedc Fo 3-ODdc- Tedc F 391 3-OH-Myr 3-OH-Tedc Ac 3-ODdc-Tedc F 392 3-OH-Myr 3-OH-Tedc Prn 3-ODdc-Tedc F 393 3-OH-Myr 3-OH-Tedc Byr 3-ODdc-Tedc F 394 3-OH-Myr 3-OH-Tedc Val 3-ODdc-Tedc F 395 3-OH-Myr 3-OH-Tedc Hxn 3-ODdc-Tedc F 396 3-OH-Myr 3- OH-Tedc Octo 3-ODdc-Tedc F 397 3-OH-Myr 3-OH-Tedc Dco 3-ODdc-Tedc F 398 3-OH-Myr 3-OH-Tedc Lau 3-ODdc-Tedc F 399 3-OH -Myr 3-OH-Tedc Myr 3-ODdc-Tedc F 400 3-OH -Myr 3-OH-Tedc Pal 3-ODdc-Tedc F 401 3-OH-Myr 3-OH-Tedc Ste 3-ODdc-Tedc F 402 3-OH-Myr 3-OH-Tedc Eicn 3-ODdc-Tedc F 403 3-OH-Myr 3-OH-Tedc 3-OAc-Byr 3-OBu-Bu F 404 3-OH-Myr 3-OH-Tedc 3-OByr-Hxn 3-OHx-Hx F 405 3-OH-Myr 3-OH-Tedc 3-OHxn-Octo 3-OOc-Oc F 406 3-OH-Myr 3-OH-Tedc 3-OOcto-Dco 3-ODc-Dc F 407 3-OH-Myr 3-OH-Tedc 3 -ODco-Lau 3-ODdc-Ddc F 408 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-ODdc-Tedc F 409 3-OH-Myr 3-OH-Tedc 3-OH-Myr 3- ODdc-Tedc F 410 3-OH-Myr 3-OH-Tedc 2-F-3-OLau-Myr 2-F-3-ODdc-Tedc F 411 3-OH-Myr 3-OH-Tedc 2-F-3 -OH-Dco 3-ODdc-Tedc F 412 3-OH-Myr 3-OH-Tedc 2-Cl-3-OLau-Myr 2-Cl-3-ODdc-Tedc F 413 3-OH-Myr 3-OH- Tedc 3-OLau-Myr 3-OTedc-Ddc F 414 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OTedc-Ddc F 415 3-OH-Myr 3-OH-Tedc 3-OLau-Lau 3-ODdc-Tedc F 416 3-OH-Myr 3-OH-Tedc 3-OMyr-Pal 3-OHdc-Hdc F 417 3-OH-Myr 3-OH-Tedc 3-OPal-Ste 3-OOdc-Odc F 418 3-OH-Myr 3-OH-Tedc 3-OSte-Eicn 3-OEi-Ei F 419 3-OH-Lau 3-OH-Ddc Fo 3-ODdc-Tedc H 420 3-OH-Lau 3-OH- Ddc Ac 3-ODdc-Tedc H 421 3-OH-Lau 3-OH-Ddc Prn 3-ODdc-Ted c H 422 3-OH-Lau 3-OH-Ddc Byr 3-ODdc-Tedc H 423 3-OH-Lau 3-OH-Ddc Hxn 3-ODdc-Tedc H 424 3-OH-Lau 3-OH-Ddc Octo 3-ODdc-Tedc H 425 Myr Tedc Fo 3-ODdc-Tedc H 426 Myr Tedc Ac 3-ODdc-Tedc H 427 Myr Tedc Prn 3-ODdc-Tedc H 428 Myr Tedc Byr 3-ODdc-Tedc H 429 Myr Tedc Hxn 3-ODdc-Tedc H430 3-OH-Myr 3-OH-Tedc Fo 3-ODdc-Tedc H431 3-OH-Myr 3-OH-Tedc Ac 3-ODdc-Tedc H432 3-OH-Myr 3- OH-Tedc Prn 3-ODdc-Tedc H 433 3-OH-Myr 3-OH-Tedc Byr 3-ODdc-Tedc H 434 3-OH-Myr 3-OH-Tedc Val 3-ODdc-Tedc H 435 3-OH -Myr 3-OH-Tedc Hxn 3-ODdc-Tedc H 436 3-OH-Myr 3-OH-Tedc Octo 3-ODdc-Tedc H 437 3-OH-Myr 3-OH-Tedc Dco 3-ODdc-Tedc H 438 3-OH-Myr 3-OH-Tedc Lau 3-ODdc-Tedc H 439 3-OH-Myr 3-OH-Tedc Myr 3-ODdc-Tedc H 440 3-OH-Myr 3-OH-Tedc Pal 3- ODdc-Tedc H 441 3-OH-Myr 3-OH-Tedc Ste 3-ODdc-Tedc H 442 3-OH-Myr 3-OH-Tedc Eicn 3-ODdc-Tedc H 443 3-OH-Myr 3-OH- Tedc 3-OAc-Byr 3-OBu-Bu H 444 3-OH-Myr 3-OH-Tedc 3-OByr-Hxn 3-OHx-Hx H 445 3-OH-Myr 3-OH-Tedc 3-OHxn-Octo 3-OOc-Oc H 446 3-OH-Myr 3-OH-Tedc 3-OOcto-Dco 3-ODc-Dc H 447 3-OH -Myr 3-OH-Tedc 3-ODco-Lau 3-ODdc-Ddc H 448 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-ODdc-Tedc H 449 3-OH-Myr 3-OH- Tedc 3-OH-Myr 3-ODdc-Tedc H 450 3-OH-Myr 3-OH-Tedc 2-F-3-OLau-Myr 2-F-3-ODdc-Tedc H 451 3-OH-Myr 3- OH-Tedc 2-F-3-OH-Dco 3-ODdc-Tedc H 452 3-OH-Myr 3-OH-Tedc 2-Cl-3-OLau-Myr 2-Cl-3-ODdc-Tedc H 453 3 -OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OTedc-Ddc H 454 3-OH-Myr 3-OH-Tedc 3-OLau-Myr 3-OTedc-Ddc H 455 3-OH-Myr 3- OH-Tedc 3-OLau-Lau 3-OTedc-Ddc H 456 3-OH-Myr 3-OH-Tedc 3-OMyr-Pal 3-OHdc-Hdc H 457 3-OH-Myr 3-OH-Tedc 3-OPal -Ste 3-OOdc-Odc H 458 3-OH-Myr 3-OH-Tedc 3-OSte-Eicn 3-OEi-Ei H 459 3-OH-Myr 3-OH-Tedc Fo 3-OTedc-Tedc H 460 3 -OH-Myr 3-OH-Tedc Ac 3-OTedc-Tedc H 461 3-OH-Myr 3-OH-Tedc Prn 3-OTedc-Tedc H 462 3-OH-Myr 3-OH-Tedc Bry 3-OTedc- Tedc H 463 3-OH-Myr 3-OH-Tedc Val 3-OTedc-Tedc H 464 3-OH-Myr 3-OH-Tedc Hxn 3-OTedc-Tedc H 465 3-OH-Myr 3-OH-Tedc Fo 3-OTedc-Ddc H 466 3-OH-Myr 3-OH-Tedc Ac 3-OTedc-Ddc H 467 3-OH-Myr 3-OH-Tedc Prn 3-OTedc-Ddc H 468 3-OH-Myr 3- OH-Tedc Bry 3-OTedc-Ddc H 469 3-O H-Myr 3-OH-Tedc Val 3-OTedc-Ddc H 470 3-OH-Myr 3-OH-Tedc Hxn 3-OTedc-Ddc H 471 3-OH-Myr 3-OH-Tedc Fo 3-ODdc-Ddc H 472 3-OH-Myr 3-OH-Tedc Ac 3-ODdc-Ddc H 473 3-OH-Myr 3-OH-Tedc Prn 3-ODdc-Ddc H 474 3-OH-Myr 3-OH-Tedc Bry 3 -ODdc-Ddc H 475 3-OH-Myr 3-OH-Tedc Val 3-ODdc-Ddc H 476 3-OH-Myr 3-OH-Tedc Hxn 3-ODdc-Ddc H 477 3-OH-Myr 3-OH -Tedc Fo 3-OTedc-Hdc H 478 3-OH-Myr 3-OH-Tedc Ac 3-OTedc-Hdc H 479 3-OH-Myr 3-OH-Tedc Prn 3-OTedc-Hdc H 480 3-OH- Myr 3-OH-Tedc Bry 3-OTedc-Hdc H 481 3-OH-Myr 3-OH-Tedc Val 3-OTedc-Hdc H 482 3-OH-Myr 3-OH-Tedc Hxn 3-OTedc-Hdc H- -------------------------------------------------- ----------------- In the above table, preferred ones are 1, 2, 3, 7, 8,
9, 12, 13, 14, 45, 46, 47, 51, 5,
2, 53, 56, 57, 58, 89, 90, 91, 9
6, 97, 98, 102, 103, 104, 108, 1
09, 110, 114, 115, 116, 120, 12
1, 122, 126, 127, 128, 132, 13
3, 134, 138, 139, 140, 144, 14
5, 146, 150, 182, 183, 184, 19
4, 234, 240, 252, 263, 264, 26
5, 276, 282, 287, 316, 322, 32
7, 380, 386, 391 and 431, and more preferably 2, 3, 8, 9, 13, 14,
46, 47, 52, 53, 57, 58, 103, 10
4, 109, 110, 115, 121, 127, 12
8, 133, 134, 139, 145, 150, 18
3, 194, 264, 276, 287, 316, 32
7, 380, 391 and 431, particularly preferably 2: 2,6-anhydro-7-O- [2-acetamide-
2-deoxy-6-O-methyl-4-O-phosphono-3
-O-{(R) -3-tetradecanoyloxytetradecyl} -β-D-glucopyranosyl] -3-{(R)-
3-hydroxydodecanamide {-4-O-} (R) -3
-Hydroxydodecyl} -3-deoxy-D-glycero-D-ido-heptonic acid, 8: 2,6-anhydro-7-O- [2-acetamide-
2-deoxy-6-O-methyl-4-O-phosphono-3
—O-{(R) -3-tetradecanoyloxytetradecyl} -β-D-glucopyranosyl] -3-tetradecanamido-4-O-tetradecyl-3-deoxy-D-glycero-D-ido-heptonic acid, 13: 2,6-anhydro-7-O- [2-acetamido-2-deoxy-6-O-methyl-4-O-phosphono-
3-O-{(R) -3-tetradecanoyloxytetradecyl} -β-D-glucopyranosyl] -3-{(R)
-3-Hydroxytetradecanamide｝ -4-O-
{(R) -3-hydroxytetradecyl} -3-deoxy-D-glycero-D-ido-heptonic acid, 46: 2,6-anhydro-7-O- [2-acetamido-2-deoxy-4- O-phosphono-3-O-｛(R)
-3-tetradecanoyloxytetradecyl｝ -β-D
-Glucopyranosyl] -3-{(R) -3-hydroxydodecanamide} -4-O-{(R) -3-hydroxydodecyl} -3-deoxy-D-glycero-D-ido-heptonic acid, 52 : 2,6-anhydro-7-O- [2-acetamide-2-deoxy-4-O-phosphono-3-O-｛(R)
-3-tetradecanoyloxytetradecyl｝ -β-D
-Glucopyranosyl] -3-tetradecanamide-4-O
-Tetradecyl-3-deoxy-D-glycero-D-ido-heptonic acid, 57: 2,6-anhydro-7-O- [2-acetamido-2-deoxy-4-O-phosphono-3-O-} (R)
-3-tetradecanoyloxytetradecyl｝ -β-D
-Glucopyranosyl] -3-{(R) -3-hydroxytetradecanamid} -4-O-{(R) -3-hydroxytetradecyl} -3-deoxy-D-glycero-D-
Id-heptonic acid, 121: 2,6-anhydro-7-O- [2-acetamido-2-deoxy-4-O-phosphono-3-O-
{(R) -3-hydroxytetradecyl {-β-D-glucopyranosyl] -3-{(R) -3-hydroxytetradecanaamide} -4-O-{(R) -3-hydroxytetradecyl} -3-deoxy-D-glycero-D-ido-heptonic acid, 127: 2,6-anhydro-7-O- [2-acetamido-2-deoxy-4-O-phosphono-3-O-
{(R) -3-dodecanoyloxytetradecyl} -β
-D-glucopyranosyl] -3-{(R) -3-hydroxytetradecanamid} -4-O-{(R) -3-hydroxytetradecyl} -3-deoxy-D-glycero-
139: 2,6-Anhydro-7-O- [2-acetamido-2,6-dideoxy-4-O-phosphono-6-fluoro-3-O-｛(R) -3 -Tetradecanoyloxytetradecyl {-β-D-glucopyranosyl] -3-
{(R) -3-hydroxydodecanamide} -4-O-
{(R) -3-hydroxydodecyl} -3-deoxy-
D-glycero-D-ido-heptonic acid, 150: 2,6-anhydro-7-O- [2-acetamide-2,6-dideoxy-6-fluoro-4-O-phosphono-3-O-} ( R) -3-Tetradecanoyloxytetradecyl {-β-D-glucopyranosyl] -3-
{(R) -3-hydroxytetradecanamide} -4-O
-{(R) -3-hydroxytetradecyl} -3-deoxy-D-glycero-D-ido-heptonic acid, 287: 2,6-anhydro-7-O- [2-acetamido-2-deoxy-3 -O-{(R) -3-dodecyloxytetradecyl} -6-O-methyl-4-O-phosphono-β-D-glucopyranosyl] -3-{(R) -3-
Hydroxytetradecanamide {-4-O-} (R) -3
-Hydroxytetradecyl} -3-deoxy-D-glycero-D-ido-heptonic acid, 327: 2,6-anhydro-7-O- [2-acetamido-2-deoxy-3-O-} (R) -3-dodecyloxytetradecyl {-4-O-phosphono-β-D-glucopyranosyl] -3-{(R) -3-hydroxytetradecanamido} -4-O-{(R) -3-hydroxy Tetradecyl} -3-deoxy-D-glycero-D-id-
Heptonic acid and 391: 2,6-anhydro-7-O- [2-acetamido-2,6-dideoxy-3-O-{(R) -3-dodecyloxytetradecyl} -6-fluoro-4 -O-phosphono-β-D-glucopyranosyl] -3-{(R)-
3-hydroxytetradecanamide {-4-O-} (R)
-3-Hydroxytetradecyl} -3-deoxy-D-
Glycero-D-id-heptonic acid.

[0051]

BEST MODE FOR CARRYING OUT THE INVENTION The compound having the general formula (I) of the present invention can be prepared by the following method by the known method (II) and the known compound (XI) (Carbohydrate Research,
222, p. 57 (1991)) as a starting material.

[0052]

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[0053]

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[0054]

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[0055]

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[0056]

Embedded image In the above steps, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meaning as described above.

In the above steps, R ⁶ and R ⁷ are the same or different and represent a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₆ -C ₁₀ aryl group.

R ⁸ is a C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group or C ₂ -C ₂₀ which may be substituted with one or more groups selected from the following (substituent group B). An alkynyl group, (Substituent group B) includes a halogen atom, a protected hydroxyl group (preferably, the protecting group is a trichloroethoxycarbonyl group or a benzyl group),
Oxo group, which may have an oxo group C ₁ -C ₂₀ alkoxy group, which may have an oxo group C ₂ -C ₂₀ alkenyloxy groups, and optionally C ₂ optionally having an oxo group -
A group consisting of C ₂₀ alkynyloxy groups.

[0059] R ⁹ is represented by the following (substituent group C) selected one or more of which may be substituted with a group C ₁ -C ₂₀ alkanoyl group having, C ₂ -C ₂₀ alkenoyl group or a C ₂ -C
_{20 is an} alkinoyl group, and (Substituent group C) includes a halogen atom, a protected hydroxyl group (preferably, the protecting group is preferably a trichloroethoxycarbonyl group or a benzyl group), an oxo group, or an oxo group. C ₁ that you may have
—C ₂₀ alkoxy group, C ₂ optionally having an oxo group
Have a -C ₂₀ alkenyloxy group and oxo group that is a group consisting of optionally C ₂ -C ₂₀ alkynyloxy group.

R ¹⁰ is a C ₁ -C ₂₀ alkyl group, a C ₂ -C ₂₀ alkenyl group or a C ₂ -C ₂₀ group which may be substituted with one or more groups selected from the following (substituent group D). (Substituent group D) is a halogen atom, a protected hydroxyl group (preferably a p-methoxybenzyl group or a trichloroethoxycarbonyl group), an oxo group, an oxo group. C optionally having a group
₁ -C ₂₀ alkoxy groups, optionally C ₂ optionally having an oxo group
Have a -C ₂₀ alkenyloxy group and oxo group that is a group consisting of optionally C ₂ -C ₂₀ alkynyloxy group.

R ¹¹ is C ₆ -C ₁₀ which may have a substituent.
An aryl group, a C ₇ -C ₁₁ aralkyl group which may have a substituent or a methyl group which may be substituted with 1 to 3 aryl groups, preferably a phenyl group, a benzyl group or a diphenylmethyl Group.

R¹²Is selected from the following (substituent group E)
C optionally substituted with one or more groups₁-C₂₀Al
Kill group, C_Two-C₂₀Alkenyl group or C_Two-C₂₀Al
A quinyl group, (Substituent group E) is a halogen atom, water
An acid group, an oxo group, and an optionally substituted oxo group₁-C
₂₀C which may have an alkoxy group or an oxo group_Two-C
₂₀May have an alkenyloxy group and an oxo group
C_Two-C₂₀A group consisting of alkynyloxy groups.

R ¹³ represents a C ₁ -C ₂₀ alkyl group, a C ₂ -C ₂₀ alkenyl group or a C ₂ -C ₂₀ group which may be substituted with one or more groups selected from the following (substituent group F). An alkynyl group (substituent group F) includes a halogen atom, a protected hydroxyl group (preferably a p-methoxybenzyl group or a trichloroethoxycarbonyl group as the protective group), an oxo group, and an oxo group; C optionally having a group
₁ -C ₂₀ alkoxy groups, optionally C ₂ optionally having an oxo group
-C ₂₀ alkenyloxy group which may have an oxo group C ₂ -C ₂₀ alkynyloxy group which may have an oxo group C ₁ -C ₂₀ alkanoyloxy group, have an oxo group And a C ₃ -C ₂₀ alkenoyloxy group which may have an oxo group and a C ₃ -C ₂₀ alkenoyloxy group.

R ¹⁴ represents a C ₁ -C ₄ alkyl group.

R ¹⁵ represents a C ₁ -C ₆ alkyl group.

R ¹⁶ represents a hydrogen atom or a halogen atom.

R¹⁷Is a hydrogen atom, halogen atom, protected
Hydroxyl group (preferably, the protecting group is preferably benzyl
It is a xycarbonyl group or a diphenylmethyl group. ),
C which may have an oxo group₁-C₆Alkoxy group,
C which may have a xo group _Two-C₆Alkenyloxy group
Or C which may have an oxo group_Two-C₆Alkynyluo
Shows a xy group.

The step of producing the compound (I) of the present invention comprises the steps of
It comprises the following three steps.

That is, (1) Step A is a step for producing an intermediate (X). (2) Step B is a step for producing intermediates (XXI), (XXIX) and (XXXII), and the method of Ba method, Bb method or Bc method can be selected according to desired compound (I). . (3) Step C comprises the intermediate (X) obtained in Step A and B
In this step, the intermediate (XXI), (XXIX) or (XXXII) obtained in the step is condensed to produce the compound (I) of the present invention.

Hereinafter, each step will be described.

(Step A) (Step A1) In this step, the 2-position azide compound (II)
This is a process for producing I), which is achieved by treating a known starting compound (II) with an azidating agent in an inert solvent in the presence of a base.

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material, but is preferably a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride; Alcohols such as methanol and ethanol, preferably methanol.

As the azide agent, a 0.4 N solution of trifluoromethanesulfonyl azide in methylene chloride is prepared and used.

The base used is preferably dimethylaminopyridine.

The reaction temperature is -20 to 30 ° C, preferably 15 to 25 ° C.

The reaction time is from 3 hours to 24 hours,
Preferably, it is 8 hours to 24 hours.

After completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and a water-immiscible organic solvent such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step A2) In this step, compound (III)
Is a step of producing a compound (IV) in which the 3-position hydroxyl group is alkylated (including the case where an alkenyl group or an alkynyl group is introduced. Hereinafter, the same definition will be used in the description of the production steps). This is achieved by generating an alkoxide of compound (III) with a strong base in a solvent and reacting with an alkylating agent.

Examples of the solvent used include ethers such as dioxane and tetrahydrofuran; amides such as formamide and dimethylformamide; and aromatic hydrocarbons such as benzene, toluene and xylene, and preferably dimethylformamide. .

Examples of the alkylating agent to be used include halogenated hydrocarbons, sulfonic esters and the like, preferably sulfonic esters. In this step, a compound represented by the formula: R ⁸ OSO ₂ CH ₃ (wherein R ⁸ has the same meaning as described above) is used.

Examples of the base to be used include alkali metals such as sodium hydroxide and potassium hydroxide; alkyllithiums such as n-butyllithium and t-butyllithium; hydrides such as potassium hydride and sodium hydride. Alkali metals and the like can be mentioned, and sodium hydride is preferable.

The reaction is carried out at a temperature of -78 ° C to 80 ° C, preferably 0 ° C to 60 ° C.

The reaction time varies depending on the reaction temperature, starting materials, reagents or solvent used, but is usually 2 to 24 hours, preferably 2 to 8 hours.

After the completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and a water-immiscible organic solvent such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step A3) In this step, compound (IV)
Is a step of producing a compound (V) in which the 1-position is deprotected, which is achieved by isomerizing the allyl group at the 1-position of the compound (IV) with a metal catalyst in an inert solvent, followed by hydrolysis. .

As the metal catalyst used, palladium
Complex such as iron, rhodium and iridium is used,
Preferably (1,5-cyclooctadiene) bis (methyldi
Phenylphosphine) iridium (I) hexafluoro
Phosphate ([Ir (COD) (PMePh _Two)_Two] PF₆).

Solvents used are, for example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride; ethers such as ether, dioxane, tetrahydrofuran; esters such as ethyl acetate; acetonitrile such as Nitriles may be mentioned, preferably ethers, and more preferably tetrahydrofuran.

The reaction temperature is 0 to 50 ° C., preferably 5 to 25 ° C.

The reaction time is from 10 minutes to 24 hours,
Preferably, it is 30 minutes to 5 hours.

Hydrolysis of the isomerized vinyl ether is carried out by reacting iodine with a mineral acid such as hydrochloric acid or sulfuric acid, an organic acid such as formic acid or p-toluenesulfonic acid, or water. The action of iodine in a mixed solvent of water.

The reaction temperature is 0 to 100 ° C., preferably 25 to 45 ° C.

The reaction time is from 10 minutes to 24 hours,
Preferably, it is 30 minutes to 5 hours.

After completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and a water-immiscible organic solvent such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step A4) This step is a step for producing a trichloroacetimidate derivative (VI) which is an intermediate, by adding a 1-position hydroxyl group of compound (V) to an inert solvent in the presence of a base. This is achieved by the action of trichloroacetonitrile.

Solvents used are, for example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride; ethers such as ether, dioxane, tetrahydrofuran; esters such as ethyl acetate; acetonitrile such as Nitriles may be mentioned, preferably halogenated hydrocarbons, and more preferably methylene chloride.

As the base, 1,8-diazabicyclo [5,4,
Organic bases such as 0] -7-undecene (DBU); and inorganic bases such as sodium hydride, potassium carbonate, and cesium carbonate are used, preferably organic bases, and more preferably 1,8-diazabicyclo [ 5,4,0] −7-undecene (D
BU).

The reaction temperature is from -25 to 50 ° C, preferably from 0 to 25 ° C.

The reaction time is 10 to 24 hours, preferably 30 minutes to 2 hours.

After completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and a water-immiscible organic solvent such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step A5) This step is a step of producing the 1-position cyano compound (VII), which is achieved by treating compound (VI) with a cyanating agent in an inert solvent in the presence of a catalyst. Is done.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Nitriles such as acetonitrile; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, etc. And halogenated hydrocarbons, preferably halogenated hydrocarbons, and particularly preferably methylene chloride.

Examples of the cyanating agent used include sodium cyanide, potassium cyanide and trimethylsilyl cyanide. Trimethylsilyl cyanide is preferred.

The catalyst to be used includes Lewis acids such as tin tetrachloride, trifluoroboron / etherate, aluminum chloride, ferric chloride and trimethylsilyl triflate, and preferably trimethyl silyl triflate.

The reaction is carried out at a temperature of from -40 ° C to 100 ° C, preferably from 10 ° C to 40 ° C.

The reaction time varies depending on the reaction temperature, the reagent or the solvent used, but is usually from 10 minutes to 10 hours, preferably from 30 minutes to 5 hours.

After completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and an organic solvent immiscible with water such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated, and anhydrous magnesium sulfate is added. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step A6) This step is carried out in an inert solvent
A step of reducing the azide group of the compound (VII) to produce a 2-position amino compound (VIII), wherein the compound (VII)
This is achieved by treating the reducing agent.

The solvent used for the reduction of the azide group is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include water-soluble ethers such as tetrahydrofuran and dioxane. Preferably it is tetrahydrofuran.

Examples of the azide group reducing agent include phosphines and aqueous ammonia. Trialkylphosphine and aqueous ammonia, such as trimethylphosphine and triethylphosphine, and aqueous ammonia, or triarylphosphine and aqueous ammonia such as triphenylphosphine, are preferred. Triphenylphosphine and aqueous ammonia are preferred.

The reaction time with the reducing agent is 1 to 24 hours, preferably 1 hour.

The reaction time is 0 to 50 ° C., preferably 0 to 25 ° C.

The reaction temperature of the reaction mixture of the compound (VII) with the phosphines and aqueous ammonia is 0 to 50 ° C., preferably room temperature.

After completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and a water-immiscible organic solvent such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step A7) In this step, compound (VII)
This is a step of producing a compound (IX) by acylating the 2-position amino group of I), which is achieved by treating the compound (VIII) with an acylating agent.

As the acylating agent, a carboxylic acid represented by the formula: R ⁹ OH (where R ⁹ has the same meaning as described above) is used.

The solvent used is tetrahydrofuran,
Ethers such as dioxane; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; amides such as N, N-dimethylformamide, preferably halogenated hydrocarbons And more preferably methylene chloride.

As the condensing agent, dicyclohexylcarbodiimide is used. At the same time, by adding 4-dimethylaminopyridine, the reaction is promoted,
By-products can be suppressed.

The reaction temperature is 0 to 50 ° C., preferably 15 to 25 ° C. (room temperature).

The reaction time is from 1 hour to 24 hours,
Preferably, it is 1 hour to 5 hours.

After completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and a water-immiscible organic solvent such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step A8) In this step, compound (IX)
Is a step of producing a compound (X) by deprotection of the 4- and 6-positions of the compound (1), conversion of a nitrile group to a carboxylic acid and esterification, and acid hydrolysis of the compound (IX) in an inert solvent. , Followed by esterification treatment.

The solvent used in the hydrolysis is a mixed solvent of an organic solvent and water. Examples of the organic solvent include alcohols such as methanol and ethanol; ethers such as diethyl ether, isopropyl ether and tetrahydrofuran; acetonitrile. And water-soluble organic solvents such as amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide, and preferably ethers (dioxane).

The acid used in the hydrolysis is a mineral acid such as hydrochloric acid or sulfuric acid, preferably hydrochloric acid.

The reaction temperature is 20 to 100 ° C., preferably 50 to 80 ° C.

The reaction time is 1 to 10 hours, preferably 2 to 5 hours.

In the treatment after the reaction, the mixture was concentrated under reduced pressure as it was,
Used for the next reaction without further purification.

The esterifying agent is not particularly limited as long as it can restore the original carboxylic acid from the produced ester under acidic conditions again. The esterifying agent is not limited to diazomethane; or an esterifying agent such as diphenyldiazomethane. And diphenyldiazomethane.

Solvents for the esterification are ethers such as tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; amides such as dimethylformamide, preferably amides. And more preferably dimethylformamide.

The reaction temperature of the esterification is from 0 to 100 ° C.
And preferably 25 to 60 ° C.

The reaction time is 30 minutes to 24 hours,
Preferably, it is 1 to 10 hours.

After completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and a water-immiscible organic solvent such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

Compound (X) obtained in this step may be compound (XXI), (XXIX) or (XXXII) described later.
To produce compound (I).

(Step B) (Method Ba) (Step Ba1) This step is a step of alkylating the 3-position hydroxyl group of compound (XI) to produce compound (XII), under the same conditions as in step A2. It is achieved by performing in.

The reagent used is represented by the formula: R ¹⁰ OSO ₂ CH
₃ (wherein R ¹⁰ has the same meaning as described above).

(Step Ba2) In this step, compound (XI)
Compound (XIII) wherein the protecting group at the 2-position of I) is deprotected
Which is achieved by deprotection under an alkaline condition in an inert solvent.

Examples of the solvent used include alcohols such as methanol and ethanol; ethers such as diethyl ether and tetrahydrofuran; nitriles such as acetonitrile; ketones such as acetone and methyl ethyl ketone. Is an alcohol (ethanol).

Examples of the alkali used include alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; sodium methoxide and sodium ethoxide. Alkali metal alkoxides may be mentioned, but alkali metal hydroxide is preferred.

The reaction is carried out at a temperature of 0 ° C. to 100 ° C., preferably 25 ° C. to 80 ° C.

The reaction time is generally 30 minutes to 24 hours, preferably 1 hour to 5 hours.

After completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and a water-immiscible organic solvent such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step Ba3) In this step, compound (XI)
This is a step of producing compound (XIV) in which the 2-position amino group of II) is protected, which is achieved by treating the compound with a protecting agent in an inert solvent under basic conditions.

Examples of the solvent used include halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; ethers such as ether, dioxane and tetrahydrofuran; and nitriles such as acetonitrile. Are halogenated hydrocarbons, particularly preferably methylene chloride.

The protecting agent to be used is one which does not prevent glycosylation in Step C1 described below, and is preferably trichloroethoxycarbonyl chloride.

The base used is pyridines such as pyridine and dimethylaminopyridine; triethylamine,
Trialkylamines such as tributylamine; alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; and the like, preferably alkali metal hydrogencarbonates (sodium hydrogencarbonate).

The reaction temperature is from -20 ° C to 60 ° C,
Preferably, it is 0 ° C to 25 ° C.

The reaction time is usually 30 minutes to 24 hours, preferably 1 hour to 5 hours.

After the completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and a water-immiscible organic solvent such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step Ba4) In this step, compound (XI)
This is achieved by deprotecting the hydroxyl-protecting groups at the 4- and 6-positions of V) by acid treatment.

Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid;
Organic acids such as acetic acid and oxalic acid can be mentioned, and are preferably organic acids, and more preferably acetic acid diluted with water (70 to 90%).

The reaction temperature is from 20 to 100 ° C., preferably from 40 to 80 ° C.

The reaction time is 10 minutes to 24 hours, preferably 30 minutes to 5 hours.

After completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and a water-immiscible organic solvent such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step Ba5) In this step, compound (X)
V) The compound (XV) in which the 6-position hydroxyl group is selectively protected
This is a process for producing I), which is achieved by treating the esterifying agent in an inert solvent in the presence of a base.

The protecting agent to be used may be any one capable of recovering the hydroxyl group at the 6-position with good yield by performing deprotection treatment. Examples thereof include alkyloxycarbonyl halides such as tert-butoxycarbonyl chloride, and benzyl. Aralkyloxycarbonyl halides such as oxycarbonyl chloride, halogenated alkoxycarbonyl halides such as trichloroethoxycarbonyl chloride, triphenylmethyl chloride, and aryl-substituted alkyl halides such as diphenylmethyl chloride. It is carbonyl chloride.

The base used is an organic base such as pyridine, dimethylaminopyridine, triethylamine, N, N-dimethylaniline, but is preferably pyridine.

Examples of the solvent used include halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; ethers such as ether, dioxane and tetrahydrofuran; and esters such as ethyl acetate. Are halogenated hydrocarbons, particularly preferably methylene chloride.

The reaction temperature is from -50 to 50 ° C, preferably from -10 to 30 ° C.

The reaction time is from 10 minutes to 24 hours,
Preferably, it is 30 minutes to 5 hours.

After completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and a water-immiscible organic solvent such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step Ba6) In this step, compound (XV)
Compound (XVII) wherein the 4-hydroxyl group of I) is phosphorylated
This is achieved by treating with a phosphorylating agent in an inert solvent in the presence of a base.

As the phosphorylating agent, a phosphoric halide represented by the formula (R ¹¹ O) ₂ P (= O) X is used. Wherein X is chlorine,
It represents a halogen atom such as bromine or iodine, and is preferably a chlorine atom. Examples of the phosphoric acid halide, as long later when converting phosphate ester compound (XXXV) to the phosphate compound (I) is deprotected, that protecting group R ¹¹ is such as it may easily be removed yield And preferably benzylphosphoryl chloride or phenylphosphoryl chloride.

The base used is an organic base such as pyridine, dimethylaminopyridine, triethylamine, N, N-dimethylaniline, but is preferably dimethylaminopyridine.

Examples of the solvent used include halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; ethers such as ether, tetrahydrofuran and dioxane; and esters such as ethyl acetate. Are halogenated hydrocarbons (methylene chloride).

The reaction temperature is 0 to 50 ° C., preferably 5 to 30 ° C.

The reaction time is from 10 minutes to 24 hours,
Preferably, it is 30 minutes to 5 hours.

After completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and a water-immiscible organic solvent such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step Ba7) This step is an optional step, and if not necessary, skip the step Ba9.
The process can proceed.

In this step, when a p-methoxybenzyl group is present in the 3-position alkyl group (R ¹⁰ ) of compound (XVII), the p-methoxybenzyl group is deprotected to produce compound (XVIII). Process, in an inert solvent,
It is achieved by treating with a deprotecting agent in the presence of water.

Examples of the solvent used include nitriles such as acetonitrile; and halogenated hydrocarbons such as methylene chloride and chloroform. Preferred is methylene chloride.

The deprotecting agent used is cerium nitrate (I
V) Ammonium (CAN), N-bromosuccinimide (N
BS), triphenylcarbenium tetrafluoroborate, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and the like, preferably 2,3-dichloro-
5,6-dicyano-p-benzoquinone (DDQ).

The reaction temperature is 0 to 30 ° C., preferably 15 to 25 ° C.

The reaction time is 30 minutes to 8 hours, preferably 1 to 5 hours.

After completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and a water-immiscible organic solvent such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step Ba8) In this step, compound (XV)
This is a step of preparing a compound (XIX) by acylating the hydroxyl group in the 3-position alkyl group (R ¹² ) in III), which is achieved by treating with an acylating agent in an inert solvent in the presence of a base.

As the acylating agent, C ₁₂ -C ₁₄ alkanoyl chloride is preferably used, and more preferably myristoyl chloride.

The solvent used is tetrahydrofuran,
Ethers such as dioxane; halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride; amides such as N, N-dimethylamide; ethers are preferred, and ethers are particularly preferred. Is tetrahydrofuran.

The base used is an organic base such as pyridine, dimethylaminopyridine, triethylamine, N, N-dimethylaniline, and preferably dimethylaminopyridine and triethylamine.

The reaction temperature is 0 to 80 ° C., preferably 0 to 25 ° C.

The reaction time is from 1 hour to 24 hours,
Preferably, it is 1 hour to 8 hours.

After completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and a water-immiscible organic solvent such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step Ba9) In this step, compound (XI)
This is a step of producing a compound (XX) in which the 1-allyl group of X) has been deprotected, and can be achieved by treating under the same conditions as in Step A3.

(Step Ba10) This step is a step of producing a trichloroacetimidate (XXI) which is one of the main intermediates, and under the same conditions as in step A4, the presence of a base in an inert solvent. This is achieved by the action of trichloroacetonitrile below.

After completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and a water-immiscible organic solvent such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Method Bb) (Step Bb1) This step is a step for producing a compound (XXII) in which the hydroxyl group at the 6-position of the compound (XV) obtained in Step Ba4 is selectively protected. XV) is achieved by treating the silylating agent in an inert solvent in the presence of a base.

The silylating agent has the formula (R ¹⁴ ) ₃ SiX ′ (wherein
R ¹⁴ has the same meaning as described above, and X ′ represents a halogen atom or a trifluoromethanesulfonyl group), but a trialkylsilyl halide or a trialkylsilyltrifluoromethanesulfonate is preferably used.
rt-butyldimethylsilyl chloride.

The base used is pyridines such as pyridine and dimethylaminopyridine; triethylamine,
Trialkylamines such as tributylamine; anilines such as aniline and N, N-dimethylaniline; 2,6
-Lutidines such as lutidine, preferably dimethylaminopyridine.

Examples of the solvent used include halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; ethers such as ether, dioxane and tetrahydrofuran; nitriles such as acetonitrile. Is methylene chloride.

The reaction temperature is from 0 to 50 ° C, preferably from 15 to 25 ° C.

The reaction time is from 1 hour to 24 hours,
Preferably, it is 1 hour to 8 hours.

After completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and an organic solvent immiscible with water such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step Bb2) In this step, compound (XX)
Compound (XXII) in which the hydroxyl group at the 4-position of (II) is phosphorylated
This is a step of manufacturing I), which is achieved by performing treatment under the same conditions as in the Ba6th step.

(Step Bb3) This step is an optional step, and if not necessary, skip the step Bb5.
The process can proceed.

In this step, compound (XIII) in which the protecting group in the 3-position alkyl group (R ¹⁰ ) of compound (XXIII) has been removed.
XIV), which is achieved by treating under the same conditions as in the Ba7th step.

(Step Bb4) In this step, compound (XX)
IV) a step of producing a compound (XXV) by acylating a hydroxyl group in the 3-position alkyl group (R ¹² );
This is achieved by treating under the same conditions as in the process.

(Step Bb5) In this step, compound (XX)
This is a step of producing the compound (XXVI) by removing the 6-position protecting group of V), which is achieved by hydrolysis under an acidic condition in an inert solvent.

The acids used for the hydrolysis include hydrochloric acid,
Examples thereof include an inorganic acid such as sulfuric acid and an organic acid such as acetic acid and oxalic acid, and preferably a 3N hydrochloric acid aqueous solution.

The solvent used is a water-soluble solvent such as dioxane and tetrahydrofuran, and is preferably tetrahydrofuran.

[0215] The reaction temperature is 20 to 80 ° C, preferably 20 to 50 ° C.

The reaction time is 30 minutes to 24 hours,
Preferably, it is 1 hour to 8 hours.

After completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and added with a water-immiscible organic solvent such as ethyl acetate. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step Bb6) In this step, compound (XX)
VI) The compound (XXV) in which the 6-position hydroxyl group is alkylated
II), which is achieved by the following method. In particular, when R ¹⁵ is a methyl group, the following method can be used. When R ¹⁵ is a C ₁ -C ₆ alkyl group, this step is carried out by treating compound (XXVI) with an alkylating agent in an inert solvent in the presence of a base or silver (II) oxide (AgO). Achieved.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent or more. Examples thereof include aliphatic hydrocarbons such as hexane, heptane and ligroin; benzene, Aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, and chlorobenzene; esters such as ethyl acetate, propyl acetate and diethyl carbonate; diethyl ether; Ethers such as diisopropyl ether, tetrahydrofuran, dioxane; acetonitrile,
Nitriles such as isobutyronitrile; amides such as formamide, N, N-dimethylformamide and N, N-dimethylacetamide can be mentioned, with preference given to ethers.

Examples of the base used include alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metals such as sodium hydride and potassium hydride. Metal hydrides: N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t- Butyl) -4-methylpyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2 ] Octane (D
ABCO), 1,8-diazabicyclo [5.4.0] undeca
Organic bases such as 7-ene (DBU) can be mentioned, preferably organic bases, more preferably triethylamine, DBN or DBU.

The alkylating agent used is represented by the formula: R
¹⁵ Z (wherein, R ¹⁵ has the same meaning as described above, and Z is an iodine atom, a bromine atom, a chlorine atom, a paratoluenesulfonyloxy group or a methanesulfonyloxy group).

The reaction is carried out at a temperature of 0 ° C. to 100 ° C., preferably 0 ° C. to 30 ° C.

The reaction time is from 10 minutes to 24 hours,
Preferably, it is 1 hour to 18 hours. In the case where R ¹⁵ is a methyl group, this step is performed by reacting the compound (XXV) in an inert solvent in the presence of a base.
This is achieved by treating I) with trimethyloxonium tetrafluoroborate.

Examples of the solvent to be used include ethers such as ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; formamide, N, N-dimethylformamide, N, Amides such as N-dimethylacetamide can be mentioned, and preferred is methylene chloride.

The base used is preferably 2,6
-Di-tert-butyl-4-merylpyridine.

The reaction is carried out at a temperature from -50 ° C to 100 ° C, preferably from 0 ° C to 30 ° C.

The reaction time is from 1 hour to 24 hours,
Preferably, it is 2 hours to 5 hours.

After the completion of the reaction, the desired compound (XXV)
II) is collected from the reaction mixture in a conventional manner. For example, after neutralizing the reaction mixture, concentrating, adding a water-immiscible organic solvent such as ethyl acetate, washing with water, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and removing the solvent. Obtained by distillation.

The obtained compound can be further purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step Bb7) In this step, compound (XX)
VII) Compound in which the allyl group at the 1-position is deprotected (XXV
III), which is achieved by performing the same processing as in step A3.

(Step Bb8) In this step, trichloroacetimidate (XXIX), one of the main intermediates
Wherein the compound (XXVIII) is converted to
This is achieved by treating under the same conditions as in step a10.

(Method Bc) (Step Bc1) This step is a step of producing a compound (XXX) in which the 6-position hydroxyl group of the compound (XXVI) obtained in the step Bb5 is converted to a halogen atom or a hydrogen atom. is there. (Step Bc1-1) In this step, the compound of formula (XXX)
^This is a production method when ¹⁶ is a halogen atom, and is carried out by the following method. When R ¹⁶ is a fluorine atom This step is achieved by treating compound (XXVI) with a fluorinating agent in an inert solvent.

Examples of the solvent used include halogenated hydrocarbons such as methylene chloride and fluorotrichloromethane; and ethers such as ether and 1,2-dimethoxyethane. ,
Methylene chloride.

Examples of the fluorinating agent used include, for example,
(2-Chloroethyl) diethylamine and diethylaminosulfur trifluoride (DAST) can be mentioned, but DAST is preferred.

The reaction is carried out at a temperature of -78 ° C to 25 ° C, preferably 0 ° C to 25 ° C.

The reaction time is from 1 hour to 18 hours, preferably from 1 hour to 5 hours. When R ¹⁶ is a chlorine atom or a bromine atom, in this step, compound (XXVI) is reacted with phosphorus trichloride, phosphorus tribromide, phosphoryl trichloride, phosphoryl tribromide, thionyl chloride or thionyl bromide in an inert solvent. Is achieved by reacting

The solvent used is preferably a halogenated hydrocarbon such as methylene chloride, chloroform and carbon tetrachloride.

The reaction is carried out at a temperature from -50 ° C to 50 ° C, preferably from -10 ° C to 30 ° C.

The reaction time is 1 hour to 18 hours, preferably 1 hour to 5 hours. When R ¹⁶ is an iodine atom This step is achieved by reacting compound (XXVI) with iodine and triphenylphosphine in an inert solvent.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent or more. Examples thereof include aliphatic hydrocarbons such as hexane, heptane and ligroin; Aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, and chlorobenzene; esters such as ethyl acetate, propyl acetate and diethyl carbonate; diethyl ether; Ethers such as diisopropyl ether, tetrahydrofuran and dioxane; alcohols such as methanol and ethanol; formamide, N, N-
Amides such as dimethylformamide and N, N-dimethylacetamide can be mentioned.
Ethers.

The reaction is carried out at a temperature of -50 ° C to 100 ° C, preferably 0 ° C to 30 ° C.

The reaction time is 1 hour to 18 hours, preferably 1 hour to 5 hours.

After completion of the reaction, the desired compound (XX)
X) is collected from the reaction mixture according to a conventional method. For example, after neutralizing the reaction mixture, concentrating, adding a water-immiscible organic solvent such as ethyl acetate, washing with water, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and removing the solvent. Obtained by distillation.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like. (Step Bc1-2) In this step, compound R
¹⁶ is a step performed when hydrogen is a hydrogen atom, and the compound in which R ¹⁶ obtained in the step Bc1-1 is a bromine atom is reacted with tetrabutyltin hydride or lithium aluminum hydride in an inert solvent. Done.

As the solvent used, for example, aliphatic hydrocarbons such as hexane, heptane and ligroin;
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane can be mentioned, and ethers are preferred.

The reaction is carried out at a temperature of -50 ° C to 50 ° C, preferably -10 ° C to 30 ° C.

The reaction time is 10 minutes to 16 hours, preferably 1 hour to 8 hours.

After completion of the reaction, the desired compound (XX)
X) is collected from the reaction mixture according to a conventional method. For example, after neutralizing the reaction mixture, concentrating, adding a water-immiscible organic solvent such as ethyl acetate, washing with water, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and removing the solvent. Obtained by distillation.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step Bc2) In this step, compound (XX)
Compound (XXI) in which the allyl group at the 1-position of X) has been deprotected
Is achieved by performing the treatment under the same conditions as in the step A3.

(Step Bc3) In this step, a trichloroacetimidate compound (XXXI) which is one of the main intermediates
This is a step of producing I), which is achieved by performing treatment under the same conditions as in the Ba10th step.

(Step C) (Step C1) In this step, the intermediates (XXI) and (XXI)
X) or (XXXII) and the intermediate (X) to produce a compound (XXXIII) having a lipid A structure, and the compound (XXI) or (XXIX)
Alternatively, it is achieved by glycosylation of (XXXII) and compound (X) in an inert solvent in the presence of an acid catalyst.

The catalyst used includes tin tetrachloride, trifluoroboron / etherate, aluminum chloride,
Lewis acids such as ferric chloride and trimethylsilyl triflate can be mentioned, and preferably trimethyl silyl triflate.

The solvents used include halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as diethyl ether; nitriles such as acetonitrile; aromatic hydrocarbons such as toluene and benzene;
Amides such as dimethylformamide; and the like, preferably halogenated hydrocarbons, and particularly preferably methylene chloride.

The reaction is carried out at a temperature of -100 to 25 ° C, preferably -78 to 0 ° C.

The reaction time is generally 10 minutes to 10 hours, preferably 30 minutes to 5 hours.

After the completion of the reaction, for example, the reaction mixture is neutralized, concentrated, and an organic solvent immiscible with water such as ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. It can be obtained by evaporating the solvent after drying with the above method.

The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization, silica gel chromatography and the like.

(Step C2) In this step, compound (XXX)
III) removing the trichloroethoxycarbonyl group;
A step of producing a compound (XXXIV) converted with an acyl group R ³ , wherein the compound (XXXIII)
This is achieved by treating the deprotecting agent with an acylating agent.

The solvent used in the deprotection step is acetic acid, and the deprotecting agent for the trichloroethoxycarbonyl group is zinc.

The reaction is carried out at a temperature of 0 to 80 ° C.
Preferably, it is 10 to 30 ° C.

The reaction time is from 1 hour to 24 hours,
Preferably, it is 1 hour to 8 hours.

As the acylating agent, a carboxylic acid represented by the formula: R ³ OH and an acid anhydride represented by the formula: (R ³ ) ₂ O are used. Can be performed. In the formula, R ³ has the same meaning as described above.

(Step C3) This step is a step for producing the desired compound (I), and comprises the 1-position protecting group of the compound (XXXIV) and the hydroxyl group in R ⁸ , R ⁹ , R ¹³ and R ¹⁷ This is a step of deprotecting the protecting group R ¹¹ and the protecting group R ¹¹ in the phosphate group.
Organic Synthesis), or using the following method. Further, the compound (XXXI)
When several types of protecting groups are present in V), the steps can be performed sequentially by combining methods according to the protecting groups.

When the protecting group is an aralkyl group This step is a step of removing the aralkyl protecting group by catalytic reduction in a hydrogen atmosphere in an inert solvent in the presence of a catalyst.

The catalyst used is palladium / carbon, palladium hydroxide, palladium hydroxide / carbon,
Palladium black may be mentioned, but is preferably palladium hydroxide / carbon.

The solvent used is tetrahydrofuran,
Ethers such as dioxane and ether; esters such as ethyl acetate; alcohols such as methanol and ethanol; and organic acids such as formic acid and acetic acid, with ethanol being preferred.

The reaction temperature is 0 to 50 ° C., preferably 15 to 25 ° C.

The reaction time is from 1 hour to 48 hours,
Preferably, it is 1 hour to 24 hours.

In the treatment after completion of the reaction, the target compound can be obtained by filtering off the catalyst from the reaction mixture and concentrating the obtained filtrate. If necessary, it can be further purified by recrystallization, reprecipitation or silica gel column chromatography.

When the protecting group is a diphenylmethyl group When the protecting group is a diphenylmethyl group, catalytic reduction under a hydrogen atmosphere is carried out in the same manner as described above, or by treatment with an acid in an inert solvent. Achieved. In particular, when a double bond or a triple bond is present in the compound (XXXIV), deprotection with an acid is used.

The acid to be used is not particularly limited as long as it is usually used as a Bronsted acid or a Lewis acid, and is preferably an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid; Fluoroacetic acid, methanesulfonic acid,
Organic acids such as p-toluenesulfonic acid.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane and ligroin; , Toluene, xylene; aromatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; halogenated hydrocarbons such as ethyl acetate, propyl acetate, butyl acetate, and diethyl carbonate. Ester; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; alcohols such as methanol, ethanol, propanol, butanol, isoamyl alcohol; ketones such as acetone, methyl ethyl ketone, cyclohexanone Water, or a mixture thereof solvents suitable, more preferably, halogenated hydrocarbons, are esters or ethers.

The reaction temperature and the reaction time vary depending on the starting material, the type of the solvent and the concentration of the acid used, etc., but are usually -10 to 100 ° C (preferably -5 to 50 ° C).
5 minutes to 48 hours (preferably 30 minutes to 10 hours).

After the completion of the reaction, the reaction mixture is collected from the reaction mixture according to a conventional method. For example, concentrating the reaction mixture,
Add a water-immiscible organic solvent such as ethyl acetate
After washing with water, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.

The obtained compound can be further purified, if necessary, by a conventional method, for example, recrystallization or silica gel column chromatography.

When the protecting group R ¹¹ in the phosphate group is a phenyl group When the protecting group R ¹¹ in the phosphate group is a phenyl group, the protecting group R ¹¹ is subjected to catalytic reduction in an inert solvent in the presence of a catalyst. Can be deprotected.

The catalyst used is preferably platinum oxide.

The solvent used is tetrahydrofuran,
Ethers such as dioxane and ether; esters such as ethyl acetate; alcohols such as methanol and ethanol; organic acids such as formic acid and acetic acid, with preference given to tetrahydrofuran.

The reaction temperature is 0 to 50 ° C., preferably 15 to 25 ° C.

The reaction time is from 1 hour to 48 hours,
Preferably, it is 1 hour to 24 hours.

In the treatment after completion of the reaction, the target compound can be obtained by filtering off the catalyst from the reaction mixture and concentrating the obtained filtrate. If necessary, it can be further purified by recrystallization, reprecipitation or silica gel column chromatography.

The ester of the compound (I) of the present invention can be produced by a usual method using a group forming an ester. If necessary, protection and deprotection of the hydroxyl group are performed before and after the esterification.

For example, (1) a method using an alkyl halide corresponding to a group forming a desired ester, (2)
Examples include a method using an alcohol corresponding to a group forming a desired ester.

In the method (1), the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
Aliphatic hydrocarbons such as heptane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; Ethers such as ter, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; acetonitrile, isobutyronitrile Nitriles; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-
Examples include amides such as 2-pyrrolidone, N-methylpyrrolidinone, and hexamethylphosphorotriamide.

In the method (1), a base catalyst is generally used, and the base catalyst is not particularly limited as long as it is used as a base in a normal reaction. Alkali metal carbonates, such as potassium carbonate, lithium carbonate; sodium hydrogen carbonate,
Alkali metal bicarbonates such as potassium bicarbonate and lithium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride;
Sodium hydroxide, potassium hydroxide, barium hydroxide,
Alkali metal hydroxides such as lithium hydroxide; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide; Alkali metal alkoxides such as potassium tert-butoxide and lithium methoxide; mercaptan alkali metals such as sodium methyl mercaptan and sodium ethyl mercaptan; N-methylmorpholine;
Triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6
-Di (tert-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5
-Ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.
0] organic bases such as undec-7-ene (DBU) or butyllithium, lithium diisopropylamide,
Organometallic bases such as lithium bis (trimethylsilyl) amide can be mentioned.

In the method (1), usually, -20 ° C.
The reaction is carried out at a temperature of from 120 to 120 ° C. (preferably from 0 to 80 ° C.) for 0.5 to 10 hours.

In the method (2), a condensing agent is usually used,
Examples of the “condensing agent” include: (a) a combination of a phosphoric ester such as diethylphosphoryl cyanide, diphenylphosphoryl azide, diethyl cyanophosphate and the following base; (a) 1,3-dicyclohexylcarbodiimide;
3-diisopropylcarbodiimide, 1-ethyl-3-
Carbodiimides such as (3-dimethylaminopropyl) carbodiimide; combinations of the carbodiimides with the following bases; the carbodiimides and N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-di Combinations of N-hydroxys such as carboximides; (c) 2,2′-dipyridyl disulfide, 2,2 ′
A combination of a disulfide such as dibenzothiazolyl disulfide and a phosphine such as triphenylphosphine or tributylphosphine; (d) N, N'-disuccinimidyl carbonate, di-2-pyridyl carbonate, S , S'-bis (1-
Carbonates such as phenyl-1H-tetrazol-5-yl) dithiocarbonate; (e) phosphinic chlorides such as N, N'-bis (2-oxo-3-oxazolidinyl) phosphinic chloride; F) N, N'-disuccinimidyl oxalate;
N, N'-diphthalimido oxalate, N, N'-bis (5-norbornene-2,3-dicarboximidyl)
Oxalate, 1,1'-bis (benzotriazolyl)
Oxalates such as oxalate, 1,1'-bis (6-chlorobenzotriazolyl) oxalate, and 1,1'-bis (6-trifluoromethylbenzotriazolyl) oxalate; Diethyl azodicarboxylate,
A combination of an azodicarboxylic acid ester such as 1,1 '-(azodicarbonyl) dipiperidine or an azodicarboxamide; a combination of the above phosphine and the following base; (h) N-ethyl-5-phenylisoxazolium −
N-lower alkyl-5-arylisoxazolium-3'-sulfonates such as 3'-sulfonate; (hetero) diheteroaryl diselenides such as di-2-pyridyldiselenide; ) Arylsulfonyltriazolides such as p-nitrobenzenesulfonyltriazolide; (sa) 2-halo-1-lower alkylpyridinium such as 2-chloro-1-methylpyridinium iodide
Halides; (S) 1,1'-oxalyldiimidazole, N, N'-
Imidazoles such as carbonyldiimidazole; (S) 3-ethyl-2-chloro-benzothiazolium
3-lower alkyl-2-halogen-benzothiazolium fluoroborates such as fluoroborate; (se) 3-lower alkyl-benzothiazole-2-serones such as 3-methyl-benzothiazole-2-cellone (So) Phosphates such as phenyldichlorophosphate and polyphosphate esters; (T) halogenosulfonyl isocyanates such as chlorosulfonyl isocyanate; (T) halogenosilanes such as trimethylsilyl chloride and triethylsilyl chloride; A combination of a lower alkanesulfonyl halide such as methanesulfonyl chloride and the following base; (T) N, N, N ', N'-tetra such as N, N, N', N'-tetramethylchloroformamidium chloride Lower alkylhalogenoformamidium It can be exemplified Rorido acids, preferably, carbodiimides, and a combination of phosphines and azodicarboxylic acid ester or azodicarboxylate amides.

In the method (2), the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
Aliphatic hydrocarbons such as heptane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethyl formate Esters such as ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetonitrile, isobutyronitrile Nitriles such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-
Amides such as methylpyrrolidinone and hexamethylphosphorotriamide can be mentioned.

In the method (2), a base catalyst can also be used. The base catalyst is not particularly limited as long as it is used as a base in a usual reaction. -Methylmorpholine, triethylamine, tributylamine, diisopropylethylamine,
Dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N,
Organic bases such as N-dimethylamino) pyridine, 2,6-di (tert-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline and N, N-diethylaniline can be mentioned.

In addition, 4- (N, N-dimethylamino) pyridine and 4-pyrrolidinopyridine may be used in combination with other bases in a catalytic amount, and may be used for effective reaction. Dehydrating agents such as molecular sieves, quaternary ammonium salts such as benzyltriethylammonium chloride, tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6, 3,4-dihydro-2H- Pyrido [1,
2-a] An acid scavenger such as pyrimidin-2-one can also be added.

The reaction is carried out at a temperature of from -20 ° C to 80 ° C, preferably from 0 ° C to room temperature.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
Usually, it is 10 minutes to 3 days, preferably 30 minutes to 1 day.

In particular, when the group forming the ester is a lower alkyl group, the solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Alcohols such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; halogens such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene. Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; acetonitrile; Nitriles such as Sobuchironitoriru; formamide, N, N- dimethylformamide, N, N- dimethylacetamide, N- methyl-2-
Amides such as pyrrolidone, N-methylpyrrolidinone, and hexamethylphosphorotriamide can be mentioned, and preferably the same alcohol as the reagent. ), In the presence of an acid catalyst (although there is no particular limitation as long as it is used as an acid catalyst in a normal reaction, preferably, hydrogen chloride, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, etc.) Inorganic acid or Brönsted acid such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, organic acid such as paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or boron trichloride, boron trifluoride, boron tribromide A suitable Lewis acid or an acidic ion exchange resin.), Methanol, ethanol,
0 ° C to 100 ° C (preferably 20 ° C to 60 ° C) with the corresponding alcohols such as propanol and butanol
And reacting for 1 to 24 hours.

After completion of the reaction, compound (I) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate are added, and after washing with water, the organic layer containing the target compound is washed. It is obtained by separating and drying over anhydrous magnesium sulfate or the like, and then distilling off the solvent.

If necessary, the obtained target compound may be prepared by a conventional method.
For example, recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds, for example, adsorption column chromatography using a carrier such as silica gel, alumina, and magnesium-silica gel type florisil; Sephadex LH-20 (manufactured by Pharmacia), Amberlite XAD-11 (manufactured by Rohm and Haas),
A method using a synthetic adsorbent such as distribution column chromatography using a carrier such as Diaion HP-20 (manufactured by Mitsubishi Kasei Corporation), or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel (preferably Is a high-performance liquid chromatography.), And can be separated and purified by eluting with an appropriate eluent.

The administration form of the compound (I) of the present invention includes, for example, oral administration by tablets, capsules, granules, powders or syrups, and parenteral administration by injections or suppositories. . These preparations are produced by known methods using additives such as excipients, binders, disintegrants, lubricants, stabilizers, and flavoring agents.

The amount of use depends on symptoms, age and the like.
01 to 50 mg / kg body weight, usually 1 adult
It can be administered once or several times a day. Also,
When used for inhibiting macroactivity, 0.01 to 10 mg / kg body weight per day can be usually administered to an adult once or several times a day.

Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, and Test Examples.

[0301]

Example 1 2,6-Anhydro-7-O- [2-acetone
Tamide-2-deoxy-4-O-phosphono-3-O-
{(R) -3-tetradecanoyloxytetradecyl}
-Β-D-glucopyranosyl] -3-{(R) -3-hi
Droxytetradecanamid {-4-O-} (R) -3-
Hydroxytetradecyl｝ -3-deoxy-D-glyce
R-D-ido-heptonynic acid (exemplary compound 57) To a solution of the compound of Reference Example 24 (3.5 mg, 0.00233 mmol) in tetrahydrofuran (1 ml) was added 3.1 mg of platinum oxide. Stir vigorously. The solution was filtered through celite and concentrated under reduced pressure. The obtained residue is chloroform 4 ml, methanol 4 ml, 0.1 M hydrochloric acid aqueous solution 3.2 ml
In chloroform, and further 4 ml of chloroform, 4 ml of 0.1 M hydrochloric acid aqueous solution
Was added for washing to remove contaminating silica gel. Remove the chloroform layer and evaporate the solvent under reduced pressure to give 3.0 mg
The target compound (yield: 95%) was obtained.

IR (CHCl ₃ solution) spectrum: 3353, 1713,
1657, 1604 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.89 (12H,
t, J = 6.6-7.3Hz), 1.28-1.75 (86H, m), 2.01 (3H, s),
2.28-2.42 (4H, m), 3.31-4.53 (20H, m), 4.99 (1H, m) Mass spectrum (m / z): 1351.9468 (M + H) ⁺

[0303]

Example 2 2,6-Anhydro-7-O- [2-acetone
Tamido-2-deoxy-6-O-methyl-4-O-phos
Hono-3-O-｛(R) -3-tetradecanoyloxy
Tetradecyl {-β-D-glucopyranosyl] -3-
{(R) -3-hydroxytetradecanamide} -4-O
-{(R) -3-hydroxytetradecyl} -3-deo
Xy-D-glycero-D-ido-heptonynic acid (Exemplified Compound 13) By performing the same operation as in Example 1 for 40.8 mg (0.0269 mmol) of the compound of Reference Example 35, 35.4 mg (yield:
96%) of the desired compound was obtained.

IR (KBr) spectrum: 3315, 2924, 2854, 1
730, 1646cm ^-1 nuclear magnetic resonance spectrum (400MHz, CDCl ₃ : CD ₃ OD = 1: 1)
δ: 0.89 (12H, t, J = 6.6-7.3Hz), 1.23-1.85 (86H, m),
2.01 (3H, s), 2.29-2.42 (4H, m), 3.41 (3H, s), 3.48-
3.92 (15H, m), 4.02-4.14 (2H, m), 4.28 (1H, dd, J = 5.
1, 9.5Hz), 4.50 (1H, d, J = 5.1Hz), 4.62 (1H, d, J = 8.8H
z), 4.95 (1H, m) Elemental analysis: C ₇₂ H ₁₃₇ N ₂ O ₁₉ P (molecular weight: 1365.83) Calculated (%) C 63.32 H 10.11 N 2.05 P 2.27 Analytical (%) C 62.80 H 9.94 N 2.15 P 2.22

[0305]

Example 3 2,6-Anhydro-7-O- [2-ace
Tamide-2,6-dideoxy-6-fluoro-4-O-
Phosphono-3-O-{(R) -3-tetradecanoylo
Xytetradecyl {-β-D-glucopyranosyl] -3
-{(R) -3-hydroxytetradecanamide} -4-
O-{(R) -3-hydroxytetradecyl} -3-de
Oxy-D-glycero-D-ido-heptoninic acid (Exemplified Compound 150) 45.3 mg (0.0301 mmol) of the compound of Reference Example 41 was subjected to the same operation as in Example 1 to obtain 40.1 mg (yield) as a white solid. (%: 98%).

IR (KBr) spectrum: 3304, 2924, 2854,
1730, 1648, 1546cm ^-1 nuclear magnetic resonance spectrum (400MHz, CD ₃ OD: CDCl ₃ = 1: 1)
δ: 0.89 (12H, t, J = 6.6Hz), 1.18-1.83 (86H, m), 2.01
(3H, s), 2.30-2.42 (4H, m), 3.48-3.92 (16H, m), 4.04-
4.14 (2H, m), 4.27 (1H, m), 4.50 (1H, d, J = 5.1Hz), 4.
65-4.69 (2H, m), 4.96 (1H, m) Elemental analysis: C ₇₁ H ₁₃₄ N ₂ O ₁₈ PF (molecular weight: 1353.80) Calculated (%) C 62.99 H 9.98 N 2.07 P 2.29 F 1.40 Analysis (%) C 61.77 H 9.72 N 2.05 P 2.38 F 1.30

[0307]

Example 4 2,6-Anhydro-7-O- [2-ace
Tamide-2-deoxy-3-O-{(R) -3-dodeci
Ruoxytetradecyl｝ -4-O-phosphono-β-D-
Glucopyranosyl] -3-{(R) -3-hydroxyte
Toradecanamide {-4-O-} (R) -3-hydroxy
Tetradecyl} -3-deoxy-D-glycero-D-i
Do-heptonic acid (exemplary compound 327) 56.4 mg (0.0386 mmol) of the compound of Reference Example 61
55.6 mg of platinum oxide was added to a solution of 1) in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure. To the residue obtained, 5 mL of chloroform, 10 mL of methanol and 0.1 mL of methanol were added.
4 mL of a 1N aqueous hydrochloric acid solution was added to dissolve, and 5 mL of chloroform and 5 mL of a 0.1N aqueous hydrochloric acid solution were added thereto for washing. Remove the chloroform layer and evaporate the solvent under reduced pressure.
The target compound (48.3 mg, yield: 9) as a white solid
6%).

Melting point: 179.0-181.0 ° C .; Optical rotation: [α] _D ²⁴ -25.5 (c = 0.78, CHCl ₃ ) IR (KBr) spectrum: 3294 (broad), 3040, 2924, 285
4, 1723, 1627 cm ^-1 nuclear magnetic resonance spectrum (400MHz, CD ₃ OD: CDCl ₃ = 5: 1)
δ: 4.59 (1H, d, J = 8.1 Hz), 4.49 (1H, d, J = 5.1 Hz),
4.23 (1H, dd, J = 5.1, 9.5 Hz), 4.14-4.03 (2H, m),
3.93-3.74 (8H, m), 3.70-3.52 (5H, m), 3.49-3.40 (5
H, m), 2.38 (1H, dd, J = 4.4, 14.6 Hz), 2.32 (1H, dd,
J = 8.1, 14.6 Hz), 2.00 (3H, s), 1.73-1.71 (4H, m),
1.60-1.29 (80H, m), 0.89 (12H, t, J = 6.6 Hz) Mass spectrum (m / z): 1331.9203 (M + Na) ⁺ elemental analysis: C ₆₉ H ₁₃₃ N ₂ O ₁₈ P (molecular weight : 1309.8) Calculated value (%) C 63.27 H 10.24 N 2.14 P 2.37 Analytical value (%) C 62.72 H 10.21 N 2.04 P 1.98

[0309]

Example 5 2,6-Anhydro-7-O- [2-acetone
Tamide-2-deoxy-3-O-{(R) -3-dodeci
Ruoxytetradecyl {-6-O-methyl-4-O-e
Suphono-β-D-glucopyranosyl] -3-{(R)-
3-hydroxytetradecanamide {-4-O-} (R)
-3-Hydroxytetradecyl} -3-deoxy-D-
Glycero-D-ido-heptonic acid (Exemplified Compound 28
7) 95.4 mg (0.0646 mmol) of the compound of Reference Example 62
By performing the same operation as in Example 4 for 1), the target compound (85.4 mg, quantitative) was obtained as a white solid.

Melting point: 181.0-183.0 ° C. Optical rotation: [α] _D ²⁴ -28.6 (c = 0.45, CHCl ₃ ) IR (KBr) spectrum: 3304 (broad), 3078, 2956, 292
3, 2854, 1733, 1654cm ^-1 nuclear magnetic resonance spectrum (400MHz, CD ₃ OD: CDCl ₃ = 5: 1)
δ: 4.59 (1H, d, J = 8.1 Hz), 4.50 (1H, d, J = 5.1 Hz),
4.24 (1H, dd, J = 5.1, 9.5 Hz), 4.09 (1H, q, J = 9.5 H
z), 4.04-3.35 (19H, m), 3.40 (3H, s), 2.39 (1H, d
d, J = 4.4, 14.6 Hz), 2.32 (1H, dd, J = 8.1, 14.6 Hz),
2.00 (3H, s), 1.75-1.72 (4H, m), 1.59-1.29 (80H,
m), 0.89 (12H, t, J = 6.6 Hz) Mass spectrum (m / z): 1345.9336 (M + Na) ⁺ elemental analysis: C ₇₀ H ₁₃₅ N ₂ O ₁₈ P (molecular weight: 1323.8) calculated ( %) C 63.51 H 10.28 N 2.12 P 2.34 Analytical value (%) C 63.23 H 10.14 N 1.94 P 2.05

[0311]

Example 6 2,6-Anhydro-7-O- [2-acetone
Tamide-2,6-dideoxy-3-O-｛(R) -3-
Dodecyloxytetradecyl} -6-fluoro-4-O
-Phosphono-β-D-glucopyranosyl] -3-
{(R) -3-hydroxytetradecanamide} -4-O
-{(R) -3-hydroxytetradecyl} -3-deo
Xy-D-glycero-D-ido-heptonynic acid (Exemplified compound 391) 46.5 mg (0.0318 mmol) of the compound of Reference Example 63
By performing the same operation as in Example 4 for 1), the target compound (39.3 mg, yield: white solid) was obtained.
94%).

Melting point: 199.0-200.5 ° C .; Optical rotation: [α] _D ²⁴ -34.5 (c = 0.70, CHCl ₃ ) IR (KBr) spectrum: 3399 (broad), 3306, 3085, 295
7, 2923, 2854, 1733, 1645 cm ^-1 nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD: CDCl ₃ = 5: 1)
δ: 4.80-4.54 (3H, m, containing 1H, d, J = 8.1 Hz,
δ4.63), 4.49 (1H, d, J = 5.1 Hz), 4.23 (1H, dd, J =
5.1, 9.5 Hz), 4.11 (1H, q, J = 9.5 Hz), 4.06-3.55 (1
3H, m), 3.49-3.40 (4H, m), 2.38 (1H, dd, J = 4.4, 14.
6 Hz), 2.33 (1H, dd, J = 8.1, 14.6 Hz), 2.00 (3H,
s), 1.77-1.69 (4H, m), 1.60-1.29 (80H, m), 0.89 (1
2H, t, J = 6.6Hz) Mass spectrum (m / z): 1333.9158 (M + Na) ⁺ elemental analysis: C ₆₉ H ₁₃₂ FN ₂ O ₁₇ P (molecular weight: 1311.8) Calculated (%) C 63.31 H 10.18 N 2.06 F 1.45 P 2.36 Analytical value (%) C 63.31 H 10.18 N 2.06 F 1.46 P 2.08

[0313]

Reference Example 1 Allyl 2-azido-2-deoxy-4,
6-O-isopropylidene-β-D-glucopyranoside Allyl 2-amino-2-deoxy 4,6-O-isopropylidene-β-D-glucopyranoside 6.35 g (24.5 mm)
ol) in a methanol (120 ml) solution, 4-dimethylaminopyridine (3.07 g, 25.1 mmol) and trifluoromethanesulfonyl azide in a 0.4 N methylene chloride solution (120 ml, 48 mmo).
l) was added and stirred at room temperature for 18 hours. This solution was concentrated under reduced pressure, and purified by silica gel chromatography.
Elution with cyclohexane-ethyl acetate (3: 2) gave 6.33 g (yield: 91%) of the target compound as a white solid having a melting point of 67 ° C.

IR (film) spectrum: 3452, 2996,
2887, 2113cm ^-1 nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ: 1.37 (3H,
s), 1.51 (3H, s), 3.21-3.26 (2H, m), 3.40 (1H, t,
J = 9.5 Hz), 3.53 (1H, t, J = 9.2 Hz), 3.78 (1H, t, J =
10.6 Hz), 3.86 (1H, dd, J = 5.5, 10.6 Hz), 4.09-4.16
(1H, m), 4.31-4.36 (1H, m), 4.45 (1H, d, J = 7.3 H
z), 5.17-5.35 (2H, m), 5.93 (1H, m) Mass spectrum (m / z): 286.1413 (M + H) ⁺ Elemental analysis: C ₁₂ H ₁₉ N ₃ O ₅ (molecular weight: 285.3) Calculated value (%) C 50.52 H 6.71 N 14.73 Analytical value (%) C 49.44 H 6.62 N 14.81

[0315]

Reference Example 2 Allyl 2-azido-3-O-Ｏ (R)-
3-benzyloxytetradecyl｝ -2-deoxy-
4,6-O-isopropylidene-β-D-glucopyrano
A solution of 4.52 g (15.8 mmol) of the azide of Reference Example 1 in dimethylformamide (60 ml) was added at 0 ° C. with sodium hydride 96
3 mg (55% oily, <22.0 mmol) was added and stirred at the same temperature for 15 minutes. To this solution was added 5.74 g of (R) -3-benzyloxy-1-methanesulfonyloxytetradecane (14.4 mmo).
l) was added and stirred at room temperature for 20 hours. Thereafter, the reaction was stopped by adding water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, purified by silica gel column chromatography, and cyclohexane-ethyl acetate (4: 1)
Elution gave 6.23 g (yield: 74%) of the desired compound.

IR (CHCl ₃ solution) spectrum: 2928, 2856, 2114 cm ⁻¹ Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3H,
t, J = 6.6 Hz), 1.26-1.62 (26H, m, containing 3H,
s, at 1.39 ppm, 3H, s, at 1.47 ppm), 1.70-1.84 (2
H, m), 3.13-3.23 (2H, m), 3.33 (1H, t, J = 8.0, 9.6H
z), 3.53-3.63 (2H, m), 3.72-3.81 (2H, m), 3.82-3.95
(2H, m), 4.13 (1H, dd, J = 6.1, 12.7 Hz), 4.31-4.39
(2H, m, containing 1H, d, J = 8.0Hz, at 4.32 ppm), 4.
53 (2H, s), 5.22-5.38 (2H, m), 5.94 (1H, m), 7.25-7.45
(5H, m) Mass spectrum (m / z): 588.4023 (M + H) ⁺ elemental analysis: C ₃₃ H ₅₃ N ₃ O ₆ (molecular weight: 587.8) calculated (%) C 67.43 H 9.09 N 7.15 analysis (%) C 67.33 H 8.99 N 7.31

[0317]

Reference Example 3 2-azido-3-O-｛(R) -3-ben
Ziroxytetradecyl｝ -2-deoxy-4,6-O
-Isopropylidene-D-glucopyranose In a solution of 6.15 g (10.5 mmol) of the 1-allyl compound of Reference Example 2 in 120 ml of tetrahydrofuran was added (1,5-cyclooctadiene) bis- (methyldiphenylphosphine) -iridium.
After adding 450 mg of hexafluorophosphate and purging with hydrogen, the red solution becomes transparent.
Stirred for hours. Thereafter, 45 ml of water, 4.5 ml of pyridine and 2.3 g of iodine were added, and the mixture was stirred at room temperature. After 12 hours, the solution was concentrated under reduced pressure, diluted with ethyl acetate, 10% aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate,
The extract was washed successively with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, purified by silica gel column chromatography, and eluted with cyclohexane-ethyl acetate (3: 1) to give 3.71 g (yield: 65%, α, β mixture, α: β = 1: 1). The target compound of 1) was obtained.

IR (CHCl ₃ solution) spectrum: 4216, 2928,
2855, 2114 cm ^-1 nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3H,
t, J = 6.6 Hz), 1.26-1.60 (26H, m, containing 1.5H,
s, at 1.39 ppm, 1.5H, s, at 1.40 ppm, 3H, s, at 1.
48 ppm), 1.71-1.90 (2H, m), 2.93 (0.5H, broad, O
H), 3.18-3.27 (1.5H, m, containing 0.5H, OH), 3.30
-3.99 (8H, m), 4.46-4.60 (2.5H, m, containing 2H,
s, at 4.52 ppm), 5.23 (0.5H, d, J = 3.3 Hz), 7.22-7.
37 (5H, m) mass spectrum (m / z): 548.3683 (M + H) ⁺ elemental analysis: C ₃₃ H ₅₃ N ₃ O ₆ (molecular weight: 547.7) calculated (%) C 65.79 H 9.02 N 7.67 analysis Value (%) C 65.20 H 9.06 N 7.52

[0319]

Reference Example 4 2,2,2-Trichloroethylimidoyl
2-azido-3-O-{(R) -3-benzyloxy
Tetradecyl} -2-deoxy-4,6-O-isopro
Pyridene-α-D-glucopyranoside 3.66 g (6.70 mmol) of the compound of Reference Example 3 and 6.8 ml (67.8 mmol) of trichloroacetonitrile in methylene chloride (20 m2)
l) 104 mg (0.683 mmol) of 1,8-diazabicyclo [5,4,0] -7-undecene was added to the solution at 0 ° C., and the mixture was stirred for 2 hours.
The reaction was quenched by adding a saturated aqueous ammonium chloride solution, diluted with ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
When eluted with ethyl acetate (4: 1), 4.08 g (yield: 88%)
The desired compound was obtained.

IR (CHCl ₃ solution) spectrum: 4216, 2116,
1676, 1603 cm ^-1 nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3
H, t, J = 6.6 Hz), 1.26-1.65 (26H, m, containing 3
H, s, at 1.41 ppm, 3H, s, at 1.50 ppm), 1.73-1.95
(2H, m), 3.52-4.07 (9H, m), 4,53 (2H, s), 6.31 (1
H, d, J = 3.8 Hz), 7.25-7.35 (5H, m), 8.70 (1H, s, N
H) Mass spectrum (m / z): 713.2606 (M + Na) ⁺ elemental analysis: C ₃₃ H ₅₃ N ₃ O ₆ (molecular weight: 692.1) calculated (%) C 55.53 H 7.14 N 8.10 Cl 15.37 analysis ( %) C 55.53 H 6.78 N 7.93 Cl 15.45

[0321]

Reference Example 5 2,6-Anhydro-3-azido-4-O
-{(R) -3-benzyloxytetradecyl} -3-
Deoxy-5,7-O-isopropylidene-D-glyce
To 4.05 g (5.85 mmol) of the compound of Reference Example 4 was added sufficiently dried molecular sieves 4A and 1.2 ml (9.0 mmol) of trimethylsilyl cyanide to form a suspension of 30 ml of methylene chloride. . The suspension was stirred at room temperature for 2 hours under a nitrogen atmosphere. After removing the water in the reaction system, 40 mg of trimethylsilyl triflate was added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate, filtered, diluted with ethyl acetate, washed with water and saturated saline,
Dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and eluted with cyclohexane-ethyl acetate (4: 1) to obtain 3.04 g (yield: 93%) of the target compound.

IR (CHCl ₃ solution) spectrum: 4216, 2928,
2856, 2119 cm ^-1 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3H,
t, J = 6.6Hz), 1.26-1.58 (26H, m, containing 3H, s,
at 1.41 ppm, 3H, s, at 1.47 ppm), 1.70-1.91 (2H,
m), 3.52-4.05 (9H, m), 4.54, 4.48 (2H, ABq, J = 11.6
Hz), 4.78 (1H, d , J = 5.4 Hz), 7.24-7.36 (5H, m) Mass spectrum (m / z): 579.3505 ( M + Na) + Elemental _{analysis: C 31 H 48 N 4 O} 5 (Molecular weight: 556.7) Calculated value (%) C 66.88 H 8.69 N 10.06 Analytical value (%) C 66.79 H 8.91 N 10.00

[0323]

Reference Example 6 3-amino-2,6-anhydro-4-O-
{(R) -3-benzyloxytetradecyl} -3-deoxy
5,7-O-isopropylidene-D-glycero-D-i
To a solution of 3.02 g (5.42 mmol) of do-heptononitrile Reference Example 5 in tetrahydrofuran (30 ml) was added triphenylphosphine at 0 ° C.
After adding 1.49 g (5.68 mmol) and stirring at the same temperature for 1 hour, 15 ml of 28% aqueous ammonia was added and stirred at 60 ° C. for 20 hours. This solution was diluted with ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and eluted with cyclohexane-ethyl acetate (9: 1, 3: 2) to obtain 2.03 g (yield: 71%) of the target compound. .

IR (CHCl ₃ solution) spectrum: 3691, 2928,
2856, 1602 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.88 (3
H, t, J = 6.9 Hz), 1.26-1.65 (28H, m, containing 3H,
s, at 1.40 ppm, 3H, s, at 1.46 ppm), 2.95 (1H, dd,
J = 6.0, 9.7 Hz), 3.22 (1H, t, J = 9.2 Hz), 3.50-3.56
(2H, m), 3.65-3.76 (3H, m), 3,91 (1H, m), 3.99 (1
H, m), 4.46, 4.55 (2H, ABq, J = 11.7 Hz), 4.74 (1H,
d, J = 6.0 Hz), 7.26-7.36 (5H, m) Mass spectrum (m / z): 553.3603 (M + Na) ⁺ elemental analysis: C ₃₁ H ₅₀ N ₂ O ₅ (molecular weight: 530.7) calculated (%) C 70.15 H 9.50 N 5.28 Analytical value (%) C 69.72 H 9.47 N 4.52

[0325]

[Reference Example 7] 2,6-anhydro-3-R (R) -3-benzyl
Oxytetradecanamide｝ -4-O-｛(R) -3-benzyl
Ruoxytetradecyl｝ -3-deoxy-5,7-O-iso
Propylidene-D-glycero-D-ido-heptononitrile
To a solution of 1.96 g (3.71 mmol) of the compound of Reference Example 6 in methylene chloride (30 ml) was added dicyclohexylcarbodiimide 963.
mg (4.67 mmol), 4-dimethylaminopyridine 574 mg
(4.70 mmol) and 1.50 g (4.48 mmol) of (R) -3-benzyloxytetradecanoic acid were added, and the mixture was stirred at room temperature for 18 hours. After the urea generated during the reaction was filtered off, the solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with cyclohexane-ethyl acetate (4: 1) to obtain 2.79 g (yield: 89%) of the target compound.

IR (CHCl ₃ solution) spectrum: 3691, 2928,
2855, 1672, 1603 cm ^-1 nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3
H, t, J = 6.6 Hz), 1.25-1.77 (48H, m, containing 3H,
s, at 1.39 ppm, 3H, s, at 1.44 ppm), 2.35 (1H, dd,
J = 6.5, 15.5 Hz), 2.54 (1H, dd, J = 3.6, 15.5 Hz),
3.21-3.30 (2H, m), 3.40 (1H, m), 3.56-3.81 (5H, m),
3.86-4.03 (2H, m), 4.40, 4.45 (2H, ABq, J = 11.7 H
z), 4.55 (2H, s), 5.25 (1H, d, J = 6.0 Hz), 7.10 (1H,
d, J = 5.5 Hz, NH), 7.25-7.40 (10H, m) Mass spectrum (m / z): 847.6199 (M + H) ⁺ elemental analysis: C ₅₂ H ₈₂ N ₂ O ₇ (molecular weight: 847.2) Calculated value (%) C 73.72 H 9.76 N 3.31 Analysis value (%) C 73.50 H 9.82 N 3.55

[0327]

Reference Example 8 diphenylmethyl 2,6-anhydro-
3-{(R) -3-benzyloxytetradecanamide}
-4-O-｛(R) -3-benzyloxytetradeci
Ru-3-deoxy-D-glycero-D-ido-hept
To 2.70 g (3.19 mmol) of the compound of Reference Example 7, 4 ml of hydrochloric acid-dioxane (15 ml) and water (3 ml) were added, and the mixture was stirred at 80 ° C. for 72 hours. The solution was concentrated under reduced pressure and dried sufficiently. The obtained residue was dissolved in dimethylformamide (15 ml), and diphenyldiazomethane (1.87 g, 9.63 mmol) was added.
Stirred for hours. The reaction was stopped by adding water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and eluted with cyclohexane-ethyl acetate (1: 1) to obtain 1.35 g (yield: 43%) of the target compound.

IR (CHCl ₃ solution) spectrum: 3691, 2928,
2855, 1672, 1603 cm ^-1 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (6H,
t, J = 6.5 Hz), 1.25-1.71 (42H, m), 1.95 (1 H, broa
d, OH), 2.29 (2H, d, J = 5.3 Hz), 3.30 (1H, broad, O
H), 3.35-3.74 (10H, m), 4.32, 4.38 (2H, ABq, J = 11.
3 Hz), 4.43 (2H, s), 4.62 (1H, d, J = 5.6 Hz), 6.84
(1H, s), 6.87 (1H, d, J = 8.8 Hz, NH), 7.23-7.33 (20
H, m) Mass spectrum (m / z): 992.6610 (M + H) ⁺ elemental analysis: C ₅₂ H ₈₂ N ₂ O ₇ (molecular weight: 992.4) calculated (%) C 75.04 H 9.04 N 1.41 analysis ( %) C 74.62 H 8.94 N 1.43

[0329]

Reference Example 9 2- (4-methoxyphenyl) -4-
1.85 g of (R) -undecyl- [1,3] dioxane (R) -1,3-dihydroxytetradecane (8.0 m
mol) in dimethylformamide (20 ml), 152 mg (0.80 mmol) of p-toluenesulfonic acid and 4-methoxy-
2.9 g of benzaldehyde dimethyl acetal (16.0 mmo
l) was added and the mixture was stirred at room temperature for 2 hours. This solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and eluted with cyclohexane-ethyl acetate (9: 1) to obtain 2.78 g (yield: 99%) of the target compound.

IR (CHCl ₃ solution) spectrum: 2928, 2856,
1616, 1518 cm ^-1 nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3H,
t, J = 6.5 Hz), 1.19-1.56 (20H, m), 1.60-1.81 (2H,
m), 3.75-3.82 (4H, m, containing 3H, s, at3.80 pp
m), 3.94 (1H, m), 4.24 (1H, m), 5.46 (1H, s), 6.89
(2H, d, J = 8.6 Hz), 7.42 (2H, d, J = 8.7 Hz) Mass spectrum (m / z): 349.22751 (M + H) ⁺ elemental analysis: C ₂₂ H ₃₆ O ₃ (molecular weight: 348.52) Calculated value (%) C 75.82 H 10.41 Analytical value (%) C 75.60 H 10.68

[0331]

Reference Example 10 (R) -3- (4-methoxybenzylo)
Xy ) -1-hydroxytetradecane To a solution of 2.71 g (7.80 mmol) of the compound of Reference Example 9 in methylene chloride (25 ml) was added 24 ml (24.0 mmol) of a 1.0 M solution of isobutylaluminum hydride in methylene chloride, and the mixture was purged with nitrogen. The mixture was stirred at -78 ° C. Two hours later, the reaction was stopped by adding a saturated aqueous solution of ammonium chloride, and an aqueous solution of potassium sodium tartrate was added, followed by stirring at room temperature for 30 minutes. The organic layer was separated, washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with cyclohexane-ethyl acetate (7: 3) to obtain 2.54 g (yield: 93%) of the target compound.

IR (CHCl ₃ solution) spectrum: 3626, 3499,
2929, 2857, 1613, 1514 cm ^-1 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3H,
t, J = 6.6 Hz), 1.27-1.84 (22H, m), 2.44 (1H, t, J =
5.4 Hz, OH), 3.62 (1H, m), 3.69-3.82 (5H, m, contai
ning 3H, at 3.80 ppm), 4.41, 4.54 (2H, ABq, J = 11.1
Hz), 6.88 (2H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.6 H
z) Mass spectrum (m / z): 350.2800 (M ⁺ ) Elemental analysis: C ₂₂ H ₃₈ O ₃ (molecular weight: 350.54) Calculated (%) C 74.77 H 11.10 Analytical value (%) C 75.38 H 10.93

[0333]

Reference Example 11 (R) -3- (4-methoxybenzylo)
Xy) -1-methanesulfonyloxytetradecane To a solution of 2.50 g (7.10 mmol) of the compound of Reference Example 10 in methylene chloride (20 ml) was added 1.5 ml of triethylamine (10.
7 mmol), methanesulfonyl chloride 1.22 g (10.7 mmo
l) was added and stirred for 1 hour. This solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, a saturated aqueous solution of sodium bicarbonate, and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography.
After elution in 3), 3.02 g (yield: 99%) of the target compound was obtained.

IR (CHCl ₃ solution) spectrum: 2929, 2857,
1613 cm ^-1 nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3H,
t, J = 6.6 Hz), 1.27 (18H, brs), 1.43-1.66 (2H, m),
1.81-1.98 (2H, m), 2.95 (3H, s), 3.54 (1H, m), 3.8
0 (3H, s), 4.26-4.51 (4H, m, containing 2H, ABq, J
= 11.0 Hz, at4.38, 4.51 ppm), 6.88 (2H, d, J = 8.7 H
z), 7.26 (2H, d, J = 8.6 Hz) Mass spectrum (m / z): 428.2584 (M ⁺ ) Elemental analysis: C ₂₃ H ₄₀ O ₅ S (molecular weight: 428.63) Calculated (%) C 64.45 H 9.41 S 7.48 Analytical value (%) C 63.99 H 9.53 S 7.57

[0335]

Reference Example 12 Allyl 2-deoxy-4,6-O-i
Sopropylidene-3-O-｛(R) -3- (4-methoxy
Cibenzyloxy) tetradecyl} -2-trifluoro
1.28 g (3.60 mmol) of acetamide-α-D-glucopyranoside starting material allyl 2-deoxy-4,6-O-isopropylidene-2-trifluoroacetamide-α-D-glucopyranoside in dimethylformamide (15 m
l) Add sodium hydride (55% oil, 205m
g) and stirred for 15 minutes.
1.29 g (3.00 mmol) of 3- (4-methoxybenzyloxy) -1-methanesulfonyloxytetradecane was added,
The mixture was stirred at room temperature for 18 hours. The reaction was stopped by adding water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography, and eluted with cyclohexane-ethyl acetate (3: 1) to give 1.74 g (yield: 84
%) Of the desired compound.

IR (CHCl ₃ solution) spectrum: 3429, 2929,
2857, 1734 cm ^-1 nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3H,
t, J = 6.5 Hz), 1.26-1.49 (26H, m, containing 3H, s,
at 1.40 ppm, 3H, s, at 1.49 ppm), 1.64-1.78 (2H,
m), 3.41-3.91 (11H, m, containing 3H, s, at 3.80 pp
m), 3.99 (1H, m), 4.13-4.21 (2H, m), 4.36-4.43 (2H, A
Bq, J = 11.2 Hz), 4.87 (1H, d, J = 3.8 Hz), 5.24-5.32 (2
H, m), 5.87 (1H, m), 6.41 (1H, d, J = 9.3 Hz, NH), 6.8
7 (2H, d, J = 8.6 Hz), 7.25 (2H, d, J = 7.9 Hz) Mass spectrum (m / z): 710.3851 (M + Na) ⁺ elemental analysis: C ₃₆ H ₅₆ F ₃ NO ₈ (Molecular weight: 687.84) Calculated value (%) C 62.86 H 8.21 N 2.04 F 8.29 Analytical value (%) C 62.36 H 8.15 N 2.07 F 7.94

[0337]

Reference Example 13 Allyl 2-amino-2-deoxy-
4,6-O-isopropylidene-3-O-｛(R) -3
-(4-methoxybenzyloxy) tetradecyl｝ -α
-D-glucopyranoside 1.45 g (2.11 mmol) of the compound of Reference Example 12 was added to ethanol 10
Dissolve in 10 ml of 1N aqueous sodium hydroxide solution at 60 ° C.
Stirred for hours. The solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, purified by silica gel column chromatography, and eluted with cyclohexane-ethyl acetate (2: 3) to obtain 1.23 g (yield: 99%) of the target compound.

IR (CHCl ₃ solution) spectrum: 2928, 2855,
1612 cm ^-1 nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3H,
t, J = 6.6 Hz), 1.26-1.62 (28H, m, containing 3H, s,
at 1.39 ppm, 3H, s, at 1.48 ppm), 1.71-1.85 (2H,
m), 2.72 (1H, dd, J = 3.7, 9.5 Hz), 3.27 (1H, t, J = 9.
1Hz), 3.49-3.86 (9H, m, containing 3H, s, at 3.80 p
pm), 4.17 (1H, m), 4.40, 4.47 (2H, ABq, J = 11.2 Hz),
4.86 (1H, d, J = 3.6 Hz), 5.19-5.34 (2H, m), 5.88 (1H,
m), 6.87 (2H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.6 Hz) Mass spectrum (m / z): 592.4207 (M + H) ⁺ elemental analysis: C ₃₄ H ₅₇ NO ₇ (Molecular weight: 591.83) Calculated value (%) C 69.00 H 9.71 N 2.37 Analysis value (%) C 68.16 H 10.21 N 2.31

[0339]

Reference Example 14 Allyl 2-deoxy-4,6-O-i
Sopropylidene-3-O-｛(R) -3- (4-methoxy
Cibenzyloxy) tetradecyl｝ -2- (2,2,
2, -trichloroethoxycarbonylamino) -α-D
- in methylene chloride (8 ml) solution of the compound of glucopyranoside Reference Example 13 1.20g (2.03 mmol), saturated aqueous sodium hydrogen carbonate solution 8 ml, chloroformate 2,2,2-trichloroethyl 534 mg (2.52 mmol) was added, 30 at room temperature Stirred for minutes. This solution was diluted with ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, purified by silica gel column chromatography, and eluted with cyclohexane-ethyl acetate (4: 1) to obtain 1.47 g (yield: 94%) of the target compound.

IR (CHCl ₃ solution) spectrum: 3440, 2929,
2857, 1744, 1613 cm ^-1 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3H,
t, J = 6.6 Hz), 1.26-1.48 (26H, m, containing 3H, s,
at 1.40 ppm, 3H, s, at 1.48 ppm), 1.62-1.78 (2H,
m), 3.38-4.02, (13H, m, containing 3H, s, at 3.80 pp
m), 4.16 (1H, m), 4.39, 4.45 (2H, ABq, J = 11.2 Hz),
4.68,4.74 (2H, ABq, J = 12.0Hz), 4.86 (1H, d, J = 3.7Hz),
5.13-5.32 (3H, m), 5.89 (1H, m), 6.88 (2H, d, J = 8.6 H
z), 7.27 (2H, d, J = 8.5 Hz) Mass spectrum (m / z): 788.3077 (M + Na) ⁺ elemental analysis: C ₃₇ H ₅₈ NO ₉ Cl ₃ (molecular weight: 767.22) calculated (%) ) C 57.92 H 7.62 N 1.83 Cl 13.86 Analytical value (%) C 57.40 H 7.38 N 1.85 Cl 13.87

[0341]

Reference Example 15 Allyl 2-deoxy-3-O-
｛(R) -3- (4-methoxybenzyloxy) tetra
Decyl II-2- (2,2,2, -trichloroethoxyca
(Rubonylamino) -α-D-glucopyranoside 885 mg (1.15 mmol) of the compound of Reference Example 14 was dissolved in an 80% aqueous acetic acid solution and stirred at 60 ° C. for 1 hour. The solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and eluted with cyclohexane-ethyl acetate (2: 3) to obtain 696 mg (83%) of the target compound.

IR (CHCl ₃ solution) spectrum: 3601, 3436,
2928, 1742, 1612 cm ^-1 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3H,
t, J = 6.6 Hz), 1.26 (18H, brs), 1.43-1.80 (4H, m), 2.
08 (1H, broad, OH), 3.41-3.54 (4H, m), 3.56-3.91 (9H,
m, containing 3H, s, at 3.81ppm), 3.99 (1H, dd, J =
6.3, 12.8Hz), 4.18 (1H, dd, J = 5.3, 12.8Hz), 4.39,
4.45 (2H, ABq, J = 11.2 Hz), 4.68,4.75 (2H, ABq, J = 12.
0Hz), 4.85 (1H, d, J = 3.5Hz), 5.21-5.32 (3H, m), 5.89
(1H, m), 6.88 (2H, d, J = 8.8Hz), 7.26 (2H, d, J = 8.5H
z) Mass spectrum (m / z): 748.2744 (M + Na) ⁺ elemental analysis: C ₃₄ H ₅₄ NO ₉ Cl ₃ (molecular weight: 727.15) calculated (%) C 56.16 H 7.49 N 1.93 Cl 14.63 analysis ( %) C 56.10 H 7.36 N 1.96 Cl 14.60

[0343]

Reference Example 16 Allyl 6-O-benzyloxycarbo
Nyl-2-deoxy-3-O-{(R) -3- (4-me
Toxylbenzyloxy) tetradecyl} -2- (2,
2,2-trichloroethoxycarbonylamino) -α-
In methylene chloride (5ml) solution of D- glucopyranoside compound 366 mg of Reference Example 15 (0.503 mmol), pyridine at 0 ℃ 60.4 mg (0.764 mmo
l), 90 μl of benzyloxycarbonyl chloride (0.630
mmol), and the mixture was stirred at the same temperature for 30 minutes, and further stirred at room temperature for 2 hours. Dilute this solution with ethyl acetate and add 1N
The extract was washed with an aqueous solution of ammonium chloride, an aqueous solution of saturated sodium bicarbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, purified by silica gel column chromatography, and cyclohexane-ethyl acetate (3:
Elution with 1) gave 419 mg (yield: 97%) of the desired compound.

IR (CHCl ₃ solution) spectrum: 3436, 2928,
2856, 1744, 1612 cm ^-1 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3H,
t, J = 6.6 Hz), 1.26-1.78 (22H, m), 3.37-3.53 (4H, m, c
ontaining OH), 3.69-3.99 (8H, m, containing3H, s, a
t 3.79ppm), 4.15 (1H, dd, J = 5.3, 13.0Hz), 4.37-4.47
(4H, m), 4.67,4.74 (2H, ABq, J = 12.1Hz), 4.84 (1H, d,
J = 3.7Hz), 5.18-5.30 (5H, m), 5.87 (1H, m), 6.87 (2H,
d, J = 8.6Hz), 7.25 (2H, d, J = 7.3Hz), 7.33-7.41 (5H,
m) Mass spectrum (m / z): 858.3133 (MH) ⁺ elemental analysis: C ₄₂ H ₆₀ NO ₁₁ Cl ₃ (molecular weight: 861.28) calculated (%) C 58.57 H 7.02 N 1.63 Cl 12.35 analytical value (%) C 58.38 H 6.93 N 1.61 Cl 12.58

[0345]

Reference Example 17 Allyl 6-O-benzyloxycarbo
Nyl-2-deoxy-4-O-diphenylphosphono-3
—O-｛(R) -3- (4-methoxybenzyloxy)
Tetradecyl} -2- (2,2,2-trichloroethoxy
(Cicarbonylamino ) -α-D-glucopyranoside 83.7 mg of 4-dimethylaminopyridine was added to a solution of 390 mg (0.453 mmol) of the compound of Reference Example 16 in methylene chloride (3 ml).
(0.679 mmol) and diphenylphosphinoyl chloride 1
40 μl (0.675 mmol) was added, and the mixture was stirred at room temperature for 1 hour.
This solution was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and eluted with cyclohexane-ethyl acetate (3: 1) to obtain 467 mg (yield: 94%) of the target compound.

IR (CHCl ₃ solution) spectrum: 3435, 2928.
2855, 1747, 1612 cm ^-1 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3H,
t, J = 6.6 Hz), 1.17-1.72 (22H, m), 3.37 (1H, m), 3.65-
3.84 (6H, m, containing 3H, s, at 3.78ppm), 3.93-4.0
4 (3H, m), 4.14 (1H, dd, J = 5.3, 12,9Hz), 4.20-4.39 (4
H, m), 4.63 (1H, m), 4.49,4.76 (2H, ABq, J = 12.1Hz),
4.87 (1H, d, J = 3.6Hz), 5.06, 5.12 (2H, ABq, J = 12.2H
z), 5.21-5.30 (3H, m), 5.86 (1H, m), 6.83 (2H, d, J =
8.6 Hz), 7.11-7.37 (17H, m) Mass spectrum (m / z): 1090.3431 (MH) ⁺ elemental analysis: C ₅₄ H ₆₉ NO ₁₄ PCl ₃ (molecular weight: 1093.47) Calculated (%) C 59.32 H 6.36 N 1.28 P 2.83 Cl 9.73 Analytical value (%) C 59.35 H 6.35 N 1.21 P 3.04 Cl 9.80

[0347]

Reference Example 18 Allyl 6-O-benzyloxycarbo
Nyl-2-deoxy-4-O-diphenylphosphono-3
—O-{(R) -3-hydroxytetradecyl} -2-
(2,2,2-trichloroethoxycarbonylamino)
-Α -D- Glucopyranoside A solution of 338 mg (0.309 mmol) of the compound of Reference Example 17 in methylene chloride (3 ml) was added with 0.3 ml of water and 84.6 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone ( 0.373 mmol) and stirred at room temperature for 1 hour. This solution was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over magnesium sulfate. Purification by silica gel column chromatography and elution with cyclohexane-ethyl acetate (7: 3) gave 283 mg (yield: 94%) of the desired compound.

IR (CHCl ₃ solution) spectrum: 3435, 2927.
2855, 1746, 1592 cm ^-1 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3H,
t, J = 6.6 Hz), 1.25-1.75 (22H, m), 3.64-3.85 (4H, m),
3.95-4.08 (3H, m), 4.15 (1H, dd, J = 5.3, 12.7Hz), 4.2
3-4.38 (2H, m), 4.63-4.75 (3H, m), 4.93 (1H, d, J = 3.6
Hz), 5.04, 5.11 (2H, ABq, J = 12.2Hz), 5.22-5.31 (2H,
m), 5.44 (1H, d, J = 9.2 Hz, NH), 5.88 (1H, m), 7.11-
7.34 (15H, m) Mass spectrum (m / z): 972.3010 (M + H) ⁺ elemental analysis: C ₄₆ H ₆₁ NO ₁₃ PCl ₃ (molecular weight: 973.31) calculated (%) C 56.77 H 6.32 N 1.44 P 3.18 Cl 10.93 Analytical value (%) C 56.60 H 6.49 N 1.45 P 3.33 Cl 11.17

[0349]

Reference Example 19 Allyl 6-O-benzyloxycarbo
Nyl-2-deoxy-4-O-diphenylphosphono-3
—O-｛(R) -3-tetradecanoyloxytetrade
Sil｝ -2- (2,2,2-trichloroethoxycarbo
Nylamino) -α-D-glucopyranoside A solution of 271 mg (0.278 mmol) of the compound of Reference Example 18 in tetrahydrofuran (3 ml) was mixed with 60 μl (0.427 mmol) of triethylamine.
l), 4-dimethylaminopyridine 51.3 mg (0.420 mmo
l) and 0.12 ml (0.438 mmol) of myristic acid chloride were added, and the mixture was stirred at room temperature for 18 hours. This solution was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and purified by silica gel column chromatography.
Elution with cyclohexane-ethyl acetate (4: 1) gave 305
mg (yield: 93%) of the target compound was obtained.

IR (CHCl ₃ solution) spectrum: 3435, 2927,
2855, 1746, 1592 cm ^-1 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3H,
t, J = 6.6 Hz), 1.19-1.71 (44H, m), 2.20 (2H, t, J = 7.5
Hz), 3.50 (1H, m), 3.68 (1H, m), 3.82 (1H, m), 3.92-
4.01 (3H, m), 4.15 (1H, dd, J = 5.3, 13.0Hz), 4.28-4.41
(2H, m), 4.63 (1H, m), 4.75 (2H, s), 4.84-4.93 (2H,
m, containing 1H, d, J = 3.6Hz, at 4.90ppm), 5.05,
5.11 (2H, ABq, J = 12.2Hz), 5.20-5.34 (2H, m), 5.78 (1
H, d, J = 10.7 Hz, NH), 5.87 (1H, m), 7.12-7.34 (15H,
m) Mass spectrum (m / z): 1182.5021 (M + H) ⁺ elemental analysis: C ₆₀ H ₈₇ NO ₁₄ PCl ₃ (molecular weight: 1183.66) calculated (%) C 60.88 H 7.41 N 1.18 P 2.62 Cl 8.99 analysis Value (%) C 61.22 H 7.46 N 1.13 P 2.72 Cl 9.18

[0351]

Reference Example 20 6-O-benzyloxycarbonyl-2
-Deoxy-4-O-diphenylphosphono-3-O-
{(R) -3-tetradecanoyloxytetradecyl}
-2- (2,2,2-trichloroethoxycarbonyla
(Mino) -α-D-glucopyranose In a solution of 136 mg (0.114 mmol) of the compound of Reference Example 19 in tetrahydrofuran (3 ml) was added (1,5-cyclooctadiene) bis- (methyldiphenylphosphine) -iridium hexafluorophosphate 3.6. mg was added and the mixture was replaced with hydrogen and the red solution became transparent. Then, the mixture was replaced with nitrogen and stirred at room temperature for 2 hours. Then 0.3 ml of water, 15 mg of pyridine, 22 iodine
mg was added and the mixture was stirred at room temperature for 1 hour. The solution was diluted with ethyl acetate, washed sequentially with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, purified by silica gel column chromatography, and eluted with cyclohexane-ethyl acetate (7: 3) to obtain 106 mg (yield: 81%) of the target compound.

IR (CHCl ₃ solution) spectrum: 3599, 3434,
3326, 2927, 2855, 1746, 1592 cm ^-1 nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.88 (3H,
t, J = 6.6 Hz), 1.20-1.77 (44H, m), 2.21 (2H, t, J = 7.5
Hz), 3.41-3.53 (2H, m, containing OH), 3.75 (1H, m),
3.83-3.95 (2H, m), 4.19-4.43 (3H, m), 4.58-4.79 (3H, m
m), 4.92 (1H, m), 5.04, 5.11 (2H, ABq, J = 12.1Hz),
5.29 (1H, m), 6.03 (1H, d, J = 8.6 Hz, NH), 7.12-7.34
(15H, m) Mass spectrum (m / z): 1164.4518 (M + Na) ⁺ elemental analysis: C ₅₇ H ₈₃ NO ₁₄ PCl ₃ (molecular weight: 1143.60) calculated (%) C 59.87 H 7.37 N 1.23 P 2.71 Cl 9.30 Analytical value (%) C 59.84 H 7.29 N 1.46 P 2.76 Cl 9.05

[0353]

[Reference Example 21] 2,2,2-Trichloroethylimide
6-O-benzyloxycarbonyl-2-deoxy
-4-O-diphenylphosphono-3-O-{(R) -3
-Tetradecanoyloxytetradecyl} -2- (2,
2,2-trichloroethoxycarbonylamino) -α-
83.1 mg (0.0726 mmol) of 6-benzyloxy-2-trichloroethoxycarbonylaminoglucose of D-glucopyranose Reference Example 20
Of methylene chloride (2 ml) was added with 80 μl (0.798 mmol) of trichloroacetonitrile, and at 0 ° C., 5 mg of 1,8-diazabicyclo [5,4,0] -7-undecene (DBU, 0.0329 mmol) was added and stirred. . After stirring at 0 ° C. for 1 hour, excess DBU was quickly removed by short silica gel column chromatography (cyclohexane-ethyl acetate 3: 1) to obtain the desired compound. This compound was used without purification.

[0354]

Reference Example 22 diphenylmethyl 2,6-anhydro
-7-O- [6-O-benzyloxycarbonyl-2-
Deoxy-4-O-diphenylphosphono-3-O-
{(R) -3-tetradecanoyloxytetradecyl}
-2- (2,2,2-trichloroethoxycarbonyla
Mino) -β-D-glucopyranosyl] -3-{(R)-
3-benzyloxytetradecanamide {-4-O-
{(R) -3-benzyloxytetradecyl} -3-de
Oxy-D-glycero-D-ido-heptonate To a solution of 54.8 mg of the compound of Reference Example 21 in methylene chloride (3 ml) was sufficiently dried molecular sieves 4A and 35.0 mg (0.0353 mmol) of the diol derivative of Reference Example 8. In addition, −78
Stirred at ° C. To this suspension was added 5 μl (0.0276 mmol) of trimethylsilyltrifluoromethanesulfonate, and the mixture was stirred. After 2 hours, the reaction was stopped by adding a saturated aqueous solution of sodium hydrogen carbonate. Dilute this solution with ethyl acetate,
The extract was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
Elution with 3) gave 65.1 mg (yield: 87%) of the desired compound.

IR (CHCl ₃ solution) spectrum: 3432, 3354,
2927, 2855, 1739, 1670 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.88 (12H,
t, J = 6.5-7.1Hz), 1.00-1.73 (86H, m), 2.19-2.26 (4H,
m), 3.04 (1H, brs, OH), 3.15 (1H, m), 3.38-3.68 (12
H, m), 3.85-3.97 (2H, m), 4.20 (1H, dd, J = 5.2, 11.9H
z), 4.27-4.53 (7H, m, containing 1H, d, J = 5.5Hz, at
4.62ppm), 4.78 (1H, ABq, J = 12.1Hz), 4.94-5.12 (3H,
m, containing 2H, ABq, J = 12.1Hz, at 5.04, 5.10Hz),
5.97 (1H, m, NH), 6.80 (1H, d, J = 8.7Hz, NH), 6.82 (1
H, s), 7.12-7.36 (35H, m) Mass spectrum (m / z): 2138.0940 (M + Na) ⁺

[0356]

Reference Example 23 diphenylmethyl 2,6-anhydro
-7-O- [2-acetamido-6-O-benzyloxy
Carbonyl-2-deoxy-4-O-diphenylphospho
No-3-O-｛(R) -3-tetradecyloxytetra
Decyl {-β-D-glucopyranosyl] -3-{(R)
-3-benzyloxytetradecanamide カ ナ -4-O-
{(R) -3-benzyloxytetradecyl} -3-de
Oxy-D-glycero-D-ido-heptonate 60.8 mg (0.0287 mmol) of the compound of Reference Example 22 was treated with acetic acid (2m
l) 40.2 mg of zinc powder was added to the solution, and the mixture was stirred at room temperature for 24 hours. The solution was filtered through celite and concentrated under reduced pressure.
The obtained residue was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and further dissolved in tetrahydrofuran (0.4 ml) -water (0.8 ml).
l, 10 μl of acetic anhydride was added, and the mixture was stirred at room temperature for 4 hours. This solution was diluted with ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate.

The solvent was distilled off under reduced pressure, purified by silica gel column chromatography, and eluted with cyclohexane-ethyl acetate (3: 2) to give 40.2 mg (yield: 70%, 2 steps).
The target compound of s) was obtained.

IR (CHCl ₃ solution) spectrum: 3432, 3365,
2927, 2855, 1738, 1668cm ^-1 NMR spectrum _{(400MHz, CDCl 3) δ:} 0.88 (12H,
t, J = 6.6-7.3Hz), 1.00-1.76 (86H, m), 1.92 (3H, s),
2.17-2.26 (4H, m), 3.08 (1H, m), 3.33-3.72 (12H, m),
3.89-4.02 (2H, m), 4.21 (1H, dd, J = 5.1, 11.9Hz), 4.2
8-4.52 (7H, m), 4,63 (1H, d, J = 5.7Hz), 5.02-5.10 (3H,
m, containing 2H, ABq, J = 12.1Hz, at5.03, 5.10ppm),
5.27 (1H, d, J = 8.2Hz), 6.64 (1H, d, J = 6.3Hz, NH),
6.78 (1H, d, J = 8.9Hz, NH), 6.81 (1H, s), 7.12-7.37 (3
5H, m) Mass spectrum (m / z): 2006.2009 (M + Na) ⁺

[0359]

Reference Example 24 2,6-Anhydro-7-O- [2-A
Cetamide-2-deoxy-4-O-diphenylphosphono
-3-O-｛(R) -3-tetradecanoyloxytet
Ladecyl {-β-D-glucopyranosyl] -3-
{(R) -3-hydroxytetradecanamide} -4-O
-{(R) -3-hydroxytetradecyl} -3-deo
Xy-D-glycero-D-ido-heptonynic acid To a solution of 9.1 mg (0.00459 mmol) of the compound of Reference Example 23 in 0.5 ml of ethyl acetate was added 10.6 mg of 20% palladium hydroxide-carbon.
Was added and stirred vigorously under a hydrogen atmosphere at room temperature for 14 hours. This solution was filtered through celite, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with chloroform-methanol (8: 1). The solvent was distilled off under reduced pressure, and the obtained residue was diluted with ethyl acetate, washed with a 0.05M aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 4.0 mg (yield: 58
%) Of the desired compound.

IR (CHCl ₃ solution) spectrum: 3691, 3606,
3415, 3358, 1716, 1662, 1602 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.88 (12H,
m, J = 6.7Hz), 1.20-1.65 (86H, m), 2.23-2.43 (4H, m),
2.00 (3H, s), 3.38-3.94 (22H, m), 4.05-4.10 (1H, m),
4.38-4.48 (2H, m), 4.65 (1H, m), 4.90 (1H, m), 4.98
(1H, m), 7.19-7.36 (10H, m) Mass spectrum (m / z): 1525.9994 (M + Na) ⁺

[0361]

Reference Example 25 Allyl 6-O-tert-butyldim
Tylsilyl-2-deoxy-3-O-{(R) -3-
(4-methoxybenzyloxy) tetradecyl} -2-
(2,2,2-trichloroethoxycarbonylamido
(D ) To a solution of 1.15 g (1.58 mmol) of the compound of Reference Example 15 in methylene chloride (5 ml) was added 304 mg of 4-dimethylaminopyridine (2.4 g).
9 mmol), 364 mg of tert-butyldimethylsilyl chloride
(2.42 mmol), and the mixture was stirred at room temperature for 3 hours. The solution was diluted with ethyl acetate, washed with water, a saturated aqueous solution of sodium bicarbonate, and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with cyclohexane-ethyl acetate (4: 1) to obtain 1.28 g (yield: 96%) of the target compound.

IR (CHCl ₃ solution) spectrum: 3437, 2955,
2929, 2856, 1742, 1613, 1514 cm ^-1 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.087 (6H,
s), 0.86-0.91 (12H, m), 1.26 (18H, brs), 1.40-1.80 (4
H, m), 3.34-3.67 (4H, m, containing OH), 3.76-3.93 (9
H, m, containing 3H, s, at 3.80 ppm), 3.98 (1H, dd,
J = 6.3, 12.8 Hz), 4.18 (1H, dd, J = 5.2, 12.9Hz), 4.4
0, 4.45 (2H, ABq, J = 11.5Hz), 4.70 (2H, s), 4.84 (1H,
d, J = 3.6Hz), 5.19-5.32 (3H, m, containing NH), 5.90
(1H, m), 6.87 (2H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.6 Hz) Mass spectrum (m / z): 862.3622 (M + Na) ⁺ Elemental analysis: C ₄₀ H ₆₈ NO ₉ PSi (molecular weight: 841.41) Calculated value (%) C 57.10 H 8.15 N 1.67 Cl 12.64 Analytical value (%) C 57.54 H 8.13 N 1.57 Cl 12.72

[0363]

Reference Example 26 Allyl 6-O-tert-butyldim
Tylsilyl-2-deoxy-4-O-diphenylphospho
No-3-O-{(R) -3- (4-methoxybenzylo)
Xy) tetradecyl} -2- (2,2,2-trichloro
Roethoxycarbonylamino) -α-D-glucopyrano
To a solution of 1.26 g (1.50 mmol) of the compound of Reference Example 25 in methylene chloride (5 ml) was added 278 mg of 4-dimethylaminopyridine (2.2 mg).
8 mmol), 0.46 ml of diphenylphosphinoyl chloride
(2.23 mmol) was added and the mixture was stirred at room temperature for 1 hour. This solution was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
After elution in 1), 1.57 g (yield: 98%) of the target compound was obtained.

IR (CHCl ₃ solution) spectrum: 3435, 2955,
2929, 2856, 1743, 1613 cm ^-1 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.002 (6H,
s), 0.86-0.92 (12H, m), 1.26 (18H, brs), 1.66-1.74 (4
H, m), 3.37 (1H, m), 3.69-3.87 (9H, m, containing 3
H, s, at 3.79ppm), 3.94-4.04 (2H, m), 4.22 (1H, dd,
J = 5.3, 12.7Hz), 4.30 (2H, s), 4.43-4.61 (2H, m), 4.7
5 (1H, m) 4.89 (1H, d, J = 3.6Hz), 5.20-5.34 (3H, m, co
ntaining NH), 5.91 (1H, m), 6.84 (2H, d, J = 8.6Hz),
7.14-7.33 (12H, m) Mass spectrum (m / z): 1094.3905 (M + Na) ⁺ elemental analysis: C ₅₂ H ₇₇ NO ₁₂ PCl ₃ Si (molecular weight: 1073.58) Calculated value (%) C 58.18 H 7.23 N 1.31 P 2.89 Cl 9.91 Analytical value (%) C 57.85 H 7.05 N 1.27 P 2.16 Cl 10.57

[0365]

Reference Example 27 Allyl 6-O-tert-butyldim
Tylsilyl-2-deoxy-4-O-diphenylphospho
No-3-O-{(R) -3-hydroxytetradecyl}
-2- (2,2,2, -trichloroethoxycarbonyl
Amino) -α-D-glucopyranoside In a solution of 1.50 g (1.40 mmol) of the compound of Reference Example 26 in methylene chloride (5 ml) was added 2,3-dichloro-5,6-dicyano-1,4-.
Add 386 mg (1.70 mmol) of benzoquinone and 0.5 ml of water,
Stirred at room temperature for 1 hour. This solution was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and purified by silica gel column chromatography.
Elution with cyclohexane-ethyl acetate (3: 1) gave 1.2
2 g (main rate: 91%) of the target compound was obtained.

IR (CHCl ₃ solution) spectrum: 4215, 3434,
2928, 2856, 1740 cm ^-1 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.002 (6H,
s), 0.82-0.90 (12H, m), 1.25-1.67 (22H, m), 3.65-3.8
7 (8H, m, containing OH), 3,93-4.04 (2H, m), 4.21 (1H,
dd, J = 5.3, 12.9Hz), 4.62 (1H, m), 4.75 (2H, s), 4.9
3 (1H, d, J = 3.7Hz), 5.22-5.34 (2H, m), 5.44 (1H, d, J
= 9.3Hz, NH), 5.91 (1H, m), 7.15-7.35 (10H, m) Mass spectrum (m / z): 974.3345 (M + Na) ⁺ elemental analysis: C ₄₄ H ₆₉ NO ₁₁ PCl ₃ Si (Molecular weight: 953.44) Calculated value (%) C 55.43 H 7.30 N 1.47 P 3.25 Cl 11.16 Analytical value (%) C 56.71 H 7.51 N 1.48 P 2.92 Cl 11.43

[0367]

Reference Example 28 Allyl 6-O-tert-butyldim
Tylsilyl-2-deoxy-4-O-diphenylphospho
No-3-O-｛(R) -3-tetradecanoyloxyte
Tradecyl II-2- (2,2,2-trichloroethoxy
Cicarbonylamino ) -α-D-glucopyranoside In a solution of 1.21 g (1.27 mmol) of the compound of Reference Example 27 in tetrahydrofuran (6 ml), 0.36 ml of triethylamine (2.56 m
mol), 326 mg of 4-dimethylaminopyridine (2.67 mmo)
l) and 0.70 ml (2.55 mmol) of myristic acid chloride were added, and the mixture was stirred at room temperature for 24 hours. This solution was diluted with ethyl acetate, washed with water, a saturated aqueous solution of sodium bicarbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, purified by silica gel column chromatography, and eluted with cyclohexane-ethyl acetate (4: 1) to obtain 1.40 g (yield: 95%) of the target compound.

IR (CHCl ₃ solution) spectrum: 3435, 2928,
2856, 1737 cm ^-1 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.013 (6H,
s), 0.86-0.92 (15H, m), 1.26 (40H, brs), 1.53-1.74 (4
H, m), 2.18 (2H, t, J = 7.3-7.7Hz), 3.55 (1H, m), 3.67-
4.07 (7H, m), 4.22 (1H, dd, J = 5.2-12.8Hz), 4.56 (1H,
m), 4.77 (2H, s), 4.83-4.91 (2H, m, containing 1H, d,
J = 3.6Hz, at 4.91ppm), 5.22-5.36 (2H, m), 5.68 (1H,
d, J = 9.4Hz, NH), 5.92 (1H, m), 7.15-7.35 (10H, m) Mass spectrum (m / z): 1200.5026 (M + K) ⁺ Elemental analysis: C ₅₈ H ₉₅ NO ₁₂ PCl ₃ Si (molecular weight: 1163.79) Calculated value (%) C 59.86 H 8.23 N 1.20 P 2.66 Cl 9.14 Analytical value (%) C 61.37 H 7.89 N 1.07 P 1.43 Cl 8.59

[0369]

Reference Example 29 Allyl 2-deoxy-4-O-diphenyl
Ruphosphono-3-O-｛(R) -3-tetradecanoyl
Xytetradecyl} -2- (2,2,2, -trichloroethoxy
To a solution of the compound of Reference Example 28 (1.35 g, 1.16 mmol) in tetrahydrofuran (9 ml) was added 3N aqueous hydrochloric acid (1.2 ml), and the mixture was stirred at room temperature for 2 hours. Dilute this solution with ethyl acetate,
Washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline,
Dried over magnesium sulfate.

The solvent was distilled off under reduced pressure, purified by silica gel column chromatography, and eluted with cyclohexane-ethyl acetate (7: 3) to obtain 1.11 g (yield: 91%) of the target compound.

IR (CHCl ₃ solution) spectrum: 3691, 3606,
3437, 2927, 2855, 1737 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.88 (6H,
t, J = 6.6Hz), 1.19-1.73 (44H, m), 2.23 (2H, t, J = 7.3-
8.1Hz), 3.52 (1H, m), 3.60-3.70 (4H, m), 3.89-4.03 (3
H, m), 4.17 (1H, dd, J = 5.1, 12.5Hz), 4.65 (1H, m),
4.73, 4.78 (2H, ABq, J = 12.5Hz), 4.91-4.95 (2H, m, con
taining 1H, d, J = 3.7Hz, at 4.95ppm), 5.23-5.35 (2H,
m), 5.82 (1H, d, J = 9.5Hz, NH), 5.89 (1H, m), 7.20-7.
38 (10H, m) Mass spectrum (m / z): 1070.4452 (M + Na) ⁺ elemental analysis: C ₅₂ H ₈₁ NO ₁₂ PCl ₃ (molecular weight: 1049.53) Calculated (%) C 59.51 H 7.78 N 1.34 P 2.95 Cl 10.13 Analytical value (%) C 59.30 H 7.90 N 1.51 P 2.94 Cl 10.24

[0372]

Reference Example 30 Allyl 2-deoxy-4-O-dife
Nylphosphono-6-O-methyl-3-O-{(R) -3
-Tetradecanoyloxytetradecyl} -2- (2,
2,2, -trichloroethoxycarbonylamino) -α
-D-glucopyranoside In a methylene chloride (5 ml) solution of 1.05 g (1.00 mmol) of the compound of Reference Example 29 at 0 ° C, 679 mg (3.31 mmol) of 2,6-di-tert-butyl-4-methylpyridine, trimethyloxonium 446 mg (3.02 mmol) of tetrafluoroborate was added, and the mixture was stirred for 3 hours. This solution was diluted with methylene chloride, washed with a saturated aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and purified by silica gel column chromatography.
Elution with hexane-ethyl acetate (7: 3) gave 966 mg (yield: 91%) of the desired compound.

IR (CHCl ₃ solution) spectrum: 3691, 3435,
2927, 2855, 1738 cm ^-1 nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.88 (6H,
t, J = 6.6-7.3Hz), 1.18-1.72 (44H, m), 2.18 (2H, t, J =
7.3-8.1Hz), 3.24 (3H, s), 3.48-3.59 (3H, m), 3.69 (1H,
m), 3.82-3.88 (2H, m), 3.96-4.04 (2H, m), 4.20 (1H,
dd, J = 5.1, 13.2Hz), 4.64-4.80 (3H, m), 4.88 (1H, m),
4.94 (1H, d, J = 3.7Hz), 5.22-5.35 (2H, m), 5.69 (1H,
d, J = 8.8 Hz, NH), 5.90 (1 H, m), 7.16-7.35 (10 H, m) Mass spectrum (m / z): 1084.4600 (M + Na) ⁺ Elemental analysis: C ₅₃ H ₈₃ NO ₁₂ PCl ₃ (Molecular weight: 1063.56) Calculated value (%) C 59.85 H 7.87 N 1.32 P 2.91 Cl 10.00 Analytical value (%) C 60.14 H 7.59 N 1.42 P 2.92 Cl 10.08

[0374]

Reference Example 31 2-deoxy-4-O-diphenylphos
Hono-6-O-methyl-3-O-{(R) -3-tetra
Decanoyloxytetradecyl} -2- (2,2,2,
-Trichloroethoxycarbonylamino) -α-D-g
For compounds of Rukopiranosu Reference Example 30 478mg (0.450mmol), by the same manner as in Reference Example 20, 334 mg (yield: 7
3%) of the desired compound was obtained.

IR (KBr) spectrum: 3436, 3352, 2953,
2921, 2851, 1726 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.88 (6H,
t, J = 6.6-7.3Hz), 1.19-1.73 (44H, m), 2.19 (2H, t, J =
7.3Hz), 3.22 (3H, s), 3.45-3.56 (3H, m), 3.72-3.94 (4
H, m, containing OH), 4.13 (1H, m), 4.56 (1H, m), 4.
71, 4.77 (2H, ABq, J = 12.5Hz), 4.90 (1H, m), 5.29 (1H,
m), 5.88 (1H, d, J = 8.8Hz, NH), 7.17-7.35 (10H, m)

[0376]

Reference Example 32 2,2,2-Trichloroethylimidimide
Ru-2-deoxy-4-O-diphenylphosphono-6
-O-methyl-3-O-｛(R) -3-tetradecanoy
Ruoxytetradecyl} -2- (2,2,2-trichloro
Roethoxycarbonylamino) -α-D-glucopyrano
The target compound was obtained by performing the same operation as in Reference Example 21 for 279 mg (0.273 mmol) of the compound of Source Reference Example 31. This compound was used for the next reaction without purification.

[0377]

Reference Example 33 Diphenylmethyl 2,6-anhydro
-7-O- [2-deoxy-4-O-diphenylphospho
No-6-O-methyl-3-O-{(R) -3-tetrade
Canoyloxytetradecyl} -2- (2,2,2-to
Lichloroethoxycarbonylamino) -β-D-gluco
Pyranosyl] -3-{(R) -3-benzyloxytet
Radecanamide {-4-O-} (R) -3-benzyloxy
Citetradecyl} -3-deoxy-D-glycero-D-
275 mg of the compound of id-heptonate reference example 32 and 180 mg of the diol form of reference example 8
(0.181 mmol), the same operation as in Reference Example 22 was carried out, and eluted with hexane-ethyl acetate (3: 2) to give 261 mg.
The target compound (yield: 72%) was obtained.

IR (CHCl ₃ solution) spectrum: 3431, 3354,
2927, 2855, 1732, 1669 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.88 (12H,
t, J = 6.6Hz), 1.25-1.76 (86H, m), 2.20-2.25 (4H, m),
3.10 (1H, s, OH), 3.17-3.25 (4H, m, containing 3H,
s, at 3.20ppm), 3.40-3.74 (13H, m), 3.82 (1H, m), 3.
98 (1H, m), 4.27-4.37 (3H, m, containing 2H, ABq, J =
11.7Hz, at 4.29, 4.33ppm), 4.40, 4.44 (2H, ABq, J = 1
1.7Hz), 4.51 (1H, m), 4.62-4.65 (3H, m, containing 1
H, d, J = 5.1Hz, at 4.62ppm), 4.78 (1H, ABq, J = 11.7H
z), 4.91 (1H, m), 5.01 (1H, m), 5.88 (1H, m, NH), 6.7
8 (1H, d, J = 8.1Hz, NH), 6.82 (1H, s), 7.17-7.35 (30H,
m)

[0379]

Reference Example 34 diphenylmethyl 2,6-anhydro
-7-O- [2-acetamide-2-deoxy-4-O-
Diphenylphosphono-6-O-methyl-3-O-
{(R) -3-tetradecanoyloxytetradecyl}
-Β-D-glucopyranosyl] -3-{(R) -3-b
Ndyloxytetradecanamid {-4-O-} (R)-
3-benzyloxytetradecyl} -3-deoxy-D
-Glycero-D-ido-heptonate The same operation as in Reference Example 23 was performed on 135 mg (0.0676 mmol) of the compound of Reference Example 33, and eluted with hexane-ethyl acetate (1: 1) to give 81.4 mg (yield: 65). %, 2 steps)
The desired compound was obtained.

IR (CHCl ₃ solution) spectrum: 3693, 3433,
3369, 2927, 2855, 1720, 1669,1600 cm ^-1 nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.88 (12H,
t, J = 6.6-7.3Hz), 1.22-1.74 (86H, m), 1.93 (3H, s),
2.20-2.24 (4H, m), 3.18 (1H, m), 3.22 (3H, s), 3.37-
3.72 (14H, m, containing OH), 3.89 (1H, m), 4.02 (1H,
m), 4.29-4.38 (3H, m, containing 2H, ABq, J = 11.0H
z, at 4.30, 4.34 ppm), 4.42 (2H, s), 4.50 (1H, m),
4.63 (1H, d, J = 5.9Hz), 5.07 (1H, m), 5.21 (1H, d, J =
8.1Hz), 6.56 (1H, d, J = 6.6Hz, NH), 6.76 (1H, d, J = 8.
8Hz, NH), 6.81 (1H, s), 7.17-7.36 (30H, m)

[0381]

Reference Example 35 2,6-Anhydro-7-O- [2-A
Cetamide-2-deoxy-4-O-diphenylphosphono
-6-O-methyl-3-O-｛(R) -3-tetradeca
Noyloxytetradecyl｝ -β-D-glucopyranosi
Ru] -3-{(R) -3-hydroxytetradekanami
Do {-4-O-} (R) -3-hydroxytetradeci
Ru-3-deoxy-D-glycero-D-ido-hept
To a solution of 73.1 mg (0.0392 mmol) of the compound of Reference Example 34 in ethanol (3 ml), 58.3 mg of 20% palladium hydroxide-carbon was added.
In addition, the mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere. The solution was filtered through celite and concentrated under reduced pressure. Purified by silica gel column chromatography, chloroform-
After elution with methanol (8: 1), the mixture was diluted with ethyl acetate, washed with a 0.05 M aqueous hydrochloric acid solution and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 42.7
mg (yield: 72%) of the target compound was obtained.

IR (KBr) spectrum: 3321, 2924, 2854, 1
731, 1651 cm ^-1 nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD) δ: 0.90 (12H,
t, J = 6.6-7.3Hz), 1.28-1.76 (86H, m), 2.00 (3H, s),
2.19 (2H, t, J = 7.3Hz), 2.34-2.37 (2H, m), 3.21 (3H,
s), 3.43-3.48 (3H, m), 3.57-4.01 (13H, m), 4.21 (1H,
m), 4.47 (1H, d, J = 5.1Hz), 4.55 (1H, m), 4.64 (1H, d,
J = 8.1Hz), 4.83 (1H, m), 7.20-7.41 (10H, m)

[0383]

Reference Example 36 Allyl 2,6-dideoxy-4-O-
Diphenylphosphono-6-fluoro-3-O-｛(R)
-3-tetradecanoyloxytetradecyl｝ -2-
(2,2,2-trichloroethoxycarbonylamido
G ) -α-D-glucopyranoside 938 mg (0.894 mmol) of the compound of Reference Example 29 was dissolved in 5 ml of 1,2-dimethoxyethane, and 0.35 ml (2.65 mmol) of diethylaminosulfur trifluoride (DAST) was added at 0 ° C. Stir for 3 hours. Water was added to this solution at 0 ° C. to stop the reaction, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, purified by silica gel column chromatography, and eluted with hexane-ethyl acetate (7: 3) to obtain 753 mg (yield: 80%) of the target compound.

IR (CHCl ₃ solution) spectrum: 3606, 3435,
2927, 2855, 1738, 1601 cm ^-1 nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.88 (6H,
t, J = 6.6-7.3Hz), 1.19-1.73 (44H, m), 2.20 (2H, t, J =
7.3Hz), 3.52 (1H, m), 3.71 (1H, t, J = 9.5Hz), 3.81-4.0
6 (4H, m), 4.20 (1H, m), 4.44-4.65 (3H, m), 4.76 (2H,
s), 4.90 (1H, m), 4.95 (1H, d, J = 3.7Hz), 5.23-5.36 (2
H, m), 5.78 (1H, d, J = 9.5Hz, NH), 5.90 (1H, m), 7.17
-7.35 (10H, m) Mass spectrum (m / z): 1072.4424 ( M + Na) + Elemental _{analysis: C 52 H 80 NO 11 PFCl} 3 ( molecular weight: 1051.52) Calculated (%) C 59.40 H 7.67 N 1.33 P 2.95 F 1.81 Cl
10.12 Analytical value (%) C 58.52 H 7.36 N 1.55 P 2.58 F 2.47 Cl
9.93

[0385]

Reference Example 37 2,6-Dideoxy-4-O-diphenyl
Ruphosphono-6-fluoro-3-O-{(R) -3-te
Tradecanoyloxytetradecyl｝ -2- (2,2,
2, -trichloroethoxycarbonylamino) -α-D
-Glucopyranose 256 mg (yield: 7) of 365 mg (0.347 mmol) of the compound of Reference Example 36 by performing the same operation as in Reference Example 20.
3%) of the desired compound was obtained.

IR (CHCl ₃ solution) spectrum: 3601, 3434,
3326, 2927, 2855, 1737 cm ^-1 nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.88 (6H,
t, J = 6.6Hz), 1.20-1.71 (44H, m), 2.22 (2H, t, J = 7.3-
8.1Hz), 3.38 (1H, brs, OH), 3.49 (1H, m), 3.76-3.95
(3H, m), 4.17 (1H, m), 4.44-4.65 (3H, m), 4.72-4.77
(2H, ABq, J = 12.1Hz), 4.92 (1H, m), 5.36 (1H, m), 6.0
7 (1H, d, J = 8.8Hz, NH), 7.18-7.35 (10H, m) Mass spectrum (m / z): 1010.4271 (M + H) ⁺

[0387]

Reference Example 38 2,2,2-Trichloroethylimidimide
2,6-dideoxy-4-O-diphenylphosphono
-6-Fluoro-3-O-{(R) -3-tetradecano
Yloxytetradecyl} -2- (2,2,2-tric
Loloethoxycarbonylamino) -α-D-glucopyr
The same operation as in Reference Example 21 was performed on 255 mg (0.252 mmol) of the compound of Noside Reference Example 37 to obtain the desired compound. This compound was used in Reference Example 39 without purification.

[0388]

Reference Example 39 Diphenylmethyl 2,6-anhydro
-7-O- [2,6-dideoxy-4-O-diphenyl
Phosphono-6-fluoro-3-O-｛(R) -3-tet
Ladecanoyloxytetradecyl} -2- (2,2,2
-Trichloroethoxycarbonylamino) -β-D-g
Lucopyranosyl] -3-{(R) -3-benzyloxy
Tetradecanamide {-4-O-} (R) -3-benzyl
Oxytetradecyl} -3-deoxy-D-glycero-
283 mg of the compound of Reference Example 39 and 201 mg of the diol derivative of Reference Example 8
By performing the same operation as in Reference Example 22 (0.203 mmol), 307 mg (yield: 76%) of the target compound was obtained.

IR (CHCl ₃ solution) spectrum: 2927, 2855,
1732, 1670, 1601 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.88 (12H,
t, J = 6.6Hz), 1.25-1.71 (86H, m), 2.21-2.26 (4H, m),
2.97 (1H, s, OH), 3.17 (1H, m), 3.43-4.01 (14H, m),
4.27-4.81 (11H, m, containing 1H, d, J = 5.9Hz, at 4.
63ppm), 5.01 (1H, m), 5.94 (1H, brs, NH), 6.81 (1H,
d, J = 11.0Hz, NH), 6.82 (1H, s), 7.17-7.35 (30H, m) Mass spectrum (m / z): 2006.0531 (M + Na) ⁺

[0390]

Reference Example 40 diphenylmethyl 2,6-anhydro
-7-O- [2-acetamide-2,6-dideoxy-4
-O-diphenylphosphono-6-fluoro-3-O-
{(R) -3-tetradecanoyloxytetradecyl}
-Β-D-glucopyranosyl] -3-{(R) -3-b
Ndyloxytetradecanamid {-4-O-} (R)-
3-benzyloxytetradecyl} -3-deoxy-D
-Glycero-D-ido-heptonate The same operation as in Reference Example 23 was carried out on 152 mg (0.0767 mmol) of the compound of Reference Example 39, whereby 94.2 mg (yield: 66%, 2 steps) of the target compound were obtained. .

IR (CHCl ₃ solution) spectrum: 3432, 3364,
2927, 2855, 1718, 1668, 1600 cm ^-1 nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.88 (12H,
t, J = 6.6Hz), 1.22-1.73 (86H, m), 2.21-2.24 (4H, m),
3.10 (1H, m), 3.39-3.69 (12H, m, containingOH), 3.9
3-4.05 (2H, m), 4.28-4.58 (8H, m, containing 2H, AB
q, J = 11.4Hz, at 4.30, 4.34ppm, 2H, s, at 4.43ppm),
4.63 (1H, d, J = 5.9Hz), 5.07 (1H, m), 5.28 (1H, d, J =
8.8Hz), 6.59 (1H, d, J = 6.6Hz, NH), 6.78 (1H, d, J = 8.
8Hz, NH), 6.81 (1H, s), 7.17-7.35 (30H, m) Mass spectrum (m / z): 1874.1609 (M + Na) ⁺

[0392]

Reference Example 41 2,6-Anhydro-7-O- [2-A
Cetamide-2,6-dideoxy-4-O-diphenylpho
Suphono-6-fluoro-3-O-{(R) -3-tetra
Decanoyloxytetradecyl｝ -β-D-glucopyra
Nosyl] -3-{(R) -3-hydroxytetradecana
Mido {-4-O-} (R) -3-hydroxytetradeci
Ru-3-deoxy-D-glycero-D-ido-hept
By performing the same operation as in Reference Example 35 on 90.3 mg (0.0487 mmol) of the compound of Reference Example 40 of carboxylic acid , 47.1 mg (yield: 64%) of the target compound was obtained.

IR (CHCl ₃ solution) spectrum: 3606, 3416,
3357, 2927, 2855, 1713, 1663, 1602 cm ^-1 nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD) δ: 0.90 (12H,
t, J = 6.6Hz), 1.23-1.75 (86H, m), 2.00 (3H, s), 2.20
(2H, t, J = 7.3Hz), 2.34-2.37 (2H, m), 3.45 (1H, m),
3.58-4.04 (13H, m), 4.20 (1H, m), 4.38-4.58 (4H, m, c
ontaining 1H, d, J = 5.1Hz, at 4.47ppm), 4.70 (1H, d,
J = 8.1Hz), 7.19-7.42 (10H, m) Mass spectrum (m / z): 1528.9941 (M + Na) ⁺

[0394]

Reference Example 42 Allyl 2-deoxy-3-O-
{(R) -3-dodecyloxytetradecyl} -4,6
-O-isopropylidene-2-trifluoroacetamide
A solution of allyl 2-deoxy-4,6-O-isopropylidene-2-trifluoroacetamide-α-D-glucopyranoside (4.23 g, 11.9 mmol) in dimethylformamide (60 mL) as a raw material of α-D-glucopyranoside At 0 ° C. with sodium hydride (60% oily, 725 mg, 18.1 mmol)
Was added and stirred for 30 minutes. (R) -3- separately synthesized
(Dodecyloxy) -1-methanesulfonyloxytetradecane (6.80 g, 14.3 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was stopped by adding water, extracted with ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and eluted with hexane-ethyl acetate (4: 1) to give 6.60 g (yield: 75%).
The desired compound was obtained.

IR (CHCl ₃ solution) spectrum: 3431, 2928,
2855, 1734 cm ^-1 nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 6.55 (1H,
d, J = 9.5 Hz, NH), 5.86 (1H, m), 5.31-5.24 (2H,
m), 4.89 (1H, d, J = 3.7 Hz), 4.20-4.13 (2H, m), 3.9
8 (1H, dd, J = 5.1, 12.5 Hz), 3.89-3.83 (2H, m), 3.7
8-3.67 (3H, m), 3.58-3.49 (2H, m), 3.41-3.29 (3H,
m), 1.67-1.21 (48H, m, containing 3H, s, δ1.51, 3
H, s, δ1.41), 0.88 (6H, t, J = 6.6 Hz) Mass spectrum (m / z): 736.5337 (M + H) ⁺ elemental analysis: C ₄₀ H ₇₂ F ₃ NO ₇ (molecular weight: 736.0) Calculated (%) C 65.28 H 9.86 N 1.90 F 7.74 Analytical value (%) C 65.35 H 9.89 N 1.90 F 7.86

[0396]

Reference Example 43 Allyl 2-deoxy-3-O-
{(R) -3-dodecyloxytetradecyl} -4,6
—O-isopropylidene-2- (2,2,2-trichloro
Roethoxycarbonylamino) -α-D-glucopyrano
4.70 g (6.39 mmol) of the compound of Sid Reference Example 42 was dissolved in 10 mL of ethanol, 10 mL of a 1 M aqueous sodium hydroxide solution was added, and the mixture was stirred at 80 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was dried with a vacuum pump.
was gotten. This amine was dissolved in methylene chloride (10 mL), saturated aqueous sodium hydrogen carbonate solution (10 mL), and 2,2,2-trichloroethyl chloroformate 1.60 g (7.55)
mmol) and stirred at room temperature for 1 hour. afterwards,
The mixture was diluted with methylene chloride, washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
Elution with ethyl acetate (4: 1) gave the desired compound (4.
54 g, yield: 87%).

IR (CHCl ₃ solution) spectrum: 3439, 2928,
2855, 1743 cm ^-1 nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 5.89 (1H,
m), 5.32-5.22 (3H, m, containing NH), 4.87 (1H, d,
J = 3.7 Hz), 4.74 (2H, s), 4.13 (1H, dd, J = 5.9, 12.
5 Hz), 3.98 (1H, dd, J = 6.6, 12.5 Hz), 3.92-3.82 (3
H, m), 3.77-3.57 (4H, m), 3.48-3.30 (4H, m), 1.68-
1.21 (48H, m, containing 3H, s, δ 1.50, 3H, s, δ
1.41), 0.88 (6H, t, J = 6.6-7.3 Hz) Mass spectrum (m / z): 814.4551 (M + H) ⁺ elemental analysis: C ₄₁ H ₇₄ Cl ₃ NO ₈ (molecular weight: 815.4) calculated value (%) C 60.39 H 9.15 N 1.72 Cl 13.04 Analytical value (%) C 59.84 H 9.04 N 1.70 Cl 12.89

[0398]

Reference Example 44 Allyl 2-deoxy-3-O-
{(R) -3-dodecyloxytetradecyl} -2-
(2,2,2-trichloroethoxycarbonylamino)
3.51 g (4.30 mmol) of the compound of -α-D-glucopyranoside Reference Example 43 was dissolved in 20 mL of an 80% aqueous acetic acid solution and stirred at 60 ° C for 4 hours. After the completion of the reaction, the solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and eluted with hexane-ethyl acetate (3: 2) to obtain the desired compound (3.15 g, yield: 95%).

IR (KBr) spectrum: 3335, 2923, 2853,
1709 cm ^-1 nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 5.90 (1H,
m), 5.32-5.22 (3H, m, containing NH), 4.87 (1H, d,
J = 3.7 Hz), 4.81, 4.69 (2H, ABq, J = 11.7 Hz), 4.19
(1H, dd, J = 5.1, 13.2 Hz), 3.99 (1H, dd, J = 6.6, 13.
2 Hz), 3.91-3.60 (8H, m, containing OH), 3.50-3.36
(4H, m), 2.17 (1H, t, OH), 1.73-1.26 (42H, m), 0.
88 (6H, t, J = 6.6 Hz) Mass spectrum (m / z): 774.4228 (M + H) ⁺ elemental analysis: C ₃₈ H ₇₀ Cl ₃ NO ₈ (molecular weight: 775.3) calculated (%) C 58.87 H 9.10 N 1.81 Cl 13.72 Analytical value (%) C 58.87 H 8.94 N 1.81 Cl 14.00

[0400]

Reference Example 45 Allyl 6-O-benzyloxycarbo
Nyl-2-deoxy-3-O-{(R) -3-dodecyl
Oxytetradecyl} -2- (2,2,2-trichloro
Ethoxycarbonylamino) -α-D-glucopyranoshi
Compounds of de Reference Example 44 526 mg (0.678 mmol)
Was added to a methylene chloride (5 mL) solution of 0.50 mL (3.50 mmol) of benzyloxycarbonyl chloride and 332 mg (4.20 mmol) of pyridine.
For 3 hours. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogen carbonate solution, water, and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
When eluted with 1), the target compound (581 mg, yield: 9)
4%).

IR (KBr) spectrum: 3522, 3329, 2923,
2853, 1725, 1709 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 7.40-7.32
(5H, m), 5.87 (1H, m), 5.30-5.20 (3H, m, containin
g NH), 5.18 (2H, s), 4.85 (1H, d, J = 3.7 Hz), 4.81,
4.68 (2H, ABq, J = 12.5 Hz), 4.46-4.39 (2H, m), 4.1
5 (1H, dd, J = 5.1, 12.5 Hz), 3.96 (1H, dd, J = 6.6, 1
2.5 Hz), 3.88 (1H, td, J = 10.3, 3.7Hz), 3.84-3.79
(2H, m), 3.69 (1H, m), 3.64 (1H, brs, OH), 3.56 (1
H, m), 3.48-3.33 (4H, m), 1.74-1.71 (2H, m), 1.59-
1.21 (40H, m), 0.88 (6H, t, J = 6.6 Hz) Mass spectrum (m / z): 908.4592 (M + H) ⁺ elemental analysis: C ₄₆ H ₇₆ Cl ₃ NO ₁₀ (molecular weight: 909.5) Calculated value (%) C 60.75 H 8.42 N 1.54 Cl 11.70 Analytical value (%) C 60.44 H 8.17 N 1.56 Cl 11.63

[0402]

Reference Example 46 Allyl 6-O-benzyloxycarbo
Nyl-2-deoxy-4-O-diphenylphosphono-3
-O-{(R) -3-dodecyloxytetradecyl}-
2- (2,2,2-trichloroethoxycarbonylamido
(No) -α-D-glucopyranoside 553 mg (0.608 mmol) of the compound of Reference Example 45
To a methylene chloride (5 mL) solution of 111 mg (0.911 mmol) of 4-dimethylaminopyridine and 0.19 mL (0.608 mmol) of diphenylchlorophosphate.
l) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate solution, water,
The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with hexane-ethyl acetate (3: 1) to obtain the desired compound (663 mg, yield: 96%).

IR (CHCl ₃ solution) spectrum: 3436, 2928,
2855, 1747 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 7.36-7.12.
(15H, m), 5.87 (1H, m), 5.30-5.21 (3H, m, containi
ng NH), 5.11, 5.06 (2H, ABq, J = 12.5 Hz), 4.89 (1H,
d, J = 3.7 Hz), 4.79, 4.67 (2H, ABq, J = 12.5 Hz), 4.6
3 (1H, q, J = 9.5 Hz), 4.36 (1H, dd, J = 1.5, 11.7 H
z), 4.29 (1H, dd, J = 5.1, 11.7 Hz), 4.14 (1H, dd, J
= 5.1, 13.2 Hz), 4.02-3.95 (3H, m), 3.80 (1H, m),
3.72-3.64 (2H, m), 3.25 (2H, t, J = 6.6 Hz), 3.20 (1
H, m), 1.63-1.61 (2H, m), 1.45-1.43 (2H, m), 1.30-
1.18 (38H, m), 0.88 (6H, t, J = 6.6 Hz) Mass spectrum (m / z): 1140.4890 (M + H) ⁺ Elemental analysis: C ₅₈ H ₈₅ Cl ₃ NO ₁₃ P (molecular weight: 1141.6 ) Calculated value (%) C 61.02 H 7.51 N 1.23 Cl 9.32 P 2.71 Analytical value (%) C 60.49 H 7.61 N 1.19 Cl 9.44 P 2.96

[0404]

Reference Example 47 6-O-benzyloxycarbonyl-2
-Deoxy-4-O-diphenylphosphono-3-O-
{(R) -3-dodecyloxytetradecyl} -2-
(2,2,2-trichloroethoxycarbonylamino)
613 mg (0.537 mmol) of the compound of -D-glucopyranose Reference Example 46
In a tetrahydrofuran (6 mL) solution of (1,5-cyclooctadiene) bis- (methyldiphenylphosphine) -iridium hexafluorophosphate.
5 mg was added, and the mixture was replaced with hydrogen. After the red solution became transparent, the mixture was replaced with nitrogen and stirred at room temperature for 1 hour. Then water 5
mL and 276 mg (1.09 mmol) of iodine were added, followed by stirring at room temperature for 30 minutes. This solution was diluted with ethyl acetate, washed with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with hexane-ethyl acetate (3: 2) to obtain the desired compound (421 mg, yield: 71%).

IR (CHCl ₃ solution) spectrum: 3600, 3435,
2928, 2855, 1747 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 7.34-7.12.
(15H, m), 5.43 (1H, d, J = 9.5 Hz, NH), 5.25 (1H, t,
J = 3.7 Hz), 5.11, 5.06 (2H, ABq, J = 11.7 Hz), 4.76,
4.69 (2H, ABq, J = 12.1 Hz), 4.62 (1H, q, J = 9.5 H
z), 4.39-4.19 (3H, m), 3.94 (1H, m), 3.84-3.64 (3
H, m), 3.41 (1H, brs, OH), 3.27-3.20 (3H, m, conta
ining 2H, t, J = 6.6 Hz, δ3.25), 1.65-1.62 (2H, m),
1.45-1.43 (2H, m), 1.30-1.18 (38H, m), 0.88 (6H,
t, J = 6.6 Hz) Mass spectrum (m / z): 1100.4601 (M + H) ⁺ elemental analysis: C ₅₅ H ₈₁ Cl ₃ NO ₁₃ P (molecular weight: 1101.6) calculated (%) C 59.97 H 7.41 N 1.27 Cl 9.66 P 2.81 Analytical value (%) C 58.85 H 7.25 N 1.22 Cl 9.73 P 2.98

[0406]

Reference Example 48 Allyl 6-O-tert-butyldim
Tylsilyl-2-deoxy-3-O-{(R) -3-do
Decyloxytetradecyl｝ -2- (2,2,2-tri
Chloroethoxycarbonylamino) -α-D-glucopi
In a methylene chloride (6 mL) solution of 1.32 g (1.70 mmol) of the compound of Reference Example 44, tert-butyldimethylsilyl chloride 385 mg (2.56 mmol) and 332 mg of 4-dimethylaminopyridine (2.72 mm)
ol) and stirred at room temperature for 3 hours. This solution was diluted with ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and eluted with hexane-ethyl acetate (9: 1) to give the desired compound (1.49).
g, yield: 99%).

IR (CHCl ₃ solution) spectrum: 3438, 2928,
2856, 1742 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 5.90 (1H,
m), 5.31-5.20 (3H, m, containing NH), 4.86 (1H, d,
J = 3.7 Hz), 4.79, 4.70 (2H, ABq, J = 12.5 Hz), 4.19
(1H, dd, J = 5.1, 12.5 Hz), 3.98 (1H, dd, J = 6.6, 12.
5 Hz), 3.89-3.76 (5H, m), 3.67-3.36 (7H, m, contai
ning OH), 1.72 (2H, q, J = 5.9 Hz), 1.62-1.21 (40H,
m), 0.91-0.86 (15H, m), 0.090 (6H, s) Mass spectrum (m / z): 910.4911 (M + Na) ⁺ Elemental analysis: C ₄₄ H ₈₄ Cl ₃ NO ₈ Si (molecular weight: 889.6 ) Calculated value (%) C 59.41 H 9.52 N 1.58 Cl 11.96 Analytical value (%) C 59.03 H 9.30 N 1.49 Cl 12.02

[0408]

Reference Example 49 Allyl 6-O-tert-butyldim
Tylsilyl-4-O-diphenylphosphono-2-deoxy
C-3-O-｛(R) -3-dodecyloxytetradeci
Ru-2- (2,2,2-trichloroethoxycarboni
Lamino) -α-D-glucopyranoside The same procedure as in Reference Example 46 was performed on 1.45 g (1.63 mmol) of the compound of Reference Example 48 to obtain the desired compound (1.81 g, yield: 99%). Was done.

IR (CHCl ₃ solution) spectrum: 3436, 2928,
2856, 1744 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 7.35-7.15
(10H, m), 5.92 (1H, m), 5.33-5.23 (3H, m, containi
ng NH), 4.90 (1H, d, J = 3.7 Hz), 4.81, 4.69 (2H, AB
q, J = 12.1 Hz), 4.55 (1H, q, J = 9.5 Hz), 4.22 (1H, d
d, J = 5.9, 13.2 Hz), 4.03-3.86 (2H, m), 3.83-3.65
(6H, m), 3.26-3.19 (3H, m), 1.65-1.18 (42H, m), 0.
91-0.85 (15H, m), 0.009 (6H, s) Mass spectrum (m / z): 1120.5409 (M + H) ⁺ Elemental analysis: C ₅₆ H ₉₃ Cl ₃ NO ₁₁ SiP (Molecular weight: 1121.8) Calculated value (%) C 59.96 H 8.36 N 1.25 Cl 9.48 P 2.76 Analytical value (%) C 59.49 H 8.23 N 1.18 Cl 9.66 P 2.81

[0410]

Reference Example 50 Allyl 4-O-diphenylphosphono-
2-deoxy-3-O-{(R) -3-dodecyloxy
Tetradecyl} -2- (2,2,2-trichloroethoxy
1.5 mL of a 3N hydrochloric acid aqueous solution was added to a solution of 1.65 g (1.47 mmol) of the compound of Reference Example 49 (cycarbonylamino ) -α-D-glucopyranoside in Reference Example 49, and stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate solution,
The extract was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, purified by silica gel column chromatography, and hexane-ethyl acetate (3: 2).
Eluting with the desired compound (1.31 g, yield: 89)
%)was gotten.

IR (KBr) spectrum: 3499, 3373, 2921,
2851, 1713, 1646 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 7.37-7.18
(10H, m), 5.89 (1H, m), 5.33-5.23 (3H, m, containi
ng NH), 4.93 (1H, d, J = 3.7 Hz), 4.76, 4.72 (2H, AB
q, J = 12.5 Hz), 4.65 (1H, q, J = 9.5 Hz), 4.17 (1H, d
d, J = 5.9, 13.2 Hz), 4.03-3.97 (2H, m), 3.88 (1H,
m), 3.70-3.59 (5H, m), 3.29-3.21 (3H, m), 1.65 (1
H, q, J = 6.6 Hz), 1.47-1.18 (40H, m), 0.88 (6H, t,
J = 6.6 Hz) Mass spectrum (m / z): 1006.4539 (M + H) ⁺ Elemental analysis: C ₅₀ H ₇₉ Cl ₃ NO ₁₁ P (molecular weight: 1007.5) Calculated (%) C 59.61 H 7.90 N 1.39 Cl 10.56 P 3.07 Analytical value (%) C 59.19 H 7.82 N 1.37 Cl 10.66 P 3.09

[0412]

Reference Example 51 Allyl 4-O-diphenylphosphono-
2-deoxy-3-O-{(R) -3-dodecyloxy
Tetradecyl} -6-O-methyl-2- (2,2,2-
Trichloroethoxycarbonylamino) -α-D-glu
385 mg (0.382 mmol) of the compound of Copyranoside Reference Example 50
To a methylene chloride (5 mL) solution of 2,6-di-ter
91 mg of t-butyl-4-methylpyridine (0.441
mmol) and 64 mg (0.435 mmol) of trimethyloxonium tetrafluoroborate, and the mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with ethyl acetate, washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with hexane-ethyl acetate (7: 3) to obtain the desired compound (357 mg, yield: 91%).

IR (CHCl ₃ solution) spectrum: 3436, 2928,
2855, 1744 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 7.35 to 7.15
(10H, m), 5.90 (1H, m), 5.33-5.23 (3H, m, containi
ng NH), 4.93 (1H, d, J = 3.7 Hz), 4.77, 4.69 (2H, AB
q, J = 11.7 Hz), 4.67 (1H, m), 4.21 (1H, dd, J = 5.1,
13.2 Hz), 4.04-3.98 (2H, m), 3.89-3.65 (4H, m), 3.
54 (1H, dd, J = 4.4, 11.0 Hz), 3.48 (1H, dd, J = 2.2,
11.0 Hz), 3.26-3.19 (6H, m, containing 3H, s, δ3.
24), 1.64-1.62 (2H, m), 1.44-1.43 (2H, m), 1.32-1.
17 (38H, m), 0.88 (6H, t, J = 6.6 Hz) Mass spectrum (m / z): 1020.4669 (M + H) ⁺ elemental analysis: C ₅₁ H ₈₁ Cl ₃ NO ₁₁ P (molecular weight: 1021.5 ) Calculated value (%) C 59.97 H 7.99 N 1.37 Cl 10.41 P 3.03 Analytical value (%) C 59.10 H 7.85 N 1.29 Cl 10.51 P 3.27

[0414]

Reference Example 52 4-O-diphenylphosphono-2-deo
Xy-3-O-｛(R) -3-dodecyloxytetrade
Sil｝ -6-O-methyl-2- (2,2,2-trichloro
Roethoxycarbonylamino) -D-glucopyranose 695 mg (0.681 mmol) of the compound of Reference Example 51
By performing the same operation as in Reference Example 47,
The target compound (483 mg, yield: 72%) was obtained.

IR (KBr) spectrum: 3426, 3339, 2922,
2851, 1721 cm ^-1 nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 7.35-7.16
(10H, m), 5.40 (1H, d, J = 9.5 Hz, NH), 5.27 (1H, t,
J = 3.7 Hz), 4.75, 4.70 (2H, ABq, J = 11.7 Hz), 4.55
(1H, q, J = 9.5 Hz), 4.13 (1H, m), 3.95 (1H, m), 3.8
5-3.65 (4H, m, containing OH), 3.51-3.43 (2H, m),
3.26-3.16 (6H, m, containing 2H, t, J = 6.6 Hz, δ3.2
5, 3H, s, δ3.21), 1.65-1.64 (2H, m), 1.44-1.42 (2
H, m), 1.32-1.17 (38H, m), 0.88 (6H, t, J = 6.6 Hz) Mass spectrum (m / z): 980.4378 (M + H) ⁺ Elemental analysis: C ₄₈ H ₇₇ Cl ₃ NO ₁₁ P (Molecular weight: 981.5) Calculated value (%) C 58.74 H 7.91 N 1.43 Cl 10.84 P 3.16 Analytical value (%) C 58.49 H 8.15 N 1.51 Cl 10.74 P 3.24

[0416]

Reference Example 53 Allyl 2,6-dideoxy-4-O-
Diphenylphosphono-3-O-｛(R) -3-dodecyl
Oxytetradecyl} -6-fluoro-2- (2,2,
2-trichloroethoxycarbonylamino) -α-D-
Compound glucopyranoside Reference Example 50 521 mg (0.517 mmol)
Was added to a solution of 1,2-dimethoxyethane (5 mL) in a nitrogen atmosphere at −40 ° C. at 0.2 ° C. (1.51 mmol) of diethylaminosulfur trifluoride (DAST), and the mixture was stirred for 30 minutes and then at 0 ° C. for 2 hours. Stirred. The reaction was quenched by adding water, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by neutral silica gel column chromatography, and eluted with hexane-ethyl acetate (3: 1) to give the desired compound (432).
mg, yield: 83%).

IR (CHCl ₃ solution) spectrum: 3691, 3436,
2928, 2855, 1744 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 7.34 to 7.16
(10H, m), 5.89 (1H, m), 5.34-5.24 (3H, m, containi
ng NH), 4.94 (1H, d, J = 3.7 Hz), 4.79, 4.68 (2H, AB
q, J = 11.7 Hz), 4.64-4.55 (2H, m), 4.46 (1H, m), 4.
20 (1H, dd, J = 5.9, 13.2 Hz), 4.05-3.90 (3H, m), 3.
83-3.65 (3H, m), 3.25 (2H, t, J = 6.6-7.3 Hz), 3.21
(1H, m), 1.65-1.57 (2H, m), 1.45-1.43 (2H, m), 1.3
2-1.17 (38H, m), 0.88 (6H, t, J = 6.6-7.3 Hz) Mass spectrum (m / z): 1008.4485 (M + H) ⁺ elemental analysis: C ₅₀ H ₇₈ Cl ₃ FNO ₁₀ P (Molecular weight: 1009.5) Calculated value (%) C 59.49 H 7.79 N 1.39 Cl 10.54 F 1.88 P
3.07 Analytical value (%) C 59.45 H 7.68 N 1.48 Cl 10.45 F 2.25 P
3.24

[0418]

Reference Example 54 2,6-Dideoxy-4-O-diphenyl
Ruphosphono-3-O-{(R) -3-dodecyloxyte
Tradecyl} -6-fluoro-2- (2,2,2-tri
Chloroethoxycarbonylamino) -D-glucopyrano
The compounds of the over scan Reference Example 53 416mg (0.412mmol)
By performing the same operation as in Reference Example 47,
The target compound (329 mg, yield: 82%) was obtained.

IR (CHCl ₃ solution) spectrum: 3602, 3435,
2928, 2855, 1745 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 7.35 to 7.17
(10H, m), 5.47 (1H, d, J = 9.5 Hz, NH), 5.31 (1H, t,
J = 3.7 Hz), 4.76, 4.71 (2H, ABq, J = 11.7 Hz), 4.60
(1H, q, J = 9.5 Hz), 4.56 (1H, m), 4.44 (1H, m), 4.1
7 (1H, m), 3.96 (1H, m), 3.85-3.65 (4H, m, contain
ing OH), 3.27-3.21 (3H, m, containing 2H, t, J = 6.6
Hz, δ3.26), 1.67-1.62 (2H, m), 1.45-1.44 (2H,
m), 1.32-1.18 (38H, m), 0.88 (6H, t, J = 6.6 Hz) Mass spectrum (m / z): 968.4178 (M + H) ⁺ elemental analysis: C ₄₇ H ₇₄ Cl ₃ FNO ₁₀ P (molecular weight: 969.4) Calculated value (%) C 58.23 H 7.69 N 1.45 Cl 10.97 F 1.96 P 3.20 Analytical value (%) C 58.27 H 7.76 N 1.43 Cl 11.20 F 2.04 P 3.25

[0420]

Reference Example 55 Diphenylmethyl 2,6-anhydro
-7-O- [6-O-benzyloxycarbonyl-2-
Deoxy-4-O-diphenylphosphono-3-O-
{(R) -3-dodecyloxytetradecyl} -2-
(2,2,2-trichloroethoxycarbonylamino)
-Β-D-glucopyranosyl] -3-{(R) -3-b
Ndyloxytetradecanamid {-4-O-} (R)-
3-benzyloxytetradecyl} -3-deoxy-D
-Glycero-D-ido-heptonate Compound 521 mg (0.473 mmol) of Reference Example 47
To a methylene chloride (10 mL) solution of was added 0.70 mL (6.98 mmol) of trichloroacetonitrile and 77 mg (0.237 mmol) of cesium carbonate, and the mixture was stirred at room temperature for 1 hour. 20m saturated sodium bicarbonate aqueous solution
L was added to stop the reaction, the reaction mixture was extracted with methylene chloride, and the organic layer was washed with saturated saline and dried over sodium sulfate. After distilling off the solvent under reduced pressure and drying with a vacuum pump, 591 mg of 1-position trichloroacetimidate is obtained.
(Quantitative) was obtained. The obtained imidate compound and diphenylmethyl 2,6-anhydro-3-{(R) -3
-Benzyloxytetradecanamide｝ -4-O-
{(R) -3-benzyloxytetradecyl} -3-deoxy-D-glycero-D-ido-heptonate 234
mg (0.236 mmol) in methylene chloride (10 m
L), and 750 mg of molecular sieves 4A
In addition, the mixture was stirred at room temperature for 1 hour to remove water from the reaction system. Thereafter, the solution was cooled to -40 ° C, and 15 μL of trimethylsilyl trifluoromethanesulfonate (0.
0829 mmol) and stirred for 2 hours. After the completion of the reaction, molecular sieves 4A was filtered off, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate.
The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with hexane-ethyl acetate (7: 3) to obtain the desired compound (365 mg, yield: 75%).

IR (CHCl ₃ solution) spectrum: 3691, 3604,
3519, 3405, 2928, 2855, 1735, 1669 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 7.35 to 7.11
(35H, m), 6.83 (1H, s), 6.81 (1H, m, NH), 5.39 (1
H, m, NH), 5.10, 5.04 (2H, ABq, J = 11.7 Hz), 4.86
(1H, m), 4.71, 4.66 (2H, ABq, J = 11.7 Hz), 4.61 (1
H, d, J = 5.9 Hz), 4.51 (1H, q, J = 9.5 Hz), 4.45-4.21
(7H, m, containing 2H, ABq, J = 11.5 Hz, δ4.44, 4.3
9, 2H, ABq, J = 11.0 Hz, δ4.33, 4.28), 4.07-3.92 (2
H, m), 3.72-3.43 (11H, m), 3.27-3.14 (4H, m), 3.02
(1H, brs, OH), 2.24 (2H, d, J = 5.9 Hz), 1.74-1.24
(84H, m), 0.88 (12H, t, J = 6.6 Hz) Mass spectrum (m / z): 2096.0845 (M + Na) ⁺ elemental analysis: C ₁₁₇ H ₁₆₈ Cl ₃ N ₂ O ₂₁ P (molecular weight: 2075.9) Calculated value (%) C 67.69 H 8.16 N 1.35 Cl 5.12 P 1.49 Analytical value (%) C 67.01 H 8.04 N 1.34 Cl 5.27 P 1.37

[0422]

Reference Example 56 Diphenylmethyl 2,6-anhydro
-7-O- [2-deoxy-4-O-diphenylphospho
No-3-O-｛(R) -3-dodecyloxytetradeci
Ru-6-O-methyl-2- (2,2,2-trichloro
Ethoxycarbonylamino) -β-D-glucopyranosi
Ru] -3-{(R) -3-benzyloxytetradecana
Mido-4-O-{(R) -3-benzyloxytetra
Decyl} -3-deoxy-D-glycero-D-ido-f
438 mg (0.446 mmol) of the compound of Reference Example 52 of ptonate
By performing the same operation as in Reference Example 55,
The target compound (298 mg, yield: 68%) was obtained.

IR (CHCl ₃ solution) spectrum: 2928, 2855,
1735, 1668 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 7.35 to 7.15
(30H, m), 6.83 (1H, s), 6.79 (1H, d, J = 9.5 Hz, N
H), 5.33 (1H, m, NH), 4.84 (1H, m), 4.75, 4.67 (2
H, ABq, J = 11.7 Hz), 4.61 (1H, d, J = 5.9 Hz), 4.54
(1H, q, J = 9.5 Hz), 4.44, 4.40 (2H, ABq, J = 11.7 H
z), 4.34-4.26 (3H, m, containing 2H, ABq, J = 11.4 H
z, δ4.33, 4.28), 4.00-3.89 (2H, m), 3.76-3.41 (13
H, m), 3.27-3.10 (7H, m, containing 3H, s, δ3.2
1), 3.03 (1H, brs, OH), 2.23 (2H, d, J = 5.9 Hz), 1.7
5-1.24 (84H, m), 0.88 (12H, t, J = 6.6 Hz) Mass spectrum (m / z): 1976.0585 (M + Na) ⁺ Elemental analysis: C ₁₁₀ H ₁₆₄ Cl ₃ N ₂ O ₁₉ P (Molecular weight: 1955.8) Calculated value (%) C 67.55 H 8.45 N 1.43 Cl 5.44 P 1.58 Analytical value (%) C 67.53 H 8.25 N 1.43 Cl 5.14 P 1.32

[0424]

Reference Example 57 Diphenylmethyl 2,6-anhydro
-7-O- [2,6-dideoxy-4-O-diphenyl
Phosphono-3-O-｛(R) -3-dodecyloxytet
Radecyl} -6-fluoro-2- (2,2,2-tric
Loloethoxycarbonylamino) -β-D-glucopyr
Nosyl] -3-{(R) -3-benzyloxytetrade
Canamide {-4-O-} (R) -3-benzyloxyte
Tradecyl} -3-deoxy-D-glycero-D-id
-230 mg (0.238 mmol) of compound of heptonate reference example 54
By performing the same operation as in Reference Example 55,
The target compound (185 mg, yield: 80%) was obtained.

IR (CHCl ₃ solution) spectrum: 2928, 2855,
1735, 1669 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 7.35 to 7.17
(30H, m), 6.83 (1H, s), 6.82 (1H, m, NH), 5.43 (1
H, m, NH), 4.90 (1H, m), 4.75, 4.67 (2H, ABq, J = 1
1.7 Hz), 4.61 (1H, d, J = 5.1 Hz), 4.57-4.26 (8H, m,
containing 2H, ABq, J = 11.7 Hz, δ4.45, 4.40, 2H, A
Bq, J = 11.4 Hz, δ4.33, 4.28), 4.02-3.92 (2H, m),
3.75-3.43 (11H, m), 3.27-3.15 (4H, m), 3.03 (1H, b
rs, OH), 2.25 (2H, d, J = 5.9 Hz), 1.74-1.25 (84H,
m), 0.88 (12H, t, J = 6.6 Hz) Mass spectrum (m / z): 1964.0414 (M + Na) ⁺ elemental analysis: C ₁₀₉ H ₁₆₁ Cl ₃ FN ₂ O ₁₈ P (molecular weight: 1943.78) Calculation Value (%) C 67.35 H 8.35 N 1.44 F 0.98 Cl 5.47 P 1.59 Analytical value (%) C 67.34 H 8.10 N 1.48 F 1.26 Cl 5.39 P 1.43

[0426]

Reference Example 58 Diphenylmethyl 2,6-anhydro
-7-O- [2-acetamido-6-O-benzyloxy
Carbonyl-2-deoxy-4-O-diphenylphospho
No-3-O-｛(R) -3-dodecyloxytetradeci
Ru-β-D-glucopyranosyl] -3-{(R) -3
-Benzyloxytetradecanamide｝ -4-O-
{(R) -3-benzyloxytetradecyl} -3-de
Oxy-D-glycero-D-ido-heptonate Compound 230 mg (0.111 mmol) of Reference Example 55
148 mg of acid-treated zinc in acetic acid (5 mL) solution of
(2.27 mmol) and stirred at room temperature. After 5 hours, the reaction solution was filtered and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over sodium sulfate.
The solvent was distilled off under reduced pressure to obtain an amine. This amine was dissolved in tetrahydrofuran (3 mL) -water (2 mL), pyridine (45 μl, 0.556 mmol) and acetic anhydride (55 μl, 0.583 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and hexane-ethyl acetate (3:
When eluted with 2), the target compound (152 mg, yield: 71)
%)was gotten.

IR (CHCl ₃ solution) spectrum: 3436, 2928,
2855, 1745, 1670 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 7.33-7.12.
(35H, m), 6.82 (1H, s), 6.80 (1H, d, J = 8.8 Hz, N
H), 6.07 (1H, d, J = 6.6 Hz, NH), 5.21 (1H, d, J = 8.1
Hz), 5.11, 5.05 (2H, ABq, J = 11.7 Hz), 4.62 (1H,
d, J = 5.1 Hz), 4.50 (1H, q, J = 9.5 Hz), 4.43 (2H,
s), 4.39-4.28 (5H, m), 4.23 (1H, dd, J = 5.1, 11.7 H
z), 4.07-4.00 (2H, m), 3.72-3.27 (14H, m, containi
ng OH), 3.03 (1H, m), 2.25 (2H, d, J = 5.1 Hz), 1.91
(3H, s), 1.73-1.26 (84H, m), 0.89 (12H, t, J = 6.6 H
z) Mass spectrum (m / z): 1964.1870 (M + Na) ⁺ elemental analysis: C ₁₁₆ H ₁₆₉ N ₂ O ₂₀ P (molecular weight: 1942.6) calculated (%) C 71.72 H 8.77 N 1.44 P 1.59 analysis (%) C 71.46 H 8.60 N 1.42 P 1.49

[0428]

Reference Example 59 Diphenylmethyl 2,6-anhydro
-7-O- [2-acetamide-2-deoxy-4-O-
Diphenylphosphono-3-O-｛(R) -3-dodecyl
Oxytetradecyl｝ -6-O-methyl-β-D-glu
Copyranosyl] -3-{(R) -3-benzyloxyte
Toradecanamide {-4-O-} (R) -3-benzylo
Xytetradecyl} -3-deoxy-D-glycero-D
229 mg (0.117 mmol) of the compound of -Id- Heptonate Reference Example 56
By performing the same operation as in Reference Example 58,
The target compound (158 mg, yield: 74%) was obtained.

IR (CHCl ₃ solution) spectrum: 3436, 2928,
2855, 1732, 1670 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 7.33-7.15
(30H, m), 6.81 (1H, s), 6.78 (1H, d, J = 8.8 Hz, N
H), 5.97 (1H, d, J = 7.3 Hz, NH), 5.15 (1H, d, J = 8.1
Hz), 4.61 (1H, d, J = 5.9 Hz), 4.52 (1H, q, J = 9.5 H
z), 4.42 (2H, s), 4.35 (1H, m), 4.33, 4.29 (2H, AB
q, J = 11.4 Hz), 4.05-3.99 (2H, m), 3.74-3.40 (14H,
m, containing OH), 3.30-3.22 (6H, m, containing 3
H, s, δ3.22), 3.11 (1H, m), 2.23 (2H, d, J = 5.1 H
z), 1.91 (3H, s), 1.74-1.25 (84H, m), 0.88 (12H, t,
J = 6.6 Hz) Mass spectrum (m / z): 1844.1700 (M + Na) ⁺ elemental analysis: C ₁₀₉ H ₁₆₅ N ₂ O ₁₈ P (molecular weight: 1822.5) calculated (%) C 71.84 H 9.13 N 1.54 P 1.70 Analytical value (%) C 71.38 H 8.96 N 1.51 P 1.53

[0430]

Reference Example 60 diphenylmethyl 2,6-anhydro
-7-O- [2-acetamide-2,6-dideoxy-4
-O-diphenylphosphono-3-O-{(R) -3-do
Decyloxytetradecyl｝ -6-fluoro-β-D-
Glucopyranosyl] -3-{(R) -3-benzyloxy
Citetradecanamide {-4-O-} (R) -3-benzyl
Ruoxytetradecyl} -3-deoxy-D-glycero
180 mg of the compound of -D-id-heptonate Reference Example 57 (0.0927 mmol)
About 1), the same operation as in Reference Example 58 was performed to obtain the desired compound (115 mg, yield: 68%).

IR (CHCl ₃ solution) spectrum: 3529, 3335,
3064, 3032, 2924, 2854, 1733, 1646 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 7.37-7.17
(30H, m), 6.82 (1H, s), 6.80 (1H, d, J = 11.7 Hz, N
H), 6.03 (1H, d, J = 6.6 Hz, NH), 5.21 (1H, d, J = 8.1
Hz), 4.61 (1H, d, J = 5.1 Hz), 4.57-4.27 (8H, m, con
taining 2H, s, δ4.42, 2H, ABq, J = 11.4 Hz, δ4.34,
4.29), 4.11-4.03 (2H, m), 3.71-3.41 (11H, m), 3.3
3-3.22 (4H, m, containing OH), 3.04 (1H, m), 2.24
(2H, d, J = 5.9 Hz), 1.91 (3H, s), 1.74-1.25 (84H,
m), 0.88 (12H, t, J = 6.6 Hz) Mass spectrum (m / z): 1832.1459 (C ₁₀₈ H ₁₆₂ FN ₂ O ₁₇ PN
a) Elemental analysis: C ₁₀₉ H ₁₆₅ N ₂ O ₁₈ P (molecular weight: 1822.5) Calculated (%) C 71.84 H 9.13 N 1.54 P 1.70 Analytical (%) C 71.38 H 8.96 N 1.51 P 1.53

[0432]

Reference Example 61 2,6-Anhydro-7-O- [2-A
Cetamide-2-deoxy-4-O-diphenylphosphono
-3-O-｛(R) -3-dodecyloxytetradeci
Ru-β-D-glucopyranosyl] -3-{(R) -3
-Hydroxytetradecanamide {-4-O-} (R)-
3-hydroxytetradecyl} -3-deoxy-D-g
Lysero-D-ido-heptonic acid Reference Example 58 Compound 115 mg (0.0593 mmol)
To a solution of 1) in ethanol (5 mL) was added 111 mg of 20% palladium hydroxide-carbon, and the mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. The reaction solution was filtered, concentrated under reduced pressure, and purified by thin-layer silica gel chromatography (developing solvent; chloroform: methanol, 5: 1). The eluted substance was dissolved in 10 mL of chloroform, and 0.05N
The residual silica gel was removed by washing with an aqueous hydrochloric acid solution, and the chloroform layer was concentrated under reduced pressure to give the target compound (62.
3 mg, yield: 72%).

IR (KBr) spectrum: 3320 (broad), 307
2, 2924, 2854, 1726, 1656 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD) δ: 7.40-7.19
(10H, m), 4.63 (1H, m), 4.53 (1H, m), 4.48 (1H, d,
J = 5.1 Hz), 4.21 (1H, m), 4.04 (1H, m), 3.93-3.52
(14H, m), 3.46 (1H, t, J = 8.1 Hz), 3.35-3.25 (3H,
m), 2.41 -2.30 (2H, m), 2.00 (3H, s), 1.76-1.20 (84
H, m), 0.90 (12H, t, J = 6.6 Hz) Mass spectrum (m / z): 1483.9815 (M + Na) ⁺

[0434]

Reference Example 62 2,6-Anhydro-7-O- [2-A
Cetamide-2-deoxy-4-O-diphenylphosphono
-3-O-｛(R) -3-dodecyloxytetradeci
Ru-6-O-methyl-β-D-glucopyranosyl]-
3-{(R) -3-hydroxytetradecanamide} -4
—O-{(R) -3-hydroxytetradecyl} -3-
Deoxy-D-glycero-D-ido-heptonic acid 136 mg of the compound of Reference Example 59 (0.0744 mmol)
By performing the same operation as in Reference Example 61 for 1), the target compound (98.2 mg, yield: 89%) was obtained.

IR (KBr) spectrum: 3318 (broad), 307
2, 2924, 2854, 1729, 1656 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD) δ: 7.40-7.19
(10H, m), 4.75 (1H, d, J = 8.1 Hz), 4.56 (1H, q, J =
8.8 Hz), 4.29 (1H, m), 4.22-4.19 (2H, m), 4.00-3.22
(18H, m), 3.20 (3H, s), 2.40 -2.33 (2H, m), 2.03
(3H, s), 1.75-1.21 (84H, m), 0.90 (12H, t, J = 6.6 H
z) Mass spectrum (m / z): 1497.9939 (M + Na) ⁺

[0436]

Reference Example 63 2,6-Anhydro-7-O- [2-A
Cetamide-2,6-dideoxy-4-O-diphenylpho
Suphono-3-O-{(R) -3-dodecyloxytetra
Decyl} -6-fluoro-β-D-glucopyranosyl]
-3-{(R) -3-hydroxytetradecanamide}-
4-O-{(R) -3-hydroxytetradecyl} -3
-Deoxy-D-glycero-D-ido-heptonynic acid 75.2 mg (0.0415 mmol) of the compound of Reference Example 60
By performing the same operation as in Reference Example 61 for 1), the target compound (48.3 mg, yield: 80%) was obtained.

[0437] IR (KBr) spectrum: 3323 (broad), 307
2, 2924, 2854, 1729, 1656 cm ^-1 Nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD) δ: 7.41-7.18
(10H, m), 4.68 (1H, d, J = 8.1 Hz), 4.58-4.36 (4H,
m, containing 1H, d, J = 5.1 Hz, δ4.49), 4.22-4.19
(2H, m), 4.03 (1H, m), 3.94-3.68 (10H, m), 3.60 (1
H, t, J = 7.3-9.5 Hz), 3.45 (1H, t, J = 8.1 Hz), 3.36-
3.25 (3H, m), 2.39 -2.30 (2H, m), 2.00 (3H, s), 1.
76-1.20 (84H, m), 0.90 (12H, t, J = 6.6 Hz) Mass spectrum (m / z): 1485.9769 (M + Na) ⁺

[0438]

[Test method] Macrophage activity suppression test (antagonist test) TNFα is produced in vitro using human monocyte cell line U937. The TNFα produced is Genzyme
Quantified by ELISA KIT.

The evaluation method was the method of Daniel-Issakani et al. (Journal of Biological Chemistry, No. 264).
Volume 20240-20247 (1989), [J. Biol. Chem., 264, 202
40-20247 (1989)]).

10 ng / ml LPS (Lipopolysaccharide)
10) U937 cells in 6 hours ^Five About 1ng per piece
Of TNFα is produced (standard production amount: 100%).

The concentration at which the amount of TNFα produced in the presence of 10 ng / ml of LPS and the production of TNFα in the presence of the compound of the present invention was reduced to 50% of the standard production amount was determined and expressed as ED ₅₀ %.

Regarding the cytotoxicity of each compound, the cell viability of J774.1 cells after 6 hours in the presence of each compound was measured by the MTT method, and the cell viability in the absence of the compound was measured. The concentration that suppresses the ratio (Cell Viability) to 50% is represented by IC ₅₀ , and the effect of the compound of the present invention is confirmed using ED ₅₀ / IC ₅₀ as an index.

[0443]

EFFECT OF THE INVENTION The lipid A1-position carboxylic acid derivative of the present invention exhibits an excellent macrophage activity inhibitory action and is useful as an anti-inflammatory agent, an anti-autoimmune disease agent or an anti-sepsis agent.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Shinichi Kurata 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Saori Kanai 1-2-58 Hiromachi, Shinagawa-ku, Tokyo No. F term in Sankyo Co., Ltd. (reference) 4C057 BB03 CC03 GG03 4C086 AA01 AA04 EA02 EA03 MA04 NA14 ZB07 ZB11 ZB35

Claims (31)

[Claims] 1. A compound of the general formula(Where R¹And R^ThreeAre the same or different and are the following (substituent group A)
C optionally substituted with one or more groups selected from
₁-C₂₀Alkanoyl group, selected from the following (substituent group A)
C optionally substituted with one or more groups_Three-C₂₀
Alkenoyl group or selected from the following (substituent group A)
C optionally substituted with one or more groups _Three-C₂₀Archi
R represents a noyl group;^TwoAnd R^FourAre the same or different and are the following (substituent group A)
C optionally substituted with one or more groups selected from
₁-C₂₀Alkyl group, selected from the following (substituent group A)
C optionally substituted with one or more groups_Two-C₂₀Al
Kenyl group, one or more selected from the following (substituent group A)
C optionally substituted with a group of_Two-C₂₀Alkynyl group
Indicates, R^FiveRepresents a hydrogen atom, a halogen atom, a hydroxyl group, an oxo group
C that you may have₁-C₆Has alkoxy and oxo groups
C that may be_Two-C₆Alkenyloxy group or oxo
C optionally having a group_Two-C₆Represents an alkynyloxy group
(Substituent group A) includes a halogen atom, a hydroxyl group, an oxo group,
C which may have an oxo group₁-C₂₀An alkoxy group,
C which may have an oxo group_Two-C₂₀Alkenyloxy
C which may have a thio group or an oxo group_Two-C₂₀Alkini
C which may have a ruoxy group or an oxo group₁-C₂₀A
C which may have a lucanoyloxy group or an oxo group_Three
-C₂₀Having an alkenoyloxy group and an oxo group
Good C_Three-C₂₀A group consisting of alkynyloxy groups
You. ), A pharmacologically acceptable salt thereof, or
That ester. 2. R ¹ is a C ₄ -C ₁₈ alkanoyl group which may have a substituent selected from (Substituent group A).
A compound according to claim 1. 3. R ¹ is a C ₈ -C ₁₆ alkanoyl group optionally having a substituent selected from (Substituent group A).
A compound according to claim 1. 4. The compound according to claim 1, wherein R ¹ is an unsubstituted or C ₁₂ -C ₁₄ alkanoyl group having a hydroxyl group selected from (Substituent group A) as a substituent. 5. The compound according to claim 1, wherein R ¹ is an unsubstituted or lauroyl group or a myristoyl group having a hydroxyl group selected from (Substituent group A) as a substituent. 6. The compound according to claim 1, wherein R ² is a C ₄ -C ₁₈ alkyl group which may have a substituent selected from (Substituent group A). 7. The compound according to claim 1, wherein R ² is a C ₈ -C ₁₆ alkyl group optionally having a substituent selected from (Substituent group A). 8. The compound according to claim 1, wherein R ² is unsubstituted or a C ₁₂ -C ₁₄ alkyl group having a hydroxyl group selected from (Substituent group A) as a substituent. 9. The compound according to claim 1, wherein R ² is unsubstituted or a dodecyl group or a tetradecyl group having a hydroxyl group selected from (Substituent group A) as a substituent. 10. The compound according to claim ₁ , wherein R ³ is an unsubstituted C ₁ -C ₁₆ alkanoyl group. 11. The compound according to claim ₁ , wherein R ³ is an unsubstituted C ₁ -C ₈ alkanoyl group. 12. The compound according to claim ₁ , wherein R ³ is an unsubstituted C ₁ -C ₄ alkanoyl group. 13. The compound according to claim 1, wherein R ³ is an acetyl group or a propionyl group. 14. The compound according to claim 1, wherein R ³ is an acetyl group. 15. The compound according to claim 1, wherein R ⁴ is a C ₄ -C ₁₈ alkyl group which may have a substituent selected from (Substituent group A). 16. The compound according to claim 1, wherein R ⁴ is a C ₈ -C ₁₆ alkyl group optionally having a substituent selected from (Substituent group A). Is 17. R ^4, as a substituent selected from (Substituent Group A) The fluorine atom, a hydroxyl group, an unsubstituted C ₁₂ -C ₁₄ alkoxy group or an unsubstituted C ₁₂ -C ₁₄ alkanoyloxy group is a C ₁₂ -C ₁₄ alkyl group having a compound according to claims 1 to 14. 18. The compound according to claim 1, wherein R ⁴ is a dodecyl group or a tetradecyl group having a dodecyloxy group or a tetradecyloxy group selected from (Substituent group A) as a substituent. 19. The compound according to claim 1, wherein R ⁴ is a dodecyl group or a tetradecyl group having a lauroyloxy group or a myristoyloxy group selected from (Substituent group A) as a substituent. 20. The compound according to claim 1, wherein R ⁵ is a halogen atom, a hydroxyl group or an unsubstituted C ₁ -C ₆ alkoxy group. 21. The compound according to claim 1, wherein R ⁵ is a fluorine atom, a hydroxyl group or a methoxy group. 22. 2,6-Anhydro-7-O- [2-acetamido-2-deoxy-6-O-methyl-4-O-phosphono-3-O-｛(R) -3-tetradecanoyl Oxytetradecyl {-β-D-glucopyranosyl] -3-
{(R) -3-hydroxytetradecanamide} -4-O
-{(R) -3-hydroxytetradecyl} -3-deoxy-D-glycero-D-ido-heptonic acid, a pharmaceutically acceptable salt thereof or an ester thereof. 23. 2,6-Anhydro-7-O- [2-acetamido-2-deoxy-4-O-phosphono-3-O-
{(R) -3-tetradecanoyloxytetradecyl}
-Β-D-glucopyranosyl] -3-{(R) -3-hydroxytetradecanamide} -4-O-{(R) -3-
Hydroxytetradecyl} -3-deoxy-D-glycero-D-ido-heptonic acid, a pharmaceutically acceptable salt thereof or an ester thereof. 24. 2,6-Anhydro-7-O- [2-acetamide-2,6-dideoxy-6-fluoro-4-O
-Phosphono-3-O-{(R) -3-tetradecanoyloxytetradecyl} -β-D-glucopyranosyl]-
3-{(R) -3-hydroxytetradecanamide} -4
—O-{(R) -3-hydroxytetradecyl} -3-
Deoxy-D-glycero-D-ido-heptonic acid, a pharmaceutically acceptable salt thereof or an ester thereof. 25. 2,6-Anhydro-7-O- [2-acetamido-2-deoxy-3-O-{(R) -3-dodecyloxytetradecyl} -6-O-methyl-4-O −
Phosphono-β-D-glucopyranosyl] -3-{(R)
-3-Hydroxytetradecanamide｝ -4-O-
{(R) -3-Hydroxytetradecyl} -3-deoxy-D-glycero-D-ido-heptonic acid, a pharmaceutically acceptable salt thereof or an ester thereof. 26. 2,6-anhydro-7-O- [2-acetamido-2-deoxy-3-O-{(R) -3-dodecyloxytetradecyl} -4-O-phosphono-β-D
-Glucopyranosyl] -3-{(R) -3-hydroxytetradecanamid} -4-O-{(R) -3-hydroxytetradecyl} -3-deoxy-D-glycero-D-
Id-heptonic acid, a pharmaceutically acceptable salt thereof or an ester thereof. 27. A 2,6-anhydro-7-O- [2-acetamide-2,6-dideoxy-3-O-｛(R) -3
-Dodecyloxytetradecyl} -6-fluoro-4-
O-phosphono-β-D-glucopyranosyl] -3-
{(R) -3-hydroxytetradecanamide} -4-O
-{(R) -3-hydroxytetradecyl} -3-deoxy-D-glycero-D-ido-heptonic acid, a pharmaceutically acceptable salt thereof or an ester thereof. [28] a pharmaceutical comprising the compound according to [1] as an active ingredient; 29. A prophylactic or therapeutic agent for inflammation, comprising the compound according to claim 1 as an active ingredient. [30] a prophylactic or therapeutic agent for an autoimmune disease, comprising the compound according to [1] as an active ingredient; (31) A preventive or therapeutic agent for sepsis, comprising the compound according to (1) as an active ingredient.