JP2588729B2 - Sphingosine derivative - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to sphingosine derivatives. More specifically, the present invention relates to a compound represented by the formula (I) which can be used as an anticancer agent in the field of medicine.

formula [In the formula, A is an amino which may have a substituent [wherein the substituent is alkyl having 1 to 6 carbons, alkylsulfonyl having 1 to 6 carbons; hydroxy, acetamide, amino or a double bond Linear or branched acyl or aroyl having 2 to 24 carbon atoms which may be substituted, which may be substituted by a linear or branched acyl, aroyl, aryl or halogen-substituted alkyl having 2 to 24 carbon atoms; Good carbamoyl or thiocarbamoyl] or azide; R ¹ is hydrogen, acetyl, benzoyl, pivaloyl, β-D
-Galactopyranosyl, 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl, 4-O- (β-D-
Galactopyranosyl) -β-D-glucopyranosyl, 2,
3,6-tri-O-acetyl-4-O- (2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -β-
D-glucopyranosyl, 5-acetamido-3,5-dideoxy-β-D-glycero-D-galact-2-nonulopyranosonoyl (N-acetylneuraminosyl), 5-
Acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-β-glycero-D-galact-2-nonulopyranosonoyl or trimethylammonium (C1-C3
Alkyl) phosphoryl, and R ² is hydrogen, acetyl, benzoyl, pivaloyl, 4-O
-([Beta] -D-galactopyranosyl)-[beta] -D-glucopyranosyl, 2,3,6-tri-O-acetyl-4-O- (2,
3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl) -β-D-glucopyranosyl, 5-acetamido-3,5-dideoxy-β-D-glycero-D-galacto-2- Nonulopyranosonoyl (N-acetylneuraminosyl), 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-β-glycero-D-galact-2-nonuro Pyranosonoyl, and n is an integer of 10 or more and 14 or less.

Provided that A is unsubstituted amino; hydroxy, acetamide,
Amino or double have binding substituted with straight-chain or branched acyl may also C2~C24 amino; when it is or azido, R ² is not hydrogen, acetyl, benzoyl or pivaloyl] conventional Technology Sphingosine is the most abundantly found in animal sphingolipids and is a _C18 long chain base with one double bond. Typical sphingolipids include sphingosine lipids in which a sphingosine-linked fatty acid is bonded to ceramide, and a glycosphingolipid in which one or more sugars are bonded to a glycoside, and a phosphate and a base (choline / ethanolamine) are bonded. The physiological significance of these sphingolipids is largely unknown, but recent studies have shown that cell growth regulation, mutual recognition and other functions, receptor functions, development and differentiation problems, neuronal function or infection and cell It is considered to play an important role in malignant transformation.

JP-A-61-12695 discloses a use as a tumor marker or a marker of a cell capable of inducing differentiation. JP-A-61-227531 discloses that ganglioside derivatives have antitumor activity. JP-A-62-39
No. 597 discloses that certain sphingosine derivatives are effective in treating wounds or ulcers.

Problems to be Solved by the Invention Various anticancer agents have been developed so far, but those which can sufficiently satisfy the problem of side effects and the like have not yet been developed. Therefore, development of an anticancer agent that is effective for all cancers and has no side effects has been desired.

Means for Solving the Problems The present inventors have found that the chemically modified sphingosine derivative represented by the formula (I) has an excellent anticancer effect, and completed the present invention.

The definitions of various terms used in this specification are as follows.

The term "acyl", straight or branched alkanoyl of C ₂ -C _24, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, myristoyl, palmitoyl, stearoyl, arachidoyl, behenoyl or Tetorakosanoiru Or aroyl such as benzoyl.

“Glycosyl” refers to β-D-galactopyranosyl,
4-O- (β-D-galactopyranosyl) -β-D-glucopyranosyl or the like or 5-acetamido-2,3,5-
Trideoxy-β-D-glycero-D-galact-2-
Nonuropyranosoyl (N-acetylneuraminosyl)
And those wherein their hydroxy is protected with an acyl such as acetyl, pivaloyl or benzoyl.

The “phosphate residue” means 2-trimethylammoniumethylphosphoryl, 2-triethylammoniumethylphosphoryl, or the like.

Examples of the amino substituent include lower alkyl, lower alkylsulfonyl, hydroxy, acetamide, acyl optionally having an amino or double bond, substituted carbamoyl, and substituted thiocarbamoyl.

"Lower alkyl means methyl, ethyl, propyl, isopropyl, butyl, pentyl or hexyl and the like.

“Lower alkylsulfonyl” means methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like.

“Acyl optionally substituted with hydroxy, acetamide or amino” means glycoloyl, aminoacetyl, acetamideacetyl, 2-acetamidopropionyl, 2-acetamido-3-carbamoylpropionyl and the like.

“Acyl optionally having a double bond” means oleoyl, linoleoyl, detracosenoyl, and the like.

"Substituted carbamoyl" means carbamoyl substituted with an acyl, aryl or substituted alkyl,
For example, benzoylcarbamoyl, phenylcarbamoyl, 2-chloroethylcarbamoyl and the like can be mentioned.

The “substituted thiocarbamoyl” means the above-mentioned substituted carbamoyl and includes, for example, benzoylthiocarbamoyl, phenylthiocarbamoyl, 2-chloroethylthiocarbamoyl and the like.

In the formula (I), preferred “R ₁ ” is hydrogen, acyl such as acetyl, pivaloyl or benzoyl, β
-D-galactopyranosyl, 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl, 4-O- (β-
D-galactopyranosyl) -β-D-glucopyranosyl, 2,3,6-tri-O-acetyl-4-O- (2,3,4,6-
Tetra-O-acetyl-β-D-galactopyranosyl)
-Β-D-glucopyranosyl or the like or 5-acetamido-3,5-dideoxy-β-D-glycero-D-galact-2-nonulopyranosonoyl (N-acetylneuraminosyl), 5-acetamido-4, 7,8,9-tetra-O-
Acetyl-3,5-dideoxy-β-D-glycero-D-
It means glucosyl such as sialosyl such as galact-2-nonulopyranosonoyl or phosphate residue such as 2-trimethylammoniumethylphosphoryl. Preferred “R ₂ ” is hydrogen, acyl such as acetyl, pivaloyl or benzoyl or 4-O- (β
-D-galactopyranosyl) -β-D-glucopyranosyl or 2,3,6-tri-O-acetyl-4-O- (2,
Glycosyl such as 3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -β-D-glucopyranosyl. Preferred "A" is amino, methylamino, methylsulfonylamino, acetamide, propionylamino, valerylamino, tetracosanoylamino,
15-tetracosenoylamino, glycoloylamino, 2
-Hydroxystearoylamino, 12-hydroxystearoylamino, aminoacetamide, N-acetylglycylamino, 2-acetamidopropionylamino, 2-
Acetamide-3-carbamoylpropionylamino, 2
-Means substituted amino or azide such as chloroethylureide, phenylureide, benzoylureide or phenylthioureide. Preferred "n" is 10,
12 or 14.

2-Amino-1,3-dihydroxy-4-octadecene used as a starting material for the compound of formula (I) is disclosed in EJReist et al., Journal of
The Organic Chemistry (J.Org.Chem.), 3rd
5, p. 127, 1987, or D. Shapiro, Journal of American Chemical Society (J. Am. Chem. Soc.), Vol. 80, 1194.
, Page 1958.
2-Amino-1,3-dihydroxy-4-hexadecene and 2-amino-1,3-dihydroxy-4-eicosene can be used as imides at the stage of the Wittig reaction in the above-mentioned literature, respectively, as imides. It can be produced by using orchid and hexadecanilidenetriphenylphosphorane. Also, 2-benzyloxycarbonylamino-amino-protected
1,3-Dihydroxy-4-octadecene is described in RHBoutin et al., Journal of
The Organic Chemistry (J.Org.Chem.), 5th
1, pp. 5320, 1986. 2-Azido-1,3-dihydroxy-4-octadecene and 5-azido-2-phenyl-4-bentadecenyl-1,3-dioxane have been described by RR Schmidt. Et al., Tetrahedron Letters (Tetr).
ahedron Letters), vol. 27, p. 481, 1986.

When the optically active sphingosine is used as a starting material, the D-form or L-form of the compound of the present invention can be obtained in an optically active form. When racemic sphingosine is used as a starting material, the compound of the present invention is generally obtained as a racemic form or, when an optically active sugar or acyl is condensed, as a mixture of diastereomers. In the latter case, those diastereomers can be made optically active, if necessary, in a certain step.

The compound of the present invention can be produced, for example, as follows.

(Step 1) This step is a step of acylating the amino of compound II to obtain the acyl derivative IA in the compound of the present invention.

The introduction of these groups is effected by the action of the corresponding carboxylic acids, acid anhydrides or acid chlorides.

As the carboxylic acid to be used, hydroxy, amino or carbamoyl or a protected form thereof (for example, tert.
-Butoxycarbonylamino or acetylamino) C ₁ -C ₁₇ alkanoic acid optionally substituted with
Acetic acid, propionic acid, butyric acid, valeric acid, stearic acid, 12
-Hydroxystearic acid, acetylglycolic acid, aminoacetic acid, tert-butoxycarbonylaminoacetic acid, acetamidoacetic acid, 2-acetamidopropionic acid or 2-acetamido-2-carbamoylpropionic acid. Acetic anhydride or propionic anhydride may be used as an acid anhydride, and chlorides of the above carboxylic acids may be used as acid chlorides.

The reaction may be performed according to a conventional method such as a peptide formation reaction, for example, an acid chloride method, an azide method, a mixed acid anhydride method, a carbodiimide method or an active ester method. When acylation is carried out by the carbodiimide method, N-hydroxy-5-norbornene-2,3-dicarboximide is preferably used.

When acylation is performed using an acid anhydride, the reaction may be performed in an alcohol-based (eg, methanol, ethanol, etc.) solvent.

(Second Step) This step is a step of cyclizing compound II ' in the presence of a base to obtain cyclic carbamate IV .

As a base, sodium hydride, potassium hydride, n
-Butyl lithium, sodium tert-butylate, sodium hydroxide, potassium hydroxide or sodium methoxide may be used. As the solvent, dimethylformamide, ether-based dioxane, glyme, diglyme, alcohol-based methanol, ethanol, or the like may be used depending on the properties of the reagent used.

The reaction can be performed at room temperature or under heating for several tens minutes to several hours.

(Third Step) This step is a step of protecting hydroxy of compound IV .

The reaction is carried out by contacting compound IV with a compound forming a protecting group according to a conventional method. Examples of the compound forming a protecting group include silyl compounds (such as hexamethyldisilazane, tert-butyldimethylsilyl chloride, and tert-butyldiphenylsilyl chloride), and alkoxy or aralkyloxy-substituted alkyl halide compounds (methoxymethyl chloride, tert-butyl −
Butoxymethyl chloride, 2-methoxyethoxymethyl chloride, benzyloxymethyl chloride, etc., unsaturated ethers (methyl vinyl ether, ethyl vinyl ether, etc.), substituted alkyl halide compounds (allyl bromide, triphenylmethyl chloride, etc.) or acyl compounds (anhydrous Acetic acid, acetyl chloride, pivaloyl chloride, benzoyl chloride, etc.). When a silyl compound or an alkoxy or aralkyloxy-substituted alkyl halide is used, the reaction is preferably performed in the presence of a base such as pyridine, triethylamine, diisopropylethylamine, and imidazole. When unsaturated ethers are used, the reaction is carried out with a small amount of mineral acid (hydrochloric acid, hydrobromic acid, etc.).
Alternatively, the reaction may be performed in the presence of an organic acid (such as picric acid, trifluoroacetic acid, benzenesulfonic acid, or p-toluenesulfonic acid). When an acyl compound or an alkyl halide compound is used, the reaction is preferably carried out in the presence of a base such as pyridine or triethylamine or an acid such as zinc chloride, hydrochloric acid, sulfuric acid, perchloric acid and the like.

As a solvent used in these reactions, chlorinated hydrocarbon-based chloroform, dichloromethane, ether-based diethyl ether, tetrahydrofuran, dimethylformamide, or the like may be used alone or in combination.

(Fourth Step) The present step is a step of obtaining a compound VI by N-alkylating a compound V.

As the alkylating agent, an alkyl halide such as methyl chloride, methyl bromide or methyl iodide may be used.

The reaction can be carried out in the presence of silver oxide, silver carbonate or mercuric cyanide in a solvent such as dimethylformamide at room temperature for several tens of hours.

Alternative methods include a method using formaldehyde-formic acid or a method using acetaldehyde-sodium cyanoborohydride.

(Fifth Step) This step is a step of obtaining a compound VII by removing the hydroxy protecting group of the compound VI .

The reaction depends on the nature of the protecting group to be removed, hydrolysis,
It is performed by a conventional method such as reduction.

The reaction for removing the silyl protecting group is carried out, if necessary, using an organic or inorganic acid such as tetrabutylammonium fluoride or acetic acid, hydrochloric acid, p-toluenesulfonic acid or the like as a catalyst, and alcoholic methanol or ethanol as a solvent. The reaction can be performed at room temperature or under heating for several tens minutes to several hours using ether-based ethyl ether, tetrahydrofuran or acetonitrile, water, or the like.

The reaction for removing the substituted alkyl protecting group can be performed by acid hydrolysis or treatment with a Lewis acid such as boron trifluoride etherate.

The reaction for removing the alkoxy or aralkyloxy-substituted alkyl protecting group can be carried out by acid hydrolysis.

The reaction for removing the acyl protecting group can be performed by hydrolysis using a base. Examples of the acid used for the hydrolysis include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid, and p-toluenesulfonic acid. And the like. As the base, an inorganic base, for example, an alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, calcium hydroxide, or a corresponding carbonate or hydrogen carbonate Salts or ammonium hydroxides or organic bases such as alkoxides or phenoxides of metals such as sodium ethoxide, sodium methoxide, methylamine, ethylamine, N, N-dimethyl-1,3
-Alkylamines such as propanediamine, trimethylamine and triethylamine.

Hydrolysis is performed under cooling or heating in alcoholic methanol, ethanol, propanol, etc., ether diethyl ether, tetrahydrofuran, etc., chlorinated hydrocarbon chloroform, dichloromethane, etc., or dimethyl sulfoxide, acetonitrile, water, etc. It is good to do in. If the acid or base is liquid, it can itself be used as a solvent.

(Step 6) This step is a step of hydrolyzing compound VII to lead to the N-alkyl derivative IB in the compound of the present invention.

The hydrolysis may be performed according to the method described in the fifth step.

In this step, decarboxylation also occurs along with the hydrolysis, and N-
The alkyl derivative IB can be obtained.

(Step 7) This step is a step of obtaining an N-alkanesulfonyl derivative IC of the compound of the present invention from compound II .

As the sulfonylating agent, a substituted sulfonic acid halide having a desired substituent such as methylsulfonyl chloride and ethylsulfonyl chloride may be used.

As a solvent, chlorinated hydrocarbon chloroform, dichloromethane, ether diethyl ether, tetrahydrofuran, alcohol methanol, ethanol,
Aromatic benzene or water may be mixed and used as necessary.

The reaction is performed at room temperature for several tens minutes to several hours in the presence of a base such as an inorganic base such as sodium hydroxide, potassium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or sodium bicarbonate, or an organic base such as triethylamine or pyridine. It is good to react.

(Eighth Step) This step is a step of protecting the 3-position hydroxy of compound IA .

This step is carried out by once protecting both hydroxy groups and then selectively deprotecting the protecting group at the 1-position.

As those that selectively protect primary hydroxy,
-Butyldiphenyl or triphenylmethyl and the like. The hydroxy protecting group at the 3-position is preferably different from those attached at the 1-position, for example, acyl such as acetyl and benzoyl.

The protection reaction or the deprotection reaction may be performed according to the third step or the fifth step, respectively.

(Ninth Step) This step is a step of phosphorylating compound VIII to obtain compound IX .

As the phosphorylating agent, β-bromoethyl phosphoryl dichloride may be used.

In this step, for example, a base such as n-butyllithium, sodium hydride or sodium amide is allowed to act on compound VIII to form a metal alkoxide, and then a phosphorylating agent is added thereto for condensation to obtain an intermediate. It can be carried out by hydrolyzing the body.

The reaction for obtaining the intermediate can be carried out in an anhydrous solvent such as ether-based diethyl ether or tetrahydrofuran at room temperature or under cooling for several tens minutes to several hours.

In the hydrolysis, an organic base such as pyridine or triethylamine or an inorganic base such as sodium carbonate or sodium hydrogencarbonate may be used as a base catalyst.

(Tenth Step) This step is a step of substituting the halogen of compound IX with a trialkylamine.

As the trialkylamine, trimethylamine, triethylamine, or the like is preferably used.

As the solvent, chlorinated hydrocarbon-based chloroform or dichloromethane, alcohol-based methanol, ethanol, propanol, isopropanol, dimethyl sulfoxide, or the like may be used as a mixture.

 The reaction can be carried out under heating for several hours.

(Eleventh Step) In this step, the hydroxy protecting group of compound X is removed,
The phosphoric acid derivative ID in the compound of the present invention is obtained.

The reaction can be carried out at room temperature for several hours in a solvent such as alcoholic methanol or ethanol using an organic base such as sodium methoxide or an inorganic base such as sodium hydroxide or lithium hydroxide as a catalyst. .

(Twelfth Step) This step is a step of condensing a saccharide with compound IV to obtain compound XI .

As the sugar donor, α-D-galactopyracinol or 4-O-β-D-galactopyranosyl-α-D-glucopyranosyl halide or O-trichloro or O-
Except for those in which the hydroxy of trifluoroacetimidate is at the 1-position, those protected with acyl (eg, acetyl, pivaloyl, benzoyl, etc.), for example, 2,3,4,
6-tetra-O-acetyl-α-D-galactopyranosyl bromide or 2,3,4,6-tetra-O-acetyl-
α-D-galactopyranosyltrichloroacetimidate or 2,3,6-tri-O-acetyl-4-O- (2,3,
4,6-tetra-O-acetyl-β-D-galactopyranosyl) -α-D-glucopyranosyl chloride or
2,3,6-tri-O-acetyl-4-O- (2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -α
-D-glucopyranosyltrichloroacetimidate and the like.

When a halide is used as the sugar donor, the reaction is carried out using silver oxide, silver carbonate, silver trifluoromethanesulfonate, silver perchlorate, mercuric cyanide, mercury bromide and / or
Alternatively, it may be performed in the presence of a desiccant such as molecular sieves or calcium sulfonate (Drierite).

As the solvent, chlorinated hydrocarbon-based dichloromethane, chloroform, 1,2-dichloroethane, aromatic benzene, ether-based ether, dioxane or nitromethane, dimethylsulfoxide, dimethylformamide, and the like may be used.

The reaction can be performed at room temperature for tens of minutes to several hours.

When imidate is used as the sugar donor, the reaction may be performed in the presence of a Lewis acid (for example, boron trifluoride etherate or trimethylsilyl trifluoromethanesulfonate) and / or molecular sieves.

As the solvent, hydrocarbon hexane, chlorinated hydrocarbon dichloromethane, chloroform, or the like may be used.

The reaction can be carried out under cooling or at room temperature for several tens minutes to several hours.

(Thirteenth Step) This step is a step of removing the hydroxy protecting group of compound XI .

The reaction may be performed according to the hydrolysis reaction described in the fifth step. This reaction simultaneously hydrolyzes and decarboxylates the cyclic carbamate.

(Step 14) This step is a step of acylating the amino of compound XII to obtain galactopyranoside or lactoside derivative IE in the compound of the present invention.

 This step may be performed according to the first step.

(Step 15) In this step, the amino of compound II is acylated to give compound XI
This is the step of obtaining II .

The introduction of these groups is effected by the action of the corresponding alkanoic acid, acid anhydride or acid chloride.

As the carboxylic acid to be used, a C ₁₄ -C ₂₄ alkanoic acid which may have a hydroxy at the α-position or one or two double bonds in a cis configuration, for example, myristic acid, palmitic acid, stearic acid Oleic acid, linoleic acid, arachidic acid, behenic acid, tetracosanoic acid, cis-15-tetracosenoic acid (nervonic acid), 2-hydroxytetracosanoic acid (cerebronic acid), 2-hydroxy-15
-Tetracosenoic acid or 2-hydroxy-17-tetracosenoic acid.

Examples of the acid anhydride or acid chloride include those corresponding to the above carboxylic acids, for example, lignoceric anhydride, nervonic anhydride or cerebronic anhydride, or lignoceric chloride, nervonic acid chloride or cerebronic acid chloride. Can be.

The reaction can be performed at room temperature in a chlorinated hydrocarbon solvent such as chloroform or dichloromethane. If necessary, the reaction may be performed in the presence of a base such as pyridine, triethylamine or 4-dimethylaminopyridine.
When a carboxylic acid is used as the acylating agent, 2-chloro-N-methylpyridinium iodide or tri-n-butylamine may be used.

When azido dioxane is used as a starting material, the azide may be reduced to an amine prior to acylation. Examples of the reducing agent include triphenylphorphine, aluminum thylium hydride, triethylamine-hydrogen sulfide, and triethylamine-mercaptan.
Examples of the solvent include alcohol-based methanol, ethanol or ether-based diethyl ether and tetrahydrofuran. The reaction can be carried out at room temperature or under heating for several hours. In addition, this process
It can also be carried out by catalytic reduction using a catalyst such as platinum or palladium.

When the 1,3-diol is protected by isopropylidene, benzylidene, methylene or ethylidene, a mineral acid such as hydrochloric acid or sulfuric acid or a trifluoroacetic acid or an organic acid such as p-toluenesulfonic acid is used.
Deprotection may be carried out by hydrolysis according to a conventional method.

(16th step) This step is a compound X III, compound a sugar condensation XI
This is the step of obtaining V. In this step, the reaction may be performed according to the twelfth step.

Prior to glycosylation, the 1- or 3-position hydroxy may be protected and used as a sugar acceptor as follows.

If only the 1-hydroxy compounds X III want to do glycosylation 1-position, with the 2-position hydroxy protecting groups respectively different in the nature of, the first place of the hydroxy protecting groups that selectively deprotected sugar It is good to use as a receptor.
(For example, when the 1-position is protected with triphenylmethyl or tert-butyldiphenylsilyl, the 3-position is protected with acetyl or benzoyl or the like.) When glycosylation is desired to be performed only on 3-hydroxy, a sugar acceptor is required. What protected the 1-position hydroxy may be used as a body.
When you want to perform a glycosidation in both positions 1 and 3 hydroxy, a method for position 1 and glycosylated in a state that does not protect both the 3-position of hydroxy of compound X III, protecting the 3-position hydroxy There is a method of glycosylating only the hydroxy at the 1-position and then removing the hydroxy-protecting group at the 3-position to glycosylate the hydroxy at the 3-position.

The hydroxy protection or deprotection reactions are tertiary, respectively.
The reaction may be performed according to the step and the fifth step.

Further, when the hydroxy R ₄ is protected, after glycosylation, it may be deprotected. If necessary, the hydroxy protecting group of the sugar may be removed.

The reaction can be performed by hydrolysis using a base catalyst. The reaction may be performed according to the hydrolysis method described in the fifth step.

By this step, a galactoside derivative or a lactoside derivative IE in the compound of the present invention can be obtained.

(Step 17) This step is a step of acylating the 3-position hydroxy of compound III .

In this step, first, a substituted alkyl such as triphenylmethyl or a protecting group such as tert-butyldimethylsilyl or tert-butyldiphenylsilyl is introduced into hydroxy at position 1, and then acetyl, pivaloyl or An acyl such as benzoyl is introduced. This is then effected by removing the hydroxy protecting group at position 1 of the compound. The protection and deprotection reactions in this step may be performed according to the third step and the fifth step, respectively.

According to this step, it is possible to obtain an azide derivative of the compound of the present invention in which IF is acylated at the 1-position and at the 3-position.

(Eighteenth Step) This step is a step for converting compound II ' to a urea derivative IG in the compound of the present invention.

This step is carried out by adding an isocyanate or isothiocyanate having a desired substituent to compound II ' and then removing the hydroxy protecting group from the resulting compound.

The deprotection reaction of the hydroxy protecting group can be performed in the fifth step or the fifth step.
It is good to carry out according to the method described in 15 steps.

Examples of the isocyanate to be used include substituted alkyl, aralkyl and aryl isocyanates such as 2-chloroethyl isocyanate, benzoyl isocyanate and phenyl isocyanate. Examples of the isothiocyanate to be used include substituted alkyl, aralkyl or aryl isothiocyanate such as 2-chloroethyl isothiocyanate, benzoyl isothiocyanate and phenyl isothiocyanate.

As the solvent, an inert solvent such as chlorinated hydrocarbon chloroform, dichloromethane, aromatic benzene, toluene, chlorobenzene, ether diethyl ether, tetrahydrofuran or acetone may be used.

The reaction can be carried out under cooling or at room temperature for several tens minutes to several hours.

(19th step) This step is a step of condensing a sugar with an azide derivative IF or a urea derivative IG to remove acetyl of the obtained compound.

Sugar donors in which the hydroxy of 2-chlorosialic acid lower alkyl ester is protected with acetyl,
For example, 5-acetamide-4,7,8,9-tetra-O-acetyl-2-chloro-2,3,5-trideoxy-β-D-glycero-D-galact-2-nonulopyranosonic acid It is preferable to use methyl ester or ethyl ester.

The glycosylation reaction may be performed according to the twelfth step.

When an azide derivative is used as the sugar acceptor, the azide may be reduced to an amine by the method described in the fifteenth step, if necessary.

Also, if necessary, a hydroxy protecting group (acetyl)
May be removed according to the fifth step.

By this step, the sialic acid derivative in the compound of the present invention
You can get IH .

When the starting material is in a racemic form, it may be resolved by a conventional method of optical resolution at an appropriate step, for example, by a method involving a diastereomer.

As the resolving agent, an acid such as (R, R) -tartaric acid or a derivative thereof, such as dibenzoyltartaric acid, diacetyltartaric acid, ditoluyltartaric acid, or mandelic acid or a derivative thereof (S) -O-acetylmandelic acid is used. The diastereomer mixture may be obtained by esterifying racemic hydroxy with the above-mentioned acid, and the mixture may be separated by crystallization or chromatography.

In the reaction scheme, R ₁ , R ₂ , and A have the same meanings as described above.

"R ₁ 'or R ₂ '" is a hydroxy protecting group, for example,
Acyl such as acetyl, pivaloyl, benzoyl, tert
Silyl, such as -butyldiphenylsilyl, tert-butyldimethylsilyl, or substituted alkyl, such as triphenylmethyl.

"R _3" is an amino protecting group means, for example, benzyloxycarbonyl or tert- butoxycarbonyl.

“R ₄ ” means lower alkyl, hydroxy which may be protected or acyl which may have a double bond.

Hereinafter, reference examples, examples and physical constants will be shown to clarify aspects of the present invention in more detail, but the scope of the present invention is not limited thereto.

The definitions of various symbols used in Reference Examples and Examples are as follows.

Me; methyl, Ph: phenyl, t-Bu: tert-butyl, Ac: acetyl, Σ: tert-butyldiphenylsilyl Also, wavy lines represent α or β configuration or a mixture thereof.

Reference Example 1 (2S, 3R) -2-acetamide-1,3-dihydroxy-4
- cis - Okitadesen I A1 Compound II bl-c [Compound described in Journal of Chemical Society (J. Org. Chem.), Vol. 35, p. 4127, 1970] 2.0 g (6.678 mmol) of anhydrous methanol 2
Dissolve in 00 ml. 3.1 ml (33.39 mmol) of acetic anhydride are added and left at room temperature for 30 minutes. The reaction mixture is concentrated to dryness under reduced pressure. The obtained residue is dissolved in a mixture of methanol and toluene, and concentrated and dried again. The obtained crystalline residue was washed with petroleum ether to give 2.06 g of Compound I A1 (yield 90
%) Is obtained.

mp. 57.5-58.5 ° C. [Α] _D -18.5 ° (23 ° C, c 0.714, CHCl ₃ ). ^{_{IR (CHCl 3) cm -1:}} . 1665 1 H-NMR (CDCl 3 + CD 3 OD) δppm: 5.7~5.2 (2H, m, -C H
= C H -), 1.97 ( 3H, s, NAc), 0.88 (3H, t, J = 6Hz, C
H ₃ ). Elemental analysis (as C ₂₀ H ₃₉ NO ₃ ) Calculated value (%): C 70.33, H 11.51, N 4.10, Actual value (%): C 70.11, H 11.49, N 4.08. Reference Examples 2 to 4 Reference Examples 1 to 4 The reaction is carried out in the same manner to obtain the compounds shown in Table 1.

Table 1 (1) Reference Example 5 (2S, 3R) -2- n- propanoylamino-1,3-dihydroxy-4-cis - octadecene I A4 0.07 ml (0.918 mmol) of n-propionic acid and N
165 mg (0.918 mmol) of -hydroxy-5-norbornene-2,3-dicarboximide are dissolved in 2.5 ml of anhydrous tetrahydrofuran. To this solution, 189 mg of dicyclohexyl dicarbimide is added and stirred at room temperature for 1 hour. The precipitated insoluble matter is filtered off to obtain a filtrate containing N- (n-propanoyloxy) -5-norbornene-2,3-dicarboximide. The filtrate was combined with 250 mg of Compound II b1-c (0.
(835 mmol) in anhydrous tetrahydrofuran (3 ml) and stirred at room temperature for a further 20 hours. After the reaction solution was concentrated to dryness under reduced pressure and the resulting residue chloroform - methanol (20: 1) and purified by silica gel column chromatography as an elution solvent a compound I A4, 225 mg (yield 75.
8%).

mp. 76-77 ° C. [Α] _D -19.5 ° (22.5 ° C, c0.672, CHCl ₃ ). ^{IR (KBr) cm -1:.} 3400,3300,1645,1542,1466 1 H-NMR (CDCl 3 + CD 3 OD (1: 1)): δppm5.73~5.23 (2
H, m, -C H = C H -), 2.23 (2H, q, J = 7.5Hz, COC H 2),
2.10 (2H, m, = CHC H 2), 1.12 (3H, t, J = 7.5Hz, CH 3), 0.8
7 (3H, t, J = 6Hz, CH 3). Elemental analysis (as C ₂₁ H ₄₁ NO ₃ · 0.1 H ₂ O) Calculated value (%): C 70.52, H 11.62, N 3.92, Actual value (%): C 70.49, H 11.65, N 3.94. 11 In the same manner as in Reference Example 5, the corresponding N- (acyloxy) -5-norbornene-2,3-dicarboximide is produced. It is reacted with Compound II b1-c in the same manner as in Reference Example 5 to obtain Compound IA .

 The results are shown in Table 2.

Reference Example 12 (2S, 3R) -2-glycolylamino-1,3-dihydroxy-4-cis-octadecene IA7 71 mg (0.6 mmol) of 2-acetylglycolic acid and 108 mg (0.6 mmol) of N-hydroxy-5-norbornene-2,3-dicarboximide are dissolved in 3 ml of anhydrous tetrahydrofuran. To this solution is added 4 mg (0.6 mmol) of dicyclohexylcarbodiimide and stirred at room temperature for 30 minutes. The precipitated insolubles were filtered off to give N- (2-acetylglycolyloxy) -5-norbornene-2,3-.
A filtrate containing dicarboximide is obtained. The filtrate is added to a solution of compound II b1-c (150 mg, 0.5 mmol) in anhydrous tetrahydrofuran (5 ml), and the mixture is stirred at room temperature for 3.5 hours. The reaction solution is concentrated to dryness under reduced pressure to obtain 331 mg of a residue.
The residue was purified by silica gel column chromatography to give (2S, 3R) -2- (2-acetylglycolyl) amino-1,3-dihydroxy-4-cis-octadecene (175 mg).
(81% yield) is obtained. The above compound was treated with anhydrous methanol
After dissolving in 10 ml, 0.1 ml of a 1 M sodium methoxide-methanol solution is added, and the mixture is left at room temperature for 45 minutes. The reaction solution is neutralized by adding an ion exchange resin Amberlite IR-120B (H ⁺ ). The resin is filtered off and washed with methanol. The filtrate and washing solution were combined, and the solvent was distilled off under reduced pressure.
g is obtained. The residue compound crystallized from ethyl acetate and n- hexane mixture I A7, 105mg (70% yield) of.

The physical constants of Compound IA7 are shown in Table 2.

Reference Example 13 (2S, 3R) -2- Gurishiruamino -1,3-dihydroxy-4-cis - octadecene I A8 1 ml of trifluoroacetic acid was added to 7 ml of a dichloromethane solution of 278 mg (0.608 mmol) of the compound I A8 ' obtained in Example 8.
And stirred at room temperature for 2 hours. After diluting the reaction solution with dichloromethane, it is washed successively with 2M sodium hydroxide and water. After the organic layer is dried over magnesium sulfate, the solvent is distilled off under reduced pressure to obtain 177 mg of a residue. The residue was crystallized from a mixture of methanol and ether to give compound IA 8 , 102 m
g is obtained.

The physical constants of Compound IA8 are shown in Table 2.

Reference Example 14 (2S, 3R) -2,3-N, O-carbonyl-1-O- (tert
-Butyldiphenylsilyl) -1,3-dihydroxy-4
−cis-octadecene V b1 Methods described in the literature [RHBoufin et al., Journal of the Organic Chemistry (J. Org. Chem.) Vol. 51, 5320]
1986]]. (2S, 3R) -2-benzyloxycarbonylamino-1,3-dihydroxy-4-cis-
After dissolving 2.0 g (4.61 mmol) of octadecene IIb2-c in 10 ml of dimethylformamide, the solution is cooled with ice under a stream of nitrogen. To this solution is added 221 mg (4.61 mmol) of 50% sodium hydride and stirred until hydrogen evolution has ceased. The reaction mixture is then heated in an oil bath to 50 ° C. for 1 hour. After cooling, the reaction solution is poured into a large amount of ice water, and the precipitated product is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 1.4 g of a residue. 5 ml of dimethylformamide without purification of the residue
Was dissolved in 753 mg (11.0 mmol) of imidazole and 1.43 ml (5.5%) of tert-butylchlorodiphenylsilane.
Mmol) and left at room temperature for 48 hours. After pouring the reaction into a large amount of water, the product is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue, n- hexane - ethyl acetate: compound (3 1) is purified by Rover column chromatography as an elution solvent V b1, 1.3 g (yield: 50
%) Is obtained.

Syrup [α] _D −37.2 ° (25 ° C., c 1.525, CHCl ₃ ). IR (CHCl ₃ ) cm ^-1 : 3460, 1760, 1112.1 H-NMR (CDCl ₃ ) δ ppm: 7.8 to 7.3 ( ¹⁰ H, m, aromatic hydrogen), 5.97 (1 H, s, NH, CD ₃ OD) 5.80-5.23 (3
H, m, -C H = C H -, - C H (O) -), 4.0~3.5 (3H,
m, -CH (N) -, - CH 2 OSiC (CH 3) 3 Ph 2), 1.03 (9H, s, -
_{C (CH 3) 3),} 0.87 (3H, t, J = 6Hz, -CH 3). Elemental analysis (as C ₃₅ H ₅₃ NO ₃ Si) Calculated value (%): C 74.55, H 9.47, N 2.40, measured value (%): C 74.66, H 9.76, N 2.30. Reference example 15 (2S, 3R) -2,3-N, O-carbonyl-1-O- (tert
-Butyldiphenylsilyl) -1,3-dihydroxy-4
−Trans-octadecene V b2 Compound II b2-t (described in Journal of the Organic Chemistry) was reacted in the same manner as in Reference Example 1,
Compound Vb2 is obtained.

Syrup [α] _D −6.0 ° (25 ° C., c 1.045, CHCl ₃ ) IR (CHCl ₃ ) cm ⁻¹ : 3460,1760,1114.1 H-NMR (CDCl ₃ ) δ ppm: 7.8 to 7.3 ( ¹⁰ H, m , Aromatic hydrogen), 6.03 to 5.30 (3H, m, -CH = CH-, NH), 5.00 (1H, t, J
= 7.5Hz, -C H (O) -), 3.80 (1H, m, -CH (N)
−), 3.60 (2H, d, −CH ₂ OSiC (CH ₃ ) ₃ Ph ₂ ), 1.03 (9H, s, C
_{(CH 3) 3), 0.87} (3H, t, J = 6Hz, -CH 3). Elemental analysis (as C ₃₅ H ₅₃ NO ₃ Si) Calculated value (%): C 74.55, H 9.47, N 2.48, Actual value (%): C 74.26, H 9.45, N 2.47. Reference example 16 (2S, 3R) -2-methylamino-2,3-N, O-carbonyl-1-O- (tert-butyldiphenylsilyl) -1,3
-Dihydroxy-4-cis-octadecene VI b1 1.647 g (2.92 mmol) of compound V b1 are dissolved in 20 ml of dimethylformamide. To this solution methyl iodide 0.73
ml (11.68 mmol) and 1.35 g (5.84 mmol) of silver oxide are added and stirred at room temperature for 48 hours. After filtering off the insolubles using Celite, the filtrate is diluted with ethyl acetate. The ethyl acetate solution is washed with water, dried over magnesium sulfate, and evaporated to give 1.4 g of a residue. The residue was purified by rover column chromatography using n-hexane-ethyl acetate (3: 1) as an eluent to give compound VI b1 , 1.09 g.
(65% yield).

Syrup _{[α] D -26.3 ° (22} ℃, c 1.173, CHCl 3) IR (CHCl 3) cm -1:. 1750,1112 1 H-NMR (CDCl 3) δppm: 7.90~7.23 (10H, m, aromatic family-based hydrogen), 5.87~5.17 (3H, m, -CH = CH -, - C H (O)
−), 3.83 to 3.50 (3H, m, −CH ₂ OSiC (CH ₃ ) ₃ Ph ₂ , −CH
(N) -), 2.78 ( 3H, s, N-C H 3), 1.03 (9H, s, C (C
_{H 3) 3), 0.87 (} 3H, t, J = 6Hz, -C H 3). Elemental analysis (as C ₃₆ H ₅₅ NO ₃ Si) Calculated value (%): C 74.81, H 9.59, N 2.42, measured value (%): C 74.32, H 9.53, N 2.48. Reference example 17 (2S, 3R) -2-methylamino-2,3-N, O-carbonyl-1-O-tert-butyldiphenylsilyl-1,3-dihydroxy-4-trans-octadecene VI b2 Compound V b2 (520 mg) was N-methylated with methyl iodide and silver oxide in the same manner as in Reference Example 3 to give the compound
VI b2, 404mg (75.8% yield). syrup. ¹ H-NMR (90 MHz, CDCl ₃ ): δ 7.80 to 7.20 ( ¹⁰ H, m, aromatic hydrogen), 6.03 to 5.48 (2 H, m, —CH ＝ CH—), 4.88 (1 H,
t, J = 7.5Hz, -CH ( O) -), 3.90~3.43 (3H, m, -C H 2 OS
_{iC (CH 3) 3 Ph 2} , -C H (N) -), 2.75 (3H, s, N-C H 3),
1.07 (9H, s, C ( C H 3) 3), 0.87 (3H, t, J = 6Hz, -C H 3). Reference Example 18 (2S, 3R) -2-aminomethyl-2,3-N, O-carbonyl-1,3-dihydroxy-4-cis-octadecene VII
b1 500 mg (0.865 mmol) of compound VI b1 are dissolved in 50 ml of anhydrous tetrahydrofuran. 1M tetra-n
-Butyl ammonium fluoride-tetrahydrofuran solution (0.4 ml) is added and left at room temperature for 30 minutes. The reaction solution is concentrated to dryness under reduced pressure. The obtained residue is n-hexane-
Purification by silica gel column chromatography using ethyl acetate (1: 1) as the eluting solvent gave Compound VII b1 , 194 mg
(66% yield).

mp. 73-74 ° C [α] _D -21.9 ° (22 ° C, c 0.604, CHCl ₃ ). ^{IR (KBr) cm -1:.} . 3450,1740,1720 1 H-NMR (90MHz, CDCl 3) 5.97~5.50 (2H, m, -CH = CH
-), 5.33 (1H, t , J = 7.5Hz, -C H (O) -), 4.0~3.5
7 (3H, m, -C H 2 OH, -C H (N) -), 2.93 (3H, s, N-C H
_{3), 2.47 (br.1H, OH} ), 0.87 (3H, t, J = 6Hz, -C H 3). Elemental analysis: (as C ₂₀ H ₃₇ NO ₃ ) Calculated value (%): C 70.75, H 10.99, N 4.13, Actual value (%): C 70.66, H 10.95, N 4.19. Example 1 (2S, 3R) -2-methylamino-1,3-dihydroxy-
4-cis-octadecene I B1 Compound VIIb1 , 475 mg (0.82 mmol) is added to a mixture of 2 M sodium hydroxide, 20 ml and 95% ethanol 10 ml, and the mixture is heated with stirring at 80 ° C. for 26 hours on an oil bath. After cooling,
The pH value is made weakly alkaline (~ 10) by adding dilute hydrochloric acid,
Pour into a large amount of ice water. The precipitated product is extracted with ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography using chloroform-methanol-water (7: 3: 1, lower layer) as an eluting solvent to give compound IB1,2 .
51 mg (97.6% yield) were obtained.

mp 32 ° -34 ° C., [α] _D −10.8 ° (21 ° C., c 0.424, CHCl ₃ ). ^{IR (KBr) cm -1:.} . 3360,3290,1461,1078,1005 1 H-NMR (90MHz, CHCl 3 + CD 3 OD (1: 1)): 5.77~5.27
(2H, m, -CH = CH -), 3.68 (2H, d, J = 6Hz, -C H 2 OH), 2.
45 (3H, s, N- C H 3), 0.87 (3H, t, -C H 3). Elemental analysis (as C ₁₉ H ₃₉ NO ₂ · 0.1 H ₂ O) Calculated value (%): C 72.36, H 12.53, N 4.44, measured value (%): C 72.42, H 12.49, N 4.64. 2S, 3R) -2-methylamino-1,3-dihydroxy-
4-trans-octadecene I B2 Compound VI b2, 400 mg 5 in (0.692 mmol) sodium 2M hydroxide 11ml) and ethanol (11ml mixture and an oil bath on 80 ° C.
Heat and stir for hours. After cooling, the pH of the reaction solution is made weakly alkaline (〜9) by adding dilute hydrochloric acid, then poured into a large amount of ice water, and the product is extracted with ethyl acetate. The organic layer is washed with water and dried over magnesium sulfate.
307 mg are obtained. The residue was treated with acetonitrile-acetic acid-water (1
Purify by silica gel column chromatography using 5: 1: 1) as the elution solvent. After dissolving the obtained acetate in a mixed solution of chloroform and methanol, an ion exchange resin Amberlite IRA-400 (OH-) is added, and the mixture is stirred for 30 minutes.
The resin is filtered off and washed with methanol. The filtrate and the combined washings concentrated under reduced pressure to dryness compounds I B2, 121 mg (yield:
55.8%).

mp 58.5-59.5 ° C. [Α] _D -1.8 ° (20 ° C, c 0.740, CHCl ₃ ). ^{IR (KBr) cm -1:.} . 3400,3320,3280,1465 1 H-NMR (90MHz, CDCl 3 + CD 3 OD): δ6.0~5.3 (2H, m,
-CH = CH -), 4.23 ( 1H, t, J = 6Hz, -C H (OH) -), 3.
70 (d, 2H, J = 4.5Hz, -C H 2 OH), 2.43 (3H, s, N-C H 3), 0.
88 (3H, t, -C H 3). Elemental analysis (as C ₁₉ H ₃₉ NO ₂ · 0.7H ₂ O) Calculated value (%): C 69.97, H 12.36, N 4.30, Actual value (%): C 69.73, H 11.88, N 4.19. 2S, 3R) -2-Methanesulfonylamino-1,3-dihydroxy-4-cis-octadecene I C1 To a solution of 400 mg (1.335 mmol) of compound II b1-c and 738 mg (5.34 mmol) of potassium carbonate in 15 ml of dichloromethane and 10 ml of purified water was added 0.4 ml of methanesulfonic acid chloride.
Add 2 ml (2.67 mmol) and stir vigorously for 1 hour 30 minutes at room temperature. The reaction mixture is poured into ice water and the organic layer is separated. The organic layer is washed with water, dried over magnesium sulfate and evaporated to give 459 mg of a residue. The residue was chloroform-
Purification by silica gel column chromatography using methanol (30: 1) as an elution solvent gives 198 mg (yield 39.2%) of compound I C1 . White powder, [α] _D -12.5 ° (24 ° C, c 1.237, CHCl ₃ ). IR (CHCl ₃ ) cm ^-1 : 3610,3520,3380,1465,1425,1405,133
0,1150. ¹ H-NMR. (90 MHz, CDCl ₃ + CD ₃ OD (1: 1)): 5.80 to 5.27
(2H, m, -CH = CH -), 3.70 (2H, d, J = 6Hz, -C H 2 OH), 3.
_{03 (3H, s, SO 2} C H 3), 0.90 (3H, t, J = 6Hz, -C H 3). Elemental analysis: (as C ₁₉ H ₃₉ NO ₄ S) Calculated value (%): C 60.44, H 10.41, N 3.71, S 8.49, Observed value (%): C 60.39, H 10.30, N 3.74, S 8.21. Example 19 (2S, 3R) -2-acetamido-3-acetyloxy-
1-tert-butyldiphenylsilyloxy-4-cis-
Octadecene VIII b1 ' 840 mg (2.46 mmol) of compound I A1 and 201 mg (2.95 mmol) of imidazole are dissolved in 8 ml of dimethylformamide. 0.77 ml (2.95 mmol) of tert-butylchlorodiphenylsilane is added to this solution and left at room temperature for 48 hours. Pour the reaction mixture into a large volume of water and extract the product with ethyl acetate. The organic layer is separated, washed successively with dilute hydrochloric acid, aqueous sodium hydrogen carbonate solution and water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. 1.52 g of the obtained residue
Is dissolved in 10 ml of anhydrous pyridine, 2 ml of acetic anhydride is added, and the mixture is left at room temperature for 48 hours. The reaction is poured into a large volume of ice water and the product is extracted with ethyl acetate. After separating the organic layer, the organic layer is sequentially washed with dilute hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. 1.61 g of the obtained residue is purified by rover column chromatography using n-hexane-ethyl acetate (2: 1) as an elution solvent, compound VIII b1 ' , 1.02 g (yield 69.5)
%)was gotten. syrup.

[Α] _D -7.2 ° (20 ° C, c 0.815, CHCl ₃ ). IR (CHCl ₃ ) cm ^-1 : 3460, 1739, 1675, 1510.1 H-NMR. (90 MHz, CDCl ₃ ): δ 7.76 to 7.31 ( ¹⁰ H, m, aromatic hydrogen), 5.90 to 5.10 (4 H, m, NH, -CH = CH - , - C H
(OAc) -), 4.31 ( 1H, m, -C H (N) -), 3.90~3.53
_{(2H, m, -C H 2} OH), 1.93,1.87 (each 3H, each s, OAc, NA
c), 1.07 (9H, s , C (C H 3) 3), 0.88 (3H, t, J = 6Hz, -C
H ₃ ). Elemental analysis: (as C ₃₈ H ₅₉ NO ₄ S) Calculated value (%): C 73.38, H 9.56, N 2.25, Actual value (%): C 73.08, H 9.73, N 2.34. Reference example 20 (2S, 3R) ) -2-Acetamide-3-acetyloxy-
1-hydroxy-4-cis-octadecene VIII b1 ′ After dissolving 1.02 g (1.717 mmol) of compound VIII b1 ' in 10 ml of anhydrous tetrahydrofuran, a 1M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added.
Add 86 ml and leave at room temperature for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure and the resulting residue n- hexane - ethyl acetate: compound (1 1) was purified by on silica gel column chromatography as an elution solvent VIII b1, 504 mg (yield: 76.5
%) Is obtained.

mp 70-70.5 °. [Α]_D −25.6 ° (20 ° C, c 0.812, CHCl_Three). IR (CHCl_Three)cm^-1: 3610,3440,1740,1670,1510.¹ H-NMR. (90 MHz, CDCl_Three+ CD_ThreeOD): δ 5.2 to 5.9 (3H, m,
-CH = CH-,-CH(O)-), 4.50 (1H, m, -CH
(N)-), 2.40-1.93 (2H, m, -CH _TwoCH =), 2.03,1.97
(Each 3H, s, OAc, NAc), 1.30 (22H, m, − (CH_Two)₁₁), 0.87
(3H, t, J = 6Hz, -CH _Three). Elemental analysis (C_{twenty two}H₄₁NO_FourCalculated value (%): C 68.71, H 10.62, N 3.76, measured value (%): C 68.89, H 10.77, N 3.65. Reference example 21 (2S, 3R) -2-acetamido-1-O- ( 2-trim
Thilammonium ethyl phosphoryl) -1,3-dihydro
Xy-4-cis-octadeceneI D1  CompoundVIII b1, 204 mg (0.531 mmol) in anhydrous tetra
Dissolve in 3 ml of hydrofuran and cool with ice under a stream of nitrogen.
10% (w / v) n-butyllithium-n-hex
Add 0.85 ml (1.327 mmol) of sun solution and stir for 1 minute
I do. Then β-bromoethyl phosphoryl dichloride 32
1 mg (1.327 mmol) in 1 ml of anhydrous tetrahydrofuran
Add the dissolved solution and stir at the same temperature for 2 hours. This reaction
Add 3 ml of 50% aqueous pyridine to the solution and leave it at room temperature overnight
You. The reaction solution is concentrated to dryness under reduced pressure. The obtained residue is
Roform-methanol-water (7: 3: 1, lower layer)
Purify by silica gel column chromatography.
The obtained (2S, 3R) -2-acetamido-3-acetylthio
Xy-1- (2-bromoethylphosphoryl) oxy-4
-Cis-octadeceneIX b1, 104 mg in chloroform-di
Mixture of methylformamide-isopropanol (3: 5: 5)
After dissolving in 13 ml of liquid, 28% (w / v) aqueous trimethylamine
2.6 ml of the solution is added, and the mixture is heated and stirred at 50 ° C for 6 hours. After cooling,
The reaction mixture is concentrated to dryness under reduced pressure. 213 mg of the obtained residue
Was dissolved in anhydrous methanol (10 ml), and 1M sodium methoxide was added.
Add an oxide-methanol solution (0.5 ml) and bring to room temperature for 6 hours
put. The reaction solution was neutralized by adding dilute hydrochloric acid, and then under reduced pressure.
Concentrate to dryness. The obtained residue is chloroform-methanol
Silka gel using aqueous solution (7: 3: 1, lower layer) as elution solvent
Compounds purified by column chromatographyI D1, 88m
g (32.7% yield) are obtained.

White powder.

[Α] _D + 6.9 ° (23 ° C, c 0.638, MeOH). ^{IR (KBr) cm -1:.} 3400,1655,1550,1468,1375 1 H-NMR (90MHz, CD 3 OD): 5.70~5.30 (2H, m, -CH = CH
−), 3.23 (9H, s, N (C H ₃ ) ₃ ), 2.0 (3H, s, NAc), 1.30
_{(22H, - (CH 2)} 11 -), 0.87 (3H, t, J = 6, -CH 3). Elemental analysis (as C ₂₅ H ₅₁ N ₂ O ₆ P · 1.3H ₂ O) Calculated value (%): C 56.64, H 10.19, N 5.29, Actual value (%): C 56.67, H 9.86, N 5.52. Reference Example 22 (2S, 3R) -2-amino-2,3-N, O-carbonyl-1
-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy) 3-hydroxy-4-cis-octadecene IX b1 2,3,4,6-tetra -O- acetyl-.alpha.-D-galactopyranosyl Puromido, 836 mg (2.03 mmol) and compound IV b1, 660mg (2.03 mmol) in anhydrous benzene 30ml
Then, 10 ml of the solvent is distilled off under a nitrogen stream. After cooling, 3.2 g of powdered molecular sieve 4A is added, and the mixture is stirred at room temperature for 30 minutes. 1.12 g of silver carbonate and 11 mg of silver perchlorate are added to this mixture, and the mixture is stirred at room temperature for 3 hours. After filtering off the insoluble matter using Celite, the filtrate is washed successively with sodium hydrogen carbonate and water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by rover column chromatography using n-hexane-acetone (3: 1) as an eluting solvent to give 215 mg of compound XI b1 (yield 16).
%) Is obtained. White powder. [Α] _D −30.6 ° (23 ° C., c 0.861, CHCl ₃ ). ¹ H-NMR. (90 MHz, CDCl ₃ ): 2.15, 2.10, 2.05, 1.97 (cach
3H, each s, 4 × OAc), 1.25 (22H, m, − (CH ₂ ) ₁₁ −), 0.87
(3H, t, J = 6Hz , -C H 3). Reference Example 23 (2S, 3R) -2-acetamide-1- (β-D-galactopyranosyloxy) -3-hydroxy-4-cis-octadecene I E1 Compound XI b1 , 215 mg (0.327 mmol) obtained above was treated with 2M
The mixture is dissolved in a mixture of 12 ml of sodium hydroxide and 12 ml of ethanol, and heated and stirred at 80 ° C. for 3 hours on an oil bath. After cooling, the reaction solution is neutralized by adding dilute hydrochloric acid, and then lyophilized. The obtained residue is extracted with 10 ml of methanol, and the insoluble matter is removed by filtration. The filtrate is concentrated to dryness under reduced pressure to obtain 368 mg of a residue. The residue is dissolved in anhydrous methanol (10 ml), acetic anhydride (0.5 ml) is added, and the mixture is left at room temperature for 2 hours. After the reaction mixture is concentrated to dryness under reduced pressure, the residue is extracted with a small amount of ethanol, and the insoluble matter is removed by filtration. The filtrate is concentrated to dryness under reduced pressure to give 220 mg of a residue. The residue chloroform - methanol (5: 1) and purified by column chromatography as an elution solvent a compound I E1, 79mg (47.3% yield).

mp 123 (semi-fused)-130 °. [Α] _D -20 ° (21 ° C, c 0.665, MeOH). IR (KBr) cm ^-1 : 3400,1655,1635,1540. ¹ H-NMR (90 MHz, CD ₃ OD): δ 5.93 to 5.23 (2H, m, -CH =
CH -), 1.93 (3H, s, NAc), 1.30 (22H, m, - (CH 2) 11 -),
0.87 (3H, t, J = 6Hz, -CH 3). Elemental analysis: C ₂₆ H ₄₉ NO ₈ · 1.7 H ₂ O Calculated value (%): C 58.44, H 9.89, N 2.62, Observed value (%): C 58.20, H 9.62, N 2.73. Reference example 24 (2S, 3R) -2-Amino-2,3-N, O-carbonyl-1
-[4-O- (2,3,4,6-tetra-O-acetyl-β-
D-galactopyranosyl) -2,3,6-tri-O-acetyl-β-D-glucopyranosyloxy] -3-hydroxy-4-cis-octadecene XI b2 In the same manner as in the synthesis of compound XI b1 , 4-O-
(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -2,3,6-tri-O-acetyl-α-D-
Condensation of glucopyranosyl bromide with compound IV b1 in benzene in the presence of silver carbonate and silver perchlorate gives compound XI b2 . (33% yield).

White powder.

[Α] _D −31.1 ° (23 ° C., c 1.136, CHCl ₃ ). ^{_{IR (CHCl 3) cm -1:}} . 1755 1 H-NMR (CDCl 3): δ 2.15,2.13,2.03,1.93 (totally
21H, eachs, 7 × OAc), 1.25 (22H, m, − (CH ₂ ) ₁₁ −), 0.87
(3H, t, J = 6Hz , -C H 3). Reference Example 25 (2S, 3R) -2-acetamide-1- [4-O- (β-
D-galactopyranosyl) -β-D-glucopyranosyloxy] -3-hydroxy-4-cis-octadecene I
E2 In the same manner as in the synthesis of compound I E1 , compound XI b2
Is subjected to a deprotection group with a 2M sodium hydroxide-ethanol mixture, and then N-acetylation is performed with acetic anhydride-methanol to obtain a compound IE2 .

mp. 217-218 °. [Α] _D -12.4 ° (25 ° C, c 0.515, CH ₃ OH). ^{IR (KBr) cm -1:.} 3400,1635 1 H-NMR (90MHz, CD 3 OD): δ 5.70~5.20 (2H, m, -CH =
CH -), 2.3~1.97 (2H, s, -C H 2 CH =), 1.90 (3H, s, NA
c), 1.30 (22H, m, − (CH ₂ ) ₁₁ −), 0.87 (3H, t, J = 6Hz, −
C H ₃ ). Elemental analysis _{(C 32 H 59 NO 13 ·} 0.5H 2 O ) Calculated value (%): C 56.95, H 8.96, N 2.08, Found (%):. C 56.85, H 8.94, N 2.26 Reference Example 26 ( 2S ^* , 3R ^* , 4E, 15'Z) -1,3-dihydroxy-2-
Tetracosenoylaminooctadecene DL-X III b1 To a solution of 4.00 g (10.4 mmol) of nervonic acid in 100 ml of dichloromethane are added 3.00 g (11.4 mmol) of 2-chloro-N-methylpyridinium iodide and 2.32 g (22.8 mmol) of triethylamine and stirred at room temperature for 30 minutes. Then, DL-Shuingosine DL-II b1-t [Journal of the American Chemical Society (J.
Am. Chem. Soc., Vol. 80, p. 1194, 1958] 3.10 g (10.4 mmol), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate is added, and the mixture is filtered. The residue is washed with methanol to obtain 6.06 g of a product DL- XIIIb1 (yield 90%). mp 7
8-80 ° C NMR (CDCl ₃ ): δ 5.34 (t, 2H, J = 4.5 Hz), 5.53 (dd, 1
H, J = 6Hz, 5Hz), 5.80 (dt, 1H, J = 15Hz, 6Hz), 6.25 (d, N
Elemental analysis: C ₄₂ H ₈₁ NO ₃ Calculated value (%): C 77.84, H 12.60, N 2.16 Actual value (%): C 77.90, H 12.59, N 2.22 Reference example 27 (2S ^* , 3R ^* , 4E, 15'Z) -3-Hydroxy-2-tetracosenoylamino-1-triphenylmethyloxyoctadecene DL-1 DL-Ceramide DL-X III b1 648mg (1.00mmol)
6 ml of pyridine and then 840 mg (3.00 mmol) of trityl chloride are added at room temperature to a solution of 20 ml of dichloromethane and 10 ml of tetrahydrofuran, and the mixture is stirred for 2.5 hours. The reaction mixture is poured into ice water and extracted twice with ether. The ether layer is washed with a saturated aqueous solution of sodium hydrogen carbonate and concentrated under reduced pressure. The residue is partitioned between dichloromethane and water, the organic layer is separated and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is separated by silica gel column chromatography (eluent: dichloromethane / ether = 20/1) to obtain 5.40 g (yield: 66%) of a wax-like product DL-1 .

NMR (CDCl ₃ ): δ 5.26 (dd, 1H, J = 16 Hz, 6 Hz), 5.34
(T, 2H, J = 4.5 Hz), 5.63 (dt, J = 16 Hz, 6 Hz) Elemental analysis: Calculated as C ₆₁ H ₉₅ NO ₃ Calculated value (%): C 82.28, H 10.75, N 1.57 Actual measured value (%) : C 82.05, H 10.63, N 1.54 Reference Example 28 (2R, 3S, 4E, 15'Z) -3- [O-acetyl- (S)
-Manderoyloxy] -2-tetracosenoylamino-1-triphenylmethyloxyoctadecene 2 and (2R, 3S, 4E, 15'Z) -3- [O-acetyl- (S)-
Manderoyloxy] -2-tetracosenoylamino-
1-triphenylmethyloxyoctadecene 3 A mixture of 3.53 g (18.2 mmol) of (S) -O-acetylmandelic acid and 15 ml of thionyl chloride is heated under reflux for 30 minutes and concentrated under reduced pressure. Benzene was added to the residue, and the mixture was concentrated under reduced pressure again. The residue was dissolved in 30 ml of toluene and used for the next reaction.

A solution of 5.40 g (6.06 mmol) of 1-O - tritylceramide DL-1 in toluene (93 ml) and pyridine (26 ml) is added dropwise with the previously prepared acid chloride solution, and the mixture is stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water and twice with ether (100 m
l). The ether layer is washed with water and then with a saturated aqueous solution of sodium hydrogen carbonate, dried and concentrated under reduced pressure. The residue was separated into diastereomers by silica gel column chromatography (eluent: dichloromethane / ether = 50/1), and Rf = 0.38, 2.60 g of product 3 was obtained from the eluted portion (40% yield, oil), and Rf = 0.26. Product 2 from elution part
2.20 g (34% yield, oil).

Compound 2 [α] _D + 27.5 ° (c 1.00, CHCl ₃ ) NMR (CDCl ₃ ) δ: 2.19 (s, 3H, Ac), 3.18 (dd, 1H, J = 4.5H)
z, 10Hz, C1H), 3.34 (dd, 1H, J = 4.5Hz, 10Hz, C1H), 4.29
(M, 1H, C2H), 5.08 (dd, 1H, J = 16Hz, 6Hz), 5.24-5.48
(M, 3H, C5H, C15'H, C16'H), 5.55 (dd, J = 6Hz, 6Hz, C3
H), 5.71 (dt, 1H, J = 16Hz, 6Hz), 5.86 (s, 1H, Mandel
CH). Compound 3 [α] _D + 23.5 ° (c 1.00, CHCl ₃ ) NMR (CDCl ₃ ) δ: 2.08 (s, 3H, Ac), 3.02 (dd, 1H, J = 10H)
z, 6Hz, C1H), 3.14 (dd, 1H, J = 10Hz, 6Hz, C1H), 4.30 (m,
1H, C2H), 5.12 (d, 1H, J = 9Hz, NH), 5.22-5.40 (m, 3H, C
4H, C15'H, C16'H), 5.46 (dd, 1H, J = 7Hz, 5Hz, C3H),
5.71 (dt, 1H, J = 15Hz, 6Hz), 5.86 (s, 1H, Mandel C
H). Reference Example 29 (2S, 3R, 4E, 15'Z) -3-hydroxy-2-tetracosenoylamino-1-triphenylmethyloxyoctadecene 4 D-mandelate 2 To a solution of 2.15 g (2.01 mmol) of methanol (100 ml) and toluene (20 ml) was added 0.2 ml of a 1N sodium methoxide solution in methanol for 2 hours.
Stir for 5 minutes at room temperature. Add Amberlite CG-5 to the reaction mixture
Add 0 and stir at room temperature for 30 minutes. The mixture is filtered, the mother liquor is concentrated under reduced pressure and the oily product 4 (about 2.0 g) is used for the next reaction without purification.

NMR (CDCl ₃ ) δ: 3.30 (dd, 1H, J = 9 Hz, 4 Hz, C1H), 3.40
(Dd, 1H, J = 9Hz, 4Hz, C1H), 3.44 (m, OH), 4.06 (m, C3
H), 4.18 (m, C2H), 5.12-5.40 (m, 3H, C4H, C15'H, C1
6'H), 5.63 (dt, 1H, J = 16Hz, 6Hz, C5H), 6.07 (d, 1H, J
= 8Hz, NH). Reference Example 30 (2S, 3R, 4E, 15'Z) -3-benzoyloxy-2-
Tetracosenoylamino-1-toluphenylmethoxyoctadecene 5 To a solution of 1.60 g (1.80 mmol) of D-ceramide 4 in toluene (40 ml) and pyridine (5.4 ml) was added 1.27 g (9.03 mmol) of benzoyl chloride at room temperature.
Stir for hours. Ether and water are added to the reaction mixture, and the mixture is separated. The ether layer is saturated aqueous sodium hydrogen carbonate solution.
Wash twice, then with water and dry. The solvent was distilled off under reduced pressure to give a residue on silica gel column chromatography (eluant dichloromethane / ether = 1000/15) in the separated product 5 1.78 g (100% yield). Oily.

[Α] _D + 25.5 ° (c 0.91, CHCl ₃ ) NMR (CDCl ₃ ) δ: 3.14 (dd, 1H, J = 9 Hz, 4 Hz, C1H), 3.44
(Dd, 1H, J = 9Hz, 4Hz, C1H), 4.50 (m, C2H), 5.33 (t, 2H,
J = 5Hz, C15'H, C16'H), 5.40 (dd, 1H, J = 16Hz, 6Hz, C
4H), 5.64 (d, 1H, J = 9Hz, NH), 5.68 (dd, 1H, J = 7Hz, 8H
z, C3H), 5.86 (dt, 1H, J = 16Hz, 6Hz, C5H). Reference Example 31 (2S, 3R, 4E, 15'Z) -3-benzoyloxy-1-
Hydroxy-2-tetracosenoylaminooctadecene
6 O-protected D-ceramide 5 To a solution of 1.60 g (1.60 mmol) of toluene (20 ml) and methanol (1 ml) was added 0.4 ml of boron trifluoride-ether, and the mixture was stirred at room temperature for 25 minutes. Toluene (20 ml), ether (20 ml) in the reaction mixture
The organic layer is washed with water until the washing becomes neutral, and dried. The solvent was distilled off under reduced pressure, the residue was separated with the on silica gel column chromatography (eluant dichloromethane / ether = 5/1) to give the product 6 830 mg (yield: 69
%).

mp 62-65 ° C [α] _D -13.0 ° (c 0.98, CHCl ₃ ) NMR (CDCl ₃ ) δ: 2.93 (broad, OH), 3.73 (m, C1H), 4.28
(M, C2H), 5.34 (t, 2H, J = 5Hz, C15'H, C16'H), 5.50
−5.65 (m, C3H, C4H), 5.86 (dt, 1H, J = 16Hz, 6Hz, C5H),
6.05 (d, 1H, J = 8Hz, NH). Elemental analysis: Calculated _{C 49 H 85 NO 4 (%} ): C 78.24, H 11.39, N 1.86, Found (%):. C 77.93, H 11.25, N 2.02 Reference Example 32 (2S, 3R, 4E, 15'Z) -3-O-benzoyl-N-tetracosenoyl-1-O- [2,3,6-tri-O-acetyl-4-O- (2,3,4,6-tetra-O-acetyl -Β-
D-galactopyranosyl) -β-D-glucopyranosyl] sphingenin I E3 ′ 3-benzoyl-D-ceramide 6 480 mg (0.638 mmol) and 2,3,6-tri-O-acetyl-4-O-
(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -α-D-glucopyranosyltrichloroacetimidate ( A ) [Angev Ande Chemie Internacional. Edition in English (Angew. Chem. Int. Ed. Engl.), Vol. 9, p. 731, 1980
Year description] 1.10 g (1.40 mmol) of dichloromethane (16 m
l) Add 3A molecular sieve to the solution and stir at room temperature for 30 minutes. Then, 8.1 ml of a 0.1 molar dichloromethane solution of boron trifluoride-ether is added dropwise at room temperature, and the mixture is stirred for 1 hour. The reaction mixture is filtered off, the mother liquor is washed with a saturated aqueous solution of sodium hydrogen carbonate, water and then with a saturated saline solution and dried. The solvent is distilled off under reduced pressure, and the residue is separated by silica gel column chromatography (eluent: ether / hexane = 9/1) to obtain 770 mg (yield: 80%) of product IE3 ' . Amorphous.

[Α] _D 1.5 ° (c 1.01, CHCl ₃ ) (2S, 3R, 4E, 15′Z) -1-O- (4-O-β-D-
Galactopyranosyl-β-D-glucopyranosyl) -N
-Tetracosenoylsphingenin I E3 O-protected lactosyl-D-ceramite I E3 ' 700 mg
To a solution of (0.510 mmol) in methanol (25 ml) is added 1 ml of a 1N sodium methoxide methanol solution, and the mixture is stirred at room temperature for 4 hours and left overnight. Amberlyst 15 is added to the reaction mixture, stirred for 30 minutes, and the mixture is filtered. The filtrate was concentrated under reduced pressure, and the residue was washed with ethanol and separated by filtration to obtain a product I.
410 mg (82% yield) of E3 are obtained.

mp 227 ° C (decomposition) [α] _D -10.5 ° (c 1.05, pyridine) SIMS mass MH ⁺ 972 (MW971) NMR (DMSO-d ₆ δ: 4.18 (d, 1H, J = 8 Hz, G1c-C1H), 4.24
(D, 1H, J = 8Hz , Ga1-C1H) Elemental _{analysis: C 54 H 101 NO 13 ·} H 2 O Calculated (%): C 65.49, H 10.48, N 1.41, Found (%): C 65.47 , H 10.10, N 1.53. Reference Example 33 (2R, 3S, 4E, 15'Z) -3-hydroxy-2-tetracosenoylamino-1-triphenylmethyloxyoctadecene 7 L- mandelate 3 2.10 g of (1.97 mmol) were reacted in the same manner as in Reference Example 13 to give the compound 7 1.75 g of oily.

Yield: quantitative [α] _D + 21.9 ° (c 1.01, CHCl ₃ ) NMR is the same as for compound 4 .

Reference Example 34 (2R, 3S, 4E, 15'Z) -3-benzoyloxy-2-
Tetracosenoylamino-1-triphenylmethyloxyoctadecene 8 1.75 g (1.97 mmol) of L-ceramide 7
The reaction was carried out in the same manner as 14 to obtain 1.39 g of an oily compound 8 .

Yield: 71% [α] _D 15.8 ° (c 1.00, CHCl ₃ ) NMR Same as Compound 5. Reference Example 35 (2R, 3S, 4E, 15′Z) -3-benzoyloxy-1-
Hydroxy-2-tetracosenoylaminooctadecene
9 O-protected-L-ceramide 8 1.20 g (1.20 mmol)
Was reacted in the same manner as in Reference Example 15 to obtain 600 mg of Compound 9 .

Yield: 66% mp. 59-62 ° C, [α] _D -14.8 ° (c 1.00, CHCl ₃ ) NMR Same as compound 6 Elemental analysis: As C ₄₉ H ₈₅ NO ₄ : Calculated value (%): C 78.24 , H 11.39, N 1.86, found (%): C 77.96, H 11.22, N 1.98. Reference Example 36 (2R, 3S, 4E, 15'Z) -3-O-benzoyl-N-tetracosenoyl-1-O -[2,3,6-tri-O-acetyl-4-O- (2,3,4,6-tetra-O-acetyl-β-
D-galactopyranosyl) -β-D-glucopyranosyl] sphingenin I E4 ′ Example 3 was obtained using 3-benzoyl-L-ceramide 9 400 mg.
Reaction and treatment in the same manner as in 20 to give an amorphous compound
440 mg of I E4 ' are obtained.

Yield: 60% [α] _D -19.9 ° (c 1.00, CHCl ₃ ) (2R, 3S, 4E, 15′Z) -1-O- (4-O-β-D-
Galactopyranosyl-β-D-gluconopyranosyl)-
N-tetracosenoylsphingenin I E4 O-protected lactosyl-L-ceramide I E4 ' 400 mg
Is reacted in the same manner as in Example 20 to obtain 237 mg of a compound IE4 .

Yield: 83% mp. 212 ° C [α] _D −23.5 ° (c 0.502, pyridine) SIMS mass MH ⁺ 972 (MW971) NMR (DMSO-d ₆ ) δ: 4.20 (d, 2H, J = 8 Hz, Ga1) And G1c-C1
H) Elemental analysis: C ₅₄ H ₁₀₁ NO ₁₃ · 1.5H ₂ O Calculated value (%): C 64.90, H 10.49, N 1.40, Actual value (%): C 65.07, H 10.37, N 1.51. Reference example 37 (2S, 3R, 5S, 1'E) -5-amino-4-pentadecenyl-2-phenyl-1,3-dioxane II b3-t Azido dioxane III b2-t [Tetrahedron Lett., 481 pages 1986] 1.24 g (3.00
Was dissolved in pyridine (5 ml), water (1.5 ml) was added, and hydrogen sulfide was introduced for 2 hours while stirring under ice-water cooling.
The reaction mixture is left sealed at room temperature for 2 days. The reaction mixture was evaporated under reduced pressure, the residue was separated by on silica gel column chromatography (eluent ethyl acetate), the product II B3-
obtain t 1.00 g (86% yield).

mp 48-50 ° C. [α] _D + 34.8 ° (c 1.00, CHCl ₃ ) NMR (CDCl ₃ ) δ: 2.82 (dt, 1H, J = 10 Hz, 5 Hz, C5H), 4.26
(Dt, J = 12Hz, 4Hz , C4H) Elemental _{analysis: C 25 H 41 NO 2 ·} 0.25H 2 O Calculated (%): C 76.57, H 10.67, N 3.57, Found (%): C 76.53, H 10.53, N 3.70. Reference Example 38 (2S, 4R, 5S, 1'E) -5-tetracosanoylamino-
4-pentadecenyl-2-phenyl-1,3-dioxane
Ten A solution of 388 mg (1.00 mmol) of aminodioxane II b3-t in tetrahydrofuran (8 ml) was stirred at room temperature for 5 minutes.
Add 5 ml of 0% aqueous sodium acetate solution. Then a solution of 0.58 g (1.50 mmol) of tetracosanoyl chloride in tetrahydrofuran (5 ml) is added dropwise and the mixture is stirred at room temperature for 2.5 hours. A saturated aqueous sodium hydrogencarbonate solution (5 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was washed with water, filtered, and the separated crystals were further washed with methanol to give 10 720 mg of a product.
(99% yield). mp 110-111 ° C Use for the next reaction without purification.

Reference Example 39 (2S, 3R, 4E) -1,3-dihydroxy-2-tetracosanoylaminooctadecene X III b2 A solution of 10 1.00 g (1.35 mmol) of 1,3-benzylidene ceramide in 10% hydrogen chloride-ethanol (20 ml) is stirred at room temperature for 2 hours. The reaction mixture is neutralized by adding a saturated aqueous sodium hydrogen carbonate solution, and the solvent is distilled off under reduced pressure. The residue was washed with water and filtered, and the crystals were further washed with methanol.
XIII b2 0.830 g (95% yield) is obtained.

mp 90-93 ° C. Elemental _{analysis: C 42 H 83 NO 3 ·} 3/4 · H 2 O Calculated (%): C 76.01, H 12.83, N 2.11, Found (%): C 76.16, H 12.61, N 1.74. Reference Example 40 (2S, 3R, 4E) -1-benzoyloxy-3-hydroxy-2-tetracosanoylaminooctadecene 11 1.92 g (13.7 mmol) of benzoyl chloride was added to a solution of 6.66 g (10.2 mmol) of ceramide XIII b2 in 400 ml of tetrahydrofuran and 100 ml of pyridine with stirring at room temperature.
(Mmol) in 50 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 2 hours. After the reaction, a saturated aqueous sodium hydrogen carbonate solution (2 ml) was added to the mixture, and the mixture was concentrated under reduced pressure, the residue was extracted with dichloromethane, and the dichloromethane layer was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: ethyl acetate / dichloromethane = 9/1) to give 4.70 g of product 11 (yield 6).
1%). mp 72-74 ° C. Elemental _{analysis: C 49 H 87 NO 4 ·} 1 / 5H 2 O Calculated (%): C 77.66, H 11.62, N 1.85, Found (%): C 77.52, H 11.62, N 2.01 Example 4 (2S, 3R, 4E) -1-O-benzoyl-N-tetracosanoyl-3-O- [2,3,6-tri-O-acetyl-4-
O- (2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -β-D-glucopyranosyl] sphingenin I E5 ′ 1-benzoylceramide 11 754mg (1.00mmol)
And O-protected-lactosyl imidate ( A ) 1.56 g (2.0
0 mmol) in dichloromethane (40 ml) was added with a 3A molecular sieve under a stream of nitrogen gas, and the mixture was stirred at room temperature for 30 minutes. Then, the reaction mixture was cooled to -4 ° C and 12.6 ml of a 0.1 molar solution of boron trifluoride-ether in dichloromethane was added dropwise, followed by stirring for 15 minutes and further stirring at room temperature for 2 hours. The reaction mixture is filtered, the mother liquor is washed with saturated aqueous sodium hydrogen carbonate solution, water and dried. The solvent was distilled off under reduced pressure, the residue was separated with the on silica gel column chromatography (eluent ether), initially unreacted starting material 11 200 mg (recovery rate 27
%), 400 mg (29% yield) of product IE5 ' are obtained.

Wax-like [α] _D -7.4 ° (c 1.00, CHCl ₃ ) SIMS mass 1394 (M + Na) ⁺ (2S, 3R, 4E) -3-O- (4-O-β-D-galactopyranosyl ) -Β-D-Glucopyranosyl-N-tetracosanoylsphingenin IE5 400 mg (0.290 mmol) of protected lactosylceramide I E5 ′ is dissolved by heating in methanol (20 ml), 0.6N solution of 1N sodium methoxide in methanol is added at room temperature, and the mixture is stirred for 20 hours. Tetrahydrofuran (20 ml) and Amberlyst 15 are added to the reaction mixture and stirred for 1 hour. The mixture was filtered using Hyflo Super Cel, the filtrate was concentrated under reduced pressure to give the residue is washed to product I E5 165 mg crystals in methanol (59% yield). mp 190-204 ° C
(Decomposition) [α] _D- 12.2 ° (c 0.692, pyridine) Elemental analysis: C ₅₄ H ₁₀₁ NO ₁₃ · H ₂ O Calculated value (%): C 65.49, H 10.48, N 1.41, Actual value (%) : C 65.59, H 10.50, N 1.46. Reference Example 41 (2S, 3R, 4E) -1-benzoyloxy-3-t-butyldiphenylsilyloxy-2-tetracosanoylaminooctadecene 12 1-Benzoylceramide 11 58.3 mg (0.480 mmol) of 4-dimethylaminopyridine in a dichloromethane solution (6 ml) of 150 mg (0.200 mmol) under a nitrogen stream while stirring, and then t-butylchlorodiphenylsilane 60
mg (0.22 mmol) was added dropwise, and the mixture was stirred for 2 hours and left overnight. Water and dichloromethane are added to the reaction mixture, and the mixture is separated and dried. After evaporating the solvent under reduced pressure, the residual oil was separated by silica gel column chromatography (eluent: dichloromethane / ether = 30/1), and the oily product 12 1 was obtained.
Obtain 50 mg (75% yield).

Reference Example 42 (2S, 3R, 4E) -3-t-butyldiphenylsilyloxy-1-hydroxy-2-tetracosanoylaminooctadecene 13 To a methanol solution (1 ml) of O-silylated ceramide 12 (110 mg, 0.11 mmol) was added dropwise a methanol solution of 1N-sodium methoxide (0.1 ml), and the mixture was stirred at room temperature for 6 hours.
The reaction mixture is left overnight. Amber list 15 in the mixture
And stirred for 30 minutes and filtered. The methanol filtrate was concentrated under reduced pressure, the residue was separated by on silica gel column chromatography (eluant dichloromethane / ether = 2/1) to give an oil product 13 58 mg (59% yield).

[Α] _D -16.0 ° (c 1.01, CHCl ₃ ) Elemental analysis: C ₅₈ N ₁₀₁ NO ₃ Si Calculated value (%): C 78.09, H 11.46, N 1.57, Observed value (%): C 77.91, H 11.47, N 1.65. Reference Example 43 (2S, 3R, 4E) -3-O-t-butyldiphenylsilyl-1-O- [2,3,6-tri-O-acetyl-4-O-
(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -β-D-glucopyranosyl] -N-tetracosanoylsphingenin 14 O-silylation-ceramide 13 1.30 g (1.46 mmol)
And O-protected-lactosylimidate ( A ) 2.50 g (3.2
(0 mmol) in dichloromethane (40 ml) was added with molecular sieve under a nitrogen gas stream, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then cooled to -3 ° C to -5 ° C and 18.5m of a 0.1 molar dichloromethane solution of boron trifluoride-ether was added.
The mixture is added dropwise and stirred at -3 ° C to 2 ° C for 1.5 hours. The mixture is filtered, the residue is washed with dichloromethane, and the combined dichloromethane layers are washed with saturated saline and saturated aqueous sodium hydrogen carbonate. The washing water is extracted again with dichloromethane (25 ml × 2). The combined dichloromethane layers are dried, and the solvent is distilled off under reduced pressure. The residue was separated by silica gel column chromatography (eluent: dichloromethane / ether = 4/1) to give 2.20 g of an oily product 14 (yield 1).
00%).

Reference Example 44 (2S, 3R, 4E) -1-O- [2,3,6-tri-O-acetyl-4-O- (2,3,4,6-tetra-O-acetyl-β-
D-galactopyranosyl) -β-D-glucopyranosyl] -N-tetracosanoylsphingenin I E6 ′ Dissolve 2.20 g (1.46 mmol) of O-silyl lactosylceramide 14 in tetrahydrofuran (30 ml).
Cool to 0 ° C. 1.6 ml of tetrabutylammonium fluoride solution in tetrahydrofuran with stirring
Is added dropwise, and the mixture is stirred at the same temperature for 1 hour and returned to room temperature for 3 hours. To the reaction mixture was added ether (50 ml) and saturated saline (20 ml).
ml), and the mixture is separated. The ether layer is concentrated under reduced pressure. The residue is dissolved in dichloromethane and dried, and the solvent is distilled off under reduced pressure.
The residue is subjected to silica gel column chromatography (eluent).
It was separated with ether / dichloromethane = 2/1) to give the product IE
6 ′ 1.61 g (87% yield) are obtained. mp 80-87 ° C. [α] _D −6.4 ° (c 1.02, CHCl ₃ ) NMR (CDCl ₃ ) δ: 3.77 (dd, 1H, J _3-4 = 9.5 Hz, J _4-5 = 9.5H)
z, G1cH4), 3.87 (dd, 1H, J _{4'-5 '} = small, J
_{5'-6 '= 7Hz, Ga1H5} '), 4.46 (d, 1H, J 1-2 = 8Hz, GIc
H1), 4.48 (d, 1H, J1' _{-2 '} = 8 Hz, Ga1H1'), 4.86 (d
_{d, 1H, J 1-2 = 8Hz} , J 2-3 = 10Hz, G1cH2), 4.95 (dd, 1H, J
_{2'-3 '} = 10.5Hz, J _3'-4' = 3.5Hz, Ga1H3 '), 5.
_{11 (dd, 1H, J 1'} -2 '= 8Hz, J 2'-3' = 10.5Hz, Ga1
H2 '), 5.19 (dd, 1H, J 2-3 = 10Hz, J 3-4 = 9.5Hz, G1cH3
), 5.34 (dd, 1H, J _{3'-4 '} = 3.5Hz, J _4'-5' = s
mall, Ga1H4 '), 4.00 (broad 1H, C2H) Elemental analysis: C ₆₈ H ₁₁₇ NO ₂₀ · H ₂ O Calculated value (%): C 63.47, H 9.32, N 1.09 Actual measured value (%): C 63.64, H 9.41, N 1.28 Example 5 (2S, 3R, 4E) -1,3-di-O- [2,3,6-tri-O-acetyl-4-O- (2,3,4,6- Tetra-O-acetyl-
β-D-galactopyranosyl) -β-D-glucopyranosyl] -N-tetracosanoylsphingenin I E7 ′ 1.10 g (0.870 mmol) of lactosylceramide I E6 ' and 2.00 g of O-protected-lactosylimidate ( A )
To a solution of (2.60 mmol) in dichloromethane (40 ml) was added molecular sieve AW-300 (1 g) under a nitrogen gas stream, followed by stirring at room temperature for 30 minutes. Then, the reaction mixture was cooled to -5 ° C, 10 ml of a 0.1 molar dichloromethane solution of boron trifluoride-ether was added dropwise, and the mixture was stirred at the same temperature for 1 hour and further at room temperature for 4 hours. The reaction mixture was filtered and the mother liquor was saturated aqueous sodium bicarbonate (2 ml), then saturated brine (10 ml)
And then dried. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 1/1), and the product I E7 ' 0.550 g
(34% yield). Oily.

_{NMR (CDCl 3) δ: 0.88} (t, J = 3Hz, 6H, C H 3 × 2), 1.16~
1.40 (m, 64H, C H 2 × 32), 1.96,2.00,2.04,2.06,2.08,2.1
_{2,2.13,2.14,2.18 (42H, COC H 3 ×} 14), 4.40~4.54 (m, 4
H, anomeric proton), 5.46 to 5.54 (m, 1H, olefin proton), 5.56 to 5.72 (m, 1H, olefin proton), 5.68 (d, J = 4 Hz, 1H, NH ). (2S, 3R, 4E) -1,3-di-O- (4-O-β-D-galactopyranosyl-β-D-glucopyranosyl) -N-
Tetracosanoyls fingenin IE7 To a solution of 550 mg (0.290 mmol) of protected dilactosylceramide I E7 ' in methanol (10 ml) was added 0.8 ml of a 1N sodium methoxide methanol solution at room temperature, followed by stirring for 20 hours. Tetrahydrofuran (20 ml) and Amberlyst 15 are added to the reaction mixture and stirred for 30 minutes. The mixture was filtered using a high floss parcel, the filtrate was concentrated under reduced pressure, product crystals remaining washed with methanol I E7 140 mg (yield: 37
%).

mp 226-230 (decomposition) [α] _D -25.0 ° (c 0.31, pyridine) Elemental analysis: C ₆₆ H ₁₂₃ NO ₂₃ · H ₂ O Calculated value (%): C 60.21, H 9.57, N 1.06, actual measurement Value (%): C 60.21, H 9.67, N 1.16. Reference Example 45 (2S, 3R, 4E, 2'R) -N-2'-t-butyldiphenylsilyloxytetracosanoylsphingenin 15 (2R) -2-t-butyldiphenylsilyloxytetracosanoic acid [Glycoconjugate
s), Volume 2, p. 105, 1985] 1.34 g (2.15 mmol)
660 mg (2.58 mmol) of 2-chloro-N-methylpyridinium iodide and 0.65 ml of triethylamine are added to a dichloromethane (15 ml) solution, and the mixture is stirred at room temperature for 30 minutes. Then, Sfingosine II b1-t [Journal of Galbohydrate Chemistry (J.Carbohyd.Che
m.), Vol. 5, p. 335, 1986] 645 mg (2.15 mmol)
And stirred at room temperature for 2.5 hours. Water is added to the reaction mixture, the organic layer is separated, dried and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: ether / dichloromethane = 1/3) to give 15 980 mg of the product (yield 5
0%). mp 45-47 ° C [α] _D + 6.8 ° (c 1.00, CHCl ₃ ) Elemental analysis: C ₅₈ H ₁₀₁ NO ₄ Si Calculated value (%): C 77.02, H 11.26, N 1.55, measured value (%) ): C 76.72, H 11.21, N 1.90. Reference Example 46 (2S, 3R, 4E, 2'R) -1-O- [2,3,6-tri-O-
Acetyl-4-O- (2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -β-D-glucopyranosyl] -N-2′-t-butyldiphenylsilyloxy Tetracosanoylsphingenin 16 and (2S, 3R, 4
E, 2'R) -1,3-di-O- [2,3,6-tri-O-acetyl-4-O- (2,3,4,6-tetra-O-acetyl-β-
D-galactopyranosyl) -β-D-glucopyranosyl] -N-2′-t-butyldiphenylsilyloxytetracosanoylsphingenin 17 15 980 mg (1.08 mmol) of 2'-silyloxyceramide 15 is dissolved in dichloromethane (10 ml), and 1.65 g (2.11 mmol) of O-protected lactosylimidate A and 3A molecular sieve are added, followed by stirring at room temperature for 30 minutes. Mix 0
The mixture was cooled to 0 ° C, 16 ml of a 0.1 molar dichloromethane solution of boron trifluoride-ether was added, and the mixture was stirred at 0 ° C for 2.5 hours. A saturated aqueous sodium hydrogen carbonate solution and dichloromethane are added to the reaction mixture, and the mixture is separated. After drying, the solvent is distilled off under reduced pressure. The residue was separated by silica gel column chromatography (eluent ether), and the monolactose form 16 700 mg (43% yield)
And obtaining Jirakutosu body 17 430 mg (19% yield) as respective oil. Intermediates 16 and 17 are used for the next reaction without purification.

Reference Example 47 (2S, 3R, 4E, 2'R) -1-O- [2,3,6-tri-O-
Acetyl-4-O- (2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -β-D-glucopyranosyl] -N-2′-hydroxytetracosanoylsphingenin I E8 ′ 2'-silyloxylactosylceramide 16 700 mg
(0.459 mmol) in tetrahydrofuran (2.5 ml) and cool to 0 ° C. To this was added 0.55 ml of a tetrahydrofuran solution of tetrabutylammonium fluoride,
Stir at 0 ° C. for 1.5 hours. The reaction mixture is partitioned between ether and water, the ether layer is separated, dried and concentrated. The residue was separated by silica gel column chromatography (eluent: ether / ethyl acetate = 6/1), and the product I E8 ' 360 mg
(61% yield). mp 100-105 ° C Elemental analysis: C ₆₈ H ₁₁₇ NO ₂₁ · H ₂ O Calculated value (%): C 62.70, H 9.21, N 1.08, Observed value (%): C 62.68, H 9.09, N 1.25. 2S, 3R, 4E, 2'R) -1-O- (4-O-β-D-galactopyranosyl-β-D-glucopyranosyl) N-
2'-hydroxytetracosanoylsphingenin I
E8 2'-hydroxylactosylceramide I E8 ' 360mg
To a solution of (0.280 mmol) in methanol (7 ml) and tetrahydrofuran (4 ml) was added 0.4 ml of a 1N sodium methoxide methanol solution, and the mixture was stirred at room temperature for 2 hours and left overnight. Add methanol and Amberlyst 15 to the reaction mixture, stir for 30 minutes and filter. The filtrate was concentrated under reduced pressure,
The residue is treated with hot ethanol and the milky supernatant is decanted. This operation was repeated three times, the ethanol extract was concentrated under reduced pressure, the product I E8 130mg (47% yield). mp 215-218
_{℃ [α] D -3.8 ° (} c 1.01, pyridine) SIMS mass 1012 (M + NA ) + Elemental _{analysis: C 54 H 103 NO 14 ·} 0.5H 2 O Calculated (%): C 64.90, H 10.49, N 1.40, actual value (%): C 65.08, H 10.48, N 1.70. Example 6 (2S, 3R, 4E, 2'R) -1,3-di-O- [2,3,6-tri-
O-acetyl-4-O- (2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -β-D-glucopyranosyl] -N-2′-hydroxytetracosanoyls Fingenin I E9 ' 2'-silyloxydilactosylceramide 17 430mg
(0.201 mmol) is treated as in Example 25 to give 200 mg (52% yield) of compound IE9 ' .

mp. 87-91 ° C Elemental analysis: C ₉₄ H ₁₅₁ NO ₃₈ Calculated value (%): C 59.32, H 8.00, N 0.74, Observed value (%): C 59.06, H 8.11, N 0.90. (2S, 3R , 4E, 2'R) -1,3-di-O- (4-O-β-
D-galactopyranosyl-β-D-glucopyranosyl)
-N-2'-hydroxytetracosanoylsphingenin I E9 O-protected-dilactosylceramide I E9 ' 200 mg (0.
105 mmol), was treated as in Example 25 to give Compound <br/> compound I E9 90 mg (65% yield).

mp. 200-203 ° C [α] _D -16.5 ° (c 0.51, pyridine) Elemental analysis: C ₆₆ H ₁₂₃ NO ₂₄ Calculated value (%): C 60.30, H 9.43, N 1.07, Observed value (%): C 60.14, H 9.78, N 1.35. Reference Example 48 (2S, 3R, 4E, 2'R) -N-2'-t-butyldiphenylsilyloxytetracosanoylsphingenin 18 (2S) -2-t-butyldiphenylsilyloxytetracosanoic acid [Glycoconjugate
s), Volume 2, p. 105, 1985] 2.30 g (3.69 mmol)
And sphingocin II b1-t 1.05 g (3.50 mmol)
The same reaction and treatment as in Reference Example 26 are performed. The obtained residue was separated by silica gel column chromatography (eluent, ether / dichloromethane = 1/6) to give an oily product 18
2.40 g (72% yield) are obtained.

IR (Film, cm ^-1 ): 3410, 1660, 1110. Reference Example 49 (2S, 3R, 4E, 2'S) -1-O- [2,3,6-tri-O-
Acetyl-4-O- (2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -β-D-glucopyranosyl] -N-2′-t-butyldiphenylsilyloxy Tetracosanoylsfingenin 19 2.25 g (2.49 mmol) of 2'-silyloxyceramide 18 was dissolved in 30 ml of dichloromethane, and 3.30 g (4.12 mmol) of O-protected lactosylimidate ( A ) and molecular sieve (AW-300) were added. And stir for 30 minutes. The mixture was cooled to 0 ° C and the boron trifluoride-ether
35 ml of a 0.1 molar dichloromethane solution is added, and the mixture is stirred at 0 ° C. for 2.5 hours and then at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution and dichloromethane are added to the reaction mixture for extraction. The organic layer is separated, dried and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: ether / hexane = 3/1) to give an amorphous product 19
g (16% yield). Compound 19 is used for the next reaction without purification.

Reference Example 50 (2S, 3R, 4E, 2'S) -1-O- [2,3,6-tri-O-
Acetyl-4-O- (2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -β-D-glucopyranosyl] -N-2′-hydroxytetracosanoylsphingenin I E10 ′ 2'-silyloxylactone ceramide 19 600 mg (0.
393 mmol) is reacted and treated in the same manner as in Example 25. The obtained residue is separated by silica gel chromatography (eluent: ether / ethyl acetate = 7/1) to obtain 370 mg (yield: 73%) of product IE10 ' . mp. 121-123
° C.

Elemental analysis: C ₆₈ H ₁₁₇ NO ₂₁ · 0.5H ₂ O Calculated value (%): C 63.13, H 9.19, N 1.08, Actual value (%): C 63.12, H 9.04, N 1.26. (2S, 3R, 4E, 2'S) -1-O- (4-O-β-D-galactopyranosyl-β-D-glucopyranosyl) -N-
2'-hydroxytetracosanoylsphingenin I
E10 2'-hydroxylactosylceramide I E10 ' 340m
g (0.264 mmol), the same reaction as in Example 25, by treating obtain product I E10 130 mg (47% yield).

mp. 210 ° C (decomposition) IR (Nujol, cm ^-1 ) 3370, 3260, 1650 (C = O). Elemental analysis: C ₅₄ H ₁₀₃ NO ₁₄ · 1 / 2H ₂ O Calculated value (%): C 64.90, H 10.49, N 1.40, measured value (%): C 64.65, H 10.29, N 1.51. Reference example 51 (2S , 3R, 4E) -1-Tolphenylmethyloxy-2-
Azido-3-hydroxyoctadecene 20 3.25 g (10 mmol) of (2S, 3R, 4E) -2-azido-1,3-dihydroxyoctadecene III b1-t is reacted in the same manner as in Reference Example 11. The resulting residue on silica gel chromatography (eluent: ether) were separated, the obtained oily product 20 4.80 g (60% yield). Compound 20 is used for the next reaction without purification.

Reference Example 52 (2S, 3R, 4E) -3-acetoxy-2-azido-1-triphenylmethyloxyoctadecene 21 Trityl body 20 9.76 g (17.2 mmol) was added to toluene (40
0 ml) and pyridine (70 ml) and 2.05 g (25.8 mmol) of acetyl chloride are added dropwise with stirring at room temperature. Stir at room temperature for 3 hours and concentrate the reaction mixture under reduced pressure. The residue is extracted with ether, and the ether layer is washed with water and dried. The solvent was distilled off under reduced pressure, the residue was separated by on silica gel column chromatography (eluant dichloromethane / carbon tetrachloride = 1/2), an oily product 21 8.85 g (86% yield)
Get.

[Α]_D -17.9 ° (c 0.99, CHCl_Three) IRcm^-1: 2100,1740 NMR (CDCl_Three) Δ: 0.88 (t, J = 3Hz, 3H, CH _Three), 1.18-1.36
(M, 22H, CH _Two× 11), 1.96 (s, 3H, COCH _Three), 1.88-2.00
(M, 2H, -CH = CHCH_Two), 3.07 ~ 3.24 (m, 2H, Ph_ThreeCCH_Two−),
3.64 to 3.72 (m, 1H, -CH−N_Three), 5.22-5.38 (m, 3H, −
CH-OAc, olefin proton), 5.60 to 5.76 (m, 1H,
Refin proton), 7.22 to 7.44 (m, 15H, C₆H_Five× 3). Reference Example 53 (2S, 3R, 4E) -3-acetoxy-2-azide-3-h
DroxyoctadeceneI F1And (2S, 3R, 4E) -1-
Acetoxy-2-azido-3-hydroxyoctadecene
 I F2  Trityloxyacetoxy compoundtwenty one 8.85g (14.8mm
Stirred in a 10% aqueous ethanol solution (170 ml) at room temperature
While dropping trifluoroacetic acid (100 ml)
Stir for 0 minutes. Reduce the reaction mixture to about 1/4 its volume
Pressure concentration. Sodium bicarbonate is added to the residue for neutralization
Then, it is extracted with dichloromethane. The organic layer is washed with water and dried
I do. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography.
Matographie (eluent dichloromethane / ether =
20/1) and the first product eluted into an oily productI F2 
1.10 g (20% yield) was obtained from the second eluted productIF
1 2.00 g (37% yield) are obtained.I F1 : mp 38-40 ℃ [α]_D −69.2 ° (c 1.00, CHCl_Three) NMR (CDCl_Three) Δ: 0.88 (t, J = 3Hz, 3H, CH _Three), 1.16 ~ 1.42
(M, 22H, CH _Two× 11), 1.85 to 2.10 (m, 2H, -CH = CHCH
_Two−), 2.10 (s, 3H, COCH _Three), 3.48 ~ 3.735.31 to 5.38 (m, 1H, -CH−OAc), 5.42 to 5.53 (m, 1H,
Refin proton, 5.78 to 5.92 (m, 1H, olefin pro
Ton). Elemental analysis: C₂₀H₃₇N_ThreeO_ThreeCalculated value (%): C 65.36, H 10.15, N 11.43 Actual value (%): C 65.14, H 9.88, N 11.36I F2 : [Α]_D -17.9 ° (c 0.93, CHCl_Three) NMR (CDCl_Three) Δ: 0.88 (t, J = 3Hz, 3H, CH _Three), 1.16 ~ 1.42
(M, 22H, CH _Two× 11), 2.01 to 2.14 (m, 2H, -CH = CHCH
_Two−), 2.11 (s, 3H, COCH _Three), 3.62 ~ 3.704.09-4.325.42 to 5.58 (m, 1H, olefin proton), 5.74 to 5.86
(M, 1H, olefin proton). Reference Example 54 (2S, 3R, 5S, 1'E) -5- [3- (2-chloroethyl
L) ureido] -2-phenyl-4-pentadecenyl-
1,3-dioxanetwenty two  1,3-benzylidenesfingosineII b3-t 1.2g (3.1
(Mmol) in dichloromethane (30 ml) at room temperature
0.39 g of 2-chloroethyl isocyanate (3.7
And the mixture is stirred at room temperature for 20 minutes. To the reaction mixture
A saturated aqueous sodium hydrogen carbonate solution is added, and the organic layer is separated.
And dried, and the solvent was distilled off under reduced pressure.twenty two1.4g (92% yield)
Get. mp 142-144 ° C [α]_D + 28.6 ° (c 1.00, CHCl_Three) Elemental analysis: C₂₈H₄₅N_TwoO_ThreeCalculated value (%) as Cl: C 68.20, H 9.20, N 5.68, Cl 7.19 Actual value (%): C 67.87, H 9.16, N 5.69, Cl 7.71 Example 7 (2S, 3R, 4E) -N- ( 2-chloroethylcarbamoy
Le) SwingeninI G1  Benzylidene bodytwenty two 1.4 g (2.8 mmol) of 10% chloride water
The ethanol-ethanol solution (30 ml) is stirred at room temperature for 3 hours.
To the reaction mixture is added a saturated aqueous sodium hydrogen carbonate solution
And concentrate under reduced pressure. The residue is washed with water and then dichloromethane.
Wash and productI G1 0.71 g (62% yield) is obtained.

mp 89-94 ° C Elemental analysis: C ₂₁ H ₄₁ N ₂ O ₃ Cl · 2 / 3H ₂ O · 1 / 4CH ₂ Cl ₂ Calculated value (%): C 59.12, H 10.04, N 6.52, Cl 10.33, actual measurement Value (%): C 59.44, H 9.67, N 6.38, Cl 10.11. Reference Example 55 (2S, 4R, 5S, 1'E) -2-phenyl-5- (3-benzoylureido) -4-pentadecenyl-1 , 3-dioxane 23 1,3-benzylidenesfingosine II b3-t 1.0 g (2.6
Mmol) in dichloromethane (20 ml) was cooled to 0 ° C. and 0.45 g (3.1
(Mmol) is added dropwise, and the mixture is stirred at the same temperature for 30 minutes and then at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the organic layer is separated and dried. The solvent was distilled off under reduced pressure,
The residue is purified by silica gel column chromatography (eluent).
Was separated with dichloromethane / ether = 1/1), washed the resulting crystals with ether, the product 23 1.29 g (94% yield)
Get.

mp 146-148 ° C [α] _D 51.3 ° (c 1.00, CHCl ₃ ) IRcm ^-1 : 1700,1680 Elemental analysis: Calculated as C ₃₃ H ₄₆ N ₂ O ₄ Calculated value (%): C 74.12, H 8.67, N 5.24 Found (%): C 74.13, H 8.76, N 5.31 example 8 (2S, 3R, 4E) -N- ( benzoyl) -3,4 Sufuingenin I G2 Benzylideneurea 23 10% of 1.1 g (2.8 mmol)
Stir the suspension of hydrogen chloride-ethanol (50 ml) at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture that had become a solution to neutralize, and concentrated under reduced pressure. The residue is extracted with dichloromethane, washed with water and dried. The solvent was distilled off under reduced pressure, the residue was separated by on silica gel column chromatography (eluent ethyl acetate / dichloromethane = 4/1) to give the product I G2 0.70 g (55% yield). _{mp 79-80 ℃ [α] D 7.0} ° (c 0.52, CHCl 3) Elemental _{analysis: C 26 H 42 N 2 O} 4 · 1/10 · H 2 O Calculated (%): C 69.94, H 9.40, N 6.25, Found (%): C 69.40, H 9.58, N 6.20. Reference Example 56 (2S, 4R, 5S, 1'E) -2-phenyl-5- (3-phenylureido) -4-pentadecenyl-1 , 3-dioxane 24 1,3 - benzyldensphingosine II b3-t 0.66 g (1.
0.24 g (2.0 mmol) of phenyl isocyanate was added to a dichloromethane solution (7 mmol) (16 ml) with stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, the organic layer is separated, washed with water and dried. The solvent is removed under reduced pressure and the residue is washed with ether to give 24 0.84 g (98% yield) of the product. mp 142−
146 ° C. [α] _D 37.5 ° (c 1.00, CHCl ₃ ) NMR (CDCl ₃ ) δ: 3.85 (dd, 1H, J = 6 Hz, 3 Hz, C5H), 3.99
(Dd, 1H, J = 6Hz , 3Hz, C4H) Elemental _{analysis: C 32 H 46 N 2 O} 3 · 1/5 · H 2 O Calculated (%): C 75.31, H 9.16, N 5.49, Found (%):. C 75.43, H 9.10, N 5.57 example 9 (2S, 3R, 4E) -N- ( phenylene) -3,4 Sufui <br/> Ngenin I G3 Benzylidene urea body 24 0.86 g (1.7 mmol), 1
By treating in the same manner as in Example 30 using a 6% hydrogen chloride-ethanol solution, unreacted raw material 24 0.38 g (recovery rate
44%) and the product is obtained I G3 0.37g (52% yield).

mp. 112-113 ° C Elemental analysis: C ₂₅ H ₄₂ N ₂ O ₃ Calculated value (%): C 71.73, H 10.11, N 6.69 Actual value (%): C 71.50, H 9.88, N 6.71 Reference example 57 (2S , 4R, 5S, 1'E) -2-Phenyl-5- (3-phenylthioureido) -4-bantadecenyl-1,3-dioxane 25 1,3-benzylidenesfingosine II b3-t 1.0 g (2.6
Phenylisothiocyanate (0.42 g, 3.0 mmol) was added dropwise to a dichloromethane solution (30 ml) of dimethylisothiocyanate (30 mmol) with stirring at room temperature, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the organic layer was separated.
Wash with water and dry. The solvent was removed under reduced pressure to give an oily product.
25 1.33 g (98% yield) are obtained. 25 is used for the next reaction without purification.

Example 10 (2S, 3R, 4E) -N- ( phenylene thio carbamoyl) Sufuingenin I G4 Benzylidenethiourea 25 1.36 g (1.59 mmol)
The 16% hydrogen chloride - is treated in a similar manner to Example 30 using ethanol, waxy product I G4 0.69 g
(61% yield).

_{NMR (CDCl 3) δ: 0.88} (t, J = 3Hz, 3H, C H 3), 1.18~1.40
_{(M, 22H, C H 2} × 11), 1.88~2.15 (m, 2H, -CH = CH-C
_{H 2), 3.45~3.98 (m,} 3H, HO-C H 2, C H -OH), 5.30~5.75
(M, 2H, olefinic protons), 7.01~7.40 (m, 5H, -C 6 H
₅ ). Reference Example 58 (2S, 3R, 4E) -2-Azido-3-hydroxyoctadecenyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-α-D- Glycero-D-galact-2-nonulopyranoside acid methyl ester
I H1 ′ Dissolve 0.900 g (1.77 mmol) of azidosphingosin IIIb1 -t in dichloromethane (30 ml), add 3 g of 3A molecular sieve and 3 g under a nitrogen gas stream, and stir at room temperature for 30 minutes. The reaction mixture was cooled to -20 ° C, and 5-acetamide-
4,7,8,9-tetra-O-acetyl-2-chloro-2,3,5-
Trideoxy-β-D-glycero-D-galact-2-
Nonylopyranosonic acid methyl ester (B) [Chemical and Pharmaceutical Buritin (Chem.
Bull.) 34, 2725, 1986] 2.11 g (4.14 mmol), 0.800 g (6.63 mmol) of 1,1,3,3-tetramethylurea and silver trifluoromethanesulfonate
1.30 g (5.37 mmol) are added in succession, stirred for 30 minutes at the same temperature, protected from light, and 4 days at room temperature. The reaction mixture was filtered using Hyflo Super Cel, the filtrate was concentrated under reduced pressure, the residue was separated by on silica gel column chromatography (eluent ethyl acetate), unreacted starting materials III b1-t 370 mg (recovered from the first eluate Rate of 41%). Then 690 mg (49% yield) of the oily product I H1 ' are obtained.

[Α] _D -2.2 ° (c 0.92, CHCl ₃ ) SIMS mass [M + NA] ⁺ 82 NMR (CDCl ₃ ) δ 0.88 (t, J = 3 Hz, 3H, CH ₃ ), 1.18 to 1.36
(M, 22H, CH ₂ × 11), 1.90 (s, 3H, NHCOC H ₃ ), 2.02,2.03,
2.08, 2.15 (15H, OCOC H ₃ × 5), 3.82 (s, 3H, COOCH ₃ ), 4.
8-5.0 (sialic acid, C4H), 5.74-5.94 (m, 1H, olefin proton). (2S, 3R, 4E) -2-azido-3-hydroxyoctadecenyl 5-acetamido-3,5-dideoxy-α-D-
Glycero-D-galact-2-nonulopyranoside acid
I H1 To a solution of 327 mg (0.39 mmol) of the O-protected sialic acid derivative I H1 ' in methanol (15 ml) was added 1N while stirring at room temperature.
Add 1.7 ml of sodium hydroxide and stir for 20 hours. Amberlyst 15 is added to the reaction mixture, stirred for 30 minutes, and filtered. The filtrate is concentrated under reduced pressure, the residue is dissolved in a small amount of methanol, Norrit SX-3 is added, and the mixture is stirred for 10 minutes. The mixture is filtered using Hyflo Super Cell, and the filtrate is concentrated under reduced pressure to obtain 230 mg (yield: 96%) of product I H1 .

mp. 151 ° C (end point of decomposition) [α] _D -15.9 ° (c 1.00, H ₂ O) IR (Nujol, cm ^-1 ): 3300 (br, s), 2100 (s, N ₃ ), 1720
(S, C = O), 1640 (s, C = O). SIMS mass (M + NA) ⁺ 639 Elemental analysis: C ₂₉ H ₅₂ N ₄ O ₁₀ · 2.8 H ₂ O Calculated value (%): C 52.21, H 8.70, N 8.40 Actual value (%): C 52.08, H 8.24 , N 8.30 Reference Example 59 (2S, 3R, 4E) -2-azido-3-acetoxyoctadecenyl 5-acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-β -D-glycero-D-galact-2-noneuropyranosidonic acid methyl ester I
H2 ' 3-acetoxy-azidosfingosine I F1 0.800 g
(2.18 mmol) in dichloromethane (40 ml)
1.80 g (6.50 mmol) of silver carbonate under a nitrogen stream while blocking light
And 4 g of 3A-Molecular sieve are added, and after stirring at room temperature for 1 hour, the mixture is cooled to -35 ° C. To this was added a dichloromethane solution (5 ml) of 2.78 g (5.45 mmol) of 2-chlorosialic acid ester B, and the mixture was stirred at the same temperature for 30 minutes and then returned to room temperature and stirred for 4 days. The reaction mixture is filtered using Hyflo Super Cell, and the filtrate is concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent ethyl acetate), unreacted starting materials from the first elution fraction I F1 550 mg
(Recovery rate 69%). The oily product I H2 'is then
200 mg (11% yield) are obtained. Compound I H1 'product I H2 by NMR comparison with' can be determined to be a β- anomer _{NMR (CDCl 3) δ: 0.88} (t, J = 3Hz, 3H, C H 3), 1.22~1.40
_{(M, 22H, C H 2} × 11), 1.90 (s, 3H, NHCOC H 3), 2.03,2.04,
2.08,2.13,2.16 (15H, OCOC H ₃ × 5), 3.82 (s, 3H, COOC
_{H 3), 5.82~5.96 (m,} 1H, olefinic proton). [Α] _D −22.4 ° (c 0.77, CHCl ₃ ) (2S, 3R, 4E) -2-azido-3-hydroxyoctadecenyl 5-acetamido-3,5-dideoxy-β-D-
Glycero-D-galact-2-nonulopyranoside acid
I H2 The obtained O-protected sialic acid derivative I H2 ′ 0.200 g (0.2
4 mmol) was reacted as in Example 33 and the product I
140 mg (95% yield) of H2 are obtained.

mp. 110-115 ° C (decomposition) [α] _D -15.4 ° (c 0.93, H ₂ O) SIMS mass (M + NA) ⁺ 639 Reference Example 60 (2S, 3R, 4E) -2-amino-3- Hydroxyoctadecenyl 5-acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-α (or β) -D-glycero-D-galact-2-nonulopyranosidone Acid methyl esters I H3 ' and I H4' To a solution of azido sialic acid ester I H1 ' 1.40 g (1.75 mmol) in tetrahydrofuran (40 ml) was added dropwise, under a nitrogen gas stream, 0.250 g (2.10 mmol) of triethylphosphine, followed by stirring at room temperature for 30 minutes. 10 ml of water is added to the mixture, stirred for 1 hour, and the mixture is concentrated under reduced pressure. The residue is extracted with dichloromethane, washed with water and dried. The solvent is distilled off under reduced pressure, and the residue is separated by silica gel column chromatography (eluent: ethyl acetate) to obtain 0.30 g (yield: 22%) of an oily product I H4 ' from the first elution. The second elution gives 0.25 g (19% yield) of the oily product IH3 ' . Sialic acid C4H is observed at δ 4.30 to 4.54 by product I H4 ′ NMR, while sialic acid C4H is observed at δ 4.61 to 4.70 in product I H3 ′ . I H3 ′ IR (CHCl ₃ , cm ⁻¹ ): 3600 (w), 3400 (m), 3370
(M), 1730 (s, C = O), 1685 (s, C = O), 1500 (s),
1365 (s), 1210 (s), 1130 (s). _{NMR (CDCl 3) δ: 0.88} (t, J = 3Hz, 3H, C H 3), 1.13~1.47
( M , 22H, C H ₂ × 11), 1.90 (s, 3H, NHCOC H ₃ ), 2.01,2.02,
2.09, 2.15 (12H, OCOC H ₃ × 4), 3.80 (s, 3H, COOC H ₃ ), 4.
61~4.70 (m, 1H, sialic acid C4 H), 5.72~5.90 (m, 1H, olefinic proton). I H4 ' IR (CHCl ₃ , cm ^-1 ): 3600 (w), 3400 (m), 3350
(M), 1730 (s, C = O), 1670 (s, C = O), 1500 (s),
1365 (s), 1210 (s), 1130 (s). _{NMR (CDCl 3) δ: 0.88} (t, J = 3Hz, 3H, C H 3), 1.15~1.42
( M , 22H, C H ₂ × 11), 1.90 (s, 3H, NHCOC H ₃ ), 2.02,2.04,
2.08, 2.16 (12H, OCOC H ₃ × 4), 3.80 (s, 3H, COOC H ₃ ), 4.
30-4.54 (m, 1H, sialic acid C4H), 5.75-5.95 (m, 1H, olefin proton). (2S, 3R, 4E) -2-amino-3-hydroxyoctadecenyl 5-acetamido-3,5-dideoxy-α-D-
Glycero-D-galact-2-nonulopyranoside acid
I H3 Example 33 was prepared in the same manner as in Example 33 except that 0.53 g (0.69 mmol) of α-anomer I H3 ′ was reacted in the same manner as in Example 33, and that Amberlyst CG-50 was used instead of Amberlyst 15.
It was treated in the same manner as the product I H3 340 mg (yield: 86%) obtained.

mp.173-177 ° C. IR (Nujol, cm- ¹ ) 3350 (br, s), 1675 (s, C = O). Elemental _{analysis: C 29 H 54 N 2 O} 10 · 1 / 5H 2 O Calculated (%): C 58.60, H 9.23, N 4.71 Found (%): C 58.55, H 9.36, N 4.73 (2S, 3R , 4E) -2-Amino-3-hydroxyoctadecenyl 5-acetamido-3,5-dideoxy-β-D-
Glycero-D-galact-2-nonulopyranoside acid
I H4 0.29 g (0.38 mmol) of β-anomer I H4 ′ was reacted and treated in the same manner as in Example 33 to give the product.
110 mg (49% yield) of I H4 can be obtained.

mp. 137-140 ° C, IR (Nujol, cm ^-1 ) 3400 (br, s), 1680 (s, C = O). Elemental _{analysis: C 29 H 54 N 2 O} 10 · 1 / 4H 2 O Calculated (%): C 57.56, H 9.26, N 4.63, Found (%):. C 57.60, H 9.14, N 4.60 Example 11 (2S, 3R, 4E) -3-hydroxy-2- (phenylureido) octadecenyl-5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-α-D-glycero-D -Galact-2-noneuropyranosidonic acid methyl ester I H5 ″ Dissolved carbamoyl staple Ingo Singh I G3 0.680 g of (1.62 mmol) in dichloromethane (100 ml), under a nitrogen gas stream, in addition to 3A molecular Kiyura sieve 3g stirred for 30 minutes at room temperature. The reaction mixture was cooled to −25 ° C. to −30 ° C., protected from light, and 1.94 g (3.80 mmol) of chlorosialyl ester B, 0.700 g (6.10 mmol) of 1,1,3,3-tetramethylurea and then silver Trifluoromethanesulfonate
1.26 g (4.92 mmol) is added, and the mixture is stirred at the same temperature for 30 minutes and further at room temperature for 4 days. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: dichloromethane / methanol = 15/1), and 1.0 g of an oily mixture of starting material IG3 and product IH5 ″ was obtained.
Get. This mixture is used for the next reaction as it is.

(2S, 3R, 4E) -3-acetoxy-2- (3-phenylureido) octadecenyl 5-acetamide-4,7,8,9
-Tetra-O-acetyl-3,5-dideoxy-D-glycero-D-galact-2-nonulopyranosidic acid methyl ester I H5 ' Oily mixture IG3 and IH5 ″ 1.0 g toluene (40 ml)
0.50 g (6.4 mmol) of acetyl chloride was added dropwise to a solution of pyridine and 6.5 ml of pyridine at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue is partitioned between saturated aqueous sodium hydrogen carbonate and dichloromethane, the organic layer is separated, washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: ethyl acetate) to give the product as an oily anomeric mixture.
0.48 g of I H5 ′ is obtained.

_{NMR (CDCl 3, δ) 0.90} (t, J = 3Hz, 3H, C H 3), 1.16~1.46
_{(M, 22H, C H 2} × 11), 1.96 (s, 3H, NHCOC H 3), 2.03,2.06,
_{2.09,2.13,2.18 (12H, COC H 3 ×} 5), 3.76 (s, 3H, COOC
_{H 3), 4.3~4.6 (m,} β- anomers of C4H sialic acid), 4.8
~ 5.0 (m, α-anomeric sialic acid C4H), 5.66 ~ 5.93
(M, 1H, olefin proton), 7.19 to 7.56 (m, 5H, C
₆ H _5). (2S, 3R, 4E) -3-Hydroxy-2- (phenylureido) octadecenyl-5-acetamido-3,5-dideoxy-D-glycero-D-galact-2-nonylopyranosic acid I H5 The O- protected sialic acid derivatives I H5 '0.48 g (0.51 mmol) were reacted in the same manner as in Example 33, by treating obtain product I H5 0.33 g (91% yield).

mp. 135-140 ° C SIMS mass [M + 2NA-H] ⁺ = 754 IR (Nujol, cm ^-1 ): 3400 (br, s), 1720 (s, C = O), 1665
(S, C = O), 1600 (s). Elemental analysis: C ₃₆ H ₅₉ N ₃ O ₁₁ · 1.2H ₂ O Calculated value (%): C 59.11, H 8.46, N 5.74 Actual value (%): C 59.01, H 8.23, N 5.78 Example 12 (2S , 3R, 4E) -3-Hydroxy-2- (phenylthioureido) octadecenyl 5-acetamide-4,7,8,9
-Tetra-O-acetyl-3,5-dideoxy-D-glycero-D-galact-2-noneuropyranosidonic acid methyl ester I H6 ' Dissolved thiocarbamoyl staple Ingo Singh I G4 1.10 g of (2.53 mmol) in dichloromethane (30 ml), under a nitrogen stream, was added 3A molecular Kiyura sieve 3g stirred for 30 minutes at room temperature. The reaction mixture was cooled to −25 ° C., protected from light, and 2.59 g (5.00 mmol) of chlorosialyl ester B , 1,1,3,
1.10 g (9.30 mmol) of 3-tetramethylurea and 1.96 g (7.60 mmol) of silver trifluoromethanesulfonate are added, and the mixture is stirred at the same temperature for 30 minutes and further at room temperature for 4 days. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: ethyl acetate) to give 0.85 g of an oily product I H6 ′ (yield 35
%).

_{NMR (CDCl 3) δ: 0.90} (t, J = 3Hz, 3H, C H 3), 1.16~1.46
_{(M, 22H, C H 2} × 11), 1.96 (s, 3H, NHCOC H 3), 2.01,2.20,
2.09, 2.12 (12H, COC H ₃ × 4), 3.80 (s, 3H, COOC H ₃ ), 4.9
~ 5.0 (m, α-anomeric sialic acid, C4H), 7.05-7.46
_{(M, 5H, C 6 H} 5). (2S, 3R, 4E) -3-hydroxy-2- (phenylthioureido) octadecenyl-5-acetamido-3,5-dideoxy-D-glycero-D-galact-2-nonylopyranosic acid I H6 To a solution of the O-protected sialic acid derivative IH6 ' 800 mg (0.84 mmol) in methanol (20 ml) was added 1N while stirring at room temperature.
Add 3.8 ml of sodium hydroxide and stir for 20 hours. Amberlite CG-50 is added to the reaction mixture, stirred for 30 minutes and filtered. The filtrate was concentrated under reduced pressure, the powder remaining was separated by HP-20 column chromatography (eluent water followed methanol) to give the product I H6 124 mg (20% yield).

mp. 190-195 ° C. [Α] _D −70.0 ° (c 1.00, H ₂ O) Elemental analysis: C ₃₆ H ₅₉ N ₃ O ₁₀ S · 0.5 CH ₃ OH · 1.2H ₂ O Calculated value (%): C 57.43, H 8.35, N 5.50, actual value (%): C 57.88, H 7.89, N 5.41. Effects of the Invention The compound (I) of the present invention has an excellent anticancer effect. The activity test was performed as described below, and the effect was determined. Table 3 shows the results of the representative compounds.

(Test Method) 3 × 10 ³ or 5 × 10 ⁵ cancer cells for MH134 mouse were diluted with physiological saline and inoculated intraperitoneally into CRT-C3M mice (Charles River, male, 5-6 weeks old). did. One test group and a control group used 7 to 10 mice. In the test group, 2 mg or 0.5 mg of the test compound per mouse was suspended in physiological saline, and 1 day after cell transplantation, 1 mg was intraperitoneally injected into the peritoneal cavity.
Dose was administered once.

The observation period was set to 60 days after transplantation.
Life Span%) was calculated.

T: Average survival days of test animals C: Average survival days of control animals It is determined that an ILS% of 30 or more is effective.

(result) The test compound numbers correspond to the compound numbers in the examples.

The compound (I) of the present invention showed an excellent anticancer effect on MH134 mouse liver cancer.

As is clear from the above results, the compound of the present invention has excellent anticancer activity and can be used as an anticancer agent in humans or animals.

The compound (I) of the present invention can be administered orally or parenterally to humans or animals. For example, Compound (I) is dissolved or suspended in a suitable solvent for injection (for example, distilled water for injection, ethanol, glycerin, propylene glucool, olive oil, peanut oil, etc.) and then injected intravenously, intramuscularly or subcutaneously. Can be administered. When used as an injection, compound (I) can be enclosed in an ampoule as a solution or suspension, but is stored in an ampoule or a vial as crystals, powders, microcrystals, or lyophilized product. It is preferable to adjust the time. Further, a stabilizer may be added. Compound (I) is a diluent (for example, starch, sucrose, lactose,
Pharmaceutical ingredients such as calcium carbonate, kaolin, etc.) and lubricants (eg, stearic acid, sodium benzoate, boric acid, silica, polyethylene glycol, etc.) are added, and powders, tablets, granules, capsules, troches, dry syrups are added. It can be orally administered by molding into such as.

When compound (I) is used for treating cancer in adults, usually 1 mg
Administer 1 to 3 times daily with a daily dose of ~ 5g. However, the dose may be appropriately increased or decreased depending on the age, medical condition, medical history, etc. of the patient.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication location C07C 335/16 C07C 335/16 C07H 15/04 C07H 15/04 // A61K 31/13 ADU A61K 31 / 13 ADU 31/215 31/215 31/655 31/655 31/66 31/66 31/70 31/70

Claims (4)

(57) [Claims] (1) Formula (I): [In the formula, A is an amino which may have a substituent [wherein the substituent is alkyl having 1 to 6 carbons, alkylsulfonyl having 1 to 6 carbons; hydroxy, acetamide, amino or a double bond Acyl or carbamoyl or thiocarbamoyl optionally substituted by acyl, aryl or halogen-substituted alkyl] or azide; R ¹ is hydrogen, acetyl, benzoyl, pivaloyl, β-D
-Galactopyranosyl, 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl, 4-O- (β-D-
Galactopyranosyl) -β-D-glucopyranosyl, 2,
3,6-tri-O-acetyl-4-O- (2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -β-
D-glucopyranosyl, 5-acetamido-3,5-dideoxy-β-D-glycero-D-galact-2-nonulopyranosonoyl (N-acetylneuraminosyl), 5-
Acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-β-glycero-D-galact-2-nonulopyranosonoyl or trimethylammonium (C1-C3
Alkyl) phosphoryl, and R ² is hydrogen, acetyl, benzoyl, pivaloyl, 4-O
-([Beta] -D-galactopyranosyl)-[beta] -D-glucopyranosyl, 2,3,6-tri-O-acetyl-4-O- (2,
3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl) -β-D-glucopyranosyl, 5-acetamido-3,5-dideoxy-β-D-glycero-D-galacto-2- Nonulopyranosonoyl (N-acetylneuraminosyl), 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-β-glycero-D-galact-2-nonuro Pyranosonoyl, and n is an integer of 10 or more and 14 or less. Provided that A is unsubstituted amino; hydroxy, acetamide,
Amino or an amino substituted with an acyl which may have a double bond; or when azide, R ² is not hydrogen, acetyl, benzoyl or pivaloyl] or a salt thereof. 2. An amino group in which A has a substituent [wherein the substituent means alkyl having 1 to 6 carbon atoms, alkylsulfonyl having 1 to 6 carbon atoms; hydroxy, acetamide, amino or double bond. And carbamoyl or thiocarbamoyl optionally substituted by acyl, aryl or halogen-substituted alkyl]. (3) R ¹ is acetyl, benzoyl, pivaloyl,
4-O- (β-D-galactopyranosyl) -β-D-glucopyranosyl, 2,3,6-tri-O-acetyl-4-O
-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -β-D-glucopyranosyl, 5-acetamido-3,5-dideoxy-β-D-glycero-D- Galact-2-nonulopyranosonoyl (N-acetylneuraminosyl) or 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-β-glycero-
The compound according to claim 1 or 2, which is D-galact-2-nonulopyranosonoyl. (4) R ² is 4-O- (β-D-galactopyranosyl) -β-D-glucopyranosyl, 2,3,6-tri-O-
Acetyl-4-O- (2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -β-D-glucopyranosyl, 5-acetamido-3,5-dideoxy-β-D −
Glycero-D-galact-2-nonulopyranosonoyl (N-acetylneuraminosyl) or 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
The compound according to any one of claims 1 to 3, which is β-glycero-D-galact-2-nonulopyranosonoyl.