JP2716657B2 - Compound having specific binding ability to adhesion molecule ELAM-1 - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[Background of the Invention]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a compound having a specific binding ability to an adhesion molecule ELAM-1.

[0002]

2. Description of the Related Art Inflamed vascular endothelial cells include EL, a kind of selectin having a function as an adhesion molecule.
It is known that AM-1 is expressed. Where EL
By using an ELAM-1 ligand that specifically binds to AM-1 as a cell recognition element and combining it with an anti-inflammatory agent, the anti-inflammatory agent can be efficiently and specifically delivered to an inflammatory site exhibiting inflammation. Can be expected.

[0003] As a ligand for ELAM-1, sialyl Lewis X expressed on the surface of neutrophils and the like is known. Sialyl Lewis X is a Lewis X having a trisaccharide structure in which galactose is β (1 → 4) -linked and N-acetylglucosamine and fucose is α (1 → 3) -linked, and sialic acid is a galactose of Lewis X α (2 → 3)
It is a combination.

[0004] However, it is difficult to obtain sialyl Lewis X in a large amount, and therefore, an inexpensive compound that specifically binds to ELAM-1 like sialyl Lewis X has been desired.

[Summary of the Invention]

Accordingly, the present invention relates to an EL device.
It is intended to provide a compound having a specific binding ability to AM-1.

Another object of the present invention is to provide a compound for use in a drug delivery system for delivering a therapeutic agent to a specific tissue.

[0007]

The compound according to the present invention comprises
It is represented by the following general formula (I).

[0008]

Embedded image [In the above formula, F is a monosaccharide selected from sialic acid, uronic acid, galactose, glucose, fucose, mannose, hexosamine, ribose and rhamnose, a monosaccharide derivative thereof, or a monosaccharide or derivative of these monosaccharides. Represents an oligosaccharide residue consisting of up to 4
Represents an integer of 0 to 10, and T ₁ is a bond, -NHCO
-, -NHCOO-, -OOCNH-, -NHCONH
-, -OCNH-, -OC (= O)-,-(O =) CO
— Or —O—, R ¹ and R ² may be the same or different and each is a hydrogen atom, an amino group which may be amidated, a hydroxyl group which may be etherified or esterified A carboxyl group which may be esterified or amidated, or at least one
Amino groups which may be amidated,
Represents a C _1-3 alkyl group substituted with a hydroxyl group which may be esterified or etherified or a carboxyl group which may be amidated or esterified, and i represents an integer of 0, 1 or 2 , ^{R 3ai} and ^{R 4ai} may represent the same meanings as defined in ^{R 1} and ^{R 2,} may be the ^{R 1} and ^{R 2} are independently identical or different, ^{R 5i} is defined by ^{R 1} Represents the same meaning as described above, but may be the same or different from R ¹ ,
R ⁶ has the same meaning as defined for R ¹ , but R ¹
May be the same or different, or R ⁶
And R ¹ or R ^3ai together form — (CH ₂ ) p
-(Where p represents an integer of 1 to 4), and represents 5 together with the carbon chain to which R ⁶ and R ¹ or R ^3ai are bonded.
May form a 7-membered saturated ring, and T _2i is T ₁
Represents the same meaning as defined in above, but may be the same as or different from T ₁ , n _i represents an integer of 0 to 10, and F _i has the same meaning as defined in F Represents
F may be the same or different, provided that n _i
= F _i when 0 represents a hydrogen atom, a _i is an integer of 0 to 4, or, ^{R 3ai} or ^{R 5i} is the following formula (I
Group represented by I):

[0009]

Embedded image (Here, T _3i may represent the same meanings as defined in T _1, may be different even identical with T _1,
R ¹⁰ and R ²⁰ represent the same meanings as defined in ^{R 1} and ^{R 2,} and ^{R 1} and ^{R 2} may be different even in the same, j is 0, 1 or 2 ^Represents an integer, and R ^30bij and R ^40bij have the same meaning as defined for R ^3ai and R ^4ai , but R ^3ai and R ^4ai
May be the same or different, and b _ij is 0 to
4 of an integer, R ^50Ij may represent the same meanings as defined in R ^5i, or different and are identical to the R ^5i, R ⁶⁰ are the same as those defined in R ⁶ Representing the meaning, R ⁶ may be the same or different,
_4ij may represent the same meanings as defined in _{T 1, T 1}
May be the same or different, and n _ij is 0 to
Represents an integer of 10, and F _ij has the same meaning as defined for F, but may be the same or different from F, provided that when n _ij = 0, F _ij represents a hydrogen atom . ), And at least one of F, F _i and F _ij represents fucose or an oligosaccharide having fucose at its non-reducing end. ]

The compound according to the present invention is represented by the following general formula (III).

Embedded image [In the formula, F _u is sialic acid, uronic acid, galactose, glucose, fucose, mannose, hexosamine, monosaccharide or monosaccharide derivative thereof is selected from ribose and rhamnose, or their monosaccharide or monosaccharide An oligosaccharide consisting of 2 to 4 derivatives, nu
Represents an integer of 0, _{T u} is a bond, -NHCO
-, -NHCOO-, -OOCNH-, -NHCONH
-, -OCNH-, -OC (= O)-,-(O =) CO
— Or —O—, wherein (R ^1v ) v and R ^2u are
May be the same or different, and each is a hydrogen atom, an amino group which may be amidated, a hydroxyl group which may be etherified or esterified, a carboxyl group which may be esterified or amidated, or ,
An alkyl group in which at least one hydrogen atom is substituted with an amino group which may be amidated, a hydroxyl group which may be esterified or etherified, or a carboxyl group which may be esterified or amidated; U represents an integer of 2 or 3, and v represents 1-3
Wherein ru and su each independently represent 0, 1 or 2; tu represents 0 or 1;
_At least one of _u represents fucose or an oligosaccharide having fucose at its non-reducing end. ]

The compound according to the present invention is ELAM-1
Has the property of being able to specifically bind to Therefore, by combining the compound according to the present invention with an anti-inflammatory agent, the anti-inflammatory agent can be specifically delivered to the inflammatory site of vascular endothelial cells. Further, since the compound according to the present invention has a sugar such as fucose as a branched chain, the compound may be used as a recognition element for a specific cell.

[Specific description of the invention] In the above general formulas (I), (II) and (III), F, F _i , F _ij and _Fu are sialic acid, uronic acid, galactose, glucose, fucose, mannose , Hexosamine, ribose and rhamnose, or an oligosaccharide residue consisting of 2 to 4 of these monosaccharides, and these monosaccharides and oligosaccharides may be derivatives thereof. The derivatives include N- or O-acyl derivatives; O-alkyl derivatives including carboxyalkyl derivatives (preferably carboxymethyl derivatives); ester derivatives with acids such as sulfuric acid, phosphoric acid, and carboxylic acid (preferably sulfate esters) Derivative); sialic acid, uronic acid or an esterified or amidated derivative of the carboxyalkyl derivative.
Here, the monosaccharide residue and the oligosaccharide residue mean those in which one hydrogen atom of the hydroxyl group (preferably the anomeric hydroxyl group) of the sugar molecule is removed. In this case, F,
_Fi and F _ij , _and- (CH ₂ ) _n -,-(CH ₂ )
_ni - and - _{(CH 2) nij} - binding and can be a α-glycosidic bond may be a β-glycosidic bond. In addition, the residue of a derivative of a monosaccharide or an oligosaccharide refers to a residue obtained by removing one hydrogen atom of a hydroxyl group (preferably a hydroxyl group at an anomeric position) of a sugar molecule, and an amino group of the sugar molecule. One in which one hydrogen atom is replaced by -CO-, the carboxyl group of the sugar molecule has-
OH is replaced by -NH- or -O-.

Further, F, F _i, monosaccharide unit of the oligosaccharide represented by F _ij and F _u is preferably which is attached via an O- glycosidic bond. Further, the oligosaccharide preferably has fucose at its non-reducing end, and is preferably a residue in which the hydrogen atom of the hydroxyl group of a sugar other than fucose has been removed.

However, in the compound according to the present invention,
At least one of F, F _i and F _ij shall represent fucose or an oligosaccharide having fucose at its non-reducing end.

## EQU1 ## which is connected to F, F _i and F _ij- (C
_{H 2) n -, - (} CH 2) ni - and - _(CH 2)
_nij - In, n, n _i and n _ij represents an integer of 0, preferably 0-8.

In the general formula (I), R ¹ and R
² may be the same or different and each represents a hydrogen atom, an amino group, a hydroxyl group, a carboxyl group or C _1-3
Represents an alkyl group. Here, the amino group, hydroxyl group and carboxyl group may be amidated, etherified or esterified. Examples of amidation, etherification and esterification include a _C1-18 alkylcarbonyl group and a protecting group for each functional group.

When a protecting group is introduced, specific examples of the protecting group include, when the functional group is an amino group, a carbamate-based protecting group (for example, a t-butyloxycarbonyl group (B
oc group), benzyloxycarbonyl group (Z group), 2,
2,2-trichloroethoxycarbonyl group, 9-fluorenylmethoxycarbonyl group, etc.), amide protecting group (for example, propionyl group, trifluoroacetyl group, formyl group, etc.), alkyl protecting group (for example, benzyl group,
Para-methoxybenzyl group) and imide-based protecting groups (for example, phthalimide).

When the functional group is a carboxyl group, an ester protecting group (for example, a methyl ester group, a benzyl ester group, a tert-butyl ester group, etc.), a hydrazide protecting group (for example, hydrazide, N-phenylhydrazide, etc.) And amide-based protecting groups (for example, N, N-dimethylformamide and the like).

When the functional group is a hydroxyl group, an ester protecting group (eg, acetyl group, benzoyl group, pivaloyl group, methyl carbonate group, etc.), an ether protecting group (eg, benzyl group, paramethoxybenzyl group, methoxymethyl group) Group, 1-ethoxyethyl group, 2- (trimethylsilyl) ethoxymethyl group, etc.), silyl protecting group (eg, t-butyldimethylsilyl group, triisopropylsilyl group, etc.), benzylidene group, isopropylidene group, etc. Can be

Further specific examples of the amidation, etherification or esterification include one or two of the amino group, hydroxyl group or carboxyl group, cholesterol, _C12-20 fatty acid, _{C12-20 Examples} include the case where an amino acid, a carboxyl group or a hydroxyl group of a fat-soluble compound selected from an aliphatic amine and a _C12-20 aliphatic alcohol is dehydrated and condensed.

Further, at least one hydrogen atom of a C _1-3 alkyl group represented by R ¹ and R ² is substituted, and the substituent is an amino group which may be amidated, esterified or etherified. Or a carboxyl group which may be esterified or amidated. Examples of amidation, etherification and esterification include those described above.

In the general formula (I), i represents an integer of 1 or 2, which means that there is one or two repeating units enclosed by large parentheses in the general formula (I).

In the general formula (I), R ⁵ⁱ has the same meaning as defined for R ¹ , but may be the same or different from R ¹ . F _i has the same meaning as defined for F, but may be the same or different from F;
T _2i has the same meaning as defined for T ₁ ,
It may be the same or different from ₁ .

Here, the subscripts of R ⁵ⁱ , F _i and T _2i
i has no particular meaning when i is 1, which represents the number of repeating units enclosed in large parentheses in the general formula (I), but when i is 2, it is the first repeating unit. I = 1, and i = 2 in the second repeating unit. As a result, in the first repeating unit, R ⁵ⁱ is represented as R ^51, and in the second repeating unit, R ⁵ⁱ is represented as R ^52, and R ⁵¹ and R ⁵² may be the same or different. Good. F _i and T _2i
The same applies to.

The same applies to the subscript i of n _i , where n ₁
And n ₂ may be the same or different.

R ⁶ has the same meaning as defined for R ¹ , but may be the same or different from R ¹ . In addition, R ⁶ and R ¹ or R ^3ai (preferably R ⁶ and R ^3ai)
1 A), together - _(CH 2) p- _(wherein, p
Represents an integer of 1 to 4), and can form a 5- to 7-membered saturated ring together with the carbon chain to which R ⁶ and R ¹ or R ^3ai are bonded.

In the general formula (I), R ^3ai and R ^3ai
4ai, although the same meanings as ^{R 1} and ^{R 2,} may be the same or different from ^{R 1} and ^{R 2.}

A _i represents an integer of 0 to 4, which means that 0 to 4 units of — (CR ^3ai R ^4ai ) — can be repeated. Where R
The subscript a of ^3ai and R ^4ai has no special meaning when _ai represents 0 or 1, but when _ai is 2 to 4, a = 1, 2 A = 2 for the 3rd repeat unit, a = 3 for the 3rd repeat unit, a for the 4th repeat unit
= 4. As a result, in each of the first to fourth repeating units, R ^3ai is R ³¹ⁱ ,
They are represented by R ³²ⁱ , R ³³ⁱ and R ^34i, and these R ³¹ⁱ , R ³²ⁱ , R ³³ⁱ and R ³⁴ⁱ may be the same or different. This is the same for ^R4ai . Further, the meaning of the subscript i defined above is the same in R ^3ai and R ^4ai , and when i is 2, for example, the first unit of the repeating unit enclosed by large parentheses in the general formula (I) R ^{31i in the} second unit (ie, R ³¹¹ ) and R ³¹ⁱ in the second unit (ie, R ³¹¹ ).
³¹² ) means that they may be the same or different.

Further, in the general formula (I), R ^3ai ,
R ^4ai and / or R ⁵ⁱ may represent a group represented by the above formula (II). The group represented by the formula (II) is
General formula _{(I) F- (CH 2)} n - having a portion substantially the same meaning, except for the portion of the. Thus, in the formula (II), _{T 3i} is the same meaning as _{T 1,} it may be the same or different from _{T 1,} R ¹⁰ and R ^{20, R 1}
And R ² have the same meanings, but may be the same or different from R ¹ and R ^2, and R ^30bij and R 2
^40bij has the same meaning as R ^3ai and R ^4ai ,
^3ai and R ^4ai may be the same or different and b
_ij represents an integer of ^0~4, R 50ij is the same meaning as ^{R 5i,} and ^{R 5i} may be identical or different,
R ⁶⁰ is the same meaning as R ^6, and R ⁶ may be the same or different, F _ij is the same meaning as F, F
May be the same or different from, T _4ij may represent the same meaning as T _1, it may be the same or different from T _1, n _ij denotes an integer of 0. Further, the subscripts b and j have the same meaning as the subscripts a and i, respectively.

Accordingly, when R ^30bij , R ^40bij and / or R ^50ij is a group represented by the formula (II) (hereinafter referred to as “group (I)
I) ^* ”). Here, in the group (II) ^* as R ^30bij , R ^40bij and / or R ^50ij , T _3i , R ¹⁰ , R ²⁰ ,
_{^{R 30bij, R 40bij, b i}} , R 50ij, R 60, F ij, T
_4ij and n _ij is the group (II) ^* is attached, formula (I
The corresponding T _3i , R ¹⁰ , R ²⁰ , R in the group represented by I)
_{^{30bij, R 40bij, b i,}} R 50ij, R 60, F ij, T 4ij
And n _ij may be the same or different. Further, a group represented by the formula (II) may be further ^present as R ^30bij , R ^40bij and / or R ^{50ij in the} group (II) ^* , but the repetition thereof is finite and the group (II) ) ^* or is absent, or, there is one first group (II) ^* is preferred that no further exists a group represented by the formula (II) to it.

The compound according to the present invention optionally has an asymmetric carbon, and stereoisomers resulting from the asymmetric carbon exist, and these isomers and mixtures thereof are included in the present invention.

[0032] Preferred compounds of the compounds according to the invention is any fucose F and F _i, the other is fucose, galactose, N- acetylgalactosamine, monosaccharide or they are selected from sialic acid or uronic acid Phosphate or sulfate (preferably sulfate) or carboxyalkyl derivative (preferably carboxymethyl derivative) of the monosaccharide, or the above monosaccharide or monosaccharide derivative having at the non-reducing end, and then galactose, glucose, N- It represents an oligosaccharide having acetylgalactosamine or N- acetylglucosamine, n and n _i are independently 0 or an integer of 2-8, more preferably n and n _i represents the same integer from 2 to 8, T ₁ and T _2i represent a bond, —NHCO— or —CONH—; ¹ , R ² , R ^3bij ,
One of R ^4bij , R ⁵ⁱ and R ^{6 is} an amino group which may be amidated, a hydroxyl group which may be etherified or esterified, or a carboxyl group which may be esterified or amidated; , And all others represent a hydrogen atom; i represents 0 or 1 (more preferably 1); and _ai represents 0, 1 or 3 (more preferably 1 or 3).

Further, another preferred compound group includes R
^One in which one of ^3ai and R ⁵ⁱ represents a group represented by the formula (II) is mentioned. Here, preferred examples of the group represented by Formula (II), in Formula (II), F _ij is a same as the preferred examples of the above F, and F _i, R ^10, R
²⁰ , one of R ^30ai , R ^40ai , R ^50ij and R ⁶⁰ may be an amino group which may be amidated, a hydroxyl group which may be etherified or esterified, or an esterified or amidated group. Represents a carboxyl group, any other represents a hydrogen atom, and j is 0 or 1
(More preferably 1), and b _i is 0, 1 or 3
(More preferably 1 or 3), n _ij represents 0 or an integer of 2 to 8, more preferably n and n _i are the same and represent an integer of 2 to 8, and T ₃ and T _4ij are And those representing a bond, -NHCO- or -CONH-.

Further, another preferable compound group includes R
¹ or R ^3ai and R ⁶ (preferably R ¹ and R ⁶ ) together ^form- (CH ₂ ) p- (where p is 1 to
R ¹ or R ^3ai and R 3
And those forming a 5- to 7-membered saturated ring with the carbon chain to which ⁶ is bonded.

According to still another aspect of the present invention, there is provided a compound represented by the above general formula (III).

In the general formula (III), (R ^1v ) v and R ^2u represent an amino group which may be amidated, a hydroxyl group which may be etherified or esterified, an esterified or amidated group. Wherein at least one hydrogen atom is an amino group which may be amidated, a hydroxyl group which may be esterified or etherified, or a carboxyl group which may be esterified or amidated the C _{1 to 3} alkyl group substituted, with a meaning identical to that R ¹ in formula (I).

Here, "u represents an integer of 2 or 3" means that two or three substituents in parentheses enclosed by u are present as substituents on the benzene ring. Here, in each of the two or three parenthesized groups, R ^2u , nu, Tu, ru, su, tu and F
_u may be the same or different. Also, v is 1
Representing an integer of ~ 3 means that R ^1v is present as 1 to 3 substituents on the benzene ring. Further, when two or three R ^1v are present, each R ^1v may be the same or different.

Further preferred compounds according to the present invention are those represented by the following general formula (Ia).

[0039]

Embedded image [In the above formula, F ₁ and F ₂ may be the same or different, and each is a monosaccharide or saccharide selected from sialic acid, uronic acid, galactose, glucose, fucose, mannose, hexosamine, ribose and rhamnose. A derivative thereof, or an oligosaccharide consisting of 2 to 4 of those monosaccharides or derivatives, and n ₁ and n
₂ may be the same or different and each represents 0
Represents an integer of 10 to 10, and T ₁ and T ₂ may be the same or different and each represents a bond, —NHCO—,
-NHCOO-, -OOCNH-, -NHCONH-,
Represents -OCNH-, -OC (= O)-,-(O =) CO- or -O-, a represents an integer of 0 to 4, and R ^{* 1} and R ^{* 2} are the same And may each represent a hydrogen atom, a hydroxyl group, an amino group or a carboxyl group, or R ^{* 1} and R ^{* 2} together form-(CH
₂ ) represents p- (where p represents an integer of 1 to 4),
A 5- to 7-membered saturated ring may be formed together with the carbon chain to which R ^{* 1} and R ^{* 2} are bonded, or R ^{* 1} and / or R ^{* 2} is represented by the following formula (IIa): Group:

[0040]

Embedded image (Here, F _3, which represent the same meanings as defined in F _1, may be different even identical with F _1, n
₃ has the same meaning as defined for n ₁ , but may be the same or different from n _1, and T ₃ and T ₄
Is the same meaning as those defined by T ₁ and T _2, the T ₁ and T ₂ may be different even in the same, b is an integer of 0 to 4, R * ³ and R ^{* 4} is R
^{* 1} and R ^{* 2} have the same meaning as defined above, but R ^{* 1}
And R ^{* 2} may be the same or different, provided that at least one of F ₁ and F ₂ is a fucose residue or an oligosaccharide having fucose at its non-reducing end. Represents a residue]

The compound according to the present invention is ELAM-1
It has a property capable of specifically binding (see Experimental Examples described later for details of the property). Therefore, by combining the compound according to the present invention with an anti-inflammatory agent, the anti-inflammatory agent can be specifically delivered to the inflammatory site of vascular endothelial cells. Further, since the compound according to the present invention has a sugar such as fucose as a branched chain, the compound may be used as a recognition element for a specific cell.

The structure of the compound of the present invention can be further modified in consideration of the above-mentioned uses.
These modified compounds are also included in the present invention. For example, a pharmaceutical compound, such as an anti-inflammatory agent, can be introduced directly into the compound according to the invention or via a suitable spacer. Here, this spacer has a role of releasing a pharmaceutical compound at a certain desired rate in vivo and / or a role of allowing the compound according to the present invention to be efficiently recognized by ELAM-1. Preferably, it can be accomplished. Specific examples of preferred spacers include polyethylene glycol, peptides, alkane derivatives, polystyrene derivatives, and other polymers.

In another embodiment, a pharmaceutical compound carrier capable of supporting a pharmaceutical compound (for example, a non-toxic polymer,
In addition, a mode in which the compound according to the present invention is introduced as a recognition element into liposomes, fine particle carriers such as lipid microspheres, and the like.

Specific examples of the non-toxic polymer capable of carrying a pharmaceutical compound in this embodiment include polypeptides (eg, albumin, poly-β-alanine, polylysine, polyglutamic acid, etc.), polyvinyl compounds (eg, polyvinyl alcohol, etc.) , Polyalcohols (eg, polyethylene glycol etc.), polysaccharides (eg, pullulan, chitosan, mannoglucan, hyaluronic acid, dextran etc.), polylactides (eg, polyglycolic acid etc.), polyesters (eg, polyethylene adipate etc.), Examples thereof include polyanhydrides (for example, poly (terephthalic acid-sebacic anhydride)), polycarbonates (for example, polyoxycarbonyloxyethylene). The introduction of the compound according to the invention into a pharmaceutical compound carrier can be direct or via a spacer. Preferable examples of the spacer in this case include a peptide consisting of about 2 to 6 amino acids, and this spacer can be introduced into the compound of the present invention by utilizing the amino group or carboxyl group of the compound of the present invention. it can.

When the pharmaceutical compound carrier is a liposome, the compound according to the present invention is immobilized on the liposome, so that a liposoluble compound can be introduced into the compound according to the present invention. Included in the scope of the invention. Specific examples of the fat-soluble compound include cholesterol, fatty acids having 12 to 18 carbon atoms, and 12
-18 aliphatic amines and C12-C18 aliphatic alcohols. These groups may further be a compound such as those represented by the following formula. That is, Y- (CH ₂ ) _k- (OCH ₂ CH ₂ ) ₁ -X wherein k and l each independently represent an integer of 0 to 5, and Y represents an amino group, a carboxyl group or a hydroxyl group. X represents a group: (Where m and q independently represent an integer of 0 to 5,
Z is a bond, -NHCO-, -NHCOO-, -OOCN
H-, -NHCONH-, -OCNH-, -OC (=
O) -, - (O = ) CO- or -O- and represents, R represents a represents) cholesterol residue or C12~20 alkyl group described above] the position of the introduction of the lipophilic ^{group, R} 1, R
^{3ai, R 5i, R 10,} R 30ai, may be any position of ^R 50ai.

The number of the fat-soluble compounds to be introduced may be one, but two may give better results.

These fat-soluble compounds can be introduced by reacting the amino acid, hydroxyl group or carboxyl group of the compound of the present invention with the amino group, hydroxyl group or carboxyl group of the fat-soluble compound and subjecting them to dehydration condensation to form an amide bond or an ester bond. Alternatively, an ether bond may be formed.

A liposome containing a pharmaceutical compound,
Lipid microspheres and the like can be prepared according to a known method, for example, Ann. Rev. Biophys. Bioeng., 9, 467 (1980).

According to another aspect of the present invention, a labeled compound can be introduced into a compound according to the present invention in order to track the pharmacokinetics of the compound according to the present invention. Preferred labeling compounds include fluorescent substances such as fluorescein and dansylated compounds, compounds in which one or more carbon atoms are converted to ¹⁴ C, and compounds in which one or more hydrogen atoms are converted to tritium.

Preparation of Compound The compound according to the present invention can be prepared by the following method.

The compounds according to the invention have the following formula (IV): F- (CH ₂ ) _n -Ta (IV) (where F and n have the same meanings as defined in the general formula (I)) , Ta represents an amino group, a carboxyl group, a hydroxyl group, a halogen atom, an alkoxy group and a tosyl group), and the following formula (V): ^Tb- (CR ¹ R ² ) [(CR ^3ai R ^4ai ) _Ai CR ⁵ⁱ Tc] _i -R ⁶ (V) (where R ¹ , R ² , R ^3ai , R ^4ai , R ⁵ⁱ ,
R ⁶ , ai and i have the same meaning as defined in formula (I), Tb represents a functional group capable of reacting with Ta, and Tc represents a hydrogen atom or a functional group capable of reacting with Ta. The compound represented by the formula: Specifically, the reaction between the compound of the formula (IV) and the compound of the formula (V) is carried out by an acid amide bond (-NHCO
-), Ester bond (-COO-), ether bond (-
O-), a reaction to form a urethane bond (-NHCOO-) or a urea bond (-NH-CO-NH-),
The reaction is carried out in a suitable solvent or without using a solvent under reaction conditions capable of forming these bonds.

More specifically, when the bond is an acid amide bond, a compound of formula (IV) where Ta = amino group and a compound of formula (V) where Tb and / or Tc = carboxylic acid, or Both compounds having an inverse relationship with Ta and Tb (and / or Tc) can be prepared under dehydration-condensation conditions, specifically in solvents that do not participate in the reaction (eg acetonitrile, dimethylformamide, methylene chloride, ethylene chloride). Suitable catalysts (for example, N-hydroxysuccinimide, N, N'-dicyclohexylcarbodiimide, 1-
(Hydroxybenzotriazole) at a reaction temperature of 0 ° C. to room temperature for 1 to 24 hours.

When the bond is an ester bond, T
A compound of formula (IV) wherein a = hydroxyl group and a compound of formula (V) wherein Tb and / or Tc = carboxylic acid, or both compounds whose relationship with Ta and Tb (and / or Tc) is reversed Under an appropriate catalyst (eg, N-hydroxysuccinimide, N, N ′) under dehydration-condensation conditions, specifically in a solvent that does not participate in the reaction (eg, acetonitrile, dimethylformamide, methylene chloride, ethylene chloride).
-Dicyclohexylcarbodiimide, 1-hydroxybenzotriazole) at a reaction temperature of 0 ° C. to room temperature for 1 to 24 hours.

Further, when the bond is an ether bond,
Formula (IV) wherein Ta is a halogen atom or an o-tosyl group
And a compound obtained by treating a compound of formula (V) wherein Tb and / or Tc = hydroxyl group with a hydride reagent such as sodium hydride, potassium hydride, or Ta and Tb (and / or Tc) Both compounds having the opposite relationship can be obtained by reacting in a solvent that does not participate in the reaction (eg, dimethylformamide, tetrahydrofuran) at a reaction temperature of room temperature to 100 ° C. for 1 to 48 hours.

Further, when the bond is a urethane bond, the compound of the formula (IV) in which Ta = amino group and the compound of the formula (V) in which Tb and / or Tc = hydroxyl group can be prepared by a conventional method (for example, 1,1). -Treated with carbonyldiimidazole), or both compounds having an inverse relationship with Ta and Tb (and / or Tc), in a solvent that does not participate in the reaction (eg, ether, Tetrahydrofuran, 1.4-dioxane)
It can be obtained by reacting at a reaction temperature of 0 ° C. to room temperature for 0.5 to 24 hours in the presence of a suitable catalyst (for example, a base such as triethylamine and sodium hydrogen carbonate).

Further, when the bond is a urea bond,
A compound of formula (IV) wherein Ta = amino group, Tb and / or
Or a compound of the formula (V) in which Tc = amino group isocyanated according to a conventional method (for example, treatment with phosgene), or a compound having an inverse relationship with Ta and Tb (and / or Tc). The compound is reacted at room temperature to 100 ° C. in the presence of a solvent that does not participate in the reaction (eg, ether, tetrahydrofuran, benzene, toluene, ethanol)
At a reaction temperature of 1 to 24 hours.

The sugar alkyl derivative represented by the formula (IV) can be produced as shown in the following (a) to (d).

(A) The sugar alkyl derivative represented by the formula (IV) can be obtained by reacting a halogenated sugar in which the hydroxyl group at the anomeric position of the sugar is substituted with halogen with an aliphatic alcohol in a solvent (eg, dichloroethane) , Methylene chloride, benzene, toluene) in the presence of activators (silver salts such as silver silicate, silver carbonate, silver perchlorate, silver trifluoromethanesulfonate, mercury salts such as mercury oxide, tin salts) Can be obtained by reacting.

The brominated saccharide is obtained by treating a saccharide whose hydroxyl group is acetylated with hydrogen bromide / acetic acid, and the fluorinated saccharide is obtained by converting the anomeric hydroxyl group of the unprotected saccharide with diethylaminosulfur trifluorolide. It can be obtained by processing.

(B) Further, the sugar alkyl derivative represented by the formula (IV) can be prepared by reacting a sugar whose hydroxyl group is acylated with a fatty acid alcohol in a solvent (eg, methylene chloride, dichloroethane) which does not participate in the reaction. Catalyst (for example, boron trifluoride / diethyl ether complex (BF ₃ .Et ₂ O), trimethylsilyl trifluoromethanesulfonate (TMS
OTf), pyridium paratoluenesulfonic acid (PPT)
S) etc.).

(C) Further, the sugar alkyl derivative represented by the formula (IV) is a compound in which the hydroxyl group at the anomeric position of the sugar is unprotected,
After treatment with a base such as 8-diazabicyclo (5,4,0) -7-undecene (DBU) and potassium carbonate and trichloroacetonitrile to give imidate, an acid catalyst (for example, BF ₃ .Et ₂ O, TMSOTf, PPT
S) in the presence of an aliphatic alcohol under the same conditions as in (b) above.

(D) Further, the sugar alkyl derivative represented by the formula (IV) can convert a sugar whose hydroxyl group is converted into an alkylthio group and an aliphatic alcohol with an activating agent (for example, N-iodosuccinimide (NIS) / The reaction can also be carried out in the presence of trifluoromethanesulfonic acid (TfOH).

The compound wherein n is 0 can be obtained by reacting a sugar with a compound represented by the formula (V).

Specific examples of the compound represented by the above formula (V) include polyhydric alcohols (eg, glycerin, ethylene glycol, sorbitol, etc.) and amino acids (eg, glycine, β-alanine, p-aminoethylphenylacetic acid) , P-aminophenylacetic acid, ornithine, 3-hydroxytyrosine, serine, etc.), aminoalcohols (eg, ethanolamine, threonine, 1-hydroxy-4-amino-2-butene, tyrosine, β-aminophenylalcohol), Oxyacids (e.g., p-oxybenzoic acid, octanedione, etc.), polycarboxylic acids (e.g., succinic acid, glutamic acid, tartaric acid, citric acid, etc.), polyvalent amines (e.g., ethylenediamine, p-
Aminoaniline, lysine, cyclohexyldiamine and the like). In particular, glutamic acid and lysine are preferred.

Further, among the compounds according to the present invention, R ^3ai
And / or a compound wherein R ⁵ⁱ is a group represented by the formula (II) is represented by the following formula (VI):

[0066]

Embedded image (Where R ¹⁰ , R ²⁰ , R ^30bij , R ^40bij , R ^50ij ,
R ⁶⁰ , T _4ij , F _ij , b _ij and n _ij represent the same meaning as defined in the formula (II), and Td represents an amino group, a carboxyl group, a hydroxyl group, a halogen atom, an alkoxy group and a tosyl group. ) And R ^3ai and / or
^{Alternatively,} it can be obtained by reacting the compound of the general formula (I) in which R ⁵ⁱ is a functional group capable of reacting with Td under the same reaction conditions as described above. When it is desired to further introduce the group (II) ^* into the group represented by the formula (II) thus obtained, the compound represented by the formula (I)
The compound represented by the above formula (VI) may be similarly introduced into R ^30bij and / or R ^50ij of the group represented by I).

Further, the compound according to the present invention is represented by R¹,
R², R^3ai, R^4ai, R⁵ⁱAnd R ⁶With other substituents
By substituting with another compound represented by the general formula (I)
It is also possible to manufacture from a compound.

Further, when the compound according to the present invention is modified so as to be suitable for its use, it is carried out as follows. For example, when a pharmaceutical compound is to be directly introduced into a compound according to the present invention, the introduction can be carried out by reacting a functional group of the pharmaceutical compound with a functional group present in the compound according to the present invention. When a drug compound is to be introduced via a spacer, for example, the reaction can be carried out by reacting the functional group of the spacer with the drug compound and the functional group of the compound according to the present invention.

Furthermore, when the compound according to the present invention is to be introduced into a pharmaceutical compound carrier capable of supporting a pharmaceutical compound, the introduction can be carried out in the same manner as described above. When the pharmaceutical compound carrier is a liposome,
Fat-soluble compounds are introduced into the compounds according to the invention. This introduction can also be carried out by utilizing the reaction between the functional group of the compound according to the present invention and the functional group of the fat-soluble compound. Especially, the introduction of lipophilic compounds via the above-mentioned spacer comprises a compound according to the invention, the following _{formula: Y- (CH 2) k -} (OCH 2 CH 2) l -X ( wherein, k and l Each independently represents an integer of 0 to 5, Y represents a functional group capable of reacting with a functional group of the compound according to the present invention, such as a carboxyl group, an amino group and a hydroxyl group, and X represents a group: (Where m and q independently represent an integer of 0 to 5,
Z is a bond -NHCO-, -NHCOO-, -OOCNH
-, -NHCONH-, -OCNH-, -OC (= O)
-,-(O =) CO- or -O-, and R represents an alkyl group having 12 to 20 carbon atoms), and a reaction condition based on the bonding mode to be used. It can be carried out by reacting the following.

The compound represented by the general formula (III) is
The following general formula (VII):

[0071]

Embedded image (In the above formula, R ^2u , ru, su, tu and u are represented by the formula (I
Represents the same meanings as defined in II), Yu is a carboxyl group, an amino group or a hydroxyl group) and a compound represented by the following formula (VIII): Y- (CH 2 ) nu-Fu (VIII) (In the above formula, Y represents a functional group capable of reacting with Yu;
And Fu have the same meaning as defined in formula (III)) under the reaction conditions based on the bonding mode to be used.

[0072]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

The compound numbers in the examples are the numbers shown in the scheme showing the synthesis process described later. In addition, “D” attached to an asymmetric carbon in the scheme represents a D-form derived from the asymmetric carbon, and represents an L-form when an asymmetric carbon exists and is not particularly specified.

The following abbreviations are used in the examples. p-
TsOH: p-toluenesulfonic acid, NEt _3: Triethylamine, Boc: butoxycarbonyl, HO-S
u: N-hydroxysuccinimide, Pal: palmitoyl, Bn: benzyl, Z: benzyloxycarbonyl, DCC: dicyclohexylcarbodiimide, TF
A: trifluoroacetic acid.

Example 1 Synthesis of compound 1-1 and compound 1-2 2,3,4-tri-O-benzyl-1-O-paranitrobenzyl-fucopyranose (α: β = 36: 64, 34
0 mg) and zinc trifluoromethanesulfonate (31 mg).
8 mg) and 6-chlorohexanol (151 mg) were dissolved in acetonitrile (15 ml), and chlorotrimethylsilane (95 mg) was further added under ice-cooling and stirring. After stirring at the same temperature for 1.5 hours, the reaction mixture was diluted with ethyl acetate, washed successively with water, 5% aqueous sodium hydrogen carbonate solution and water, dried, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using silica gel (70 g) (n-hexane-ethyl acetate = 10: 1) to give Compound 1.
-1 (165 mg), compound 1-2 (65 mg), and compound 1-1 and compound 1-2 (73 mg) were obtained, respectively.

Compound 1-1 Colorless oil [α] _D -42.4 ° (c 0.88, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.11 (3H, d,
J = 6.6 Hz), 1.32-1.40 (2H, m),
1.40-1.48 (2H, m), 1.56-1.68
(2H, m), 1.76 (2H, m), 3.43 (1
H, m), 3.51 (2H, t, J = 6.6 Hz),
3.60 (1H, m), 3.66 (1H, d, J = 2.
9Hz), 3.86 (1H, q, J = 6.6Hz),
3.93 (1H, dd, J = 2.9, 10.0 Hz),
4.02 (1H, dd, J = 3.7, 10.0 Hz),
4.65 (1H, d, J = 11.7 Hz), 4.67
(1H, d, J = 12.0 Hz) 4.74 (1H, d, J
J = 11.7 Hz), 4.78 (1 H, dJ = 3.7 H)
z), 4.81 (1H, d, J = 12.1 Hz), 4.
88 (1H, d, J = 11.7 Hz), 4.98 (1
H, d, J = 11.7 Hz), 7.24-7.41 (1
5H, m).

Compound 1-2 Colorless oil [α] _D + 8.8 ° (c 0.99, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, d,
J = 6.4 Hz), 1.36-1.48 (4H, m),
1.60-1.68 (2H, m), 1.70-1.86
(2H, m), 3.44 (1H, qlike), 3.4
7 (1H, m), 3.49 (2H, t, J = 6.6H
z), 3.51 (1H, dd, J = 9.8, 2.9H
z), 3.55 (1H, br.d), 3.79 (1H,
dd, J = 9.8, 7.6 Hz), 3.93 (1H, d
t, J = 9.5, 6.4 Hz), 4.30 (1H, d,
J = 7.6 Hz), 4.70, 4.72, 4.77,
4.79, 4.98 (each, d, J = 12.0H
z), 7.25-7.37 (15H, m).

Synthesis of Compound 1-3 Compound 1-1 (1.03 g) was dissolved in dimethylformamide (15 ml), and sodium azide (0.24 g) was dissolved.
g) was added and the mixture was stirred at 60 ° C. for 6 days. The reaction solution was diluted with ethyl acetate, washed with water, dried and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane-ethyl acetate 15: 1) using silica gel (100 g) to give compound 1-3 (0.94 g) as a colorless oil.

[0079] _{[α] D -39.0 ° (c1.08} , CHCl 3) IR (CHCl 3): 2098cm -1 1 H-NMR (CDCl 3) δ: 1.10 (3H, d,
J = 6.6 Hz), 1.34-1.42 (4H, m),
1.54-1.68 (4H, m), 3.24 (2H,
t, J = 7.0 Hz), 3.40-3.46 (1H,
m), 3.58-3.64 (1H, m), 3.66 (1
H, d, J = 2.9 Hz), 3.86 (1H, q, J =
6.6 Hz), 3.93 (1H, dd, J = 2.9, 1)
0.0 Hz), 4.03 (1H, dd, J = 3.7, 1
0.0Hz), 4.66 (1H, d, J = 11.5H)
z), 4.67 (1H, d, J = 12.0 Hz), 4.
74 (1H, d, J = 12.0 Hz), 4.78 (1
H, d, J = 3.7 Hz), 4.81 (1H, d, J =
12.0 Hz), 4.87 (1H, d, J = 12.0H)
z), 4.98 (1H, d, J = 11.5 Hz), 7.
24-7.41 (15H, m).

Synthesis of Compound 1-4 Compound 1-2 (20 mg) was treated with dimethylformamide (1
ml), sodium azide (10 mg) was added, and the mixture was stirred at 80 ° C for 24 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using silica gel (10 g) hexane-ethyl acetate 15: 1) to give compound 1-
4 (18 mg) was obtained as a colorless oil.

[0081] _{[α] D + 6.2 ° (} c0.99, CHCl 3) IR (CHCl 3): 2098cm -1 1 H-NMR (CDCl 3) δ: 1.17 (3H, d,
J = 6.3 Hz), 1.32-1.47 (4H, m),
1.52-1.58 (2H, m), 1.58-1.70
(2H, m), 3.21 (2H, t, J = 7.1H
z), 3.44 (1H, q, J = 6.6 Hz), 3.4
6 (1H, m), 3.50 (1H, dd, J = 9.8,
3.2Hz), 3.55 (1H, br.d) 3.79
(1H, dd, J = 9.8, 7.6 Hz), 3.93
(1H, dt, J = 9.3, 6.3 Hz), 4.30
(1H, d, J = 7.6 Hz), 4.70, 4.72,
4.79, 4.97 (each 1H, d, J = 12.
0 Hz), 4.74, 4.93 (1H, d, J = 11.1).
0 Hz), 7.24-7.38 (15H, m).

Synthesis of Compound 1-5 Compound 1-4 (0.90 g) and p-toluenesulfonic acid (0.31 g) were dissolved in ethanol (30 ml).
Add Lindlar catalyst (1.80g) and add 50ps at room temperature
Catalytic reduction was performed for 5 hours with i. After filtering the catalyst, the filtrate was concentrated under reduced pressure to obtain compound 1-5 (1.12 g) as a colorless foam.

Synthesis of Compound 1-6 N-tert-butyloxycarbonyl-L-glutamic acid (74 mg) was dissolved in acetonitrile (20 ml).
N-hydroxysuccinimide (76 mg) and N, N '
-Dicyclohexylcarbodiimide (136 mg) was added, and the mixture was stirred at room temperature for 4 hours. Compound 1- was added to the reaction mixture.
5 (466 mg) and triethylamine (134 mg) were added, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were filtered and purified by column chromatography (chloroform-methanol 100: 1) using silica gel (60 g) to obtain Compound 1-6 (288 mg) as a colorless powder.

[0084] _{[α] D -34.0 ° (c1.45} , CHCl 3) IR (KBr): 1686,1647cm -1 1 H-NMR (CDCl 3) δ: 1.10 (6H, d,
J = 6.6 Hz), 1.28-1.37 (8H, m),
1.43 (9H, m), 1.45-1.52 (4H,
m), 1.55-1.62 (4H, m), 1.85-
1.95 (1H, m), 2.02-2.10 (1H,
m), 2.21-2.39 (2H, m), 3.16-
3.29 (4H, m), 3.38-3.46 (2H,
m), 3.54-3.61 (2H, m), 3.66 (2
H, d, J = 2.9 Hz), 3.86 (2H, q, J =
6.6 Hz), 3.90-3.96 (2H, m), 4.
00-4.05 (2H, m), 4.65 (2H, d, J
= 11.7 Hz), 4.67 (2H, d, J = 12.0)
Hz), 4.74 (2H, d, J = 11.7 Hz),
4.77 (1H, d, J = 3.4 Hz), 4.78 (1
H, d, J = 3.4 Hz), 4.81 (2H, d, J =
12.0 Hz), 4.87 (1H, d, J = 11.7H)
z), 4.88 (1H, d, J = 11.7 Hz), 4.
98 (2H, d, J = 11.7 Hz), 7.24- 7.
41 (30H, m).

Synthesis of Compound 1 Compound 1-6 (230 mg) was added to ethyl acetate (20 ml).
And 10% Pd-C (460 mg) in a mixed solvent of
Catalytic reduction was performed at psi for 3 days. After filtration of the catalyst, the filtrate was concentrated under reduced pressure, and the residue was washed with ether to give Compound 1.
(113 mg) as a colorless powder.

[0086] _{[α] D -80.9 ° (c0.78} , MeOH) IR (KBr): 3368,1695,1653cm -1 1 H-NMR (CD 3 OD) δ: 1.21 (6H, d,
J = 6.6 Hz), 1.34-1.44 (8H, m),
1.44 (9H, s), 1.47-1.57 (4H,
m), 1.57-1.68 (4H, m), 1.80-
1.88 (1H, m), 1.95-2.04 (1H,
m), 2.25 (2H, m), 3.94 (2H, q, J
= 6.6 Hz), 4.73 (2H, d, J = 2.7H)
z).

Example 2 Synthesis of Compound 2-1 To a solution of 1,8-octanediol (10.0 g) in methylene chloride (100 ml) was dissolved pyridine (2
0.0 ml) and methanesulfonyl chloride (5.
30 ml) and stirred at the same temperature for 2 hours. The reaction solution was diluted with methylene chloride, washed with 2% hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off under reduced pressure. (14.9 g) Subsequently, the residue was washed with dimethylformamide (100 m
l), sodium azide (6.67 g) was added, and the mixture was stirred at 80 ° C for 24 hours. The reaction solution was cooled to room temperature, and after adding ethyl acetate (300 ml), the precipitate was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (300 g) (n-
By purifying with hexane-ethyl acetate 5: 1), compound 2-1 (5.85 g) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ + D ₂ O) δ:
3.64 (2H, t, J = 7.1 Hz), 3.26 (2
H, t, J = 7.1 Hz), 1.64-1.53 (4
H, m), 1.41-1.31 (8H, m).

IR (CHCl ₃ ): 3692, 2100 cm ⁻¹ .

Synthesis of Compounds 2-2 and 2-3 2,3,4-tri-O-benzyl-1-O-paranitrobenzyl-fucopyranose (α: β = 36: 64,5.
00g) and zinc trifluoromethanesulfonate (4.
68 g) and Compound 2-1 (2.94 g) were dissolved in acetonitrile (150 ml), and chlorotrimethylsilane (1.63 ml) was added at 0 ° C. After stirring at the same temperature for 2 hours, the reaction solution was diluted with ethyl acetate, washed with water and a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using silica gel (500 g) (n-hexane-ethyl acetate).
12: 1) to give compound 2-2 (9
80 mg), compound 2-3 (353 mg), and a mixture of compound 2-2 and compound 2-3 (2.86 g), respectively.

[0091] Compounds 2-2 colorless oil ^{_{[α] D 24 -33.9 ° (}} c1.00, CHCl 3) IR (CHCl 3): 2100cm -1 1 H-NMR (CDCl 3) δ: 7.41 −7.25
(15H, m), 4.98,4,88,4.74,4.
66 (each 1H, d, J = 11.7 Hz);
81, 4.67 (each 1H, d, J = 12.0H
z), 4.78 (1H, d, J = 3.7 Hz, H-
1), 4.02 (1H, dd, J = 10.0, 3.7H
z), 3.93 (1H, dd, J = 10.0, 2.7H
z), 3.86 (1H, q, J = 6.6 Hz), 3.6
6 (1H, br.d), 3.58 (1H, dt, J = 1)
0.0, 7.1 Hz), 3.43 (1H, dt, J = 1)
0.0, 6.6 Hz), 3.24 (2H, t, J = 7.
1 Hz), 1.66-1.55 (4H, m), 1.39
−1.27 (8H, m), 1.10 (3H, d, J =
6.6 Hz).

Compound 2-3 colorless oil ¹ H-NMR (CDCl ₃ ) δ: 7.38-7.26
(15H, m), 4.98, (1H, d, J = 11.7)
Hz), 4.94, 4.76 (each 1H, d, J
= 11.0 Hz), 4.79 (1H, d, J = 12.0)
Hz), 4.73-4.69 (2H, m), 4.31
(1H, d, J = 7.8 Hz), 3.93 (1H, d
t, J = 9.5, 6.6 Hz), 3.79 (1H, d
d, J = 9.8, 7.8 Hz), 3.55 (1H, b
r. d), 3.40 (1H, dd, J = 9.8, 2.,.
Hz), 3.46 (1H, dt, J = 9.5, 6.8H)
z), 3.44 (1H, q, J = 6.3 Hz), 3.2
3 (2H, t, J = 7.1 HZ), 1.68-1.53
(4H, m), 1.44-1.26 (8H, m), 1.
17 (3H, d, J = 6.3 Hz).

Synthesis of compound 2-4 Ethanol (1) in which compound 2-2 (400 mg) was dissolved
To the solution (3 ml) was added a Lindlar catalyst (400 mg) and paratoluenesulfonic acid (132 mg), and the mixture was stirred at room temperature under a medium-pressure hydrogen stream (50 psi) for 2 hours. By removing the catalyst from the reaction solution by filtration and concentrating the filtrate under reduced pressure,
Compound 2-4 (410 mg) was obtained as a crude product.

Synthesis of Compound 2-5 In a solution of Compound 2-4 (410 mg) in dimethylformamide (5.0 ml) was added N-methylmorpholine (183 μl) and N-tert-butyloxycarbonyl-
L-glutamic acid (85.5 mg), 1-hydroxybenzotriazole (112 mg), and N, N'-dicyclohexylcarbodiimide (157 mg) were added,
Stirred at 0 ° C. for 12 hours. After filtering off the insoluble matter and concentrating the filtrate, the residue was diluted with methylene chloride, and 5% citric acid,
After washing with saturated sodium hydrogen carbonate and drying, the solvent was distilled off under reduced pressure. Subsequently, the obtained residue was subjected to silica gel (9
Column chromatography (methylene chloride-methanol 50: 1) and polymer gel (125 g).
Compound 2 was purified by column chromatography (methylene chloride-methanol 1: 1) using g).
-5 (93 mg) was obtained as a colorless oil.

[0095] ^{_{[α] D 27 -14.6 ° (}} c1.00, CHCl 3) IR (CHCl 3): 1666cm -1 1 H-NMR (CDCl 3) δ: 7.41-7.25
(30H, m), 6.56 (1H, m), 5.93 (1
H, m), 5.68 (1H, m), 4.98, 4.8
8, 4.74, 4.65 (each 2H, d, J = 1
1.7 Hz), 4.81, 4.67 (each 2H,
d, J = 12.2 Hz), 4.79-4.77 (2H,
m), 4.06 (1H, m), 4.02 (2H, dd,
J = 10.3, 3.7 Hz), 3.94 (2H, dd,
J = 10.3, 2.7 Hz), 3.86 (2H, q, J
= 6.6 Hz), 3.61-3.54 (2H, m) 3.
46-3.39 (2H, m), 3.29-3.17 (4
H, m), 2.34 (1H, ddd, J = 14.9,
7.8, 5.3 Hz), 2.26 (1H, ddd, J =
14.9, 7.7, 5.1 Hz), 2.05 (1H,
m), 1.92 (1H, m), 1.61-1.56 (4
H, m), 1.53-1.45 (4H, m), 1.43.
(9H, s), 1.37-1.25 (16H, m),
1.10 (6H, d, J = 6.6 Hz).

Synthesis of Compound 2 Methanol (7 m) in which Compound 2-5 (90 mg) was dissolved
l) -Palladium-carbon (10%, 100 mg) was added to a solution of ethyl acetate (1 ml), and the mixture was added under a medium pressure hydrogen stream (50
psi) and stirred at room temperature for 40 hours. After the catalyst was filtered off from the reaction solution, the filtrate was concentrated, and the residue was purified with silica gel (20
Purification by column chromatography using g) (methylene chloride-methanol-water 7: 3: 1 (lower layer)) gave compound 2 (46 mg) as a colorless powder.

[0097] [α] _D ²⁷ -89.6 ° (c0.31, MeOH) IR (KBr ): 3454,1649cm -1 1 H-NMR (CD 3 OD) δ: 4.73 (2H, b
r. s), 3.98 (1H, m), 3.94 (2H,
q, J = 6.6 Hz), 3.77-3.68 (4H,
m), 3.68-3.62 (4H, m), 3.47-
3.40 (2H, m), 3.24-3.12 (4H,
m), 2.30-2.20 (2H, m), 2.00 (1
H, m), 1.83 (1H, m), 1.68-1.57
(4H, m), 1.55-1.46 (4H, m), 1.
44 (9H, s), 1.42-1.30 (8H, m),
1.20 (6H, d, J = 6.6 Hz).

Example 3 Synthesis of compound 3-2 2-bromethyl 2,3,4-tri-acetyl-α-L-fu
DM of copyranoside (Compound 3-1) (14.46 g)
NaN ₃ (7.09 g) was added to the F (120 ml) solution, and the mixture was stirred and reacted at room temperature for 19 hours. After ethyl acetate and water were added and the layers were separated, the organic layer was dried and purified by silica gel column chromatography (CHCl ₃ ) to obtain 12.54 g of compound 3-2 (96% yield).

R _F 0.51 (Toluene-AcOEt 2: 1) [α] _D ²⁰ -135 ゜ (c 1.17 CHCl ₃ ) IR (Neat): 2120, 1750, 1228 cm
_{^{-1 1 H-NMR (CDCl 3}} ): δppm, J in Hz 1.16 (d, 3H, J = 6.6), 1.99,2.0
9, 2.17 (s, 3H × 3), 3.28, 3.47,
3.62, 3.87 (m, 1H × 4), 4.19 (q,
1H, J = 6.6), 5.12 (d, 1H), 5.14
(Dd, 1H, J = 3.9, 10.5), 5.32 (d
d, 1H, J = 1.2, 3.4), 5.38 (dd, 1
H, J = 3.4, 10.5).

Synthesis of compound 3-3 Methanol (70 ml) of compound 3-2 (4.50 g)
After adding p-toluenesulfonic acid (2.37 g) and a Lindlar catalyst (5.00 g) to the solution and reacting with Parr for 2 hours, a Lindlar catalyst (1.00 g) was further added and reacted for 2 hours. After filtering the catalyst, the solvent was distilled off under reduced pressure to give 5.84 g of compound 3-3 (yield 92.3).
%)Obtained.

Synthesis of Compound 3-4 N-hydroxysuccinimide (1.02 g) and dicyclohexylcarbodiimide (1.83 g) were added to a solution of Boc-L-Glutamic acid (1.00 g) in dichloromethane (50 ml), and the mixture was added at room temperature. The filtrate after stirring for 7 hours was added to a solution of compound 3-3 (4.29 g) and triethylamine (1.03 g) in dichloromethane (20 ml), and the mixture was stirred and reacted at room temperature for 3 hours. The reaction solution is washed with water, dried, and the solvent is distilled off under reduced pressure. Silica gel column chromatography (Nacalai, CHCl ₃ -MeO
H 100: 1) to give 2.84 g of compound 3-4.
(80% yield).

R _F 0.72 (CHCl ₃ -MeOH 10: 1) [α] _D ²³ -106 ゜ (c 0.98 CHCl ₃ ) IR (KBr): 1747,1674,1528,13
^{72,1252,1230,1067cm -1 1 H-NMR (CDCl} 3): δppm, J in Hz 1.14,1.15 (d, 3H × 2, J = 6.4),
1.43 (s, 9H), 1.99, 2.00, 2.0
9, 2.10, 2.17 (s, 3H × 6), 5.05,
5.06 (d, 1H, J = 3.8).

Synthesis of Compound 3 Compound 3-4 (145 mg) was dissolved in methanol (2
ml) solution, a 3% sodium methoxide-methanol solution (200 μl) was added, and the mixture was stirred at 0 ° C. for 10 minutes.
The reaction solution was treated with a cation exchange resin (Dowex 50w).
H ⁺ ), the insolubles were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (methanol) using a polymer gel (50 g) to give compound 3 (101 mg). Was obtained as a colorless powder.

[Α] _D ²⁷ -95.2 ゜ (c 0.99
(MeOH) ¹ H-NMR (CDCl ₃ ) δ: 5.23 (1H, d,
J = 3.7 Hz), 5.21 (1H, d, J = 3.4H)
z), 4.76 (1H, trick), 4.55 (1
H, dd, J = 10.0, 3.4 Hz), 4.54 (1
H, dd, J = 10.0, 3.7 Hz), 4.43 (1
H, dd, J = 10.0, 3.4 Hz), 4.41 (1
H, dd, J = 10.0, 3.4 Hz), 4.23 (1
H, q, J = 6.8 Hz), 4.19 (1H, J = 6.8 Hz).
8 Hz), 4.13 (1H, br.d), 4.09 (2
H, br. d), 4.03-3.96 (2H, m),
3.79 (1H, m), 3.74-3.66 (4H,
m), 3.60 (1H, m), 2.71-2.67 (2
H, m), 2.58 (1H, m), 2.46 (1H,
m), 1.50 (3H, d, J = 6.8 Hz), 1.4
8 (3H, d, J = 6.8 Hz), 1.44 (9H,
s).

Example 4 Synthesis of Compound 4-1 Compound 3-3 (300 mg) was dissolved in dichloromethane (10 m
l) Triethylamine (72 mg) and palmitoyl chloride (180 mg) were added to the solution, and the mixture was stirred and reacted at room temperature for 1.5 hours. The reaction solution was washed with water, dried and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Merck CHCl ₃ ) to give compound 4-1.
Was obtained in an amount of 194 mg (57% yield).

R _F 0.30 (Toluene-MeOH 10: 1) [α] _D ²¹ -88.4 ゜ (c 1.01 CHCl ₃ ) m. p. 67.5-68.5 ° C IR (KBr): 1747, 1639, 1373, 12
^{51,1232,1074cm -1 1 H-NMR (CDCl} 3): δppm, J in Hz 0.88 (t, 3H, J = 6.6), 1.15 (d, 3
H, J = 6.6), 2.01, 2.08, 2.18
(S, 3H × 3), 4.13 (q, 1H, J = 6.
6), 5.30 (d, 1H, J = 3.4).

Synthesis of Compound 4 Compound 4-1 (173.4 mg) was treated with methanol (3 m
l) To the solution, a methanol solution of 28% sodium methoxide (10 μl) was added, and the mixture was stirred and reacted at room temperature for 1.5 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified by gel filtration (LH-20, CHCl ₃ -MeOH 1: 1) to obtain 120.0 mg of compound 4 (88.8% yield).

R _F 0.28 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁷ -76.7 ゜ (c 0.49, CHCl _{3
-MeOH- H 2 O10: 10: 3} ) IR (KBr): 1645,1076,1034cm -1 1 H-NMR (CDCl 3: CD 3 OD = 1: 1): δ
ppm, J in Hz 0.89 (t, 3H, J = 6.
8), 1.24 (d, 3H, J = 6.8), 4.80
(D, 1H, J = 2.7).

Synthesis of compound 5-1 Compound 5-1 was synthesized in the same manner as in the synthesis of compound 3-4 except that benzyloxycarbonyl-D-glutamic acid (1.14 g) was used instead of Boc-L-glutamic acid. .
04 g (yield 82%) was obtained.

R _F 0.74 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁶ -116 ゜ (c1.01 CHCl ₃ ) IR (KBr): 1747, 1660, 1373, 12
^{55,1231,1067cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.13 (d, 3H × 2, J = 6.4), 1.98,
1.99, 2.07, 2.16, 2.17 (s, 3H ×
6), 5.27, 5.30 (d, 1H × 2, J = 2.
4), 5.30 (s, 2H).

Synthesis of Compounds 5-2L and 5-2D To compound 3-4 (300.0 mg) was added trifluoroacetic acid (1.5 ml), and the mixture was stirred at room temperature for 1 hour. Distilled off, CH ₂ Cl ₂ (3m
l), triethylamine (700 μl) and N-hydroxysuccinimide palmitate were added, and the mixture was stirred and reacted at room temperature for 3 hours. The reaction solution was washed with water and dried, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (Merck, CHCl ₃ -MeOH)
100: 1) to give Compound 5-2L in 290.3.
mg (83.6% yield).

R _F 0.70 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁴ -103 ゜ (c1.00, CHCl ₃ ) IR (KBr): 1749, 1641, 1373, 12
^{50,1231,1069cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 0.88 (t, 3H, J = 6.8), 1.14, 1.1
5 (d, 3H, J = 6.6), 1.99, 2.09,
2.17 (s, 3H × 6), 5.28, 5.29 (d,
1H × 2, J = 3.4), 6.99 (d, 1H, J =
6.8).

A solution of compound 5-1 (2.230 g) in ethanol (50 ml) was added with p-toluenesulfonic acid (0.4 ml).
65 g) and 10% Pd / C (223 mg).
Catalytic reduction was performed for 1 hour at arr. The catalyst was removed by filtration to obtain 2.323 g (100% yield) of a deprotected product. Triethylamine (52 mg) was added to a solution of a part (400.0 mg) in dichloromethane (3 ml) followed by palmitic acid N
-Hydroxysuccinimide ester (164 mg) was added, and the mixture was stirred and reacted at room temperature for 3 hours. The reaction solution was washed with water, dried and evaporated under reduced pressure to remove the solvent, and then subjected to silica gel column chromatography (Merck, CHCl ₃ -MeO).
H 50: 1) to give compound 5-2D as 346.8.
mg (81.0% yield).

R _F 0.66 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁵ -103 ゜ (c1.01 CHCl ₃ ) IR (KBr): 1749, 1639, 1373, 12
^{50,1229,1069cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 0.88 (t, 3H, J = 6.8), 1.139, 1.
145 (d, 3H × 2, J = 6.6), 1.98, 2.
00, 2.08, 2.10, 2.17 (s, 3H ×
6), 5.28, 5.30 (d, 1H × 2, J = 3.
4), 6.87 (d, 1H, J = 7.1).

Synthesis of Compounds 5-L and 5-D Compound 5-2L (254.7 mg) was dissolved in methanol (6 m
l) To the solution was added a methanol solution of 28% sodium methoxide (20 μl), and the mixture was stirred and reacted at room temperature for 2 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified by gel filtration (LH-20, CHCl ₃ -MeoH 1: 1), and 165.7 mg of compound 5-L (86.5% yield).
Obtained.

R _F 0.62 (CHCl ₃ -MeOH-
H ₂ O 10: 5: 1) [α] _D ²⁷ -85.5} (c 1.01 CHCl _{3
-MeOH- H 2 O10: 10: 3} ) IR (KBr): 3400,1637,1559,10
^{82cm -1 1 H-NMR (CDCl} 3: CD 3 OD = 1: 1): δ
ppm, J in Hz 0.89 (t, 3H, J = 6.8), 1.25 (d, 3
H × 2, J = 6.6), 4.80, 4.82 (d, 1H)
× 2, J = 2.7).

Similarly, compound 5-2D (305.9)
222.7 mg of compound 5-D (yield: 96. mg).
9%).

R _F 0.59 (CHCl ₃ -MeOH-
H ₂ O 10: 5: 1) [α] _D ²⁵ -74.5 ゜ (c 1.01 CHCl ₃
-MeOH 1: 1) IR (KBr): 3389,1639,1545,10
^{76cm -1 1 H-NMR (CDCl} 3: CD 3 OD = 1: 1): δ
ppm, J in Hz 0.89 (t, 3H, J = 6.8), 1.25 (d, 3
H × 2, J = 6.6), 4.80, 4.82 (d, 1H)
× 2, J = 2.4).

Example 6 Synthesis of Compounds 6-1L and 6-1D Tertiary butyloxycarbonyl- (γ-benzyl) -succinyl -L-glutamic acid (Boc-L-Glu (OB
n) -OSu) (473 mg) in dichloromethane (10
ml) solution, triethylamine (120 mg) and then compound 3-3 (500.0 mg) were added, and the mixture was stirred and reacted at room temperature for 3 hours. The reaction solution was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Merck, CHCl ₃ ) to give compound 6-1.
522.8 mg (yield 81.0%) of L was obtained.

R _F 0.20 (Toluene-MeOH 10: 1) [α] _D ¹⁸ -76.8 ゜ (c 0.94, CHCl ₃ ) IR (KBr): 1747, 1678, 1369, 12
^{48,1229,1167,1067,1053cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.14 (d, 3H, J = 6.6), 1.43 (s, 9
H), 1.99, 2.10, 2.17 (s, 3H ×
3), 5.14 (s, 2H), 5.35 (d, 1H, J
= 3.2).

Tertiary butyloxycarbonyl-γ-benzyl-D-glutamic acid (Boc-D-Glu (OBn)
-OH) (1.00 g) in dichloromethane (10 ml)
375 mg of N-hydroxysuccinimide and 673 mg of dicyclohexylcarbodiimide were added to the solution, and the mixture was added at room temperature.
After stirring for an hour, the filtrate obtained was combined with compound 3-3 (1.3
62 g) and a solution of triethylamine (327 mg) in dichloromethane (10 ml), and reacted by stirring at room temperature for 4 hours. The reaction solution was washed with water, dried, and the solvent was distilled off under reduced pressure.
erck, CHCl ₃ ) to obtain 1.403 g (yield 79.8%) of compound 6-1D.

R _F 0.21 (Toluene-MeOH 10: 1) [α] _D ²⁰ -77.7 {(c 0.74, CHCl ₃ ) IR (KBr): 1747, 1678, 1369, 12
^{50,1231,1167,1067,1053cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.14 (d, 3H, J = 6.4), 1.43 (s, 9
H), 1.99, 2.08, 2.17 (s, 3H ×
3), 5.13 (s, 2H), 5.30 (d, 1H, J
= 3.4).

Synthesis of Compounds 6-2L and 6-2D Compound 6-1L (1.875 g) was added to ethanol (50 m
l) To the solution was added 187 mg of 10% Pd / C,
It was catalytically reduced at rr for 2 hours. After filtering off the catalyst, the solvent was distilled off under reduced pressure to give 1.675 g of compound 6-2L (yield 1).
00%).

Compound 6-2D was converted to 775.0 m in the same manner as described above except that Compound 6-1D (0.900 g) was used.
g (99.9% yield).

Synthesis of Compounds 6-3LL, 6-3DD and 6-3DL Trifluoroacetic acid (1.5 ml) was added to compound 3-4 (250.0 mg), and the mixture was stirred at room temperature for 1 hour and then triturated under reduced pressure. The fluoroacetic acid was distilled off, and dichloromethane (2 m
l) and triethylamine (316 μl) were added.
To this solution, dichloromethane (5 ml), N-hydroxysuccinimide (36 mg) and DCC (64.5 mg) were added to compound 6-2 L (160.0 mg), and the mixture was stirred at room temperature for 2.5 hours and filtered. The filtrate was added,
The mixture was reacted by stirring at room temperature for 3 hours. Wash the reaction solution with water,
After drying, the solvent was distilled off under reduced pressure, and silica gel column chromatography (Merck, CHCl ₃ -MeOH)
50: 1) to give compound 6-3LL at 319.8 m
g (85.0% yield).

R _F 0.62 (CHCl ₃ -MeOH 10: 1) [α] _D ²³ -107 ゜ (c 1.02, CHCl ₃ ) IR (KBr): 1749, 1654, 1371, 12
^{50,1231,1069cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.10, 1.12, 1.12 (d, 3H × 3, J =
6.6), 1.43 (s, 9H), 1.98, 1.9.
9, 2.06, 2.08, 2.14, 2.15 (s, 3
H × 9), 5.24, 5.27, 5.28 (d, 1H ×
3, J = 3.2).

To a solution of compound 5-1 (2.23 g) in ethanol (50 ml) was added p-toluenesulfonic acid (0.4 ml).
65 g) and 10% Pd / C (223 mg)
Catalytic reduction with Parr for 1 hour. Next, the catalyst was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 2.323 g (100% yield) of a debenzyloxycarbonyl compound. Part of it (4
22.0 mg), and triethylamine (5
4 mg) in dichloromethane (5 ml).
-2D (250.7 mg) in dichloromethane (8 m
l), HO-Su (56 mg) and DCC (101 mg)
Was added, and the mixture was stirred at room temperature for 2 hours, and then the filtrate obtained by filtration was added. The mixture was stirred and reacted at room temperature for 2 hours. The reaction solution was washed with water, dried, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (Merck, CHCl _3-
Purification with MeOH 50: 1) gave compound 6-3DD as 4
51.3 mg (76.5% yield) were obtained.

R _F 0.71 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁶ -111 ゜ (c 0.80, CHCl ₃ ) IR (KBr): 1747, 1657, 1371, 12
^{50,1231,1069cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.12, 1.14 (d, 3H × 3, J = 6.4),
1.42 (s, 9H), 1.98, 2.08, 2.16
(S, 3H × 9), 5.27, 5.28 (d, 1H ×
3, J = 3.4).

In place of compound 6-2D, compound 6-2L
(250 mg), using the same method as in the synthesis of compound 6-3DD, to give compound 6-3DL
Was obtained in an amount of 452.7 mg (yield: 77.0%).

R _F 0.57 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁶ -102 ゜ (c1.00, CHCl ₃ ) IR (KBr): 1749, 1655, 1373, 12
^{50,1231,1067cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.12, 1.13 (d, 3H × 3, J = 6.6),
1.43 (s, 9H), 1.98, 1.99, 2.0
0, 2.08, 2.16, 2.17 (s, 3H × 9),
5.27, 5.28, 5.29 (d, 1H × 3, J =
3.2).

Synthesis of Compounds 6-4LL, 6-4DD and 6-4DL Compound 6-3LL (208.2 mg) was added to TFA (81.
5 ml), and stirred at room temperature for 1 hour.
A was distilled off. Then, dichloromethane (2 ml), triethylamine (300 μl) and N-partimidate
Hydroxysuccinimide ester (62 mg) was added, and the mixture was stirred and reacted at room temperature for 3 hours. The reaction solution was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, CHCl ₃ -MeO).
H 50: 1) to give compound 6-4LL in 193.
6 mg (84.2% yield) was obtained.

R _F 0.59 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁵ -111 ゜ (c1.01, CHCl ₃ ) IR (KBr): 1749, 1641, 1373, 12
^{50,1229,1067cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 0.88 (t, 3H, J = 6.5), 1.11, 1.1
3, 1.14 (d, 3H × 3, J = 6.6), 1.9
8, 1.99, 2.01, 2.07, 2.09, 2.1
5, 2.16 (s, 3H × 9), 5.24, 5.29
(D, 1H × 3, J = 3.2).

In place of compound 6-3LL, compound 6-3D
D (201.8 mg) and reacted in the same manner as described above, and silica gel column chromatography (Merc).
k, CHCl ₃ -MeOH 75: 1) to give 153.4 mg (68.8% yield) of compound 6-4DD.

R _F 0.75 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁴ -116 ゜ (c 0.81, CHCl ₃ ) IR (KBr): 1747, 1637, 1373, 12
^{50,1230,1070cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 0.88 (t, 3H, J = 6.8), 1.12, 1.1
3, 1.14 (d, J = 6.6), 1.98, 1.9
9, 2.08, 2.09, 2.10, 2.16 (s, 3
H × 9), 5.26, 5.28 (d, 1H × 3, J =
3.4).

In place of compound 6-3LL, compound 6-3D
L (202.6 mg) and reacted in the same manner as described above, and silica gel column chromatography (Merc).
k, CHCl ₃ -MeOH 50: 1) to give 176.3 mg (yield 78.8%) of compound 6-4DL.

R _F 0.69 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁶ -101 ゜ (c1.00, CHCl ₃ ) IR (KBr): 1747, 1641, 1373, 12
^{50,1229,1070cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 0.88 (t, 3H, J = 6.8), 1.12, 1.1
5 (d, 3H × 3, J = 6.8), 1.98, 1.9
9,2.00,2.07,2.08,2.16,2.1
7 (s, 3H × 9), 5.26, 5.28, 5.30
(D, 1H × 3, J = 3.5).

Synthesis of Compounds 6-LL, 6-DD and 6-DL Compound 6-4LL (168.2 mg) in methanol (3
ml) solution, a methanol solution of 28% sodium methoxide (10 μl) was added thereto, and the mixture was stirred at room temperature for 2 hours to be reacted. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified by gel filtration (LH-20, CHCl ₃ -MeOH 1: 1) to obtain 114.0 mg of compound 6-LL (yield 91.5).
%)Obtained.

R _F 0.54 (CHCl ₃ -MeOH-
H ₂ O 10: 5: 1) [α] _D ²⁶ -88.3} (c1.00, CHCl _{3
-MeOH -H 2 O10: 10: 3} ) IR (KBr): 3449,1637,1076cm -1 1 H-NMR (CDCl 3: CD 3 OD = 1: 1): δ
ppm, J in Hz 0.89 (t, 3H, J = 6.8), 1.25 (d, 3
H × 3, J = 6.6), 4.81, 4.82, 4.83
(1H × 3).

A solution of 28% sodium methoxide in methanol (20 μl) was added to a solution of compound 6-4DD (141.6 mg) in methanol (6 ml).
The mixture was reacted by stirring for 5 hours. The solvent was distilled off from the reaction solution under reduced pressure to obtain 104.5 m of compound 6-DD as a white powder.
g (99.6% yield).

R _F 0.47 (CHCl ₃ -MeOH-
H ₂ O 10: 5: 1) [α] _D ²⁷ −80.0 ゜ (c 0.99, CHCl _{3
-MeOH -H 2 O10: 10: 3} ) IR (KBr): 3450,1639,1076cm -1 1 H-NMR (C 5 D 5 N): δ ppm, J in
Hz 0.87 (t, 3H, J = 6.6), 1.48-1.5
3 (m, 3H × 3), 5.25, 5.26, 5.27
(D, 1H × 3, J = 3.7).

A methanol solution (20 μl) of 28% sodium methoxide was added to a solution of compound 6-4DL (167.3 mg) in methanol (7.5 ml), and the mixture was stirred and reacted at room temperature for 3.5 hours. The solvent was distilled off from the reaction solution under reduced pressure to give compound 6-DL as a white powder.
8 mg (99.0% yield) was obtained.

R _F 0.47 (CHCl ₃ -MeOH-
H ₂ O 10: 5: 1) [α] _D ²⁷ -78.8} (c1.00, CHCl _{3
-MeOH -H 2 O10: 10: 3} ) IR (KBr): 3443,1639,1076cm -1 1 H-NMR (C 5 D 5 N): δ ppm, J in
Hz 0.87 (t, 3H, J = 6.8), 1.48-1.5
3 (m, 3H × 3), 5.24, 5.27 (d, 1H ×
3, J = 3.7).

Example 7 Synthesis of Compound 7-1 Pentaaceto-β-D-galactose (20.00 g)
N- (benzyloxycarbonyl) ethanolamine (15 g) and boron trifluoride / diethyl ether (39.8 ml) were added to a dichloromethane (100 ml) solution, and the mixture was stirred and reacted at room temperature for 21 hours. The reaction mixture was neutralized with aqueous sodium bicarbonate and separated, the organic layer was dried, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Nacalai, CHCl ₃ ) to give compound 7-1. .164 g (67.5% yield) was obtained.

R _F 0.29 (Toluene-MeOH 10: 1) [α] _D ²³ -1.57 ゜ (c1.02, CHCl ₃ ) IR (KBr): 1747, 1720, 1525, 13
^{71,1232,1060cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.99, 2.00, 2.03, 2.15 (s, 3H ×
4), 3.34-3.48 (m, 2H), 3.66-
3.72 (m, 1H), 3.89 (t, 2H, J = 6.
6), 4.14 (dd, 2H), 4.45 (d, 1H,
J = 8.1), 5.00 (dd, 1H, J = 3.4, 1
0.5), 5.10 (s, 2H), 5.18 (dd, 1
H), 5.39 (d, 1H, J = 3.4), 7.36.
(5H).

To a solution of compound 7-1 (8.50 g) in ethanol (150 ml) was added p-toluenesulfonic acid (3.
079 g) and 10% Pd / C (850 mg) were added, and the mixture was catalytically reduced with Parr for 4 hours. After the catalyst was filtered off from the reaction solution, the solvent was distilled off under reduced pressure to obtain 9.217 g of compound 7-2 (yield: 100%).

Synthesis of Compound 7-3 Compound 6-2L (300 mg) was dissolved in dichloromethane (8 m
l) in a solution of HO-Su (67.5 mg) and DCC (1
32 mg), and the mixture was stirred at room temperature for 2 hours and filtered.
l), and reacted by stirring at room temperature for 3 hours.
The reaction solution is washed with water, dried, and the solvent is distilled off under reduced pressure. Silica gel column chromatography (YMC, CHCl ₃ −
Purification with MeOH 150: 1) gave compound 7-3 to 39
2.9 mg (78.7% yield) was obtained.

R _F 0.70 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁷ -53.4 ゜ (c 0.79, CHCl ₃ ) IR (KBr): 1740, 1371, 1231, 10
^{67cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.14 (d, 3H, J = 6.4), 1.43 (s, 9
H), 1.99, 2.01, 2.05, 2.09, 2.
10, 2.17 (s, 3H × 7), 4.50 (d, 1
H, J = 8.1), 5.28 (dd, 1H, J = 1.
0, 3.4).

Synthesis of Compound 7-4 To Compound 7-3 (227.7 mg) was added TFA (2 ml), and the mixture was stirred at room temperature for 2 hours. TFA was distilled off under reduced pressure, and dichloromethane (3 ml) and triethylamine (300 μm) were added.
l) and N-hydroxysuccinimide palmitate (94.6 mg) were added, and the mixture was stirred and reacted at room temperature for 3 hours. The reaction solution was washed with water, dried, and the solvent was distilled off under reduced pressure. Dichloromethane (10 ml) and HO-Su (97
mg) and DCC (190 mg) were added and reacted at room temperature with stirring for 3 hours. The reaction solution was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (YMC, CHCl ₃ -MeOH 100: 1) to obtain 201.4 mg of compound 7-4 (yield: 77.4 mg). 1%)
Obtained.

R _F 0.84 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁸ -49.2 ゜ (c 0.71, CHCl ₃ ) IR (KBr): 1751, 1639, 1371, 12
^{27,1072,1060cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 0.88 (t, 3H, J = 6.8), 1.14 (d, 3
H, J = 6.6), 1.99, 2.00, 2.05.
2.09, 2.16 (s, 3H × 7), 4.53 (d,
1H, J = 7.8), 5.28 (dd, 1H, J = 1.
0, 3.4).

Synthesis of Compound 7 Compound 7-4 (170.0 mg) in methanol (3 m
l) To the solution, a methanol solution of 28% sodium methoxide (20 μl) was added, and the mixture was stirred and reacted at room temperature for 1 hour. The solvent was distilled off from the reaction solution under reduced pressure, and gel filtration (L
H-20, CHCl ₃ -MeOH 1: 1) to give 118.7 mg of compound 7 as a white powder (yield 9).
6.2%).

R _F 0.64 (CHCl ₃ -MeOH-
H ₂ O 10: 5: 1) [α] _D ²⁴ -40.6 ゜ (c1.00, CHCl ₃
-MeOH 1: 1) IR (KBr ): 3400,1637,1074cm -1 1 H-NMR (CDCl 3 -CD 3 OD = 1: 1):
δ ppm, J inHz 0.89 (t, 3H, J = 7.0), 1.25 (d, 3
H, J = 6.6), 4.25 (d, 1H, J = 7.
8), 4.80 (d, 1H, J = 2.9).

Example 8 Synthesis of Compounds 8-1L and 8-1D Tertiary butyloxycarbonyl-L-glutamic acid (0.
HO- in a solution of 50 g) of dichloromethane (25 ml).
Su (0.51 g) and DCC (0.92 g) were added, and the mixture was stirred at room temperature for 2 hours and filtered.
-2 (2.39 g) and triethylamine (0.51
5 g) in dichloromethane (10 ml) and stirred at room temperature for 2 hours to react. The reaction solution is washed with water, dried, and the solvent is distilled off under reduced pressure. Silica gel column chromatography (YMC, CHCl ₃ -MeOH 100:
Purification was performed in 1) to obtain 1.262 g of compound 8-1L (yield 6).
2.8%).

R _F 0.64 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁵ −0.71 ゜ (c 0.99, CHCl ₃ ) IR (KBr): 1753, 1670, 1360, 12
^{30,1076,1059cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.44 (s, 9H), 1.99, 2.05, 2.0
8, 2.09, 2.16 (s, 3H × 8), 4.50,
4.51 (d, 1H × 2, J = 8.0).

HO-Su (0.63 g) and DCC (1.13 g) were added to a solution of benzyloxycarbonyl-D-glutamic acid (0.70 g) in dichloromethane (20 ml).
After stirring at room temperature for 2 hours, the filtrate obtained by filtration was added to a solution of compound 7-2 (2.95 g) and triethylamine (0.64 g) in dichloromethane (10 ml), and the mixture was stirred at room temperature for 3 hours. And reacted. The reaction solution was washed with water, dried, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (YMC, CHCl ₃ -MeOH)
75: 1) to give 1.781 g of compound 8-1D.
(69.6% yield).

R _F 0.77 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁶ -5.73 (c 0.82, CHCl ₃ ) IR (KBr): 1751, 1668, 1371, 12
^{31,1078,1059cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.99, 2.05, 2.06, 2.07, 2.15
2.16 (s, 3H × 8), 4.45 (d, 1H × 2)
J = 7.8).

Synthesis of Compounds 8-2L and 8-2D Tert -butyloxycarbonyl- (γ-benzyl) -succinyl -L-glutamic acid (Boc-L-Glu (OB
n) -OSu) (1.70 g) in dichloromethane (40
ml) solution, triethylamine (431 mg) and then compound 7-2 (2.00 g) were added, and the mixture was stirred and reacted at room temperature for 2 hours. The reaction solution was washed with water, dried and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Merck, CHCl ₃ ) to give compound 8-2L.
1.901 g (yield 75.4%) was obtained.

R _F 0.31 (Toluene-MeOH 1
0: 1) [α] _D ²⁷ + 1.10 ° (c 0.82, CHCl ₃ ) IR (KBr): 1753, 167, 1369, 12
^{25,1171,1076,1065cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.43 (s, 9H), 1.99, 2.05, 2.0
8, 2.15 (s, 3H × 4), 4.49 (d, 1H,
J = 7.8), 5.13 (s, 2H).

Tert-butyl-γ-benzyl-D-glutamic acid (Boc-D-Glu (OBn) -OH) (1.1
HO-Su in a solution of 4 g) in dichloromethane (10 ml).
(428 mg) and DCC (767 mg) were added, and the mixture was stirred at room temperature for 2 hours and then filtered. The filtrate obtained was filtered to obtain compound 7-2 (1.678 g) and triethylamine (36
2 mg) in dichloromethane (10 ml).
The mixture was reacted by stirring at room temperature for 3 hours. The reaction solution was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Merck, CHCl ₃ ) to obtain 1.555 g of Compound 8-2D (yield: 73.5%).

R _F 0.31 (Toluene-MeOH 10: 1) [α] _D ²⁷ −3.75 ° (c1.04, CHCl ₃ ) IR (KBr): 1753, 1676, 1369, 12
^{25,1171,1078,1055cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.44 (s, 9H), 1.99, 2.05, 2.0
6, 2.16 (s, 3H × 4), 4.50 (d, 1H,
J = 8.1), 5.13 (s, 2H).

Synthesis of Compound 8-3L Compound 8-2L (1.403 g) in ethanol (50 m
l) Add 140 mg of 10% Pd / C to the solution and add
The reaction was reduced with rr for 1 hour. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to obtain 1.096 g of Compound 8-3L (yield: 8
9.5%).

Synthesis of Compound 8-4 (a to c) Compound 8-1L (441.7 mg) was added to TFA (2 ml).
After stirring at room temperature for 1 hour, TFA was distilled off under reduced pressure. The residue was dissolved in dichloromethane (2 ml) and triethylamine (500 μl), and to this solution was added compound 6-2L (250 mg) in dichloromethane (8 m
l) HO-Su (56 mg) and DCC (10
1 mg), and the mixture was stirred at room temperature for 1.5 hours. Then, the filtrate obtained by filtration was added, and the mixture was stirred and reacted at room temperature for 17 hours. The reaction solution is washed with water, dried, and the solvent is distilled off under reduced pressure. Silica gel column chromatography (YMC, CHCl 3)
Purification with _3- MeOH (50: 1) afforded 549.8 mg (86.0%) of compound 8-4a.

R _F 0.60 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁸ -39.2 ゜ (c 1.20, CHCl ₃ ) IR (KBr): 1750, 1657, 1371, 12
^{30,1061cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.11 (d, 3H, J = 6.6), 1.42 (s, 9
H), 1.98, 1.99, 2.05, 2.06, 2.
08 (s, 3H × 11), 4.50, 4.51 (d, 1
H × 2, J = 7.8), 5.34 (d, 1H, J = 3.
4).

Compound 7-3 (377.0 mg) was added to TFA.
(4 ml), and the mixture was stirred at room temperature for 2 hours.
The residue obtained by distilling A was dissolved in dichloromethane (2 ml) and triethylamine (500 μl).
HO-Su (51 mg) and DCC were added to a solution of compound 8-3L (250.0 mg) in dichloromethane (8 ml).
(100 mg) was added, the mixture was stirred at room temperature for 3 hours, and the filtrate obtained by filtration was added. The mixture was stirred and reacted at room temperature for 3 hours. After the reaction solution was washed with water and dried, the solvent was distilled off under reduced pressure.
Silica gel column chromatography (YMC, CHC
l ₃ -MeOH50: 81.2% 470.5mg (yield purified Compound 8-4b 1)) was obtained.

R _F 0.63 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁸ -37.4 (c1.03, CHCl ₃ ) IR (KBr): 1749, 1655, 1371, 12
^{29,1061cm -1 1 H-NMR (CDCl} 3): δ
ppm, J in Hz 1.13 (d, 3H, J = 6.6), 1.42 (s, 9
H), 1.98, 1.99, 2.05, 2.06, 2.
07, 2.08, 2.15, 2.16 (s, 3H × 1
1), 4.51, 4.53 (d, 1H × 2, J = 8.
0), 5.28 (d, 1H, J = 3.4).

Compound 7-3 (306.4 mg) was added to TFA.
(3 ml), and the mixture was stirred at room temperature for 2 hours.
A was distilled off. The residue was dissolved in dichloromethane (3 ml) and triethylamine (300 μl), and to this solution was added HO-Su (41.4 mg) and DCC (81 mg) to a solution of compound 6-2L (184.2 mg) in dichloromethane (8 ml). After stirring at room temperature for 3 hours, a filtrate obtained by filtration was added, and the mixture was stirred and reacted at room temperature for 4 hours. The reaction solution was washed with water, dried, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (Nacalai, Japan)
Purification with CHCl ₃ -MeOH 50: 1) gives compound 8
319.1 mg (yield: 70.6%) of -4c was obtained.

R _F 0.78 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁸ -71.3 ゜ (c 0.77, CHCl ₃ ) IR (KBr): 1749, 1657, 1371, 12
^{29,1061cm -1 1 H-NMR (CDCl} 3): δ
ppm, J in Hz 1.12, 1.14 (d, 3H × 2, J = 6.6),
1.43 (s, 9H), 1.99, 2.00, 2.0
5, 2.07, 2.08, 2.09, 2.16 (s, 3
H × 10), 4.52 (d, 1H, J = 8.1), 5.
26, 5.29 (d, 1H × 2, J = 3.4).

Synthesis of Compound 8-5 (a to c) Compound 8-4a (250.0 mg) was added to TFA (3 ml).
Was added and stirred at room temperature for 1 hour. After that, T
The FA was distilled off, and dichloromethane (2 ml), triethylamine (300 μl) and N-hydroxysuccinimide palmitate (67.6 mg) were added to the residue, and the mixture was stirred and reacted at room temperature for 5 hours. The reaction solution was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, CHCl ₃ -MeO).
H 50: 1) to give compound 8-5a as 204.6.
mg (74.7% yield).

R _F 0.77 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁸ -40.5 ゜ (c 0.97, CHCl ₃ ) IR (KBr): 1751, 1639, 1371, 12
^{29,1068cm -1 1 H-NMR (CDCl} 3): δ
ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.11 (d, 3
H, J = 6.6), 1.98, 1.99, 2.02.
2.05, 2.06, 2.08, 2.15, 2.16
(S, 3H × 11), 4.52 (d, 1H × 2, J =
7.8), 5.25 (d, 1H, J = 3.2).

Compound 8-4b (202.5 mg) was added with TF
A (1.5 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. Thereafter, TFA was distilled off under reduced pressure, and dichloromethane (3 ml), triethylamine (500 μl) and palmitic acid N-hydroxysuccinimide ester (54 mg) were added to the residue, and the mixture was stirred and reacted at room temperature for 4 hours. The reaction solution was washed with water, dried, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (Nacalai, Japan)
Purification with CHCl ₃ -MeOH 50: 1) gives compound 8
188.4 mg (yield: 84.9%) of -5b was obtained.

R _F 0.90 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁵ -37.5 ゜ (c 0.77, CHCl ₃ ) IR (KBr): 1751, 1641, 1371, 12
^{30,1061cm -1 1 H-NMR (CDCl} 3): δ
ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.13 (d, 3
H, J = 6.6), 1.99, 2.05, 2.07,
2.09, 2.16 (s, 3H × 11), 4.51. ,
4.52 (d, 1H × 2, J = 7.8), 5.28
(D, 1H, J = 3.2).

Compound 8-4c (198.9 mg) was added with TF
A (1.5 ml) was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, TFA was distilled off under reduced pressure, and dichloromethane (2 ml), triethylamine (400 μl) and N-hydroxysuccinimide palmitate (5 ml) were added to the residue.
6 mg), and reacted by stirring at room temperature for 3 hours.
The reaction solution was washed with water, dried, and then the solvent was distilled off under reduced pressure. Silica gel column chromatography (Nacalai, CHCl3)
Purification with _3- MeOH (50: 1) afforded 177.6 mg of compound 8-5c (81.2% yield).

R _F 0.74 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁷ -77.5 ゜ (c1.00, CHCl ₃ ) IR (KBr): 1751, 1643, 1371, 12
^{29,1069cm -1 1 H-NMR (CDCl} 3): δ
ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.12, 1.1
4 (d, 3H × 2, J = 6.6), 1.99, 2.0
0, 2.05, 2.06, 2.07, 2.09, 2.1
5, 2.16 (s, 3H × 10), 4.53 (d, 1
H, J = 8.1), 5.25, 5.29 (d, 1H ×
2, J = 3.4).

Synthesis of Compounds 8-a, 8-b and 8-c Compound 8-5a (195.2 mg) was added to methanol (3 m
l) and chloroform (2 ml) in a mixed solvent solution,
28% sodium methoxide in methanol solution (20μ
l) was added, and the mixture was stirred and reacted at room temperature for 1.5 hours.
The solvent was distilled off from the reaction solution under reduced pressure to obtain 137.3 mg (yield 99.5%) of compound 8-a as a white powder.

R _F 0.25 (CHCl ₃ -MeOH
—H ₂ O 10: 5: 1) [α] _D ²⁷ −29.4} (c 1.01, CHCl _{3
-MeOH -H 2 O10: 10: 3} ) IR (KBr): 3431,1637,1074cm -1 1 H-NMR (CDCl 3: CD 3 OD = 1: 1): δ
ppm, J in Hz 0.89 (t, 3H, J = 6.8), 1.25 (d, 3
H, J = 6.6), 4.26, 4.27 (d, 1H ×
2, J = 7.8), 4.28 (1H).

In place of compound 8-5a, compound 8-5b
The reaction was carried out in the same manner as described above except that (178.3 mg) was used, and compound 8-b was obtained as a white powder by 116.9.
mg (92.8% yield).

R _F 0.47 (CHCl ₃ -MeOH
-H ₂ O 10: 5: 1) [α] _D ²⁶ -27.0 ゜ (c 0.99, CHCl _{3
-MeOH -H 2 O10: 10: 3} ) IR (KBr): 3435,1636,1076cm -1 1 H-NMR (CDCl 3: CD 3 OD = 1: 1): δ
ppm, J in Hz 0.89 (t, 3H, J = 6.8), 1.25 (d, 3
H, J = 6.6), 4.26, 4.28 (d, 1H ×
2, J = 7.6), 4.81 (d, 1H, J = 2.
0).

In place of compound 8-5a, compound 8-5c
The reaction was carried out in the same manner as described above, except that (169.4 mg) was used, to obtain 119.5 of compound 8-c as a white powder.
mg (97.5% yield).

R _F 0.64 (CHCl ₃ -MeOH
—H ₂ O 10: 5: 1) [α] _D ²⁶ −57.8} (c1.00, CHCl _{3
-MeOH -H 2 O10: 10: 3} ) IR (KBr): 3450,1639,1076cm -1 1 H-NMR (CDCl 3: CD 3 OD = 1: 1): δ
ppm, J in Hz 0.89 (t, 3H, J = 6.8), 1.23 (d, 3
H × 2, J = 6.6), 4.26, (d, 1H, J =
7.6), 4.81, 4.82 (d, 1H × 2, J =
1.5).

Example 9 Synthesis of Compounds 9-1a and 9-1b Tert -butyloxycarbonyl-α-benzyl-D-glutamic acid (1.00 g) in dichloromethane (10 ml)
HO-Su (375 mg) and DCC (673) were added to the solution.
mg) and stirred at room temperature for 2 hours, followed by filtration. The filtrate obtained was filtered using compound 3-3 (1.362 g) and triethylamine (327 mg) in dichloromethane (10 m
l) The mixture was added to the solution, and reacted by stirring at room temperature for 3 hours.
The reaction mixture was washed with water, the solvent was distilled off under reduced pressure after drying, silica gel column chromatography (Nacalai, CHCl ₃
-MeOH 100: 1) to give 1.157 g (yield 59.8%) of compound 9-1.

R _F 0.58 (CHCl ₃ -MeOH 25: 1) [α] _D ²⁵ -75.2 (c 0.90, CHCl ₃ ) IR (KBr): 1749, 1716, 1660, 13
71, 1254, 1229, 1166, 1065, 10
^{53cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.12 (d, 3H, J = 6.6), 1.43 (s, 9
H), 1.99, 2.06, 2.17 (s, 3H ×
3), 5.29 (dd, 1H, J = 1.0, 3.4),
7.36 (5H).

In place of compound 3-3, compound 7-2 (1.
The reaction was carried out in the same manner as described above except that 518 g) was used, to obtain 1.252 g of compound 9-1b (yield: 59.4%).
Obtained.

R _F 0.51 (CHCl ₃ -MeOH 25: 1) [α] _D ²⁶ + 1.20 ° (c1.00, CHCl ₃ ) IR (KBr): 1753, 1715, 1664, 13
^{69,1227,1169,1076,1057cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.43 (s, 9H), 1.99, 2.04, 2.0
5, 2.16 (s, 3H × 4), 4.48 (dd, 1
H, J = 8.1), 7.36 (5H).

Synthesis of Compounds 9-2a and 9-2b Compound 9-1a (522.0 mg) was added to TFA (4 ml).
After stirring at room temperature for 1 hour, TFA was distilled off under reduced pressure. The residue was dissolved in a mixed solvent of dichloromethane (5 ml) and triethylamine (700 μl), and HO-Su (101 mg) and DCC (198 mg) were added to a solution of compound 6-2L (450.0 mg) in dichloromethane (15 ml). The mixture was stirred at room temperature for 2 hours, filtered, and the filtrate obtained was added. The mixture was stirred at room temperature for 3 hours to react. The reaction mixture was washed with water, dried, the solvent was distilled off under reduced pressure, silica gel column chromatography (Nacalai, CHCl ₃ -MeOH 50: 1) to give the compound 9-2a with 794.9Mg (yield 90. 6%).

R _F 0.74 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁷ -77.9 ゜ (c 0.99, CHCl ₃ ) IR (KBr): 1747, 1653, 1371, 12
^{31,1166,1067cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.11, 1.14 (d, 3H × 2, J = 6.6),
1.44 (s, 9H), 1.99, 2.05, 2.0
8, 2.16 (s, 3H × 6), 5.27, 5.29
(D, 1H × 2, J = 3.4), 7.36 (5H).

Compound 9-1b (1.084 g) was added to TFA
(6 ml) was added, and the mixture was stirred at room temperature for 1 hour, and then TFA was distilled off under reduced pressure. The residue was diluted with dichloromethane (15 m
l) and triethylamine (1 ml), and dissolved in a mixed solvent. To this solution, compound 6-2L (858.0 mg) was added.
Of HO-Su (19 ml) in dichloromethane (20 ml) solution.
3 mg) and DCC (377 mg).
After stirring for an hour, the filtrate obtained by filtration was added, and the mixture was added at room temperature for 3 hours.
The mixture was stirred for an hour to react. The reaction solution was washed with water, dried, and evaporated under reduced pressure. The solvent was distilled off under reduced pressure and purified by silica gel column chromatography (Nacalai, CHCl ₃ -MeOH 50: 1) to obtain 1.437 g of compound 9-2b (yield 81. 6
%)Obtained.

R _F 0.34 (CHCl ₃ -MeOH 25: 1) [α] _D ²⁷ -34.4 ゜ (c 0.99, CHCl ₃ ) IR (KBr): 1749, 1670, 1371, 12
^{29,1169,1063cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 1.13 (d, 3H, J = 6.6), 1.44 (s, 9
H), 1.96, 1.99, 2.05, 2.07, 2.
15, 2.16 (s, 3H × 7), 4.48 (dd, 1
H, J = 8.1), 5.33 (d, 1H, J = 3.
4), 7.37 (5H).

Synthesis of Compounds 9-3a and 9-3b Compound 9-2a (466.9 mg) was added to TFA (4 ml).
And stirred at room temperature for 1.5 hours.
A was distilled off. To the residue were added dichloromethane (6 ml), triethylamine (600 μl) and N-hydroxysuccinimide palmitate (165 mg), and the mixture was stirred and reacted at room temperature for 2.5 hours. The reaction mixture was washed with water, dried, the solvent was distilled off under reduced pressure, silica gel column chromatography (Nacalai, CHCl ₃ -Me
OH 50: 1) to give compound 9-3a as 364.
1 mg (yield 69.3%) was obtained.

R _F 0.38 (CHCl ₃ -MeOH 25: 1) [α] _D ²⁴ -83.3 ゜ (c1.00, CHCl ₃ ) IR (KBr): 1749, 1639, 1371, 12
^{29,1069cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 0.88 (t, 3H, J = 6.8), 1.12, 1.1
3 (d, 3H × 2, J = 6.8), 1.96, 1.9
9, 2.05, 2.06, 2.16 (s, 3H × 6),
5.27, 5.28 (d, 1H × 2, J = 3.4),
7.36 (5H).

Compound 9-2b (1.004 g) was added to TFA.
(7 ml) was added, and the mixture was stirred at room temperature for 1.5 hours, and then TFA was distilled off under reduced pressure. The residue was diluted with dichloromethane (10
ml), triethylamine (1.2 ml) and palmitic acid N-hydroxysuccinimide ester (330
mg), and the mixture was stirred and reacted at room temperature for 16 hours.
The reaction solution was washed with water, dried, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (YMC, CHCl _3).
-MeOH 50: 1) to give compound 9-3b as 9
66.2 mg (85.9% yield) were obtained.

R _F 0.59 (CHCl ₃ -MeOH 20: 1) [α] _D ²⁸ -36.3 ゜ (c1.01, CHCl ₃ ) IR (KBr): 1751, 1637, 1371, 12
^{27,1169,1065cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 0.88 (t, 3H, J = 6.8), 1.13 (d, 3
H, J = 6.6), 1.96, 1.99, 2.03.
2.04, 2.05, 2.14, 2.16 (s, 3H ×
7), 4.48 (d, 1H, J = 8.1), 5.29
(D, 1H, J = 3.4), 7.36 (5H).

Synthesis of Compounds 9-4a and 9-4b Compound 9-3a (240.8 mg) was added to ethanol (33
ml) and THF (2.6 ml) in a mixed solvent solution.
10% Pd / C (24 mg) was added, and the mixture was catalytically reduced with Parr for 1 hour. Next, the catalyst was filtered off, and the solvent was distilled off from the filtrate under reduced pressure. The resulting residue in dichloromethane (5 m
l) Add HO-Su (24.7 mg) and DCC
(48.3 mg), and the mixture was stirred at room temperature for 2 hours.
A 2.0 M NH ₃ methanol solution (0.5 ml) was added, and the mixture was stirred and reacted at room temperature for 2 hours. The reaction mixture was washed with water, dried, the solvent was distilled off under reduced pressure, silica gel column chromatography (YMC, CHCl ₃ -MeOH
50: 1) to purify 171.8 mg of compound 9-4a.
(Yield: 77.0%).

R _F 0.60 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁷ -93.4 ゜ (c1.00, CHCl ₃ ) IR (KBr): 1749, 1641, 1371, 12
^{48,1299,1069cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 0.88 (t, 3H, J = 6.8), 1.14, 1.1
5 (d, 3H × 2, J = 6.6), 1.99, 2.0
7, 2.16, 2.17 (s, 3H × 6), 5.26,
5.29 (d, 1H × 2, J = 3.2).

To a solution of compound 9-3b (937.9 mg) in a mixed solvent of ethanol (100 ml) and THF (10 ml) was added 10% Pd / C (94 mg).
The reaction was reduced with rr for 1 hour. Then, the catalyst was filtered off, and the solvent was distilled off from the filtrate under reduced pressure to remove the debenzylated product to 873.1 m.
g (100% yield). A part of this compound (452.
3 mg) in dichloromethane (5 ml) was added to HO-S
u (146.3 mg) and DCC (93.0 mg) were added, and the mixture was stirred at room temperature for 2 hours. Then, a 2.0 M NH ₃ methanol solution (1 ml) was added, and the mixture was stirred and reacted at room temperature for 17 hours. After the reaction solution was washed with water and dried, the solvent was distilled off under reduced pressure, and silica gel column chromatography (Y
Purification with MC and CHCl ₃ -MeOH 50: 1) gave 335.2 mg (yield 74.1%) of compound 9-4b.

R _F 0.56 (CHCl ₃ -MeOH 10: 1) [α] _D ²⁶ -45.2 ゜ (c1.00, CHCl ₃ ) IR (KBr): 1751, 1643, 1371, 12
^{99,1070cm -1 1 H-NMR (CDCl} 3): δ
ppm, J in Hz 0.89 (t, 3H, J = 6.8), 1.15 (d, 3
H, J = 6.6), 1.99, 2.05, 2.06.
2.07, 2.16, 2.17 (s, 3H × 7), 4.
49 (d, 1H, J = 7.8), 5.26 (d, 1H,
J = 3.4).

Synthesis of Compounds 9-a and 9-b Compound 9-4a (169.3 mg) was added to methanol (3 m
l) A solution of 28% sodium methoxide in methanol (10 μl) was added to the solution, and the mixture was stirred and reacted at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain Compound 9 as a white powder.
As a result, 118.3 mg (yield: 89.6%) of -a was obtained.

R _F 0.64 (CHCl ₃ -MeOH
-H ₂ O 10: 5: 1) [α] _D ²⁷ -70.6 ゜ (c 0.51, CHCl _{3
-MeOH -H 2 O10: 10: 3} ) IR (KBr): 3398,1639,1076cm -1 1 H-NMR (CDCl 3: CD 3 OD = 1: 1): δ
ppm, J in Hz 0.89 (t, 3H, J = 6.8), 1.25 (d, 3
H × 2, J = 6.6), 4.81, 4.82 (d, 1
H, J = 3.4).

A methanol solution (10 μl) of 28% sodium methoxide was added to a solution of compound 9-4b (308.1 mg) in methanol (7 ml), and the mixture was stirred and reacted at room temperature for 1.5 hours. The solvent was distilled off from the reaction solution under reduced pressure to obtain 232.2 mg (yield 99.8%) of compound 9-b as a white powder.

R _F 0.61 (CHCl ₃ -MeOH
—H ₂ O 10: 5: 1) [α] _D ²⁷ −32.9} (c 0.556, CHCl ₃
—MeOH—H ₂ O 10: 10: 3) IR (KBr): 3400,1661,1637,10
^{70cm -1 1 H-NMR (CDCl} 3: CD 3 OD = 1: 1): δ
ppm, J in Hz 0.89 (t, 3H, J = 6.6), 1.24 (d, 3
H, J = 6.6), 4.26 (d, 1H, J = 7.
6), 4.81 (d, 1H, J = 2.9).

Example 10 Synthesis of Compounds 10-1a and 10-1b Compound 9-3a (363.8 mg) was added to ethanol (50
ml) and THF (4 ml) in a mixed solvent solution.
36% of Pd / C was added thereto, and the mixture was catalytically reduced with Parr for 1 hour. Next, the catalyst was filtered off, and the solvent was distilled off from the filtrate under reduced pressure to obtain 337.1 mg of the debenzylated product (yield: 100).
%)Obtained. To a solution of this compound in methanol (10 ml) was added a 10% hexane solution of trimethylsilyldiazomethane (4 ml) under ice-cooling, and the mixture was stirred and reacted for 20 minutes. The solvent was distilled off from the reaction solution under reduced pressure, and silica gel column chromatography (YMC, CHCl ₃ -MeO
H 50: 1) to give compound 10-1a as 302.
4 mg (88.6% yield) was obtained.

R _F 0.35 (CHCl ₃ -MeOH 25: 1) [α] _D ²⁶ -83.4 ゜ (c1.00, CHCl ₃ ) IR (KBr): 1749, 1647, 1373, 12
^{29,1067cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 0.88 (t, 3H, J = 6.8), 1.13, 1.1
4 (d, 3H × 2, J = 6.6), 1.98, 1.9
9, 2.05, 2.06, 2.16 (s, 3H × 6),
3.76 (s, 3H), 5.28 (d, 1H × 2, J =
3.4).

To a mixed solvent solution of compound 9-3b (937.9 mg) in ethanol (100 ml) and THF (10 ml) was added 10% Pd / C (94 mg).
The reaction was reduced with arr for 1 hour. Then, after the catalyst was removed by filtration, the solvent was distilled off from the filtrate under reduced pressure to remove the debenzylated product.
73.1 mg (100% yield) were obtained. In MeOH (6 ml) solution of a portion of this compound (420.8mg), under ice-cooling 10% TMS-CH ₂ N ₂ solution in hexane (3.
5 ml) and stirred for 20 minutes to react. The solvent was distilled off from the reaction solution under reduced pressure, and silica gel column chromatography (YMC, CHCl ₃ -MeOH 75:
Purification by 1) afforded 373.5 mg of compound 10-1b (87.7% yield).

R _F 0.34 (CHCl ₃ -MeOH 25: 1) [α] _D ²⁶ -38.2 ゜ (c 0.99, CHCl ₃ ) IR (KBr): 1751, 1647, 1371, 12
^{29,1070cm -1 1 H-NMR (CDCl} 3): δ ppm, J in H
z 0.88 (t, 3H, J = 6.8), 1.14 (d, 3
H, J = 6.6), 1.98, 1.99, 2.05.
2.06, 2.16 (s, 3H × 7), 3.75 (s,
3H), 4.49 (d, 1H, J = 7.8), 5.28
(D, 1H, J = 3.4).

Synthesis of Compounds 10-2a and 10-2b Compound 10-1a (298.0 mg) of methanol (5
To this solution, a methanol solution (20 μl) of 28% sodium methoxide was added, and the mixture was stirred and reacted at room temperature for 1 hour. The solvent was distilled off from the reaction solution under reduced pressure, and silica gel column chromatography (YMC, CHCl ₃ -Me
OH 5: 1) to give compound 10- as a white powder.
137.6 mg (yield 59.6%) of 2a was obtained.

[0204] _{R F 0.86 (CHCl 3 -MeOH 2} : 1) [α] D 28 -71.3 ° (c1.01, MeOH) IR (KBr ): 3400,1643,1078cm -1 1 H-NMR (CD ₃ OD): δ ppm, J in H
z 0.90 (t, 3H, J = 6.8), 1.20, 1.2
1 (d, 3H × 2, J = 6.6), 4.76, 4.78
(D, 1H × 2, J = 2.2).

To a solution of compound 10-1b (348.2 mg) in methanol (7 ml) was added a 28% sodium methoxide solution in methanol (10 μl), and the mixture was stirred and reacted at room temperature for 2 hours. The solvent was distilled off from the reaction solution under reduced pressure, and silica gel column chromatography (YMC, C
HCl _3- MeOH 25:10) to give 187.5 mg of compound 10-2b as a white powder (yield 71.0).
0%).

R _F 0.70 (CHCl ₃ -MeOH 2: 1) [α] _D ²⁷ -30.7 ゜ (c 0.505, CHCl ₃ −
_{MeOH-H 2 O 10: 10} : 3) IR (KBr): 3422,1637,1074cm -1 1 H-NMR (CD 3 OD): δ ppm, J in H
z 0.90 (t, 3H, J = 6.8), 1.21 (d, 3
H, J = 6.6), 3.67 (s, 3H), 4.24
(D, 1H, J = 7.3).

Synthesis of Compounds 10-a and 10-b Compound 10-2a (104.0 mg) was added to methanol (3
0.1N sodium hydroxide (1.15m
l) was added, and the mixture was stirred and reacted at room temperature for 24 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the solution was subjected to gel filtration (LH-2).
0, MeOH) to give compound 10- as a white powder.
98.2 mg (yield 93.6%) of a was obtained.

R _F 0.49 (CHCl ₃ -MeOH-H
₂ O 10: 5: 1) [α] _D ²⁷ -68.5 ゜ (c 1.05, CHCl ₃ -M
_{eOH-H 2 O 10: 10} : 3) IR (KBr): 3400,1639,1558,10
^{78,1038cm -1 1 H-NMR (CDCl} 3: CD 3 OD = 1: 1): δ
ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.24 (d, 3
H, J = 6.6), 4.83-4.80 (m, 2H).

To a solution of compound 10-2b (138.8 mg) in methanol (3 ml) was added 0.1 N sodium hydroxide (1.504 ml), and the mixture was stirred and reacted at room temperature for 68 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified by gel filtration (LH-20, MeOH) to obtain 135.1 mg (yield 96.5%) of compound 10-b as a white powder.

R _F 0.39 (CHCl ₃ -MeOH-H
₂ O 10: 5: 1) [α] _D ²⁷ -28.2 ゜ (c 1.02, CHCl ₃ -M
_{eOH-H 2 O 10: 10} : 3) IR (KBr): 3400,1637,1560,10
^{76,1041cm -1 1 H-NMR (CDCl} 3: CD 3 OD = 1: 1): δ
ppm, J in Hz 0.89 (t, 3H, J = 6.8), 1.24 (d, 3
H, J = 6.6).

Example 11 Synthesis of Compound 11-1 Compound 1-3 (653 mg) and tert-butyloxycarbonyl-L-glutamic acid β-benzyl ester α-N-
Hydroxysuccinimide ester (Boc-Glu
(OBn) -OSu (402 mg) was dissolved in a methylene chloride (30 ml) solution, and triethylamine (187) was added.
mg) and stirred at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride, washed sequentially with water, 10% aqueous citric acid, and water. After drying, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using silica gel (70 g) (chloroform-methanol 200 : 1) to give compound 11-1 (659 mg) as colorless crystals.

[0212] [α] _D ²⁵ -29.6 ° _{(c1.09, CHCl 3) IR (} KBr): 1728,1686,1659cm -1 1 H-NMR (CDCl 3) δ: 7.41-7.25
(20H, m), 6.13 (1H, br, s), 5.2
3 (1H, br, s), 5.14, 5.11 (1H, e
ach d, J = 12.7 Hz), 4.98, 4.65
(1H, reach, J = 11.5 Hz), 4.88,
4.81, 4.74, 4.67 (1H, each d,
J = 11.7 Hz), 4.77 (1H, d, J = 3.7)
Hz, f-1), 4.10 (1H, m), 4.02 (1
H, dd, J = 10.3, 3.7 Hz), 3.93 (1
H, dd, J = 10.0, 2.9 Hz), 3.86 (1
H, q, J = 6.6 Hz), 3.57 (1H, dt, J
= 10.0, 6.8 Hz), 3.42 (1H, dt, J)
= 10.0, 6.8 Hz), 3.22-3.18 (2
H, m), 2.55 (1H, m), 2.42 (1H,
m), 2.12 (1H, m), 1.91 (1H, m),
1.62-1.54 (2H, m), 1.49-1.43
(2H, m), 1.38-1.27 (4H, m), 1.
43 (9H, s), 1.10 (3H, d, J = 6.6H
z).

Synthesis of Compound 11-2 Compound 11-1 (360 mg) was added to ethanol (5 ml).
And 10% palladium-carbon (360 mg) and 1,4-cyclohexadiene (666 μl) were added.
The mixture was stirred at room temperature for 30 minutes. After the reaction solution was filtered, the solvent was distilled off from the filtrate under reduced pressure to remove compound 11-2 (282 m
g) was obtained as a colorless foam.

¹ H-NMR (CDCl ₃ ) δ: 7.39
−7.24 (15H, m), 6.73 (1H, br,
s), 5.49 (1H, br, s), 4.96-4.6.
3 (each 1H, d, J = 11.8 Hz), 4.8
4, 4.80, 4.74, 4.64 (each 1H,
d, J = 11.8 Hz), 4.77 (1H, J = 3.8)
Hz), 4.21 (1H, m), 4.02 (1H, d
d, J = 10.3, 3.8 Hz), 3.93 (1H, d
d, J = 10.3, 3.0 Hz), 3.86 (1H,
q, J = 6.6 Hz), 3.67 (1H, br, d),
3.57 (1H, ddd, J = 9.9, 7.1, 7.1
Hz), 3.41 (1H, ddd, J = 9.9, 6.
6,6.6 Hz), 3.28-3.16 (2H, m),
2.47, 2.35, 2.03, 1.91 (each
1H, m), 1.64-1.54 (2H, m), 1.5
2-1.45 (2H, m), 1.42 (9H, s),
1.36-1.29 (4H, m), 1.11 (3H,
d, J = 6.6 Hz).

Synthesis of Compound 11-3 Ethanol (7) in which Compound 1-4 (168 mg) was dissolved
ml) solution, a Lindlar catalyst (150 mg) and paratoluenesulfonic acid (57 mg) were added, and the mixture was stirred under a medium-pressure hydrogen stream (50 psi) at room temperature for 2 hours. By removing the catalyst from the reaction solution by filtration and concentrating the filtrate under reduced pressure,
Compound 11-3 (208 mg) was obtained as a crude product.

[0216]Synthesis of Compound 11-4  Compound 11-3 (208 mg) dissolved in dimethylform
Muamide (3.0 ml) solution in N-methylmorpholine
(86 μl), compound 11-2 (214 mg), 1-h
Droxybenzotriazole (53 mg) and N,
N'-dicyclohexylcarbodiimide (74.5 m
g) was added and the mixture was stirred at room temperature for 12 hours. Remove insoluble matter by filtration
The filtrate is concentrated, and the residue is diluted with ethyl acetate.
And wash with 5% citric acid and saturated sodium bicarbonate
After drying, the solvent was distilled off under reduced pressure. The resulting residue is
Column chromatography using Rica gel (70 g)
(Methylene chloride-methanol 50: 1) and polymer
Column chromatography using gel (150g)
(Methylene chloride-methanol 1: 1)
To give compound 11-4 (242 mg) as a colorless powder
I got it.

[0217] [α] _D ²⁴ -14.1 ° _{(c0.58, CHCl 3) IR (} KBr): 1688,1645cm -1 1 H-NMR (CDCl 3) δ: 7.41-7.24
(30H, m), 6.59 (1H, m), 5.89 (1
H, m), 5.71 (1H, m), 4.97 (2H,
d, J = 11.7 Hz), 4.92, 4.76 (eac
hd, J = 11.0 Hz), 4.88, 4.78,
4.72, 4.65 (each d, J = 11.7H)
z), 4.81, 4.69 (each 1H, d, J =
12.0 Hz), 4.77 (1H, d, J = 3.4H)
z), 4.74, 4.66 (each 1H, d, J =
12.2 Hz), 4.30 (1H, d, J = 7.6H)
z), 4.06 (1H, m), 4.02 (2H, dd,
J = 10.3, 3.4 Hz), 3.93 (1H, dd,
J = 10.3, 2.7 Hz), 3.92 (1H, q, J
= 6.6 Hz), 3.86 (1H, q, J = 6.6H)
z), 3.79 (1H, dd, J = 9.8, 7.6H
z), 3.66 (1H, br, d), 3.57 (1H,
ddd, J = 10.0, 6.8, 6.8 Hz), 3.5
4 (1H, br, d), 3.50 (1H, dd, J =
9.8, 2.9 Hz), 3.45 (1H, m), 3.4
1 (1H, m), 3.27-3.13 (5H, m),
2.32 (1H, ddd, J = 14.9, 7.8, 5.
1 Hz), 2.24 (1H, ddd, J = 14.9,
7.6, 5.1 Hz), 2.04 (1H, m), 1.9
0 (1H, m), 1.66-1.54 (4H, m),
1.52-1.42 (4H, m), 1.42 (9H,
s), 1.42-1.28 (8H, m), 1.17 (3
H, d, J = 6.3 Hz), 1.10 (3H, d, J =
6.6 Hz).

[0218] methanol was dissolved synthesis of Compound 11 11-4 (160mg) (14ml) - in a mixed solution of ethyl acetate (4 ml)-1,2-ethylene dichloride (2 ml), palladium - carbon (1
0%, 200 mg) and under a medium pressure hydrogen stream (50 ps).
i) and stirred at room temperature for 12 hours. After the catalyst was separated by filtration from the reaction solution, the filtrate was concentrated, and the residue was silica gel (18 g).
The compound 11 (67 mg) was obtained as a colorless powder by purifying by column chromatography (methylene chloride-methanol-water 7: 3: 1 (lower layer)).

[Α] _D ²⁵ -45.1 ゜ (c 0.52, M
eOH) IR (KBr): 3429,1697,1654cm -1 1 H-NMR (CD 3 OD) δ: 4.73 (1H, d,
J = 2.9 Hz), 4.17 (1H, m), 3.98
(1H, m), 3.93 (1H, q, J = 6.6H
z), 3.84 (1H, ddd, J = 9.5, 6.6,
6.6 Hz), 3.75-3.70 (2H, m), 3.
68-3.63 (2H, m), 3.61 (1H, q, J
= 6.6 Hz), 3.59 (1H, m), 3.51 (1
H, ddd, J = 9.8, 6.6, 6.6 Hz), 3.
46-3.41 (3H, m), 3.25-3.13 (4
H, m), 2.30-2.21 (2H, m), 1.99
(1H, m), 1.83 (1H, m), 1.66-1.
59 (4H, m) 1.55-1.47 (4H, m),
1.44 (9H, s), 1.45-1.33 (8H,
m), 1.26 (3H, d, J = 6.6 Hz), 1.2
0 (3H, d, J = 6.6 Hz).

[0220]Example 12 Synthesis of Compound 12  Compound 1 (20.0 mg) was added to trifluoroacetic acid at 0 ° C.
(1.00 ml) and stirred at the same temperature for 1 hour. Anti
After concentrating the reaction solution under reduced pressure, the resulting residue is
Column chromatography using (22 g) (methano
Compound 12 (19 mg) as a colorless resin
Obtained as a product.

[Α] _D ²⁷ -55.7 (c 0.63, MeOH) ¹ H-NMR (CD ₃ OD) δ: 4.73 (2H, b
r, s), 3.93 (2H, q, J = 6.6 Hz),
3.87 (1H, m), 3.74-3.71 (3H,
m), 3.71-3.63 (4H, m), 3.55 (1
H, m), 3.44 (2H, dt, J = 9.5, 6.3).
Hz), 3.21-3.15 (2H, m), 3.21-
3.15 (2H, m), 2.43-2.35 (2H,
m), 2.14 to 2.04 (2H, m), 1.67-
1.60 (4H, m), 1.58-1.49 (4H,
m), 1.47-1.34 (8H, m), 1.20 (6
H, d, J = 6.6 Hz).

Example 13 Synthesis of Compound 13 To Compound 3 (40.0 mg) was added trifluoroacetic acid (1.00 ml) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the obtained residue was purified by column chromatography (methanol) using a polymer gel (45 g) to give Compound 13 (37 mg, 91%).
Was obtained as a colorless resin.

[Α] _D ²⁷ -76.7 ゜ (c 0.49, M
eOH) ¹ H-NMR (CD ₃ OD) δ: 4.77 (2H, b
r, s), 3.92-3.86 (3H, m), 3.82.
-3.72 (6H, m), 3.67 (2H, br,
s), 3.57-3.51 (2H, m), 3.51-
3.47 (2H, m), 3.39-3.29 (2H,
m) 2.48-2.37 (2H, m), 2.15-2.
07 (2H, m), 1.21 (3H, d, J = 6.3H
z).

¹³ C-NMR (CDCl ₃ ) δc: 17
4.2, 169.8, 100.5, 100.4, 73.
6, 71.6, 71.5, 70.0, 69.9, 67.
8, 67.7, 67.5, 67.3, 54.1, 40.
5,40.3,32.2,28.3,16.6.

Example 14 Synthesis of Compound 14 To a solution of compound 12 (32 mg) in dimethylformamide was added fluorescein-isothiocyanate (47 m).
g) was added and the mixture was stirred at room temperature for 12 hours. After concentrating the reaction solution, the residue was subjected to column chromatography using silica gel (18 g) (methylene chloride-methanol-water 7:
3: 1 (lower layer)) and column chromatography (methanol) using a polymer gel (30 g) to obtain Compound 14 (17 mg) as a yellow powder.

¹ H-NMR (CD ₃ OD) δ: 8.25
(1H, br, s), 7.86 (1H, dd, J = 8.
3,1.7 Hz), 7.16 (1H, d, J = 8.3H)
z), 6.86-6.72 (2H, m), 6.67 (2
H, d, J = 2.2 Hz), 6.56 (2H, dd, J)
= 8.8, 2.2 Hz), 4.73 (1H, d, J =
3.4 Hz), 4.72 (1H, d, J = 3.2H)
z), 3.93 (1H, q, J = 6.6 Hz), 3.9
2 (1H, q, J = 6.6 Hz), 3.75-3.70
(4H, m), 3.66 (1H, m), 3.65 (2
H, br, s), 3.63 (1H, m), 3.43 (1
H, m), 3.40 (1H, m), 3.24 (1H, d
t, J = 10.3, 6.6 Hz), 3.23 (1H, d
t, J = 10.3, 6.6 Hz), 3.16 (2H, d
t, J = 9.5, 6.8 Hz), 3.14 (1H, d
t, J = 9.5, 6.8 Hz), 2.41-2.30
(2H, m), 2.18 (1H, m), 2.06 (1
H, m), 1.70-1.28 (16H, m), 1.1
9 (3H, d, J = 6.6 Hz), 1.18 (3H, d, J = 6.6 Hz)
d, J = 6.6 Hz).

Example 15 Synthesis of Compound 15-1 N, N'-dimethylformamide solution (200 ml) in which 6-chloro-1-hexanol (20.0 g) was dissolved
Was added with sodium azide (14.2 g), and the mixture was stirred at 80 ° C for 12 hours. After the reaction solution was cooled to room temperature and the precipitate was filtered, the filtrate was condensed under reduced pressure, and the residue was subjected to column chromatography (n-gel) using silica gel (200 g).
The compound 15-1 (20.6 g) was obtained as a colorless oil by purifying with hexane-ethyl acetate 5: 2).

[0228] ^{_{IR (CHCl 3): 2100cm -1}} 1 H-NMR (CDCl 3) δ: 3.66 (2H, d
t, J = 5.1, 6.6 Hz), 3.28 (2H, t,
J = 6.8 Hz), 1.64-1.56 (4H, m),
1.45-1.39 (4H, m), 1.34 (1H,
t, J = 5.1 Hz).

Synthesis of Compound 15-2 To a methylene chloride solution (30 ml) containing Molecular Sieves 4A (3 g) was added acetobromo-α-D-galactose (1.00 g) and compound 15-1 (1.04 g).
g) was dissolved, and the mixture was stirred at room temperature for 2 hours. Then, silver silicate (5.0 g) was added at -20 ° C, and the mixture was stirred at the same temperature for 2 hours and at room temperature for 2 hours. After filtering the reaction solution, the filtrate (methylene chloride) was washed with water, dried and the solvent was distilled off under reduced pressure. Subsequently, the obtained residue was dissolved in pyridine (5 ml), acetic anhydride (3 ml) was added, and the mixture was stirred at room temperature for 10 hours. The reaction solution was diluted with ethyl acetate, washed with 2% hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, then dried, and the solvent was distilled off under reduced pressure.
Compound 15-2 (833 mg) was obtained as a colorless oily substance by purifying by column chromatography (n-hexane-ethyl acetate 3: 1) using g).

[0230] [α] _D ²⁷ -11.3 ° _{(c1.18, CHCl 3) IR (} CHCl 3): 2100,1749cm -1 1 H-NMR (CDCl 3) δ: 5.39 (1H, d
d, J = 3.4, 1.0 Hz), 5.20 (1H, d
d, J = 10.5, 8.1 Hz), 5.02 (1H, d
d, J = 10.5, 3.4 Hz), 4.45 (1H,
d, J = 8.1 Hz), 4.19 (1H, dd, J = 1)
1.2, 6.3 Hz), 4.13 (1H, dd, J = 1)
1.2, 7.1 Hz), 3.91-3.87 (2H,
m), 3.48 (1H, dt, J = 9.5, 6.8H)
z), 3.26 (2H, t, J = 7.0 Hz), 2.1
5, 2.05, 2.05, 1.99 (each 3H,
s), 1.66-1.53 (4H, m), 1.42-
1.34 (4H, m).

Synthesis of Compound 15-3 Methanol (7 mg) in which Compound 15-2 (90 mg) was dissolved
ml) solution, a Lindlar catalyst (80 mg) and paratoluenesulfonic acid (37.5 mg) were added, and the mixture was stirred under a medium-pressure hydrogen stream (50 psi) at room temperature for 2 hours. The catalyst was removed by filtration from the reaction solution, and the filtrate was concentrated under reduced pressure to obtain Compound 15-3 (114 mg) as a crude product.

Synthesis of Compound 15-4 N-hydroxysuccinimide (22.7 mg) and N, N'-dicyclohexylcarbodiimide (40.6 mg) were added to a solution of compound 11-2 (150 mg) in methylene chloride (1.5 ml). ) And stirred at 0 ° C. for 3 hours. Thereafter, a methylene chloride solution (1.5 ml) in which compound 15-3 (114 mg) and triethylamine (36 μl) were dissolved was added, and the mixture was stirred at room temperature for 12 hours. The insoluble material was removed by filtration, and the filtrate was diluted with methylene chloride and washed with saturated saline. After drying, the solvent is distilled off under reduced pressure,
The residue was subjected to column chromatography using silica gel (10 g) (toluene-acetone-methanol 250:
100: 3) to give compound 15-4.
(85 mg) was obtained as a colorless oil.

[Α] _D ²⁷ −21.6 ゜ (c 1.10, CHCl ₃ ) IR (CHCl ₃ ): 1749, 1707, 1670c
^{m -1 1 H-NMR (CDCl} 3) δ: 7.41-7.24
(15H, m), 6.60 (1H, br, s), 6.0
2 (1H, br, s), 5.68 (1H, d, J = 6.
5Hz), 5.39 (1H, dd, J = 3.4, 0.7)
Hz), 5.19 (1H, dd, J = 10.5, 8.1)
Hz), 5.02 (1H, dd, J = 10.5, 3.4)
Hz), 4.97, 4.87, 4.74, 4.65 (e
ach 1H, d, J = 11.7 Hz), 4.80,
4.67 (each 1H, d, J = 12.0 Hz),
4.77 (1H, d, J = 3.7 Hz), 4.45 (1
H, d, J = 8.1 Hz), 4.19 (1H, dd, J)
= 11.2, 6.3 Hz), 4.12 (1H, dd, J)
= 11.2, 7.1 Hz), 4.06 (1H, m),
4.02 (1H, dd, J = 10.0, 3.7 Hz),
3.93 (1H, dd, J = 10.0, 2.7 Hz),
3.91-3.84 (3H, m), 3.67 (1H, b
r, d), 3.58 (1H, ddd, J = 9.8, 7.
1,6.8 Hz), 3.47 (1H, ddd, J = 9.
5,6.8,6.6 Hz), 3.42 (1H, ddd,
J = 9.7, 6.8, 6.6 Hz), 3.29-3.1
7 (4H, m), 2.35 (1H, m), 2.27 (1
H, m), 2.15, 2.05, 2.05, 1.98
(Each 3H, s), 1.93 (1H, m), 1.
63-1.55 (4H, m), 1.53-1.45 (4
H, m), 1.43 (9H, s), 1.39-1.29
(8H, m), 1.11 (3H, d, J = 6.3H
z).

Synthesis of Compound 15-5 A 3% solution of sodium methoxide in methanol (200 μl) was added to a solution of compound 15-4 (115 mg) in methanol (3 ml), and the mixture was stirred at 0 ° C. for 2 hours. After the reaction solution was neutralized with a cation exchange resin (Dowex 50w H ⁺ ), insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel (12 g) (methylene chloride-methanol 8: 1) to give compound 15-5 (93 mg) as a colorless powder.

[Α] _D ²⁷ -28.1 ゜ (c 1.13, CHCl ₃ ) IR (CHCl ₃ ): 3421, 1688, 1645c
^{m -1 1 H-NMR (CD} 3 OD) δ: 7.42-7.25
(15H, m), 4.90, 4.61 (each 1
H, d, J = 11.7 Hz), 4.77 (2H, s),
4.75, 4.67 (each 1H, d, J = 11.
7Hz), 4.20 (1H, d, J = 7.6Hz),
3.98 (1H, m), 3.95-3.94 (2H,
m), 3.91 (1H, q, J = 6.6 Hz), 3.8
9 (1H, ddd, J = 9.8, 6.8, 6.6H
z), 3.83 (1H, br, d), 3.80 (1H,
br, s), 3.75 (1H, dd, J = 11.2,
6.6 Hz), 3.72 (1H, dd, J = 11.2,
5.6 Hz), 3.62 (1H, J = 9.8, 6.6,
6.6 Hz), 3.54 (1H, ddd, J = 9.8,
6.6, 6.6 Hz), 3.50 (1H, dd, J =
9.8, 7, 6 Hz), 3.48 (1H, m), 3.4
5 (1H, dd, J = 9.8, 3.2 Hz), 3.40
(1H, ddd, 9.8, 6.3, 6.3 Hz), 3.
23-3.13 (4H, m), 2.26-2.23 (2
H, m), 2.00 (1H, m), 1.83 (1H,
m), 1.65-1.57 (4H, m), 1.53-
1.46 (4H, m), 1.43-1.31 (8H,
m), 1.43 (9H, s), 1.13 (3H, d, J
= 6.6 Hz).

Synthesis of Compound 15 Compound 15-5 (70 mg) was dissolved in methanol (7
ml) solution in palladium hydroxide-carbon (20%, 14%).
0 mg), and the mixture was stirred at room temperature under a medium-pressure hydrogen stream (50 psi) for 48 hours. After filtering off the catalyst from the reaction solution,
The filtrate was concentrated, and the residue was subjected to column chromatography using silica gel (10 g) (methylene chloride-methanol-methanol).
Water 7: 3: 1 (lower layer)) and polymer gel (25 g)
Compound 15 (30 mg) was obtained as a colorless powder by purifying by column chromatography (methanol) using.

[0237] [α] _D ²⁵ -52.1 ° (c0.34, MeOH) IR (KBr ): 3350,1699,1655cm -1 1 H-NMR (CD 3 OD) δ: 4.73 (1H, d ,
J = 2.7 Hz), 4.20 (1H, d, J = 7.3H)
z), 3.98 (1H, m), 3.93 (1H, q, J
= 6.6 Hz), 3.90 (1H, ddd, J = 9.
5,6.8,6.8 Hz), 3.83 (1H, br,
d), 3.77-3.70 (4H, m), 3.69-
3.63 (2H, m), 3.54 (1H, ddd, J =
9.5, 6.6, 6.6 Hz), 3.59-3.47
(2H, m), 3.45 (1H, dd, J = 9.8,
3.2Hz), 3.44 (1H, m), 3.25-3.
14 (4H, m), 2.29-2.23 (2H, m),
2.00 (1H, m), 1.83 (1H, m), 1.6
8-1.59 (4H, m), 1.56-1.47 (4
H, m), 1.44 (9H, s), 1.46-1.31.
(8H, m), 1.20 (3H, d, J = 6.6H
z).

Example 16 Synthesis of Compound 16-1 2- (Trimethylsilyl) ethyl O- (methyl 6-Acetamido-4,
7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-ga
lacto-2-nonulopyranosylonate)-(2 → 3) -2,4-di-O-ace
tyl-6-O-benzoyl- β-D-galactopyranoside (Compound 1
6-1) was converted to J. Carbohydrate Chemistry, 8 (2) 265-283.
(1989).

Synthesis of Compound 16-2 Compound 16-2 was synthesized from compound 16-1 according to the method described in J. Carbohydrate Chemistry, 8 (2), 265-283 (1989).

Synthesis of Compound 16-3 Compound 9-2 (300 mg) and Compound 15-1 (131 mg) were dissolved in a methylene chloride solution (10 ml) containing Molecular Sieves 4A (4 g), and the mixture was dissolved at room temperature.
Stirred for hours. Thereafter, boron trifluoride diethyl ether complex (112 μl) was added at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. After the reaction solution was filtered, the filtrate was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using silica gel (20 g) (methylene chloride-methanol 50: 1).
The compound 9-3 (230 mg) was obtained as a colorless oil.

[Α] _D ²⁷ -17.8 ° (c 1.03, CHCl ₃ ) IR (CHCl ₃ ): 2100, 1744, 1690c
^{m -1 1 H-NMR (CDCl} 3) δ: 8.03 (2H,
m), 7.56 (1H, m), 7.23 (2H, m),
5.56 (1H, ddd, J = 9.5, 5.6, 2.7)
Hz), 5.37 (1H, dd, J = 9.5, 2.4H)
z), 5.08-5.03 (3H, m), 4.88 (1
H, m), 4.61 (1H, d, J = 8.0 Hz),
4.58 (1H, dd, J = 10.0, 3.1 Hz),
4.43 (1H, dd, J = 11.0, 6.3 Hz),
4.35 (1H, dd, J = 12.5, 2.4 Hz),
4.21 (1H, dd, J = 11.0, 7.1 Hz),
4.04 (1H, m), 4.00 (1H, dd, J = 1)
2.5, 5.6 Hz), 3.99 (1H, dd, J =
7.1, 6.3 Hz), 3.88 (1H, dt, J =
9.5, 6.3 Hz), 3.76 (3H, s), 3.6
3 (1H, dd, J = 10.7, 2.4 Hz) 3.54
(1H, dt, 9.5, 6.6 Hz), 3.25 (2
H, t, J = 7.0 Hz), 2.59 (1H, dd, J)
= 12.7, 4.6 Hz), 2.21, 2.13, 2.
11, 2.08, 2.04, 2.00, 1.85 (ea
ch 3H, s), 1.72 (1H, dd, 12.7,
12.3 Hz), 1.67-1.54 (4H, m),
1.42-1.33 (4H, m).

Synthesis of Compound 16-4 To a solution of Compound 16-3 (130 mg) in methanol (5 ml) was added a Lindlar catalyst (100 mg) and paratoluenesulfonic acid (26 mg), and the mixture was added under a medium pressure hydrogen stream (50 psi). ) The mixture was stirred at room temperature for 2 hours. The same catalyst (100 mg) was further added, and the mixture was stirred under the same conditions for 1 hour. The catalyst was removed by filtration from the reaction solution, and the filtrate was concentrated under reduced pressure to obtain Compound 16-4 (123 mg) as a crude product.

Synthesis of Compound 16-5 In a solution of Compound 11-2 (125 mg) in methylene chloride (1.5 ml) was dissolved N-hydroxysuccinimide (17.5 mg) and N, N'-dicyclohexylcarbodiimide (31. 0 mg) and stirred at 0 ° C. for 3 hours. Thereafter, methylene chloride solution (1.5 ml) in which compound 16-4 (123 mg) and triethylamine (25 μl) were dissolved was added, and the mixture was stirred at room temperature for 12 hours.
After filtering off the insoluble matter, the filtrate was diluted with methylene chloride, washed with saturated saline, dried, and the solvent was distilled off under reduced pressure.
The residue was purified by column chromatography (toluene-acetone 7: 4) using silica gel (20 g) to give compound 16-5 (93 mg) as a colorless powder.

[Α] _D ²⁷ -26.2 ° (c 1.06, CHCl ₃ ) IR (CHCl ₃ ): 1744, 1690, 1676c
^{m -1 1 H-NMR (CDCl} 3) δ: 8.03 (2H, d,
J = 7.1 Hz), 7.57 (1H, m), 7.45−
5.14 (17H, m), 6.67 (1H, m), 6.
07 (1H, br, s), 5.73 (1H, br, s)
s), 5.57 (1H, ddd, J = 9.3, 5.8,
2.4 Hz), 5.36 (1H, dd, J = 9.3,
2.7 Hz), 5.09 (1H, br, d, 11.0H)
z), 5.06 (1H, d, J = 3.4 Hz), 5.0
5 (1H, dd, J = 10.2, 8.1 Hz), 4.9
7, 4.87, 4.74, 4.65 (each 1H,
d, J = 11.7 Hz), 4.89 (1H, m), 4.
81, 4.66 (each 1H, d, J = 12.0H
z), 4.77 (1H, d, J = 3.4 Hz), 4.6
1 (1H, d, J = 8.1 Hz), 4.59 (1H, d
d, J = 10.2, 3.4 Hz), 4.44 (1H, d
d, J = 11.0, 6.6 Hz), 4.35 (1H, d
d, J = 12.4, 2.4 Hz), 4.21 (1H, d
d, J = 11.0, 7.1 Hz), 4.10-3.98
(5H, m), 3.93 (1H, dd, J = 10.0,
2.7Hz), 3.89-3.84 (2H, m), 3.
77 (3H, s), 3.64 (1H, dlike),
3.64 (1H, dd, J = 10.7, 2.7 Hz),
3.57 (1H, dt, J = 10.0, 7.1 Hz),
3.53 (1H, dt, J = 9.5, 6.8 Hz),
3.42 (1H, dt, J = 10.0, 6.3 Hz),
3.31-3.15 (4H, m), 2.59 (1H, d
d, J = 12.7, 4.6 Hz), 2.35 (1H,
m), 2.26 (1H, m), 1.72 (1H, dd,
J = 12.7, 12.5 Hz), 1.65-1.58
(4H, m), 1.52-1.46 (4H, m), 1.
40-1.30 (8H, m), 1.11 (3H, d, J
= 6.3 Hz), 2.22, 2.13, 2.11, 2.
09, 2.05, 2.01, 1.85 (each 3
H, s), 1.43 (9H, s).

Synthesis of Compound 16-6 To a solution of Compound 16-5 (118 mg) in methanol (2 ml) was added a 3% sodium methoxide-methanol solution (400 μl), and the mixture was stirred at room temperature for 2 hours. After the reaction solution was neutralized with a cation exchange resin (Dowex 50w H ⁺ ), insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. Next, a 0.1N aqueous sodium hydroxide solution (2.0 ml) and 1,4-dioxane (1.0 m
l) was added thereto, and the mixture was stirred at room temperature for 1 hour, and then neutralized with a cation exchange resin (Dowex 50w H ⁺ ). Then, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure, and further purified by column chromatography (methanol) using a polymer gel (90 g) to obtain Compound 16-6 (89 mg) as a colorless powder.

[0246] ^{_{[α] D 27 -23.1 ° (}} c1.05, CHCl 3) IR (CHCl 3): 3422,1697cm -1 1 H-NMR (CD 3 OD) δ: 7.41-7.24
(15H, m), 4.90, 4.61 (each d,
J = 11.2 Hz), 4.79 (1H, d, J = 2.4)
Hz), 4.77 (2H, s), 4.75, 4.66
(Each 1H, d, J = 11.7 Hz), 4.26
(1H, d, J = 7.8 Hz), 4.04-3.26
(21H, m), 3.24-3.12 (4H, m),
2.81 (1H, br, d, J = 12.9 Hz);
27-2.23 (2H, m), 2.00 (1H, m),
2.00 (3H, s), 1.88-1.79 (2H,
m), 1.65-1.55 (4H, m), 1.54-
1.46 (4H, m), 1.46-1.30 (8H,
m), 1.43 (9H, s), 1.13 (3H, d, J
= 6.3 Hz).

Synthesis of Compound 16 Methanol (7 mg) in which Compound 16-6 (70 mg) was dissolved
ml) solution in palladium hydroxide-carbon (20%, 70%).
mg), and the mixture was stirred at room temperature under a medium-pressure hydrogen stream (50 psi) for 12 hours. After filtering off the catalyst from the reaction solution, the filtrate was concentrated, and the residue was purified by column chromatography (methanol) using a polymer gel (45 g) to obtain Compound 16 (49 mg) as a colorless powder.

[0248] ^{_{[α] D 27 -31.0 ° (}} c0.51, MeOH) IR (KBr): 3456,1695,1650cm -1 1 H-NMR (D 2 O) δ: 4.87 (1H, d , J =
3.7 Hz), 4.46 (1H, d, J = 8.1H)
z), 4.09 (1H, dd, J = 10.0, 3.0H
z), 4.07 (1H, qlike), 3.96 (1
H, d, J = 3.0 Hz), 3.96-3.58 (16
H, m), 3.54 (1H, dd, J = 10.0, 8.
1Hz), 3.53 (1H, m), 3.25 (1H,
m), 3.22-3.14 (4H, m), 2.77 (1
H, dd, J = 12.5, 4.6 Hz), 2.39−
2.30 (2H, trick), 2.05 (1H,
m), 2.04 (3H, s), 1.89 (1H, m),
1.81 (1H, dd, J = 12.5, 12.2H
z), 1.67-1.60 (4H, m), 1.57-
1.49 (4H, m), 1.44 (9H, s), 1.4
3-1.30 (8H, m), 1.22 (3H, d, J =
6.6 Hz).

Example 17 Synthesis of Compound 17-1 To compound 1-6 (1.28 g) was added trifluoroacetic acid (10.0 ml) at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes and concentrated under reduced pressure. Thus, compound 17-1 (1.30 g) was obtained as a crude product.

Synthesis of Compound 17-2 N-methylmorpholine (286 μl) and tert-butyloxycarbonyl-L were added to a solution of compound 17-1 (1.30 mg) in dimethylformamide (10.0 ml).
-Glutamic acid α-benzyl ester (Boc-Glu
-OBn, 371 mg), 1-hydroxybenzotriazole (176 mg) and N, N'-dicyclohexylcarbodiimide (248 mg) were added, and the mixture was stirred at 0 ° C for 12 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with 10% citric acid and saturated sodium hydrogen carbonate, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using silica gel (150 g) (methylene chloride-methanol 3).
0: 1) to give compound 17-2 (1.
09g) as a colorless powder.

[Α] _D ²⁵ -32.0 ° (c 0.56, CHCl ₃ ) IR (KBr): 1738, 1717, 1688, 16
^{37cm -1 1 H-NMR (CDCl} 3) δ: 7.41-7.24
(35H, m), 6.83 (1H, m), 6.66 (1
H, m), 6.23 (1H, m), 5.27 (1H,
d, J = 8.1 Hz), 5.19, 5.13 (each
1H, d, J = 12.2 Hz), 4.97, 4.65
(Each 2H, d, J = 11.7 Hz), 4.8
7, 4.86, 4.74, 4.73 (each 1H,
d, J = 11.7 Hz), 4.80, 4.67 (eac
h2H, d, J = 12.0 Hz), 4.78-4.7.
6 (2H, m), 4.39-4.30 (2H, m),
4.02 (2H, dd, J = 10.0, 3.7 Hz),
3.93 (1H, dd, J = 10.0, 2.4 Hz),
3.92 (1H, dd, J = 10.0, 2.2 Hz),
3.86 (1H, q, J = 6.6 Hz), 3.66 (2
H, br, s), 3.59-3.55 (2H, m),
3.43-3.39 (2H, m), 3.25-3.15
(4H, m), 2.35 (1H, m), 2.30-2.
20 (3H, m), 2.10 (1H, m), 1.85
(1H, m), 1.72-1.64 (3H, m), 1.
64-1.56 (3H, m), 1.52-1.44 (2
H, m), 1.42 (9H, s), 1.40-1.28
(10H, m), 1.10 (3H, d, J = 6.6H
z).

Synthesis of Compound 17-3 Compound 17-2 (250 mg) was added to ethanol (4 ml).
-Dissolved in a mixed solution of methylene chloride (2 ml) and 10%
Palladium-carbon (250 mg) and 1,4-cyclohexadiene (316 μl) were added, and the mixture was stirred at room temperature for 20 minutes. After filtering the reaction solution, the solvent was distilled off from the filtrate under reduced pressure to obtain Compound 17-3 (224 mg) as a colorless foam.

¹ H-NMR (CDCl ₃ ) δ: 7.42
−7.24 (30H, m), 6.96 (1H, br,
s), 6.86-6.76 (2H, m), 5.37 (1
H, br, s), 4.97, 4.96, 4.64 (ea
ch 1H, d, J = 11.7 Hz), 4.88-4.
85 (2H, br, d), 4.83-4.80 (2H,
br, s), 4.78-4.72 (4H, m), 4.6.
8 (1H, d, J = 12.0 Hz), 4.67 (1H,
br, d), 4.64 (1H, d, J = 12.2H)
z), 4.43 (1H, m), 4.33 (1H, m),
4.05-3.98 (3H, m), 3.93 (1H, d
d, J = 10.0, 2.7 Hz), 3.86 (1H,
q, J = 6.6 Hz), 3.84 (1H, q, J = 6.
6Hz), 3.66 (2H, br, s), 3.57 (2
H, ddd, J = 9.8, 7.1, 7.1 Hz), 3.
40 (2H, ddd, J = 9.8, 6.4, 6.4H
z), 3.29 (1H, br, s), 3.23-3.1.
5 (2H, m), 3.09 (1H, br, s), 2.4
2-2.30 (3H, m), 2.30-2.14 (3
H, m), 1.90 (1H, m), 1.74 (1H,
m), 1.64-1.53 (4H, m), 1.51-
1.44 (4H, m), 1.42 (9H, s), 1.3
8-1.27 (8H, m), 1.10 (3H, d, J =
6.3 Hz), 1.10 (3H, d, J = 6.3H)
z).

Synthesis of Compound 17-4 N-methylmorpholine (57 μl), compound 11-2 (150 mg), 1-hydroxybenzotriazole were added to a solution of compound 17-3 (224 mg) in dimethylformamide (3.0 ml). (35 mg) and N,
N'-dicyclohexylcarbodiimide (49.5 m
g) was added and the mixture was stirred at room temperature for 12 hours. The insoluble material was removed by filtration, and the filtrate was concentrated. Dilute the residue with methylene chloride and add 5
% Citric acid and saturated sodium bicarbonate, and after drying, the solvent was distilled off under reduced pressure. The residue was silica gel (45 g).
Compound 17 was purified by column chromatography using methylene chloride (methylene chloride-methanol 30: 1).
-4 (212 mg) was obtained as a colorless powder.

[0255] ^{_{[α] D 25 -34.9 ° (}} c1.04, CHCl 3) IR (KBr): 1695,1636cm -1 1 H-NMR (CDCl 3) δ: 7.40-7.23
(46H, m), 7.04 (1H, d, J = 7.8H
z), 6.68-6.57 (2H, m), 5.60 (1
H, d, J = 7.8 Hz), 4.97 (3H, d, J =
11.7 Hz), 4.87, 4.87, 4.86 (ea
ch 1H, d, J = 11.7 Hz), 4.80 (3
H, d, J = 12.0 Hz), 4.78-4.75 (3
H, m), 4.73 (3H, d, J = 11.7 Hz),
4.68-4.63 (6H, m), 4.44 (1H,
m), 4.20 (1H, m), 4.06-4.00 (3
H, m), 3.94-3.91 (3H, m), 3.86
(3H, q, J = 6.3 Hz), 3.66 (3H, b
r, d), 3.56 (3H, m), 3.41 (3H,
m), 3.30-3.13 (6H, m), 2.43-
2.26 (3H, m), 2.21 (1H, m), 2.0
2-1.94 (3H, m), 1.76-1.74 (2
H, m), 1.70 (1H, m), 1.64-1.55
(4H, m), 1.52-1.42 (4H, m), 1.
41 (9H, s), 1.38-1.26 (14H,
m), 1.10 (9H, d, J = 6.3 Hz).

[0256] methanol was dissolved synthesis of Compound 17 17-4 (160mg) (12ml) - ethyl acetate (4 ml) - in a mixed solution of tetrahydrofuran (4 ml), palladium - carbon (10
%, 200 mg) under a medium pressure hydrogen stream (50 ps).
i) The mixture was stirred at room temperature for 40 hours. After the catalyst was separated by filtration from the reaction solution, the filtrate was concentrated, and the residue was silica gel (18 g).
The compound 17 (68 mg) was obtained as a colorless powder by purifying by column chromatography using methylene chloride-methanol-water 7: 3: 1 (lower layer).

[0257] ^{_{[α] D 25 -102.9 ° (}} c0.53, MeOH) IR (KBr): 3418,1651cm -1 1 H-NMR (CD 3 OD) δ: 4.73 (3H, d,
J = 2.7 Hz), 4.28 (1H, dd, J = 7.
1,4.9 Hz), 3.98 (1H, dd, J = 8.
5, 5.1 Hz), 3.93 (3H, q, J = 6.6H)
z), 3.75-3.70 (6H, m), 3.67-
3.63 (6H, m), 3.46-3.41 (3H,
m), 3.25-3.14 (6H, m), 2.35 (2
H, t, J = 7.3 Hz), 2.25 (2H, J = 7.3 Hz).
6Hz), 2.12-1.98 (2H, m), 1.92
-1.78 (2H, m), 1.68-1.57 (6H,
m), 1.56-1.48 (6H, m), 1.44 (9
H, s), 1.46-1.32 (12H, m), 1.2
0 (9H, d, J = 6.6 Hz).

Example 18 Synthesis of Compound 18-1 In a solution of compound 17-3 (141 mg) in dimethylformamide (3.0 ml) was added N-methylmorpholine (31 μl), compound 9-4 (143 mg), Hydroxybenzotriazole (19 mg) and N, N '
-Dicyclohexylcarbodiimide (27 mg) was added, and the mixture was stirred at room temperature for 12 hours. After removing the insoluble matter by filtration and concentrating the filtrate, the residue was diluted with methylene chloride, and 5%
Washed with citric acid and saturated sodium bicarbonate. After drying, the solvent was distilled off under reduced pressure, and the residue was silica gel (45 g).
Compound 18 was purified by column chromatography using methylene chloride (methylene chloride-methanol 30: 1).
-1 (147 mg) was obtained as a colorless powder.

[0259] ^{_{[α] D 28 -32.0 ° (}} c1.01, CHCl 3) IR (KBr): 1749,1655cm -1 1 H-NMR (CDCl 3) δ: 8.03 (2H,
m), 7.56 (1H, m), 7.43 (2H, m),
7.41-7.25 (3H, m), 7.07 (1H, b
r, d, J = 7.6 Hz), 6.75 (1H, br,
s), 6.63 (1H, br, s), 5.61 (1H,
br, d, J = 7.3 Hz), 5.57 (1H, dd)
d, J = 9.5, 5.4, 2.4 Hz), 5.38 (1
H, dd, J = 9.5, 2.4 Hz), 5.10 (1
H, br, d, J = 9.8 Hz), 5.06 (1H,
d, J = 3.2 Hz), 5.04 (1H, dd, J =
9.8, 7.6 Hz), 4.97 (2H, d, J = 1)
1.5 Hz), 4.89 (1H, m), 4.87, 4.
86, 4.74, 4.74 (each 1H, d, J =
11.7 Hz), 4.80 (2H, d, J = 12.0H)
z), 4.77 (2H, d, J = 3.4 Hz), 4.6
7 (2H, d, J = 12.0 Hz), 4.65 (2H, d, J = 12.0 Hz)
d, J = 11.5 Hz), 4.61 (1H, d, J =
7.6 Hz), 4.59 (1H, dd, J = 9.8,
3.2 Hz), 4.44 (1H, dd, J = 11.0,
6.6 Hz), 4.44 (1H, m), 4.35 (1
H, dd, J = 12.4, 2.4 Hz), 4.21 (1
H, dd, J = 11.0, 7.1 Hz), 4.21 (1
H, m), 4.05 (1H, qlike), 4.03-
3.98 (3H, m), 3.95-3.91 (2H,
m), 3.90-3.83 (3H, m), 3.77 (3
H, s), 3.66 (2H, br, s), 3.64 (1
H, dd, J = 11.3, 3.1 Hz), 3.60 −
3.54 (2H, m), 3, 34-3.14 (6H,
m), 2.59 (1H, dd, J = 12.7, 4.6H)
z), 2.22, 2.1, 3, 2.11, 2.09,
2.05, 2.01, 1.85 (each 3H, s),
1.72 (1H, dd, J = 12.7, 4.6 Hz),
1.66-1.54 (6H, m), 1.53-1.44
(6H, m), 1.42 (9H, s), 1.39-1.
24 (12H, m), 1.10 (6H, d, J = 6.3)
Hz).

Synthesis of Compound 18 To a solution of compound 18-1 (92 mg) in methanol (1.8 ml) was added a 3% sodium methoxide-methanol solution (200 μl), and the mixture was stirred at 0 ° C. for 12 hours. The reaction solution is converted to a cation exchange resin (Dowex 50w H ⁺ )
After neutralization by filtration, the insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. Next, methylene chloride (2.0 m
l), 1,4-dioxane (4.0 ml) and 0.5
An N sodium hydroxide aqueous solution (2.0 ml) was added, and the mixture was stirred at room temperature for 1 hour. Cation exchange resin (Dowex 50w H
Neutralized using ⁺ ), the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was treated with methanol (10 ml)-
Ethyl acetate (4 ml) -1,2-dichloroethane (0.
5 ml), and palladium hydroxide-carbon (20%, 160 mg) was added thereto.
psi) and stirred at room temperature for 48 hours. After the catalyst was filtered off from the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (methanol) using a polymer gel (45 g) to give compound 18 (18 mg).
Was obtained as a colorless powder.

[0261] ^{_{[α] D 25 -54.9 ° (}} c0.53, MeOH) IR (KBr): 3350,1655cm -1 1 H-NMR (D 2 O) δ: 4.88 (2H, br,
d), 4.46 (1H, d, J = 7.8 Hz), 4.2
1 (1H, m), 4.12-4.05 (2H, m),
4.07 (2H, q, J = 6.6 Hz), 3.97 −
3.59 (22H, m), 3.57-3.50 (2H,
m), 3.30-3.12 (6H, m), 2.77 (1
H, dd, J = 12.4, 4.2 Hz), 2.42 (2
H, t, J = 7.1 Hz), 2.38-2.26 (3
H, m), 2.08 (1H, m), 1.99-1.86
(2H, m), 1.82 (1H, J = 12.4, 12.
0 Hz), 1.70-1.58 (6H, m), 1.58
-1.48 (6H, m), 1.45 (9H, s), 1.
38-1.30 (12H, m), 1.23 (6H, d,
J = 6.6 Hz).

Example 19 Synthesis of Compound 19-1 The compound was synthesized according to the description in Carbohydrate Research, 230 , 117-149 (1992).

Synthesis of Compound 19-2 To a solution of compound 19-1 (119 mg) in 1,4-dioxane (8.0 ml) was added a 20% aqueous sodium hydroxide solution (1.0 ml). Stirred for hours. The reaction solution was diluted with methylene chloride, washed with 2% hydrochloric acid, dried, and then the solvent was distilled off to give Compound 19-2.
(112 mg) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 7.41
-7.25 (15H, m), 4.98, 4.88, 4.
74, 4.67 (each 1H, d, J = 11.7H
z), 4.82, 4.65 (each 1H, d, J =
12.2 Hz), 4.77 (1H, d, J = 3.7H)
z), 4.02 (1H, dd, J = 10.0, 3.7H
z), 3.94 (1H, dd, J = 10.0, 2.7H
z), 3.86 (1H, q, J = 6.6 Hz), 3.6
6 (1H, br, d), 3.58 (1H, dt, J =
9.8, 7.1 Hz), 3.42 (1H, dt, J =
9.8, 6.4 Hz), 2.35 (2H, t, J = 7.
6 Hz), 1.67-1.54 (4H, m), 1.38
−1.25 (8H, m), 1.10 (3H, d, J =
6.6 Hz).

Synthesis of Compound 19-3 To a solution of compound 19-2 (112 mg) in ethyl acetate (1.0 ml) was added 1-hydroxybenzotriazole (35 mg) and N, N'-dicyclohexylcarbodiimide (45 mg). The mixture was stirred at room temperature for 3 hours. Next, the insoluble matter was removed by filtration, and the residue obtained by concentrating the filtrate was dissolved in dimethylformamide (1.0 ml), and then trifluoroacetic acid salt of L-lysine (20.5 m
g) and triethylamine (33 μl) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and methanol (3.0 ml) and a 10% trimethylsilyldiazomethane-hexane solution (1.5 ml) were added to the residue. After stirring at room temperature for 20 minutes, the solution was concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (20 g) (toluene-acetone-methanol 100: 10:
The compound 19-3 (52 m
g) was obtained as a colorless oil.

[Α] _D ²⁸ -32.8 ° (c 0.60, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 7.40-7.24
(30H, m), 6.10 (1H, d, J = 7.8H
z), 5.68 (1H, m), 4.97, 4.87,
4.73, 4.65 (each 2H, d, J = 11.
7Hz), 4.80, 4.67 (each 2H, d,
J = 12.2 Hz), 4.78 (2H, d, J = 3.4)
Hz), 4.02 (2H, dd, J = 10.0, 3.4)
Hz), 3.93 (2H, dd, J = 10.0, 2.4)
Hz), 3.86 (2H, q, J = 6.6 Hz), 3.
73 (3H, s), 3.66 (2H, br, s), 3.
57 (2H, m), 3.22 (2H, m), 2.21
(2H, t, J = 7.8 Hz), 2.13 (2H, t,
J = 7.8 Hz), 1.84 (1H, m), 1.72-
1.55 (2H, m), 1.52 (1H, m), 1.3
7-1.25 (18H, m), 1.10 (6H, d, J
= 6.3 Hz).

[0267] methanol was dissolved synthesis of Compound 19 19-3 (40mg) (7
ml) solution, palladium-carbon (10%, 50mg)
Under a medium-pressure hydrogen stream (50 psi) at room temperature.
Stirred for hours. After the catalyst was filtered off from the reaction solution, the filtrate was concentrated, and the residue was purified by column chromatography (methanol) using a polymer gel (25 g) to obtain Compound 19 (20 mg) as a colorless resin. .

[Α] _D ²⁵ −83.0 ° (c 0.65, M
eOH) ¹ H-NMR (CD ₃ OD) δ: 4.73 (2H, d,
J = 2.4 Hz), 4.36 (1H, dd, J = 9.
3, 5.1 Hz), 3.94 (2H, q, J = 6.6H)
z), 3.74-3.70 (4H, m), 3.70 (3
H, s), 3.67-3.63 (4H, m), 3.46.
-3.41 (2H, m), 3.17-3.14 (2H,
t, J = 7.1 Hz), 2.24 (2H, t, J = 7.
6 Hz), 2.16 (2H, t, J = 7.6 Hz),
1.83 (1H, m), 1.69 (1H, m), 1.6
5-1.55 (8H, m), 1.55-1.48 (2
H, m), 1.43-1.30 (18H, m), 1.2
0 (6H, d, J = 6.6 Hz).

Example 20 Synthesis of Compound 20-1 To compound 11-1 (300 mg) was added trifluoroacetic acid (2.0 ml) at 0 ° C., the mixture was stirred at the same temperature for 30 minutes, and concentrated under reduced pressure to give the compound. 20-1 was obtained as a crude product. (303mg)

Synthesis of Compound 20-2 To a solution of compound 17-1 (303 mg) in methylene chloride (3.0 ml) was added N-methylmorpholine (116 mg).
μl) and N- (palmitoyloxy) -succinimide (187 mg) were added, and the mixture was stirred at 0 ° C. for 12 hours.
After concentrating the reaction solution under reduced pressure, the residue was silica gel (70
The compound 20-2 (292 mg) was obtained as a colorless powder by purifying by column chromatography (n-hexane-ethyl acetate-methanol 12: 7: 0.19) using g).

[0271] ^{_{[α] D 25 -30.7 ° (}} c1.02, CHCl 3) IR (KBr): 3298,1730,1634cm -1 1 H-NMR (CDCl 3) δ: 7.41-7.25
(20H, m), 6.33 (1H, d, J = 7.6H
z), 6.29 (1H, m), 5.15, 5.10 (e
ach 1H, d, J = 12.5 Hz), 4.97,
4.65 (each 1H, d, J = 11.5 Hz),
4.87, 4.74 (each 1H, d, J = 11.
7 Hz), 4.81, 4.67 (each 1H, d,
J = 12.0 Hz), 4.77 (1H, d, J = 3.7)
Hz), 4.41 (1H, m), 4.02 (1H, d
d, J = 10.0, 3.7 Hz), 3.93 (1H, d
d, J = 10.0, 2.7 Hz), 3.86 (1H,
q, J = 6.3 Hz), 3.66 (1H, br, s),
3.57 (1H, ddd, J = 9.8, 7.1, 7.1
Hz), 3.42 (1H, ddd, J = 9.8, 6.
6,6.6 Hz), 3.25-3.14 (4H, m),
2.60 (1H, ddd, J = 17.1, 7.1, 7.
1 Hz), 2.40 (1H, ddd, J = 17.1,
6.6, 6.6 Hz), 2.16 (2H, t, J = 7.
1Hz), 2.02 (1H, m), 1.95 (1H,
m), 1.64-1.56 (2H, m), 1.50-
1.42 (2H, m), 1.40-1.20 (30H,
m), 1.10 (3H, d, J = 6.3 Hz), 0.8
8 (3H, t, J = 6.8 Hz).

Synthesis of Compound 20-3 Compound 20-2 (110 mg) was added to ethanol (4 ml).
And 1,2-dichloroethane (1 ml) in a mixed solvent, and 10% palladium-carbon (150 mg) and 1,4-
Add cyclohexadiene (208 μl) and add 3
Stirred for 0 minutes. After filtering the reaction solution, the solvent was distilled off from the filtrate under reduced pressure to obtain Compound 20-3 (95 mg) as a colorless foam.

¹ H-NMR (CDCl ₃ ) δ: 7.40
−7.23 (15H, m), 7.01 (1H, m),
6.62 (1H, d, J = 7.6 Hz), 4.97,
4.86, 4.73, 4.64 (each 1H, d,
J = 11.7 Hz), 4.81, 4.67 (each
1H, d, J = 12.0 Hz), 4.76 (1H, J =
3.7 Hz), 4.56 (1H, m), 4.02 (1
H, dd, J = 10.0, 3.7 Hz), 3.93 (1
H, dd, J = 10.0, 2.7 Hz), 3.85 (1
H, q, J = 6.6 Hz), 3.66 (1H, br,
d), 3.57 (1H, ddd, J = 10.0, 6.
8, 6.8 Hz), 3.41 (1H, ddd, J = 1)
0.0, 6.6, 6.6 Hz), 3.25 (1H,
m), 3.17 (1H, m), 2.43, 2.34,
2.03, 1.92 (each 1H, m), 2.19
(2H, t, J = 7.6 Hz), 1.63-1.55
(2H, m), 1.52-1.45 (2H, m), 1.
38-1.20 (30H, m), 1.11 (3H, d,
J = 6.6 Hz), 0.88 (3H, t, J = 7.1H)
z).

Synthesis of Compound 20-4 The compound was synthesized as described in Chem, Pharm. Bull., 40 , 2300-2303 (1992).

Synthesis of Compound 20-5 To a solution of Compound 20-4 (64.5 mg) in methanol (5 ml) was added a Lindlar catalyst (70 mg) and paratoluenesulfonic acid (19 mg), and the mixture was added under a medium pressure hydrogen stream. (50 psi) The mixture was stirred at room temperature for 2 hours. The same catalyst (50 mg) was further added, and the mixture was stirred under the same conditions for 1 hour.
The catalyst was filtered off from the reaction solution, and the filtrate was concentrated under reduced pressure to obtain Compound 20-5 (85 mg) as a crude product.

Synthesis of Compound 20-6 N-Methylmorpholine (22 μl) 5 (85 mg), 1-hydroxybenzotriazole (20.5 mg) and N, N'-dicyclohexylcarbodiimide (29 mg) were added at room temperature.
Stirred for hours. After removing the insoluble matter by filtration and concentrating the filtrate, the residue was diluted with methylene chloride, washed with 5% citric acid and saturated sodium hydrogen carbonate, dried, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography using silica gel (30 g) (methylene chloride-methanol 30: 1) and column chromatography using polymer gel (125 g) (methylene chloride-methanol).
The compound 20-6 (90 m
g) was obtained as a colorless powder.

[0277] ^{_{[α] D 26 -23.4 ° (}} c1.04, CHCl 3) IR (KBr): 1745,1657cm -1 1 H-NMR (CDCl 3) δ: 7.41-7.25
(15H, m), 7.01 (1H, m), 6.88 (1
H, m), 6.12 (1H, m), 5.39 (1H,
m), 5.33 (1H, br, d), 5.17 (1H,
d, J = 9.0 Hz), 4.97, 4.65 (each
1H, d, J = 11.5 Hz), 4.88, 4.74
(Each 1H, d, J = 11.7 Hz), 4.83
(1H, m), 4.81, 4.67 (each 1H,
d, J = 12.0 Hz), 4.77 (1H, d, J =
3.4 Hz), 4.35-4.28 (2H, m), 4.
13-4.05 (3H, m), 4.02 (1H, dd,
J = 10.0, 3.6 Hz), 3.93 (1H, dd,
J = 10.0, 2.7 Hz), 3.86 (1H, q, J
= 6.6 Hz), 3.79 (3H, s), 3.74 (1
H, m), 3.67 (1H, br, s), 3.57 (1
H, m), 3.42 (1H, m), 3.30-3.15
(5H, m), 2.59 (1H, dd, J = 12.7,
4.4 Hz), 2.43 (1H, m), 2.27 (1
H, m), 2.21 (2H, t, J = 7.8 Hz),
2.15, 2.14, 2.04, 2.03, 1.88
(Each 3H, s), 1.95 (1H, dd, J =
12.7, 12.5 Hz), 1.66-1.56 (4
H, m), 1.56-1.44 (4H, m), 1.40.
-1.20 (38H, m), 1.10 (3H, d, J =
6.6 Hz), 0.86 (3H, t, J = 7.1H)
z).

Synthesis of Compound 20 Methanol (3%) in which Compound 20-6 (75 mg) was dissolved
ml) -benzene (1 ml) mixed solution, 3% sodium methoxide-methanol solution (200 μl) was added,
Stirred at 0 ° C. for 12 hours. After the reaction solution was neutralized with a cation exchange resin (Dowex 50w H ⁺ ), insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue is then
It was dissolved in a mixed solvent of methanol (7 ml) and benzene (5 ml), palladium-carbon (10%, 70 mg) was added, and the mixture was stirred at room temperature under a medium-pressure hydrogen stream (50 psi) for 24 hours. The catalyst was filtered off from the reaction solution, the filtrate was concentrated under reduced pressure, and the obtained residue was added to 1,4-dioxane (2.0 m
l) and 0.1 N aqueous sodium hydroxide solution (1.0 m
l) was added and the mixture was stirred at room temperature for 1 hour. Then, the mixture was neutralized with a cation exchange resin (Dowex 50w H ⁺ ), insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure.
Column chromatography using g) (methanol)
Compound 20 (26 mg) was obtained as a colorless powder.

[0279] ^{_{[α] D 25 -33.0 ° (}} c0.52, MeOH) IR (KBr): 3367,1637cm -1 1 H-NMR (CD 3 OD) δ: 4.63 (1H, d,
J = 2.9 Hz), 4.18 (1H, m), 3.80 −
3.30 (14H, m), 3.16-3.03 (4H,
m), 2.71 (1H, m), 2.18 (4H, m),
1.93 (1H, m), 1.91 (3H, s), 1.7
9 (1H, m), 1.58-1.46 (5H, m),
1.46-1.36 (6H, m), 1.35-1.13
(36H, m), 1.11 (3H, d, J = 6.6H
z), 0.80 (3H, t, J = 7.1 Hz).

Example 21 Synthesis of Compound 21-1 Sodium hydride (580 mg, dispersed in 60% mineral oil)
After washing with hexane, tetrahydrofuran (50 m
l) and suspended at room temperature in 2- [2- (2-octadecyloxyethoxy) ethoxy] ethanol (4.86 g).
Of tetrahydrofuran (15 ml) was added dropwise. After the reaction mixture was heated and stirred at 60 ° C. for 1 hour, a solution of ethyl bromoacetate (1.9 ml) in tetrahydrofuran (3 ml) was added under ice-cooling, left at room temperature, and reacted by stirring for 18 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the extract was washed with water and saturated saline, and then dried. After the solvent was distilled off, the residue (6.15 g) was subjected to silica gel column chromatography (hexane-ethyl acetate 4: 4).
Purification was performed in 1) to give the ester compound 21-1 as 4.66.
g (85% yield).

R _F 0.49 (hexane-ethyl acetate
_{1: 1) IR (CHCl 3} ): 1750cm -1 1 H-NMR (CDCl 3) δ (ppm) in 500M
Hz: 0.88 (t, 3H), 1.29 (t, 3H),
3.44 (t, 2H), 4.15 (s, 2H), 4.2
1 (q, 2H).

Synthetic ester of compound 21-2 Compound 21-1 (4.6 g) was dissolved in a mixed solvent of methanol (10 ml) and tetrahydrofuran (5 ml), and an aqueous solution of potassium hydroxide (1.09 g) (1.
(5 ml) was added dropwise, and the mixture was stirred and reacted at room temperature for 25 hours. After the reaction solution was poured into saline and extracted with methylene chloride, the aqueous layer was made acidic with citric acid and extracted with methylene chloride. The extract was washed with water and saturated saline, and then dried. The solvent was distilled off to give carboxylic acid compound 825 at 3.63.
g (yield 80%).

[0283] R _F 0.54 (butanol - acetic acid - water 4: 1: 1) IR ( KBr): 3500,1730,1700cm -1 1 H-NMR (CDCl 3) δ (ppm) in 500M
Hz: 0.88 (t, 3H), 3.47 (t, 2H),
3.6-3.8 (m, 12H), 4.15 (s, 2
H).

Synthesis of Compound 21-3 To a solution of 2- [2- (2-chloroethoxy) ethoxy] ethanol (8.4 mg, 50 mmol) in dimethylformamide (20 ml) was added sodium azide (24.3 g,
0.37 mol), and the mixture was stirred and reacted at 50 ° C. for 3 days. Purification was performed using "HP-20" (150 ml, water), and 3.28 g of 2- [2- (2-azidoethoxy) ethoxy] ethanol (compound 21-3) (37% yield).
I got

[0285] R _F 0.58 (ethyl ^{acetate) IR (neat): 3450,2100cm -1} 1 H-NMR (CDCl 3) δ (ppm) in 500M
Hz: 3.41 (t, 2H), 3.62-3.63
(M, 2H), 3.68-3.70 (m, 6H), 3.
73-3.76 (m, 2H).

Synthesis of Compound 21-4 i) Sodium hydride (900 mg, dispersed in 60% mineral oil) previously washed with hexane was suspended in dimethylformamide (10 ml), and the azide compound (3. 28 g) of dimethylformamide (10 ml)
After the solution was added dropwise, the mixture was returned to room temperature and stirred for 1 hour. ii) Chloroacetic acid (2.28 g) was added to Bu ₄ NOH (30 ml, 1M methanol solution), and then the solvent was distilled off. Toluene was further added and the solvent was distilled off. The residue was dissolved in dimethylformamide (17 ml), added dropwise to the reaction mixture of i), and reacted by stirring overnight. Benzyl bromide (5.3 ml) was added to the reaction mixture, and the mixture was further stirred for 5 days to react. The reaction solution was poured into saline and extracted with ethyl acetate. The extract was washed with water and saturated saline, and then dried. After evaporating the solvent, the residue (8.5 g) was purified by silica gel column chromatography (hexane-ethyl acetate 9: 1-ethyl acetate) to obtain 1.60 g (yield 39%) of benzyl compound 21-4. ) Got.

[0287] R _F 0.46 (hexane - ethyl acetate 1: 1) IR (KBr) : 1755,2100cm -1 1 H-NMR (CDCl 3) δ (ppm) in 500M
Hz: 3.37 (t, 2H), 3.66 (m, 6H),
3.71-3.74 (m, 2H), 4.21 (s, 2
H), 5.20 (s, 2H).

Synthesis of Compound 21-6 i) Toluenesulfonic acid (106 ml) was added to a solution of the benzyl compound 21-4 (150 mg) in ethanol (8 ml).
g) and Lindlar's catalyst (75 mg) were added, and the mixture was stirred with shaking under hydrogen pressure (50 psi) for 1 hour. The catalyst was removed by filtration with Celite, the solvent was distilled off, and triethylamine (0.13 ml) was added to a solvent of the obtained amino compound 849 in methylene chloride (4 ml) (compound 21-5). ii) Dicetyl acetic acid (234 mg) and N-hydroxysuccinimide (58 mg) in methylene chloride (10 m
l) To the solution was added N, N'-dicyclohexylcarbodiimide (104 mg) at room temperature, and the mixture was stirred for 1 hour. A methylene chloride solution of the amino compound 21-5 obtained in i) was added dropwise thereto, and the mixture was stirred and reacted at room temperature for 14 hours. The reaction mixture was poured into water and extracted with methylene chloride. The extract was washed with water and brine, and dried. After the solvent was distilled off, acetonitrile was added to the residue, and the soluble portion (137
mg) was purified by silica gel column chromatography (chloroform-toluene 9: 1) to obtain 125 mg (34% yield) of amide compound 15-6.

R _F 0.35 (hexane-ethyl acetate 6: 4) IR (KBr): 3450, 3300, 1750, 16
^{45,1630,1573,1550cm -1 1 H-NMR (CDCl} 3) δ (ppm) in 500M
Hz: 0.88 (t, 6H), 1.99 (sestet, 1
H), 3.4-3.8 (m, 12H), 4.20 (s,
2H), 5.19 (s, 2H), 6.00 (t, 1
H), 7.2 (m, 5H).

Synthesis of Compound 21-7 i) 10% palladium carbon (10 mg) was added to a mixed solvent solution of amide compound 21-6 (50 mg) in toluene (10 ml) and ethyl acetate (10 ml), and the mixture was stirred at room temperature. The reaction was carried out with shaking and stirring for 1.5 hours under hydrogen pressure (50 psi). The solvent was distilled off from the reaction solution to obtain 44 mg (quant) of the carboxylic acid compound 21-7.

R _F 0.80 (chloroform-methanol 4: 1) IR (chloroform): 3690, 3620, 303
^{0,1740,1660cm -1 1 H-NMR (CDCl} 3) δ (ppm) in 500M
Hz: 0.88 (t, 6H), 3.4-3.8 (m, 1
2H), 4.17 (s, 2H), 6.25 (t, 1
H).

Synthesis of Compound 21-8 In a solution of compound 17-1 (200 mg) in dimethylformamide (3.0 ml) was added N-methylmorpholine (69 μl), compound 21-7 (164 mg), and 1-hydroxybenzotriazole. (42 mg) and N,
N'-Dicyclohexylcarbodiimide (58 mg) was added, and the mixture was stirred at 0 ° C for 12 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methylene chloride, washed with 10% citric acid and saturated sodium hydrogen carbonate, dried, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (methylene chloride-methanol 50: 1) using silica gel (45 g) to give compound 21-8 as a mixture (220 mg) with unreacted compound 21-7. This was used for the next reaction without further purification.

[0293] ^{_{IR (CHCl 3): 1661cm -1}} 1 H-NMR (CDCl 3) δ: 7.66 (1H, d,
J = 7.8 Hz), 7.40-7.24 (30H,
m), 6.79 (1H, trick), 6.30 (1
H, trick), 6.09 (1H, m), 4.97,
4.87, 4.87, 4.75, 4.65 (each
1H, d, J = 11.7 Hz), 4.81, 4.67
(Each 1H, d, J = 12.0 Hz), 4.78
-4.76 (2H, m), 4.39 (1H, m), 4.
06, 4.00 (each 1H, d, J = 15.6H
z), 4.02 (2H, dd, J = 10.0, 3.7H
z), 3.93 (2H, br, d), 3.86 (2H,
q, J = 6.6 Hz), 1.10 (3H, d, J = 6.
6 Hz).

[0294]Synthesis of Compound 21  Dissolve compound 21-8 (110 mg) obtained in the above reaction
Methanol (7 ml) -ethyl acetate (7 ml)
The palladium-carbon (10%, 110 mg) was added to the combined solution.
In addition, 48 hours at room temperature under a medium pressure hydrogen flow (50 psi)
While stirring. After filtering the catalyst from the reaction solution, the filtrate is concentrated.
And the residue is subjected to column chromatography using silica gel (30 g).
Tomography (methylene chloride-methanol 30: 1)
Chromatography using gel and polymer gel (75 g)
Compound 2 was purified by laffy (methanol).
1 (48 mg) was obtained as a colorless powder.

[0295] ^{_{[α] D 24 -40.9 ° (}} c0.52, MeOH) IR (KBr): 3294,1645cm -1 1 H-NMR (Pyridine-d 5 + D 2 O) δ: 5.23
(2H, br, d), 5.12 (1H, m), 4.58
(2H, dd, J = 10.0, 3.4 Hz), 4.46
(2H, dd, J = 10.0, 3.2 Hz), 4.24
(2H, q, J = 6.4 Hz), 4.22 (2H,
s), 4.18 (2H, br, s), 3.85-3.7
4 (6H, m), 3.74-3.64 (6H, m),
3.57-3.47 (2H, m), 3.45-3.35
(4H, m), 2.80-2.64 (3H, m), 2.
57 (1H, m), 2.47 (1H, m), 2.02-
1.92 (2H, m), 1.66-1.47 (14H,
m), 1.56 (6H, d, J = 6.4 Hz), 1.4
3-1.20 (60H, m), 0.88 (6H, t, J
= 7.1 Hz).

Example 22 Synthesis of compound 22-1 The compound was synthesized according to Carbohydrate Research, 212 , 277-281 (1991).

Synthesis of Compound 22-2 Compound 22-1 (490 ml) was added to a solution of molecular sieves 3A (1.3 g) in acetonitrile (9 ml).
g) and compound 15-1 (276 mg) were added, and the mixture was stirred at room temperature for 2 hours. For 2 hours.
After the reaction solution was filtered, the filtrate was washed with an aqueous solution of sodium thiosulfate and an aqueous solution of saturated sodium bicarbonate, and after drying, the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography twice (70 g, toluene-acetone 4: 1).
And 100 g of methylene chloride-methanol 50:
Purification according to 1) gave compound 22-2 (341 mg).

Compound 22-2; colorless oil [α] _D ²⁵ -13.8 ° (c 1.15, CHCl ₃ ) IR (KBr): 2100, 1749, 1690, 16
^{59cm -1 1 H-NMR (CDCl} 3) δ: 5.39 (1H, dd
d, J = 8.5, 5.6, 2.7 Hz), 5.33 (1
H, dd, J = 8.5, 2.0 Hz), 5.12 (1
H, br, d, J = 8.1 Hz), 4.84 (1H, d
dd, J = 12.4, 9.8, 4.6 Hz), 4.31
(1H, dd, J = 12.5, 2.7 Hz), 4.12
-4.04 (3H, m), 3.80 (3H, s), 3.
76 (1H, dd, J = 9.3, 6.3 Hz), 3.2
7 (2H, t, J = 7.1 Hz), 3.22 (1H, d
t, J = 9.3, 6.6 Hz), 2.58 (1H, d
d, J = 12.9, 4.6 Hz), 2.15, 2.1
4, 2.04, 2.03, 1.88 (each 3H,
s), 1.95 (1H, dd, J = 12.9, 12.4)
Hz), 1.64-1.52 (4H, m), 1.43-
1.34 (4H, m).

Synthesis of Compound 22-3 Compound 22-2 (150 mg, 0.250 mmol) was dissolved in methanol (10 ml) solution, and Lindlar catalyst (150 mg) and paratoluenesulfonic acid (48 m
g, 0.250 mmol) and stirred at room temperature under a medium-pressure hydrogen stream (50 psi) for 3 hours. The same catalyst (7
After stirring for 2 hours under the same conditions, the catalyst was removed by filtration from the reaction solution, and the filtrate was concentrated under reduced pressure to obtain Compound 22-3 (189 mg) as a crude product.

Synthesis of Compound 22-4 Compound 22-3 (189 mg) was dissolved in acetonitrile (3 ml) solution, compound 11-2 (201 mg) in dimethylformamide (2 ml), N-methylmorpholine (33 μl), -Hydroxybenzotriazole (46 mg) and N, N'-dicyclohexylcarbodiimide (65 mg) were added, and the mixture was stirred at 0 ° C for 12 hours. After removing the insoluble matter by filtration and concentrating the filtrate, the residue was diluted with methylene chloride, washed with 5% citric acid and a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography using silica gel (45 g) (methylene chloride-methanol 3).
0: 1) to give compound 22-4 (210 mg,
58%) as a colorless powder.

[0301] ^{_{[α] D 24 -23.3 ° (}} c1.09, CHCl 3) IR (CHCl 3): 1745,1672cm -1 1 H-NMR (CDCl 3) δ: 7.41-7.25
(15H, m), 6.69 (1H, br, s), 6.1
8 (1H, br, s), 5.74 (1H, br, s),
5.39 (1H, ddd, J = 9.3, 5.6, 2.7)
Hz), 5.32 (1H, dd, J = 8.5, 1.7H)
z), 5.15 (1H, br, s), 4.97, 4.6
5 (each 1H, d, J = 11.5 Hz), 4.8
8, 4.74 (each 1H, d, J = 11.7H
z), 4.84 (1H, m), 4.81, 4.67 (e
ach 1H, d, J = 12.2 Hz), 4.77 (1
H, d, J = 3.7 Hz), 4.32 (1H, dd, J)
= 12.5, 2.0 Hz), 4.11-4.04 (4
H, m), 4.02 (1H, dd, J = 10.3, 3.
7 Hz), 3.93 (1H, dd, J = 10.3, 2.
9Hz), 3.86 (1H, q, J = 6.6Hz),
3.79 (3H, m), 3.74 (1H, dt, J =
9.5, 6.6 Hz), 3.67 (1H, br, d),
3.57 (1H, dt, J = 10.0, 6.8 Hz),
3.42 (1H, dt, J = 10.0, 6.6 Hz),
3.30-3.16 (5H, m), 2.57 (1H, d
d, J = 12.7, 4.6 Hz), 2.35 (1H, d
dd, J = 13.6, 8.0, 5.6 Hz), 2.26
(1H, ddd, J = 13.6, 7.6, 5.4H
z), 2.15, 2.14, 2.04, 2.03, 1..
88 (each 3H, s), 1.94 (1H, dd,
J = 12.7, 12.5 Hz), 1.71-1.45
(8H, m), 1.43 (9H, s), 1.40-1.
29 (8H, m), 1.10 (3H, d, J = 6.6H
z).

Synthesis of Compound 22 Methanol (2) in which Compound 22-4 (75 mg) was dissolved
ml) solution, 1% sodium methoxide-methanol solution (100 μl) was added, and the mixture was stirred at 0 ° C. for 48 hours.
After the reaction solution was neutralized with a cation exchange resin (Dowex 50w H ⁺ ), insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure.
Next, the obtained residue was dissolved in methanol (12 ml), and palladium-carbon (10%, 120 mg) was added.
The mixture was stirred at room temperature under a medium-pressure hydrogen stream (50 psi) for 30 hours. The catalyst was filtered off from the reaction solution, and the filtrate was concentrated under reduced pressure. Then, water (1.0 ml) and a 0.1 N aqueous sodium hydroxide solution (1.0 ml) were added, and the mixture was stirred at room temperature for 1 hour. Neutralize with a cation exchange resin (Dowex 50w H ⁺ ), remove insolubles by filtration, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (methanol) using a polymer gel (70 g). Compound 22
(83 mg) as a colorless powder.

[Α] _D ²² -41.1 ° (c 0.62, MeOH) ¹ H-NMR (CD ₃ OD) δ: 4.73 (1H, d,
J = 2.9 Hz), 3.98 (1H, m), 3.93
(1H, q, J = 6.6 Hz), 3.87-3.81
(2H, m), 3.77 (1H, m), 3.75-3.
60 (7H, m), 3.57-3.49 (2H, m),
3.25-3.12 (5H, m), 2.25 (2H,
t, J = 7.1 Hz), 2.01 (3H, s), 2.0
0 (1H, m), 1.83 (1H, m), 1.70-
1.59 (3H, m), 1.59-1.46 (6H,
m), 1.44 (9H, s), 1.44-1.29 (8
H, m), 1.20 (3H, d, J = 6.6 Hz).

Example 23 Synthesis of Compound 23-1 The compound was synthesized according to the description in J. Carbohydrate Chemistry, 10 (4), 549-560 (1991). Synthesis of Compound 23-2 and Compound 23-3 Compound 23-1 (2.00 ml) was added to a methylene chloride (30 ml) solution containing Molecular Sieves 4A (4.5 g).
g) and (1R, 2R) -trans-1,2-cyclohexanediol (1.50 g), and the mixture was stirred at room temperature for 12 hours. Then, at -40 ° C., N-iodosuccinimide (1.93 g) and trifluoromethane were added. Romethanesulfonic acid (76
μl) and stirred at the same temperature for 2 hours. After filtering the reaction solution, the filtrate was washed with an aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution, and then dried, and then the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography twice (200 g, n-hexane-ethyl acetate).
8: 1 and 100 g, n-hexane-ethyl acetate 1
0: 1) to give compound 23-2 (341 m).
g), compound 23-3 (735 mg) and compound 23
A mixture of Compound-2 and Compound 23-3 (228 mg) was obtained. Compound 23-2 colorless oil ^{_{[α] D 23 -53.2 ° (}} c0.58, CHCl 3) IR (CHCl 3): 3632,3450cm -1 1 H-NMR (CDCl 3) δ: 7.41- 7.26
(15H, m), 4.98, 4.65 (each 1
H, d, J = 11.5 Hz), 4.97 (1H, d, J)
= 3.7 Hz), 4.86, 4.74 (each 1
H, d, J = 11.7 Hz), 4.81, 4.67 (e
ach 1H, d, J = 12.0 Hz), 4.07 (1
H, dd, J = 10.3, 3.7 Hz), 4.06 (1
H, m), 3.94 (1H, dd, J = 10.3, 2.
7 Hz), 3.69 (1H, br, d), 3.62 (1
H, s, OH, disappeared by D ₂ O treatment), 3.44 (1H,
m), 3.24 (1H, ddd, J = 11.0, 8.
8, 4.4 Hz), 2.05-1.98 (2H, m),
1.75-1.66 (2H, m), 1.35-1.15
(4H, m), 1.13 (3H, d, J = 6.6H
z).

[0305] Compound 23-3 colorless crystals ^{_{[α] D 24 -8.9 ° (}} c1.03, CHCl 3) IR (CHCl 3): 3454cm -1 1 H-NMR (CDCl 3 + D 2 O) δ: 7 .37-
7.26 (15H, m), 4.96, 4.73, 4.6
9, 4.68 (each 1H, d, J = 11.7H
z), 4.93, 4.87 (each 1H, d, J =
11.0 Hz), 4.55 (1H, d, J = 8.1H)
z), 3.86 (1H, dd, J = 9.5, 8.1H)
z), 3.57 (1H, br, d), 3.55 (1H,
dd, J = 9.5, 2.7 Hz), 3.46 (1H,
q, J = 6.3 Hz), 3.37 (1H, m), 3.3
0 (1H, ddd, J = 11.2, 8.8, 4.4H
z), 2.05 (1H, m), 1.93 (1H, m),
1.74-1.60 (2H, m), 1.35 (1H,
m), 1.27-1.15 (3H, m), 1.18 (3
H, d, J = 6.3 Hz).

Compound 23-2 can also be synthesized by the following method. Synthesis of Compound 23-4 To a solution of (1R, 2R) -trans-1,2-cyclohexanediol (232 mg) in pyridine (2 ml) was added benzoyl chloride (255 μl).
Stirred at C for 30 minutes. Add methanol (2 ml),
After the reaction solution was concentrated, it was diluted with methylene chloride. The extract was washed with 1N hydrochloric acid, then dried and the solvent was distilled off under reduced pressure.
The obtained residue was subjected to column chromatography using silica gel (45 g) (n-hexane: ethyl acetate 5:
Compound 23-4 (312m
g) was obtained as colorless crystals. ^{_{[Α] D 20.5 -54.1 ° (}} c1.00, CHCl 3) IR (CHCl 3): 3600,1713cm -1 1 H-NMR (CDCl 3) δ: 8.07-8.05
(2H, dlike), 7.57 (1H, tlik)
e), 7.46-7.43 (2H, trick), 4.
85 (1H, m), 3.74 (1H, m), 2.25
(1H, d, J = 3.9 Hz), 2.19-2.08
(2H, m), 1.80-1.72 (2H, m), 1.
50-1.30 (4H, m).

Synthesis of Compound 23-5 2,3,4-Tri-O-benzyl-1-O-paranitrobenzyl-fucopyranose (α: β = 36: 64, 1.
59 g), zinc trifluoromethanesulfonate (1.4)
9 g) and Compound 23-4 (900 mg) were dissolved in methylene chloride (150 ml), and chlorotrimethylsilane (520 µl) was added at 0 ° C. After stirring at the same temperature for 2 hours, the reaction solution was diluted with methylene chloride, washed with water and a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (n-hexane-ethyl acetate 10: 1) using silica gel (300 g) to give Compound 2.
3-5 (1.38 g) was obtained as a colorless oil. ^{_{[Α] D 20.5 -102 ° (}} c1.06, CHCl 3) IR (CHCl 3): 1715cm -1 1 H-NMR (CDCl 3) δ: 8.00 (2H, dl
ike), 7.54 (1H, trick), 7.40
(2H, trick), 7.37-7.22 (15H,
m), 5.14 (1H, m), 4.97 (1H, d, J
= 3.7 Hz), 4.88, 4.78, 4.61, 4.
51 (each 1H, d, J = 11.7 Hz);
77, 4.67 (each 1H, d, J = 12.2H
z), 3.98 (1H, dd, J = 10.0, 3.7H
z), 3.86 (1H, q, J = 6.3 Hz), 3.9
4 (1H, dd, J = 10.0, 2.7 Hz), 3.7
6 (1H, m), 3.32 (1H, br, d), 2.1
8-2.06 (2H, m), 1.82-1.70 (2
H, m), 1.52-1.24 (4H, m), 0.93
(3H, d, J = 6.6 Hz).

Conversion of Compound 23-5 to Compound 23-2
In a mixed solution of methanol (6.5 ml) -benzene (2.0 ml) in which the exchange compound 23-5 (890 mg) was dissolved,
28% sodium methoxide-methanol solution (2.0%
ml) and stirred at room temperature for 10 minutes. The reaction solution was diluted with diethyl ether, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using silica gel (45 g) (n-hexane-ethyl acetate-methanol 4:
By purifying in 1), compound 23-2 (743 m
g) was obtained as a colorless oil.

Synthesis of Compound 23-6 Compound 16-2 (300 mg) and Compound 23-2 (486 mg) were dissolved in a methylene chloride solution (6 ml) containing Molecular Sieves 4A (2 g), and the mixture was stirred at room temperature for 3 hours. At 0 ° C., boron trifluoride diethyl ether complex (75 μl) was added, and the mixture was stirred at the same temperature for 3 hours. After the reaction solution was filtered through celite, the filtrate was washed with a saturated aqueous solution of sodium hydrogencarbonate, dried, and the solvent was distilled off under reduced pressure.
0: 200: 5) to give compound 23-
6 (368 mg) was obtained as a colorless powder.

[0310] ^{_{[α] D 27 -42.5 ° (}} c1.02, CHCl 3) IR (KBr): 1751cm -1 1 H-NMR (CDCl 3) δ: 8.02 (1H,
m), 7.50 (1H, m), 7.40-7.22 (1
7H, m), 5.58 (1H, ddd, J = 9.3,
6.1, 2.7 Hz), 5.33 (1H, dd, J =
9.3, 2.7 Hz), 5.06 (1H, d, J = 1)
0.5 Hz), 4.99 (1H, d, J = 2.9H)
z), 4.97, 4.75 (each 1H, d, J =
12.0 Hz), 4.91 (1H, dd, J = 10.
3,7.8 Hz), 4.91 (1H, d, J = 3.2H)
z), 4.86 (1H, ddd, J = 12.3, 10.
5,4.6 Hz), 4.86, 4.75, 471, 4.
3. 67 (each 1H, d, J = 12.0 Hz);
66 (1H, d, J = 7.8 Hz), 4.53 (1H,
dd, J = 10.3, 3.4 Hz), 4.35 (1H,
dd, J = 12.2, 2.7 Hz), 4.26 (1H,
dd, J = 10.7, 6.6 Hz), 4.09-4.0.
2 (4H, m), 3.99 (1H, dd, J = 10.
3,2.9 Hz), 3.96 (1H, dd, J = 12.
2,6.1 Hz), 3.90 (1H, dd, J = 7.
6,6.6 Hz), 3.77 (3H, s), 3.68
(1H, m), 3.64 (1H, br, d), 3.61
(1H, dd, J = 10.7, 2.9 Hz), 3.57
(1H, m), 2.56 (1H, dd, J = 12.7,
4.6 Hz), 2.18, 2.12, 2.08, 2.0
2,2.00, 1.90, 1.85 (each 3H,
s), 1.71 (1H, dd, J = 12.7, 12, 3)
Hz), 1.41 (1H, m), 1.33-1.19.
(4H, m), 1.14 (3H, d, J = 6.6H
z).

Synthesis of Compound 23-7 To a solution of Compound 23-6 (120 mg) in methanol (4 ml) was added a 3% sodium methoxide-methanol solution (400 μl), and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was neutralized with a cation exchange resin (Dowex 50w H ⁺ ), insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. Then, the obtained residue was added with a 1N aqueous sodium hydroxide solution (3.0 ml) and 1,4-dioxane (2.0 ml), stirred at room temperature for 15 hours, and then with a cation exchange resin (Dowex 50w H ⁺ ). The compound 23-7 (87 mg) was obtained as a colorless powder by neutralization, filtration of insolubles, concentration of the filtrate under reduced pressure, and purification by column chromatography (methanol) using a polymer gel (70 g).

[Α] _D ²⁷ -61.1 ° (c 1.02, MeOH) ¹ H-NMR (CD ₃ OD) δ: 7.43-7.22
(15H, m), 4.93 (1H, d, J = 3.7H
z), 4.88, 4.60 (each d, J = 11.
2Hz), 4.80 (2H, s), 4.73, 4.68
(Each d, J = 11.5 Hz), 4.70 (1
H, q, J = 6.6 Hz), 4.35 (1H, d, J =
7.6 Hz), 4.06 (1H, dd, J = 10.3,
2.7 Hz), 4.00 (1H, dd, J = 9.5,
2.2Hz), 3.94 (1H, dd, 10.3, 2.
7Hz), 3.92-3.80 (5H, m), 3.78
-3.68 (3H, m), 3.66-3.47 (6H,
m), 3.43 (1H, m), 2.85 (1H, br,
d, J = 10.3 Hz), 2.12 to 2.02 (2H,
m), 2.01 (3H, s), 1.76 (1H, m),
1.78-1.68 (2H, m), 1.40-1.17
(4H, m), 1.14 (3H, d, J = 6.6H
z).

Synthesis of Compound 23 To a solution of compound 23-7 (75 mg) in methanol (7.5 ml) was added palladium hydroxide-carbon (20).
%, 115 mg) under a medium pressure hydrogen stream (50 ps).
i) and stirred at room temperature for 54 hours. After filtering off the catalyst from the reaction solution, the filtrate was concentrated, and the residue was purified by column chromatography (methanol) using a polymer gel (45 g) to obtain Compound 23 (45 mg) as a colorless powder.

[0314] ^{_{[α] D 26 -54.3 ° (}} c1.00, MeOH) IR (KBr): 3401,1614cm -1 1 H-NMR (D 2 O) δ: 4.98 (1H, d, J =
3.9 Hz), 4.64 (1H, q, J = 6.6H)
z), 4.57 (1H, d, J = 7.8 Hz), 4.0
8 (1H, dd, J = 9.8, 2.9 Hz), 4.12
(1H, m), 3.95 (1H, br, d), 3.92
(1H, dd, J = 10.5, 3.2 Hz), 3.92
-3.90 (1H, m), 3.88 (1H, br,
d), 3.85 (1H, dd, J = 10.3, 10.3)
Hz), 3.77 (1H, dd, J = 10.5, 3.7)
Hz), 3.74-3.59 (8H, m), 3.70
(1H, br, d), 3.55-3.51 (1H, br, d)
m), 3.51 (1H, dd, J = 9.8, 7.8H)
z), 2.76 (1H, dd, J = 12.5, 4.4H
z), 2.18-2.06 (2H, m), 2.04 (3
H, s), 1.82 (1H, dd, J = 12.5, 1)
2.5 Hz), 1.34-1.20 (6H, m), 1.
19 (3H, d, J = 6.6 Hz).

¹³ C-NMR (D ₂ O) δc: 177.
8, 176.8, 102.7, 102.7, 98.3,
80.9, 79.9, 78.8, 77.4, 75.6,
74.8, 74.6, 72.4, 72.2, 71.2,
70.9, 70.8, 70.4, 69.3, 65.4,
64.2, 54.5, 42.4, 32.4, 32.0,
26.0 (x2), 24.9, 18.0.

Example 24 Synthesis of Compound 24-1 Ethylene glycol (10.0 g, 0.161 mmol)
l) was dissolved in a methylene chloride solution at −78 ° C. with pyridine (50.0 ml) and benzoyl chloride (18.7 ml).
Was added and stirred at the same temperature for 1 hour. Methanol (50m
After l) was added and the temperature was raised to room temperature, the reaction solution was concentrated.
The concentrated solution diluted with ethyl acetate was washed with 2% hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off. The residue was subjected to column chromatography using silica gel (350 g) (n-hexane-ethyl acetate 5:
The compound 24-1 (21.
4g) was obtained as a colorless oil.

IR (CHCl ₃ ): 3620, 350
^{0,1720cm -1 1 H-NMR (CHCl} 3) δ: 8.08-8.06
(2H, m), 7.58 (1H, m), 7.45 (2
H, m), 4.49-4.47 (2H, m), 3.98
-3.95 (2H, m), 2.03 (1H, t, J =
5.9 Hz).

Synthesis of Compound 24-2 and Compound 24-3 Compound 23-1 (2.00 g) was added to a solution of molecular sieves 4A (4.5 g) in methylene chloride (30 ml).
And compound 24-1 (2.15 g) were added, and the mixture was stirred at room temperature for 2 hours, then N-iodosuccinimide (1.93 g) and trifluoromethanesulfonic acid (76
μl) and stirred at the same temperature for 2 hours. After the reaction solution was filtered, the filtrate was washed with an aqueous solution of sodium thiosulfate and an aqueous solution of saturated sodium hydrogen carbonate, dried, and the solvent was distilled off.
The residue was purified by column chromatography (n-hexane-ethyl acetate 6: 1) using silica gel (200 g) to give compound 24-2 and compound 24-3.
Was obtained as an approximately 1: 1 mixture (2.45 g). In ¹ H-NMR, 1H for each of the α and β forms is represented as 1H.

¹ H-NMR (CDCl ₃ ) δ: 8.04
−8.01 (4H, m), 7.56-7.50 (2H,
m), 7.42-7.19 (34H, m), 4.92-
4.62 (13H, m), 4,57-4.47 (4H,
m), 4.41 (1H, d, J = 7.8 Hz), 4.2
2 (1H, ddd, J = 11.5, 4.9, 3.4H
z), 4.05 (1H, dd, J = 10.5, 3.7H
z), 3.95 (1H, dd, J = 10.0, 2.9H
z), 3.94-3.85 (4H, m), 3.84 (1
H, dd, J = 9.8, 7.8 Hz), 3.63 (1
H, m), 3.55 (1H, m), 3.51 (1H, d
d, J = 9.8, 2.9 Hz), 3.46 (1H, q,
J = 6.3 Hz), 1.17 (3H, d, J = 6.3H)
z), 1.07 (3H, d, J = 6.6 Hz).

Synthesis of Compound 24-4 and Compound 24-5 A mixture of Compound 24-2 and Compound 24-3 (2.16
To a solution of g) in methanol (2 ml) was added a 3% sodium methoxide-methanol solution (400 μl), and the mixture was stirred at room temperature for 2 hours. After the reaction solution was neutralized with a cation exchange resin (Dowex 50w H ⁺ ), insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue obtained is 2
Silica gel column chromatography (200 g,
n-hexane-ethyl acetate 3: 2 and 90 g, n
-Hexane-ethyl acetate 3: 2) to give Compound 24-4 (454 mg) and Compound 24-5 (245 m
g), and a mixture (908 mg) of compound 24-4 and compound 24-5 was obtained.

[0321] Compound 24-4 colorless oil [α] ^{_{D 23 -39.9 ° (c0.56, CHCl}} 3) IR (CHCl 3): 3450cm -1 1 H-NMR (CHCl 3 + D 2 O) δ: 7.41-
7.27 (15H, m), 4.98, 4.65 (eac
h 1H, d, J = 11.5 Hz), 4.87, 4.7
5 (each 1H, d, J = 11.7 Hz), 4.8
3,4.65 (each 1H, d, J = 12.2H
z), 4.81 (1H, d, J = 3.9 Hz), 4.0
7 (1H, dd, J = 10.3, 3.9 Hz), 3.9
4 (1H, dd, J = 10.3, 2.9 Hz), 3.9
4 (1H, m), 3.75-3.60 (5H, m),
1.13 (3H, d, J = 6.6 Hz).

[0322] Compound 24-5 colorless oil [α] ^{_{D 23 + 6.1 ° (c0.54,}} CHCl 3) IR (CHCl 3): 3450cm -1 1 H-NMR (CHCl 3 + D 2 O) δ: 7 .28-
7.27 (15H, m), 4.98, 4.69 (eac
h 1H, d, J = 11.7 Hz), 4.88, 4.8
3 (each 1H, d, J = 11.0 Hz), 4.7
8, 4.73 (each 1H, d, J = 12.0H
z), 4.34 (1H, d, J = 7.8 Hz), 3.8
9 (1H, ddd, J = 11.5, 5.4, 2.7H
z), 3.84 (1H, dd, J = 9.8, 7.8H
z), 3.82 (1H, ddd, J = 11.5, 6.6)
Hz) 3.71 (1H, ddd, J = 12.5, 6.
6, 2.7 Hz), 3.65 (1H, dd, J = 9.
8, 2.9 Hz), 3.51 (1H, q, J = 6.6H)
z), 1.19 (3H, d, J = 6.6 Hz).

Synthesis of Compound 24-6 Compound 16-2 (200 mg) and Compound 24-4 (258 mg) were dissolved in a methylene chloride solution (10 ml) containing Molecular Sieves 4A (4 g).
After stirring for 2 hours, boron trifluoride diethyl ether complex (75 μl) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. After the reaction solution was filtered through celite, the filtrate was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography using silica gel (45 g) (toluene-acetone 3:
Purification was performed in 1) to give Compound 24-6 (193 mg) as a colorless powder.

[0324] [α] ^{_{D 27 -32.2 ° (c1.07, CHCl}} 3) IR (CHCl 3): 1747,1690cm -1 1 H-NMR (CHCl 3) δ: 8.03 (2H,
m), 7.54 (1H, m), 7.43-7.24 (1
7H, m), 5.53 (1H, ddd, J = 9.3,
5.4, 2.7 Hz), 5.37 (1H, dd, J =
9.3, 2.7 Hz), 5.08-5.04 (3H,
m), 4.97, 4.86, 4.73, 4.64 (ea)
ch 1H, d, J = 11.7 Hz), 4.88 (1
H, ddd, J = 12.3, 10.3, 4.4 Hz),
4.82 (1H, d, J = 3.7 Hz), 4.78,
4.68 (each 1H, d, J = 12.2 Hz),
4.60 (1H, dd, J = 10.0, 3.4 Hz),
4.40 (1H, dd, J = 11.0, 6.6 Hz),
4.33 (1H, dd, J = 12.3, 2.7 Hz),
4.21 (1H, dd, J = 11.0, 6.8 Hz),
4.07-3.98 (5H, m), 3.94 (1H, d
d, J = 10.0, 2.7 Hz), 3.90 (1H,
q, J = 6.6 Hz), 3.79-3.67 (3H,
m), 3.64 (1H, d, J = 2.7 Hz), 3.6
2 (1H, dd, J = 10.7, 2.7 Hz), 2.5
8 (1H, dd, J = 12.5, 4.4 Hz), 3.7
7, 2.17, 2.12, 2.09, 2.05, 2.0
4, 2.01, 1.85 (each 3H, s), 1.
70 (1H, dd, J = 12.5, 12.5 Hz).

Synthesis of Compound 24-7 To a solution of Compound 24-6 (145 mg) in methanol (4 ml) was added a 3% sodium methoxide-methanol solution (400 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was treated with a cation exchange resin (Dowex 50w).
After neutralization with H ⁺ ), insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. Next, a 1N aqueous sodium hydroxide solution (3.0 ml) and 1,4-dioxane (1.5 ml) were added to the obtained residue.
After stirring at room temperature for 15 hours, the mixture was neutralized with a cation exchange resin (Dowex 50w H ⁺ ), and the insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and column chromatography (methanol) using polymer gel (70 g) and column chromatography (methylene chloride-methanol-water 6) using silica gel (20 g) were used.
5:35:10) to give compound 24-7 (9
0 mg) as a colorless powder.

[0326] [α] ^{_{D 27 -39.1 ° (c1.02, MeOH}} ) IR (KBr): 3400,1614cm -1 1 H-NMR (CD 3 OD) δ: 7.42-7.39
(4H, m), 7.35-7.24 (11H, m),
4.88, 4.60 (each d, J = 11.2H
z), 4.77 (2H, s), 4.73, 4.72 (e
ach d, J = 12.0 Hz), 4.33 (1H,
d, J = 7.8 Hz), 4.09-4.02 (3H,
m), 4.00-3.96 (2H, m), 3.94 (1
H, dd, J = 10.1, 3.4 Hz), 3.86 (1
H, ddd, J = 8.5, 5.1, 2.9 Hz);
83-3.62 (11H, m), 3.59 (1H, d
d, J = 9.5, 7.8 Hz), 3.52 (1H,
m), 3.50 (1H, m), 2.83 (1H, dd,
J = 12.5, 4.4 Hz), 2.01 (3H, s),
1.77 (1H, m), 1.14 (3H, d, J = 6.
6 Hz).

Synthesis of Compound 24 Methanol (1) containing Compound 24-7 (70 mg) dissolved therein
0 ml) solution in palladium hydroxide-carbon (20%, 7%).
0 mg), and the mixture was stirred at room temperature under a medium-pressure hydrogen stream (50 psi) for 12 hours. After the catalyst was filtered off from the reaction solution, the filtrate was concentrated, and the residue was purified by column chromatography (methanol) using a polymer gel (45 g) to obtain Compound 24 (49 mg) as a colorless powder.

[0328] [α] ^{_{D 26 -46.5 ° (c0.52, MeOH}} ) IR (KBr): 3427,1620cm -1 1 H-NMR (D 2 O) δ: 4.94 (1H, d, J =
3.9 Hz), 4.53 (1H, d, J = 8.1H)
z), 4.16 (1H, q, J = 6.6 Hz), 4.1
0 (1H, dd, J = 9.3, 2.7 Hz), 4.12
(1H, m), 3.96 (1H, br, d, J = 2.7)
Hz), 3.91 (1H, dd, J = 9.5, 3.4H)
z), 3.85 (1H, dd, J = 10.0, 10.0)
Hz), 3.93-3.85 (4H, m), 3.81
(1H, dr, d, J = 3.2 Hz), 3.77 (1
H, dd, J = 9.5, 3.9 Hz), 3.77-3.
60 (8H, m), 3.58 (1H, dd, J = 9.
3,8.1 Hz), 2.77 (1H, dd, J = 12.
2,4.6 Hz), 2.04 (3H, s), 1.81
(1H, dd, J = 12.2, 12.2 Hz), 1.2
1 (3H, d, J = 6.6 Hz).

Example 25 Synthesis of Compound 25-1 To a solution of molecular sieves 4A (4 g) in methylene chloride (40 ml) was added acetobromo-α-D-galactose (4.00 g) and compound 15-1 (2.08 g). After dissolving and stirring at room temperature for 2 hours, silver silicate (10 g) was added at -20 ° C, and the mixture was stirred at 0 ° C for 2 hours. After the reaction solution was filtered, the filtrate (methylene chloride) was washed with water and dried, and the solvent was distilled off under reduced pressure. Subsequently, the obtained residue was dissolved in methanol (20 ml), a 28% sodium methoxide-methanol solution (500 μl) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was converted to a cation exchange resin (Dowex).
After neutralization with 50 w H ⁺ ), insolubles were filtered off,
The filtrate was concentrated under reduced pressure and purified by column chromatography using silica gel (18 g) (methylene chloride-methanol 15: 2) to give compound 25.
-1 (1.83 g) was obtained as a colorless powder.

[0330] [α] ^{_{D 25 -14.5 ° (c1.01, MeOH}} ) IR (KBr): 3400,2102cm -1 1 H-NMR (CD 3 OD) δ: 4.10 (1H, d,
J = 7.6 Hz), 3.90 (1H, dt, J = 9.
5,6.8 Hz), 3.82 (1H, m), 3.75
(1H, dd, J = 11.2, 6.6 Hz), 3.72
(1H, dd, J = 11.2, 5.6 Hz), 3.55
(1H, dt, J = 9.5, 6.8 Hz), 3.52-
3.47 (2H, m), 3.45 (1H, dd, J = 1
0.0, 3.4 Hz), 3.28 (2H, t, J = 7.
1 Hz), 1.67-1.56 (4H, m), 1.47
-1.37 (4H, m).

Synthesis of Compound 25-2 To a solution of Compound 25-1 (2.18 g) in ethanol (80 ml) was added a Lindlar catalyst (3.00 g) and paratoluenesulfonic acid (1.36 g). The mixture was stirred at room temperature under a hydrogen stream (50 psi) for 4 hours. After filtering off the catalyst from the reaction solution, the filtrate was concentrated under reduced pressure to give Compound 2
5-2 (2.93 g) was obtained as a crude product.

Synthesis of Compound 25-3 To a solution of Compound 25-2 (2.93 g) in ethanol (20 ml) was added triethylamine (1 ml),
Di-tert-butyl carbonate (2.03 g) was added, and the mixture was stirred at room temperature for 12 hours. Subsequently, pyridine (25 ml) and acetic anhydride (15 ml) were added to the residue obtained by concentrating the reaction solution.
Was added and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with 2% hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off under reduced pressure. The residue was purified on silica gel (150
Purification by column chromatography using n) (n-hexane-ethyl acetate-methanol 60: 40: 1) gave compound 25-3 (2.63 g) as a colorless oil.

[0333] [α] ^{_{D 25 -10.1 ° (c0.57, CHCl}} 3) IR (CHCl 3): 1747,1709cm -1 1 H-NMR (CHCl 3) δ: 5.39 (1H, d
r, d, J = 3.2 Hz), 5.20 (1H, dd, J)
= 10.5, 8.1 Hz), 5.02 (1H, dd, J)
= 10.5, 3.4 Hz), 4.53 (1H, dr,
s), 4.45 (1H, d, J = 8.1 Hz), 4.1.
9 (1H, dd, J = 11.2, 6.3 Hz), 4.1
3 (1H, dd, J = 11.2, 7.1 Hz), 3.9
0 (1H, dd, J = 7.1, 6.3 Hz), 3.89
(1H, m), 3.47 (1H, dt, J = 9.5,
6.8 Hz), 3.15-3.04 (2H, m), 2.
15, 2.05, 1.99 (each 3H, s),
1.62-1.55 (2H, m), 1.55-1.42
(2H, m), 1.44 (9H, m), 1.38-1.
28 (4H, m).

Synthesis of Compound 25-4 To a solution of Compound 25-3 (1.68 g) in ethanol (30 ml) was added a 28% sodium methoxide-methanol solution (0.5 ml), and the mixture was stirred at room temperature for 10 minutes. . The reaction solution was treated with a cation exchange resin (Dowex 50).
After neutralization with (wH ⁺ ), insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. Subsequently, the obtained residue was dissolved in methanol (15 ml), and dibutyltin oxide (844) was dissolved.
mg) and heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and benzene (20 ml) and allyl bromide (0.8 ml) were added to the residue.
0 ml) and tetra-n-butylammonium bromide (990 mg), and the mixture was heated under reflux for 2 hours. Then, the reaction solution was concentrated and the residue obtained was added with pyridine (10 m
l) and acetic anhydride (6 ml) were added, and the mixture was stirred at room temperature for 12 hours. The reaction solution is concentrated under reduced pressure, the residue is diluted with ethyl acetate, washed with 2% hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, then dried, and the solvent is distilled off under reduced pressure. Column chromatography (n-hexane-ethyl acetate-methanol 2:
The compound 25-4 (1.15) was purified by 1).
g) was obtained as a colorless oil.

[0335] [α] ^{_{D 24 + 7.1 ° (c0.57,}} CHCl 3) IR (CHCl 3): 1745,1708cm -1 1 H-NMR (CHCl 3) δ: 5.78 (1H, dd
dd, J = 15.6, 10.5, 6.1, 5.1H
z), 5.41 (1H, dd, J = 3.4, 1.0H
z), 5.24 (1H, m), 5.17 (1H, m),
5.08 (1H, dd, J = 10.0, 8.1 Hz),
4.54 (1H, dr, s), 4.38 (1H, d, J
= 8.1 Hz), 4.16 (2H, d, J = 6.6H)
z), 4.12 (1H, m), 3.91 (1H, m),
3.87 (1H, dt, J = 9.5, 6.4 Hz),
3.80 (1H, ddd, J = 6.6, 6.6, 1.0
Hz), 3.51 (1H, dd, J = 10.0, 3.4)
Hz), 3.45 (1H, dt, J = 9.5, 6.8H)
z), 3.143.04 (2H, m), 2.14, 2..
08, 2.07, 2.05 (each 3H, s),
1.62-1.52 (2H, m), 1.50-1.42
(2H, m), 1.44 (9H, s), 1.38-1.
28 (4H, m).

Synthesis of Compound 25-5 Methanol (3) in which Compound 25-4 (645 g) was dissolved
0 ml) solution at -78 ° C with ozone-oxygen gas until the reaction turned pale blue (about 5 minutes). After removing excess ozone gas by passing oxygen gas (for 10 minutes), dimethyl sulfide (5 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure, and the residue is subjected to column chromatography (n) using silica gel (45 g).
-Hexane-ethyl acetate-methanol 200: 30
0: 5) to give the desired product (aldehyde form) as a crude product (5
77 mg). Subsequently, the above crude product (57
Tert-butyl alcohol (20 ml) and 2-methyl-2-butene (5 ml) were added to and dissolved in sodium perchlorate (2.67 g) and sodium dihydrogen phosphate dihydrate (3.7 mg). Aqueous solution (10 m
l) was added and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, washed with water and an aqueous solution of sodium thiosulfate,
Then, after drying and distilling off the solvent under reduced pressure, to the residue were added methanol (810 ml) and a 10% trimethylsilyldiazomethanehexane solution (5 ml), and the mixture was stirred at room temperature for 1.5 hours. After concentration of the reaction solution, the residue was silica gel (120
Purification by column chromatography using n) (n-hexane-ethyl acetate-methanol 300: 200: 5) gave compound 25-5 (410 mg) as a colorless oil.

[0337] [α] ^{_{D 25 + 12.4 ° (c1.07,}} CHCl 3) IR (CHCl 3): 1747,1708cm -1 1 H-NMR (CHCl 3) δ: 5.44 (1H, d
d, J = 3.4, 1.0 Hz), 5.10 (1H, d
d, J = 10.0, 8.1 Hz), 4.53 (1H, d
r, s), 4.43 (1H, d, J = 8.1 Hz),
4.18 (1H, dd, J = 11.5, 6.6 Hz),
4.15 (1H, dd, J = 11.5, 6.6 Hz),
4.11, 4.10 (each 1H, d, J = 17.
1 Hz), 3.87 (1H, dt, J = 9.5, 6.3)
Hz), 3.79 (1H, dd, J = 6.8, 6.6,
1.0 Hz), 3.73 (3H, s), 3.66 (1
H, dt, J = 9.5, 6.6 Hz), 3.46 (1
H, dd, J = 10.0, 3.4 Hz), 3.14 −
3.05 (2H, m), 2.14, 2.14, 2.07
(Each 3H, s), 1.64-1.52 (2H,
m), 1.50-1.42 (2H, m), 1.44 (9
H, s), 1.40-1.28 (4H, m).

Synthesis of Compound 25-6 To a solution of compound 25-5 (109 mg) in methylene chloride (1 ml) was added trifluoroacetic acid (1.0 ml) at 0 ° C.
l) was added and the mixture was stirred at the same temperature for 30 minutes, and then the reaction solution was concentrated under reduced pressure to give Compound 25-6 (105 m
g) was obtained as a crude product.

Synthesis of Compound 25-7 To a solution of Compound 11-2 (120 mg) in dimethylformamide (1.5 ml) was added 1-hydroxybenzotriazole (32 mg) and N, N'-dicyclohexylcarbodiimide (42 mg). After stirring at 0 ° C. for 12 hours, a solution of compound 25-6 (105 mg) and N-methylmorpholine (26 μl) in dimethylformamide (1.5 ml) was added, and the mixture was stirred at 0 ° C. for 10 hours. After removing the insoluble matter by filtration and concentrating the filtrate, the residue was diluted with ethyl acetate, washed with 5% citric acid and saturated sodium hydrogen carbonate, then dried and the solvent was distilled off under reduced pressure.
The residue was purified by column chromatography (methylene chloride-methanol 30: 1) using silica gel (40 g) to give compound 25-7 (172 ml) as a colorless powder.

[0340] [α] ^{_{D 24 -11.3 ° (c0.99, CHCl}} 3) IR (KBr): 1749,1688,1645cm -1 1 H-NMR (CHCl 3) δ: 7.14-7.24
(15H, m), 6.63 (1H, dr, s), 6.0
5 (1H, dr, s), 5.70 (1H, dr, d),
5.44 (1H, dt, d, J = 3.4 Hz), 5.0
9 (1H, dd, J = 9.8, 8.1 Hz), 4.9
7, 4.65 (each 1H, d, J = 11.5H
z), 4.87, 4.67 (each 1H, d, J =
12.0 Hz), 4.77, 4.74 (each 1
H, d, J = 11.7 Hz), 4.77 (1H, d, J)
= 3.7 Hz), 4.42 (1H, d, J = 8.1H)
z), 4.18 (1H, dd, J = 11.2, 6.6H)
z), 4.14 (1H, dd, J = 11.2, 6.6H)
z), 4.07 (1H, m), 4.02 (1H, dd,
J = 10.0, 3.7 Hz), 3.93 (1H, dd,
J = 10.0, 3.4 Hz), 3.88 (1H, m),
3.86 (1H, q, J = 6.6 Hz), 3.78 (1
H, dd, J = 6.6, 6.6 Hz), 3.72 (3
H, s), 3.67 (1H, dr, s), 3.66 (1
H, dd, J = 9.8, 3.4 Hz), 3.57 (1
H, dt, J = 9.8, 7.1 Hz), 3.45 (1
H, dt, J = 9.5, 6.6 Hz), 3.42 (1
H, dt, J = 9.8, 6.6 Hz), -3.40 (2
H, m), 3.29-3.16 (4H, m), 2.35
(1H, m), 2.27 (1H, m), 2.14, 2..
14, 2.06 (each 3H, s), 2.04 (1
H, m), 1.93 (1H, m), 1.65-1.53
(4H, m), 1.52-1.45 (4H, m), 1.
43 (9H, s), 1.40-1.28 (4H, m),
1.10 (3H, d, J = 6.6 Hz).

Synthesis of Compound 25 A 3% sodium methoxide-methanol solution (1.5 ml) was added to a mixed solution of methanol (2 ml) and benzene (1 ml) in which compound 25-7 (140 mg) was dissolved, and the mixture was stirred at room temperature for 2 hours. Stirred. After the reaction solution was neutralized with a cation exchange resin (Dowex 50w H ⁺ ), insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. Subsequently, 1,4-dioxane (4.5 ml) and 0.1 aqueous sodium hydroxide solution were added to the obtained residue, and the mixture was stirred at room temperature for 15 minutes. After neutralization with a cation exchange resin (Dowex 50w H ⁺ ), insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (12 ml), palladium-carbonic acid (10%, 120 mg) was added, and the mixture was stirred at room temperature under a medium-pressure hydrogen stream (50 psi) for 24 hours. After the catalyst was filtered off from the reaction solution, the filtrate was concentrated, and the residue was purified by column chromatography (methanol) using a polymer gel (70 g) to give Compound 25 (83 m 2).
g) was obtained as a colorless powder.

[0342] [α] ^{_{D 25 -50.3 ° (C0.38, MeOH}} ) IR (KBr): 3420,1701,1653cm -1 1 H-NMR (CD 3 OD) δ: 4.88 (1H, d ,
J = 3.9 Hz), 4.43 (1H, d, J = 7.8H)
z), 4.28, 4.24 (each 1H, d, J =
16.6 Hz), 4.14 (1H, d, J = 3.2H)
z), 4.07 (1H, q, J = 6.6 Hz), 3.9
4 (2H, m), 3.86 (1H, dd, J = 10.
3, 3.2 Hz), 3.83-3.75 (4H, m),
3.73-3.66 (3H, m), 3.66 (1H, d
d, J = 10.0, 7.8 Hz), 3.53 (1H, d
d, J = 10.0, 3.2 Hz), 3.53 (1H,
m), 3.26 (1H, m), 3.23-3.13 (3
H, m), 2.40-2.30 (2H, m), 2.05
(1H, m), 1.89 (1H, m), 1.70-1.
59 (4H, m), 1.59-1.49 (4H, m),
1.45 (9H, s), 1.44-1.30 (8H,
m), 1.23 (3H, d, J = 6.6 Hz).

Example 26 Synthesis of Compound 26-1 Compound 25-1 (3.26 g) was treated with methanol (50 ml).
l), dibutyltin oxide (2.93 g) was added, and the mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and benzene (20 ml), paramethoxybenzyl chloride (4.35 ml) and tetra-n-butylammonium bromide (3.45 g) were added to the residue, and the mixture was heated under reflux for 2 hours. Next, pyridine (20 ml) and acetic anhydride (12 ml) were added to the residue obtained by concentrating the reaction solution, and the mixture was stirred at room temperature for 12 hours. The reaction solution is concentrated under reduced pressure, the residue is diluted with ethyl acetate, washed with 2% hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, then dried, and the solvent is distilled off under reduced pressure. The compound 26 was purified by column chromatography (n-hexane-ethyl acetate-methanol 3: 1) used.
-1 (3.61 g) was obtained as a colorless oil.

[0344] [α] _D ²⁴ +29.1 ° _{(c1.04, CHCl 3) IR (} CHCl 3): 2100,1745cm -1 1 H-NMR (CDCl 3) δ: 7.19 (2H, A 2
B ₂ , J = 8.8 Hz), 5.41 (2H, A ₂ B ₂ ,
J = 8.8 Hz), 5.48 (1H, br.s), 5.
08 (1H, dd, J = 10.0, 8.1 Hz);
62, 4.33 (each 1H, d, J = 12.0H
z), 4.33 (1H, d, J = 8.1 Hz), 4.1
8 (1H, dd, J = 12.9, 6.6 Hz), 4.1
5 (1H, dd, J = 12.9, 6.6 Hz), 3.8
6 (1H, dt, J = 9.8, 6.3 Hz), 3.81
(3H, s), 3.78 (1H, trick), 3.5
0 (1H, dd, J = 10.0, 3.4 Hz), 3.4
3 (1H, dt, J = 9.5, 6.8 Hz), 3.25
(2H, t, J = 7.1 Hz), 2.15, 2.08,
2.03 (each 3H, s), 1.64-1.50
(4H, m), 1.41-1.28 (4H, m).

[0345]Synthesis of compound 26-2  Methanol in which compound 26-1 (2.60 g) was dissolved
(30 ml) solution in 28% sodium methoxide
Add a ethanol solution (0.3 ml) and stir at room temperature for 2 hours
did. The reaction solution was treated with a cation exchange resin (Dowex 50w).
 H⁺), The insolubles are removed by filtration, and the filtrate is reduced.
It concentrated under pressure. Subsequently, the obtained residue is treated with dimethylforma.
After dissolving in amide (30 ml), sodium hydride (6
0%, 1.13 g) and stirred at 0 ° C. for 30 minutes.
Benzyl bromide (2.24 ml) was added, and the mixture was added at room temperature for 20 minutes.
After stirring for an hour, methanol (10 ml) and 28%
Sodium methoxide-methanol solution (7 ml) was added.
And stirred for 30 minutes. Dilute the reaction with ethyl acetate,
Wash with saturated brine, then dry and evaporate the solvent under reduced pressure
I left. A column using silica gel (150 g) for the residue
Chromatography (n-hexane-ethyl acetate-meta
The compound 26-
2 (2.67 g) was obtained as a colorless oil.

[0346] [α] _D ²⁵ -6.5 ° _{(c1.02, CHCl 3) IR (} CHCl 3): 2100cm -1 1 H-NMR (CDCl 3) δ: 7.38-7.21
(17H, m), 6.84 ( 2H, A 2 B 2, J = 8.
5Hz), 4.93, 4.60, 4.40, 5.44
(1H, dd, J = 3.4, 1.0 Hz), 5.10
(1H, dd, J = 10.0, 8.1 Hz), 4.53
(1H, br.s), 4.43 (1H, d, J = 8.1)
Hz), 4.18 (1H, dd, J = 11.5, 6.6)
Hz), 4.15 (1H, dd, J = 11.5, 6.6)
Hz), 4.11, 4.10 (each 1H, d, J =
17.1 Hz), 3.87 (1H, dt, J = 9.5,
6.3 Hz), 3.79 (1H, dd, J = 6.8,
6.6, 1.0 Hz), 3.73 (3H, s), 3.6
6 (1H, dt, J = 9.5, 6.6 Hz), 3.46
(1H, dd, J = 10.0, 3.4 Hz), 3.14
-3.05 (2H, m), 2.14, 2.14, 2.0
7 (each 3H, s), 1.64-1.52 (2
H, m), 1.50-1.42 (2H, m), 1.44
(9H, s), 1.40-1.28 (4H, m).

Synthesis of Compound 26-3 Compound 26-2 (1.34 g) was dissolved in methanol (20 ml) -toluene (5 ml) mixed solution, and Lindlar catalyst (1.00 g) and paratoluenesulfonic acid monohydrate were added. (369 mg) and added under a medium pressure hydrogen stream (50 psi).
) And stirred at room temperature for 2 hours. The catalyst was removed by filtration from the reaction solution, and the filtrate was concentrated under reduced pressure to give Compound 26-3.
(1.77 g) was obtained as a crude product.

Synthesis of Compound 26-4 A solution of Compound 26-3 (1.77 g) in dimethylformamide (15 ml) was added to Compound 11-2 (1.3 ml).
1g), N-methylmorpholine (213 μl), N-hydroxysuccinimide (309 mg) and N, N ′
-Dicyclohexylcarbodiimide (435 mg) was added, and the mixture was stirred at 0 ° C for 12 hours. After concentrating the reaction solution, the residue was diluted with methylene chloride, washed with 5% citric acid and saturated sodium hydrogen carbonate, dried, and the solvent was distilled off under reduced pressure. The obtained residue is silica gel (150 g).
The compound 26-4 (2.29 g) was obtained as a colorless powder by purifying with column chromatography using (n-hexane: ethyl acetate: methanol 50: 50: 1).

[Α] _D ²⁴ -13.9 ゜ (c1.03, CHCl ₃ ) IR (CHCl ₃ ): 3300, 1688, 1643c
^{m -1 1 H-NMR (CDCl} 3) δ: 7.41-7.22
(32H, m), 6.84 ( 2H, A 2 B 2, J = 8.
5Hz), 6.57 (1H, trick), 5.84
(1H, br, d), 5.68 (1H, br.s),
4.97, 4.90, 4.74, 4.60, 4.40,
4.40 (each 1H, d, J = 11.7 Hz),
4.95, 4.87 (each 1H, d), 4.80
(1H, d, J = 12.2 Hz), 4.77 (1H,
d, J = 3.9 Hz), 4.66 (2H, d), 4.6
5,4.63 (each 1H, d, J = 11.5H
z), 4.32 (1H, d, J = 7.8 Hz), 4.0
5 (1H, m), 4.02 (1H, dd, J = 10.
0, 3.7 Hz), 3.93 (1H, dd, J = 10.
0, 2.9 Hz), 3.91 (1H, dt, J = 9.
8, 6.6 Hz), 3.86 (1H, q, J = 6.6H)
z), 3.85 (1H, dlike), 3.80 (3
H, s), 3.77 (1H, dd, J = 9.8, 7.6)
Hz), 3.66 (1H, br.d), 3.61-3.
54 (3H, m), 3.53-3.44 (3H, m),
3.41 (1H, dt, J = 9.8, 6.6 Hz),
3.26-3.13 (4H, m), 2.32 (1H, d
dd, J = 14.9, 8.1, 5.1 Hz), 2.23
(1H, ddd, J = 14.9, 7.6, 5.1H
z), 2.03 (1H, m), 1.93 (1H, m),
1.73-1.66 (2H, m), 1.66-1.54
(2H, m), 1.42 (9H, s), 1.52-1.
27 (12H, m), 1.10 (3H, d, J = 6.6)
Hz).

Synthesis of Compound 26-5 To a solution of compound 26-4 (790 mg) in methylene chloride (10 ml) was added water (0.5 ml) and 2,3-
Dichloro-5,6-dicyano-p-benzoquinone (DD
Q, 191 mg) and stirred at room temperature for 30 minutes. The reaction solution was diluted with methylene chloride, washed with saturated sodium hydrogen carbonate, dried, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography using silica gel (45 g) (toluene: acetone: methanol 6).
00: 100: 7) to give compound 26-
5 (520 mg) was obtained as a colorless powder.

[Α] _D ²⁵ -14.5 ° (c 1.02, CHCl ₃ ) IR (CHCl ₃ ): 3317, 1688, 1643c
^{m -1 1 H-NMR (CDCl} 3) δ: 7.41-7.24
(25H, m), 6.58 (1H, br.s), 5.8
9 (1H, br.s), 5.69 (1H, br.d),
4.97, 4.95, 4.67, 4.65 (each
1H, d, J = 11.2 Hz), 4.80, 4.66
(Each 1H, d, J = 12.2 Hz), 4.78
(1H, d), 4.77 (1H, d, J = 3.7H
z), 4.74, 4.63 (each 1H, d, J =
11.7 Hz), 4.49, 4.43 (each 1
H, d, J = 12.0 Hz), 4.32 (1H, d, J)
= 7.6 Hz), 4.05 (1H, m), 4.02 (1
H, dd, J = 10.3, 3.7 Hz), 3.93 (1
H, dd, J = 10.3, 2.9 Hz), 3.92 (1
H, q, J = 6.3 Hz), 3.89-3.83 (2
H, m), 3.66 (1H, br.d), 3.66 −
3.60 (2H, m), 3.57 (1H, dt, J =
9.8, 7.1 Hz), 3.55 (1H, dd, J =
9.8, 7.6 Hz), 3.57 (1H, dt, J =
9.8, 6.8 Hz), 3.41 (1H, dt, J =
9.8, 6.6 Hz), 3.27-3.14 (4H,
m), 2.36-2.20 (3H, m), 2.03 (1
H, m), 1.91 (1H, m), 1.66-1.54
(4H, m), 1.42 (9H, s), 1.52-1.
27 (12H, m), 1.10 (3H, d, J = 6.3)
Hz).

Synthesis of compound 26-6 To a solution of compound 26-5 (386 mg) in dimethylformamide (4 ml) was added sulfur trioxide pyridine complex (210 ml), and the mixture was stirred at 55 ° C for 3 hours. After concentrating the reaction solution, it was dissolved in methanol (5 ml), and a cation exchange resin (Dowex 50w Na ⁺ ) was added.
Stirred for 0 minutes. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography using silica gel (45 g) (methylene chloride: methanol).
Compound 26-6 (265 mg) was obtained by purification by column chromatography (methanol) using 10: 1) and a polymer gel (200 cc). (Contaminants derived from the reagent still remained, but proceeded to the next step as it was.)

¹ H-NMR (CD ₃ OD) δ: 7.46
−7.40 (2H, dlike), 7.41 to 7.38
(2H, dride), 7.38-7.19 (26H,
m), 5.03 (1H, d, J = 11.5 Hz), 4.
89, 4.89, 4.60 (each 1H, d, J =
11.2 Hz), 4.88-4.72 (5H, m),
4.66 (1H, d), 4.64 (1H, d, J = 1)
1.7 Hz), 4.43, 4.39 (each 1H,
d, J = 12.0 Hz), 4.39 (1H, d, J =
7.6 Hz), 4.31 (1H, br.d), 3.97
(1H, m), 3.95-3.92 (2H, m), 3.
90 (1H, q, J = 6.6 Hz), 3.84 (1H,
J = 9.8, 6.1 Hz), 3.79 (1H, br.
s), 3.68 (1H, dd, J = 6.3, 6.1H)
z), 3.62 (1H, dd, J = 9.5, 7.6H)
z), 3.61 (1H, m), 3.51 (1H, m),
3.51 (1H, dd, J = 9.8, 6.3 Hz),
3.42 (1H, dd, J = 9.8, 6.1 Hz),
3.39 (1H, dt, J = 10.0, 6.3 Hz),
3.23-3.07 (4H, m), 2.29-2.18
(3H, m), 1.99 (1H, m), 1.82 (1
H, m), 1.64-1.54 (4H, m), 1.42.
(9H, s), 1.53-1.25 (12H, m),
1.13 (3H, d, J = 6.6 Hz).

Synthesis of Compound 26 To a solution of Compound 26-6 (240 mg) in methanol (20 ml) was added palladium-carbon (10%, 20%).
0 mg), and the mixture was stirred at room temperature for 12 hours under a medium-pressure hydrogen stream (50 psi). After the catalyst was filtered off from the reaction solution, the filtrate was concentrated, and the residue was subjected to column chromatography (methylene chloride: methanol: water) using silica gel (20 g).
65:35:10 (lower layer)) and polymer gel (200
Compound 26 (120 mg) was obtained as a colorless powder by purifying by column chromatography (methanol) using cc).

[0355] [α] _D ²³ -42.8 ° (c0.31, MeOH) IR (KBr ): 3454,1700,1654cm -1 1 H-NMR (CD 3 OD) δ: 4.73 (1H, d ,
J = 3.2 Hz), 4.31 (1H, d, J = 7.8H)
z), 4.23 (1H, br.s), 4.23 (1H,
dd, J = 9.3, 3.2 Hz), 3.98 (1H,
m), 3.94 (1H, q, J = 6.8 Hz), 3.9
0 (1H, dt, J = 9.5, 6.8 Hz), 3.76
-3.71 (3H, m), 3.71-3.63 (3H,
m), 3.69 (1H, dd, J = 9.3, 7.8H
z), 3.54 (1H, m), 3.44 (1H, dt,
J = 9.8, 6.3 Hz), 3.25-3.12 (2
H, m), 2.31-2.20 (2H, trick),
2.00 (1H, m), 1.83 (1H, m), 1.6
8-1.58 (4H, m), 1.56-1.46 (4
H, m), 1.44 (9H, s), 1.46-1.32.
(8H, m), 1.20 (3H, d, J = 6.8H
z).

Conversion of Compound 26-4 to Compound 15 To a mixed solution of compound 26-4 (320 mg) dissolved in methanol (10 ml) -tetrohydrofuran (10 ml) was added palladium-carbon (10%, 300 mg). The mixture was stirred at room temperature under a medium-pressure hydrogen stream (50 psi) for 12 hours. After filtering off the catalyst from the reaction solution, the filtrate was concentrated,
The residue was subjected to column chromatography on silica gel (18 g) (methylene chloride: methanol: water 7: 3: 1).
(Lower layer)) and purified by column chromatography (methanol) using a polymer gel (200 cc) to obtain Compound 15 (146 mg) as a colorless powder.

Example 27 Synthesis of Compound 27 A solution of Compound 5 (51 mg) in methanol (0.5 ml), succimidyl propionate (CH ₃ CH ₂ CO ₂₎
Su, 17.4 mg) and N-methylmorpholine (8
μl) and stirred at 0 ° C. for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to column chromatography using silica gel (10 g) (ethylene chloride-methanol-
Water (7: 3: 1 (lower layer)) and polymer gel (90 cc) were purified by column chromatography (methanol) to obtain Compound 27 (43 mg) as a colorless powder.

[Α] _D ²⁵ -95.2 ゜ (c 0.13, M
eOH) ¹ H-NMR (CD ₃ OD) δ: 4.73 (2H, d,
J = 2.7 Hz), 4.28 (1H, dd, J = 9.
0, 5.3 Hz), 3.93 (2H, q, J = 6.6H)
z), 3.77-3.60 (8H, m), 3.44 (2
H, dt, J = 9.8, 6.3 Hz), 3.22-3.
14 (4H, m), 2.26 (2H, q, J = 7.8H
z), 2.24 (2H, trick), 2.04 (1
H, m), 1.89 (1H, m), 1.68-1.57
(4H, m), 1.55-1.47 (4H, m), 1.
46-1.32 (8H, m), 1.20 (6H, d, J
= 6.6 Hz), 1.13 (3H, t, J = 7.6H)
z).

The synthesis process of the above embodiment is shown as a scheme as follows.

[0360]

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[0373]

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[0375]

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[0379]

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[0380]

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[0384]

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[0386]

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Evaluation of binding ability to ELAM-1 In vitro ELAM- of the compound according to the present invention
The binding ability to 1 was evaluated as follows.

First, normal human umbilical vein endothelial cells (HUVEC) were cultured on a plate until they became completely dense, and recombinant human IL-1β was added thereto, whereby ELAM-1 was expressed on the cell surface. . Thereafter, several compounds according to the present invention were added as inhibitors to the plates at various concentrations and reacted. Add ³ H to plate
-Thymidine labeled HL-60 cells were added. After washing the plate with MEM (minimum essential medium) containing 0.4% bovine serum albumin,
The radioactivity of the bound HL-60 cells was measured with a liquid scintillation counter.

For comparison, the two -O- (CH ₂ ) _6- of the compound of Example 1 were replaced with-(OCH ₂ CH ₂ ) _3.
-Compound (Comparative Compound 1) and Example 1
Two of the six compounds -O- _{(CH 2) 6} - together - (O
CH ₂ CH ₂ ) ₃ -Substituted Compound (Comparative Compound 2)
Was prepared, and its binding ability to ELAM-1 was evaluated in the same manner as the compound according to the present invention.

The ability of the inhibitor to bind to ELAM-1 was evaluated by a relative value obtained from the following equation. Wherein the positive control and the negative control are H
The values of the radioactivity of the plate where UVEC was treated with IL-1β but no inhibitor was added and the plate where ILEC was not treated and no inhibitor was added.

[0392]

(Equation 1)

The relationship between the relative value and the inhibitor concentration is shown in FIG.
As shown in FIG. From these results, it is clear that the compound according to the present invention has a competitive specific binding ability to ELAM-1.

[Brief description of the drawings]

FIG. 1: In vitro E of compounds according to the invention
It is a graph showing the binding ability to LAM-1.

FIG. 2. In vitro E of compounds according to the invention.
It is a graph showing the binding ability to LAM-1.

FIG. 3. In vitro E of compounds according to the invention.
It is a graph showing the binding ability to LAM-1.

FIG. 4. E in vitro of compounds according to the invention.
It is a graph showing the binding ability to LAM-1.

FIG. 5 shows in vitro E of compounds according to the invention.
It is a graph showing the binding ability to LAM-1.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Shiro Miyoshi 206-1, Aku, Mishima-shi, Shizuoka Prefecture No.5 Tamura Heights 5 (72) Inventor Osamu Yamada 2074-47, large section leap door, Hasuda City, Saitama

Claims (12)

(57) [Claims] 1. A compound represented by the following general formula (I). Embedded image [Wherein F is a monosaccharide selected from sialic acid, uronic acid, galactose, glucose, fucose, mannose, hexosamine, ribose and rhamnose, or a monosaccharide derivative thereof, or a monosaccharide or monosaccharide derivative thereof. Represents an oligosaccharide residue consisting of 2 to 4, n represents an integer of 0 to 10, and T ₁ represents a bond, -NHCO-, -NHCOO-, -OO
CNH-, -NHCONH-, -OCNH-, -OC
(= O)-,-(O =) CO- or -O-, wherein R ¹ and R ² may be the same or different, each being a hydrogen atom, an amino group which may be amidated, A hydroxyl group which may be etherified or esterified, a carboxyl group which may be esterified or amidated, or an amino group wherein at least one hydrogen atom may be amidated, esterification or ether ^Represents an optionally substituted hydroxyl group or a C _1-3 alkyl group substituted by a carboxyl group which may be amidated or esterified, i represents an integer of 1 or 2, R ^3ai and R ^4ai may represent the same meanings as defined in ^{R 1} and ^{R 2,} and ^{R 1} and ^{R 2} may be different even in the same, R5 ⁱ is defined for ^{R 1} It represents the same meaning as thing, R
¹ may be the same or different, and R ⁶ has the same meaning as defined for R ¹ , but R ^1
May be the same or different, or R ⁶ and R ¹ or R ^3ai together form — (CH
₂ ) represents p- (where p represents an integer of 1 to 4),
R ⁶ and R ¹ or R ^3ai may form a 5- to 7-membered saturated ring together with the carbon chain to which they are bound. T _2i has the same meaning as defined for T ₁ ,
₁ may be the same or different; n _i represents an integer of 0 to 10; F _i has the same meaning as defined for F; However, when n _i = 0, F _i represents a hydrogen atom, a _i represents an integer of 0 to 4, or R ^3ai or R ⁵ⁱ is represented by the following formula (II). The group to be formed: (Where T _3i has the same meaning as defined for T ₁ ,
₁ or different and be identical to the, R ¹⁰ and R ²⁰ represent the same meanings as defined in R ¹ and R ^2, be the same or different from the R ¹ and R ² J represents an integer of 0, 1 or 2; R ^30bij and R ^40bij represent R ^3ai and R
Represent the same meanings as defined in ^4ai, may be the ^{R 3ai} and ^{R 4ai} not be the same or different, _{b ij} represents an integer of ^{0~4, R} 50ij ^is defined in ^{R 5i} R ⁵ⁱ may be the same or different, and R ⁶⁰ has the same meaning as defined for R ⁶ ,
⁶ may be the same or different, and T _4ij has the same meaning as defined for T ₁ ,
The T ₁ may be different even in the same, n _ij is an integer of 0, F _ij is the same meaning as defined in F, it is the same and F May also be different, provided that n _ij =
When 0, F _ij represents a hydrogen atom. _Wherein at least one of F, F _i and F _ij represents fucose or an oligosaccharide having fucose at its non-reducing end. ] Wherein is any fucose residues F and F _i, the other is fucose, galactose, N- acetylgalactosamine, monosaccharide or phosphoric acid or sulfuric acid of monosaccharide is selected from the sialic acid or uronic acid The compound according to claim 1, which is an ester or carboxyalkyl derivative, or an oligosaccharide having the monosaccharide or the monosaccharide derivative at the non-reducing end and then having galactose, glucose, N-acetylgalactosamine or N-acetylglucosamine. . Wherein an integer n and _{n i} are independently 0 or 2 to 8, _{T 1} and _{T 2i} bond, -NHCO- or -CON
H-, wherein ^one of R ¹ , R ² , R ^3ai , R ^4ai , R ⁵ⁱ and R ^{6 is} an amino group which may be amidated, a hydroxyl group or an ester which may be etherified or esterified The compound according to claim 1, wherein the compound represents a carboxyl group which may be amidated or amidated, all the others represent a hydrogen atom, i represents 1, and ai represents 1 or 3. 4. One of R ^3ai and R ⁵ⁱ is a group represented by the formula (II), wherein F ^ij is fucose, galactose, N-acetylgalactosamine, sialic acid Or a monosaccharide selected from uronic acid, or a phosphate or sulfate or carboxyalkyl derivative of these monosaccharides, or the above monosaccharide or monosaccharide derivative at the non-reducing end, and then galactose, glucose, N-acetylgalactosamine Or an oligosaccharide having N-acetylglucosamine; R ¹⁰ , R ²⁰ , R ^30bij , R ^40bij , R
^{One of 50ij} and R ^{60 represents} an amino group which may be amidated, a hydroxyl group which may be etherified or esterified, or a carboxyl group which may be esterified or amidated; There represents a hydrogen atom, j represents 1, _{b i} represents 1 or 3, _{n ij} represents an integer of 0 or 2 to 8, _{T 3i} and _{T 4ij} bond, -NHCO- or -C
2. The compound according to claim 1, which represents ONH-. 5. R ¹ and R ⁶ together form — (CH ₂ )
p- (where p represents an integer of 1 to 4),
¹ and R ⁶ form a saturated ring of 5- to 7-membered together with the carbon chain attached, a compound according to claim 1. 6. A compound represented by the following general formula (III). Embedded image [In the formula, F _u is sialic acid, uronic acid, galactose, glucose, fucose, mannose, hexosamine, monosaccharide or monosaccharide derivative thereof is selected from ribose and rhamnose, or their monosaccharide or monosaccharide represents an oligosaccharide consisting of 2-4 derivatives, nu denotes an integer of 0, _{T u} is a bond, -NHCO -, - NHCOO -, - OO
CNH-, -NHCONH-, -OCNH-, -OC
(= O)-,-(O =) CO- or -O-, wherein (R ^1V ) v and R ^2u may be the same or different, and may be a hydrogen atom or an amidated respectively. A good amino group, a hydroxyl group which may be etherified or esterified, a carboxyl group which may be esterified or amidated, or an amino group or ester wherein at least one hydrogen atom may be amidated _Represents a C _1-3 alkyl group substituted by a hydroxyl group which may be esterified or etherified or a carboxyl group which may be esterified or amidated; u represents an integer of 2 or 3; represents an integer of 1 to 3, ru and su are each independently 0, 1 or 2, tu is 0 or 1, at least one fucosyltransferase of _{F u} Represents an oligosaccharide having scan or fucose to its non-reducing end. ] 7. The compound according to claim ¹ , wherein R ¹ , R ² , R ^3ai , R ^4ai , R ⁵ⁱ and R ⁶ , and R ¹⁰ , R ²⁰ , R ^30bij , R
^The amino group, the carboxyl group or the hydroxyl group of a compound in which one or two of ^40bij , R ^50ij and R ⁶⁰ are an amino group, a carboxyl group or a hydroxyl group, a fatty acid having 12 to 20 carbon atoms, and an aliphatic having 12 to 20 carbon atoms Amine, a carboxyl group of a fat-soluble compound selected from aliphatic alcohols having 12 to 20 carbon atoms and cholesterol,
The compound according to any one of claims 1 to 5, which can be obtained by dehydration condensation of an amino group or a hydroxyl group. 8. The compound according to claim 6, wherein (R ^1v )
the amino group, the carboxyl group or the hydroxyl group of a compound in which one or two of v is an amino group, a carboxyl group or a hydroxyl group; a fatty acid having 12 to 20 carbon atoms;
The compound according to claim 6, which can be obtained by dehydration-condensing a carboxyl group, an amino group or a hydroxyl group of a fat-soluble compound selected from 20 aliphatic amines, aliphatic alcohols having 12 to 20 carbon atoms and cholesterol. 9. The compound according to claim ¹ , wherein R ¹ , R ² , R ^3ai , R ^4ai , R ⁵ⁱ and R ⁶ , and R ¹⁰ , R ²⁰ , R ^30bij , R
^An amino group, a carboxyl group or a hydroxyl group of a compound in which one or two of ^40bij , R ^50ij and R ⁶⁰ are an amino group, a carboxyl group or a hydroxyl group are dehydrated and condensed with Y of a fat-soluble compound represented by the following formula. The compound according to claim 1, which can be obtained by: _{Y- (CH 2) k- (OCH} 2 CH 2) in 1 -X [the above formulas, k and l each independently represents an integer of from to 0 to 5, Y represents an amino group, a carboxyl group or a hydroxyl group, X is a group: (Where m and q independently represent an integer of 0 to 5,
Z is a bond, -NHCO-, -NHCOO-, -OOCN
H-, -NHCONH-, -OCNH-, -OC (=
O) -, - (O = ) CO- or -O- and represents, R represents a a a) cholesterol residue or _C 12 _{~ 20} alkyl group 10. The compound according to claim 6, wherein one or two of (R ^1v ) v is an amino group, a carboxyl group or a hydroxyl group, and the amino group, the carboxyl group or the hydroxyl group is represented by the following formula: The compound according to claim 6, which can be obtained by subjecting the fat-soluble compound Y to be obtained to dehydration condensation. _{Y- (CH 2) k- (OCH} 2 CH 2) in 1 -X [the above formulas, k and l each independently represents an integer of from to 0 to 5, Y represents an amino group, a carboxyl group or a hydroxyl group, X is a group: (Where m and q independently represent an integer of 0 to 5,
Z is a bond, -NHCO-, -NHCOO-, -OOCN
H-, -NHCONH-, -OCNH-, -OC (=
O)-,-(O =) CO- or -O-, and R represents a cholesterol residue or a _C12-20 alkyl group). 11. A drug-liposome derivative, wherein the compound according to claim 9 or 10 is combined with a liposome containing a pharmaceutical compound by utilizing its lipophilic group. 12. A compound represented by the following general formula (Ia). Embedded image [Wherein F ₁ and F ₂ may be the same or different and each is a monosaccharide or a monosaccharide selected from sialic acid, uronic acid, galactose, glucose, fucose, mannose, hexosamine, ribose and rhamnose, Represents a monosaccharide derivative thereof, or an oligosaccharide residue composed of 2 to 4 monosaccharides or monosaccharide derivatives thereof, wherein n ₁ and n ₂ may be the same or different, and Represents an integer of 10 to 10, and T ₁ and T ₂ may be the same or different and each represents a bond, -NHCO-, -NHCOO-,-
OOCNH-, -NHCONH-, -OCNH-, -O
Represents C (= O)-,-(O =) CO- or -O-, a represents an integer of 0 to 4, and R ^{* 1} and R ^{* 2} may be the same or different each represent a hydrogen atom, a hydroxyl group, or represents an amino group or a carboxyl group, or the ^{R * 1} and ^{R * 2} together - _(CH 2) p- _(where, p is an integer of 1 to 4 Represents a 5- to 7-membered saturated ring together with the carbon chain to which R ^{* 1} and R ^{* 2} are bonded,
Or R ^{* 1} and / or R ^{* 2} is a group represented by the following formula (IIa): (Where F ₃ has the same meaning as defined for F ₁ , but F ₁
And n ₃ may have the same meaning as defined for n ₁ , but n ₁
Or different and are identical to the, T ₃ and T _4, represent the same meanings as those defined by T ₁ and T _2, the T ₁ and T ₂ are independently identical or different B represents an integer of 0 to 4, R ^{* 3} and R ^{* 4} have the same meaning as defined for R ^{* 1} and R ^{* 2} , but R ^{* 1} and R ^{* 2} are Which may be the same or different), provided that at least one of F ₁ and F ₂ represents a fucose residue or an oligosaccharide residue having fucose at its non-reducing end. Do