JPH10109998A - Fucose derivative, medicine containing the same as active ingredient, and intermediate for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new fucose derivative having a specific structure, capable of inhibiting the bonding of a selection of cell adhesion molecule to a sialyl- Lewis x sugar chain, and useful for preventing and treating inflammatory diseases, reperfusion diseases after ischemia, etc. SOLUTION: The new fucose derivative of formula I [X<1> is an atomic group of formula II, etc.; R<1> is a branched long chain alkyl; R<2> is a group of the formula: CONHR<3> (R<3> is a lower alkyl, phenyl), carboxyl, H; (n) is 0, 1, 2] inhibits the bonding of a selection of cell adhesion molecule to a sialyl-Lewis x sugar chain and is useful as an active ingredient for preventing or treating inflammatory diseases or reperfusion diseases after ischemia, etc. The compound of formula I is obtained by glycosylating a compound of formula III (Boc is tert-butoxycarbonyl; Bn is benzyl; R<4> is a group of the formula: CONHR<3> , etc.,) with a glycosyl donor of formula IV and subsequently treating the reaction product with trifluoroacetic acid(TFA) to remove the protecting group.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel fucose derivative, a drug containing the same as an active ingredient, and an intermediate for producing the same. More specifically, the following formula (I) useful as a compound that inhibits the binding between a selectin that is a cell adhesion molecule and a sialyl-Lewis x (hereinafter abbreviated as sialyl Lex) sugar chain:

[0002]

Embedded image (Where X ¹ is the following formula (1), (2) or (3)

[0003]

Embedded image Wherein R ¹ represents a branched long-chain alkyl group, R ² represents -CONHR ³ , a carboxyl group or a hydrogen atom, n represents an integer of 0, 1 or 2, R ³ represents a lower alkyl group or a phenyl group. ) Or a pharmaceutically acceptable salt thereof and an intermediate for the production thereof.

[0004] The present invention further relates to intermediates for the production of these novel fucose derivatives or pharmaceutically provided salts thereof.

[0005]

2. Description of the Related Art Recently, the role of selectin, a cell adhesion molecule, in various inflammatory diseases has attracted attention. For example, types such as E-selectin (sometimes called ELAM-1), P-selectin (sometimes called GMP-140) or L-selectin (sometimes called LECAM-1) are known. However, these selectins are expressed in various cells during the process of inflammation. For example, E-selectin is TNFα (tumo
r necrosis factor α), IL-1
(Interleukine 1) is an adhesion molecule mainly expressed on vascular endothelial cells by stimulation such as interleukine 1. P-selectin is mainly expressed on platelet α-granules and Weibel parade bodies of vascular endothelial cells by stimulation of thrombin and histamine. L-selectin is an adhesion molecule expressed on white blood cells.

In general, cell infiltration is one of the most important findings of inflammation, and it is known that inflammatory cells in blood infiltrate into tissues after adhering to vascular endothelial cells. As a pre-stage of adhesion to vascular endothelial cells, a phenomenon in which inflammatory cells roll along the blood vessel wall is known, and is called rolling. This rolling is an important process as the first step of cell invasion,
It is mediated by the interaction between the various selectins described above and the sialyl Lex sugar chain (selectin ligand) present on the inflammatory cell surface.

Accordingly, these selectins and sialyl L
Attempts have been made to treat various inflammatory diseases by inhibiting the binding to ex sugar chains and preventing the adhesion of inflammatory cells. As selectin ligands (counter ligands) that inhibit the adhesion of inflammatory cells, peptidic counter ligands are known in addition to some sialyl Lex derivatives (for example, WO95 / 04751,
WO95 / 10296), these are compounds having only fucose as a sugar moiety.

[0008] Drugs containing these selectin counter ligands as active ingredients (selectin inhibitors) inhibit various inflammatory cells such as atopic dermatitis, contact hypersensitivity and photosensitivity by inhibiting the adhesion of inflammatory cells. And autoimmune chronic diseases such as rheumatoid arthritis and chronic thyroiditis.

[0009] In ischemia-reperfusion injury, it has been reported that various selectins are involved in endothelial cell damage associated with neutrophil infiltration [Stroke, 25,
202-210, (1994)]. In fact, it has been reported that a sialyl Lex derivative, which is a counter ligand of selectin, can suppress the impairment of a reperfusion model [J. Clin. Invest. , 93, 1140-
1148, (1994)]. Therefore, selectin inhibitors have an effective inhibitory effect on ischemia-reperfusion injury (eg, US Pat. No. 5,444,050).

[0010]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel fucose derivative which inhibits the binding between selectin and sialyl Lex, a pharmaceutically acceptable salt thereof, a drug containing these as an active ingredient, and production of these. It is to provide an intermediate for use.

[0011]

As a result of various studies, the present inventors have found that a glycopeptide having a long-chain alkyl group represented by the above general formula (I) can inhibit the binding between selectin and sialyl Lex. Have a strong inhibitory effect,
The present invention has been completed.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention has the following formula (I)

[0013]

Embedded image [Wherein X ¹ is (1), (2) or (3)

[0014]

Embedded image Wherein R ¹ represents a branched long-chain alkyl group, R ² represents -CONHR ³ , a carboxyl group or a hydrogen atom, n represents an integer of 0, 1 or 2, R ³ represents a lower alkyl group or a phenyl group. Or a pharmaceutically acceptable salt thereof.

In the present specification, the term “branched long-chain alkyl group” means a group having a total number of carbon atoms of 23 to 4 branched at the α-position or the β-position.
0 represents an alkyl group, and specific examples thereof include 1- (decyl) tridecyl group, 1- (dodecyl) tridecyl group, and 1
-(Dodecyl) pentadecyl group, 1- (dodecyl) heptadecyl group, 1- (dodecyl) nonadecyl group, 1- (tetradecyl) pentadecyl group, 1- (tetradecyl) heptadecyl group, 1- (tetradecyl) nonadecyl group, 1
-(Hexadecyl) heptadecyl group, 1- (hexadecyl) nonadecyl group, 1- (octadecyl) nonadecyl group, 2- (hexyl) tridecyl group, 2- (octyl)
Tridecyl group, 2- (decyl) tridecyl group, 2- (dodecyl) tridecyl group, 2- (dodecyl) pentadecyl group, 2- (dodecyl) heptadecyl group, 2- (dodecyl) nonadecyl group, 2- (tridecyl) pentadecyl group , 2- (tetradecyl) pentadecyl group, 2- (tetradecyl) heptadecyl group, 2- (tetradecyl) nonadecyl group, 2- (hexadecyl) heptadecyl group, 2-
(Hexadecyl) nonadecyl group, 2- (octadecyl)
Examples include a nonadecyl group.

The lower alkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms, specifically, a methyl group,
Ethyl group, n-propyl group, iso-propyl group, n-
Examples thereof include a butyl group, a sec-butyl group and a tert-butyl group.

The pharmaceutically acceptable salts of the compounds of the present invention include, for example, inorganic base salts such as sodium salt, potassium salt and calcium salt and organic base salts such as arginine salt and lysine salt.

Among the compounds represented by the above formula (I),
Examples of preferred compounds are those in which R ¹ is a branched long-chain alkyl group having a total of 23 to 31 carbon atoms, R ² is a carboxyl group, N ²
A methylcarbamoyl group, an N-phenylcarbamoyl group or a hydrogen atom, wherein n is an integer of 0 to 2; As the pharmaceutically acceptable salt, a sodium salt is preferable as the inorganic base salt, and an arginine salt is preferable as the organic base salt.

In the formula (I), there are stereoisomers derived from the peptide moiety in addition to the stereoisomers derived from the anomeric carbon at the anomeric position of fucose. The stereoisomer derived from the peptide moiety is defined by the above formula (I)

[0020]

Embedded image (In the formula, R ¹ , R ² , X ¹ and n are the same as those described above.) In the case where R ² is —CONHR ³ or a carboxyl group, it represents a stereoisomer derived from asymmetric carbons a and b. , R ² represents a stereoisomer derived from asymmetric carbon a when it is a hydrogen atom, and the present invention includes all these stereoisomers and a mixture thereof.

Specific examples of the compound (I) of the present invention are listed below. -[N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucopyranosyl) -L-seryl] -L-glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucopyranosyl) -L-seryl] -D-glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucopyranosyl) -D-seryl] -L-glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucopyranosyl) -D-seryl] -D-glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -O-
(Β-L-fucopyranosyl) -L-seryl] -L-glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -O-
(Β-L-fucopyranosyl) -L-seryl] -D-glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -O-
(Β-L-fucopyranosyl) -D-seryl] -L-glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -O-
(Β-L-fucopyranosyl) -D-seryl] -D-glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -S-
(Α-L-fucopyranosyl) -L-cysteinyl] -L
-Glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -S-
(Α-L-fucopyranosyl) -L-cysteinyl] -D
-Glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -S-
(Α-L-fucopyranosyl) -D-cysteinyl] -L
-Glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -S-
(Α-L-fucopyranosyl) -D-cysteinyl] -D
-Glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -S-
(Β-L-fucopyranosyl) -L-cysteinyl] -D
-Glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucofuranosyl) -L-seryl] -L-glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucofuranosyl) -L-seryl] -D-glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucofuranosyl) -D-seryl] -L-glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucofuranosyl) -D-seryl] -D-glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucofuranosyl) -L-seryl] -D-glutamic acid · [N- (2-tetradecylhexadecanoyl) -O-
(L-fucofuranosyl) -L-seryl] -L-aspartic acid 1-methylamide 4-N- [N- (2-tetradecylhexadecanoyl) -O- (α-L-fucofuranosyl) -L-seryl]
Aminobutyric acid 5-N- [N- (2-tetradecylhexadecanoyl) -O- (α-L-fucofuranosyl) -L-seryl]
Aminovaleric acid [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucofuranosyl) -L-seryl] -D-glutamic acid 1-anilide • [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucofuranosyl) -L-seryl] -D-glutamic acid 1-methylamide sodium salt • [N- (2-tridecylpentadecanoyl) -O-
(Α-L-fucofuranosyl) -D-seryl] -L-glutamic acid 1-methylamide • [N- (2-dodecyltetradecanoyl) -O- (α
-L-fucofuranosyl) -D-seryl] -L-glutamic acid 1-methylamide • [N- (2-undecyltridecanoyl) -O- (α
-L-fucofuranosyl) -D-seryl] -L-glutamic acid 1-methylamide • [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucofuranosyl) -L-seryl] -D-glutamic acid 1-methylamide L-arginine salt • [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucopyranosyl) -L-seryl] -D-glutamic acid 1-methylamide L-arginine salt The present invention further provides the following formula (II)

[0022]

Embedded image (Where X ² is the following formula (4) or (5)

[0023]

Embedded image And A ¹ represents tert-
R ⁴ represents —CONHR ³ , a benzyloxycarbonyl group or a hydrogen atom, Ac represents an acetyl group, Bn represents a benzyl group, n represents 0, 1 or 2; And R ³ represents a lower alkyl group or a phenyl group. ), The following formula (I
II)

[0024]

Embedded image (Wherein, Y represents an oxygen atom or a sulfur atom, A ² represents a hydrogen atom or a branched long-chain alkylcarbonyl group,
R ⁴ represents —CONHR ³ , a benzyloxycarbonyl group or a hydrogen atom; Ac represents an acetyl group; Bn represents a benzyl group; n represents an integer of 0, 1 or 2;
³ represents a lower alkyl group or a phenyl group. ) Or the following formula (IV)

[0025]

Embedded image (In the formula, A ¹ represents a tert-butoxy group or a branched long-chain alkyl group, R ⁴ represents —CONHR ³ , a benzyloxycarbonyl group or a hydrogen atom, Ac represents an acetyl group, and Bn represents a benzyl group. And n represents an integer of 0, 1 or 2, and R ³ represents a lower alkyl group or a phenyl group.) The present invention provides an intermediate for producing the compound (I).

The meanings of the abbreviations and symbols used in the present specification are shown below. Bn: benzyl group Boc: tert-butoxycarbonyl group Boc ₂ O: di-tert-butyl dicarbonate DMF: N, N-dimethylformamide WSC: 1-ethyl-3- (dimethylaminopropyl)
Carbodiimide hydrochloride HOBt: 1-hydroxy-1H-benzotriazole monohydrate TFA: trifluoroacetic acid THF: tetrahydrofuran AgOTf: silver trifluoromethanesulfonate SnCl ₂ : anhydrous tin chloride TMU: 1,1,3,3-tetramethyl Urea Ph: phenyl group TEA: triethylamine Pd (OH) ₂ / C: palladium hydroxide carbon Boc-Ser: N-tert-butoxycarbonyl-
L-serine Boc-D-Ser: N-tert-butoxycarbonyl-D-serine Boc-serine: N-tert-butoxycarbonyl-
L-serine or N-tert-butoxycarbonyl-
D-serine or a mixture thereof Boc-Ser (OBn): N-tert-butoxycarbonyl-O-benzyl-L-serine Boc-D-Ser (OBn): N-tert-butoxycarbonyl-O-benzyl-D- Serine Boc-serine (OBn): N-tert-butoxycarbonyl-O-benzyl-L-serine or N-ter
t-butoxycarbonyl-O-benzyl-D-serine or a mixture thereof DCC: dicyclohexylcarbodiimide HPLC: high-performance liquid chromatography Ac: acetyl group NaOMe: sodium methylate DAST: diethylaminosulfatrifluoride DMSO: dimethylsulfoxide NaH: hydrogenation Sodium PhCH ₂ Br: benzyl bromide n-Bu ₃ P: n-tributylphosphine The production method of the compound of the present invention is described below. (1) Compound (Ia) wherein X ^{1 is an} atom in the general formula (I)
Production Caudan (1), Compound] (1-1) The compound of (Ia) alpha-anomer [Ia
Production of (α)]: The α-anomer [Ia (α)] is, for example, represented by the following formula (Scheme 1a)

[0027]

Embedded image (Wherein, R ¹ represents a branched long-chain alkyl group, and R ² represents —C
ONHR ^3, a carboxyl group or a hydrogen atom, R ⁴
Represents -CONHR ³ , a benzyloxycarbonyl group or a hydrogen atom; n represents an integer of 0, 1 or 2;
³ represents a lower alkyl group or a phenyl group. ).

First, a glycosyl donor (VI) [Jo
urnal of the American Che
medical Society, 112, 3693-36
Compound (V) is glycosylated using p. 95 (see 1990). The reaction is carried out, for example, by reacting compound (V) and glycosyl donor (VI) in a solvent such as methylene chloride in the presence of AgOTf, SnCl ₂ and TMU, preferably at a low temperature of −40 to −50 ° C. for several hours to 24 hours. React
Compound (II-1) is obtained. Since the compound (II-1) is usually obtained as a mixture of α- and β-anomer, if necessary, the α-anomer is separated and purified by recrystallization or HPLC or other various chromatographies, and then subjected to the next reaction. Alternatively, compound (II-1) is subjected to the following reaction in the form of a mixture of α- and β-anomer, and then the desired α-anomer [Ia (α) in compound (II-2) or final product (Ia) is obtained. )] Can be separated and purified.

Next, the Boc group of the compound (II-1) is cleaved and removed. The reaction is carried out, for example, by adding 10 equivalents to a solvent amount of TFA in a solvent such as methylene chloride or without a solvent and stirring the mixture at 0 ° C. to room temperature for 0.5 to 3 hours. After the completion of the reaction, TFA (and solvent) is distilled off under reduced pressure, and usually, the mixture is neutralized with a base such as sodium hydrogen carbonate or TEA and immediately used for the next reaction.

Then, the carboxylic acid (R ¹ -COOH) is condensed in an inert solvent such as DMF using a condensing agent to obtain a compound (II-2). Examples of the condensing agent include, for example, DCC and WSC. If necessary, the condensing reaction is usually carried out at 0 ° C. to room temperature for 2 to 24 hours in the presence of a condensing auxiliary such as HOBt. The molar ratio of the compound to be subjected to the reaction was such that 0.8 to 1.2 mol of carboxylic acid (R ¹ -COOH), 1.0 to 1.5 mol of condensing agent, 1.0 to 1.5 mol.

Finally, compound (II-2) is hydrogenolyzed to obtain compound (Ia). This hydrocracking is carried out in ethanol or 1,4-dioxane, if necessary, with water, hydrochloric acid,
Acetic acid and the like are added, and the reaction is performed at room temperature to 60 ° C. under a hydrogen stream or under pressure under a catalyst such as 10% palladium carbon, 20% palladium hydroxide carbon or platinum. (1-2) β-anomer of compound (Ia) [Ia
Production of (β)]: Since a mixture of α-anomer and β-anomer is formed in the glycosylation reaction of the above-mentioned scheme 1a, β-anomer [Ia (β)] is produced in the same manner as in the production of α-anomer. be able to.

Alternatively, the β-anomer [Ia (β)]
Is, for example, the following formula (Scheme 2a)

[0033]

Embedded image (Wherein R ¹ , R ² , R ⁴ and n are the same as described above).

First, glycosyl donor (VII) [C
arbohydrate Research, 200,
391-402 (1990)] to glycosylate compound (V). That is, for example, in a solvent such as methylene chloride, AgOTf, preferably compound (V) a glycosyl donor (VII) in the presence of SnCl ₂ -
The reaction is carried out at 25 to -15 ° C for several hours to 24 hours to selectively obtain compound (III-1).

Then, the carboxylic acid (R ¹ -COOH) is condensed in an inert solvent such as DMF using a condensing agent to obtain a compound (III-2). Examples of the condensing agent include, for example, DCC and WSC. If necessary, the condensing reaction is usually carried out at 0 ° C. to room temperature for 2 to 24 hours in the presence of a condensing auxiliary such as HOBt. The molar ratio of the compound subjected to the reaction was 0.8 to 1.2 mol of carboxylic acid (R ¹ -COOH) ^per 1 mol of compound (III-1),
1.0-1.5 mol of condensing agent, 1.0-1.5 condensing aid
Is a mole.

Finally, the compound (III-2) is hydrogenolyzed, followed by deprotection of the acetyl group to give the β-anomer [Ia
(Β)]. This hydrogenolysis is carried out in ethanol or 1,4-dioxane, if necessary, by adding water, hydrochloric acid, acetic acid or the like, under a catalyst such as 10% palladium carbon, 20% palladium hydroxide carbon or platinum, or in a stream of hydrogen. Perform under pressure at room temperature to 60 ° C. The deprotection of the acetyl group is usually carried out using a 28% NaOMe / methanol solution in a lower alcohol such as methanol or ethanol and stirring at room temperature for 0.5 to 1.5 hours. (2) Compound (Ib) wherein X ^{1 is an} atom of the general formula (I)
The compound (Ib) of the present invention can be prepared by the following formula (Scheme 1b) according to the method for producing the compound (Ia) shown in the above-mentioned Scheme 1a.

[0037]

Embedded image (Wherein R ¹ , R ² , R ⁴ and n are the same as described above).

That is, the glycosyl donor (VIII) is described in the literature [Biological & Pharmaceut].
ical Bulletin, 18 (11), 1487
-1491 (1995)] except that the compound [Ia
(Α)] and [Ia (β)], and a mixture of α-anomer and β-anomer is obtained by glycosylation of compound (V).
In 3) or (II-4), the target anomer is separated and then led to the final target, or a mixture of both anomers is led to the final target (Ib) and then separated and purified to obtain the α-anomer [Ib ( α)] or β-anomer [Ib
(Β)] can be produced. (3) Compound (Ic) wherein X ^{1 is a group represented by the} general formula (I)
Production Caudan (3), Compound] (3-1) The compound of (Ic) alpha-anomer [Ic
Production of (α)]: The α-anomer [Ic (α)] can be produced by, for example, Scheme 3

[0039]

Embedded image (In the formula, R ¹ , R ² , R ³ , R ⁴ and n are the same as described above.)
Can be manufactured via

First, the known compound (IX) [Tetrahedro
n: Asymmetry Vol.5, No.12, pp.2351-2366 (1994)))
And a known compound (X) [Journal of the American Chemic
al Society, 107, 7105-7109 (1985)].
Obtain I). That is, for example, in an inert solvent such as DMF,
Compound (IX) and compound (X) are reacted at 0 ° C. to room temperature for 0.5 to 3 hours in the presence of a base such as NaH to obtain compound (XI).

Next, compound (XI) and compound (XII)
Is condensed with a condensing agent to obtain compound (IV-1). Examples of the condensing agent include, for example, DCC and WSC. If necessary, the condensing reaction is usually carried out at 0 ° C. to room temperature for 2 to 24 hours in the presence of a condensing auxiliary such as HOBt. The molar ratio used for the reaction was as follows: Compound (XI) 1
0.8 to 1.2 moles of compound (XII), 1.0 to 1.5 moles of condensing agent, and 1.0 to 1.5 moles of condensing auxiliary with respect to moles.

In this case, in addition to the above-described method using a condensing agent, condensation can also be performed by a mixed acid anhydride method described below. That is, after dissolving compound (XI) in an aprotic solvent such as THF or DMF, and adding an equivalent amount of a tertiary amine such as TEA or N-methylmorpholine, ethyl chloroformate or the like is preferably added at -20 to 5 ° C. An acid chloride such as chlorocarbonate or pivaloyl chloride is added to prepare a mixed acid anhydride. Next, the above-mentioned compound (XII) is added and reacted at 0 ° C. to room temperature for preferably 2 to 24 hours to obtain the desired compound (IV-1).

Next, the Boc group of the compound (IV-1) is cleaved and removed. The reaction is carried out, for example, by adding TFA in a solvent such as methylene chloride or in the absence of a solvent in an amount of 10 equivalents to no solvent, and usually stirring at 0 ° C. to room temperature for 0.5 to 3 hours. After the completion of the reaction, TFA (and solvent) is distilled off under reduced pressure, and usually, the mixture is neutralized with a base such as sodium hydrogen carbonate or TEA and immediately used for the next reaction. That is, immediately after cleavage, for example, a carboxylic acid (R ¹⁾ is added in an inert solvent such as DMF.
-COOH) and a compound (IV-
Obtain 2).

Finally, the compound (IV-2) is hydrogenolyzed to cleave the benzyl group, and then the acetyl group is cleaved and removed to obtain the desired product [Ic (α)]. This hydrocracking,
Water in ethanol or 1,4-dioxane, if needed;
Add hydrochloric acid, acetic acid, etc., 10% palladium carbon, 20
% Palladium hydroxide carbon or platinum, and the mixture is stirred under a hydrogen stream or under pressure at room temperature to 60 ° C. for 2 to 10 hours. Cleavage of the acetyl group is usually carried out in a lower alcohol such as methanol or ethanol in 28% NaOMe.
/ Methanol solution with stirring at room temperature for 0.5 to 1.5 hours. (3-2) β-anomer of compound (Ic) [Ic
Production of (β)]: The β-anomer [Ic (β)] can be produced, for example, according to the following method (Scheme 2b) according to the method for producing the compound [Ia (β)] shown in Scheme 2a.

[0045]

Embedded image (Wherein R ¹ , R ² , R ⁴ and n are the same as described above).

First, glycosyl donor (VII) [Ca
Compound (XIII) is glycosylated using rbohydrate Research, 200, pp. 391-402 (1990))]. That is,
For example, in a solvent such as methylene chloride, AgOTf, SnC
The compound (XIII) is reacted with the glycosyl donor (VII) in the presence of l ₂ to selectively obtain the compound (III-3).

Next, the compound (III-4) is obtained by condensing carboxylic acid (R ¹ -COOH) in an inert solvent such as DMF using a condensing agent. Examples of the condensing agent include, for example, DCC or WSC, and if necessary, in the presence of a condensing auxiliary such as HOBt, usually at 0 ° C.
The condensation reaction is carried out by stirring at room temperature for 2 to 24 hours. The molar ratio used for the reaction is such that 0.8 to 1.2 mol of carboxylic acid (R ¹ -COOH), 1.0 to 1.5 mol of condensing agent, 1 0.0-1.5 mol.

Finally, the compound (III-4) is hydrogenolyzed to cleave the benzyl group, and then the acetyl group is cleaved and removed to obtain the desired product [Ic (β)]. This hydrogenolysis is performed by adding water, hydrochloric acid, acetic acid and the like, if necessary, in ethanol or 1,4-dioxane, and adding 10% palladium carbon,
The reaction is carried out at room temperature to 60 ° C. in the presence of a catalyst such as 20% palladium hydroxide carbon or platinum, under a hydrogen stream or under pressure. The cleavage of the acetyl group is usually carried out by using a 28% NaOMe / methanol solution in a lower alcohol such as methanol or ethanol and stirring at room temperature for 0.5 to 1.5 hours.

The compound of the present invention (I)
a), (Ib) and (Ic) can be converted into their pharmaceutically acceptable salts by conventional methods.

Next, a method for producing the starting compound used in the production methods (1) to (3) will be described. (1) Compound (V) (Starting Schemes 1a, 1b, 2a)
Production method of compound) (1-1) Compound (Va) wherein R ⁴ is-
Compound which is CONHR ³ ]: Compound (Va) is, for example, represented by the following formula (Scheme 4)

[0051]

Embedded image (Wherein, R ³ and n are the same as described above).

First, the known compound (XIV) is condensed with a lower alkylamine or aniline to give the compound (XIV)
V) is prepared. In this case, in addition to the above-described method using a condensing agent, condensation can also be performed by a mixed acid anhydride method described below. That is, the compound (XIV) is dissolved in an aprotic solvent such as THF or DMF, and TEA or N-
After adding an equivalent amount of a tertiary amine such as methylmorpholine, a mixed acid anhydride is prepared preferably by adding a chlorocarbonate such as ethyl chloroformate or an acid chloride such as pivaloyl chloride at -20 to 5 ° C. Next, a lower alkylamine or aniline is added, preferably for 2 to 24 hours,
The reaction is carried out at 0 ° C. to room temperature to obtain the desired compound (XV).

Next, the Boc group was removed from compound (XV) with TFA in the same manner as described above to obtain compound (XIIa).
Subsequently, the compound (Va) can be produced by performing a condensation reaction with Boc-serine by a method using a condensing agent such as DCC or WSC described above (route A).

On the other hand, the compound (XIIa) and the serine derivative (XVII) are condensed by a method using a condensing agent or a mixed acid anhydride method, and the resulting compound (XVI) is hydrogenolyzed and then odorized in the presence of a base. The compound (Va) can also be derived by reacting benzyl chloride (Root B). This hydrogenolysis is carried out by the compound (II-2) of the above-mentioned scheme 1a.
May be carried out in the same manner as in the case of producing the compound (Ia) from the compound (Ia).
It can be carried out in an aprotic polar solvent such as F in the presence of TEA or sodium bicarbonate with stirring at 0 ° C. to room temperature for 3 to 24 hours.

Although the stereochemistry is not shown in Scheme 4, if the optically active form of compound (XIV) is used as a raw material and reacted with optically active Boc-serine or optically active compound (XVII), A stereoisomer of compound (Va) can be obtained. (1-2) Compound (Vb) [Compound wherein R ⁴ is a benzyloxycarbonyl group in formula (V)]: Compound (V
b) is, for example, the following formula (Scheme 5)

[0056]

Embedded image (Wherein, n is the same as described above).

That is, the known compound (XIIb) or a salt thereof is neutralized by adding an equal amount of a base such as TEA, if necessary, and then Bo is added with a condensing agent such as DCC or WSC in the same manner as described above.
Compound (Vb) can be produced by performing a condensation reaction with c-serine.

The optically active form of compound (XIIb) contains B
By condensing oc-Ser or Boc-D-Ser, a stereoisomer of compound (Vb) can be easily obtained. (1-3) Compound (Vc) [Compound (V) in which R ⁴ is a hydrogen atom]: Compound (Vc) is, for example, a compound represented by the following formula (Scheme 6)

[0059]

Embedded image (Wherein, n is the same as described above).

That is, known aminocarboxylic acids (XVII
After Boc-forming the amino group of I) according to a conventional method,
The compound (XI) is obtained by benzyl esterifying a carboxyl group.
X). Subsequently, the Boc group of compound (XIX) is cleaved in the same manner as in the production of compound (Va) to give compound (X
Compound (Vc) can be produced by obtaining X) and condensing it with Boc-serine.

The stereoisomer of compound (Vc) can be easily obtained by reacting optically active Boc-serine. (2) Compound (XIII) (starting compound of scheme 2b)
Preparation method a compound of objects) (XIII), for example the following formula (Scheme 7)

[0062]

Embedded image (Wherein, R ³ , R ⁴ and n are the same as described above).

First, the compound (XX) is subjected to a condensation reaction between Boc-cystine (XXI) and the amino compound (XII) by the above-mentioned method using a condensing agent such as DCC or WSC.
II) is obtained. Next, the disulfide bond of the compound (XXII) is reductively cleaved to give the compound (XI)
II) can be produced. The reaction is usually performed in a lower alcohol such as methanol or ethanol, if necessary, by adding water,
The reaction can be carried out by stirring at 0 ° C. to room temperature for 0.5 to 2 hours in the presence of n-Bu ₃ P.

The amino compound (XIIa) or (XIIa)
b) stereoisomer and optically active Boc-cystine (XX
By reacting I), a stereoisomer of compound (XIII) can be obtained.

The medicament containing the fucose derivative (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is orally or parenterally administered to a patient. The dose varies depending on the administration method, the age, weight, or medical condition of the patient, but is generally 0.1 to 6 as fucose derivative (I) per patient.
A suitable range is 00 mg / day, which is administered once a day or divided into two to four times a day.

The dosage forms for oral administration include tablets, granules,
Fine granules and capsules are included. Such preparations are manufactured by a conventional method, and the tablets, granules and fine granules are prepared from the fucose derivative (I) of the present invention or a pharmaceutically acceptable salt thereof and a usual pharmaceutical additive such as lactose and synthetic silicic acid. Aluminum, glucose, mannitol, crystalline cellulose, excipients such as starch, carboxymethyl cellulose, disintegrants such as sodium alginate, magnesium stearate,
It is prepared by mixing a lubricant such as talc or a binder such as hydroxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc., and a capsule is prepared by appropriately filling the above granules and powders into capsules.

The injection is a fucose derivative (I) of the present invention.
Or a pharmaceutically acceptable salt thereof is dissolved or suspended in sterile water, and to this is added a tonicity agent such as mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, mannose, etc., if necessary. Further, it is manufactured by adding a stabilizer such as sodium sulfite and albumin and a preservative such as benzyl alcohol and aseptically encapsulating in an ampoule or vial.

[0068]

The compound of the formula (I) or a salt thereof according to the present invention comprises E-selectin, P-selectin and / or
Alternatively, it strongly inhibits the binding between L-selectin and sialyl Lex (see Test Examples 1 and 2) and suppresses pinna edema and cell infiltration in animal models of inflammation (Test Examples 3 to 5). Furthermore, the compounds of the general formula (I) of the present invention or salts thereof have low toxicity. For example, 1000 mg / kg of the present compound c [N- (2-tetradecylhexadecanoyl) -O- (α-L-fucofuranosyl) -D-seryl] -L-glutamic acid 1-methylamide (the compound of Example 19) is added. The mice were orally administered to the mice, and the progress of one week was observed. No abnormalities were observed. Therefore, the compound of the general formula (I) of the present invention or a salt thereof is useful as a drug. (Test Example 1) Binding inhibition test between P-selectin and sialyl Lex (1) Test compound • Compound of the present invention a [N- (2-tetradecylhexadecanoyl) -O- (α-L-fucofuranosyl)- L-seryl] -L-glutamic acid 1-methylamide (compound of Example 17) Compound b of the present invention [N- (2-tetradecylhexadecanoyl) -O- (α-L-fucofuranosyl) -L-seryl] -D-glutamic acid 1-methylamide (compound of Example 18) Compound of the present invention c [N- (2-tetradecylhexadecanoyl) -O- (α-L-fucofuranosyl) -D-seryl] -L-glutamic acid 1-methylamide (Example 1
9) Compound of the present invention d [N- (2-tetradecylhexadecanoyl) -O- (α-L-fucofuranosyl) -D-seryl] -D-glutamic acid 1-methylamide (compound of Example 20) -Compound e of the present invention e 4-N- [N- (2-tetradecylhexadecanoyl) -O-([alpha] -L-fucofuranosyl)
-L-seryl] aminobutyric acid (compound of Example 23) Compound of the present invention f 5-N- [N- (2-tetradecylhexadecanoyl) -O- (α-L-fucofuranosyl)
-L-seryl] aminovaleric acid (compound of Example 24) Compound g of the present invention [N- (2-tetradecylhexadecanoyl) -O- (α-L-fucofuranosyl) -L-seryl] -D- Glutamic acid 1-anilide (Example 27)
Compound h) Compound h of the present invention [N- (2-tetradecylhexadecanoyl) -O- (α-L-fucofuranosyl) -L-seryl] -D-glutamic acid 1-methylamide sodium salt (Example 28) Compound) Compound i of the present invention [N- (2-tetradecylhexadecanoyl) -O- (α-L-fucopyranosyl) -L-seryl] -L-glutamic acid 1-methylamide (compound of Example 45) Invention compound j [N- (2-tetradecylhexadecanoyl) -O- (α-L-fucopyranosyl) -L-seryl] -D-glutamic acid 1-methylamide (compound of Example 46) Compound of the invention k [ N- (2-tetradecylhexadecanoyl) -O- (α-L-fucopyranosyl) -D-seryl] -L-glutamic acid 1-methylamide (the compound of Example 47 Compound of the present invention l [N- (2-tetradecylhexadecanoyl) -O- (α-L-fucopyranosyl) -D-seryl] -D-glutamic acid 1-methylamide (compound of Example 48) Compound m [N- (2-tetradecylhexadecanoyl) -O- (β-L-fucopyranosyl) -L-seryl] -L-glutamic acid 1-methylamide (Compound of Example 57) Compound of the present invention n [N -(2-tetradecylhexadecanoyl) -O-([beta] -L-fucopyranosyl) -L-seryl] -D-glutamic acid 1-methylamide (compound of Example 58)-Compound of the present invention o [N- (2- Tetradecylhexadecanoyl) -O- (β-L-fucopyranosyl) -D-seryl] -L-glutamic acid 1-methylamide (Compound of Example 59) Compound of the present invention p N- (2-tetradecylhexadecanoyl) -O- (β-L-fucopyranosyl) -D-seryl] -D-glutamic acid 1-methylamide (compound of Example 60) Compound of the present invention q [N- (2 -Tetradecylhexadecanoyl) -S- (α-L-fucopyranosyl) -L-cysteinyl] -L-glutamic acid 1-methylamide (compound of Example 69) Compound r of the present invention [N- (2-tetradecylhexa) Decanoyl) -S- (α-L-fucopyranosyl) -L-cysteinyl] -D-glutamic acid 1-methylamide (compound of Example 70) Compound of the present invention s [N- (2-tetradecylhexadecanoyl)- S- (α-L-fucopyranosyl) -D-cysteinyl] -L-glutamic acid 1-methylamide (compound of Example 71) Compound of the present invention t [N (2-tetradecylhexadecanoyl) -S- (α-L-fucopyranosyl) -D-cysteinyl] -D-glutamic acid 1-methylamide (compound of Example 72) Compound of the present invention u [N- (2-tetra Decyl hexadecanoyl) -S- (β-L-fucopyranosyl) -L-cysteinyl] -D-glutamic acid 1-methylamide (compound of Example 75) Known compound X Sialyl Lex (positive control compound)

(2) Test method The test was carried out according to a method using a selectin IgG chimera reported by Foxall, C. et al. [J. Cell Biol., 117, pp. 895-902 (1992)]. 50% sialyl Lex-penta-ceramide
After dissolving in methanol / distilled water, the solution was put into a 96-well plate at 100 pmol / well, and allowed to stand at room temperature overnight to evaporate the solvent. Wash the plate with distilled water,
% BSA (Bovine Serum Albumin) and 50 mM imidazole buffer (pH 7.0) containing 1 mM calcium chloride.
In 2), blocking was performed at room temperature for 1 hour. On the other hand, biotin-labeled anti-human IgGFc and streptavidin-labeled alkaline phosphatase were combined with 1 mM BSA and 1 mM calcium chloride in 50 mM imidazole buffer (pH
To each of those diluted 500 times in 7.2), 40 μg was added.
/ Ml of P-selectin IgG chimera was added and incubated at room temperature for 30 minutes to prepare a complex solution.

A 10 mM aqueous solution was prepared by dissolving the test compound in DMSO (only in the case of the test compound h, in distilled water). .2) to prepare solutions at eight concentrations (from 20 μM to 2-fold dilution). Equal volumes of each concentration solution of the test compound and the above complex solution were mixed and incubated at room temperature for 30 minutes to prepare a reaction solution.

After the blocking is completed, the blocking solution of the plate is discarded and 50 mM imidazole buffer solution (pH
After washing in 7.2), the above reaction solution (50 μl / well)
Was added and incubated at 37 ° C. for 45 minutes. next,
Plates are washed with 50 mM imidazole buffer (pH 7.2)
And 3 times each with distilled water, and 50 μl of 1M diethanolamine (pH 9.8) containing 0.01% magnesium chloride and 1 mg / ml paranitrophenyl phosphate.
/ Well put and color was developed for 1-2 hours. Then 405
The absorbance at nm was measured. Using the absorbance (A) of the well containing no test compound as a control, the absorbance (X) of the well containing each concentration of the test compound was measured, and the following formula was used.

[0072]

(Equation 1) After calculating the binding ratio (%) at each concentration according to, the IC ₅₀ was calculated by the probit method. (3) Test results Table 1 (described later) shows the results together with the results of Test Example 2. (Test Example 2) Binding inhibition test between L-selectin and sialyl Lex (1) Test compound Same as the test compound of Test Example 1. (2) Test method P-selectin IgG chimera (40 μg / ml) was
The test was performed in the same manner as in Test Example 1 except that the selectin IgG chimera (40 μg / ml) was used. (3) Test results Table 1 shows the results together with the results of Test Example 1.

[0073]

[Table 1]

(Test Example 3) Auricular edema inhibitory effect (1) Test compound • Compound c of the present invention [N- (2-tetradecylhexanoyl) -O- (α-L-fucofuranosyl) -D-seryl]
-L-glutamic acid 1-methylamide (compound of Example 19) (2) Test method A 6-week-old female BALB / c mouse was intraperitoneally injected with 0.5 ml of a physiological saline solution containing 3 μl of ovalbumin and 4 mg of aluminum hydroxide gel. It was sensitized by internal injection. Two weeks later, an inflammatory reaction was induced by injecting 10 μl of ovalbumin adjusted to 1 mg / ml using phosphate buffered saline into both auricles of mice. In the non-inflammation group, phosphate buffered saline was injected subcutaneously into the auricles of both sides of the sensitized animal.

The test compound was dissolved in a 0.01 N sodium hydroxide solution in physiological saline so as to have a concentration of 1 mg / ml, and then diluted with physiological saline to induce 2, 5, 8
Three hours later, injection was performed in a volume of 0.1 ml / 10 g body weight from the tail vein in three times to obtain a test compound administration group. The group injected with only physiological saline was used as a control group. Twenty-four hours after the induction of the reaction, the pinna was cut out to a diameter of 6 mm and the weight was measured, and the pinna weight per unit area was used as an index of edema. The edema inhibition rate was determined by the following equation.

[0076]

(Equation 2) Wexp: Average pinna weight of test compound administration group Wnega: Average pinna weight of non-inflammation-induced group Wcont: Average pinna weight of control group (3) Test results The results are shown in Table 2.

[0077]

[Table 2] Test Example 4 Cell Invasion Inhibitory Effect (1) Test Compound • Compound c of the present invention [N- (2-tetradecylhexanoyl) -O- (α-L-fucofuranosyl) -D-seryl] -L-glutamic acid 1- Methylamide (Example 1
(9 compounds) (2) Test method Reports from Bradley (PP) and others [Journal of I
nvestigative Dermatology, 78, 206-209 (1982))
According to myeloperoxidase (hereinafter MP
O) activity was used as an indicator of cell invasion. After homogenizing and centrifuging the pinna tissue whose weight was measured in Test Example 3, the supernatant was measured for the MPO activity of 450 n of o-dianisidine according to the method of Bradley et al.
The absorbance at m (hereinafter referred to as OD) was measured as an index. The cell infiltration inhibition rate was determined by the following equation.

[0078]

(Equation 3) ODexp: average OD of test compound administration group OD nega: average OD of non-inflammation-induced group ODcont: average OD of control group (3) Test results The results are shown in Table 3.

[0079]

[Table 3] Test Example 5 Effect of suppressing thioglycolate-induced intraperitoneal inflammatory reaction (1) Test compound Compound of the present invention c [N- (2-tetradecylhexadecanoyl) -O- (α-L-fucofuranosyl) -D-seryl] -L-glutamic acid 1-methylamide (Example 1
Compound No. 9) Compound of the present invention k [N- (2-tetradecylhexadecanoyl) -O- (α-L-fucopyranosyl) -D-seryl] -L-glutamic acid 1-methylamide (Example 4)
(7) Compounds (2) Test Method An inflammation was induced by injecting 1 ml of a 3% thioglycolate medium intraperitoneally into 11-week-old male BALB / C mice.
A physiological saline solution was injected intraperitoneally to the non-inflammatory group. Two hours later, the mice were exsanguinated and killed, and then 0.1% BSA, 0.
The exuded cells were collected by washing the peritoneal cavity with a phosphate buffered saline containing 5 mM EDTA and 10 U / ml heparin. The cells were subjected to hemolysis, and the cells were treated with 50%
After dissolution in M potassium phosphate buffer, the supernatant MP
O activity was measured according to the method of Bradley et al.

The test compound was dissolved in a physiological saline solution containing 0.0012 M arginine so as to have a concentration of 1 mg / ml, and the solution was divided into two portions, immediately before and 1 hour after the initiation of the reaction, by 0.1 ml / 10 g body weight from the tail vein. To give a test compound administration group. The group injected with only physiological saline was used as a control group.

The cell infiltration inhibition rate was determined from Equation 3 as in Test Example 4. (3) Test results The results are shown in Table 4.

[0082]

[Table 4] From the above results, it is clear that the compound of the present invention strongly inhibits the binding between P-selectin and L-selectin and sialyl Lex, and suppresses edema and cell infiltration even in an inflammation animal model. Therefore, the compound of the present invention is useful as a selectin inhibitor, and various inflammations such as atopic dermatitis, inflammatory dermatitis such as contact hypersensitivity and photosensitivity, autoimmunity such as rheumatoid arthritis and chronic thyroiditis. For the treatment or prevention of chronic diseases and ischemia-reperfusion injury.

[0083]

The present invention will be described more specifically with reference to the following Reference Examples and Examples. Reference Example 1 N-tert-butoxycarbonyl-L-seryl-L-
Glutamic acid 1-methylamide-5-benzyl ester
[In the compound (Va), R ³ is a methyl group;
Production of a stereoisomer of a compound wherein is 1 : (1) N-tert-butoxycarbonyl-L-glutamic acid 1-methylamido-5-benzyl ester [in the compound (XV), R ³ is a methyl group; Is 1
S-form of the compound of formula: N-tert-butoxycarbonyl-L-glutamic acid 5-benzyl ester (1
0.0g) in a THF (100 ml) solution containing TEA.
(3.9 g), followed by addition of ethyl chlorocarbonate (4.2 g) under ice-cooling and stirring. After stirring for 2 minutes, a 40% methylamine methanol solution (6.9 g) was added, and the mixture was gradually returned to room temperature. While stirring for 2 hours. Then, ethyl acetate (200 ml) was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in that order, dried, and the solvent was distilled off. The precipitated solid was collected by filtration and washed with ether to give N-tert-butoxycarbonyl-L
-Glutamic acid 1-methylamide-5-benzyl ester (9.3 g) was obtained as colorless crystals. Melting point: 124-125 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.37 (s, 9H), 1.66-1.82 (m, 1H),
1.83-2.00 (m, 1H), 2.35 (t, 2H, J = 7.6Hz), 2.57 (d, 3H, J = 4.5
Hz), 3.83-3.95 (m, 1H), 5.08 (s, 2H), 6.90 (d, 1H, J = 8.2Hz),
7.25-7.45 (m, 5H), 7.76 (d, 1H, J = 4.6Hz).

(2) N-tert-butoxycarbonyl-L-seryl-L-glutamic acid 1-methylamide-
5-benzyl ester: the compound of the above (1) (8.5
TFA (50 ml) was added to a methylene chloride solution (50 ml) containing g) under ice-cooling and stirring, followed by stirring for 1 hour. The syrup obtained by distilling off the solvent was chloroform (100 m
1), washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off to obtain a deprotected product as a syrup. This was dissolved in DMF (110 ml) and Boc-
Ser (5.0 g) was added, followed by WSC under ice-cooling and stirring.
(6.0 g) and HOBt (4.3 g) were added, and the mixture was stirred at room temperature for 18 hours. Chloroform (200m
l) was added thereto, washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried and evaporated. The resulting residue was purified by silica gel medium pressure liquid chromatography (chloroform: MeOH = 50: 1 to 50: 1).
9: 1) to give the title stereoisomer (6.0 g) as colorless crystals. Melting point: 110-113 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.37 (s, 9H), 1.68-1.86 (m, 1H),
1.90-2.11 (m, 1H), 2.30-2.45 (m, 2H), 2.56 (d, 3H, J = 4.6H
z), 3.55 (t, 2H, J = 5.4Hz), 3.90-4.15 (m, 1H), 4.20-4.35 (m,
1H), 4.98 (t, 1H, J = 5.4Hz), 5.10 (s, 2H), 6.79 (d, 1H, J = 7.5H
z), 7.25-7.45 (m, 5H), 7.78 (d, 1H, J = 4.6Hz), 7.96 (d, 1H, J =
8.5Hz).

Reference Example 2 N-tert-butoxycarbonyl-L-seryl-D-
Glutamic acid 1-methylamide-5-benzyl ester
[In the compound (Va), R ³ is a methyl group;
Is 1 ) N-tert-butoxycarbonyl-D-glutamic acid 1-methylamide-5-benzyl ester [in compound (XV), R ³ is a methyl group, and n is Is 1
R-compound of the formula: N-tert-butoxycarbonyl-D-glutamic acid 5-benzyl ester (5.
0 g) in a THF (50 ml) solution containing TEA (1.9).
g), followed by addition of ethyl chlorocarbonate (2.1 g) under ice-cooling and stirring, and after stirring for 2 minutes, a 40% methylamine methanol solution (2.9 g) was added, and the mixture was gradually returned to room temperature for 2 hours. Stirred. Then, ethyl acetate (150 ml) was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated aqueous solution of sodium chloride in that order, dried, and the solvent was distilled off. The precipitated solid was collected by filtration and washed with ether to obtain N-tert-butoxycarbonyl-D-glutamic acid 1-methylamide-5-benzyl ester (4.5 g) as colorless crystals.

Melting point: 120-123 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 1.37 (s, 9H), 1.65-1.82 (m, 1H),
1.83-2.00 (m, 1H), 2.36 (t, 2H, J = 7.7Hz), 2.57 (d, 3H, J = 4.5
Hz), 3.82-3.98 (m, 1H), 5.08 (s, 2H), 6.90 (d, 1H, J = 8.2Hz),
7.25-7.45 (m, 5H), 7.76 (d, 1H, J = 4.5Hz).

(2) (N-tert-butoxycarbonyl-L-seryl) -D-glutamic acid 1-methylamide-5-benzyl ester: The compound of the above (1) (4.0
TFA (40 ml) was added to a methylene chloride solution (40 ml) containing g) under ice-cooling and stirring, followed by stirring for 1 hour. The syrup obtained by distilling off the solvent was chloroform (80 ml).
And washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off to obtain a deprotected product as a syrup. Then, Boc-Ser (1.4 g) was added to THF (6
0 ml), TEA (0.90 g) was added, followed by addition of ethyl chlorocarbonate (0.95 g) under ice-cooling and stirring, followed by stirring for 2 minutes and THF containing the syrup (1.7 g) obtained earlier. (10 ml) solution was added and stirred for 3 hours. Ethyl acetate (140 ml) was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in that order, dried and evaporated. The obtained residue is subjected to silica gel medium pressure liquid chromatography (chloroform:
(MeOH = 20: 1 to 10: 1) to give the title stereoisomer (0.8 g) as colorless crystals. Melting point: 124-127 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.38 (s, 9H), 1.66-1.88 (m, 1H),
1.92-2.12 (m, 1H), 2.30-2.42 (m, 2H), 2.57 (d, 3H, J = 4.6H
z), 3.54 (t, 2H, J = 5.6Hz), 3.86-4.00 (m, 1H), 4.13-4.30 (m,
1H), 4.88 (t, 1H, J = 5.7Hz), 5.07 (s, 2H), 6.82 (d, 1H, J = 6.9H
z), 7.30-7.45 (m, 5H), 7.77 (d, 1H, J = 4.5Hz), 8.03 (d, 1H, J =
8.1Hz).

Reference Example 3 N-tert-butoxycarbonyl-D-seryl-L-
Glutamic acid 1-methylamide-5-benzyl ester
[In the compound (Va), R ³ is a methyl group;
Is : 1. (1) N-tert-butoxycarbonyl-O-benzyl-D-seryl-L-glutamic acid 1-methylamide-5-benzyl ester [Compound (XVI)
Stereoisomer of a compound in which R ³ is a methyl group and n is 1]: N-tert-butoxycarbonyl-L-glutamic acid 1-methylamide-5-benzyl ester [3.2 g, see Reference Example 1 (1) ] Was added to a methylene chloride solution (25 ml) under ice-cooling and stirring, and the mixture was stirred for 3 hours. The syrup obtained by distilling off the solvent was dissolved in chloroform (100 ml), washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off to obtain a deprotected product as a syrup. This is added to DMF (50
ml of Boc-D-Ser (OBn) (2.
5g), followed by WSC (2.1 g) under ice-cooling and stirring.
And HOBt (1.7 g) were added, and the mixture was stirred at room temperature for 20 hours. Ethyl acetate (150 ml) was added to the reaction solution, and 1
The extract was washed successively with N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried and evaporated. The precipitated solid was collected by filtration and washed with ether to give a stereoisomer (3.6 g) as colorless crystals.

Melting point: 106-108 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 1.38 (s, 9H), 1.68-1.86 (m, 1H),
1.91-2.12 (m, 1H), 2.23-2.40 (m, 2H), 2.54 (d, 3H, J = 4.6H
z), 3.58 (d, 2H, J = 5.9Hz), 4.05-4.32 (m, 2H), 4.45 (s, 2H),
5.06 (s, 2H), 7.00 (d, 1H, J = 6.8Hz), 7.15-7.43 (m, 10H), 7.7
1 (d, 1H, J = 4.5Hz), 8.19 (d, 1H, J = 8.2Hz).

(2) N-tert-butoxycarbonyl-D-seryl-L-glutamic acid 1-methylamide-
5-benzyl ester: the compound of the above (1) (2.0
g) containing ethanol (70 ml) in 20% Pd
(OH) _{2 /} C (1.0 g) and pressurized with hydrogen (3-4
(Atmospheric pressure) at 30 ° C. for 25 hours. Next, the catalyst was removed by filtration, and the solvent was distilled off to remove the compound (1.4 g).
Was obtained as a syrup. This was dissolved in DMF (25 ml) and TEA (1.2 g) followed by benzyl bromide (2.
1 g) and stirred at room temperature for 19 hours. Then, chloroform (100 ml) was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in that order, dried, and the solvent was distilled off. The obtained residue was purified by silica gel medium pressure liquid chromatography (chloroform: MeOH = 20: 1 to 9: 1) to give the title stereoisomer (0.9 g) as colorless crystals.

Melting point: 127-128 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.38 (s, 9H), 1.65-1.85 (m, 1H),
1.90-2.15 (m, 1H), 2.30-2.40 (m, 2H), 2.58 (d, 3H, J = 4.6H
z), 3.54 (t, 2H, J = 5.6Hz), 3.85-4.00 (m, 1H), 4.13-4.29 (m,
1H), 4.88 (t, 1H, J = 5.6Hz), 5.07 (s, 2H), 6.82 (d, 1H, J = 6.9H
z), 7.30-7.45 (m, 5H), 7.77 (d, 1H, J = 4.6Hz), 8.03 (d, 1H, J =
(8.3Hz).

Reference Example 4 N-tert-butoxycarbonyl-D-seryl-D-
Glutamic acid 1-methylamide-5-benzyl ester
[In the compound (Va), R ³ is a methyl group;
[1] (N-tert-butoxycarbonyl-O-benzyl-D-seryl) -D-glutamic acid 1-methylamide-5-benzyl ester [compound (XVI) Stereoisomer of a compound in which R ³ is a methyl group and n is 1]: N-tert-butoxycarbonyl-D-glutamic acid 1-methylamide-5-benzyl ester [4.0 g, see Reference Example 2 (1) ] Was added to a methylene chloride solution (30 ml) under ice-cooling and stirring, and the mixture was stirred for 2 hours. The syrup obtained by distilling off the solvent was dissolved in chloroform (100 ml), washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off to obtain a deprotected product as a syrup. This is added to DMF (50
ml) and Boc-D-Ser (OBn) (3.
3g) followed by WSC (2.7 g) under ice-cooling and stirring.
And HOBt (2.2 g) were added, and the mixture was stirred at room temperature for 17 hours. Ethyl acetate (160 ml) was added to the reaction solution, and 1
The extract was washed successively with N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried and evaporated. The precipitated solid was collected by filtration and washed with ether to give a stereoisomer (5.1 g) as colorless crystals.

Melting point: 104-118 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 1.37 (s, 9H), 1.70-1.88 (m, 1H),
1.88-2.08 (m, 1H), 2.28-2.42 (m, 2H), 3.59 (d, 2H, J = 5.5H
z), 4.10-4.32 (m, 2H), 4.47 (s, 2H), 5.06 (s, 2H), 7.06 (d, 1
H, J = 7.7Hz), 7.20-7.45 (m, 10H), 7.69 (d, 1H, J = 4.4Hz), 8.0
0 (d, 1H, J = 8.2Hz).

(2) N-tert-butoxycarbonyl-D-seryl-D-glutamic acid 1-methylamide-
5-benzyl ester: the compound of the above (1) (2.0
g) in ethanol (40 ml) solution containing 20% Pd
(OH) 2 / C (0.5 g) was added and pressurized with hydrogen (3-4
(Atmospheric pressure) at 30 ° C. for 6 hours. Next, the catalyst was removed by filtration, and the solvent was distilled off to obtain a deprotected compound (1.3 g) as a syrup. This was dissolved in DMF (30 ml) and TEA (1.0 g) was added, followed by benzyl bromide (1.5 g).
g) was added and stirred at room temperature for 30 hours. Then, chloroform (100 ml) was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in that order, dried, and the solvent was distilled off. The obtained residue was purified by medium pressure liquid chromatography on silica gel (chloroform: MeOH = 20: 1 to 9: 1) to give the title stereoisomer (0.8 g) as colorless crystals.

Melting point: 110-112 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 1.37 (s, 9H), 1.70-1.85 (m, 1H),
1.90-2.10 (m, 1H), 2.30-2.45 (m, 2H), 2.56 (d, 3H, J = 4.5H
z), 3.55 (t, 2H, J = 5.6Hz), 3.90-4.05 (m, 1H), 4.15-4.30 (m,
1H), 4.99 (t, 1H, J = 5.5Hz), 5.07 (s, 2H), 6.80 (d, 1H, J = 7.5H
z), 7.25-7.45 (m, 5H), 7.78 (d, 1H, J = 4.6Hz), 7.97 (d, 1H, J =
8.1Hz).

Reference Example 5 N-tert-butoxycarbonyl-L-seryl-L-
Aspartic acid 1-methylamido-4-benzyles
Ter [In the compound (Va), R ³ is a methyl group
Preparation of a stereoisomer of a compound wherein n is 0] : (1) N-tert-butoxycarbonyl-L-aspartic acid 1-methylamido-4-benzyl ester [in compound (XV), R ³ is And n
S-isomer of a compound wherein is 0]: TEA was added to a solution of N-tert-butoxycarbonyl-L-aspartic acid 4-benzyl ester (2.0 g) in THF (20 ml).
(0.8 g), followed by addition of ethyl chlorocarbonate (0.9 g) under ice-cooling and stirring. After stirring for 5 minutes, a 40% methylamine methanol solution (1.2 g) was added, and the mixture was gradually returned to room temperature. While stirring for 3 hours. Then, ethyl acetate (100 ml) was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride in that order, dried and evaporated. The obtained residue was purified by medium pressure liquid chromatography on silica gel (n-hexane: ethyl acetate = 1: 1 to 1: 2) to give N-tert-butoxycarbonyl-L-aspartic acid 1-methylamide-
4-Benzyl ester (1.9 g) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.50 (s, 9H), 2.87
(d, 3H, J = 5.0Hz), 2.90-3.10 (m, 2H), 5.22 (s, 2H), 7.45-7.6
0 (m, 5H).

(2) N-tert-butoxycarbonyl-L-seryl-L-aspartic acid 1-methylamide-
4-benzyl ester: the compound of the above (1) (1.8
TFA (20 ml) was added to a methylene chloride solution (20 ml) containing g) under ice-cooling and stirring, followed by stirring for 1 hour. The syrup obtained by distilling off the solvent was chloroform (100 m
1), washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off to obtain a deprotected product as a syrup. This was dissolved in DMF (35 ml) and Boc-S
er (0.9 g) was added, followed by WSC while stirring under ice-cooling.
(0.8 g) and HOBt (0.6 g) were added, and the mixture was stirred at room temperature for 14 hours. Ethyl acetate (50 ml) was added to the reaction solution.
Was added, washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride in that order, dried, and the solvent was distilled off. The obtained residue was purified by silica gel medium pressure liquid chromatography (chloroform alone) to give N-tert-
Butoxycarbonyl-L-seryl-L-aspartic acid 1-methylamide-4-benzyl ester (0.2
g) was obtained as a colorless syrup.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (s, 9H), 2.80-
3.10 (m, 2H), 2.94 (d, 3H, J = 5.0Hz), 3.70-4.00 (m, 2H), 4.05
-4.60 (m, 2H), 5.15 (s, 2H), 7.30-7.55 (m, 5H).

Reference Example 6 4-N- (N-tert-butoxycarbonyl-L-se
Ryl) aminobutyric acid benzyl ester [Compound (Vc)
In the above, production of the S-form of the compound wherein n is 1] : (1) 4-N-tert-butoxycarbonylaminobutyric acid benzyl ester [compound (XIX) wherein n is 1]: 4-aminobutyric acid (2 Water (30 ml) was added to 1,4-dioxane (60 ml) containing 1.6 g), and 1N sodium hydroxide (100 ml) was added with stirring under ice cooling.
And 1,4-dioxane containing Boc ₂ O (6.0 g)
A solution of water (60 ml, 30 ml) was added, and the mixture was stirred at room temperature for 18 hours. After distilling off the solvent, citric acid was added and the pH = 3.
The mixture was extracted with ethyl acetate, washed with water, dried and evaporated. The syrup obtained was DMF (40 ml)
And benzyl bromide (12.1 g) and potassium carbonate (6.5 g) were added thereto, followed by stirring at room temperature for 15 hours. Ethyl acetate (100 ml) was added to the reaction solution, washed successively with water and a saturated aqueous solution of sodium chloride, dried, and the solvent was distilled off.
The obtained residue is subjected to silica gel medium pressure liquid chromatography (n-hexane alone to n-hexane: ethyl acetate = 3:
Purification in 1) gave 4-N-tert-butoxycarbonylaminobutyric acid benzyl ester (5.7 g) as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.43 (s, 9H), 1.70-
2.15 (m, 2H), 2.42 (t, 2H, J = 6.8Hz), 3.17 (q, 2H, J = 6.8Hz),
5.15 (s, 2H), 7.40-7.60 (m, 5H).

(2) 4-N- (N-tert-butoxycarbonyl-L-seryl) aminobutyric acid benzyl ester: A solution of the above compound (0.9 g) in methylene chloride (10 ml) was added to TFA (10 ml) under ice-cooling and stirring. 4 ml) and add
Stir for 1 hour. The syrup obtained by distilling off the solvent was dissolved in chloroform (20 ml), washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off to obtain a deprotected product as a syrup. This was dissolved in DMF (10 ml), Boc-Ser (0.6 g) was added, and then WSC (0.5 g) and HOBt (0.4 g) were added under ice-cooling and stirring.
g) was added and the mixture was stirred at room temperature for 17 hours. Ethyl acetate (50 ml) was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in that order, dried, and the solvent was distilled off. The obtained residue is purified by preparative thin-layer chromatography (chloroform: MeOH = 20: 1).
To give 4-N- (N-tert-butoxycarbonyl-L-seryl) aminobutyric acid benzyl ester (0.
3g) was obtained as a colorless syrup.

¹ H-NMR (CDCl ₃ ) δ: 1.43 (s, 9H), 1.70-
2.00 (m, 2H), 2.39 (t, 2H, J = 7.0Hz), 3.28 (q, 2H, J = 7.0Hz),
3.70-4.30 (m, 3H), 5.17 (s, 2H), 7.20-7.45 (m, 5H).

Reference Example 7 5-N- (N-tert-butoxycarbonyl-L-se
Benzyl) aminovaleric acid benzyl ester [compound (V
In c), the production of the S-form of the compound wherein n is 2] : (1) 5-N-tert-butoxycarbonylaminovaleric acid benzyl ester [n in the compound (XIX)
Is 2]: water (100 ml) containing 5-aminovaleric acid (3.6 g) and sodium hydroxide (2.5 g)
1,4-Dioxane (30 ml) containing Boc ₂ O (10.1 g) was added to the solution under ice-cooling and stirring, and the mixture was added at room temperature for 3.5 minutes.
Stirred for hours. The reaction solution was adjusted to pH = 2 to 3 by adding concentrated hydrochloric acid, extracted twice with chloroform and once with ethyl acetate, dried, and the solvent was distilled off. The obtained syrup was added to DMF (10
0 ml), benzyl bromide (15.7 g) and sodium hydrogen carbonate (5.2 g) were added, and the mixture was stirred at room temperature for 20 hours. Chloroform (100 ml) was added to the reaction solution, washed successively with water and a saturated aqueous solution of sodium chloride, dried and evaporated. The resulting residue was subjected to silica gel medium pressure liquid chromatography (n-hexane: ethyl acetate = 1: 7).
To 1: 4) to give 5-N-tert-butoxycarbonylaminovaleric acid benzyl ester (5.3 g) as a colorless syrup.

¹ H-NMR (CDCl ₃ ) δ: 1.58 (s, 9H), 1.50-
2.10 (m, 4H), 2.50 (t, 2H, J = 6.0Hz), 3.25 (q, 2H, J = 7.2Hz),
5.21 (s, 2H), 7.30-7.50 (m, 5H).

(2) 5-N- (N-tert-butoxycarbonyl-L-seryl) aminovaleric acid benzyl ester: ice-cooled to a methylene chloride solution (10 ml) containing the above compound (1) (1.0 g). TFA (4 ml) with stirring
Was added and stirred for 1 hour. The syrup obtained by evaporating the solvent was dissolved in DMF (10 ml), and the solution was stirred under ice-cooling and stirred.
A (1.5 g) and Boc-Ser (0.8 g) were added, followed by WSC (0.7 g) and HO under ice-cooled stirring.
Bt (0.5 g) was added, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate (50 ml) was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in that order, dried, and the solvent was distilled off. The resulting residue was subjected to silica gel medium pressure liquid chromatography (n-hexane:
(Ethyl acetate = 1: 1 to ethyl acetate alone) to give 5-
N- (N-tert-butoxycarbonyl-L-seryl) aminovaleric acid benzyl ester (1.0 g) was obtained as a colorless syrup.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (s, 9H), 1.50-
1.90 (m, 4H), 2.30-2.55 (m, 2H), 3.10-3.55 (m, 2H), 3.85-4.
35 (m, 3H), 5.15 (s, 2H), 7.40-7.55 (m, 5H).

Reference Example 8 N-tert-butoxycarbonyl-L-seryl-L-
Glutamic acid 1,5-dibenzyl ester [compound
Stereoisomers of the compound in which (n) is 1 in (Vb)]
Production of L-glutamic acid 1,5-dibenzyl ester p-toluenesulfonic acid salt (10.0 g), Boc
-WSC was added to a DMF (200 ml) solution containing Ser (4.1 g) and TEA (2.0 g) under ice-cooling and stirring.
(5.0 g) and HOBt (4.0 g) were added, and the mixture was stirred at room temperature for 20 hours. Ethyl acetate (200m
l) was added thereto, washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in that order, dried, and the solvent was distilled off. The precipitated solid was collected by filtration and washed with ether to give N-tert-butoxycarbonyl-L-seryl-
L-glutamic acid 1,5-dibenzyl ester (9.
7g) were obtained as colorless crystals.

Melting point: 93-95 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 1.36 (s, 9H), 1.80-1.98 (m, 1H),
1.99-2.12 (m, 1H), 2.43 (t, 2H, J = 7.6Hz), 3.40-3.62 (m, 2
H), 4.00 (dd, 1H, J = 6.8,12.2Hz), 4.32-4.46 (m, 1H), 4.78
(t, 1H, J = 5.8Hz), 5.07 (s, 2H), 5.11 (s, 1H), 6.70 (d, 1H, J =
8.0Hz), 7.29-7.45 (m, 10H), 8.23 (d, 1H, J = 7.8Hz).

Reference Example 9 N-tert-butoxycarbonyl-L-seryl-D-
Glutamic acid 1-anilide-5-benzyl ester
[In the compound (Va), R ³ is a phenyl group;
Production of a stereoisomer of the compound wherein is 1 : (1) N-tert-butoxycarbonyl-D-glutamic acid 1-anilide-5-benzyl ester [in the compound (XV), R ³ is a phenyl group, and n R-form of the compound wherein is 1]: N-tert-butoxycarbonyl-D-glutamic acid 5-benzyl ester (2.0
g) in a THF (30 ml) solution containing TEA (0.78).
g), followed by addition of ethyl chlorocarbonate (0.84 g) under ice-cooling and stirring. After stirring for 2 minutes, aniline (1.
4g) and stirred for 23 hours while gradually returning to room temperature. Then, ethyl acetate (100 ml) was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in that order, dried, and the solvent was distilled off. The precipitated solid was collected by filtration, washed with ether and Nt
ert-butoxycarbonyl-D-glutamic acid 1-
Anilide-5-benzyl ester (1.4 g) was obtained as colorless crystals.

Melting point: 114-116 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 1.38 (s, 9H), 1.78-2.08 (m, 2H),
2.44 (t, 2H, J = 7.6Hz), 4.10 (dd, 1H, J = 8.1,13.6Hz), 5.07
(s, 2H), 7.05 (t, 1H, J = 7.4Hz), 7.12 (d, 1H, J = 7.8Hz), 7.20-
7.42 (m, 7H), 7.59 (dd, 2H, J = 1.1,8.6Hz), 9.98 (s, 1H).

(2) N-tert-butoxycarbonyl-L-seryl-D-glutamic acid 1-anilide-5-
Benzyl ester: TF was added to a methylene chloride solution (10 ml) containing the compound of the above (1) (1.3 g) under ice-cooling and stirring.
A (10 ml) was added and the mixture was stirred for 2 hours. The syrup obtained by distilling off the solvent was dissolved in chloroform (50 ml), washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off to obtain a deprotected product as a syrup. Next, B
oc-Ser (0.65 g) was dissolved in THF (50 ml), TEA (0.34 g) was added, ethyl chlorocarbonate (0.36 g) was added under ice-cooling and stirring, and the mixture was stirred for 3 minutes and obtained first. A THF (5 ml) solution containing syrup was added and stirred for 4 hours. Then, chloroform (100 m
l) was added thereto, washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in that order, dried, and the solvent was distilled off. The obtained residue is purified by preparative thin-layer chromatography (n-hexane: ethyl acetate 2: 3) to give (N-tert-butoxycarbonyl-L-seryl).
-D-Glutamic acid 1-anilide-5-benzyl ester (0.81 g) was obtained as colorless crystals. Melting point: 93-98 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.36 (s, 9H), 1.80-2.00 (m, 1H),
2.02-2.22 (m, 1H), 2.30-2.50 (m, 2H), 3.58 (t, 2H, J = 5.6H
z), 3.92-4.06 (m, 1H), 4.48-4.54 (m, 1H), 4.95 (t, 1H, J = 5.7
Hz), 5.04 (d, 1H, J = 12.6Hz), 5.09 (d, 1H, J = 13.0Hz), 6.82
(d, 1H, J = 7.0Hz), 7.06 (t, 1H, J = 7.4Hz), 7.22-7.44 (m, 7H),
7.61 (d, 2H, J = 7.8Hz), 8.20 (d, 1H, J = 8.0Hz), 9.75 (s, 1H).

Reference Example 10 (2,3,4-tri-O-acetyl) -L-fucopyrano
Production of sil-fluoride [compound (VII)] : (2,3,4-tri-O-acetyl) -L-fucopyranose (13.1 g) was dissolved in methylene chloride (100 ml), and DAST (ice) was stirred under ice-cooling and stirring. 10.9 g) and stirred under ice cooling for 4 hours. Then, the reaction solution was iced (200 g).
After the mixture was separated, the organic layer was dried and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 4-1: 1) to give (2,3,4-tri-O-acetyl) -L-fucopyranosyl-fluoride ( 10.6 g) was obtained as a mixture of α and β-anomer. α-Anomer ¹ H-NMR (CDCl ₃ ) δ: 1.20 (d, 3H, J = 6.5 Hz), 2.01 (s, 3
H), 2.12 (s, 3H), 2.18 (s, 3H), 4.29-4.48 (m, 1H), 5.06-5.30
(m, 1H), 5.30-5.48 (m, 2H), 5.70 (dd, 1H, J = 2.6,53.7Hz) .β-anomer ¹ H-NMR (CDCl ₃ ) δ: 1.28 (d, 3H, J = 6.4Hz), 2.00 (s, 3
H), 2.10 (s, 3H), 2.20 (s, 3H), 3.90-4.06 (m, 1H), 4.94-5.13
(m, 1H), 5.23 (dd, 1H, J = 7.5,46.9Hz), 5.30-5.48 (m, 1H).

Reference Example 11 (Nt-butoxycarbonyl-L-cysteinyl)-
D-glutamic acid 1-methylamido-5-benzyl
Stele [In the compound (XIII), R ⁴ is methyl
Stereoisomer of a compound which is a bamoyl group and n is 1]
Production of (1) a cystine derivative [in the general formula (XXII),
R ⁴ is a methylcarbamoyl group and n is 1; a stereoisomer of the compound]: N-tert-butoxycarbonyl-D-glutamic acid 1-methylamide-5-benzyl ester [2.5 g, Reference Example 2 (1) TFA (25 ml) was added to a methylene chloride solution (25 ml) containing ice-cooling and stirring.
ml) and stirred for 2 hours. The syrup obtained by distilling off the solvent was dissolved in chloroform (100 ml), washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off to obtain a deprotected product as a syrup. This is DM
Fc (100 ml), Boc-L-cystine (1.6 g) was added, and then WSC (2.
0g) and HOBt (1.6 g).
Stirred for hours. Next, the mixture was concentrated under reduced pressure, and ethyl acetate (120 ml) was added to the obtained residue. The precipitated solid was collected by filtration to obtain the desired product (2.4 g) as colorless crystals.

Melting point: 180-182 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 1.37 (s, 18H), 1.65-1.9 (m, 2H),
1.9-2.18 (m, 2H), 2.2-2.45 (m, 4H), 2.57 (d, 6H, J = 4.2Hz),
2.75-2.95 (m, 2H), 2.95-3.18 (m, 2H), 4.05-4.35 (m, 2H), 5.
06 (s, 4H), 7.24 (d, 2H, J = 7.2Hz), 7.34 (s, 10H), 7.78 (d, 2H,
J = 4.1 Hz), 8.19 (d, 2H, J = 7.7 Hz). (2) (Nt-butoxycarbonyl-L-cysteinyl) -D-glutamic acid 1-methylamide-5-benzyl ester: the above (1) Was dissolved in a mixed solvent of methanol-water (80-0.8 ml), and
Added -bu ₃ P and stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure, and ether was added for crystallization (Nt
-Butoxycarbonyl-L-cysteinyl) -D-glutamic acid 1-methylamide-5-benzyl ester (1.7 g) was obtained as colorless crystals. Melting point: 112-114 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.38 (s, 9H), 1.67-1.88 (m, 1H),
1.9-2.1 (m, 1H), 2.25-2.45 (m, 2H), 2.58 (d, 3H, J = 4.5Hz),
2.6-2.8 (m, 2H), 3.9-4.08 (m, 1H), 4.12-4.32 (m, 1H), 5.07
(s, 2H), 7.14 (d, 1H, J = 7.0Hz), 7.25-7.4 (m, 5H), 7.79 (d, 1H
H, J = 4.5Hz), 8.21 (d, 1H, J = 8.2Hz).

Reference Example 12 N-tert-butoxycarbonyl-D-seryl-L-
Glutamic acid 1-methylamide-5-benzyl ester
[In the compound (Va), R ³ is a methyl group;
Of the compound wherein is 1] : N-tert
-Butoxycarbonyl-L-glutamic acid 1-methylamide-5-benzyl ester [5.0 g, Reference Example 1
TFA (50 ml) was added to a methylene chloride solution (50 ml) containing the mixture (see (1)) under ice-cooling and stirring, followed by stirring for 3 hours. The syrup obtained by distilling off the solvent was dissolved in chloroform (120 ml), washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off to obtain a deprotected product as a syrup. This was dissolved in DMF (80 ml),
Boc-D-Ser (2.9 g) was added, followed by WSC (3.6 g) and HOBt (2.8 g) under ice-cooling and stirring.
Was added and stirred at room temperature for 20 hours. Ethyl acetate (150 ml) was added to the reaction solution, washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried, and the solvent was distilled off. The precipitated solid was collected by filtration and washed with ether to give the title stereoisomer (4.4 g) as colorless crystals. Melting point: 126-128 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.44 (s, 9H), 1.90-2.11 (m, 1H), 2.
12-2.30 (m, 1H), 2.35-2.64 (m, 2H), 2.76 (d, 3H, J = 4.5Hz),
3.60-3.80 (m, 1H), 3.97 (dd, 1H, J = 3.4,11.2Hz), 4.04-4.20
(m, 1H), 4.35-4.55 (m, 1H), 5.08 (d, 1H, J = 12.3Hz), 5.14 (d,
1H, J = 12.3Hz), 5.66 (d, 1H, J = 5.7Hz), 6.77 (d, 1H, J = 4.5H
z), 7.28-7.50 (m, 5H).

Example 1 [N-tert-butoxycarbonyl-O- (2,3,
4-tri-O-benzyl-α-L-fucofuranosyl)-
L-seryl] -L-glutamic acid 1-methylamide-
5-benzyl ester [in the general formula (II-3),
R ⁴ is a methylcarbamoyl group and n is 1
-Anomer] : Molecular sieves 4Å
(1.0 g) in methylene chloride (10 ml), AgOTf
(1.17 g) and SnCl ₂ (0.88 g) were added and cooled to −40 to −50 ° C. under argon, and TMU was added.
(1.3 g), followed by (2,3,4-tri-O-
(Benzyl) -L-fucofuranosyl-fluoride [1.5
g, Compound (VIII)] in methylene chloride (2 ml) and N-tert-butoxycarbonyl-L-seryl-L-glutamic acid 1-methylamide-5-benzyl ester [1.0 g, stereoisomer of Reference Example 1] Was added and the mixture was stirred at the same temperature for 1 hour, and then stirred for 23 hours while gradually returning to room temperature. 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. The resulting residue is purified by preparative thin-layer chromatography (n-hexane: ethyl acetate =
Purification by 1: 1) and crystallization from ether gave the title stereoisomer (0.54 g) as colorless crystals.

[Α] _D -34.2 ° (c = 0.1,
MeOH) Melting point: 132-133 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.07 (d, 3H, J = 6.2 Hz), 1.30 (s, 9)
H), 1.68-1.85 (m, 1H), 1.85-2.10 (m, 1H), 2.30-2.45 (m, 2
H), 2.54 (d, 3H, J = 4.5Hz), 3.50 (t, 1H, J = 6.6Hz), 3.60-3.80
(m, 3H), 3.95-4.10 (m, 2H), 4.15-4.40 (m, 2H), 4.40-4.70
(m, 6H), 5.05 (s, 2H), 5.12 (d, 1H, 3.7Hz), 7.15-7.40 (m, 20
H), 7.80 (d, 1H, J = 4.5 Hz), 7.96 (d, 1H, J = 8.3 Hz). Elemental analysis (as C ₄₈ H ₅₉ N ₃ O ₁₁ ): Calculated value (%) C, 67. N, 4.92 Found (%) C, 67.48; H, 6.94; N, 4.91

Example 2 [N-tert-butoxycarbonyl-O- (2,3,
4-tri-O-benzyl-α-L-fucofuranosyl)-
L-seryl] -D-glutamic acid 1-methylamide-
5-benzyl ester [in the general formula (II-3),
R ⁴ is a methylcarbamoyl group and n is 1
-Anomer] : Molecular sieves 4Å
(1.0 g) in methylene chloride (10 ml), AgOTf
(0.89 g) and SnCl ₂ (0.66 g) were added and cooled to −40 to −50 ° C. under argon, and TMU was added.
(1.0 g), followed by (2,3,4-tri-O-
(Benzyl) -L-fucofuranosyl-fluoride [1.1
g, Compound (VIII)] in methylene chloride (2 ml) and N-tert-butoxycarbonyl-L-seryl-D-glutamic acid 1-methylamide-5-benzyl ester [0.75 g, stereoisomer of Reference Example 2] Of methylene chloride (5 ml) was added, and the mixture was stirred at the same temperature for 1 hour and then stirred for 19 hours while gradually returning to room temperature. 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. The resulting residue is purified by preparative thin-layer chromatography (n-hexane: ethyl acetate =
2: 3) and crystallized from ether to give the title stereoisomer (0.45 g) as colorless crystals.

[Α] _D -19 ° (c = 0.1, Me
OH) Melting point: 122-126 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.07 (d, 3H, J = 6.2 Hz), 1.33 (s, 9
H), 1.68-1.85 (m, 1H), 1.90-2.08 (m, 1H), 2.21-2.42 (m, 2
H), 2.57 (d, 3H, J = 4.5Hz), 3.45-3.60 (m, 1H), 3.58-3.70 (m,
2H), 3.70-3.82 (m, 1H), 4.00 (d, 2H, J = 4.5Hz), 4.10-4.30
(m, 2H), 4.35-4.65 (m, 6H), 5.03 (s, 2H), 5.05 (broad s, 1
H), 6.93 (d, 1H, J = 6.7Hz), 7.15-7.40 (m, 20H), 7.79 (d, 1H, J
= 4.4 Hz), 8.19 (d, 1H, J = 7.6 Hz). Elemental analysis (as C ₄₈ H ₅₉ N ₃ O ₁₁ ): Calculated value (%) C, 67.51; H, 6.96; N, 4.92 found (%) C, 67.34; H, 6.93; N, 4.94.

Example 3 [N-tert-butoxycarbonyl-O- (2,3,
4-tri-O-benzyl-α-L-fucofuranosyl)-
D-seryl] -L-glutamic acid 1-methylamide-
5-benzyl ester [in the general formula (II-3),
R ⁴ is a methylcarbamoyl group and n is 1
-Anomer] : Molecular sieves 4Å
(1.0 g) in methylene chloride (10 ml), AgOTf
(0.89 g) and SnCl ₂ (0.66 g) were added and cooled to −40 to −50 ° C. under argon, and TMU was added.
(1.0 g), followed by (2,3,4-tri-O-
(Benzyl) -L-fucofuranosyl-fluoride [1.1
g, Compound (VIII)] in methylene chloride (2 ml) and N-tert-butoxycarbonyl-D-seryl-L-glutamic acid 1-methylamide-5-benzyl ester [0.75 g, stereoisomer of Reference Example 3] Was added and the mixture was stirred at the same temperature for 1 hour, and then stirred for 22 hours while gradually returning to room temperature. 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. The resulting residue is purified by preparative thin-layer chromatography (n-hexane: ethyl acetate =
2: 3) and crystallized from ether to give the title stereoisomer (0.41 g) as colorless crystals.

[Α] _D -21 ° (c = 0.1, Me
OH) Melting point: 110-116 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.07 (d, 3H, J = 6.2 Hz), 1.36 (s, 9
H), 1.65-1.85 (m, 1H), 1.90-2.12 (m, 1H), 2.32 (t, 2H, J = 7.2
Hz), 2.57 (d, 3H, J = 4.5Hz), 3.45-3.70 (m, 3H), 3.78-3.91
(m, 1H), 3.95-4.05 (m, 1H), 4.10-4.30 (m, 2H), 4.35-4.72
(m, 6H), 5.02 (s, 2H), 5.09 (s, 1H), 7.16 (d, 1H, J = 7.0Hz), 7.
20-7.45 (m, 20H), 7.79 (d, 1H, J = 4.0Hz), 8.17 (d, 1H, J = 7.9H
. z) Elemental analysis (as _{C 48 H 59 N 3 O 11} ): Calculated (%) C, 67.51; H , 6.96; N, 4.92 Found (%) C, 67.47; H, 6.97; N, 4.87

Example 4 [N-tert-butoxycarbonyl-O- (2,3,3
4-tri-O-benzyl-α-L-fucofuranosyl)-
D-seryl] -D-glutamic acid 1-methylamide-
5-benzyl ester [in the general formula (II-3),
R ⁴ is a methylcarbamoyl group and n is 1
-Anomer] : Molecular sieves 4Å
(1.0 g) in methylene chloride (10 ml), AgOTf
(0.89 g) and SnCl ₂ (0.66 g) were added and cooled to −40 to −50 ° C. under argon, and TMU was added.
(1.0 g), followed by (2,3,4-tri-O-
(Benzyl) -L-fucofuranosyl-fluoride [1.1
g, Compound (VIII)] in methylene chloride (2 ml) and N-tert-butoxycarbonyl-D-seryl-D-glutamic acid 1-methylamide-5-benzyl ester [0.75 g, stereoisomer of Reference Example 4] Was added and the mixture was stirred at the same temperature for 1 hour, and then stirred for 18 hours while gradually returning to room temperature. 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. The resulting residue is purified by preparative thin-layer chromatography (n-hexane: ethyl acetate =
2: 3) and crystallized from ether to give the title stereoisomer (0.41 g) as a colorless solid.

[Α] _D -17 ° (c = 0.1, Me
OH) Melting point: 99-104 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.08 (d, 3H, J = 6.3 Hz), 1.33 (s, 9
H), 1.70-1.89 (m, 1H), 1.90-2.05 (m, 1H), 2.32-2.45 (m, 2
H), 3.45-3.75 (m, 3H), 3.80-3.91 (m, 1H), 3.94-4.10 (m, 2
H), 4.10-4.25 (m, 1H), 4.25-4.38 (m, 1H), 4.36-4.70 (m, 6
H), 5.05 (s, 2H), 7.10 (d, 1H, J = 7.9Hz), 7.15-7.42 (m, 20H),
7.81 (d, 1H, J = 4.5Hz), 7.95 (d, 1H, J = 7.9Hz).

Example 5 [N-tert-butoxycarbonyl-O- (2,3,
4-tri-O-benzyl-L-fucofuranosyl) -L-
Seryl] -L-glutamic acid 1,5-dibenzyles
In the general formula (II-3), R ⁴ is benzyl
Α and β- of a compound in which n is 1
Anomer mixture] : Molecular sieves 4 シ ー
(0.5 g) in methylene chloride (2 ml), AgOTf
(0.51 g) and SnCl ₂ (0.38 g) were added and cooled to −40 to −50 ° C. under nitrogen, and TMU (0.4
7g), followed by (2,3,4-tri-O-benzyl) -L-fucofuranosyl-fluoride [0.66 g,
Compound (VIII)] in methylene chloride (2 ml) and N-tert-butoxycarbonyl-L-seryl-
L-glutamic acid 1,5-dibenzyl ester (0.
52 g of a methylene chloride (4 ml) solution of Reference Example 8) was added, and the mixture was stirred at the same temperature for 1 hour.
Stir for 7 hours. 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.
The obtained residue was purified by silica gel medium pressure liquid chromatography (n-hexane: ethyl acetate = 4: 1 to 1: 1) to obtain [N-tert-butoxycarbonyl-.
A mixture of α- and β-anomers of O- (2,3,4-tri-O-benzyl-L-fucofuranosyl) -L-seryl] -L-glutamic acid 1,5-dibenzyl ester (0.
76 g, α-form: β-form = 2: 1) was obtained as a syrup.

¹ H-NMR (DMSO-d ₆ ) δ: 1.07 (d, J = 6.2H
z), 1.14 (d, J = 5.6Hz), 1.30 (s), 1.80-1.95 (m), 2.00-2.15
(m), 2.40-2.50 (m), 3.50-3.60 (m), 3.60-3.75 (m), 4.00-4.
10 (m), 4.20-4.65 (m), 5.06 (s), 5.07 (d, J = 5.1Hz), 5.11 (d,
J = 3.3Hz), 7.15-7.45 (m), 8.30-8.45 (m).

Example 6 [N-tert-butoxycarbonyl-O- (2,3,
4-tri-O-benzyl-L-fucofuranosyl) -L-
Seryl] -L-aspartic acid 1-methylamide-4
-Benzyl ester [in the general formula (II-3), R
⁴ is a methylcarbamoyl group, and n is 0.
And β-anomer mixture] : methylene chloride (2 ml) in molecular sieves 4 (0.5 g), Ag
OTf (0.26 g) and SnCl ₂ (0.20 g)
And cooled to −40 to −50 ° C. under nitrogen, and TMU
(0.24 g), followed by (2,3,4-tri-O).
-Benzyl) -L-fucofuranosyl-fluoride [0.
39 g, compound (VIII)] in methylene chloride (2 m
l) solution and [N-tert-butoxycarbonyl-
L-seryl] -L-aspartic acid 1-methylamido-4-benzyl ester (0.22 g, Reference Example 5) in methylene chloride (4 ml) was added, and the mixture was stirred at the same temperature for 1 hour, and then gradually returned to room temperature. Stir for 15 hours. 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. The resulting residue is purified by preparative thin-layer chromatography (chloroform: MeOH = 1).
0: 1) to give [N-tert-butoxycarbonyl-O- (2,3,4-tri-O-benzyl-L-fucofuranosyl) -L-seryl] -L-aspartic acid 1-methylamide- Α of 4-benzyl ester
And β-anomer mixture (0.23 g, α-form: β-form =
2: 1) as a syrup.

¹ H-NMR (DMSO-d ₆ ) δ: 1.08 (d, J = 6.2H
z), 1.15 (d, J = 6.1 Hz), 1.34 (s), 1.36 (s), 2.69 (s), 2.75-2.
90 (m), 3.50-3.60 (m), 3.60-3.80 (m), 3.85-3.95 (m), 4.10-
4.15 (m), 4.40-4.70 (m), 5.05 (s), 5.06 (s), 5.11 (d, J = 4.1H
z), 7.15-7.45 (m), 7.60-7.80 (m) .8.24 (d, J = 8.2Hz).

Example 7 4-N- [N-tert-butoxycarbonyl-O-
(2,3,4-tri-O-benzyl-L-fucofuranosi
L) -L-seryl] aminobutyric acid benzyl ester
In the general formula (II-3), R ⁴ is a hydrogen atom, n is 1
Mixture of α and β-anomers of a compound] : Preparation of molecular sieves 4 (0.5 g) in methylene chloride (2 ml), AgOTf (0.53 g) and SnCl
₂ (0.40 g), cool to −40 to −50 ° C. under nitrogen, add TMU (0.49 g), followed by (2,3,
4-Tri-O-benzyl) -L-fucofuranosyl-fluoride [0.69 g, compound (VIII)] in methylene chloride (2 ml) and 4-N- (N-tert-butoxycarbonyl-L-seryl) aminobutyric acid The benzyl ester (0.40 g, Reference Example 6) methylene chloride (8
ml) solution and stirred at the same temperature for 1 hour, and then stirred for 13 hours while gradually returning to room temperature. 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. The resulting residue was purified by preparative thin-layer chromatography (cyclohexane: ethyl acetate = 2: 1) to give 4-N- [N-tert-butoxycarbonyl-O- (2,3,4-tri-O -Benzyl-L-
Fucofuranosyl) -L-seryl] aminobutyric acid benzyl ester α and β-anomer mixture (0.56 g,
α-form: β-form = 2: 1) was obtained as a syrup.

[Α] _D -7 ° (c = 0.1, CHC
l ₃ ) Melting point: 94-97 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.16 (d, J = 6.6 Hz), 1.40 (s), 1.60-
1.80 (m), 2.10-2.45 (m), 2.90-3.30 (m), 3.40-3.85 (m), 3.8
5-4.25 (m), 4.40-4.70 (m), 5.08 (s), 7.10-7.50 (m).

Example 8 5-N- [N-tert-butoxycarbonyl-O-
(2,3,4-tri-O-benzyl-L-fucofuranosi
L) -L-seryl] aminovaleric acid benzyl ester
[In the general formula (II-3), R ⁴ is a hydrogen atom, and n is
Α- and β-anomer mixture of the compound represented by Formula 2]
Structure : Molecular sieves 4 (0.5 g) in methylene chloride (4 ml), AgOTf (0.75 g) and S
nCl ₂ (0.57 g) was added under nitrogen to -40 to -50.
C., and TMU (0.70 g) was added, followed by (2,3,4-tri-O-benzyl) -L-fucofuranosyl-fluoride [0.98 g, compound (VIII)]
Of methylene chloride (4 ml) and 5-N- (Nt
A solution of tert-butoxycarbonyl-L-seryl) aminovaleric acid benzyl ester (0.59 g, Reference Example 7) in methylene chloride (8 ml) was added, and the mixture was stirred at the same temperature for 1 hour and then gradually returned to room temperature for 18 hours. did. 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. The resulting residue was purified by silica gel medium pressure liquid chromatography (n-hexane: ethyl acetate = 10: 1 to 1: 1) to give 5-N
-[N-tert-butoxycarbonyl-O- (2,
3,4-tri-O-benzyl-L-fucofuranosyl)-
L-seryl] aminovaleric acid benzyl ester α and β-anomer mixture (0.90 g, α-form: β-form = 2:
1) was obtained as a syrup.

[Α] _D -9 ° (c = 0.1, CHC
l ₃ ) ¹ H-NMR (DMSO-d ₆ ) δ: 1.07 (d, J = 6.2 Hz), 1.14 (d, J = 6.
2Hz), 1.32 (s), 1.35 (s), 1.35-1.55 (m), 2.30 (t, J = 7.1Hz),
2.90-3.10 (m), 3.45-3.75 (m), 3.85-3.95 (m), 3.97-4.10
(m), 4.10-4.20 (m), 4.40-4.70 (m), 5.06 (s), 5.07 (s), 5.08
(d, J = 4.1Hz), 6.68 (d, J = 7.5Hz), 7.20-7.40 (m), 7.85-7.95
(m).

Example 9 [N- (2-tetradecylhexadecanoyl) -O-
(2,3,4-tri-O-benzyl-α-L-fucofura
Nosyl) -L-seryl] -L-glutamic acid 1-methyl
Luamide-5-benzyl ester [general formula (II-4)
In the formula, R ¹ is a 1-tetradecylpentadecyl group, R ⁴
Is a methylcarbamoyl group and n is 1
Production of Nomer] : The compound of Example 1 (0.4 g) was dissolved in methylene chloride (2 ml), and TFA (2
ml) and stirred for 2 hours. The reaction solution was concentrated, chloroform (50 ml) was added, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off. The syrup of the obtained deprotected product was dissolved in DMF (30 ml), and 2-tetradecylhexadecanoic acid (0.21 g) was added thereto.
(0.11 g) and stirred for 18 hours while gradually returning to room temperature. Chloroform (80 ml) was added to the reaction solution, and the mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried, and the solvent was distilled off. The obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 20: 1) to give the title stereoisomer (0.22 g) as colorless crystals.

[Α] _D -14 ° (c = 0.1, CH
Cl ₃ ) Melting point: 139-142 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m, 6H), 1.00-1.55
(m, 55H), 1.72-1.85 (m, 1H), 1.90-2.05 (m, 1H), 2.10-2.25
(m, 1H), 2.25-2.45 (m, 2H), 3.49-3.60 (m, 1H), 3.60-3.70
(m, 1H), 3.72 (d, 2H, J = 6.1Hz), 3.95-4.05 (m, 2H), 4.25-4.4
0 (m, 1H), 4.38-4.73 (m, 7H), 5.05 (s, 2H), 5.13 (d, 1H, J = 3.4
Hz)), 7.20-7.45 (m, 20H), 7.75 (d, 1H, J = 4.7Hz), 7.94 (d, 1
H, J = 8.2 Hz), 8.02 (d, 1H, J = 7.8 Hz). Elemental analysis (as C ₇₃ H ₁₀₉ N ₃ O ₁₀ ): Calculated (%) C, 73.76; H, 9.24 N, 3.54 Found (%) C, 73.83; H, 9.26; N, 3.57

Example 10 [N- (2-tetradecylhexadecanoyl) -O-
(2,3,4-tri-O-benzyl-α-L-fucofura
Nosyl) -L-seryl] -D-glutamic acid 1-methyl
Luamide-5-benzyl ester [general formula (II-4)
In the formula, R ¹ is a 1-tetradecylpentadecyl group, R ⁴
Is a methylcarbamoyl group and n is 1
Production of Nomer] : The compound of Example 2 (0.4 g) was dissolved in methylene chloride (3 ml), and TFA (3
ml) and stirred for 2 hours. The reaction solution was concentrated, chloroform (50 ml) was added, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off. The syrup of the obtained deprotected product was dissolved in DMF (30 ml), and 2-tetradecylhexadecanoic acid (0.21 g) was added thereto.
(0.11 g) and stirred for 22 hours while gradually returning to room temperature. Chloroform (80 ml) was added to the reaction solution, and the mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried, and the solvent was distilled off. The obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 20: 1) to give the title stereoisomer (0.27 g) as colorless crystals.

[Α] _D -14 ° (c = 0.1, CH
Cl ₃ ) Melting point: 127-129 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m, 6H), 1.06 (d, 3H, J
= 6.1Hz), 1.10-1.60 (m, 55H), 1.65-1.85 (m, 1H), 1.85-2.10
(m, 1H), 2.10-2.25 (m, 1H), 2.25-2.40 (m, 2H), 2.55 (d, 3H, J
= 4.5Hz), 3.49-3.60 (m, 1H), 3.60-3.70 (m, 2H), 3.70-3.85
(m, 1H), 3.95-4.05 (m, 2H), 4.15-4.25 (m, 1H), 4.39-4.72
(m, 7H), 5.01 (s, 2H), 5.04 (d, 1H, J = 3.3Hz), 7.15-7.40 (m, 2
0H), 7.84 (d, 1H, J = 4.6Hz), 8.11 (d, 1H, J = 6.7Hz), 8.28 (d, 1
H, J = 8.2 Hz). Elemental analysis (as C ₇₃ H ₁₀₉ N ₃ O ₁₀ ): Calculated (%) C, 73.76; H, 9.24; N, 3.54 Found (%) C H, 9.25; N, 3.33.

Example 11 [N- (2-tetradecylhexadecanoyl) -O-
(2,3,4-tri-O-benzyl-α-L-fucofura
Nosyl) -D-seryl] -L-glutamic acid 1-methyl
Luamide-5-benzyl ester [general formula (II-4)
In the formula, R ¹ is a 1-tetradecylpentadecyl group, R ⁴
Is a methylcarbamoyl group and n is 1
Production of Nomer] : The compound of Example 3 (0.37 g) was dissolved in methylene chloride (3 ml), and TFA was stirred under ice-cooling.
(3 ml) was added and stirred for 2 hours. Concentrate the reaction,
Chloroform (50 ml) was added, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off. The resulting deprotected syrup was dissolved in DMF (30 ml),
-Add tetradecyl hexadecanoic acid (0.20 g),
Subsequently, WSC (0.13 g) and HOB were added under ice-cooling and stirring.
t (0.10 g), and gradually return to room temperature for 20 minutes.
Stirred for hours. Chloroform (50 ml) was added to the reaction solution, and the mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried and evaporated. The obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 20: 1) to give the title stereoisomer (0.23 g) as colorless crystals.

[Α] _D -19 ° (c = 0.1, CH
Cl ₃ ) Melting point: 114-117 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m, 6H), 1.06 (d, 3H, J
= 6.2Hz), 1.10-1.50 (m, 52H), 1.65-1.85 (m, 1H), 1.88-2.12
(m, 1H), 2.15-2.30 (m, 1H), 2.30-2.42 (m, 2H), 2.55 (d, 3H, J
= 4.5Hz), 3.45-3.72 (m, 3H), 3.80-3.95 (m, 1H), 3.95-4.05
(m, 2H), 4.16-4.30 (m, 1H), 4.38-4.72 (m, 7H), 5.00 (s, 2H),
5.10 (d, 1H, J = 3.1Hz), 7.15-7.45 (m, 20H), 7.84 (d, 1H, J = 4.
7 Hz), 8.16 (d, 1H, J = 6.7 Hz), 8.26 (d, 1H, J = 8.1 Hz). Elemental analysis (as C ₇₃ H ₁₀₉ N ₃ O ₁₀ ): Calculated value (%) 76; H, 9.24; N, 3.54 found (%) C, 73.80; H, 9.24; N, 3.57

Example 12 [N- (2-tetradecylhexadecanoyl) -O-
(2,3,4-tri-O-benzyl-α-L-fucofura
Nosyl) -D-seryl] -D-glutamic acid 1-methyl
Luamide-5-benzyl ester [general formula (II-4)
In the formula, R ¹ is a 1-tetradecylpentadecyl group, R ⁴
Is a methylcarbamoyl group and n is 1
Production of Nomer] : The compound of Example 4 (0.35 g) was dissolved in methylene chloride (3 ml), and TFA was stirred under ice cooling.
(3 ml) was added and stirred for 2 hours. Concentrate the reaction,
Chloroform (50 ml) was added, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off. The resulting deprotected syrup was dissolved in DMF (30 ml),
-Tetradecylhexadecanoic acid (0.19 g) was added,
Subsequently, WSC (0.12 g) and HOB were added under ice-cooling and stirring.
t (0.09 g), and gradually return to room temperature for 20 minutes.
Stirred for hours. Chloroform (80 ml) was added to the reaction solution, and the mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried, and the solvent was distilled off. The obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 20: 1) to give the title stereoisomer (0.25 g) as colorless crystals.

[Α] _D -15.0 ° (c = 0.1,
CHCl ₃ ) Melting point: 125-126 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m, 6H), 1.07 (d, 3H, J
= 6.2Hz), 1.10-1.60 (m, 52H), 1.70-1.85 (m, 1H), 1.88-2.05
(m, 1H), 2.16-2.30 (m, 1H), 2.30-2.41 (m, 2H), 3.53 (t, 1H, J
= 6.3Hz), 3.60-3.72 (m, 2H), 3.80-3.92 (m, 1H), 4.00 (d, 2H,
J = 4.6Hz), 4.19-4.31 (m, 1H), 4.40-4.72 (m, 7H), 5.06 (s, 2
H), 5.12 (s, 1H), 7.20-7.45 (m, 20H), 7.71 (d, 1H, J = 4.8Hz),
8.01 (d, 2H, J = 7.7 Hz). Elemental analysis (as C ₇₃ H ₁₀₉ N ₃ O ₁₀ ): Calculated (%) C, 73.76; H, 9.24; N, 3.54 Found (%) C, 73.50; H, 9.14; N, 3.51

Example 13 [N- (2-tetradecylhexadecanoyl) -O-
(2,3,4-tri-O-benzyl-L-fucofuranosi
L) -L-seryl] -L-glutamic acid 1,5-dibe
Benzyl ester [in the general formula (II-4), R ¹ is
1-tetradecylpentadecyl group, R ⁴ is benzyloxy
Α- and β-adhesions of a compound having a cyclocarbonyl group and n is 1
Nomer mixture] : Compound of Example 5 (0.28
g) was dissolved in methylene chloride (1 ml), TFA (0.3 ml) was added under ice-cooling and stirring, and the mixture was stirred for 5 hours. The reaction solution was concentrated, chloroform (15 ml) was added, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off. The syrup of the obtained deprotected product was added to DMF (10 ml)
Dissolved in 2-tetradecylhexadecanoic acid (0.14
g), followed by WSC (0.09 g) under ice-cooling and stirring.
And HOBt (0.07 g) were added, and the mixture was stirred for 15 hours while gradually returning to room temperature. Add chloroform (5
0 ml), and washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride, dried and evaporated. The resulting residue is subjected to silica gel medium pressure liquid chromatography (n-hexane: ethyl acetate = 1).
0: 1 to 4: 1, chloroform: MeOH = 20: 1)
[N- (2-tetradecylhexadecanoyl) -O- (2,3,4-tri-O-benzyl-L-fucofuranosyl) -L-seryl] -L-glutamic acid
A mixture of α and β-anomers of 1,5-dibenzyl ester (0.06 g, α-form: β-form = 2: 1) was obtained as colorless crystals.

¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m), 1.
07 (d, J = 6.3Hz), 1.00-1.50 (m), 1.80-1.95 (m), 2.00-2.10
(m), 2.10-2.25 (m), 2.42 (t, J = 8.6 Hz), 3.50-3.60 (m), 3.65
-3.80 (m), 3.85-3.90 (m), 3.95-4.00 (m), 4.35-4.70 (m), 5.
06 (s), 5.11 (s), 7.20-7.40 (m), 7.99 (d, J = 7.7Hz), 8.38 (d,
J = 7.4Hz).

Example 14 [N- (2-tetradecylhexadecanoyl) -O-
(2,3,4-tri-O-benzyl-L-fucofuranosi
1-methyl-L-seryl] -L-aspartate
Amido-4-benzyl ester [in general formula (II-4)
R ¹ is a 1-tetradecylpentadecyl group, and R ⁴ is
A methylcarbamoyl group, α of a compound wherein n is 0, and
Preparation of β-Anomer Mixture] : Compound of Example 6 (0.
21 g) was dissolved in methylene chloride (2 ml), TFA (2 ml) was added under ice-cooling and stirring, and the mixture was stirred for 4 hours. The reaction solution was concentrated, chloroform (20 ml) was added, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off. The syrup of the obtained deprotected product was dissolved in DMF (5 ml), and 2-tetradecylhexadecanoic acid (0.13
g), followed by WSC (0.05 g) under ice-cooling and stirring.
And HOBt (0.04 g) were added, and the mixture was stirred for 16 hours while gradually returning to room temperature. Add chloroform (2
0 ml), and washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride, dried and evaporated. The obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 20: 1) to give N- (2-tetradecylhexadecanoyl)-.
A mixture of α- and β-anomers of O- (2,3,4-tri-O-benzyl-L-fucofuranosyl) -L-seryl] -L-aspartic acid 1-methylamide-4-benzyl ester (0.09 g, α Body: β form = 2: 1).

¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m), 1.
07 (d, J = 6.3Hz), 1.10-1.60 (m), 2.10-2.25 (m), 3.50-3.85
(m), 3.85-3.95 (m), 3.95-4.05 (m), 4.10-4.15 (m), 4.25-4.
30 (m), 4.40-4.70 (m), 5.05 (s), 5.12 (s), 7.10-7.45 (m).

Example 15 4-N- [N- (2-tetradecylhexadecanoyl)
-O- (2,3,4-tri-O-benzyl-α-L-f
Cofuranosyl) -L-seryl] aminobutyric acid benzyl ester
Stele [In the general formula (II-4), R ¹ is 2-tert.
A radisylpentadecyl group, R ⁴ is a hydrogen atom, and n is 1
Production of α-anomer of compound] : The compound of Example 7 (0.21 g) was dissolved in methylene chloride (2 ml), TFA (2 ml) was added under ice-cooling and stirring, and the mixture was stirred for 2 hours.
The reaction solution was concentrated, chloroform (20 ml) was added, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off. The syrup of the obtained deprotected product was added to DMF (5 m
l) and dissolved in 2-tetradecylhexadecanoic acid (0.1).
12 g), followed by WSC (0.05 g) under ice-cooling and stirring.
g) and HOBt (0.04 g) were added, and the mixture was stirred for 16 hours while gradually returning to room temperature. Chloroform (20 ml) was added to the reaction solution, and the mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous solution of sodium chloride, dried and evaporated. The resulting residue is purified by preparative thin-layer chromatography (cyclohexane: ethyl acetate =
2: 1) to give 4-N- [N- (2-tetradecylhexadecanoyl) -O- (2,3,4-tri-O-benzyl-α-L-fucofuranosyl) -L-seryl Aminobutyric acid benzyl ester (0.03 g) was obtained.

Melting point: 74-82 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m, 6H), 1.07 (d, 3H, J
= 6.2Hz), 1.00-1.50 (m, 52H), 1.63 (q, 2H, J = 7.3Hz), 2.25-
2.35 (m, 2H), 2.90-3.00 (m, 2H), 3.10-3.20 (m, 2H), 3.50-3.
75 (m, 4H), 3.95-4.05 (m, 2H), 4.35-4.70 (m, 7H), 5.05 (s, 2
H), 7.20-7.40 (m, 20H), 7.90-8.05 (m, 2H).

Example 16 5-N- [N- (2-tetradecylhexadecanoyl)
-O- (2,3,4-tri-O-benzyl-α-L-f
Cofuranosyl) -L-seryl] benzyl aminovalerate
Ester [In the general formula (II-4), R ¹ is 1-
A tradecylpentadecyl group, R ⁴ is a hydrogen atom, n is 2
Production of α-Anomer of Certain Compound] : The compound of Example 8 (0.56 g) was dissolved in methylene chloride (4 ml), and TFA (4 ml) was added with stirring under ice-cooling, followed by stirring for 1 hour.
The reaction solution was concentrated, chloroform (20 ml) was added, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off. The syrup of the obtained deprotected product was added to DMF (20 m
l) and dissolved in 2-tetradecylhexadecanoic acid (0.1).
37 g), followed by WSC (0.15
g) and HOBt (0.12 g) were added, and the mixture was stirred for 19 hours while gradually returning to room temperature. Ethyl acetate (20 ml) was added to the reaction solution, and the mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous solution of sodium chloride, dried and evaporated. The resulting residue is purified by preparative thin-layer chromatography (cyclohexane: ethyl acetate =
2: 1) to give 5-N- [N- (2-tetradecylhexadecanoyl) -O- (2,3,4-tri-O-benzyl-α-L-fucofuranosyl) -L-seryl. Aminovaleric acid benzyl ester (0.16 g) was obtained.

[Α] _D -28 ° (c 0.1, CH
Cl ₃ ) Melting point: 98-99 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m, 6H), 1.10 (d, 3H, J
= 6.3Hz), 1.10-1.55 (m, 56H), 2.28 (t, 2H, J = 7.1Hz), 2.90-
3.00 (m, 2H), 3.55-3.80 (m, 4H), 4.00-4.05 (m, 2H), 4.40-4.
70 (m, 7H), 5.06 (s, 2H), 7.20-7.40 (m, 20H), 7.50-7.65 (m, 2
H).

Example 17 [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucofuranosyl) -L-seryl] -L-glu
Tamic acid 1-methylamide [odor of the general formula (Ib)
R ¹ is a 1-tetradecyl pentadecyl group, R ² is methyl
Α-anomer of a compound having a rucarbamoyl group and n is 1
Production of 20% Pd (OH) ₂ / C in a solution of the compound of Example 9 (0.15 g) in ethanol (25 ml).
(0.25 g) and added under hydrogen pressure (3 to 4 atm).
Stirred at C for 6 hours. After removing the catalyst by filtration, the solvent was distilled off, water (5 ml) was added to the obtained residue, and the mixture was freeze-dried to obtain the title stereoisomer (72 mg) as a colorless powder.

[Α] _D -27 ° (c = 0.05, M
MeOH) Melting point: gradually melts from around 60 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.83-0.87 (m, 6H), 1.03 (d, 3H, J
= 6.4Hz), 1.10-1.60 (m, 52H), 1.65-1.81 (m, 1H), 1.83-2.05
(m, 1H), 2.10-2.35 (m, 3H), 2.58 (d, 3H, J = 4.5Hz), 3.35-3.5
8 (m, 3H), 3.68-3.85 (m, 2H), 3.87 (dd, 1H, J = 5.3,9.7Hz), 4.
15-4.25 (m, 1H), 4.42-4.56 (m, 1H), 4.71 (d, 1H, 3.8Hz), 5.1
4 (s, 1H), 7.72 (d, 1H, J = 4.6Hz), 7.80-7.95 (m, 1H), 8.00 (d,
1H, J = 7.9Hz), 12.05 (bs, 1H).

Example 18 [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucofuranosyl) -L-seryl] -D-glu
Tamic acid 1-methylamide [odor of the general formula (Ib)
R ¹ is a 1-tetradecyl pentadecyl group, R ² is methyl
Α-anomer of a compound having a rucarbamoyl group and n is 1
Over] Preparation of ethanol of the compound of Example 10 (0.20g) (30ml) was added _{20% Pd (OH) 2 /} C
(0.20 g) and added under hydrogen pressure (3-4 atm).
Stirred at C for 5 hours. After removing the catalyst by filtration, the solvent was distilled off, water (5 ml) was added to the obtained residue, and the mixture was freeze-dried to obtain the title stereoisomer (79 mg) as a colorless powder. [Α] _D -20 ° (c = 0.1, MeOH) Melting point: melting gradually from around 110 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.83-0.87 (m, 6H), 1.01 (d, 3H, J
= 6.4Hz), 1.10-1.60 (m, 52H), 1.60-1.78 (m, 1H), 1.85-2.02
(m, 1H), 2.12-2.30 (m, 3H), 2.58 (d, 3H, J = 3.5Hz), 3.40-3.5
5 (m, 2H), 3.65-3.78 (m, 2H), 3.88 (dd, 1H, J = 6.0,10.2Hz),
4.10-4.25 (m, 1H), 4.33-4.50 (m, 1H), 4.70 (d, 1H, 4.0Hz),
5.12 (s, 1H), 7.87 (d, 1H, J = 4.8Hz), 7.96 (d, 1H, J = 7.2Hz),
8.09 (d, 1H, J = 7.1Hz), 12.05 (bs, 1H).

Example 19 [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucofuranosyl) -D-seryl] -L-glu
Tamic acid 1-methylamide [odor of the general formula (Ib)
R ¹ is a 1-tetradecyl pentadecyl group, R ² is methyl
Α-anomer of a compound having a rucarbamoyl group and n is 1
Production of 20% Pd (OH) ₂ / C in a solution of the compound of Example 11 (0.50 g) in ethanol (50 ml).
(0.40 g) and added under hydrogen pressure (3-4 atm).
Stirred at C for 5 hours. After removing the catalyst by filtration, the solvent was distilled off, the obtained residue was dissolved in methanol (10 ml), water (30 ml) was added, and the precipitated solid was collected by filtration to give the title stereoisomer (0.29 g). Obtained as a colorless powder. [Α] _D -21 ° (c = 0.1, MeOH) Melting point: 134-138 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.70-0.95 (m, 6H), 1.03 (d, 3H, J
= 6.3Hz), 1.10-1.55 (m, 52H), 1.56-1.80 (m, 1H), 1.80-2.08
(m, 1H), 2.11-2.30 (m, 3H), 2.57 (d, 3H, J = 4.5Hz), 3.40-3.5
8 (m, 1H), 3.63 (dd, 1H, J = 5.1,10.2Hz), 3.70-3.85 (m, 3H),
4.10-4.25 (m, 1H), 4.30-4.45 (m, 1H), 4.46 (d, 1H, 4.9Hz),
4.50-4.70 (m, 1H), 4.75 (d, 1H, J = 3.5Hz), 5.11 (d, 1H, J = 5.6
Hz), 7.76 (d, 1H, J = 4.5 Hz), 7.83 (d, 1H, J = 8.2 Hz), 8.07 (d, 1
H, J = 7.1 Hz), 12.02 (s, 1H). Mass spectrum (m / e): 828 (M + H) ⁺ elemental analysis (as C ₄₅ H ₈₅ N ₃ O ₁₀ .1H ₂ O): Calculated value (%) ) C, 63.87; H, 10.36; N, 4.97 found (%) C, 64.14; H, 10.18; N, 4.73.

Example 20 [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucofuranosyl) -D-seryl] -D-glu
Tamic acid 1-methylamide [odor of the general formula (Ib)
R ¹ is a 1-tetradecyl pentadecyl group, R ² is methyl
Α-anomer of a compound having a rucarbamoyl group and n is 1
Over] Preparation of ethanol of the compound of Example 12 (0.22g) (30ml) was added _{20% Pd (OH) 2 /} C
(0.20 g) and added under hydrogen pressure (3-4 atm).
Stirred at C for 4 hours. After removing the catalyst by filtration, the solvent was distilled off, water (5 ml) was added to the obtained residue, and the mixture was freeze-dried to obtain the title stereoisomer (0.13 g) as a colorless powder.

[Α] _D -12 ° (c = 0.1, Me
OH) Melting point: 109-113 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.83-0.88 (m, 6H), 1.02 (d, 3H, J
= 6.3Hz), 1.10-1.50 (m, 52H), 1.60-1.80 (m, 1H), 1.80-2.00
(m, 1H), 2.15-2.30 (m, 3H), 2.58 (d, 3H, J = 4.5Hz), 3.40-3.5
5 (m, 1H), 3.55-3.65 (m, 1H), 3.65-3.85 (m, 2H), 4.15-4.25
(m, 1H), 4.40-4.55 (m, 1H), 4.77 (d, 1H, 3.9Hz), 5.14 (d, 1H,
J = 5.0Hz), 7.69 (d, 1H, J = 4.7Hz), 7.85 (d, 1H, J = 7.8Hz), 8.0
2 (d, 1H, J = 8.2Hz), 12.00 (bs, 1H).

Example 21 [N- (2-tetradecylhexadecanoyl) -O-
(L-fucofuranosyl) -L-seryl] -L-glutami
Acid [In the general formula (Ib), R ¹ is 1-tetradecyl
Lupentadecyl group, R ² is a carboxyl group, and n is 1.
Mixture of α and β-anomers of the compound of the formula (13): Preparation of the compound of Example 13 (0.05 g) in ethanol (25
1) 20% Pd (OH) _{2 /} C (0.05 g) was added to the solution, and the mixture was stirred at 30 ° C. under hydrogen pressure (3 to 4 atm) for 15 hours. After removing the catalyst by filtration, the solvent was distilled off, and water (2 ml) and dioxane (2 ml) were added to the obtained residue, followed by freeze-drying to obtain [N- (2-tetradecylhexadecanoyl) -O- (L -Fucofuranosyl) -L-seryl]
Α- and β-anomeric mixture of L-glutamic acid (2
2 mg, α-form: β-form = 2: 1) was obtained as a colorless powder.

[Α] _D -30 ° (c = 0.1, Me
OH) Melting point: 57-65 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.90 (m), 1.01 (d, J = 6.4H)
z), 1.08 (d, J = 6.3Hz), 1.10-1.60 (m), 1.70-1.85 (m), 1.85-
2.05 (m), 2.15-2.40 (m), 3.40-3.60 (m), 3.65-3.80 (m), 4.2
0-4.30 (m), 4.50-4.60 (m), 4.71 (d, J = 4.1Hz), 7.85-8.05
. (m) Elemental Analysis (as _{C 44 H 82 N 2 O 11} · 3H 2 O): Calculated: C, 60.80; H, 10.20 ; N, 3.22 Analytical values: C, 60.81 H, 9.90; N, 3.05

Example 22 [N- (2-tetradecylhexadecanoyl) -O-
(L-fucofuranosyl) -L-seryl] -L-aspara
Formic acid 1-methylamide [in the general formula (Ib),
R ¹ is a 1-tetradecylpentadecyl group, R ² is methylca
Α and β-ano of a compound having a rubamoyl group and n is 0
Mer mixture] Preparation of the compound of Example 14 (0.09
g) in a solution of ethanol (30 ml) in 20% Pd (O
H) ₂ / C (0.08 g) was added, and the mixture was stirred at 30 ° C. for 14 hours under hydrogen pressure (3 to 4 atm). After removing the catalyst by filtration, the solvent was distilled off, and water (1 ml) and dioxane (2 ml) were added to the obtained residue, followed by freeze-drying to obtain [N- (2
-Tetradecylhexadecanoyl) -O- (L-fucofuranosyl) -L-seryl] -L-aspartic acid 1-
A mixture of α and β-anomers of methylamide (40 m
g, α-form: β-form = 2: 1) as a colorless powder. Melting point: 75-78 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.83-0.87 (m), 1.03 (d, J = 5.8H
z), 1.09 (d, J = 6.1 Hz), 1.10-1.55 (m), 2.10-2.30 (m), 2.57
(d, J = 3.3Hz), 2.60-2.75 (m), 3.15-3.25 (m), 3.40-3.60
(m), 3.60-3.80 (m), 3.90-4.05 (m), 4.40-4.55 (m), 4.60-4.
75 (m), 7.50-7.65 (m), 7.95-8.05 (m).

Example 23 4-N- [N- (2-tetradecylhexadecanoyl)
-O- (α-L-fucofuranosyl) -L-seryl] ami
Nobutyric acid [in the general formula (Ib), R ¹ is 1-tetrade
A silpentadecyl group, wherein R ² is a hydrogen atom and n is 1
Preparation of α-anomer of compound: 20% in a solution of the compound of Example 15 (0.03 g) in ethanol (20 ml)
Pd (OH) _{2 /} C (0.03 g) was added, and the mixture was stirred at 30 ° C. under hydrogen pressure (3 to 4 atm) for 17 hours. After removing the catalyst by filtration, the solvent was distilled off, and water (1 ml) and dioxane (1 ml) were added to the obtained residue, followed by lyophilization to give 4-N- [N- (2-tetradecylhexadecanoyl).
-O-([alpha] -L-fucofuranosyl) -L-seryl] aminobutyric acid (15 mg) was obtained as a colorless powder.

[Α] _D -16 ° (c = 0.1, MeO
H) Melting point: 61-67 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.83-0.87 (m, 6H), 1.01 (d, 3H, J
= 6.4Hz), 1.10-1.50 (m, 52H), 1.55-1.70 (m, 2H), 2.19 (t, 2
(H, J = 7.4Hz), 3.00-3.15 (m, 2H), 3.25-3.35 (m, 1H), 3.40-3.
50 (m, 3H), 3.60-3.80 (m, 2H), 3.80-3.90 (m, 1H), 4.40-4.50
(m, 1H), 4.68 (d, 1H, J = 4.2Hz), 7.78 (t, 1H, J = 5.4Hz), 7.90
(d, 1H, J = 8.4Hz).

Example 24 5-N- [N- (2-tetradecylhexadecanoyl)
-O- (α-L-fucofuranosyl) -L-seryl] ami
Novaleric acid [In the general formula (Ib), R ¹ is 1-tetra
A decylpentadecyl group, R ² is a hydrogen atom, and n is 2
Preparation of α-Anomer of Compound] : 20% of a solution of the compound of Example 16 (0.06 g) in ethanol (30 ml)
Pd (OH) _{2 /} C (0.06 g) was added, and the mixture was stirred at 30 ° C. for 14 hours under hydrogen pressure (3 to 4 atm). After removing the catalyst by filtration, the solvent was distilled off, and water (1 ml) and dioxane (1 ml) were added to the obtained residue, followed by lyophilization to give 5-N- [N- (2-tetradecylhexadecanoyl).
-O-([alpha] -L-fucofuranosyl) -L-seryl] aminovaleric acid (41 mg) was obtained as a colorless powder.

[Α] _D -29 ° (c = 0.1, Me
OH) Melting point: 111-116 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.83-0.87 (m, 6H), 1.01 (d, 3H, J
= 6.4Hz), 1.10-1.55 (m, 52H), 2.19 (t, 2H, J = 6.9Hz), 3.00-
3.10 (m, 2H), 3.25-3.35 (m, 1H), 3.35-3.50 (m, 3H), 3.65-3.
75 (m, 2H), 3.80-3.85 (m, 1H), 4.30-4.50 (m, 2H), 4.68 (d, 1
H, J = 4.2Hz), 7.71 (t, 1H, J = 5.5Hz), 7.90 (d, 1H, as J = 8.4 Hz). Elemental analysis _{(C 44 H 84 N 2 O} 9 · 1.5H 2 O ): Calculated: C, 65.07; H, 10.80; N, 3.45 Analytical value: C, 65.02; H, 10.43; N, 3.38.

Example 25 [N-tert-butoxycarbonyl-O- (2,3,
4-tri-O-benzyl-α-L-fucofuranosyl)-
L-seryl] -D-glutamic acid 1-anilide-5-
Benzyl ester [in the general formula (II-3), R ⁴
Is a phenylcarbamoyl group and n-is 1
Anomer] : Molecular sieves 4Å (1.
0g) in methylene chloride (10 ml) and AgOTf (0.
77 g) and SnCl ₂ a (0.57 g) was added, and cooled under argon -40~-50 ℃, TMU (0.87
g), followed by (2,3,4-tri-O-benzyl) -L-fucofuranosyl-fluoride [0.98 g,
Compound (VIII)] in methylene chloride (2 ml) and N-tert-butoxycarbonyl-L-seryl-
Methylene chloride (5 ml) of D-glutamic acid 1-anilide-5-benzyl ester (0.75 g, Reference Example 9)
The solution was added, and the mixture was stirred at the same temperature for 1 hour, and then stirred for 20 hours while gradually returning to room temperature. 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. The obtained residue was purified by preparative thin-layer chromatography (n-hexane: ethyl acetate = 1: 1) and crystallized from ether to give [N-tert-butoxycarbonyl-O- (2,3,4). -Tri-O-benzyl-α-L-fucofuranosyl) -L-seryl] -D-glutamic acid 1-anilide-5-benzyl ester (0.
46 g) were obtained as colorless crystals.

Melting point: 135-139 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 1.04 (d, 3H, J = 6.2 Hz), 1.32 (s, 9
H), 1.82-2.00 (m, 1H), 2.00-2.20 (m, 1H), 2.30-2.50 (m, 2
H), 3.47-3.58 (m, 1H), 3.58-3.70 (m, 2H), 3.70-3.85 (m, 1
H), 4.00 (d, 2H, J = 4.6Hz), 4.32-4.50 (m, 7H), 5.02 (s, 2H),
5.07 (s, 1H), 6.87 (d, 1H, J = 6.9Hz), 7.05 (t, 1H, J = 7.3Hz),
7.14-7.42 (m, 22H), 7.61 (d, 2H, J = 7.8Hz), 8.33 (d, 1H, J = 7.
5Hz), 9.93 (s, 1H).

Example 26 [N- (2-tetradecylhexadecanoyl) -O-
(2,3,4-tri-O-benzyl-α-L-fucofura
Nosyl) -L-seryl] -D-glutamic acid 1-ani
Lido-5-benzyl ester [in the general formula (II-4)
R ¹ is a 1-tetradecyl pentadecyl group, R ⁴ is
Phenylcarbamoyl group, α-ano of a compound wherein n is 1
Mer] Preparation of the compound of Example 25 (0.41 g) was dissolved in methylene chloride (8 ml), TFA under ice-cooling and stirring
(8 ml) was added and stirred for 2 hours. Concentrate the reaction,
Chloroform (50 ml) was added, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off. The syrup of the obtained deprotected product was dissolved in DMF (40 ml),
-Tetradecylhexadecanoic acid (0.2 g) followed by WSC (0.13 g) and HOBt under ice-cooled stirring.
(0.1 g), and the mixture was stirred for 22 hours while gradually returning to room temperature. Chloroform (100 ml) was added to the reaction solution, and the mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried and evaporated. The obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 20: 1) to give [N-
(2-tetradecylhexadecanoyl) -O- (2,
3,4-Tri-O-benzyl-α-L-fucofuranosyl) -L-seryl] -D-glutamic acid 1-anilide-5-benzyl ester (0.28 g) was obtained as colorless crystals.

Melting point: 131-135 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m, 6H), 0.94-1.60
(m, 55H), 1.78-1.96 (m, 1H), 2.00-2.50 (m, 4H), 3.49-3.71
(m, 3H), 3.72-3.88 (m, 1H), 3.94-4.08 (m, 2H), 4.44 (dd, 2H,
J = 4.1,11.5Hz), 4.52-4.70 (m, 5H), 5.00 (s, 1H), 5.04 (d, 1
(H, J = 3.3Hz), 7.03 (t, 1H, J = 7.4Hz), 7.15-7.41 (m, 22H), 7.6
9 (d, 2H, J = 7.8Hz), 8.15 (d, 1H, J = 6.8Hz), 8.47 (d, 1H, J = 8.0Hz)
. Hz), 9.80 (s, 1H) as the element analysis _{(C 78 H 111 N 3 O} 10): Calculated (%) C, 74.90; H , 8.94; N, 3.36 Found (% ) C, 74.67; H, 8.97; N, 3.21.

Example 27 [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucofuranosyl) -L-seryl] -D-glu
Tamic acid 1-anilide [In the general formula (Ib), R
¹ is a 1-tetradecylpentadecyl group, R ² is phenylca
Α-anomer of a compound having a rubamoyl group and n is 1]
Production : 20% Pd (OH) ₂ (0.20 g) in a solution of the compound of Example 26 (0.23 g) in ethanol (40 ml)
g), and the mixture was stirred at 30 ° C. for 7 hours under hydrogen pressure (3 to 4 atm). After removing the catalyst by filtration, the solvent was distilled off, and water (5 ml) was added to the obtained residue to crystallize [N- (2
-Tetradecylhexadecanoyl) -O- (α-L-fucofuranosyl) -L-seryl] -D-glutamic acid 1
-Anilide (127 mg) was obtained.

Melting point: 150-153 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.83-0.87 (m, 6H), 1.00 (d, 3H, J
= 6.3Hz), 1.08-1.55 (m, 52H), 1.75-1.91 (m, 1H), 1.98-2.18
(m, 1H), 2.18-2.32 (m, 3H), 3.45-3.60 (m, 2H), 3.69-3.82
(m, 2H), 3.88 (dd, 1H, J = 6.6,10.0Hz), 4.34-4.54 (m, 2H), 4.
72 (d, 1H, J = 3.7Hz), 5.12 (s, 1H), 7.04 (t, 1H, J = 7.4Hz), 7.2
8 (t, 2H, J = 7.6Hz), 7.68 (d, 1H, J = 8.6Hz), 8.08-8.23 (m, 2
H), 12.50 (bs, 1H). Mass spectrum (m / e): 890 (M + H) ⁺

Example 28 [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucofuranosyl) -L-seryl] -D-glu
Tamic acid 1-methylamide [odor of the general formula (Ib)
R ¹ is a 1-tetradecyl pentadecyl group, R ² is methyl
Α-anomer of a compound having a rucarbamoyl group and n is 1
Preparation of the sodium salt of the compound of Example 18 (0.
20 g) of methanol (30 ml) and water (10 m
1) sodium hydroxide solution (0.12
ml) and stirred for 5 minutes. Then, methanol is distilled off under reduced pressure, and the residue is freeze-dried to give sodium [N- (2-tetradecylhexadecanoyl) -O- (α-L-fucofuranosyl) -L-seryl] -D-glutamic acid 1-methylamide sodium. The salt (141 mg) was obtained as a colorless solid.

Melting point: 147-154 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 0.83-0.87 (m, 6H), 1.01 (d, 3H,
J = 6.3Hz), 1.10-1.55 (m, 52H), 1.60-2.05 (m, 4H), 2.10-2.3
2 (m, 1H), 2.55 (d, 3H, J = 3.5Hz), 3.20-3.35 (m, 2H), 3.40-3.
65 (m, 3H), 3.66-3.76 (m, 1H), 3.77-3.86 (m, 1H), 3.86-4.04
(m, 2H), 4.35 (s, 1H), 4.66 (d, 1H, 4.2Hz), 8.23 (d, 1H, J = 7.4
Hz), 9.19 (d, 1H, J = 5.8Hz).

Example 29 [N- (2-undecyltridecanoyl) -O- (2
3,4-tri-O-benzyl-α-L-fucofuranosi
1) -D-seryl] -L-glutamic acid 1-methyla
Mido-5-benzyl ester [in the general formula (II-4)
R ¹ is a 1-undecyldodecyl group, R ⁴ is methyl
Α-anomer of a compound having a carbamoyl group and n is 1]
Preparation of : The compound of Example 3 (0.46 g) was dissolved in methylene chloride (5 ml), and TFA (5 ml) was stirred under ice-cooling.
Was added and stirred for 2.5 hours. The reaction solution was concentrated, chloroform (100 ml) was added, washed with a saturated aqueous solution of sodium carbonate, dried, and the solvent was distilled off. The obtained syrup of the deprotected product was dissolved in DMF (15 ml), 2-undecyltridecanoic acid (0.2 g) was added, and then WSC (0.16 g) and HOBt (0. 12
g) was added, and the mixture was stirred for 19 hours while gradually returning to room temperature. Ethyl acetate (120 ml) was added to the reaction solution, and the mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried, and the solvent was distilled off. The obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 20: 1) to give the title stereoisomer (0.38 g) as colorless crystals.

Melting point: 117-119 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.8-0.95 (m, 6H), 1.1-1.45 (m, 42
H), 1.75-2.1 (m, 2H), 2.1-2.3 (m, 1H), 2.3-2.6 (m, 2H), 2.64
(d, 3H, J = 4.7Hz), 3.5-3.7 (m, 2H), 3.81 (dd, 1H, J = 5.2,6.8H
z), 3.95-4.2 (m, 3H), 4.3-4.7 (m, 8H), 4.94 (d, 1H, J = 4.3H
z), 5.04 (d, 1H, J = 12Hz), 5.1 (d, 1H, J = 12Hz), 6.35 (q, 1H, J =
4.6Hz), 6.82 (d, 1H, J = 6.1Hz), 6.97 (d, 1H, J = 8.1Hz), 7.15-
7.4 (m, 20H) (as _{C 67 H 97 N 3 O 10} ) Elementary analysis:. Calculated (%) C, 72.80; H , 8.87; N, 3.80 Found (%) C, 72.76; H, 8.88; N, 3.80

Example 30 [N- (2-dodecyltetradecanoyl) -O- (2
3,4-tri-O-benzyl-α-L-fucofuranosi
1) -D-seryl] -L-glutamic acid 1-methyla
Mido-5-benzyl ester [in the general formula (II-4)
R ¹ is a 1-dodecyltridecyl group, R ⁴ is methylca
Α-anomer of a compound having a rubamoyl group and n is 1]
Production : The compound of Example 3 (0.55 g) was dissolved in chloroform (5 ml), TFA (5 ml) was added under ice cooling and stirring, and the mixture was stirred for 3.5 hours. The reaction solution was concentrated, chloroform (80 ml) was added, washed with a saturated aqueous solution of sodium carbonate, dried, and the solvent was distilled off. The obtained deprotected syrup was dissolved in DMF (28 ml), and 2-dodecyltetradecanoic acid (0.28 g) was added. Then, under ice-cooling and stirring, WSC (0.19 g) and HOBt (0.15 g) were added.
And stirred for 20 hours while gradually returning to room temperature. Ethyl acetate (100 ml) was added to the reaction solution, and the mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried, and the solvent was distilled off. The resulting residue is purified by preparative thin-layer chromatography (chloroform: Me
OH = 20: 1) to give the title stereoisomer (0.51
g) was obtained as colorless crystals.

Melting point: 120-122 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.8-0.95 (m, 6H), 1.05-1.45 (m, 42)
H), 1.45-1.65 (m, 2H), 1.75-2.05 (m, 2H), 2.1-2.3 (m, 1H),
2.3-2.5 (m, 2H), 2.65 (d, 3H, J = 4.8Hz), 3.5-3.68 (m, 2H), 3.
81 (dd, 1H, J = 5.1,6.8Hz), 3.99 (dd, 1H, J = 5.4,10.5Hz), 4.0
7 (dd, 1H, J = 4.3,7.4Hz), 4.1-4.2 (m, 1H), 4.3-4.7 (m, 8H),
4.95 (d, 1H, J = 4.3Hz), 5.04 (d, 1H, J = 12.4Hz), 5.1 (d, 1H, J =
12.3 Hz), 6.94 (d, 1 H, J = 7.8 Hz), 7.15-7.4 (m, 20 H). Elemental analysis (as C ₆₁ H ₁₀₁ N ₃ O ₁₀ ): Calculated value (%) C, 73.10; H, 9.01; N, 3.71 found (%) C, 73.12; H, 9.10; N, 3.63.

Example 31 [N- (2-tridecylpentadecanoyl) -O-
(2,3,4-tri-O-benzyl-α-L-fucofura
Nosyl) -D-seryl] -L-glutamic acid 1-methyl
Luamide-5-benzyl ester [general formula (II-4)
In the formula, R ¹ is a 1-tridecyltetradecyl group, and R ⁴ is
Α-ano of a compound in which a methylcarbamoyl group and n is 1
Mer] Preparation of the compound of Example 3 (0.6 g) was dissolved in chloroform (5 ml), under ice-cooling and stirring TFA (5 m
l) was added and stirred for 2 hours. The reaction solution was concentrated, chloroform (80 ml) was added, washed with a saturated aqueous solution of sodium carbonate, dried, and the solvent was distilled off. The syrup of the obtained deprotected product was dissolved in DMF (40 ml), and 2-tridecylpentadecanoic acid (0.33 g) was added thereto.
g) was added, and the mixture was stirred for 21 hours while gradually returning to room temperature. Ethyl acetate (100 ml) was added to the reaction solution, and the mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried, and the solvent was distilled off. The obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 30: 1) to give the title stereoisomer (0.32 g) as colorless crystals.

Melting point: 110-116 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.8-0.95 (m, 6H), 1.05-1.65 (m, 51
H), 1.75-2.1 (m, 2H), 2.1-2.3 (m, 1H), 2.3-2.6 (m, 2H), 2.65
(d, 3H, J = 4.6Hz), 3.5-3.7 (m, 2H), 3.75-3.85 (m, 1H), 3.9-
4.2 (m, 1H), 4.3-4.75 (m, 7H), 4.95 (d, 1H, J = 3.9Hz), 5.0-5.
15 (m, 2H), 6.32 (q, 1H, J = 4.8Hz), 6.73 (d, 1H, J = 6.2Hz), 6.9
. 5 (d, 1H, J = 8.2Hz), ( as _{C 71 H 105 N 3 O 10} ) 7.15-7.4 (m, 20H) Elemental analysis: Calculated (%) C, 73.40; H , 9. 14; N, 3.62 found (%) C, 73.39; H, 9.16; N, 3.50

Example 32 [N- (2-undecyltridecanoyl) -O- (α-
L-fucofuranosyl) -D-seryl] -L-glutamine
Acid 1-methylamide [in the general formula (Ib), R ¹
Is a 1-undecyldodecyl group, R ² is methylcarbamoy
Α-anomer of a compound in which n is 1 ): Preparation of the compound of Example 29 (0.35 g) in ethanol (30 m
l) solution 20% Pd a (OH ₂ /C(0.3g) was added to a hydrogen pressure (3-4 atm) was stirred for 6 hours under room temperature.
After the catalyst was removed by filtration, the solvent was distilled off, and the obtained residue was added with ether:
Crystallization was performed by adding n-hexane (1: 1) to give the title stereoisomer (0.22 g) as colorless crystals.

Melting point: 141-145 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m, 6H), 1.03 (d, 3H, J
= 6.4Hz), 1.1-1.55 (m, 40H), 1.55-1.8 (m, 1H), 1.8-2.05 (m,
1H), 2.08-2.35 (m, 3H), 2.57 (d, 3H, J = 4.5Hz), 3.42-3.6 (m,
1H), 3.62 (dd, 1H, J = 5.3,10.6Hz), 3.7-3.9 (m, 3H), 4.1-4.3
(m, 1H), 4.3-4.45 (m, 1H), 4.5-4.8 (m, 2H), 5.17 (s, 1H), 7.7
7 (d, 1H, J = 4.7Hz), 7.89 (d, 1H, J = 7.7Hz), 8.13 (d, 1H, J = 7.1
Hz), 12.05 (bs, 1H). Elemental analysis (as C ₃₉ H ₇₃ N ₃ O ₁₀ .1H ₂ O): Calculated (%) C, 61.47; H, 9.92; N, 5.51. Obtained value (%) C, 61.71; H, 9.82; N, 5.45 Mass spectrum: 744 (M + H) ⁺

Example 33 [N- (2-dodecyltetradecanoyl) -O- (α-
L-fucofuranosyl) -D-seryl] -L-glutamine
Acid 1-methylamide [in the general formula (Ib), R ¹
Is a 1-dodecyltridecyl group, and R ² is methylcarbamoy.
Α-anomer of a compound in which n is 1 ): Preparation of the compound of Example 30 (0.35 g) in ethanol (30 m
1) 20% Pd (OH) _{2 /} C (0.3 g) was added to the solution, and the mixture was stirred at 30 ° C. for 4 hours under hydrogen pressure (3 to 4 atm). After removing the catalyst by filtration, the solvent was distilled off, and the precipitated crystals were collected by filtration to give the title stereoisomer (0.19 g) as colorless crystals. Melting point: 138-145 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.9 (m, 6H), 1.03 (d, 3H, J =
6.4Hz), 1.1-1.55 (m, 40H), 1.55-1.8 (m, 1H), 1.85-2.1 (m, 1
H), 2.1-2.35 (m, 3H), 2.57 (d, 3H, J = 4.5Hz), 3.45-3.6 (m, 1
H), 3.6-3.7 (m, 1H), 3.7-3.85 (m, 3H), 4.1-4.28 (m, 1H), 4.3
-4.42 (m, 1H), 4.42-4.5 (m, 1H), 4.55-4.7 (m, 1H), 4.7-4.8
(m, 1H), 5.05-5.2 (m, 1H), 7.76 (q, 1H, J = 4.8Hz), 7.84 (d, 1
H, J = 8.2 Hz), 8.08 (d, 1 H, J = 7.3 Hz). Elemental analysis (as C ₄₁ H ₇₇ N ₃ O ₁₀ .0.5H ₂ O): Calculated value (%) C, 63.05 N, 5.38 Found (%) C, 62.93; H, 9.85; N, 5.44 Mass spectrum: 772 (M + H) ^<+>;

Example 34 [N- (2-tridecylpentadecanoyl) -O- (α
-L-fucofuranosyl) -D-seryl] -L-glutamic
Acid 1-methylamide [in the general formula (Ib), R
¹ is a 1-tridecyltetradecyl group, R ² is methylcar
Α-anomer of a compound having a bamoyl group and n is 1]
Concrete: Ethanol (30ml) was added 20% Pd of the compound of Example _{31 (0.28g) (OH) 2} /C(0.2
3 g) and stirred at 30 ° C. for 5 hours under hydrogen pressure (3 to 4 atm). After the catalyst was removed by filtration, the solvent was distilled off, and ether was added to the obtained residue to cause crystallization, whereby the title stereoisomer (0.16 g) was obtained as colorless crystals. Melting point: 146-149 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m, 6H), 1.03 (d, 3H, J
= 6.3Hz), 1.1-1.55 (m, 48H), 1.55-1.8 (m, 1H), 1.85-2.07
(m, 1H), 2.1-2.35 (m, 3H), 2.57 (d, 3H, J = 4.5Hz), 3.45-3.6
(m, 1H), 3.6-3.7 (m, 1H), 3.7-3.85 (m, 3H), 4.1-4.28 (m, 1
H), 4.3-4.45 (m, 1H), 7.76 (q, 1H, J = 4.6Hz), 7.84 (d, 1H, J =
8.3 Hz), 8.08 (d, 1H, J = 7.0 Hz). Elemental analysis (as C ₄₃ H ₈₁ N ₃ O ₁₀ .0.5H ₂ O): Calculated value (%) C, 63.83; H, 10 N, 5.19 Found (%) C, 63.70; H, 10.10; N, 5.00 Mass spectrum: 800 (M + H) ⁺

Example 35 [N- (2-pentadecylheptadecanoyl) -O-
(2,3,4-tri-O-benzyl-α-L-fucofura
Nosyl) -D-seryl] -L-glutamic acid 1-methyl
Luamide-5-benzyl ester [general formula (II-4)
In the formula, R ¹ is a 1-pentadecylhexadecyl group,
Α- of the compound in which ⁴ is a methylcarbamoyl group and n is 1
Production of Anomer] : The compound of Example 3 (0.5 g) was dissolved in chloroform (5 ml), and TFA was stirred under ice cooling.
(5 ml) was added and stirred for 3 hours. Concentrate the reaction,
Ethyl acetate (100 ml) was added, washed with a saturated aqueous solution of sodium carbonate, dried, and the solvent was distilled off. The obtained deprotected syrup was dissolved in DMF (30 ml), 2-pentadecylheptadecanoic acid (0.28 g) was added, and the mixture was heated and dissolved. After returning to room temperature, WSC (146 mg) and H
After adding OBt (116 mg) and stirring at 50 ° C. for 4 hours,
Stirred overnight at room temperature. Ethyl acetate (200m
l) was added thereto, washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in that order, dried, and the solvent was distilled off. The obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 20: 1) to give the title stereoisomer (0.42 g) as colorless crystals.

Melting point: 117-119 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.75-0.95 (m, 6H), 1.05-1.65 (m, 5
9H), 1.75-2.1 (m, 2H), 2.1-2.3 (m, 1H), 2.3-2.55 (m, 2H), 2.
65 (d, 3H, J = 4.75Hz), 3.5-3.7 (m, 2H), 3.81 (dd, 1H, J = 5.2,
6.7Hz), 3.9-4.2 (m, 4H), 4.25-4.75 (m, 7H), 4.96 (d, 1H, J =
4.3Hz), 5.05 (d, 1H, J = 12.5Hz), 5.1 (d, 1H, J = 12.4Hz), 6.28
(q, 1H, J = 4.5Hz), 6.66 (d, 1H, J = 6.2Hz), 6.93 (d, 1H, J = 8.0H
z), 7.15-7.4 (m, 20H).

Example 36 [N- (2-pentadecylheptadecanoyl) -O-
(Α-L-fucofuranosyl) -D-seryl] -L-glu
Tamic acid 1-methylamide [odor of the general formula (Ib)
R ¹ is a 1-pentadecylhexadecyl group, R ² is methyl
Α-anomer of a compound having a rucarbamoyl group and n is 1
Over] Preparation of ethanol of the compound of Example 35 (0.68g) (150ml) was added _{20% Pd (OH) 2 /} C
(0.6 g), and the mixture was stirred at room temperature under hydrogen pressure (3 to 4 atm) for 6.5 hours. After removing the catalyst by filtration, the solvent was distilled off, and the precipitated solid was filtered from water to give the title stereoisomer (0.39
g) was obtained as colorless crystals.

Melting point: 141-144 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m, 6H), 1.04 (d, 3H, J
= 6.4Hz), 1.1-1.55 (m, 56H), 1.6-1.8 (m, 1H), 1.85-2.05 (m,
1H), 2.1-2.35 (m, 3H), 2.58 (d, 3H, J = 4.5Hz), 3.45-3.6 (m, 1
H), 3.6-3.85 (m, 4H), 4.1-4.28 (m, 1H), 4.3-4.45 (m, 2H), 4.
56 (bs, 1H), 4.7-4.8 (m, 1H), 5.06 (bs, 1H), 7.72 (q, 1H, J = 4.
8Hz), 7.79 (d, 1H, J = 8.4Hz), 8.02 (d, 1H, J = 6.9Hz), 12.0 (b
s, 1H). Mass spectrum: 878 (M + Na) ⁺

Example 37 [N-tert-butoxycarbonyl-O- (2,3,
4-tri-O-benzyl-α-L-fucopyranosyl)-
L-seryl] -L-glutamic acid 1-methylamide-
5-benzyl ester [in the general formula (II-1),
R ⁴ is a methylcarbamoyl group and n is 1
-Anomer] : Molecular sieves 4Å
(1.0 g) to AgOTf (1.2 g), SnCl
₂ (0.9 g) and chloroform (20 ml) were added, and the mixture was stirred at room temperature under nitrogen for 6 hours. Then, -40 to-
After cooling to 50 ° C., TMU (1.4 ml) was added, followed by chloroform (2 ml) of (2,3,4-tri-O-benzyl) -L-fucopyranosyl-fluoride [1.5 g, compound (VI)]. ) Solution and N-tert-butoxycarbonyl-L-seryl-L-glutamic acid 1-methylamido-5-benzyl ester [1.0 g, Reference Example 1
Stereoisomers] in chloroform (6 ml),
After stirring at the same temperature for 1 hour, the mixture was stirred for 17 hours while gradually returning to room temperature. After filtering the reaction solution, the filtrate was concentrated and the resulting residue was purified by silica gel medium pressure liquid chromatography (n-hexane: ethyl acetate = 1: 2 → 2: 1) to give the title stereoisomer (0.66 g) ) Was obtained as colorless crystals.

[Α] _D −53 ° (c = 0.17, C
HCl ₃ ) Melting point: 141-142 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.09 (d, 3H, J = 6.5 Hz), 1.45 (s, 9)
H), 1.65-1.9 (m, 1H), 2.05-2.55 (m, 3H), 2.74 (d, 3H, J = 4.8H
z), 3.4-3.5 (m, 1H), 3.63 (d, 1H, J = 1.6Hz), 3.75-3.9 (m, 2
H), 4.02 (dd, 1H, J = 3.6,10.1Hz), 4.12-4.28 (m, 2H), 4.35-
4.5 (m, 1H), 4.5-4.95 (m, 7H), 5.06 (s, 2H), 6.04 (bs, 1H), 6.
33 (bs, 1H), 7.05 (d, 1H, J = 8.3Hz), 7.2-7.4 (m, 20H) Elemental analysis (as _{C 48 H 59 N 3 O 11} · 0.5H 2 O):. Calculated (%) C, 66.80; H, 7.01; N, 4.87 Found (%) C, 66.99; H, 6.71; N, 4.80.

Example 38 [N-tert-butoxycarbonyl-O- (2,3,3
4-tri-O-benzyl-α-L-fucopyranosyl)-
L-seryl] -D-glutamic acid 1-methylamide-
5-benzyl ester [in the general formula (II-1),
R ⁴ is a methylcarbamoyl group and n is 1
-Anomer] : Molecular sieves 4Å
(1.0 g) to AgOTf (0.94 g), SnCl ₂
(0.69 g) and chloroform (10 ml) were added, and the mixture was stirred at room temperature under nitrogen for 5 hours. Then, -40 to-
After cooling to 50 ° C, TMU (1.06 g) was added, followed by chloroform (1 ml) of (2,3,4-tri-O-benzyl) -L-fucopyranosyl-fluoride [1.2 g, compound (VI)]. ) Solution and N-tert-butoxycarbonyl-L-seryl-D-glutamic acid 1-methylamide-5-benzyl ester [0.8 g, Reference Example 2
Stereoisomers] in chloroform (3 ml),
After stirring at the same temperature for 1 hour, the mixture was stirred for 14 hours while gradually returning to room temperature. After the reaction solution was filtered, the filtrate was concentrated, and the obtained residue was purified by silica gel medium pressure liquid chromatography (n-hexane: ethyl acetate = 1: 1 → 1: 2) to give the title stereoisomer (1. 03g) was obtained as a syrup.

[Α] _D -43 ° (c = 0.1, CH
Cl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.11 (d, 3H, J = 6 Hz), 1.45 (s, 9H),
1.8-2.0 (m, 1H), 2.0-2.25 (m, 1H), 2.3-2.6 (m, 2H), 2.71 (d,
3H, J = 5Hz), 3.47 (dd, 1H, J = 5,10Hz), 3.65 (d, 1H, J = 2Hz), 3.
81 (q, 1H, J = 7Hz), 3.92 (dd, 1H, J = 3,10Hz), 4.03 (dd, 1H, J =
4,10Hz), 7.0-7.4 (m, 20H).

Example 39 [N-tert-butoxycarbonyl-O- (2,3,3
4-tri-O-benzyl-α-L-fucopyranosyl)-
D-seryl] -L-glutamic acid 1-methylamide-
5-benzyl ester [in the general formula (II-1),
R ⁴ is a methylcarbamoyl group and n is 1
-Anomer] : Molecular sieves 4Å
(0.5 g) to AgOTf (0.59 g), SnCl ₂
(0.43 g) and chloroform (10 ml) were added, and the mixture was stirred at room temperature under nitrogen for 5 hours. Then, -40 to-
After cooling to 50 ° C., TMU (0.66 g) was added, followed by chloroform (1 ml) of (2,3,4-tri-O-benzyl) -L-fucopyranosyl-fluoride [0.75 g, compound (VI)]. )) Solution and a solution of N-tert-butoxycarbonyl-D-seryl-L-glutamic acid 1-methylamido-5-benzyl ester [0.5 g, stereoisomer of Reference Example 3] in chloroform (3 ml), and the mixture was added at the same temperature. After stirring for 1 hour, slowly return to room temperature for 1 hour.
Stir for 7 hours. After filtering the reaction solution, the filtrate was concentrated and the resulting residue was purified by preparative thin-layer chromatography (cyclohexane: ethyl acetate = 1: 1) to give the title stereoisomer (0.38 g) as colorless crystals. Was. [Α] _D -59 ° (c = 0.1, CHCl ₃ ) Melting point: 77-81 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.13 (d, 3H, J = 6.5 Hz), 1.43 (s, 9
H), 1.7-2.1 (m, 1H), 2.1-2.3 (m, 1H), 2.3-2.6 (m, 2H), 2.67
(d, 3H, J = 4.8Hz), 3.5-3.7 (m, 2H), 3.8-4.0 (m, 3H), 4.0-4.2
5 (m, 2H), 4.25-4.45 (m, 1H), 4.5-5.0 (m, 7H), 5.0-5.2 (m, 2
. H), 5.5 (bs, 1H), 6.07 (bs, 1H), 7.1-7.45 (m, 20H) Elemental analysis (as _{C 48 H 59 N 3 O 11} ): Calculated (%) C, 67.51 N, 4.92 Found (%) C, 67.56; H, 6.94; N, 4.52;

Example 40 [N-tert-butoxycarbonyl-O- (2,3,
4-tri-O-benzyl-α-L-fucopyranosyl)-
D-seryl] -D-glutamic acid 1-methylamide-
5-benzyl ester [in the general formula (II-1),
R ⁴ is a methylcarbamoyl group and n is 1
-Anomer] : Molecular sieves 4Å
(1.3 g) to AgOTf (0.93 g), SnCl ₂
(0.69 g) and chloroform (8 ml) were added,
Stirred at room temperature under nitrogen for 4 hours. Then, -40 to -50
C., TMU (0.66 g) was added, followed by (2,3,4-tri-O-benzyl) -L-fucopyranosyl-fluoride [0.95 g, compound (VI)] in chloroform (1 ml). A solution and a solution of N-tert-butoxycarbonyl-D-seryl-D-glutamic acid 1-methylamide-5-benzyl ester [0.77 g, stereoisomer of Reference Example 4] in chloroform (3 ml) were added. After stirring for 2 hours, gradually return to room temperature for 2 hours.
Stirred for 0 hours. After filtering the reaction solution, the filtrate was concentrated and the resulting residue was purified twice by preparative thin-layer chromatography (cyclohexane: ethyl acetate = 1: 2) and (1: 1) to give the title stereoisomer (0 .33 g) as colorless crystals.

Melting point: 109-116 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.13 (d, 3H, J = 6.5 Hz), 1.44 (s, 9
H), 1.6-1.75 (m, 1H), 2.0-2.15 (m, 1H), 2.15-2.4 (m, 2H), 2.
71 (d, 3H, J = 4.8Hz), 3.55-3.7 (m, 2H), 3.75-4.0 (m, 3H), 4.0
7 (dd, 1H, J = 3.7,10.2Hz), 4.1-4.25 (m, 1H), 4.25-4.4 (m, 1
H), 4.6-5.0 (m, 7H), 5.07 (s, 2H), 5.52 (bs, 1H), 6.4 (bs, 1
H), 7.1-7.5 (m, 20H)

Example 41 [N- (2-tetradecylhexadecanoyl) -O-
(2,3,4-tri-O-benzyl-α-L-fucopyra
Nosyl) -L-seryl] -L-glutamic acid 1-methyl
Lumid-5-benzyl ester [general formula (II-2)
In the formula, R ¹ is a 1-tetradecylpentadecyl group, R ⁴
Is a methylcarbamoyl group and n is 1
Production of Nomer] : The compound of Example 37 (0.6 g) was dissolved in chloroform (6 ml), and TFA was stirred under ice cooling.
(6 ml) and stirred at room temperature for 1 hour. The reaction solution was concentrated, ethyl acetate (40 ml) was added, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off. The syrup of the obtained deprotected product was dissolved in DMF (27 ml), 2-tetradecylhexadecanoic acid (0.32 g) was added, and after heating and dissolution, the temperature was returned to room temperature. WSC (0.18 mg)
And HOBt (0.14 mg) were added, and the mixture was stirred at room temperature for 17 hours. Chloroform (100 ml) was added to the reaction solution, and the mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried and evaporated. The obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 25: 1) to give the title stereoisomer (0.6 g) as colorless crystals.

[Α] _D -44 ° (c = 0.24, CH
Cl ₃ ) Melting point: 133-135 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.8-0.95 (m, 6H), 1.13 (d, 3H, J = 6.
5Hz), 1.1-1.6 (m, 52H), 1.7-2.0 (m, 2H), 2.0-2.25 (m, 1H),
2.25-2.55 (m, 2H), 2.71 (d, 3H, J = 4.8Hz), 3.37 (dd, 1H, J = 5.
9,9.4Hz), 3.67 (d, 1H, J = 1.7Hz), 3.85-3.95 (m, 2H), 4.06 (d
d, 1H, J = 3.6,10.1Hz), 4.21 (dd, 1H, J = 2.8,9.5Hz), 4.3-4.4
5 (m, 1H), 4.5-4.6 (m, 1H), 4.55-4.95 (m, 7H), 5.06 (s, 2H),
6.2-6.3 (m, 1H), 6.82 (d, 1H, J = 6.7Hz), 7.06 (d, 1H, J = 8Hz),
7.15-7.4 (m, 20H) (as _{C 73 H 109 N 3 O 10} ) Elementary analysis:. Calculated (%) C, 73.76; H , 9.24; N, 3.54 Found (%) C, 73.61; H, 9.07; N, 3.43.

Example 42 [N- (2-tetradecylhexadecanoyl) -O-
(2,3,4-tri-O-benzyl-α-L-fucopyra
Nosyl) -L-seryl] -D-glutamic acid 1-methyl
Lumid-5-benzyl ester [general formula (II-2)
In the formula, R ¹ is a 1-tetradecylpentadecyl group, R
Α- of the compound in which ⁴ is a methylcarbamoyl group and n is 1
Preparation of Anomer] : Compound of Example 38 (0.52 g)
Was dissolved in chloroform (4 ml), and TF was stirred under ice-cooling.
A mixed solvent of A (2 ml) and chloroform (4 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, ethyl acetate (20 ml) was added, washed with a saturated aqueous solution of sodium carbonate and a saturated aqueous solution of sodium chloride, dried, and the solvent was distilled off. The syrup of the obtained deprotected product was added to DMF (1
0 ml), and 2-tetradecylhexadecanoic acid (0.33 g) was added.
(128 mg) and HOBt (102 mg)
Stirred at room temperature for 19 hours. Add chloroform (10
0 ml), washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in that order, dried and evaporated. The obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 25: 1) to give the title stereoisomer (330 mg) as colorless crystals.

[Α] _D -29 ° (c = 0.1, CH
Cl ₃ ) Melting point: 119-120 ° C ¹ H-NMR (CDCl ₃ ) δ: 0.75-0.95 (m, 6H), 1.1-1.7 (m, 52
H), 1.13 (d, 3H, J = 6Hz), 1.75-2.0 (m, 2H), 2.0-2.2 (m, 1H),
2.25-2.6 (m, 2H), 2.73 (d, 3H, J = 5Hz), 3.37 (dd, 1H, J = 5,9H
z), 3.67 (s, 1H), 3.85 (q, 1H, J = 6Hz), 3.97 (dd, 1H, J = 2,10H
z), 4.06 (dd, 1H, J = 3, 10Hz), 7.0-7.4 (m, 20H).

Example 43 [N- (2-tetradecylhexadecanoyl) -O-
(2,3,4-tri-O-benzyl-α-L-fucopyra
Nosyl) -D-seryl] -L-glutamic acid 1-methyl
Lumid-5-benzyl ester [general formula (II-2)
In the formula, R ¹ is a 1-tetradecylpentadecyl group, R ⁴
Is a methylcarbamoyl group and n is 1
Production of Nomer] : The compound of Example 39 (0.31 g) was dissolved in chloroform (7 ml), and TFA was stirred under ice cooling.
(7 ml) and stirred at room temperature for 1 hour. The reaction solution was concentrated, ethyl acetate (20 ml) was added, washed with a saturated aqueous solution of sodium carbonate, dried, and the solvent was distilled off. The resulting deprotected syrup was dissolved in DMF (30 ml),
-Tetradecylhexadecanoic acid (0.17 g) was added,
After dissolution by heating, the temperature was returned to room temperature, and WSC (90 mg) and HO
Bt (72 mg) was added, and the mixture was stirred at room temperature for 14 hours. Ethyl acetate (100 ml) was added to the reaction solution, and the mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried, and the solvent was distilled off. The resulting residue is purified by preparative thin-layer chromatography (chloroform: Me
OH = 25: 1) to give the title stereoisomer (115 m
g) was obtained as colorless crystals.

[Α] _D -44 ° (c = 0.1, CHC
l ₃₎ ^{mp: 118~120 ℃ 1 H-NMR (} CDCl 3) δ: 0.8-0.95 (m, 6H), 1.12 (d, 3H, J = 6.
5Hz), 1.15-1.7 (m, 52H), 1.75-1.92 (m, 1H), 1.92-2.1 (m, 1
H), 2.1-2.3 (m, 1H), 2.3-2.6 (m, 2H), 2.66 (d, 3H, J = 4.8Hz),
3.45-3.65 (m, 2H), 3.78-3.95 (m, 3H), 4.08 (dd, 1H, J = 4.2,1
0.2Hz), 4.15-4.25 (m, 2H), 4.6-5.0 (m, 7H), 5.05 (d, 1H, J = 1
1.9Hz), 5.1 (d, 1H, J = 12.3Hz), 6.0-6.1 (m, 1H), 6.47 (d, 1H,
. J = 6.7Hz), 7.15-7.4 ( m, 20H) Elemental analysis (as _{C 73 H 109 N 3 O 10} ): Calculated (%) C, 73.76; H , 9.24; N, 3. 54 found (%) C, 73.48; H, 9.13; N, 3.47.

Example 44 [N- (2-tetradecylhexadecanoyl) -O-
(2,3,4-tri-O-benzyl-α-L-fucopyra
Nosyl) -D-seryl] -D-glutamic acid 1-methyl
Lumid-5-benzyl ester [general formula (II-2)
In the formula, R ¹ is a 1-tetradecylpentadecyl group, R ⁴
Is a methylcarbamoyl group and n is 1
Production of Nomer] : The compound of Example 40 (0.42 g) was dissolved in chloroform (9 ml), and TFA was stirred under ice cooling.
(9 ml), and the mixture was stirred under ice cooling for 3 hours. The reaction solution was concentrated, ethyl acetate (40 ml) was added, washed with a saturated aqueous solution of sodium carbonate, dried, and the solvent was distilled off. The obtained residue was purified by preparative thin-layer chromatography (chloroform: methanol = 10: 1) to obtain a deprotected syrup. This syrup was dissolved in DMF (10 ml), and 2-tetradecylhexadecanoic acid (0.18 g) was dissolved.
, And after heating and dissolving, WSC (80 mg) and HOB
t (70 mg) was added, and the mixture was stirred at 50 ° C. for 5 minutes and then at room temperature for 14 hours. Ethyl acetate (50 ml) was added to the reaction solution.
Was added, and the mixture was washed successively with 0.1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried and evaporated. The obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 30: 1) to give the title stereoisomer (318 mg) as colorless crystals.

[Α] _D -19 ° (c = 0.1, CHC
l ₃₎ ^{mp: 130~132 ℃ 1 H-NMR (} CDCl 3) δ: 0.8-0.95 (m, 6H), 1.13 (d, 3H, J = 6.
5Hz), 1.1-1.7 (m, 53H), 1.9-2.4 (m, 4H), 2.69 (d, 3H, J = 4.8H
z), 3.56 (dd, 1H, J = 9.1,10.8Hz), 3.69 (d, 1H, J = 1.8Hz), 3.7
5-4.0 (m, 3H), 4.1 (dd, 1H, J = 3.5,6.5Hz), 4.2-4.35 (m, 1H),
4.45-4.55 (m, 1H), 4.63 (d, 1H, J = 11.6Hz), 4.68-4.9 (m, 4
H), 4.95 (d, 1H, J = 11.6Hz), 5.03 (d, 1H, J = 3.7Hz), 5.07 (s, 2
H), 6.34 (q, 1H, J = 4.8Hz), 6.43 (d, 1H, J = 6.1Hz), 7.1-7.5
. (m, 20H) (as _{C 73 H 109 N 3 O 10} ) Calcd (%) C, 73.76; H , 9.24; N, 3.54 Found (%) C, 73 .51; H, 9.15; N, 3.47

Example 45 [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucopyranosyl) -L-seryl] -L-glu
Tamic acid 1-methylamide [odor of general formula (Ia)
R ¹ is a 1-tetradecyl pentadecyl group, R ² is methyl
Α-anomer of a compound having a rucarbamoyl group and n is 1
Over] Preparation of ethanol of the compound of Example 41 (100mg) (50ml) was added _{20% Pd (OH) 2 /} C
(100 mg), and the mixture was stirred at room temperature under hydrogen pressure (3 to 4 atm) for 15 hours. After removing the catalyst by filtration, the solvent was distilled off, water (5 ml) was added to the obtained residue, and the precipitated solid was collected by filtration to obtain the title stereoisomer (51 mg) as a colorless powder.

[Α] _D -45 ° (c = 0.08, Me
OH) Melting point: 171-173 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m, 6H), 1.06 (d, 3H, J
= 6.5Hz), 1.1-1.6 (m, 52H), 1.6-2.0 (m, 2H), 2.1-2.3 (m, 3
H), 2.58 (d, 3H, J = 4.5Hz), 3.4-3.6 (m, 3H), 3.74 (q, 1H, J = 6.
9Hz), 3.86 (dd, 1H, J = 5.7, 9.3Hz), 4.15-4.4 (m, 3H), 4.45
4.6 (m, 2H), 7.63 (d, 1H, J = 8.2Hz), 7.82 (q, 1H, J = 4.4Hz), 8.
09 (d, 1H, J = 8.7Hz).

Example 46 [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucopyranosyl) -L-seryl] -D-glu
Tamic acid 1-methylamide [odor of general formula (Ia)
R ¹ is a 1-tetradecyl pentadecyl group, R ² is methyl
Α-anomer of a compound having a rucarbamoyl group and n is 1
-] : 98% of the compound of Example 42 (30 mg)
20% Pd in 1,4-dioxane (10 ml) aqueous solution
(OH) ₂ / C (30 mg) and pressurized with hydrogen (3-4
The mixture was stirred at room temperature for 4 hours. After removing the catalyst by filtration, the solvent was distilled off, and the obtained residue was dissolved in methanol (2 ml).
Water (2 ml) was added, and the precipitated solid was collected by filtration to give the title stereoisomer (17 mg) as a colorless powder.

[Α] _D -40 ° (c = 0.1, MeO
H) Melting point: 183-187 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m, 6H), 1.05 (d, 3H, J
= 6.5Hz), 1.1-1.55 (m, 52H), 1.55-1.75 (m, 1H), 1.75-2.0
(m, 1H), 2.05-2.3 (m, 3H), 2.57 (d, 3H, J = 4.5Hz), 3.3-3.55
(m, 4H), 3.67 (q, 1H, J = 6.8Hz), 3.85 (dd, 1H, J = 4.3,9.2Hz),
4.1-4.35 (m, 3H), 4.45-4.55 (m, 2H), 7.68 (d, 1H, 8Hz), 7.86
. (q, 1H, J = 4.5Hz), 8.13 (d, 1H, J = 7.9Hz), 11.9 (bs, 1H) Elemental analysis (as _{C 45 H 85 N 3 O 10} · 1H 2 O): Calculated (%) C, 63.87; H, 10.36; N, 4.97 found (%) C, 63.65; H, 10.25; N, 4.77.

Example 47 [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucopyranosyl) -D-seryl] -L-glu
Tamic acid 1-methylamide [odor of general formula (Ia)
R ¹ is a 1-tetradecyl pentadecyl group, R ² is methyl
Α-anomer of a compound having a rucarbamoyl group and n is 1
Over] Preparation of ethanol (50ml) was added 20% Pd of the compound of Example _{43 (80mg) (OH) 2} / C (8
0 mg), and the mixture was stirred at room temperature under hydrogen pressure (3 to 4 atm) for 4 hours. After removing the catalyst by filtration, the solvent was distilled off, water (5 ml) was added to the obtained residue, and the precipitated solid was collected by filtration to obtain the title stereoisomer (46 mg) as a colorless powder.

[Α] _D -62 ° (c = 0.1, MeO
H) Melting point: 179-183 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.9 (m, 6H), 1.06 (d, 3H, J =
6.4Hz), 1.1-1.55 (m, 52H), 1.6-1.8 (m, 1H), 1.8-2.1 (m, 1
H), 3.1-3.3 (m, 3H), 2.58 (d, 3H, J = 4.5Hz), 3.4-3.6 (m, 3H),
3.6-3.85 (m, 2H), 4.1-4.3 (m, 1H), 4.34 (d, 1H, J = 4.5Hz), 4.
4-4.55 (m, 1H), 7.45 (d, 1H, 4.4Hz), 7.97 (d, 1H, J = 7.0Hz),
8.05 (d, 1H, J = 8.0 Hz). Elemental analysis (as C ₄₅ H ₈₅ N ₃ O ₁₀ ): Calculated value (%) C, 65.26; H, 10.34; N, 5.07 Actual value (%) C, 64.87; H, 10.27; N, 4.80

Example 48 [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucopyranosyl) -D-seryl] -D-glu
Tamic acid 1-methylamide [odor of general formula (Ia)
R ¹ is a 1-tetradecyl pentadecyl group, R ² is methyl
Α-anomer of a compound having a rucarbamoyl group and n is 1
-] : 98 of the compound of Example 44 (300 mg)
20% P in aqueous 1,4-dioxane (100 ml)
d (OH) ₂ / C (300 mg) was added and hydrogen pressurization (3
4 atm) at room temperature for 4 hours. After removing the catalyst by filtration, the solvent was distilled off, the obtained residue was dissolved in methanol (12 ml), water (12 ml) was added, and the precipitated solid was collected by filtration to give the title stereoisomer (202 mg) as a colorless powder. As obtained.

[Α] _D −32 ° (c = 0.1, MeO
H) Melting point: 155-157 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.9 (m, 6H), 1.05 (d, 3H, J =
6.5Hz), 1.1-1.55 (m, 52H), 1.6-2.05 (m, 2H), 2.1-2.3 (m, 3
H), 2.57 (d, 3H, J = 4.5Hz), 3.55-3.8 (m, 2H), 4.1-4.25 (m, 1
H), 4.4-4.6 (m, 1H), 4.6-4.7 (m, 1H), 7.66 (q, 1H, J = 4.4Hz),
7.83 (d, 1H, J = 8.4 Hz), 7.92 (d, 1 H, J = 8.3 Hz). Elemental analysis (as C ₄₅ H ₈₅ N ₃ O ₁₀ .1.5 H ₂ O): Calculated value (%) C H, 10.37; N, 4.91 Found (%) C, 63.39; H, 10.35; N, 4.71.

Example 49 [O- (2,3,4-tri-O-acetyl-β-L-F
Copyranosyl) -L-seryl] -L-glutamic acid 1
-Methylamide-5-benzyl ester [general formula (II)
In I-1), R ⁴ is a methylcarbamoyl group, and n is
1 ): methylene chloride (8 ml) in molecular sieves 4 (1.0 g),
AgOTf (1.17 g) and SnCl ₂ (0.87
g) and stirred at room temperature under argon for 0.5 hour,
And cooled to (2,3,4-tri-O-acetyl) -L
-Fucopyranosyl-fluoride [1.0 g, compound (V
II)] in methylene chloride (3 ml) and N-te
rt-butoxycarbonyl-L-seryl-L-glutamic acid 1-methylamide-5-benzyl ester [1.
0 g, stereoisomer of Reference Example 1] methylene chloride (5 m
l) The solution was added, and the mixture was stirred for 12 hours while gradually returning to room temperature. After removing the insoluble matter by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was separated by preparative thin-layer chromatography (chloroform: MeOH = 9: 1) to give the title stereoisomer (1.0 g). Obtained as syrup. This syrup was subjected to the next reaction without further purification.

Example 50 [O- (2,3,4-tri-O-acetyl-β-L-F
Copyranosyl) -L-seryl] -D-glutamic acid 1
-Methylamide-5-benzyl ester [general formula (II)
In I-1), R ⁴ is a methylcarbamoyl group, and n is
1 ): methylene chloride (8 ml) in molecular sieves 4 (1.0 g),
AgOTf (1.17 g) and SnCl ₂ (0.87
g) and stirred at room temperature under argon for 0.5 hour,
And cooled to (2,3,4-tri-O-acetyl) -L
-Fucopyranosyl-fluoride [1.0 g, compound (V
II)] in methylene chloride (3 ml) and N-te
rt-butoxycarbonyl-L-seryl-D-glutamic acid 1-methylamide-5-benzyl ester [1.
0 g, stereoisomer of Reference Example 2] methylene chloride (5 m
l) The solution was added, and the mixture was stirred for 19.5 hours while gradually returning to room temperature. After removing the insoluble matter by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 9: 1) to give the title stereoisomer (0.91 g) in syrup. As obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.20 (d, 3H, J = 6.3H
z), 1.98 (s, 3H), 2.03 (s, 3H), 2.08 (t, 1H, J = 2.7Hz), 2.16
(s, 3H), 2.15-2.35 (m, 1H), 2.38-2.57 (m, 2H), 2.79 (d, 3H, J
= 4.7Hz), 3.56 (t, 1H, J = 5.1Hz), 3.72-3.95 (m, 2H), 3.99 (d
d, 1H, J = 3.8,9.4Hz), 4.44 (d, 1H, J = 7.6Hz), 4.39-4.52 (m, 1
H), 5.00 (dd, 1H, J = 3.3,10.5Hz), 5.04-5.18 (m, 3H), 5.23
(d, 1H, J = 3.3Hz), 6.67 (d, 1H, J = 4.5Hz), 7.28-7.40 (m, 5H),
8.00 (d, 1H, J = 8.6Hz).

Example 51 [O- (2,3,4-tri-O-acetyl-β-L-F
Copyranosyl) -D-seryl] -L-glutamic acid 1
-Methylamide-5-benzyl ester [general formula (II)
In I-1), R ⁴ is a methylcarbamoyl group, and n is
1 ): Preparation of molecular sieves 4 (1.0 g) in methylene chloride (10 m
l), AgOTf (1.41 g) and SnCl
₂ (1.04 g), stirred for 0.5 hours at room temperature under argon, cooled to -20 ° C, and
-Acetyl) -L-fucopyranosyl-fluoride [1.
2 g, compound (VII)] in methylene chloride (3 ml) and N-tert-butoxycarbonyl-D-seryl-L-glutamic acid 1-methylamide-5-benzyl ester [1.2 g, stereoisomer of Reference Example 3] Of methylene chloride (5 ml) was added, and the mixture was stirred for 21 hours while gradually returning to room temperature. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 9: 1) to syrup the title stereoisomer (1.24 g). As obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (d, 3H, J = 6.4 Hz), 1.99 (s, 3
H), 2.07 (s, 3H), 2.13 (s, 3H), 2.15-2.40 (m, 3H), 2.40-2.60
(m, 2H), 2.80 (d, 3H, J = 4.7Hz), 3.49-3.62 (m, 1H), 3.70 (dd,
1H, J = 3.8,13.6Hz), 3.76-3.88 (m, 1H), 4.02-4.16 (m, 1H),
4.95-5.20 (m, 3H), 5.23 (d, 1H, J = 2.6Hz), 6.78 (d, 1H, J = 4.7
Hz), 7.35 (s, 5H), 7.87 (d, 1H, J = 8.2Hz).

Example 52 [O- (2,3,4-tri-O-acetyl-β-L-F
Copyranosyl) -D-seryl] -D-glutamic acid 1
-Methylamide-5-benzyl ester [general formula (II)
In I-1), R ⁴ is a methylcarbamoyl group, and n is
1 ): methylene chloride (8 ml) in molecular sieves 4 (1.0 g),
AgOTf (1.17 g) and SnCl ₂ (0.87
g) and stirred for 0.5 hours at room temperature under argon.
Cool to 20 ° C and (2,3,4-tri-O-acetyl)
-L-fucopyranosyl-fluoride [1.0 g, compound (VII)] in methylene chloride (3 ml) and N-
A solution of tert-butoxycarbonyl-D-seryl-D-glutamic acid 1-methylamide-5-benzyl ester [1.0 g, stereoisomer of Reference Example 4] in methylene chloride (5 ml) was added, and the mixture was gradually cooled to room temperature. Stirred for hours. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure.
The obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 9: 1) to give the title stereoisomer (0.95 g) as a syrup. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (d, 3H, J = 6.4 Hz), 1.99 (s, 3
H), 2.05 (s, 3H), 2.12 (s, 3H), 2.35-2.55 (m, 2H), 2.76 (d, 3
(H, J = 4.6Hz), 3.50-3.66 (m, 1H), 3.74-3.96 (m, 3H), 4.37-4.
55 (m, 1H), 4.51 (d, 1H, J = 7.6Hz), 5.02 (dd, 1H, 3.4,10.4H
z), 5.10 (s, 2H), 5.21 (d, 1H, J = 3.2Hz), 7.08 (q, 1H, J = 4.8H
z), 7.25-7.38 (m, 5H), 7.93 (d, 1H, J = 8.4Hz).

Example 53 [N- (2-tetradecylhexadecanoyl) -O-
(2,3,4-tri-O-acetyl-β-L-fucopyra
Nosyl) -L-seryl] -L-glutamic acid 1-methyl
Lumid-5-benzyl ester [general formula (III-
In 2), when R ¹ is 1-tetradecylpentadecyl
Wherein R ⁴ is a methylcarbamoyl group and n is 1
Of the compound of Example 49 (1.0
g) and 2-tetradecylhexadecanoic acid (0.74
g) in DMF (5 ml) by heating and returning to room temperature.
C (0.47 g) and HOBt (0.25 g) were added, and the mixture was stirred at room temperature for 12 hours. Chloroform (50 ml) was added to the reaction solution, and the mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried and evaporated. The obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 15: 1) to give the title stereoisomer (0.57 g) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.85-0.90 (m, 6H), 1.19-1.30 (m, 5
5H), 1.38-1.57 (m, 2H), 1.70 (s, 2H), 1.99 (s, 3H), 2.08 (s, 3
H), 2.11 (s, 3H), 2.51-2.59 (m, 2H), 2.84 (d, 3H, J = 4.7Hz),
3.78-3.85 (m, 2H), 3.94 (dd, 1H, J = 4.6,9.0Hz), 4.41-4.54
(m, 2H), 4.47 (d, 1H, J = 7.2Hz), 4.96-5.10 (m, 2H), 5.12 (S,
2H), 5.24-5.29 (m, 1H), 6.50 (d, 1H, J = 6.3Hz), 6.72 (d, 1H,
J = 4.7Hz), 6.94 (d, 1H, J = 8.3Hz), 7.34 (s, 5H).

Example 54 [N- (2-tetradecylhexadecanoyl) -O-
(2,3,4-tri-O-acetyl-β-L-fucopyra
Nosyl) -L-seryl] -D-glutamic acid 1-methyl
Lumid-5-benzyl ester [general formula (III-
In 2), when R ¹ is 1-tetradecylpentadecyl
Wherein R ⁴ is a methylcarbamoyl group and n is 1
Of the compound of Example 50 (0.91
g) and 2-tetradecylhexadecanoic acid (0.74
g) was dissolved in DMF (50 ml) by heating and then returned to room temperature.
SC (0.43 g) and HOBt (0.34 g) were added, and the mixture was stirred at room temperature for 18 hours. Ethyl acetate (1
50 mL), and washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in that order, dried, and the solvent was distilled off. The obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 20: 1) to give the title stereoisomer (0.96 g) as a syrup.

¹ H-NMR (CDCl ₃ ) δ: 0.80-1.00 (m, 6H),
1.19 (d, 3H, J = 6.4Hz), 1.20-1.38 (m, 52H), 1.38-1.66 (m, 2
H), 1.70 (s, 2H), 1.98 (s, 3H), 2.07 (s, 3H), 2.13 (s, 3H), 2.1
7-2.40 (m, 2H), 2.79 (d, 3H, J = 4.7Hz), 3.74-3.92 (m, 2H), 3.
99 (dd, 1H, J = 4.4,9.4Hz), 4.37-4.56 (m, 2H), 4.49 (d, 1H, J =
7.3Hz), 4.95-5.20 (m, 4H), 5.20-5.30 (m, 1H), 6.44 (d, 1H, J
= 5.6Hz), 6.96 (d, 1H, J = 7.9Hz), 7.35 (s, 5H).

Example 55 [N- (2-tetradecylhexadecanoyl) -O-
(2,3,4-tri-O-acetyl-β-L-fucopyra
Nosyl) -D-seryl] -L-glutamic acid 1-methyl
Lumid-5-benzyl ester [general formula (III-
In 2), when R ¹ is 1-tetradecylpentadecyl
Wherein R ⁴ is a methylcarbamoyl group and n is 1
Of the compound of Example 51 (1.20)
g) and 2-tetradecylhexadecanoic acid (0.89
g) was dissolved in DMF (50 ml) by heating and then returned to room temperature.
SC (0.57 g) and HOBt (0.45 g) were added, and the mixture was stirred at room temperature for 16.5 hours. Ethyl acetate (120 ml) was added to the reaction solution, and the mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated aqueous solution of sodium chloride.
After drying, the solvent was distilled off. The obtained residue is purified by preparative thin-layer chromatography (chloroform: MeOH = 20: 1).
To give the title stereoisomer (1.20 g) as a syrup.

¹ H-NMR (CDCl ₃ ) δ: 0.80-0.95 (m, 6H),
0.96-1.68 (m, 60H), 1.99 (s, 3H), 2.04 (s, 3H), 2.10 (s, 3H),
2.40-2.64 (m, 2H), 2.75 (d, 3H, J = 4.7Hz), 3.78 (dd, 1H, 3.3,
11.0Hz), 3.83-4.05 (m, 2H), 4.40-4.67 (m, 2H), 4.59 (d, 1H,
J = 7.7Hz), 5.02 (dd, 1H, J = 3.3,10.4Hz), 5.06-5.20 (m, 3H),
5.25 (d, 1H, J = 3.2Hz), 6.62 (d, 1H, J = 8.2Hz), 6.70 (d, 1H, J =
4.8Hz), 7.20-7.42 (m, 5H).

Example 56 [N- (2-tetradecylhexadecanoyl) -O-
(2,3,4-tri-O-acetyl-β-L-fucopyra
Nosyl) -D-seryl] -D-glutamic acid 1-methyl
Lumid-5-benzyl ester [general formula (III-
In 2), when R ¹ is 1-tetradecylpentadecyl
Wherein R ⁴ is a methylcarbamoyl group and n is 1
Of the compound of Example 52 (0.94
g) and 2-tetradecylhexadecanoic acid (0.77
g) was dissolved in DMF (50 ml) by heating and then returned to room temperature.
SC (0.44 g) and HOBt (0.35 g) were added, and the mixture was stirred at room temperature for 20 hours. Ethyl acetate (1
50 mL), and washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in that order, dried, and the solvent was distilled off. The precipitated solid was collected by filtration from n-hexane-ether (3: 1) to give the title stereoisomer (0.83).
g) was obtained as colorless crystals.

Melting point: 103-105 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.80-0.95 (m, 6H), 1.05-1.75 (m, 6
0H), 1.99 (s, 3H), 2.05 (s, 3H), 2.11 (s, 3H), 2.20-2.42 (m, 1
H), 2.43-2.63 (m, 2H), 2.74-2.80 (m, 1H), 2.84 (d, 3H, 4.7H
z), 3.79 (dd, 1H, J = 8.5,11.2Hz), 3.86-3.97 (m, 1H), 3.98-
4.08 (m, 1H), 4.37-4.52 (m, 1H), 4.50-4.73 (m, 1H), 4.63 (d,
1H, J = 7.7Hz), 4.99 (dd, 1H, J = 3.2,10.4Hz), 5.04-5.07 (m, 3
H), 5.25 (d, 1H, J = 2.7Hz), 6.46 (d, 1H, J = 5.9Hz), 6.65 (d, 1
(H, J = 4.8Hz), 7.27-7.42 (m, 5H).

Example 57 [N- (2-tetradecylhexadecanoyl) -O-
(Β-L-fucopyranosyl) -L-seryl] -L-glu
Tamic acid 1-methylamide [General formula [Ia (β)]
R ¹ is a 1-tetradecyl pentadecyl group, and R ² is
Stereoisomerism of a compound in which a methylcarbamoyl group and n is 1
Body] Preparation of methanol (40 ml) was added Pd / C (0.1g) of the compound of Example 53 (0.3 g) was added,
Stirred at room temperature under hydrogen for 1 hour. After removing the catalyst by filtration, the solvent was distilled off, and the obtained residue was dissolved in methanol (30 ml).
A 28% NaOMe / methanol solution (1.5 ml) was added, and the mixture was stirred at room temperature for 0.5 hour. Next, DOWEX 50
After adding W-X8 (4.0 g) and stirring for 3 minutes, the insoluble matter was removed by filtration, the solvent was distilled off, and the precipitated solid was collected by filtration from water to obtain the title stereoisomer (145 mg) as a colorless powder. Was.

[Α] _D -9 ° (c = 0.1, MeO
H) Melting point: gradually melted from around 160 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.82-0.87 (m, 6H), 1.13 (d, 3H, J
= 6.4Hz), 1.18-1.41 (m, 52H), 1.65-1.73 (m, 1H), 1.83-1.93
(m, 1H), 2.12-2.19 (m, 3H), 2.53 (d, 3H, J = 4.5Hz), 3.34-3.5
8 (m, 3H), 3.68-3.75 (m, 1H), 4.06-4.15 (m, 2H), 4.38-4.48
(m, 2H), 4.70 (s, 1H), 7.54 (d, 1H, J = 4.7Hz), 7.87-7.95 (m, 2
H), 12.01 (bs, 1H). Mass spectrum (m / e): 828
(M + H) ⁺ Elemental Analysis (as _{C 45 H 85 N 3 O 10} · 2H 2 O): Calculated: C, 62.54; H, 10.38 ; N, 4.86 Analytical values: C, 62.82 H, 10.01; N, 4.65

Example 58 [N- (2-tetradecylhexadecanoyl) -O-
(Β-L-fucopyranosyl) -L-seryl] -D-glu
Tamic acid 1-methylamide [General formula [Ia (β)]
R ¹ is a 1-tetradecyl pentadecyl group, and R ² is
Stereoisomerism of a compound in which a methylcarbamoyl group and n is 1
Body] Preparation of ethanol (30ml) was added Pd / C (0.1g) of the compound of Example 54 (0.4 g) was added,
Stirred at room temperature under hydrogen for 2 hours. After removing the catalyst by filtration, the solvent was distilled off, and the obtained residue was dissolved in methanol (30 ml).
A 28% NaOMe / methanol solution (0.15 g) was added, and the mixture was stirred at room temperature for 0.5 hour. Next, DOWEX 50
After adding W-X8 (10 g) and stirring for 3 minutes, the insoluble material was removed by filtration, the solvent was distilled off, and the precipitated solid was collected by filtration from water to obtain the title stereoisomer (0.3 g) as a colorless powder. Was.

[Α] _D + 5 ° (c = 0.1, MeO
H) Melting point: 198-199 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.70-0.93 (m, 6H), 0.95-1.55
(m, 55H), 1.55-1.80 (m, 1H), 1.80-2.04 (m, 2H), 2.06-2.30
(m, 4H), 2.57 (d, 3H, J = 4.3Hz), 3.40-3.68 (m, 2H), 3.70-3.8
9 (m, 1H), 4.00-4.24 (m, 2H), 4.13 (d, 1H, J = 6.9Hz), 4.23-4.
47 (m, 2H), 4.68 (s, 1H), 7.77 (d, 1H, J = 4.6Hz), 7.99 (d, 1H, J
= 6.7 Hz), 8.02 (d, 1H, J = 8.0 Hz), 12.10 (s, 1H). Mass spectrum (m / e): 828 (M + H) ⁺ elemental analysis (C ₄₅ H ₈₅ N ₃ O ₁₀ .1) .5H as ₂ O): calculated: C, 63.20; H, 10.37 ; N, 4.91 analytical values: C, 63.25; H, 10.10 ; N, 4.69

Example 59 [N- (2-tetradecylhexadecanoyl) -O-
(Β-L-fucopyranosyl) -D-seryl] -L-glu
Tamic acid 1-methylamide [General formula [Ia (β)]
R ¹ is a 1-tetradecylpentadecyl group, R ²
Is a methylcarbamoyl group and n is 1
Production of Compound ] Pd / C (50 mg) was added to a solution of the compound of Example 55 (0.25 g) in ethanol (30 ml), and the mixture was stirred under hydrogen at room temperature for 2 hours. After removing the catalyst by filtration, the solvent was distilled off, and the obtained residue was dissolved in methanol (20 ml). A 28% NaOMe / methanol solution (74 mg) was added, followed by stirring at room temperature for 0.5 hour. Next, DOWEX5
After adding 0W-X8 (10 g) and stirring for 3 minutes, chloroform (10 ml) was added, the insolubles were removed by filtration, the solvent was distilled off, and the precipitated solid was filtered from water to give the title stereoisomer (0.1%).
3g) was obtained as a colorless powder. [Α] _D -4 ° (c = 0.1, MeOH) Melting point: Melting gradually from around 163 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.80-0.90 (m, 6H), 1.14 (d, 3H, J
= 6.4Hz), 0.95-1.55 (m, 52H), 1.60-1.80 (m, 1H), 1.80-2.08
(m, 1H), 2.16-2.36 (m, 3H), 2.58 (d, 3H, J = 4.3Hz), 3.42-3.6
0 (m, 3H), 3.82-4.00 (m, 1H), 4.08 (d, 1H, J = 6.8Hz), 4.10-4.
28 (m, 1H), 4.27-4.50 (m, 2H), 4.69 (s, 1H), 4.83 (s, 1H), 7.8
0 (d, 1H, J = 4.6Hz), 7.89 (d, 1H, J = 8.0Hz), 8.00 (d, 1H, J = 7.3
Hz), 12.00 (s, 1H). Mass spectrum (m / e): 828 (M + H) ⁺ elemental analysis (as C ₄₅ H ₈₅ N ₃ O ₁₀ .1.5H ₂ O): Calculated: C, 63. 20; H, 10.37; N, 4.91 Analytical value: C, 63.45; H, 10.13; N, 4.59

Example 60 [N- (2-tetradecylhexadecanoyl) -O-
(Β-L-fucopyranosyl) -D-seryl] -D-glu
Tamic acid 1-methylamide [General formula [Ia (β)]
R ¹ is a 1-tetradecyl pentadecyl group, and R ² is
Stereoisomerism of a compound in which a methylcarbamoyl group and n is 1
Production of Compound: Pd / C (50 mg) was added to a solution of the compound of Example 56 (0.3 g) in ethanol (30 ml),
The mixture was stirred at room temperature under hydrogen for 1.5 hours. After removing the catalyst by filtration, the solvent was distilled off, and the obtained residue was dissolved in methanol (20 ml), and a 28% NaOMe / methanol solution (0.11 g) was used.
Was added and stirred at room temperature for 0.5 hour. Next, DOWEX
50W-X8 (10 g) was added, and the mixture was stirred for 3 minutes. The insoluble material was removed by filtration, the solvent was distilled off, and the precipitated solid was filtered from water to give the title stereoisomer (0.16 g) as a colorless powder. Obtained.

[Α] _D + 6 ° (c = 0.1, MeO
H) Melting point: melting gradually from around 147 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.80-0.90 (m, 6H), 0.95-1.60
(m, 55H), 1.60-1.82 (m, 1H), 1.82-2.07 (m, 1H), 2.08-2.36
(m, 3H), 2.59 (d, 3H, J = 4.5Hz), 3.46-3.85 (m, 3H), 3.94 (dd,
1H, J = 4.6,9.8Hz), 4.07 (d, 1H, J = 7.3Hz), 4.12-4.30 (m, 1
H), 4.30-4.66 (m, 2H), 4.67-4.80 (m, 1H), 7.56 (d, 1H, J = 4.7
Hz), 7.92 (d, 1H, J = 7.4 Hz), 7.98 (d, 1H, J = 8.2 Hz), 12.10 (s,
1H). Mass spectrum (m / e): 828 (M + H) ⁺ elemental analysis (as C ₄₅ H ₈₅ N ₃ O ₁₀ .1.5H ₂ O): Calculated: C, 63.20; H, 10.37 N, 4.91 Anal. Found: C, 63.49; H, 10.00; N, 4.67.

Example 61 [N- (t-butoxycarbonyl) -S- (2,3,4
-Tri-O-acetyl-α-L-fucopyranosyl) -L
-Cysteinyl] -L-glutamic acid 1-methylamido
De-5-benzyl ester [in the general formula (IV-1)
Wherein R ⁴ is a methylcarbamoyl group and n is 1
Stereoisomer] of production: (1) [N- (t- butoxycarbonyl) -S- (2,
3,4-Tri-O-acetyl-α-L-fucopyranosyl) -L-cysteine [stereoisomer of compound (XI)]: 2,3,4-tri-O-acetyl-1-thio-α
-L-fucopyranose [0.49 g, compound (IX)]
Was dissolved in DMF (2 ml), and 60% sodium hydride (64 mg) was added under ice-cooling and stirring. After 3 minutes, N- (t
-Butoxycarbonyl) -L-serine β-lactone [0.2 g, stereoisomer of compound (X)] was added, and the mixture was stirred for 5 minutes and then at room temperature for 1 hour. The reaction mixture was diluted with diluted hydrochloric acid to make it weakly acidic, and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After drying, the solvent was distilled off under reduced pressure. The resulting residue is subjected to silica gel medium pressure liquid chromatography (chloroform: methanol = 2
0: 1) to give [N- (t-butoxycarbonyl) -S- (2,3,4-tri-O-acetyl-
α-L-fucopyranosyl)]-L-cysteine (0.1
8g) was obtained as a yellow solid.

¹ H-NMR (DMSO-d ₆ ) δ: 1.07 (d, 3H, J = 6
Hz), 1.38 (s, 9H), 1.95 (s, 3H), 2.01 (s, 3H), 2.14 (s, 3H), 2.
72 (dd, 1H, J = 9,13Hz), 2.92 (dd, 1H, J = 5,13Hz), 3.96 (b, 1
H), 4.3-4.5 (m, 1H), 5.05-5.2 (m, 3H), 5.60 (d, 1H, J = 5 Hz). (2) [N- (t-butoxycarbonyl) -S- (2,
3,4-Tri-O-acetyl-α-L-fucopyranosyl) -L-cysteinyl] -L-glutamic acid 1-methylamide-5-benzyl ester: N- (t-butoxycarbonyl) -L-glutamic acid 1-methylamide- 5-benzyl ester [0.55 g, general formula (XV)
Wherein R ³ is a methyl group and n is 1
Is dissolved in methylene chloride (8 ml) and TFA (4 m
l) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and deprotected (0.81 g, R
³ is a methyl group, and n is 1; a stereoisomer of the compound] was obtained as a TFA salt. Next, the TFA salt of the obtained deprotected product was dissolved in DMF (3 ml), and diisopropylethylamine (0.97 ml) and HO were added under ice-cooling and stirring.
Bt (0.31 g), the compound of the above (1) (0.77 g)
g) in DMF (6 ml) and WSC (0.39
g) was added and the mixture was stirred at room temperature for 18.5 hours. The reaction solution was poured into ice water (100 ml), extracted with ethyl acetate (× 3), washed with water and dried, and the solvent was distilled off. The resulting residue is subjected to silica gel medium pressure liquid chromatography (chloroform: Me
OH = 100: 0 → 300: 1) and [N-
(T-Butoxycarbonyl) -S- (2,3,4-tri-O-acetyl-α-L-fucopyranosyl) -L-cysteinyl] -L-glutamic acid 1-methylamide-5
-Benzyl ester (0.88 g) was obtained as a syrup.

¹ H-NMR (CDCl ₃ ) δ: 1.19 (d, 3H, J = 6.5H
z), 1.45 (s, 9H), 1.99 (s, 3H), 2.06 (s, 3H), 2.16 (s, 3H), 2.3
5-2.68 (m, 2H), 2.75 (dd, 1H, J = 7.9,13.8Hz), 2.79 (d, 3H, J =
4.8Hz), 3.06 (dd, 1H, J = 5.1,13.7Hz), 4.1-4.27 (m, 1H), 4.3
-4.5 (m, 2H), 5.13 (s, 2H), 5.1-5.32 (m, 3H), 5.66 (d, 1H, J =
5.5Hz), 6.5 (bs, 1H), 7.17 (d, 1H, J = 7.9Hz), 7.3-7.45 (m, 5
H).

Example 62 [N- (t-butoxycarbonyl) -S- (2,3,4
-Tri-O-acetyl-α-L-fucopyranosyl) -L
-Cysteinyl] -D-glutamic acid 1-methylamido
De-5-benzyl ester [in the general formula (IV-1)
Wherein R ⁴ is a methylcarbamoyl group and n is 1
Production of N- (t-butoxycarbonyl) -D-glutamic acid 1-methylamide-5-benzyl ester [1.2 g, R in the general formula (XV)
R isomer of a compound wherein ³ is a methyl group and n is 1] is dissolved in methylene chloride (18 ml), TFA (9 ml) is added, and the mixture is stirred at room temperature for 1 hour, and then the reaction solution is concentrated to remove the deprotected compound. [1.95 g, compound (XIIa), R-form of compound in which R ³ is a methyl group and n is 1] was obtained as a TFA salt. Next, the TFA salt of the obtained deprotected product was dissolved in DMF (7 ml), and diisopropylethylamine (2.5 ml) and HOBt (0.68
g), the compound of Example 61 (1) (1.7 g) and WSC (0.85 g) were added, and the mixture was stirred at room temperature for 20.5 hours. The reaction solution was poured into ice water (170 ml), extracted with ethyl acetate (× 3), washed with water and dried, and the solvent was distilled off. The resulting residue was subjected to silica gel medium pressure liquid chromatography (chloroform: MeOH = 100: 0 → 500: 1 → 30).
[N- (t-butoxycarbonyl) -S- (2,3,4-tri-O-acetyl-α-L-fucopyranosyl) -L-cysteinyl]-
D-glutamic acid 1-methylamide-5-benzyl ester (1.52 g) was obtained as a syrup.

¹ H-NMR (CDCl ₃ ) δ: 1.16 (d, 3H, J = 6.4H
z), 1.44 (s, 9H), 1.99 (s, 3H), 2.06 (s, 3H), 2.16 (s, 3H), 2.3
5-2.6 (m, 2H), 2.76 (d, 3H, J = 4.7Hz), 2.75-2.9 (m, 1H), 3.02
(dd, 1H, J = 5.1,13.8Hz), 4.1-4.2 (m, 1H), 4.3-4.55 (m, 2H),
5.12 (s, 2H), 5.15-5.3 (m, 3H), 5.46 (d, 1H, J = 6.0Hz), 5.67
(d, 1H, J = 5.5Hz), 6.88 (bs, 1H), 7.3-7.4 (m, 5H).

Example 63 [N- (t-butoxycarbonyl) -S- (2,3,4
-Tri-O-acetyl-α-L-fucopyranosyl) -D
-Cysteinyl] -L-glutamic acid 1-methylamido
De-5-benzyl ester [in the general formula (IV-1)
Wherein R ⁴ is a methylcarbamoyl group and n is 1
Stereoisomer] of production: (1) [N- (t- butoxycarbonyl) -S- (2,
3,4-tri-O-acetyl-α-L-fucopyranosyl) -D-cysteine [stereoisomer of compound (XI)]: N- (t-butoxycarbonyl) -D-serine
β-lactone [1.50 g, stereoisomer of compound (X)] and 2,3,4-tri-O-acetyl-1-thio-α
-L-fucopyranose [2.45 g, compound (IX)]
Was dissolved in DMF (15 ml), and then 60% under ice-cooling and stirring.
Sodium hydride (0.32 g) was added and the mixture was stirred for 40 minutes, brought to room temperature and further stirred for 30 minutes. After ice water (50 ml) was added to the reaction solution, an aqueous solution of potassium hydrogen sulfate was further added to adjust the pH to 3. This solution was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride. After drying, the solvent was distilled off under reduced pressure, and the residue obtained was subjected to silica gel medium pressure liquid chromatography (chloroform: M
[N- (t-butoxycarbonyl) -S- (2,3,4-tri-O-acetyl-α-L-fucopyranosyl)]-D-cysteine (2. MeOH = 10: 1). 0 g).

¹ H-NMR (CDCl ₃ ) δ: 1.22 (d, 3H, J = 7H
z), 1.46 (s, 9H), 2.00 (s, 3H), 2.09 (s, 3H), 2.18 (s, 3H), 2.9
9 (dd, 1H, J = 4,15Hz), 3.24 (dd, 1H, J = 5,14Hz), 4.4-4.55 (m,
1H), 4.55-4.75 (m, 1H), 5.10-5.35 (m, 3H), 5.71 (d, 1H, J = 5H
z), 5.75 (d, 1H, J = 8 Hz). (2) [N- (t-butoxycarbonyl) -S- (2,
3,4-Tri-O-acetyl-α-L-fucopyranosyl) -D-cysteinyl] -L-glutamic acid 1-methylamide-5-benzyl ester: N- (t-butoxycarbonyl) -L-glutamic acid 1-methylamide- 5-benzyl ester [0.71 g, general formula (XV)
Wherein R ³ is a methyl group and n is 1
Is dissolved in methylene chloride (7 ml), TFA (2 ml) is added to the mixture under ice-cooling and stirring, and the mixture is stirred at room temperature for 1 hour. , R ³ is a methyl group and n is 1 in the S form] as a syrup. Next, the compound of the above (1) (1.0 g) and TEA (0.23
g) was dissolved in THF (7 ml), ethyl chlorocarbonate (0.24 g) was added with stirring under ice-cooling, and the mixture was stirred for 5 minutes. A THF (3 ml) solution was added, and the mixture was stirred under ice-cooling for 15 minutes and then at room temperature for 12 hours. The solvent is distilled off under reduced pressure,
The obtained residue was purified by silica gel medium pressure liquid chromatography (chloroform: MeOH = 20: 1) to give [N- (t-butoxycarbonyl) -S- (2,3,4).
-Tri-O-acetyl-α-L-fucopyranosyl) -D
-Cysteinyl] -L-glutamic acid 1-methylamide-5-benzyl ester (1.08 g) was obtained as a syrup.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (d, 3H, J = 6.4H
z), 1.46 (s, 9H), 1.99 (s, 3H), 2.06 (s, 3H), 2.17 (s, 3H), 2.3
-2.7 (m, 2H), 2.7-2.9 (m, 4H), 3.1-3.3 (m, 1H), 4.2-4.6 (m, 3
H), 5.05-5.35 (m, 5H), 5.56 (d, 1H, J = 6.6Hz), 5.67 (d, 1H, J =
5.6Hz), 6.49 (bs, 1H), 7.15 (d, 1H, J = 7.9Hz), 7.3-7.5 (m, 5
H).

Example 64 [N- (t-butoxycarbonyl) -S- (2,3,4
-Tri-O-acetyl-α-L-fucopyranosyl) -D
-Cysteinyl] -D-glutamic acid 1-methylamido
De-5-benzyl ester [in the general formula (IV-1)
Wherein R ⁴ is a methylcarbamoyl group and n is 1
Production of N- (t-butoxycarbonyl) -D-glutamic acid 1-methylamide-5-benzyl ester [0.36 g, in the general formula (XV),
R ³ is a methyl group and R is a compound in which n is 1] in methylene chloride (5 ml), and stirred under ice-cooling with TFA.
(5 ml) was added and stirred for 3 hours. Concentrate the reaction,
Chloroform (50 ml) was added, washed with a saturated aqueous solution of sodium carbonate, dried, and the solvent was distilled off to remove the deprotected compound [R compound of compound (XIIa) in which R ³ is a methyl group and n is 1] ] Was obtained. Then, the obtained syrup of the deprotected product and the compound of Example 63 (1) (0.5 g) were dissolved in DMF (20 ml), and WSC (0.29 g) and HOBt (0.
23 g) was added and the mixture was stirred at room temperature for 20 hours. Ethyl acetate (100 ml) was added to the reaction solution, and the mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried, and the solvent was distilled off. The resulting residue is purified by preparative thin-layer chromatography (ethyl acetate: n-hexane =
1: 1) and [N- (t-butoxycarbonyl) -S- (2,3,4-tri-O-acetyl-α-L
-Fucopyranosyl) -D-cysteinyl] -D-glutamic acid 1-methylamide-5-benzyl ester (0.
46 g) was obtained as a syrup.

¹ H-NMR (CDCl ₃ ) δ: 1.18 (d, 3H, J = 6.5H
z), 1.47 (s, 9H), 1.98 (s, 3H), 2.05 (s, 3H), 2.16 (s, 3H), 2.3
5-2.6 (m, 2H), 2.77 (d, 3H, J = 4.7Hz), 3.0-3.2 (m, 1H), 4.2-
4.6 (m, 3H), 5.11 (s, 2H), 5.05-5.35 (m, 3H), 5.66 (d, 1H, J =
5.5Hz), 5.8 (d, 1H, J = 7.1Hz), 6.96 (q, 1H, J = 4.7Hz), 7.2-7.
4 (m, 5H), 7.52 (d, 1H, J = 7.8Hz).

Example 65 [N- (2-tetradecylhexadecanoyl) -S-
(2,3,4-tri-O-acetyl-α-L-fucopyra
Nosyl) -L-cysteinyl] -L-glutamic acid 1-
Methylamide-5-benzyl ester [general formula (IV-
In 2), R ¹ is 2-tetradecylpentadecyl
Wherein R ⁴ is a methylcarbamoyl group and n is 1
The production of stereoisomers]: the compound of Example 61 (0.88
g) was dissolved in a methylene chloride solution (18 ml), and TFA was added.
(9 ml) and stirred at room temperature for 1 hour. The reaction solution was concentrated, chloroform (50 ml) was added, washed with a cold 5% aqueous sodium hydrogen carbonate solution, dried, and the solvent was distilled off. Syrup of the obtained deprotected product, 2-tetradecylhexadecanoic acid (0.55 g), HOBt (0.24 g)
Was dissolved in DMF (63 ml), and the mixture was dissolved in
(0.3 g) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into ice water (630 ml), extracted with ethyl acetate (× 3), washed with a 5% aqueous sodium hydrogen carbonate solution, and dried.
The solvent was distilled off. The resulting residue is purified by silica gel medium pressure liquid column chromatography (chloroform: MeOH = 1).
00: 0 → 300: 1) and purified with [N- (2-tetradecylhexadecanoyl) -S- (2,3,4-tri-O-acetyl-α-L-fucopyranosyl) -L- Cysteinyl] -L-glutamic acid 1-methylamide-5
-The benzyl ester (0.8 g) was obtained as a syrup.

¹ H-NMR (CDCl ₃ ) δ: 0.8-0.95 (m, 6H), 1.
17 (d, 3H, J = 6.5Hz), 1.2-1.55 (m, 52H), 1.99 (s, 3H), 2.04
(s, 3H), 2.15 (s, 3H), 2.3-2.65 (m, 2H), 2.79 (d, 3H, J = 4.8H
z), 2.84 (dd, 1H, J = 6.2,13.7Hz), 3.0 (dd, 1H, J = 5.7,13.8H
z), 4.3-4.45 (m, 2H), 4.5-4.66 (m, 1H), 5.13 (s, 2H), 5.13-
5.3 (m, 3H), 5.75 (d, 1H, J = 4.8Hz), 6.2 (d, 1H, J = 7.0Hz), 6.4
4 (q, 1H, J = 4.8Hz), 7.19 (d, 1H, J = 7.5Hz), 7.25-7.4 (m, 5H).

Example 66 [N- (2-tetradecylhexadecanoyl) -S-
(2,3,4-tri-O-acetyl-α-L-fucopyra
Nosyl) -L-cysteinyl] -D-glutamic acid 1-
Methylamide-5-benzyl ester [general formula (IV-
In 2), R ¹ is 2-tetradecylpentadecyl
Wherein R ⁴ is a methylcarbamoyl group and n is 1
Of the compound of Example 62 (0.2
g) was dissolved in methylene chloride solution (4 ml), and TFA was added.
(2 ml) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated, chloroform (50 ml) was added, washed with a 5% aqueous sodium hydrogen carbonate solution, dried, and the solvent was distilled off.
A syrup of the obtained deprotected product, 2-tetradecylhexadecanoic acid (0.13 g), and HOBt (55 mg) were added to DM.
F (12.5 ml), and the mixture was dissolved in WSC (6
9 mg) and stirred at room temperature for 15.5 hours. The reaction solution was poured into ice water (120 ml), extracted with ethyl acetate (× 3), washed with a 5% aqueous sodium hydrogen carbonate solution, and dried.
The solvent was distilled off. The resulting residue is purified by silica gel medium pressure liquid column chromatography (chloroform: MeOH = 1).
00: 0 → 500: 1) and purified with [N- (2-tetradecylhexadecanoyl) -S- (2,3,4-tri-O-acetyl-α-L-fucopyranosyl) -L- Cysteinyl] -D-glutamic acid 1-methylamide-5
-Benzyl ester (0.15 g) was obtained as a syrup.

¹ H-NMR (CDCl ₃ ) δ: 0.8-0.95 (m, 6H), 1.
15 (d, 3H, J = 6.5Hz), 1.1-1.7 (m, 52H), 1.99 (s (3H), 2.05 (s,
3H), 2.15 (s, 3H), 2.35-2.65 (m, 2H), 2.76 (d, 3H, J = 4.7Hz),
2.85-3.0 (m, 2H), 4.3-4.55 (m, 3H), 5.13 (s, 2H), 5.15-5.3
(m, 3H), 5.74 (d, 1H, J = 4.9Hz), 6.35 (bs, 1H), 6.74 (bs, 1H).

Example 67 [N- (2-tetradecylhexadecanoyl) -S-
(2,3,4-tri-O-acetyl-α-L-fucopyra
Nosyl) -D-cysteinyl] -L-glutamic acid 1-
Methylamide-5-benzyl ester [general formula (IV-
In 2), R ¹ is 2-tetradecylpentadecyl
Wherein R ⁴ is a methylcarbamoyl group and n is 1
Of the compound of Example 63 (0.5
g) was dissolved in a methylene chloride solution (5 ml), TFA (2.5 ml) was added under ice-cooling and stirring, and the mixture was stirred for 1 hour. The reaction solution was concentrated, chloroform (50 ml) was added, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off. The syrup of the obtained deprotected product was added to DMF (30 m
l) and dissolved in 2-tetradecylhexadecanoic acid (0.1).
3g) and HOBt (0.1 g) were added, and WSC (0.16 g) was added with stirring under ice-cooling, followed by stirring at room temperature for 15 hours. Ethyl acetate (100 ml) was added to the reaction solution, and the mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried, and the solvent was distilled off. The resulting residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 20: 1) to give [N- (2-tetradecylhexadecanoyl) -S- (2,3,4-tri-O). -Acetyl-α-L-fucopyranosyl) -D-cysteinyl] -L-glutamic acid 1-methylamide-
5-benzyl ester (0.23 g) was obtained as a syrup.

¹ H-NMR (CDCl ₃ ) δ: 0.8-0.95 (m, 6H), 1.
19 (d, 3H, J = 6.5Hz), 1.1-1.7 (m, 57H), 1.98 (s, 3H), 2.05 (s,
3H), 2.15 (s, 3H), 1.9-2.3 (m, 1H), 2.3-2.7 (m, 2H), 2.76 (d,
3H, J = 4.8Hz), 2.84 (dd, 1H, J = 5.4,14.3Hz), 3.1 (dd, 1H, J =
6.2, 14.1 Hz), 4.3-4.5 (m, 2H), 4.5-4.7 (m, 1H), 5.0-5.3 (m,
5H), 5.68 (d, 1H, J = 5.5Hz), 6.6-6.8 (m, 2H), 7.2-7.5 (m, 6
H).

Example 68 [N- (2-tetradecylhexadecanoyl) -S-
(2,3,4-tri-O-acetyl-α-L-fucopyra
Nosyl) -D-cysteinyl] -D-glutamic acid 1-
Methylamide-5-benzyl ester [general formula (IV-
In 2), R ¹ is 2-tetradecylpentadecyl
Wherein R ⁴ is a methylcarbamoyl group and n is 1
The production of stereoisomers]: the compound of Example 64 (0.46
g) was dissolved in a methylene chloride solution (5 ml), TFA (5 ml) was added under ice-cooling and stirring, and the mixture was stirred for 3 hours. The reaction solution was concentrated, chloroform (80 ml) was added, washed with a saturated aqueous solution of sodium carbonate, dried, and the solvent was distilled off.
The syrup of the obtained deprotected product was dissolved in DMF (50 ml), and 2-tetradecylhexadecanoic acid (0.29 g) was dissolved.
After heating and dissolving, the temperature was returned to room temperature, and WSC (0.18 g) and HOBt (0.15 g) were added, followed by stirring at room temperature for 22 hours. Ethyl acetate (120 ml) was added to the reaction solution, and 1
After washing sequentially with N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, the mixture was dried and the solvent was distilled off. The resulting residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 20: 1) to give [N- (2-
Tetradecylhexadecanoyl) -S- (2,3,4-
Tri-O-acetyl-α-L-fucopyranosyl) -D-
Cysteinyl] -D-glutamic acid 1-methylamide-5-benzyl ester (0.21 g) was obtained as a syrup.

¹ H-NMR (CDCl ₃ ) δ: 0.8-0.95 (m, 6H), 1.
18 (d, 3H, J = 6.5Hz), 1.0-1.9 (m, 52H), 1.98 (s, 3H), 2.06 (s,
3H), 2.16 (s, 3H), 2.35-2.66 (m, 2H), 2.8 (d, 3H, J = 4.8Hz),
2.87 (dd, 1H, J = 5.6,14.1Hz), 3.01 (dd, 1H, J = 5.7,14.0Hz),
4.33-4.5 (m, 2H), 4.59-4.7 (m, 1H), 5.08-5.35 (m, 6H), 5.67
(d, 1H, J = 5.5Hz), 6.42 (d, 1H, J = 7.3Hz), 6.46 (d, 1H, J = 4.9H
z), 7.14 (d, 1H, J = 7.5Hz), 7.28-7.45 (m, 5H).

Example 69 [N- (2-tetradecylhexadecanoyl) -S-
(Α-L-fucopyranosyl) -L-cysteinyl] -L
-Glutamic acid 1-methylamide [general formula [Ic
(Α)] wherein R ¹ is 2-tetradecylpentadecyl
And R ² is a methylcarbamoyl group and n is 1.
Things stereoisomer] of production: (1) [N- (2- tetradecylhexadecanoyl) -
S- (2,3,4-Tri-O-acetyl-α-L-fucopyranosyl) -L-cysteinyl] -L-glutamic acid 1-methylamide: the compound of Example 65 (0.8 g)
To a suspension of methanol (300 ml) was added 10% palladium carbon (0.6 g), and the mixture was stirred at room temperature under hydrogen pressure (4 to 5 atm) for 6 hours. After the catalyst was removed by filtration, the solvent was distilled off and [N- (2-tetradecylhexadecanoyl) -S
-(2,3,4-tri-O-acetyl-α-L-fucopyranosyl) -L-cysteinyl] -L-glutamic acid
1-methylamide (0.6 g) was obtained. (2) [N- (2-tetradecylhexadecanoyl)-
S- (α-L-fucopyranosyl) -L-cysteinyl]
-L-glutamic acid 1-methylamide: The compound of the above (1) (0.28 g) was dissolved in methanol (45 ml), and a 28% NaOMe / methanol solution (0.12 m
l) was added and the mixture was stirred at room temperature for 1.5 hours. Then, DOW
EX50W-X8 (5.0 g) was added, and the mixture was stirred at room temperature for 10 minutes, followed by filtering off insolubles and washing with a mixed solvent of chloroform-methanol. The filtrate and the washing solution were combined, concentrated under reduced pressure, and the precipitated solid was collected by filtration, washed with methanol, and washed with [N-
(2-tetradecylhexadecanoyl) -S- (α-L
-Fucopyranosyl) -L-cysteinyl] -L-glutamic acid 1-methylamide (0.12 g) was obtained as a colorless powder.

Melting point: 186-188 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.9 (m, 6H), 1.11 (d, 3H, J =
6.4Hz), 1.1-1.55 (m, 52H), 1.6-1.8 (m, 1H), 1.8-2.0 (m, 1
H), 2.1-2.25 (m, 3H), 2.58 (d, 3H, J = 4.4Hz), 3.35-3.45 (m, 1
H), 3.45-3.5 (m, 1H), 3.84 (dd, 1H, J = 5.4,9.8Hz), 3.95-4.1
(m, 1H), 4.1-4.25 (m, 1H), 4.3-4.45 (m, 1H), 5.21 (d, 1H, J =
5.4Hz), 7.75 (q, 1H, J = 4.7Hz), 7.88 (d, 1H, J = 7.9Hz), 8.14
(d, 1H, J = 7.9 Hz), 12.05 (bs, 1H). Mass spectrum: 844 (M + H) ⁺

Example 70 [N- (2-tetradecylhexadecanoyl) -S-
(Α-L-fucopyranosyl) -L-cysteinyl] -D
-Glutamic acid 1-methylamide [general formula [Ic
(Α)] wherein R ¹ is 2-tetradecylpentadecyl
And R ² is a methylcarbamoyl group and n is 1.
Things stereoisomer] of production: (1) [N- (2- tetradecylhexadecanoyl) -
S- (2,3,4-tri-O-acetyl-α-L-fucopyranosyl) -L-cysteinyl] -D-glutamic acid 1-methylamide: the compound of Example 66 (0.24
g) in a suspension of methanol (100 ml) was added with 10% palladium carbon (0.2 g), and the mixture was pressurized with hydrogen (4 to 5).
The mixture was stirred at room temperature under atmospheric pressure for 6 hours. After removing the catalyst by filtration, the solvent was distilled off and [N- (2-tetradecylhexadecanoyl)-
S- (2,3,4-tri-O-acetyl-α-L-fucopyranosyl) -L-cysteinyl] -D-glutamic acid 1-methylamide (129 mg) was obtained. (2) [N- (2-tetradecylhexadecanoyl)-
S- (α-L-fucopyranosyl) -L-cysteinyl]
-D-glutamic acid 1-methylamide: The compound of the above (1) (127 mg) was dissolved in methanol (20 ml), a 28% NaOMe / methanol solution (53 μl) was added, and the mixture was stirred at room temperature for 80 minutes. Next, DOWEX 50
After adding W-X8 (5.0 g) and stirring at room temperature for 10 minutes, methanol was added and insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography (chloroform: methanol = 5: 1), and a mixed solvent of chloroform-methanol (4: 1) was added to the obtained solid, followed by filtration. The filtrate was concentrated under reduced pressure to give [N- (2
-Tetradecylhexadecanoyl) -S-([alpha] -L-fucopyranosyl) -L-cysteinyl] -D-glutamic acid 1-methylamide (0.12 g) was obtained as a colorless powder. Melting point: 195-199 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m, 6H), 1.11 (d, 3H, J
= 6.4Hz), 1.0-1.6 (m, 52H), 1.6-1.8 (m, 1H), 1.85-2.05 (m, 1
H), 2.1-2.3 (m, 3H), 2.56 (d, 3H, J = 4.5Hz), 2.7-2.85 (m, 1
H), 3.85 (dd, 1H, J = 5.3,9.8Hz), 3.9-4.1 (m, 1H), 4.1-4.22
(m, 1H), 4.25-4.4 (m, 1H), 4.47 (d, 1H, J = 4.5Hz), 5.21 (d, 1
H, J = 5.4 Hz), 7.76 (q, 1H, J = 4.7 Hz), 8.22 (d, 1H, J = 7.3 Hz). Mass spectrum: 844 (M + H) ⁺

Example 71 [N- (2-tetradecylhexadecanoyl) -S-
(Α-L-fucopyranosyl) -D-cysteinyl] -L
-Glutamic acid 1-methylamide [general formula [Ic
(Α)] wherein R ¹ is 2-tetradecylpentadecyl
And R ² is a methylcarbamoyl group and n is 1.
Of the compound of Example 67 (0.2
g) in a suspension of methanol (50 ml), 10% palladium carbon (0.2 g) was added, and hydrogen pressure (5 atm) was applied.
The mixture was stirred overnight at room temperature. After removing the catalyst by filtration, the solvent was distilled off, and the obtained residue was dissolved in methanol (10 ml).
A NaOMe / methanol solution (50 mg) was added, and the mixture was stirred at room temperature for 35 minutes. Then, DOWEX50W-X8
(5.0 g) was added and the mixture was stirred at room temperature for 5 minutes. Then, chloroform-methanol (5: 1, 5 ml) was added, and the insoluble material was removed by filtration. ) -S- (α-L-fucopyranosyl) -D-cysteinyl] -L-glutamic acid 1-methylamide (0.1 g) was obtained as a colorless powder.

Melting point: 182-192 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.65-0.95 (m, 6H), 1.09 (d, 3H, J
= 6.4Hz), 1.0-1.58 (m, 52H), 1.6-1.82 (m, 1H), 1.85-2.05
(m, 1H), 2.05-2.32 (m, 3H), 2.57 (d, 3H, J = 4.3Hz), 2.62-2.8
2 (m, 2H), 3.87 (dd, 1H, J = 5.6,9.7Hz), 3.9-4.05 (m, 1H), 4.1
-4.26 (m, 1H), 4.3-4.55 (m, 1H), 5.36 (d, 1H, J = 5.3Hz), 7.61
(d, 1H, J = 4.6Hz), 7.98 (d, 1H, J = 7.9Hz), 8.12 (d, 1H, J = 7.7H
z), 12.1 (bs, 1H). Mass spectrum: 844 (M + H) ⁺

Example 72 [N- (2-tetradecylhexadecanoyl) -S-
(Α-L-fucopyranosyl) -D-cysteinyl] -D
-Glutamic acid 1-methylamide [general formula [Ic
(Α)] wherein R ¹ is 2-tetradecylpentadecyl
And R ² is a methylcarbamoyl group and n is 1.
Of the compound of Example 68 (0.1
Activated carbon (1.0 g) was added to a suspension of 8 g) in methanol (30 ml), and the mixture was stirred at room temperature for 15 minutes. 10% palladium carbon (0.14 g) is added to the obtained methanol solution, and hydrogen pressure (3 to 4 atm) is applied.
The mixture was stirred at room temperature for 4 hours. After removing the catalyst by filtration, the solvent was distilled off.
The obtained residue was dissolved in methanol (30 ml), and 28
% NaOMe / methanol solution (66 mg) was added and the mixture was stirred at room temperature for 0.5 hour. Next, DOWEX 50W-X
8 (5.0 g) was added, and the mixture was stirred at room temperature for 3 minutes. The insoluble matter was removed by filtration, the solvent was distilled off, and the precipitated solid was collected by filtration from water.
-(2-tetradecylhexadecanoyl) -S- (α-
L-Fucopyranosyl) -D-cysteinyl] -D-glutamic acid 1-methylamide (15 mg) was obtained as a colorless powder.

Melting point: melting slowly from 155 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.65-0.95 (m, 6H), 1.09 (d, 3H, J
= 6.4Hz), 1.0-1.58 (m, 52H), 1.6-1.82 (m, 1H), 1.85-2.05
(m, 1H), 2.05-2.32 (m, 3H), 2.57 (d, 3H, J = 4.3Hz), 2.62-2.8
2 (m, 2H), 3.87 (dd, 1H, J = 5.6,9.7Hz), 3.95-4.1 (m, 1H), 4.1
-4.26 (m, 1H), 4.3-4.55 (m, 1H), 5.36 (d, 1H, J = 5.3Hz), 7.61
(d, 1H, J = 4.6Hz), 7.98 (d, 1H, J = 7.9Hz), 8.12 (d, 1H, J = 7.7H
z), 12.1 (bs, 1H). Mass spectrum: 844 (M + H) ⁺

Example 73 [O- (2,3,4-tri-O-acetyl-β-L-F
Copyranosyl) -L-cysteinyl] -D-glutamine
Acid 1-methylamide-5-benzyl ester [general formula
In (III-3), R ⁴ is methylcarbamoyl
Of stereoisomers of the compound wherein the group n is 1]: methylene chloride (8 g) was added to molecular sieves 4 (1.0 g).
ml), AgOTf (1.1 g) and SnCl
₂ (0.8 g) was added, and the mixture was stirred at room temperature under argon for 0.5 hour, cooled to −20 ° C., and treated with (2,3,4-tri-O-acetyl) -L-fucopyranosyl fluoride [1 0.4 g,
Compound (VII)] in methylene chloride (3 ml) and N-tert-butoxycarbonyl-L-cysteinyl-D-glutamic acid 1-methylamide-5-benzyl ester [1.0 g, compound of Reference Example 11] in methylene chloride ( 5 ml), and the mixture was stirred for 18 hours while gradually returning to room temperature. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative thin-layer chromatography (chloroform: MeOH = 9: 1) to obtain [O
-(2,3,4-tri-O-acetyl-β-L-fucopyranosyl) -L-cysteinyl] -D-glutamic acid
1-methylamide-5-benzyl ester (0.9 g)
Was obtained as a syrup. ¹ H-NMR (CDCl ₃ ) δ: 1.2 (d, 3H, J = 6.9 Hz), 1.98 (s, 3H),
2.06 (s, 3H), 2.18 (s, 3H), 2.3-2.6 (m, 4H), 2.77 (d, 3H, J = 4.
7Hz), 2.98 (dd, 1H, J = 4.8, 14.0Hz), 3.08 (dd, 1H, J = 7.1, 14.
0Hz), 3.59 (dd, 1H, 4.8,6.9Hz), 3.77-3.9 (m, 1H), 4.35-4.5
5 (m, 1H), 4.51 (d, 1H, J = 9.7Hz), 5.04 (dd, 1H, J = 3.4,10.0H
z), 5.08 (d, 1H, J = 12.4Hz), 5.13 (d, 1H, J = 12.4Hz), 5.17 (t,
1H, J = 9.9Hz), 5.26 (dd, 1H, J = 0.5,3.1Hz), 7.07 (q, 1H, J = 4.
4Hz), 7.25-7.4 (m, 5H), 7.99 (d, 1H, J = 8.4Hz).

Example 74 N- (2-tetradecylhexadecanoyl) -S-
(2,3,4-tri-O-acetyl-β-L-fucopyra
Nosyl) -L-cysteinyl] -D-glutamic acid 1-
Methylamide-5-benzyl ester [general formula (III
-4), wherein R ¹ is 2-tetradecylpentadecyl
Wherein R ⁴ is a methylcarbamoyl group and n is 1
Of the compound of Example 73 (0.9
g) and 2-tetradecylhexadecanoic acid (0.7
g) was dissolved in DMF (50 ml) by heating, cooled to room temperature, added with WSC (0.4 g) and HOBt (0.3 g), and stirred for 21 hours. Ethyl acetate (120m
l) was added thereto, washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in that order, dried, and the solvent was distilled off. The obtained residue is purified by preparative thin-layer chromatography (chloroform: MeOH = 20: 1) to give [N- (2-tetradecylhexadecanoyl) -S].
-(2,3,4-tri-O-acetyl-β-L-fucopyranosyl) -L-cysteinyl] -D-glutamic acid
1-methylamide-5-benzyl ester (0.9 g)
Was obtained as colorless crystals.

Melting point: 104-105 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.8-0.95 (m, 6H), 1.05-1.35 (m, 55
H), 1.36-1.5 (m, 1H), 1.5-1.65 (m, 1H), 2.0 (s, 3H), 2.07 (s,
3H), 2.19 (s, 3H), 2.45-2.6 (m, 2H), 2.67 (dd, 1H, J = 7.6, 14.
3Hz), 2.76 (d, 3H, J = 4.7Hz), 3.34 (dd, 1H, J = 7.0,14.4Hz),
3.75-3.88 (m, 1H), 4.32-4.5 (m, 1H), 4.42 (d, 1H, J = 9.9Hz),
5.03 (dd, 1H, 3.2,10.0Hz), 5.09 (d, 1H, J = 12.3Hz), 5.16 (d,
1H, J = 12.2Hz), 5.27 (d, 1H, J = 3.1Hz), 5.35 (t, 1H, J = 9.9H
z), 6.48 (d, 1H, J = 5.9Hz), 6.7 (q, 1H, J = 4.8Hz), 7.09 (d, 1H,
. J = 8.1Hz), as 7.3-7.45 (m, 5H) Elemental analysis _{(C 58 H 97 N 3 O} 12 S): Calculated: C, 65.59; H, 9.22 ; N, 3.96 Analytical values: C, 65.41; H, 9.17; N, 3.65.

Example 75 [N- (2-tetradecylhexadecanoyl) -S-
(Β-L-fucopyranosyl) -L-cysteinyl] -D
-Glutamic acid 1-methylamide [general formula [Ic
(Β)], wherein R ¹ is 2-tetradecylpentadecyl
And R ² is a methylcarbamoyl group and n is 1.
Of the compound of Example 74 (0.4
10% palladium carbon (0.35 g) was added to a solution of g) in methanol (30 ml), and the mixture was stirred at room temperature under hydrogen pressure (3 to 4 atm) for 5 hours. After removing the catalyst by filtration, the solvent was distilled off, and the obtained residue was dissolved in methanol (30 ml).
A 28% NaOMe / methanol solution (0.15 g) was added, and the mixture was stirred at room temperature for 0.5 hour. Next, DOWEX 50
After adding W-X8 (5.0 g) and stirring at room temperature for 3 minutes, the insoluble material was removed by filtration, the solvent was distilled off, and the precipitated solid was collected by filtration from ether and [N- (2-tetradecylhexadecanoyl). )
-S- (β-L-fucopyranosyl) -L-cysteinyl] -D-glutamic acid 1-methylamide (0.2
g) was obtained as a colorless powder. Melting point: 169-172 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.7-0.95 (m, 6H), 1.12 (d, 3H, J =
6.4Hz), 0.95-1.55 (m, 52H), 1.56-1.8 (m, 1H), 1.85-2.08
(m, 1H), 2.1-2.35 (m, 3H), 2.56 (d, 3H, J = 4.3Hz), 2.81 (d, 2
H, J = 7.3Hz), 3.0-3.6 (m, 4H), 4.05-4.23 (m, 1H), 4.46 (d, 1
H, J = 8.6Hz), 4.25-4.4 (m, 1H), 7.81 (q, 1H, J = 4.7Hz), 8.11
(d, 1H, J = 8.3 Hz), 8.15 (d, 1H, J = 6.6 Hz), 12.5 (bs, 1H). Mass spectrum: 844 (M + H) ⁺ elemental analysis (C ₄₅ H ₈₅ N ₃ O ₉ S) · 0.5H as ₂ O): calculated: C, 63.35; H, 10.16 ; N, 4.92 analytical values: C, 63.47; H, 10.01 ; N, 4.71

Example 76 [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucofuranosyl) -D-seryl] -L-glu
Tamic acid 1-methylamide [odor of the general formula (Ib)
R ¹ is a 1-tetradecyl pentadecyl group, R ² is methyl
Α-anomer of a compound having a rucarbamoyl group and n is 1
-] Production of L-arginine salt : The compound of Example 19 (50 mg) was suspended in ion-exchanged water (50 ml), sonicated, added with L-arginine (10.5 mg), dissolved by heating, Lyophilization gave the L-arginine salt of the title compound (56 mg) as a colorless powder. Melting point: 175 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m, 6H), 1.08 (d, 3H, J
= 6.5Hz), 1.1-1.5 (m, 54H), 1.5-2.2 (m, 9H), 2.55 (d, 3H, J =
4.2Hz), 3.6-3.8 (m, 5H), 3.9-4.05 (m, 1H), 4.1-4.2 (m, 1H),
4.2-4.4 (m, 1H), 4.69 (d, 1H, J = 4.2Hz), 7.47 (d, 1H, J = 3.9H
z), 8.51 (d, 1H, J = 7.3Hz), 8.85 (bs, 1H).

Example 77 [N- (2-tetradecylhexadecanoyl) -O-
(Α-L-fucopyranosyl) -D-seryl] -L-glu
Tamic acid 1-methylamide [odor of general formula (Ia)
R ¹ is a 1-tetradecyl pentadecyl group, R ² is methyl
Α-anomer of a compound having a rucarbamoyl group and n is 1
-] : Preparation of the compound of Example 47 (4
(1.7 mg) of ion-exchanged water (10 ml), and after sonication, L-arginine (8.8 mg) was added, ion-exchanged water (10 ml) was added, heated, and freeze-dried. The L-arginine salt of the title compound (46 mg) was obtained as a colorless powder. Melting point: 187 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.95 (m, 6H), 1.04 (d, 3H, J
= 6.5Hz), 1.1-1.5 (m, 54H), 1.5-1.7 (m, 4H), 1.7-1.9 (m, 2
H), 2.0-2.15 (m, 2H), 2.15-2.3 (m, 1H), 2.54 (d, 3H, J = 4.4H
z), 3.55-3.8 (m, 4H), 4.0-4.1 (m, 1H), 4.3-4.45 (m, 1H), 4.6
3 (d, 1H, J = 3.0Hz), 7.69 (q, 1H, J = 4.1Hz), 7.91 (d, 1H, 5.9H
z), 8.8-8.95 (m, 1H).

Example 78 Preparation of Tablets To 100 parts by weight of the compound of Example 19, 30 parts by weight of lactose, 20 parts by weight of crystalline cellulose, 5 parts by weight of hydroxypropylmethylcellulose and 20 parts by weight of carboxymethylcellulose were added 150 parts by weight of distilled water. After sufficient kneading, the kneaded material is crushed and dried. To the obtained dried product, 5 parts by weight of magnesium stearate is added and mixed to obtain granules. The granules are 8 mm in diameter and 180 mg in weight using a tableting machine.
Of the compound 10 of Example 19 in one tablet.
A tablet containing 0 mg is obtained.

[0258] was dissolved by adding distilled water for injection to a mixture of compound 0.5 part by weight of sorbitol 5 parts by weight of Example 19 Example 79 injections, and 100 parts by weight, filtering the solution through a membrane filter I do. The filtrate was filled into ampoules purged with nitrogen in an amount of 5 g, sealed, and sterilized at 120 ° C. for 15 minutes to obtain an injection containing 25 mg of the compound of Example 19 in one ampule.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 38/00 ABG C07K 5/023 ADA 5/03 AED A61K 37/02 ABF C07H 15/04 ABG C07K 5/023 ADA 5/03 AED (72) Inventor Kiriko Kurokawa 2-1-1, Shioji, Nishinari-ku, Osaka (72) Inventor Hiroshi Omoto 1-33-504, Tomobuchi-cho, Miyakojima-ku, Osaka (72) Inventor Hiroto Kondo Osaka 6-A-210, 6-A, Mayugaoka-Higashi, Suita-shi, Fufu-shi (72) Inventor Yukihisa Wada 1-6-7-1405, Tomobuchi-cho, Miyakojima-ku, Osaka-shi No. (72) Inventor Tadayuki Saito 1-15-110, Tomobuchi-cho, Miyakojima-ku, Osaka-shi

Claims (7)

[Claims] 1. A compound represented by the following formula (I): (Wherein X ¹ represents the following formula (1), (2) or (3): Wherein R ¹ represents a branched long-chain alkyl group, R ² represents -CONHR ³ , a carboxyl group or a hydrogen atom, n represents an integer of 0, 1 or 2, R ³ represents a lower alkyl group or a phenyl group. Or a pharmaceutically acceptable salt thereof. 2. The following formula (II): (Wherein X ² represents the following formula (4) or (5): And A ¹ represents tert-
Represents a butoxy group or a branched long chain alkyl group, Bn represents a benzyl group, R ⁴ is -CONHR ^3, represents a benzyloxycarbonyl group or a hydrogen atom, n represents an integer of 0, 1 or 2, R ³ Represents a lower alkyl group or a phenyl group. ). 3. The following formula (III): (Wherein, Y represents an oxygen atom or a sulfur atom, A ² represents a hydrogen atom or a branched long-chain alkylcarbonyl group,
R ⁴ represents —CONHR ³ , a benzyloxycarbonyl group or a hydrogen atom; Ac represents an acetyl group; Bn represents a benzyl group; n represents an integer of 0, 1 or 2;
³ represents a lower alkyl group or a phenyl group. ). 4. A compound represented by the following formula (IV): (In the formula, A ¹ represents a tert-butoxy group or a branched long-chain alkyl group, R ⁴ represents —CONHR ³ , a benzyloxycarbonyl group or a hydrogen atom, Ac represents an acetyl group, and Bn represents a benzyl group. And n represents an integer of 0, 1 or 2, and R ³ represents a lower alkyl group or a phenyl group. 5. A drug comprising the fucose derivative (I) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 6. A selectin inhibitor comprising the fucose derivative (I) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 7. A drug for preventing or treating an inflammatory disease or reperfusion injury after ischemia, comprising the fucose derivative (I) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.