JP2839916B2 - Lipid A 3-position ether analogue - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Purpose] (Industrial application field) The present invention relates to a novel lipid A3-position ether analog having an antitumor effect based on microphage activation and a salt thereof.

(Prior art) The immune system and phagocytic system, which are responsible for the body's defense mechanism, maintain normal self not only against foreign foreign substances, but also against the expression of endogenous abnormal cells and abnormal tissue formation. The elucidation of this biological defense mechanism has become an important research area. Macrophages are activated by non-specific factors such as immunological factors and bacterial surface substances, enhance their ability to kill microorganisms and tumor cells, and play an important role in host defense. As a substance that activates this macrophage, a lipid A-related compound is known.

However, this lipid A is present in the outermost layer of the cell wall of Gram-negative bacteria and is a toxic component (endotoxin) that is not secreted outside the cells, and thus has problems such as lethal toxicity and pyrogenicity. Therefore, development of lipid A-related immunostimulants and antitumor agents that do not have these side effects represented by lipid A and retain biological activities such as tumor necrosis, enhancement of antibody production, and TNF induction are desired.

(Problems to be Solved by the Invention) The inventors of the present invention have conducted intensive studies over many years on the synthesis of lipid A analogs having macrophage activating activity and their pharmacological activities, and as a result, have found that known lipid A derivatives Have different structures, i.e., a novel lipid A3-position ether analogue having a halogen atom and a hydroxyl group or an aliphatic acyl group having 10 to 20 carbon atoms substituted by an aliphatic acyloxy group having 10 to 20 carbon atoms, Novel lipid A in which an alkyl group having 10 to 20 carbon atoms is ether-linked to a hydroxyl group at the 3-position
The present inventors have found that an analog has an excellent macrophage activating action and is useful as an immunostimulant or an antitumor agent, and thus completed the present invention.

〔Constitution〕

The novel lipid A 3-position ether analog of the present invention has the general formula Wherein ^one of R ¹ and R ⁷ is a hydrogen atom,
An (O) (OR ⁹ ) group (wherein R ⁹ represents a hydrogen atom or a hydroxyl-protecting group) or a hydroxyl-protecting group, and the other is a group of the formula —P (O) (OR ⁹ ) In the formula, R ⁹ has the same meaning as described above.)

R ² , R ⁵ and R ⁶ may be the same or different, and may have a halogen atom, a hydroxyl group, a protected hydroxyl group or an aliphatic acyloxy group having 10 to 20 carbon atoms and an aliphatic acyloxy group having 10 to 20 carbon atoms. Shows an acyl group.

R ³ represents a halogen atom, a hydroxyl group, a protected hydroxyl group or an alkyl group having 10 to 20 carbon atoms which may have an aliphatic acyloxy group having 10 to 20 carbon atoms.

R ⁴ and R ⁸ are the same or different and each represent a hydrogen atom or a hydroxyl-protecting group. ] Is represented.

In the above general formula (I), the term “protecting group for hydroxyl group” in the definition of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ includes a protecting group in a reaction and a living body. Indicates a protecting group upon administration, and includes, for example, an alkylcarbonyl group such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, myristoyl, tridecanoyl, palmitoyl, stearoyl, chloroacetyl, Halogenated alkylcarbonyl groups such as dichloroacetyl, trichloroacetyl and trifluoroacetyl; lower alkoxyalkylcarbonyl groups such as methoxyacetyl; (E) -2-methyl-2
Aliphatic acyl groups such as unsaturated alkylcarbonyl groups such as butenoyl; arylcarbonyl groups such as benzoyl, α-naphthoyl and β-naphthoyl, and halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl. , 2,4,6-trimethylbenzoyl,
Lower alkylated arylcarbonyl groups such as 4-toluoyl, lower alkoxylated arylcarbonyl groups such as 4-anisoyl, nitrated arylcarbonyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl, 2
Aromatic acyl groups such as lower alkoxycarbonylated arylcarbonyl groups such as-(methoxycarbonyl) benzoyl, arylated arylcarbonyl groups such as 4-phenylbenzoyl; tetrahydropyran-2-yl, 3
-Bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-
A tetrahydropyranyl or tetrahydrothiopyranyl group such as 4-yl; a tetrahydrofuranyl or tetrahydrothiofuranyl group such as tetrahydrofuran-2-yl or tetrahydrothiofuran-2-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, Tri-lower alkylsilyl groups such as t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl and triisopropylsilyl; 1 to 1 such as diphenylmethylsilyl, diphenyl-t-butylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl A silyl group such as a tri-lower alkylsilyl group substituted with two aryl groups; methoxymethyl,
1,1-dimethyl-1, methoxymethyl, ethoxymethyl,
Lower alkoxymethyl groups such as propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis ( Alkoxymethyl groups such as halogenated lower alkoxymethyl such as 2-chloroethoxy) methyl; lower alkoxylated ethyl groups such as 1-ethoxyethyl, 1-methyl-1-methoxyethyl and 1- (isopropoxy) ethyl; Substituted ethyl groups such as ethyl halide groups such as 2,2,2-trichloroethyl and arylselenyl ethyl groups such as 2- (phenylzelenyl) ethyl; benzyl, phenethyl, 3-phenylpropyl, α
Lower alkyl group substituted with 1 to 3 aryl groups such as naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4
1 to 3 aryl groups in which the aryl ring is substituted by lower alkyl, lower alkoxy, nitro, halogen, cyano groups such as cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl, piperonyl; An aralkyl group such as a lower alkyl group substituted with a lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, or 2-trimethylsilylethoxycarbonyl; An alkoxycarbonyl group such as a lower alkoxycarbonyl group substituted with a halogen or a tri-lower alkylsilyl group; an alkenyloxycarbonyl group such as vinyloxycarbonyl and allyloxycarbonyl; benzyloxycarbonyl The aryl ring is substituted with one or two lower alkoxy or nitro groups such as 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl; An aralkyloxycarbonyl group; a protecting group in a reaction such as an allyl group; and a protecting group for administration to a living body such as pivaloyloxymethyloxycarbonyl.

Examples of the `` aliphatic acyl group having 10 to 20 carbon atoms '' in the definition of R ² , R ³ , R ⁵ and R ⁶ include, for example, nonylcarbonyl,
Decylcarbonyl, 3-methylnonylcarbonyl, 8-
Methylnonylcarbonyl, 3-ethyloctylcarbonyl, 3,7-dimethyloctylcarbonyl, undecylcarbonyl, dodecylcarbonyl, tridecylcarbonyl, tetradecylcarbonyl, pentadecylcarbonyl, hexadecylcarbonyl, 1-methylpentadecylcarbonyl, 14- Methylpentadecylcarbonyl, 13,1
3-dimethyltetradecylcarbonyl, heptadecylcarbonyl, 15-methylhexadecylcarbonyl, octadecylcarbonyl, 1-methylheptadecylcarbonyl and nonadecylcarbonyl, preferably a straight chain having 12 to 16 carbon atoms Or a branched aliphatic acyl group.

The “halogen atom” in the definition of R ² , R ³ , R ⁵ and R ⁶ represents fluorine, chlorine, bromine or iodine.

“An alkyl group having 10 to 20 carbon atoms” in the definition of R ³
As decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, dodecyl, tridecyl, tetradecyl , Pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, 4,8,12-trimethyltridecyl, 1
-Methylpentadecyl, 14-methylpentadecyl, 13,1
3-dimethyltetradecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, eicosyl and 3,7,11,15-tetramethylhexadecyl, preferably carbon number 10 to 16 linear or branched alkyl groups.

“Hydroxyl protecting group” in the definition of R ⁹ includes phenyl, 4-methylphenyl, 4-methoxyphenyl, 2
- chlorophenyl, 3-nitro aryl group such as phenyl or the may be an aralkyl group in the protection group of the hydroxyl groups of R ^1, preferably a phenyl group or a benzyl group.

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

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

In the compound (I), preferable compounds include: (1) a compound in which R ¹ is a hydrogen atom or a group of the formula —P (O) (OH) ₂ (2) R ⁷ is a compound of the formula —P (O) (OH) Compounds having _two groups (3) R ² , R ⁵ and R ⁶ may have a halogen atom, a hydroxyl group or an aliphatic acyloxy group having 12 to 16 carbon atoms, and an aliphatic acyl having 12 to 16 carbon atoms. Compound (4) wherein R ³ is a halogen atom, a hydroxyl group or an alkyl group having 10 to 16 carbon atoms which may have an aliphatic acyloxy group having 12 to 16 carbon atoms. (5) R ⁴ And compounds in which R ⁸ is a hydrogen atom Representative compounds of the present invention include, for example, the compounds described in Table 1, but the present invention is not limited to these compounds.

The lipid A3-position ether analog of the present invention can be produced by the method described below.

In the above formulas, R ² _a and R ⁵ _a is a group having the same meaning as the same said R ² and R ^5, R ² _a and R ⁵ _b are the same or different wherein R ²
And a group of the same meaning as R ^5.

R ³ and R ⁶ are as defined above.

R ¹ ′ and R ⁷ ′ represent the “hydroxyl protecting group” in the definition of R ¹ and R ⁷ .

R ² ′, R ⁴ ′, R ⁵ ′, R ⁶ ′ and R ⁸ ′ are, for example, such as the aliphatic acyl group; the alkoxycarbonyl group; the alkenyloxycarbonyl group; the aralkyloxycarbonyl group or the aralkyl group. "Amino or hydroxyl protecting group" is shown.

R ² _a "and _{^{R 5 a", R 5 b}} " and R ^6" are the same or the same or different, wherein R ^2, R ⁵ and "halogen atom, a protected hydroxy group or 10 carbon atoms in the definition of R ⁶ And an aliphatic acyl group having 10 to 20 carbon atoms which may have 1 to 20 aliphatic acyloxy groups.

R ³ ″ represents the “halogen atom, protected hydroxyl group or C 10 to C 20 alkyl group which may have a C 10 to C 20 aliphatic acyloxy group” in the definition of R ³ .

R ⁹ ′ represents the “hydroxyl protecting group” in the definition of R ⁹ .

R ¹⁰ and R ¹¹ are the same or different and include, for example, a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl ,
n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 3,3-dimethylbutyl, 2,2-
Dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, linear or branched alkyl groups having 1 to 6 carbon atoms such as 2,3-dimethylbutyl, or For example, aryl groups having 5 to 12 carbon atoms such as phenyl and naphthyl can be mentioned.

[Method A]

In the first step, glucosamine hydrochloride (II) is converted from trifluoroacetic acid and a condensing agent such as dicyclohexylcarbodiimide (DCC), trifluoroacetic anhydride and triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine (DMAP), N, N-dimethylaniline, 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), 1,4-diazabicyclo [2,2,2] Octane, 1,8-diazabicyclo [5,4,
0] Amide (III) by reacting an organic base such as undec-7-ene (DBU) or a trifluoroacetate such as ethyl trifluoroacetate with the above organic base.
This is the step of manufacturing.

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. Preferably, halogenated hydrocarbons such as methylene chloride and chloroform; ether, tetrahydrofuran, Ethers such as dioxane and dimethoxyethane; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and isoamyl alcohol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide And sulfoxides such as dimethyl sulfoxide.

The reaction is carried out at a temperature of from 0 ° C. to 100 ° C., preferably at room temperature, and the reaction time varies depending mainly on the reaction temperature, the type of the starting compound or the solvent used, but is usually 0.1.
1 hour to 24 hours.

In the second step, the amide compound (III) is converted to a compound of the general formula R
^In this step, a glycoside bond is formed with an alcohol having 1'OH (eg, methanol, ethanol, benzyl alcohol, allyl alcohol) to produce compound (IV).

As the solvent, a large excess of an alcohol having the general formula R ¹ 'OH, which is a reaction reagent, is used.

The acid used is not particularly limited as long as it is generally an acid, but preferably includes mineral acids such as hydrochloric acid and sulfuric acid and organic acids such as p-toluenesulfonic acid. Can also be used.

The reaction is carried out at a temperature of 0 ° C. to 200 ° C., preferably at a reflux temperature, and the reaction time varies depending mainly on the reaction temperature, the type of the starting compound and the type of the solvent used, but is usually 0.1 hour to 24 hours. Time.

In the third step, the alcohols at the 4- and 6-positions of the compound (IV) are protected with a diol such as isopropylidene, benzylidene or ethylidene in a solvent under an acid catalyst to give the compound (V). This is the manufacturing process.

As the reagent used for protecting the diol, usually,
There is no particular limitation as long as it is used for protecting the diol, but preferably, an aldehyde derivative such as benzaldehyde, a ketone derivative such as acetone, 2,2-dimethoxypropane, or a dimethoxy compound such as dimethoxybenzyl Can be mentioned.

The solvent is not particularly limited as long as it does not inhibit the reaction, but is preferably a halogenated hydrocarbon such as methylene chloride or chloroform, an ether such as dioxane or tetrahydrofuran, or a hydrocarbon such as hexane or pentane. Examples include hydrogens, aromatic hydrocarbons such as benzene and toluene, esters such as ethyl acetate, and polar solvents such as dimethylformamide and acetone.

The acid catalyst used is not particularly limited as long as it is usually used as an acid.Preferably, an organic acid such as paratoluenesulfonic acid, camphorsulfonic acid, or pyridinium paratoluenesulfonate or an inorganic acid such as hydrochloric acid is used. Can be mentioned.

The reaction temperature depends on the acid catalyst used, the starting compound, etc.
Although it varies, it is usually carried out at 0 to 100 ° C., and the reaction time is usually from 0.1 hour to 24 hours, varying mainly depending on the reaction temperature, the starting compound or the kind of the solvent used.

Fourth Step (1) In the step of alkylating compound (V), an alkylating agent R ³ ″ -X (where R ³ ″ has the same meaning as described above, wherein compound (V) is activated, X represents a halogen atom such as chlorine, bromine or iodine: an alkylcarbonyloxy group such as acetoxy or propionyloxy, chloroacetyloxy, dichloroacetyloxy,
Halogenated alkylcarbonyloxy groups such as trichloroacetyloxy and trifluoroacetyloxy, lower alkoxyalkylcarbonyloxy groups such as methoxyacetyloxy, and unsaturated alkylcarbonyloxy groups such as (E) -2-methyl-2-butenoyloxy An aliphatic acyloxy group such as a group; an arylcarbonyloxy group such as benzoyloxy, a halogenated arylcarbonyloxy group such as 2-bromobenzoyloxy or 4-chlorobenzoyloxy, 2,4,6-trimethylbenzoyloxy, -Lower alkylated arylcarbonyloxy groups such as toluoyloxy, lower alkoxylated arylcarbonyloxy groups such as 4-anisoyloxy, 4-nitrobenzoyloxy, 2-nitrobenzoyloxy Aromatic acyloxy groups such as arylcarbonyloxy groups; trihalogenomethyloxy groups such as trichloromethyloxy; lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; trifluoromethanesulfonyloxy and pentafluoroethanesulfonyl A leaving group such as a halogeno lower alkanesulfonyloxy group such as oxy; an arylsulfonyloxy group such as benzenesulfonyloxy and p-toluenesulfonyloxy; )
And in a solvent in the presence of a base.

The solvent is not particularly limited as long as it does not inhibit the reaction, but preferably, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, ether, dimethoxyethane, dioxane, and ether such as tetrahydrofuran , Hydrocarbons such as hexane, aromatic hydrocarbons such as benzene and toluene, esters such as ethyl acetate, and polar solvents such as dimethyl sulfoxide and dimethylformamide.

The base used is preferably sodium hydride, inorganic bases such as alkali metal hydrides such as potassium hydride, potassium carbonate, alkali metal carbonates such as sodium carbonate or triethylamine, pyridine, DB
Organic bases such as U, DBN, N, N-dimethylaniline, N, N-diethylaniline and 4- (N, N-dimethylamino) pyridine (DMAP) can be mentioned.

The reaction is carried out at a temperature of 0 ° C. to 150 ° C., preferably at room temperature, and the reaction time varies mainly depending on the reaction temperature, the type of the starting compound and the type of the solvent used.
Hours to one day.

(2) A step of treating the above ether compound with an acid according to a conventional method to obtain a diol compound in which an acetal or ketal bond has been cleaved. As the acid to be used, a hydrated dioxane or tetrahydrofuran solution containing acetic acid, hydrochloric acid or sulfuric acid is preferably used.

The reaction temperature is 0 ° C to 100 ° C, and the reaction time is usually 10 minutes to several hours.

(3) This is a step of acylating the primary hydroxyl group portion of the diol compound according to a conventional method. As the acylating agent to be used, an acyl halide such as acetic anhydride-pyridine or acetyl chloride or benzoyl chloride and a base such as triethylamine, sodium carbonate or potassium carbonate can be preferably used.

The reaction temperature is 0 ° C to 30 ° C, and the reaction time is usually several minutes to 1 hour.

(4) This is a step of producing a compound in which the remaining secondary hydroxyl group of the above diol monoacyl compound is protected by an R ⁴ ′ group. The reaction is carried out according to a conventional method in the same manner as in the alkylation in the step (1) or the acylation in the step (3). Preferably, benzylation is carried out by reacting benzyl 2,2,2-trichloroacetimidate in the presence of a catalytic amount of trifluoromethanesulfonic acid in addition to the reaction conditions in the above step (1). .

(5) This is a step of producing the compound (VI) by hydrolyzing the acyl protecting group of the primary hydroxyl group of the compound obtained above according to a conventional method. As the hydrolysis reagent used, ammonia water-methanol can be preferably mentioned.

In the fifth step, compound (VI) is converted to a halogeno sugar (Wherein R ⁵ ′, R ⁶ ′, R ⁷ ′ and R ⁸ ′ have the same meanings as described above) to produce disaccharide (VII).
The halogeno sugar used is preferably 1-bromo-
1,2-dideoxy-3,4,6-triacetyl-2-trifluoroacetamide-D-glucose can be mentioned.

The solvent is not particularly limited as long as it does not inhibit the reaction, but preferably, methylene chloride, halogenated hydrocarbons such as chloroform, ether, dimethoxyethane, tetrahydrofuran, ethers such as dioxane, benzene, Examples include aromatic hydrocarbons such as toluene.

The reaction temperature is from 0 ° C. to around the reflux temperature of the solvent used, and the reaction time varies depending mainly on the reaction temperature, the type of the starting compound or the solvent used, but is usually from 1 hour to 1 hour.
Days.

Sixth step (1) Protecting groups R ⁶ ′, R ⁷ ′ for the hydroxyl group of compound (VII) and
In this step, R ⁸ ′ is removed according to a conventional method to obtain a triol compound. As the protective group, an acyl group such as acetyl is preferable, and the removal reaction is carried out using aqueous ammonia / methanol as in the reaction of the fourth step (5).

(2) A step of acetalizing or ketalizing the above triol compound according to a conventional method.

 The reaction conditions are the same as in the third step.

(3) This is a step of producing the diamino compound (VIII) by removing the protecting groups R ² ′ and R ⁵ ′ of the amino group of the acetal or ketal compound according to a conventional method. As the protecting group to be removed, an acyl group such as trifluoroacetyl is preferable, and the hydrolysis is performed using 1N-sodium hydroxide or potassium hydroxide solution as a hydrolysis reagent, such as methanol or ethanol. The reaction is carried out in an alcohol or an ether such as tetrahydrofuran or dioxane at 0 ° C. to 60 ° C. for 30 minutes to 1 day.

Seventh Step (1) This is a step of producing a diamide compound by acylating the diamino compound (VIII).

As an acylation method, the compound (VIII) is converted to a compound represented by the general formula Carboxylic acids having (wherein, R ² _a "or R ⁵ _a" have the same meanings as defined above.) 2 equivalents, dicyclohexylcarbodiimide (DCC),
An acylating agent reacted or activated in the presence of 2 equivalents of a condensing agent such as carbonyldiimidazole (Wherein, R ² _a "and R ⁵ _a" represents the same meanings as defined above, X 'has the formula OR ² _a "(or OR ⁵ _a") group; fats; halogen atom in the definition of the above X A leaving group such as an aromatic acyloxy group; an aromatic acyloxy group; a lower alkanesulfonyloxy group; a halogeno lower alkanesulfonyloxy group; an arylsulfonyloxy group) in a solvent in the presence of a base.

The solvent is not particularly limited as long as it does not inhibit the reaction, but preferably, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, ethers, dioxane, ethers such as tetrahydrofuran, hexane Hydrocarbons such as benzene, aromatic hydrocarbons such as toluene, esters such as ethyl acetate,
Examples include polar solvents such as dimethyl sulfoxide and dimethylformamide.

As the base used, preferably, an organic base can be mentioned, for example, triethylamine, pyridine, DB
U, DBN, N, N-dimethylaniline, N, N-diethylaniline, 4- (N, N-dimethylamino) pyridine.

The reaction is carried out at a temperature of 0 ° C. to 100 ° C., preferably 20 ° C. to 50 ° C., and the reaction time mainly depends on the reaction temperature,
Although it varies depending on the type of the starting compound or the solvent used, it is usually 0.1 hour to 24 hours.

(2) The above diamide compound is esterified to form R ⁶ ″
This is a step of producing a compound (IX) into which a group has been introduced.

The reaction of this step is carried out in an agitation manner with the above-mentioned step (1). Preferably, DCC is carried out using a fatty acid R ⁶ ″ —OH (where R ⁶ ″ has the same meaning as described above). -4- (N, N-dimethylamino) pyridine is reacted as a condensing agent, or a salt chloride of a fatty acid is once prepared according to a conventional method, and ethers such as ether, tetrahydrofuran, dimethoxyethane and dioxane, or methylene chloride are prepared. , In solvents such as halogenated hydrocarbons such as chloroform,
The ester is obtained by reacting in the presence of an organic base (eg, triethylamine, DBN, DBU; pyridine, DMAP, DABCO, N, N-dimethylaniline, etc.) at 0 ° C. to 50 ° C. for 5 minutes to 1 day. be able to.

Eighth step (1) In this step, the acetal or ketal bond of compound (IX) is cleaved according to a conventional method to obtain a diol compound.

The reaction in this step is the same as the reaction in the fourth step (2).

(2) A step of protecting the primary hydroxyl group portion of the diol compound by acylation according to a conventional method. Preferably 4- (N, N-dimethylamino) pyridine (DMAP),
In the presence of an organic base such as pyridine or triethylamino, an acylating agent such as benzyl chloroformate is
The reaction is carried out by equivalent reaction. The reaction temperature is 0 ° C to 50 ° C, and the reaction time is 10 minutes to 1 day.

(3) A step of subjecting the hydroxyl group of the diol monoacyl compound to phosphoric esterification.

Phosphoric acid esterification is carried out by forming an anion with a base in a solvent and then reacting with a phosphorylating agent.

The solvent is not particularly limited as long as it does not inhibit the reaction, but preferably includes ethers such as ether, dioxane and tetrahydrofuran, and halogenated hydrocarbons such as chloroform and methylene chloride.

The base used is also not particularly limited as long as it normally forms an anion, but is preferably n-butyllithium, a lithium compound such as phenyllithium or DB.
Organic bases such as U, DBN, DMAP, triethylamine and pyridine can be mentioned.

As the phosphoric esterifying agent, a reagent usually used for phosphorylation such as dibenzyl chlorophosphate and diphenyl chlorophosphate is used.

The reaction is carried out at a temperature of -78 to 50 ° C, preferably,
−78 ° C. to room temperature, the reaction time depends mainly on the reaction temperature, the type of the starting compound or the solvent used,
Usually 10 minutes to 24 hours.

(4) A step of producing the compound (X) by removing the protecting group R ¹ ′ of the hydroxyl group at the 1-position of the above-mentioned phosphate compound according to a conventional method.

Preferably, the R ¹ ′ group is an allyl group, and the reaction is carried out in a solvent in the presence of a catalyst to remove the double bond by transferring the double bond to an enol ether type, and immediately adding pyridine-iodine-water. can do.

The solvent is not particularly limited as long as it does not inhibit the reaction, but preferably, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, ethers, dioxane, ethers such as tetrahydrofuran, hexane Hydrocarbons such as benzene, aromatic hydrocarbons such as toluene, esters such as ethyl acetate,
Examples include polar solvents such as dimethyl sulfoxide and dimethylformamide.

As the catalyst to be used, palladium chloride, a palladium catalyst such as palladium acetate, 1,5-cyclooctadiene-bis [methyldiphenylphosphine] rhodium hexafluorophosphate, a rhodium catalyst such as rhodium acetate, 1,5- Double bond transfer agents such as iridium catalysts such as cyclooctadiene-bis [methyldiphenylphosphine] iridium hexafluorophosphate can be mentioned.

The reaction use varies depending on the catalyst, solvent and the like used, but is usually carried out at 0 to 100 ° C. The reaction time varies depending on the reaction temperature in addition to the above, but is usually 1 to 5 hours.

Ninth Step (1) In the ninth step, the monophosphate compound (X) is further phosphorylated.

This reaction can be carried out in the same manner as in the reaction of the eighth step (3).

(2) This is a step of producing the target compound ( _Ia ) by removing the hydroxyl-protecting group of the diphosphate ester according to a conventional method.

Preferably, the protecting group is an aralkyl group such as benzyl and an aryl group such as phenyl, and the reaction is carried out by catalytic reduction at room temperature using a catalyst such as palladium carbon or platinum oxide. .

The solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in the reaction, but alcohols such as methanol, ethanol, and isopropanol; diethyl ether, tetrahydrofuran, ethers such as dioxane, and toluene. Benzene, aromatic hydrocarbons such as xylene, hexane, aliphatic hydrocarbons such as cyclohexane, esters such as ethyl acetate and propyl acetate, fatty acids such as acetic acid, or an organic solvent thereof and water. Are preferred.

The compound (X) was subjected to the reaction of removing a hydroxyl-protecting group in the ninth step (2) to obtain a compound represented by the general formula: A monophosphate type target compound having the following formula:

According to the above [Method A], a derivative in which the amide groups R ² _a NH and R ⁵ _a NH of the target compound of the present invention represent the same group can be produced.

[Method B]

Tenth step (1) In this step, the amino group-protecting group R ² ′ of the compound (VI) is removed in a conventional manner to produce an amino compound.

In the reaction of this step, an acyl group such as trifluoroacetyl is suitable as the protecting group, and the reaction conditions are the same as in the sixth step (3).

(2) A step of producing an amide compound (XI) by acylating an amino compound.

This reaction is used as an acylating agent. And under the same reaction conditions as in the seventh step (1).

Eleventh step (1) The above compound (XI) is converted to a halogeno sugar Reacted with disaccharide This is the step of manufacturing.

 The reaction conditions are the same as in the fifth step.

(2) The protecting groups R ⁶ ′, R ⁷ ′ and R for the hydroxyl groups of the above disaccharides
^In this step, ⁸ 'is removed according to a conventional method to obtain a triol compound.

In the reaction of this step, an acyl group such as acetyl is suitable as the protecting group, and the removal reaction is performed under the same reaction conditions as in the sixth step (1).

(3) This is a step of acetalizing or ketalizing the above triol compound according to a conventional method.

The reaction conditions are the same as in the third step and the sixth step (2).

(4) This is a step of producing an amino compound (XII) by removing the protecting group R ⁵ ′ of the amino group of the acetal or ketal compound according to a conventional method.

 The reaction conditions are the same as in the sixth step (3).

Twelfth step (1) The above amino compound (XII) is acylated
This is a step of producing an amide compound into which an R ⁵ _b ″ group has been introduced.

The reaction is carried out with 1 equivalent of the acylating agent. Or And under the same reaction conditions as in the seventh step (1).

(2) a step of esterifying the above amide compound to produce a compound (XIII) into which an R ⁶ ″ group has been introduced.

The reaction of this step is carried out under the same reaction conditions as in the above-mentioned seventh step (2), but preferably, the fatty acid R ⁶ ″ -OH is used to prepare a DC.
The reaction is carried out by reacting C-4- (N, N-dimethylamino) pyridine as a condensing agent or by reacting an acid chloride of a fatty acid in the presence of an organic base.

Thirteenth Step (1) In this step, the acetal or ketanol bond of the compound (XIII) is cleaved according to a conventional method to obtain a diol compound.

The reaction in this step is the same as the reaction in the fourth step (2) and the eighth step (1).

(2) A step of protecting the primary hydroxyl group portion of the diol compound by acylation according to a conventional method.

The reaction in this step is the same as the reaction in the eighth step (2).

(3) This is a step of subjecting the hydroxyl group of the monoacylated diol compound to phosphoric esterification.

The reaction in this step is the same as the reaction in the eighth step (3).

(4) This is a step of producing the compound (XIV) by removing the protecting group R ¹ ′ of the hydroxyl group at the 1-position of the above-mentioned phosphate ester compound according to a conventional method.

Preferably, R ¹ 'is an allyl group, and the reaction conditions are the same as in the eighth step (4).

Fourteenth step (1) In this step, the monophosphate compound (XIV) is further phosphorylated at the 1-position.

This reaction can be carried out in the same manner as the reaction in the eighth step (3) and the ninth step (1).

(2) This is a step of producing the target compound (I _b ) by removing the hydroxyl-protecting group of the diphosphate ester according to a conventional method.

Preferably, the protecting group is an aralkyl group such as benzyl and an aryl group such as phenyl, and the reaction conditions are the same as in the ninth step (2).

The compound (XIV) was subjected to the reaction of removing a hydroxyl-protecting group in the ninth step (2) to obtain a compound represented by the general formula: A monophosphate type target compound having the following formula:

According to the above-mentioned [Method B], a derivative in which the amide groups R ² _a NH and R ⁵ _b NH of the target compound of the present invention represent different groups can be produced.

〔effect〕

The novel lipid A3-position ether analog of the present invention has an excellent macrophage activating effect and has low toxicity, and thus is useful as an immunostimulating agent or an antitumor agent.

The administration form of the compound (I) of the present invention includes, for example,
Examples include oral administration using tablets, capsules, granules, powders, syrups, and the like, and parenteral administration using injections, suppositories, and the like. These formulations contain excipients,
It is manufactured by a known method using additives such as a binder, a disintegrant, a lubricant, a stabilizer, and a flavoring agent. The dosage varies depending on symptoms, age and the like, but it can be usually administered to an adult at a dose of 0.01 to 50 mg / kg body weight once or several times a day.

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

[Method A]

Example I (a) N-trifluoroacetylglucosamine 160 g (0.742 mol) of D-(+)-glucosamine hydrochloride was dissolved in 2200 ml of methanol (99.6%), and triethylamine was dissolved.
Add 187.9 g (1.86 mol). Further, 115.9 g of ethyl trifluoroacetate was added dropwise under ice cooling, and the mixture was stirred at room temperature overnight. Concentrate under reduced pressure, benzene 250ml × 2, ethyl acetate 250
ml were sequentially added, concentrated under reduced pressure, and dried sufficiently with a vacuum pump. The crude trifluoroacetyl compound obtained here was advanced to the next step without purification.

Example I (b) Allyl 2-deoxy-2-trifluoroacetylamide-D-glucopyranoside 1850 ml of a 2% acetic acid-allyl alcohol solution was added to the crude trifluoroacetyl compound obtained in Example I (a). Plus 30
Heated to reflux for minutes. The mixture was cooled to about 50 ° C. with ice water and filtered through celite. The liquid was concentrated and dried sufficiently with a vacuum pump.

The crude allyl ether obtained here proceeded to the next step without purification.

Example I (c) Allyl 2-deoxy-2-trifluoroacetamide-4,6-O-isopropylidene-D-glucopyranoside The crude allyl ether obtained in the above I (b) was converted into N,
Dissolve in 740 ml of N-dimethylformamide, add 370 ml of 2,2-dimethoxypropane, and further add pyridinium p.
-7.5 g of toluenesulfonate was added and the mixture was stirred at room temperature overnight. It concentrated under reduced pressure and diluted with ethyl acetate. The precipitate was excessively removed, and the liquid was washed with aqueous sodium hydrogen carbonate, water and brine. The extract was dried over anhydrous magnesium sulfate and concentrated by passing through celite and activated carbon. The residue was applied to a silica gel column, and the cyclohexane: ethyl acetate = 3: 2 was obtained by separating and purifying 80.5 g and 77.3 g of α- and β-ether bonds at the 1-position, respectively. Both α-form and β-form can be used for the subsequent reaction.

(Α-allyl form)

MS spectrum m / z: 356 (M ⁺⁺ 1), 340,298,282,256,24
0,222,211,193,168,126,109,101. (Β-allyl form) MS spectrum m / z: 356 (M ⁺⁺ 1), 340,298,280,256,24
0,222,211,193,168,155,145,126,114,101. Example I (d) Allyl 2-deoxy-2-trifluoroacetamido-3-O-[(3'RS) -3'-benzyloxydecanyl] -4,6-O-isopropylidene-α- D-Glucopyranoside Allyl 2-deoxy-2- obtained in the above I (c)
Trifluoroacetamide-4,6-O-isopropylidene-α-D-glucopyranoside 41.3 g, (3RS) -3-
43.7 g of benzyloxy-1-mesyloxydecane was dissolved in 250 ml of dry dimethylformamide, and 5 ml of the solution was added under ice-cooling.
Slowly add 17.7 g of 5% sodium hydride and add
Stirred for hours. The reaction solution was diluted with ethyl acetate 1 and neutralized by adding 24 g of acetic acid at 15 to 20 ° C. Next, the extract was washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 70 g of the title compound. The obtained compound was used crude in the deprotection step.

Example I (e) Allyl 2-deoxy-2-trifluoroacetamido-3-O- [3'RS) -3'-benzyloxydecanyl] -α-D-glucopyranoside. 70 g of the 4,6-O-isopropylidene glycopyranoside compound obtained in the above I (d) was dissolved in 700 ml of 80% acetic acid and stirred at 50 ° C. for 0.5 hour.

The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate 1.5, washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate.

The mixture was concentrated under reduced pressure, and the residue was concentrated in a 5-fold amount of silica gel (Merck:
Purification by silica gel 60 (230 to 400 mesh)) flash chromatography (cyclohexane: ethyl acetate = 5: 5) gave 40.5 g of the title compound. mp.101 ~ 103 ℃ IR spectrum (Neat): 3300, 1690, 1550, 1460, 1180 NMR spectrum (60 MHz: CDCl ₃ ) δ _ppm : 0.7 to 2.4 (16H,
m), 3.2-4.4 (10H, m), 4.45 (2H, s), 4.7-6.2 (5H,
m), 6.48 (1H, d, I = 10 Hz), 7.32 (5H, s). MS spectrum m / z: 562 (M ⁺ ), 504,455,414,397,348,316,
258. Example I (f) Allyl 2-deoxy-2-trifluoroacetamido-3-O-[(3'RS) -3'-benzyloxydecanyl] -6-acetyl-α-D-glucopyrano side. 40 g of the allylglucopyranoside compound obtained in the above I (e) and 16 ml of pyridine were added to dry tetrahydrofuran (fres).
hly distilled fmom LiAlH ₄ ) was dissolved in 240 ml, and a solution of 8.7 g of acetic anhydride in 40 ml of dry tetrahydrofuran was gradually added thereto under ice-cooling. After stirring for 10 minutes under ice cooling, the mixture was further stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to remove the solvent, pyridine and acetic anhydride, and flash chromatography was performed on a 45-fold amount of silica gel (cyclohexane: ethyl acetate = 8:
Purification in 2) gave 30.6 g of the title compound. In addition, 8.4 g of a diacetyl compound was obtained as a by-product.

IR spectrum (Nujal): 3450, 3280, 1770, 1560, 1450 NMR spectrum (60 MHz: CDCl ₃ ) δ _ppm : 0.4 to 2.0 (17H,
m), 2.08 (3H, s), 3.2-4.6 (12H, m), 4.7-6.2 (5H,
. m), 6.44 (1H, d, J = 10Hz), 7.30 (5H, s) MS spectrum ^{m / z: 604 (M +} ) 446,300,358,282,222 as Elemental analysis _{C 30 H 44 NO 8 F 3} , Calculated; C , 59.69; H, 7.35; N, 2.32; F, 9.44 Found: C = 59.37; H, 7.40; N, 2.32; F, 9.56 Example I (g) Allyl 2-deoxy-2-trifluoroacetamide-3 -O- [3'RS) -3'-benzyloxydecanyl] -4-benzyl-6-acetyl-α-D-glucopyranoside. 30.1 g of the 6-acetylglycopyranoside compound obtained in the above I (f) is dried in methylene chloride (alumino B Spar 1 column, molecular sieve 4A dried) 400 m
and 0.75 g of trifluoromethanesulfonic acid was added. To this, a solution of 25.2 g of benzyltrichloroacetimidate in 100 ml of dry methylene chloride was gradually added under ice-cooling in a nitrogen stream, and the mixture was stirred overnight at room temperature.

The reaction solution was concentrated under reduced pressure, the residue was diluted with 600 ml of ethyl acetate, washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (18: 1 volume, silica gel: ethyl acetate = 9: 1) to obtain 11.6 g of the title compound.

IR spectrum (Neat): 3300,1730,1550,1450,1370 NMR spectrum (60 MHz: CDCl ₃ ) δ _ppm : 0.6 to 2.0 (17H,
m), 2.05 (3H, s), 3.1-4.7 (14H, m), 4.7-6.2 (5H,
m), 6.40 (1H, d, J = 8z), 6.9 to 7.4 (10H, m) MS spectrum m / z; 692 (M ⁺ ) 639,602,544,529,496,454,4
38 Elemental analysis value C ₃₇ H ₅₀ NO ₈ F ₃ Calculated value: C, 64.05; H, 7.26; N, 2.02; F, 8.21 Observed value: C, 63.91; H. 7.45; N, 1.98; F, 8.28 Example I (h) Allyl 2-deoxy-2-trifluoroacetamido-3-O-[(3'RS) -3'-benzyloxydecanyl] -4-benzyl-α-D-glucopyranoside. 11.1 g of the 6-acetylglucopyranoside compound obtained in I (g) was dissolved in 470 ml of methanol, 52 ml of aqueous ammonia was added thereto, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was diluted with 500 ml of ethyl acetate and washed with a saturated sodium chloride solution. Concentrate under reduced pressure to a residue of 70
Purification by twice the same amount of silica gel flash chromatography (cyclohexane: ethyl acetate = 75: 25) gave 5.62 g of the title compound.

IR spectrum (CHCl ₃ ): 3600, 3420, 1730, 1530, 1495, 1450 NMR spectrum (60 MHz: CDCl ₃ ) δ _ppm : 0.6 to 2.0 (17H,
m), 3.2-4.6 (13H, m), 4.45 (2H, s), 4.6-6.2 (5H,
m), 6.44 (1H, d, J = 10Hz), 7.32 (10H, s) MS spectrum m / z: 652 (M ⁺ ), 594,560,502,454,396,348,
268. Elemental analysis: C ₃₅ H ₄₈ NO ₇ F ₃ Calculated: C, 64.50; H, 7.42; N, 2.15; F, 8.74 Found: C, 64.79; H, 7.29; N, 2.27; F, 8.54 Example I (f) 2-trifluoroacetamido-2-deoxy-1,3,4,
6-tetraacetyl-β-D-glucopyranose. 22.5 g of tetraacetylglucosamine was dissolved in 150 ml of pyridine, and 30 ml of trifluoroacetic anhydride was gradually added thereto under ice cooling. After stirring for 10 minutes on ice and at room temperature for 10 minutes, trifluoroacetic anhydride and pyridine were distilled off under reduced pressure. next,
Dilute the residue with 500 ml of ethyl acetate and add 10% hydrochloric acid, water,
Washed with saturated sodium bicarbonate, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the powder of the concentrated residue was dissolved in 100 ml of ethanol, and 100 ml of hexane was added thereto.
Was added and reprecipitated to obtain 22 g of the title compound.

NMR spectrum (60 MHz, CDCl ₃ ) δ _ppm : 2.05 (6H, s), 2.0
7 (3H, s), 2.10 (3H, s), 3.70 ~ 4.70 (4H, m), 5.12 (1
H, t, J = 8.5Hz), 5.43 (H, t, J = 8.5Hz), 5.80 (1H, d, J =
8.5Hz), 7.52 (1H, d, J = 10Hz). Example I (j) 1-bromo-2-trifluoroacetyl-2-deoxy-3,4,6-triacetyl-D-glucopyranose. 15 g of the tetraacetylglucopyranose compound obtained in the above I (i) was dissolved in 20 ml of acetic acid, and the mixture was cooled to 16 ° C under water cooling.
A 30% solution of hydrobromic acid in acetic acid (20 ml) was slowly added. Thereafter, the mixture was stirred at room temperature for 0.5 hour. The reaction solution was diluted with 200 ml of ethyl acetate, and the solution was poured into an ice-cooled solution of a saturated sodium hydrogen carbonate solution (NaHCO ₃ 84 g, H ₂ O 840 ml). The ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate, and the ethyl acetate layers were combined, washed with water and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Vacuum concentration residue
Purification by flash chromatography on 50 times the amount of silica gel (cyclohexane: ethyl acetate = 6: 4) gave 10.8 g of the title compound. White powder.

This compound is unstable when left at room temperature, but can be stored by cooling.

NMR spectrum (60 MHz: CDCl ₃ ) δ _ppm : 2.04 (3H, s), 2.0
6 (3H, s), 2.10 (3H, s), 4.00 to 4.60 (4H, m), 5.00 to 5.
60 (2H, m), 6.53 (1H, d, J = 4Hz), 6.84 (1H, d, J = 8H
z). Example I (k) Allyl 2-deoxy-2-trifluoroacetamido-3-O-[(3'RS) -3'-benzyloxydecanyl] -4-benzyl-6-[(2-deoxy-2 -Trifluoroacetamide-3,4,6-O-triacetyl)-
β-D-glucopyranosyl] -α-D-glucopyranoside. 2.71 g of the benzyloxydecanylglucopyranoside compound obtained in the above I (h) was dissolved in 80 ml of dry nitromethane, and 1.42 g of anhydrous calcium sulfate was added thereto and stirred. Next, 1-bromo-3, obtained in I (j) was added thereto.
4,6-triacetyl-D-glucopyranose compound 1.93
g and mercury cyanide (2.1 g) were added and stirred at room temperature for 1 hour.
Further, 3.86 g of the 1-bromo compound was added, and the mixture was stirred overnight at 27 to 29 ° C. The reaction solution was concentrated, and the residue was diluted with 250 ml of ethyl acetate, washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate.

After concentration under reduced pressure, the residue was flash-chromatographed 50 times with silica gel (cyclohexane: ethyl acetate = 7: 3).
Then, 4.43 g of the title compound was obtained.

NMR spectrum (60 MHz, CDCl ₃ ) δ _ppm ; 0.7 to 2.2 (17H,
m), 2.03 (9H, s), 3.1-6.2 (26H, m), 6.3-6.9 (2H,
m), 7.29 (10H, s ) Elemental analysis _{C 49 H 64 N 2 O 15} F 6 Calculated: C, 56.86; H.6.23; N.2.71 ; F.11.01 Found: C; 56.55; H, 6.21: N.2.75; F.10.87 Example I (l) Allyl 2-deoxy-2-trifluoroacetamido-3-O-[(3'RS) -3'-benzyloxydecanyl] -4-benzyl- 6- [2-deoxy-2-trifluoroacetamido-β-D-glucopyranosyl] -α
-D-glucopyranoside.

4.43 g of the triacetylglucosamine disaccharide compound obtained in the above I (k) was dissolved in 200 ml of methanol,
To this was added 20 ml of aqueous ammonia, and the mixture was stirred at room temperature for 4 hours. The methanol and aqueous ammonia in the reaction mixture were concentrated and dried under reduced pressure, and the residue was purified by flash chromatography on silica gel (30 times volume) (ethyl acetate) to obtain 2.21 g of the title compound. Glassy solid.

Example I (m) allyl 2-deoxy-2-trifluoroacetamido-3-O-[(3'RS) -3'-benzyloxydecanyl] -4-benzyl-6-[(2-deoxy-2 -Trifluoroacetamide-4,6-O-isopropylidene)
-Β-D-glucopyranosyl] -α-D-glucopyranoside. 2.25 g of the triol glucosamine disaccharide compound obtained in the above I (l) was dried in 15 ml of dimethylformamide.
Then, 25 ml of 2,2-dimethoxypropane and 0.5 g of pyridinium p-toluenesulfonate were added thereto, followed by stirring at room temperature for 4 hours. After distilling off 2,2-dimethoxypropane and dimethylformamide from the reaction solution under reduced pressure,
The residue was diluted with 250 ml of ethyl acetate, washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The concentrated residue was purified by 30-fold silica gel flash chromatography (cyclohexane: ethyl acetate = 6: 4) to obtain 2.2 g of the title compound.

Example I (n) allyl 2-deoxy-2-amino-3-O-[(3 '
RS) -3'-Benzyloxydecanyl] -4-benzyl-6-[(2-deoxy-2-amino-4,6-O-isopropylidene) -β-D-glucopyranosyl] -α-D
-Glucopyranoside. 2.6 g of the 2-trifluoroacetamidoglucosamine disaccharide compound obtained in the above I (m) was added to ethanol
The resultant was dissolved in 220 ml, and IN-sodium hydroxide (55 ml) was added thereto, followed by stirring at room temperature overnight. The reaction solution was concentrated, diluted with 400 ml of ethyl acetate, washed with water and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure to dryness, 2.0 g of the title compound was obtained. Viscous oil.

IR spectrum (CHCl ₃ ): 1730,1450,1380,1260 NMR spectrum (60 MHz, CDCl ₃ ) δ _ppm ; 0.7-1.7 (17H,
m), 1.42 (3H, s), 1.49 (3H, s), 1.89 (4H, s), 2.5-4.
6 (22H, m), 4.6~6.2 (5H, m), 7.33 (10H, s) MS spectrum ^{m / z: 756 (M +} ), 761,741,705,655 Elemental analysis C ₄₂ H ₆₄ N ₂ O ₁₀ Calculated: C, 66.64; H, 8.52; N, 3.70 Found: C, 66.40; H, 8.25; N, 3.47 Example I (o) Allyl 2-deoxy-2-[(3'R) -3'-benzyloxy Myristoylamide] -3-O-[(3'R
S) -3'-Benzyloxydecanyl] -4-benzyl-6-{[2-deoxy-2-((3'R) -3'-benzyloxymyristoylamide) -4,6-O-isopropylidene ] -Β-D-glucopyranosyl｝ -α-D-
Urcopyranoside. 3.29 g of the 2-aminoglucosamine disaccharide compound obtained in the above I (n) and 2.24 g of N, N'-dicyclohexylcarbodiimide were dissolved in 70 ml of dry methylene chloride, and (R) -3-benzyloxytetradecanoic was added thereto. A solution of 3.64 g of acid in 10 ml of dry methylene chloride was gradually added at room temperature, and the mixture was further stirred at room temperature for 1.5 times. The precipitate was removed from the reaction solution by filtration, and then methylene chloride was distilled off from the solution. The concentrated residue was purified by flash chromatography on a 200-fold amount of silica gel (cyclohexane: ethyl acetate = 6: 4) to obtain 3.84 g of the title compound.

IR spectrum (CHCl ₃ ): 3450, 3350, 1660, 1510 Elemental analysis value Calculated as C ₈₄ H ₁₂₈ N ₂ O ₁₄ Calculated: C, 72.59; H, 9.28; N, 2.02 Observed: C, 72.28; H, 9.12; N , 2.15 Example I (p) Allyl 2-deoxy-2-[(3'R) -3'-benzyloxymyristoylamide] -3-O-[(3'R
S) -3'-Benzyloxydecanyl] -4-benzyl-6- {2-deoxy-2-((3'R) -3'-benzyloxymyristoylamide) -3-O- (3'R)
-3'-benzyloxymyristoyl-4,6-O-isopropylidene] -β-D-glucopyranosyl ノ -α-D
-Glucopyranoside. 3.84 g of the 2-benzyloxymyristoylamide disaccharide compound obtained in the above I (o), 0.85 g of N, N'-dicyclohexylcarbodiimide and 0.034 g of 4- (N, N-dimethylamino) pyridine are added to 60 ml of dry methylene chloride. The mixture was dissolved, and a solution of 1.38 g of (R) -3-benzyloxytetradecanoic acid in 15 ml of dry methylene chloride was gradually added thereto at room temperature, followed by stirring at room temperature for 1.5 hours. The precipitate was removed from the reaction solution, the solution was concentrated to dryness, and the residue was purified by flash chromatography on 200 times the volume of silica gel (cyclohexane: ethyl acetate = 75: 25) to give the title compound in 3.7 times.
2 g were obtained.

IR spectrum (CHCl ₃ ): 3450, 3350, 1730, 1665, 1510 Elemental analysis: C ₁₀₅ H ₁₆₀ N ₂ O ₁₆ Calculated: C, 73.91; H, 9.45; N, 1.64 Actual: C, 74.19; H, 9.54 N, 1.80 Example I (q) Allyl 2-deoxy-2-[(3'R) -3'-benzyloxymyristoylamide] -3-O-[(3'R
S) -3'-Benzyloxydecanyl] -4-benzyl-6-{[2-deoxy-2-((3'R) -3'-benzyloxymyristoylamide) -3-O- (3 '
R) -3'-Benzyloxymyristoyl] -β-D-
Glucopyranosyl｝ -α-D-glucopyranoside. Dissolve 3.72 g of the benzyloxymyristoyl disaccharide compound obtained in the above I (p) in 300 ml of 90% acetic acid,
This was heated and stirred at 75 ° C. for 1 hour. Acetic acid was distilled off from the reaction solution, and the crystalline residue was dissolved in ethyl acetate and poured into 400 ml of a 10% sodium hydrogen carbonate solution. The ethyl acetate phase was separated, the aqueous phase was extracted with ethyl acetate, and the ethyl acetate phase was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate.

The concentrated and dried product was purified by flash chromatography on a 180-fold amount of silica gel (cyclohexane: ethyl acetate = 5: 5) to obtain 3.39 g of the title compound.

IR spectrum (CHCl ₃ ): 3450, 3350, 1730, 1670, 1510, 1450, 1070. Elemental analysis: C ₁₀₂ H ₁₅₆ N ₂ O ₁₆ Calculated: C, 73.52; H, 9.44; N, 1.68 Found: C, 73.58; H, 9.28; N, 1.97 Example I (r) Allyl 2-deoxy-2-[(3'R) -3'-benzyloxymyristoylamide] -3-O-[(3'R
S) -3'-Benzyloxydecanyl] -4-benzyl-6-{[2-deoxy-2-((3'R) -3'-benzyloxymyristoylamide) -3-O- (3 '
R) -3'-Benzyloxymyristoyl-6-benzyloxycarbonyl] -β-D-glucopyranosyl｝-
α-D-glucopyranoside. 3.6 g of the diol glucosamine disaccharide compound obtained in the above I (q) and 0.4 g of 4-N, N-dimethylaminopyridine are dissolved in 60 ml of dry methylene chloride, and a solution of 0.55 g of carbobenzoxycyclolide in 10 ml of dry methylene chloride is added thereto. Was gradually added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solvent was concentrated under reduced pressure, the residue was dissolved in 500 ml of ethyl acetate, washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. 28 concentrated residue
Purification was performed by flash chromatography on silica gel (cyclohexane: ethyl acetate = 7: 3) in a 0-fold amount to obtain 2.5 g of the title compound.

IR spectrum (CHCl ₃ ): 3500, 3400, 1740, 1670, 1520, 1460, 1270, 1070 Elemental analysis: C ₁₁₀ H ₁₆₂ N ₂ O ₁₈ Calculated: C, 73.38; H, 9.07; N, 1.56 Actual: C , 72.80; H, 9.07; N, 1.74 Example I (s) Allyl 2-deoxy-2-[(3'R) -3'-benzyloxymyristoylamide] -3-O-[(3'R
S) -3'-Benzyloxydecanyl] -4-benzyl-6-{[2-deoxy-2-((3'R) -3'-benzyloxymyristoylamide) -3-O- (3 '
R) -3'-Benzyloxymyristoyl] -4-diphenylphosphonyl-6-benzyloxycarbonyl]-
β-D-glucopyranosyl｝ -α-D-glucopyranoside. Dissolve 1.0 g of benzyloxycarbonylglucosamine disaccharide obtained in the above I (r) and 0.41 g of 4- (N, N-dimethylamino) pyridine in 18 ml of dry methylene chloride, and add 0.45 g of diphenylchlorophosphate to dry chloride. A 5 ml solution of methylene was slowly added at room temperature and stirred for another hour.

After concentration under reduced pressure, the residue was diluted with 200 ml of ethyl acetate, washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate.

The residue was evaporated to dryness under reduced pressure, and the residue was flash-chromatographed on 50 volumes of silica gel (cycloxane: ethyl acetate = 7.3)
And 1.0 g of the title compound was obtained.

IR spectrum (CHCl ₃ ): 3450,3350,1730,1665,1595,1490,1455,1270,
960 Elemental analysis: C ₁₂₂ H ₁₇₁ N ₂ O ₂₁ P Calculated: C, 72.09; H, 8.48; N, 1, 38; P, 1.52 Found: C, 72.30; H, 8.36; N, 1.63; P , 1.49 Example I (t) 2-Deoxy-2-[(3'R) -3'-benzyloxymyristoylamide] -3-O-[(3'RS) -3 '
-Benzyloxydecanyl] -4-benzyl-6-
{[2-deoxy-2-((3'R) -3'-benzyloxymyristoylamide) -3-O- (3'R)-
3'-benzyloxymyristoyl-4-diphenylphosphoryl-6-benzyloxycarbonyl] -β-D-
Glucopyranosyl｝ -α-D-glucopyranose. 1.7 g of the 1-allyl glucosamine disaccharide compound obtained in the above I (s) was dried in 80 ml of tetrahydrofuran.
Dissolved in bis (methyldiphenylphosphine)
0.05 g of cyclo-octadiene iridium (I) hexafluorophosphate was added. The air in the reaction vessel was sucked with an aspirator and replaced with nitrogen. Next, after sucking this nitrogen, it was replaced with hydrogen and stirred for several minutes to activate the iridium complex.

Then, the mixture is replaced with nitrogen and stirred for 3 hours in the same manner.
After the reaction, 10 ml of water, 0.4 g of iodine and 0.26 g of pyridine were added, and after stirring at room temperature for 15 minutes, the solvent was concentrated under reduced pressure. The residue was diluted with 200 ml of ethyl acetate, and 5% sodium sulfite solution, saturated sodium hydrogen carbonate solution, and the like. The extract was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate.

After concentration under reduced pressure, the residue was flash-chromatographed on a 400-fold silica gel (cyclohexane: ethyl acetate = 7:
Purification in 3) gave 1.5 g of the title compound.

IR spectrum (CHCl ₃ ): 3350,1740,1670,1595,1495,1270,960 Elemental analysis: C ₁₁₉ H ₁₆₇ N ₂ O ₂₁ P Calculated: C, 71.73; H, 8.45; N, 1.41; P, 1.55 value: C, 71.25; H, 8.25 ; N, 1.56; P, 1.43 mass spectrum m / z: FAB-MS QM + 2013 (M 1990 + Na +), 1160 cf: C 119 H 167 N 2 O 21 P = 1990 Example I (u) 2-deoxy-2-[(3'R) -3'-hydroxytetradecanoylamide] -3-O-[(3'RS) -3 '
-Hydroxydecanyl] -6-O-Ｏ [2-deoxy-
2-((3'R) -3'-hydroxytetradecanoylamide) -4-O-((3'R) -3'-hydroxytetradecanoyl)]-β-D-glucopyranosyl-4-
Phosphate｝ -α-D glucopyranosyl-1-phosphate 500 mg of the compound obtained in the above step I (t) is dissolved in 15 ml of dry tetrahydrofuran, and 0.2 ml of n-butyllithium (1.6 M Hexane solution) slowly, and 2 minutes later 97 mg of benzyl phosphorochloridate
Of tetrahydrofuran was added dropwise. Five minutes later, at the same temperature, 1 g of 10% palladium carbon was added for catalytic reduction. After 15 minutes, the temperature was returned from -78 ° C to room temperature, and the reduction was further performed for 3 hours. The reaction solution was passed, and 200 mg of platinum oxide was added to the solution, followed by catalytic reduction at room temperature for 2 hours. Thereafter, the reaction solution was filtered, tetrahydrofuran was distilled off under reduced pressure, the residue was subjected to silica gel chromatography, and purified with chloroform: methanol: water: triethylamine = 50: 20: 3: 0.2 to obtain 100 mg of the desired compound ( 30%).

MS spectrum m / z: NEG FAB / MS; 1333 [MH] ^- [Method B] Example II (a) Allyl 2-deoxy-2-trifluoroacetamide-3-O-[(3'R)- 3'-Benzyloxytetradecanyl] -4,6-O-isopropylidene-α-D-glucopyranoside Allyl 2-deoxy-2-trifluoroacetamide-4 obtained in Example I (c) above. 18.7 g of, 6-O-isopropylidene-α-D-glucopyranoside was dried.
Dissolve in 150 ml of N, N-dimethylformamide and add 21 g of (3
R) -3-Benzyloxy-1-mesyloxytetradecane was added, and sodium hydride (55 g or more, oiliness was slowly added thereto under ice-cooling. After 5 minutes, the mixture was returned to room temperature and stirred for 3 hours. After a period of time, the mixture was diluted with ethyl acetate, unreacted sodium hydride was decomposed with acetic acid, washed with aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate, and filtered under reduced pressure. The compound obtained here was used for the next reaction without purification.

Example II (b) Allyl 2-deoxy-2-trifluoroacetamido-3-O-((3'R) -3'-benzyloxytetradecanyl) -α-D-glucopyranoside Said II (a) The compound obtained in the above was suspended in an 80% aqueous acetic acid solution and stirred at 50 ° C. for 1 hour. After 1 hour, the aqueous acetic acid solution was distilled off under reduced pressure, diluted with ethyl acetate, and washed with aqueous sodium hydrogen carbonate and brine. After drying over magnesium sulfate, the mixture was passed through and ethyl acetate was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and purified with cyclohexane: ethyl acetate = 1: 1 to obtain 16.3 g of the desired compound.

NMR spectrum (270 MHz, CDCl ₃ ) δ _ppm : 0.86 to 0.91 (3H,
m), 1.26 to 1.97 (23H, m), 3.45 to 3.77 (9H, m), 3.99 (1
H, dd, J = 6.6,12.8 (Hz), 4.11 ~ 4.22 (2H, m), 4.44 (1
H, d, J. = 11.5Hz), 4.51 (1H, d, J = 11.5Hz), 4.85 (1H,
d, J = 3.7Hz), 5.23-5.32 (2H, m), 5.79-5.94 (1H,
m), 6.44 (1H, d, J = 9.5 Hz), 7.26 to 7.38 (5H, m) IR spectrum (KBr): 3320,1701,1556 MS spectrum m / z: 618 [M ⁺ 1], 560,511,470,442,404,364,351,316,258,22
2,192,180 Elemental analysis C ₃₂ H ₅₀ F ₃ NO ₇ Calculated: C, 62.22; H, 8.16 ; N, 2.27; F, 9.23 Found; C, 62.11; H, 8.11 ; N, 2.27; F, 9.29 carried Example II (c) Allyl 2-deoxy-2-trifluoroacetamido-3-O-[(3'R) -3'-benzyloxytetradecanyl] -6-O-acetyl-α-D-glucopyrano Side 16.3 g of the compound obtained in II (b) was dissolved in 100 ml of dry tetrahydrofuran, and 6 ml of pyridine was added. Further, under ice-cooling, 2.7 g of acetic anhydride was added dropwise, and the temperature was returned to room temperature. The mixture was stirred overnight at room temperature. afterwards,
Acetic anhydride, pyridine and tetrahydrofuran were distilled off under reduced pressure. The residue was purified by chromatography on silica gel with cyclohexane: ethyl acetate 3: 1 to give 13.7 g of the desired compound (7.
8.7%).

NMR spectrum (270 MHz, CDCl ₃ ) δ _ppm : 0.88 (3H, t, J =
6.6Hz), 1.25 ~ 1.81 (22H, m) .2.12 (3H, s), 3.41 ~ 3.5
5 (4H, m), 3.68 to 3.83 (3H, m), 3.97 to 4.04 (1H, m), 4.
12 ~ 4.25 (3H, m), 4.41 (1H, d, d, J = 4.4,12.1Hz) 4.44
(1H, d, J = 11.4Hz), 4.51 (1H, d, J = 11.4Hz), 4.86 (1
H, d, J = 3.7Hz), 5.24-5.32 (2H, m), 5.80-5.94 (1H,
m), 6.41 (1H, d, J = 9.5 Hz), 7.25 to 7.37 (5H, m) IR spectrum (KBr): 1739,1707,1556 MS spectrum m / z: 660 [M ⁺⁺ 1], 602,553,512,484,446,380,359,300,282,
222 Elemental analysis value As C ₃₄ H ₅₂ F ₃ NO ₈ Calculated value: C, 61.90; H, 7.94; N, 2.12; F, 8.64 Actual value: C, 62.34; H, 8.05; N, 2.15; F, 8.80 Example II (d) Allyl 2-deoxy-2-trifluoroacetamido-3-O-[(3'R) -3'-benzyloxytetradecanyl] -4-O-benzyl-6-O-acetyl-α
-D-glucopyranoside 12.45 g of the compound obtained in the above II (c) was dried with N, N-
Dissolved in 250 ml of dimethylformamide, added 6.25 g of benzyl bromide, further added sodium hydride at −25 ° C., stirred at −20 to −10 ° C. for 1 hour, and confirmed by thin layer chromatography. Room temperature stirring 30
Minutes.

After confirming that the raw materials had disappeared, the reaction product was slowly transferred into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried and dried over magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure.
Used for the next reaction without purification.

Example II (e) Allyl 2-deoxy-2-trifluoroacetamido-3-O-[(3'R) -3'-benzyloxytetradecanyl] -4-O-benzyl-α-D-glucopyr Nocide 12.9 g of the compound obtained in II (d) was dissolved in 450 ml of methyl alcohol, and 50 ml of aqueous ammonia was added at room temperature. The mixture was stirred at room temperature overnight. Thereafter, methyl alcohol and aqueous ammonia were distilled off under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel chromatography and purified with cyclohexane: ethyl acetate = 3: 1 to obtain 6.6 g of the desired compound.

NMR spectrum (270 MHz, CDCl ₃ ) δ _ppm : 0.88 (3H, t, J =
6.6Hz), 1.23 ~ 1.86 (23H, m), 3.42 ~ 3.46 (1H, m), 3.5
8 to 3.90 (6H, m), 3.92 to 4.01 (2H, m), 4.13 to 4.19 (2H,
m), 4.41 (1H, d, J = 11.7Hz), 4.47 (1H, d, J = 11.7Hz),
4.64 (1H, d, J = 11.0Hz), 4.83 (1H, d, J = 11.0Hz), 4.86
(1H, d, J = 4.0Hz), 5.22-5.30 (2H, m), 5.78-5.92 (1
H, m), 6.44 (1H, d, J = 9.5Hz), 7.27 ~ 7.34 (10H, m) IR spectrum . (KBr): 3290,1699,1545 MS spectrum ^{m / z: 707 (M +} ), 650,616,543,510,452,405,348,268,222,181 Calculated elemental analysis _{C 39 H 56 F 3 NO 7} : C, 66.17; H, 7.97; N, 1.98; F, 8.05 Found: C, 66.46; H, 8.02; N, 2.27; F, 8.04 Example II (f) Allyl 2-deoxy-2-amino-3-O-[(3 '
R) -3'-Benzyloxytetradecanyl] -4-O
-Benzyl-α-D-glucopyranoside 6.5 g of the compound obtained in II (e) above is suspended in 100 ml of ethyl alcohol, and 50 ml of 1N aqueous sodium hydroxide is further added. Stirred for hours. The reaction solution was concentrated, diluted with ethyl acetate, and washed with water and brine.
The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to silica gel chromatography, and purified with cyclohexane: ethyl acetate = 1: 1 to obtain the target compound in 5.1.
Obtained in a yield of 3 g (91.3%).

NMR spectrum (270 MHz, CDCl ₃ ) δ _ppm : 0.88 (3H, t, J =
6.6Hz), 1.25 ~ 1.56 (23H, m), 1.81 ~ 1.88 (2H, m), 2.6
9 (1H, dd, J = 3.7,9.5Hz), 3.39 ~ 3.44 (2H, m), 3.53 ~
3.57 (1H, m), 3.67 ~ 3.81 (4H, m), 3.94 ~ 4.03 (2H,
m), 4.11-4.18 (1H, m), 4.45 (1H, d, J = 11.7Hz), 4.57
(1H, d, J = 11.7Hz), 4.63 (1H, d, J = 11.0Hz), 4.81 (1
H, d, J = 11.0Hz), 4.85 (1H, d, J = 3.7Hz), 5.16-5.31
(2H, m), 5.85-5.91 (1H, m), 7.26-7.33 (10H, m) MS spectrum m / z: 612 [M ⁺⁺ 1], 554,520,462,399,351,293,234,216,186,
162. Elemental analysis C ₃₇ H ₅₇ NO ₆ Calculated: C, 72.63; H, 9.39 ; N, 2.29 Found: C, 72.50; H, 9.49 ; N, 2.19 Example II (g) Allyl 2-deoxy -2-[(3'R) -3'-benzyloxymyristoylamide] 3-O-[(3'R)
-3 ″ -benzyloxytetradecanyl] -4-O-benzyl-α-D-glucopyranoside 4.5 g of the compound obtained in II (f) was dissolved in dry dichloromethane, and 2.7 g of R- 3-Benzyloxymyristic acid was added, and 1.8 g of N, N'-dicyclohexylcarbodiimide was further added, and the mixture was stirred at room temperature for 1 hour, followed by excessive removal of dust and dichloromethane under reduced pressure. The residue was dissolved in ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. : Purified with ethyl acetate = 2: 1 to yield 6.44 g of the target compound
(94%).

NMR spectrum (270 MHz, CDCl ₃ ) δ _ppm : 0.85 to 0.90 (6H,
m), 1.08 to 1.90 (42H, m), 2.26 to 2.43 (2H, m), 3.41 to
3.87 (11H, m), 4.01 (1H, dd, J = 5.5,12.8Hz), 4.16 ~
4.20 (1H, m), 4.29 (1H, d, J = 11.7Hz), 4.45 (1H, d, J =
11.7Hz), 4.48 (1H, d, J = 11.4Hz), 4.54 (1H, d, J = 11.4
Hz), 4.61 (1H, d, J = 11.0Hz), 4.76 (1H, d, J = 3.7Hz),
4.83 (1H, d, J = 11.0Hz), 5.09 ~ 5.21 (2H, m), 5.68 ~ 5.
81 (1H, m), 6.42 (1H, d, J = 9.2Hz), 7.23 ~ 7.33 (15H,
m) IR spectrum (KBr): 3320, 1640, 1548, 1129, 1086 Elemental analysis: C ₅₈ H ₈₉ NO ₈ Calculated: C, 75.04; H, 9.66; N, 1.51 Found: C, 74.70; H, 9.65; N, 1.75 Example II (h) Allyl 2-deoxy-2-[(3'R) -3'-benzyloxymyristoylamide] -3-O-[(3 '
R) -3'-Benzyloxytetradecanyl] -4-O
-Benzyl-6-O-[(2-deoxy-2-trifluoroacetamido-3,4,6-O-triacetyl) -β-
D-glucopyranosyl] -α-D-glucopyranoside 5.9 g of the compound obtained in II (g) and 1-bromo-3,4,6-triacetyl-D- obtained in I (j) Dissolve 8.85 g of a glucopyranose compound in 250 ml of dry chloroform, 2.6 g of calcium sulfate (anhydrous), and 4.28 g of mercuric cyanide.
82 g was added and the mixture was heated under reflux for 5 hours. After reflux,
Chloroform was distilled off under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography and purified with cyclohexane: ethyl acetate = 3: 2 to obtain 6.14 g (73.7%) of the desired compound.

NMR spectrum (270 MHz, CDCl ₃ ) δ _ppm : 0.88 (6H, t, J =
6.2 ~ 6.9Hz), 1.17 ~ 1.86 (42H, m), 2.02 (3H, s), 2.03
(3H, s), 2.04 (3H, s), 2.27 to 2.43 (2H, m), 3.28 to 3.8
3 (10H, m), 3.96 ~ 4.30 (6H, m), 4.38 (1H, d, J = 11.7H
z), 4.43 (1H, d, J = 11.7Hz), 4.44 to 4.56 (3H, m), 4.63
~ 4.82 (3H, m), 5.06 ~ 5.29 (4H, m), 5.68 ~ 5.86 (1H,
m), 6.46 (1H, d, J = 9.5Hz), 6.70 (1H, d, J = 8.8Hz), 7.
23〜7.32 （15H, m） IR spectrum (KBR): 1752, 1714, 1643, 1376, 1254, 1225. Elemental analysis: calculated as C ₇₂ H ₁₀₅ F ₃ N ₂ O _16. Calculated: C, 65.93; H, 8.07; N, 2.14; F, 4.35. : C, 65.40; H, 8.02; N, 2.26; F, 4.47 Example II (i) Allyl 2-deoxy-2-[(3'R) -benzyloxymyristoylamide] -3-O-[(3 ' R)-
3'-benzyloxytetradecanyl] -4-O-benzyl-6-O-[(2-deoxy-2-trifluoroacetamido) -β-D-glucopyranosyl] -α-D-
Glucopyranoside. 6.1 g of the compound obtained in the above II (h) was suspended in 270 ml of methyl alcohol, 30 ml of aqueous ammonia was added, and the mixture was stirred at room temperature for 3 hours. Since the suspension did not react, 100 ml of tetrahydrofuran was added and dissolved. The mixture was stirred overnight at room temperature. Thereafter, methyl alcohol, ammonia, and tetrahydrofuran were distilled off under reduced pressure, the residue was subjected to silica gel chromatography, and purified with ethyl acetate to obtain 4.33 g of the target compound (78.
5%).

NMR spectrum (270 MHz, DMSO-d ₆ ) δ _ppm : 0.84 (6H, t, J
= 6.4 ~ 6.8Hz), 1.12 ~ 1.75 (42H, m), 2.20 (1H, dd, J
= 5.7,14.9Hz), 2.47 ~ 2.55 (1H, m), 3.14 ~ 4.06 (19H,
m), 4.32 to 4.64 (8H, m), 5.07 to 5.30 (4H, m), 5.73 to 5.
85 (1H, m), 7.22 ~ 7.34 (15H, m), 8.05 (1H, d, J = 8.8H
z), 9.27 (1H, d, J = 8.8 (Hz) IR spectrum (KBr): 1710,1643,1543,1214 Example II (j) Allyl 2-deoxy-2-[(3'R) -3'-benzyloxymyristoylamide] -3-O-[(3 '
R) -3'-Benzyloxytetradecanyl] -4-O
-Benzyl-6-O-[(2-deoxy-2-trifluoroacetamido-4,6-O-isopropylidene) -β
-D-glucopyranosyl] -α-D-glucopyranoside 4.33 g of the compound obtained in the above II (i) is dissolved in dry N, N-dimethylformamide, and 50 ml of 2,2-dimethoxypropane, 1 g of pyridinium- p-Toluenesulfonate was sequentially added, and the mixture was stirred at room temperature overnight. Thereafter, the reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and the precipitate was excessively removed.
The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate, water and brine, and dried over magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and purified with cyclohexane: ethyl acetate = 1: 1 to obtain the desired compound in a yield of 2.64 g (59.0%).

NMR spectrum (270 MHz, CDCl ₃ ) δ _ppm : 0.88 (6H, t, J =
6.6Hz), 1.19 ~ 1.85 (48H, m), 2.25 ~ 2.43 (2H, m), 3.0
0 (1H, b, -OH), 3.28 to 4.23 (18H, m), 4.35 to 4.55 (5H,
m), 4.72 ~ 4.83 (3H, m), 5.07 ~ 5.21 (2H, m), 5.69 ~ 5.
83 (1H, m), 6.43 (1H, d, J = 9.2Hz), 6.76 (1H, d, J = 7.0
Hz), 7.23-7.34 (15H, m) IR spectrum (KBr): 1706,1644,1212,1183 Elemental analysis: C ₆₉ H ₁₀₃ F ₃ N ₂ O ₁₃ Calculated: C, 67.62; H, 8.47; N, 2.29; F, 4.65 Found: C, 67.21; H, 8.46; N, 2.34; F, 4.50 Example II (k) Allyl 2-deoxy-2-[(3'R) -3'-benzyloxymyristoylamide] -3-O-[(3 '
R) -3'-Benzyloxytetradecanyl] -4-O
-Benzyl-6-O-[(2-deoxy-2-amino-
4,6-O-isopropylidene) -β-D-glucopyranosyl] -α-D-glucopyranoside 2.25 g of the compound obtained in II (j) is dissolved in 150 ml of ethyl alcohol, and 10 ml of 1N water is added. An aqueous sodium oxide solution was added, and the mixture was stirred at room temperature for 3 hours. Thereafter, ethyl alcohol was distilled off under reduced pressure, diluted with ethyl acetate,
Washed with water and saline. The ethyl acetate layer was dried over magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and purified with ethyl acetate to obtain 1.34 g (63.7%) of the target compound.

NMR spectrum (270 MHz, CDCl ₃ ) δ _ppm : 0.88 (6H, t, J =
6.3 ~ 6.9Hz), 1.18 ~ 1.38 (40H, m), 1.43 (3H, s), 1.49
(3H, s), 1.50-2.15 (5H, m), 2.25-2.45 (2H, m), 2.7
9 (1H, d, d, J = 8.1, 9.2Hz), 3.19 to 3.28 (1H, m), 3.39 to
3.95 (13H, m), 4.00 to 4.11 (2H, m), 4.17 to 4.28 (2H,
m), 4.39 (1H, d, J = 11.7Hz), 4.45 (1H, d, J = 11.7Hz),
4.47 (1H, d, J = 11.4Hz), 4.53 (1H, d, J = 11.4Hz), 4.59
(1H, d, J = 11.0Hz), 4.76 (1H, d, J = 3.7Hz), 4.85 (1H,
d, J = 11.0Hz), 5.07 ~ 5.21 (2H, m), 5.68 ~ 5.83 (1H,
m), 6.39 (1H, d, J = 9.5Hz), 7.22-7.32 (15H, m) IR spectrum (KBr): 1642,1542,1379. Example II (l) Allyl 2-deoxy-2-[(3'R) -3'-benzyloxymyristoylamide] -3-O-[(3 "
R) -3 "-benzyloxytetradecanyl] -4-O
-Benzyl-6-O-{[(2-deoxy-2- (3 '
R) -3'-Dodecanoyloxymyristoylamide)
-4,6-O-isopropylidene] -β-D-glucopyranosyl｝ -α-D-glucopyranoside 1.3 g of the compound obtained in II (k) was dissolved in 50 ml of dry dichloromethane, and R-3 0.51 g of -dodecanoyloxymyristate was added, and 0.28 g of N, N'-dicyclohexylcarbodiimide was further added, followed by stirring at room temperature for 1 hour. Thereafter, dicyclomethane was distilled off under reduced pressure, the residue was diluted with ethyl acetate, and washed with aqueous sodium hydrogen carbonate, water, and brine. The ethyl acetate layer was dried over magnesium sulfate, filtered, and ethyl acetate was distilled off under reduced pressure. The residue was purified with cyclohexane: ethyl acetate = 1: 1 to obtain the desired compound (1.29 g, 73.7%).

NMR spectrum (270 MHz, CDCl ₃ ) δ _ppm : 0.88 (12H, t, J =
6.2 ~ 6.6Hz), 1.02 ~ 2.02 [86H, m, ｛1.44 (3H, s), 1.50
(Including 3H, s).] 2.20 to 2.43 (6H, m), 3.27 to 4.28 (19H, m), 4.39 (1H, d,
J = 11.7Hz), 4.44 (1H, d, J = 11.7Hz), 4.45-4.56 (3H,
m), 4.75-4.84 (3H, m), 5.02-5.21 (3H, m), 5.67-5.
82 (1H, m), 6.02 (1H, d, J = 6.2Hz), 6.41 (1H, d, J = 9.2
Hz), 7.23-7.31 (15H, m) IR spectrum (KBr): 1730,1644,1547,1467,1379. Example II (m) Allyl 2-deoxy-2-[(3'R) -3'-benzyloxymyristoylamide] -3-O-[(3 ′
R) -3'-Benzyloxytetradecanyl] -4-O
-Benzyl-6-O-{[2-deoxy-2-((3 '
R) -3'-Dodecanoyloxymyristoylamide)
-3-O-((3'R) -3'-myristoyloxymyristoyl) -4,6-O-isopropylidene]-[beta] -D
-Glucopyranosyl｝ -α-D-glucopyranoside 1.2 g of the compound obtained in the above II (l) was dissolved in 50 ml of dry dichloromethane, and 386 mg of R-3-myristoyloxymyristate, 4- (N, N-dimethyl) Amino) pyridine 10
4 mg was added, and 207 mg of N, N'-dicyclohexylcarbodiimide was further added, followed by stirring at room temperature for 2 hours. Thereafter, dichloromethane was distilled off under reduced pressure and diluted with ethyl acetate.
The precipitate was excessively removed, and the ethyl acetate layer was washed with aqueous sodium hydrogen carbonate, water and brine, and dried over magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and purified with cyclohexane: ethyl acetate = 3: 1 to obtain 1.34 g (87.9%) of the target compound.

NMR spectrum (270 MHz, CDCl ₃ ) δ _ppm : 0.88 (18H, t, J =
6.2 ~ 6.9Hz), 1.13 ~ 1.79 (128H, m), 2.17 ~ 2.42 (8H,
m), 2.47-2.67 (2H, m), 3.29-4.08 (17H, m), 4.13-
4.27 (1H, m), 4.36 to 4.55 (5H, m), 4.68 to 4.85 (3H,
m), 5.07 ~ 5.23 (4H, m), 5.69 ~ 5.85 (1H, m), 6.04 (1
H, d, J = 6.2Hz), 6.39 (1H, d, J = 9.2Hz), 7.22 ~ 7.33 (1
5H, m) IR spectrum (KBr): 1739,1645,1550,1467,1377.

Elemental analysis: C ₁₂₁ H ₂₀₄ N ₂ O ₁₈ Calculated: C, 73.59; H, 10.41; N, 1.42 Found: C, 73.35; H, 10.84; N, 1.37 Example II (n) Allyl 2-deoxy -2-[(3'R) -3'-benzyloxymyristoylamide] 3-O-[(3'R)
-3'-benzyloxytetradecanyl] -4-O-benzyl-6-O-{[2-deoxy-2-((3'R)
-3'-dodecanoyloxymyristoylamide) -3
-O-((3′R) -3′-myristoyloxymyristoyl)]-β-D-glucopyranosyl｝ -α-D-glucopyranoside 1.27 g of the compound obtained in the above II (m) was converted into II (b ) To give the desired compound in a yield of 660 mg (53%).

NMR spectrum (270 MHz, CDCl ₃ ) δ _ppm : 0.88 (18H, t, J =
6.6 ~ 6.9Hz), 1.11 ~ 1.83 (122H, m), 2.17 ~ 2.42 (8H,
m), 2.47 ~ 2.57 (2H, m), 3.34 ~ 4.08 (19H, m), 4.15 ~
4.27 (1H, m), 4.36 ~ 4.57 (5H, m), 4.67 ~ 4.80 (3H,
m), 4.94 to 5.23 (4H, m), 5.69 to 5.83 (1H, m), 5.91 (1
H, d, J = 8.4Hz), 6.41 (1H, d, J = 9.6Hz), 7.21 ~ 7.33 (1
5H, m) IR spectrum (KBr): 1735,1710,1657,1640,1545,1455,1076.

Elemental analysis: C ₁₁₈ H ₂₀₀ N ₂ O ₁₈ Calculated: C, 73.25; H, 10.42; N, 1.45 Found: C, 72.84; H, 10.34; N, 1.68 Example II (o) Allyl 2-deoxy- 2-[(3'R) -3'-benzyloxymyristoylamide] -3-O-[(3 '
R) -3'-Benzyloxytetradecanyl] -4-O
-Benzyl-6-O-{[2-] deoxy-2-
((3′R) -3′-dodecanoyloxymyristoylamide) -3-O-((3′R) -3′-myristoyloxymyristoyl) -6-O-benzyloxymethyl-β-D-glucopyranosyl -Α-D-glucopyrazoside 646 mg of the compound obtained in the above II (n) is dissolved in 10 ml of dry dichloromethane, and benzyloxymethyl chloride is dissolved.
57.5 mg and tetramethylurea 43 mg were added, and the mixture was heated under reflux for 2 days. Thereafter, dichloromethane was distilled off under reduced pressure, diluted with ethyl acetate, and washed with aqueous sodium hydrogen carbonate and brine. The ethyl acetate layer was dried over magnesium sulfate,
The ethyl acetate was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and purified with cyclohexane: ethyl acetate = 2: 1 to obtain the desired compound in a yield of 513 mg (74.8%).

NMR spectrum (270 MHz, CDCl ₂ ) δ _ppm : 0.88 (18H, t, J =
6.6Hz), 1.13 to 1.85 (112H, m), 2.16 to 2.43 (8H, m), 2.
46-2.63 (2H, m), 3.28 (1H, d, J = 3.3Hz, OH), 3.32-4.
23 (18H, m), 4.36 ~ 4,89 (12H, m), 4.94 ~ 5.22 (4H,
m), 5.64-5.82 (1H, m), 5.88 (1H, d, J = 8.4HZ), 6.37
(1H, d, J = 9.2Hz), 7.21 ~ 7.31 (20H, m) IR spectrum (KBr): 1730, 1720, 1650, 1635 Elemental analysis: C ₁₂₆ H ₂₀₈ N ₂ O ₁₉ Calculated: C, 73.64; H, 10.20; N, 1.36 Found: C, 73.24; H, 10.07; N, 1.33 Example II (p) Allyl 2-deoxy-2-[(3'R) -3'-benzyloxymyristoylamide] -3-O- [3'R)
-3'-benzyloxytetradecanyl] -4-O-benzyl-6-O-{[2-deoxy-2-((3'R)
-3'-dodecanoyloxymyristoylamide) -3
-O-((3'R) -3'-myristoyloxymyristoyl) -4-O-diphenylphosphoryl-6-O-benzyloxymethyl]-[beta] -D-glucopyranosyl}-
α-D-Glucopyranoside 490 mg of the compound obtained in the above II (o) is dissolved in 20 ml of dry dichloromethane, 160 mg of diphenylchlorophosphate is added, and 35 mg of 4- (N, N-dimethylamino) pyridine is further added. Was added and stirred at room temperature for 6 hours. Thereafter, dichloromethane was distilled off under reduced pressure. The residue was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residue was subjected to silica gel chromatography,
Purification was performed with cyclohexane: ethyl acetate = 3: 1 to quantitatively obtain 544 mg of the desired compound.

NMR spectrum (270 MHz, CDCl ₃ ) δ _ppm : 0.88 (18H, t, J =
5.5 ~ 7.3Hz), 1.08 ~ 1.85 (122H, m), 2,14 ~ 2.50 (10H,
m), 3.35-4.25 (18H, m), 4.36-4.80 (11H, m), 5.06-
5.25 (4H, m), 5.62 to 5.80 (2H, m), 6.28 to 6.38 (2H,
m), 7.12-7.35 (30H, m) IR spectrum (KBr) 1735,1725,1660,1642.

Example II (q) 2-deoxy-2 [(3'R) -3'-benzyloxymyristoylamide] -3-O-[(3'R) -3'-
Benzyloxytetradecanyl] -4-O-benzyl-
6-O-{[2-deoxy-2-((3'R) -3'-
Dodecanoyloxymyristoylamide) -3-O-
((3′R) -3′-myristoyloxymyristoyl) -4-O-diphenylphosphoryl-6-O-benzyloxymethyl] -β-D-glucopyranosyl｝ -α-
D-Glucopyranose 500 mg of the compound obtained in the above II (p) was dissolved in 10 ml of dry terahydrofuran, and 10 mg of 1,5-cyclooctadiene-bis- [methyldiphenylphosphine] iridium hexafluorophosphate was added.

The inside of the reaction vessel was replaced with nitrogen and further replaced with hydrogen. After confirming that the color of the solution had changed from red to colorless, it was immediately replaced with nitrogen and stirred at room temperature for 3 hours. Then water
5 ml, 200 mg of iodine and 0.5 mg of pyridine were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, diluted with ethyl acetate,
The mixture was washed with aqueous sodium thiosulfate solution, aqueous sodium hydrogen carbonate solution and brine. Dry over magnesium sulfate and pass. Ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography and purified with cyclohexane: ethyl acetate = 3: 1 to obtain 355 mg (72.3%) of the target compound in a yield.

NMR spectrum (270 MHz, CDCl ₃ ) δ _ppm : 0.88 (18H, t, J =
6.2 ~ 9.2Hz), 1.13 ~ 1.86 (122H, m), 2.18 ~ 2.46 (10H,
m), 3.13 ~ 4.28 (14H, m), 4.36 ~ 4.81 (13H, m), 5.00 ~
5.21 ~ (2H, m), 5.49 ~ 5.57 (2H, m), 6.35 ~ 6.51 (2H, m
m), 7.12-7.35 (3H, m) IR spectrum (KBr): 1740,1705,1660,1643,1590,1555 Example II (r) Dibenzyl 2-deoxy-2-[(3'R) -3'-
Benzyloxytetradecanoylamide] -3-O-
[(3′R) -3′-benzyloxytetradecanyl]
-4-O-benzyl-6-O-{[2-deoxy-2-
((3'R) -3'-dodecanoyloxytetradecanoylamide] -3-O-((3'R) -3'-tetradecanoyloxytetradecanoyl) -4-O-diphenylphosphoryl-6 -O-benzyloxymethyl] -β-
D-glucopyranosyl｝ -α-D-glucopyranosyl-
1-phosphate Dissolve 325 mg of the compound obtained in II (q) in 15 ml of dry tetrahydrofuran, and slowly add n-butyllithium (0.12 ml of a 16M-hexane solution) at −78 ° C. in a nitrogen stream for 2 minutes. After that, benzyl phosphorochloridate 55.8m
g) It was added dropwise. Five minutes later, the disappearance of the raw materials was confirmed in a thin layer, and a mixture of 0.1 ml of acetic acid and 1 ml of tetrahydrofuran was added at -70 ° C, and the mixture was returned to room temperature. 50 ml of ethyl acetate was added, and the mixture was washed with aqueous sodium hydrogen carbonate and brine. After drying over magnesium sulfate, the mixture was filtered and ethyl acetate was distilled off under reduced pressure.

The residue was subjected to silica gel chromatography, and cyclohexane:
Purification was performed with ethyl acetate = 2: 1 to obtain 146 mg (40.3 mg) of the target compound.
%).

NMR spectrum (270 MHz, CDCl ₃ ) δ _ppm : 0.88 (18H, t, J =
5.9 ~ 6.9Hz), 1.09 ~ 1.86 (122H, m), 2.12 ~ 2.45, (10
H, m), 3.11 ~ 4.21 (13H, m), 4.37 ~ 4.81 (13H, m), 4.93
~ 5.21 (6H, m), 5,40 ~ 5.69 (2H, m), 6.39 (1H, d, J = 7.
3 Hz), 6.48 (1 H, d, J = 9.9 Hz), 7.12 to 7.65 (40 H, m) IR spectrum (Film): 1733, 1675, 1590 Elemental analysis: C ₁₄₉ H ₂₂₆ N ₂ O ₂₅ P ₂ Calculated: C, 71.37; H, 9.09; N, 1.12; P, 2.47 Found: C, 71.14; H, 8.93; N, 1.03; P, 2.18 Example II (s) 2-deoxy-2-[(3'R) -3 '-(hydroxy) tetradecanoylamide] -3-O-[(3'R)
-3 '-(hydroxy) tetradecanyl] -6-O-
{[2-deoxy-2- (3'R) -3'-dodecanoyloxytheoladecanoylamide] -3-O-((3 '
R) -3′-Tetradecanoyloxytetradecanoyl) -4-O-phosphoryl-β-D-glucopyranosyl｝ -α-D-glucopyranosyl-1-phosphate 125 mg of the compound obtained in II (r) above 15m
l, dissolved in a mixed solvent of 10 ml of tetrahydrofuran, 10%
Palladium-carbon was added and catalytically reduced at room temperature for 3 hours. Then, 50 mg of platinum oxide was added to the solution, and the mixture was catalytically reduced again at room temperature for 2 hours.

After that, the solvent was distilled off under reduced pressure to obtain 55 mg of the desired compound. The compound obtained is very unstable in the absence of solvent and decomposes in the refrigerator for tens of hours.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Tetsuo Hiraoka 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Jo Akamatsu 1-26-21, Shimizu, Suginami-ku, Tokyo (72) Inventor Masahiro Nishijima 1-4-29-A-101, Miyamae-ku, Miyazaki-ku, Kawasaki-shi, Kanagawa Prefecture (56) References JP-A-54-122226 (JP, A) Eur. J. Biochem. , Vol. 136 (1983) p. 195-200 (58) Fields investigated (Int. Cl. ⁶ , DB name) C07H 1/00-23/00 WPI (DIALOG) CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) General formula Wherein ^one of R ¹ and R ⁷ is a hydrogen atom,
An (O) (OR ⁹ ) group (wherein R ⁹ represents a hydrogen atom or a hydroxyl-protecting group) or a hydroxyl-protecting group, and the other is a group of the formula —P (O) (OR ⁹ ) In the formula, R ⁹ has the same meaning as described above.) R ² , R ⁵ and R ⁶ are the same or different and are each a halogen atom, a hydroxyl group, a protected hydroxyl group or an aliphatic acyloxy group having 10 to 20 carbon atoms which may have an aliphatic acyloxy group having 10 to 20 carbon atoms. Shows an acyl group. R ³ represents a halogen atom, a hydroxyl group, a protected hydroxyl group or an alkyl group having 10 to 20 carbon atoms which may have an aliphatic acyloxy group having 10 to 20 carbon atoms. R ⁴ and R ⁸ are the same or different and each represent a hydrogen atom or a hydroxyl-protecting group. ] The compound represented by these, and its salt.