JP2812981B2 - Intermediate of disaccharide derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention provides the following 1) (Wherein, Y ₁ represents an optionally substituted benzyl group or an alkyl group, Y ₂ represents a protecting group for an amino group, Y ₃ represents a protecting group for a phosphono group, Y ₄ represents a protecting group for a hydroxyl group, ₁ is -COA ₁ , -COZA
₂ , A ₁ is an alkyl group having 1 to 30 carbon atoms which may be substituted with one or more hydroxyl groups protected by a hydroxyl protecting group,
Z represents an alkylene group having 1 to 9 carbon atoms, A ₂ represents a cyclic alkyl group having 3 to 12 carbon atoms which may be substituted with one or more hydroxyl groups protected by a hydroxyl-protecting group, and Q ₁ represents Hydrogen or an alkyl group having 1 to 20 carbon atoms, Q ₂ is hydrogen, an alkyl group having 1 to 6 carbon atoms, -CONH ₂ , -COOY ₅ or -CH ₂ OY ₆ , and Y ₅ is a protecting group for a carboxyl group. , Y ₆ is a hydroxyl-protecting group, and n1 is 0
An integer of 10, the compound represented by n2 and n3 represents an integer of 1 to 20, respectively) (where, Y ₁ is a methyl group, Y ₂ is an acetyl group, Y ₃ is a phenyl group, Y ₄ is acetyl group 2) reacting a compound of formula (I) with a trialkylsilyl halide or hydrogen halide and a Lewis acid, (Wherein, Y ₂ , R ₁ , Y ₃ and Y ₄ are the same as above, and X ₁ represents a halogen atom.) 3) Formula (Ia) (Wherein Ya represents a benzyl group which may be substituted, and Y ₂ , R ₁ , Y ₃ and Y ₄ are the same as above) with a hard acid in the presence of a soft nucleophile Formula (III) characterized in that (Wherein Y ₂ , Y ₃ , Y ₄ and R ₁ are the same as described above) 4) Formula (IV) (Wherein X ₂ represents a halogen atom, Y ₇ represents an amino-protecting group, and Y ₈ , Y ₉ and Y ₁₀ each represent a hydroxyl-protecting group). Formula (V) in the presence of a halogenide (Wherein, Z ₁ and Z ₂ each represent an alkylene group having 1 to 6 carbon atoms, and Y ₁₁ represents a protecting group for a carboxyl group). Wherein Y ₇ , Y ₈ , Y ₉ , Y ₁₀ , Y ₁₁ , Z ₁ and Z ₂ are the same as defined above, and 5) Formula (VII) (Wherein, Y ₁₂ represents an optionally substituted benzyl group or an alkyl group, and Y ₇ , Y ₈ , Y ₉ and Y ₁₀ are the same as described above). The present invention relates to a method for producing a compound of the formula (VI), which comprises reacting a compound of the formula (V) in the presence of hydrogen and a Lewis acid.

Compounds of formula (I) according to the present invention, as well as compounds of formula (I
The process for producing the compounds of the formulas (I), (III) and (VI) is useful in the following formula (VIII) which is useful as an antitumor agent. (Where R is Or Wherein Z ₃ represents an alkylene group having 1 to 6 carbon atoms, Z ₁ and
Z ₂ is the same as described above, and R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are each -COA ₁₁ , -COZA ₂₁ , A ₁₁ represents an alkyl group having 1 to 30 carbon atoms which may be substituted with one or more hydroxyl groups, and A ₂₁ represents a cyclic alkyl group having 3 to 12 carbon atoms which may be substituted with one or more hydroxyl groups. To Q
Is hydrogen, an alkyl group having 1 to 6 carbon atoms, -CONH _2, refers to -COOH or _{-CH 2 OH, Z, Q 1} , n 1, n 2 and n ₃ are as defined above. ) Are useful as a production intermediate of the compound represented by the formula (1) and a production method of the production intermediate.

<Prior art> Lipid A derivatives are expected to be used as preventive and therapeutic agents for various infectious diseases and as antitumor agents.
-48497, 61-53295, 61-227586, 63-183594, etc., have been synthesized. However, these compounds have excellent antitumor activity and have a natural lipid A
However, it was hard to say that the toxicity was improved as compared with that of Example 1, and the practicality was insufficient. Therefore, compounds having useful physiological activity and improved toxicity have been desired.

<Constitution of the Invention> The present invention relates to a compound of the formula (I) and a compound of the formula (II)
The invention relates to a process for the preparation of the compounds of the formulas I) and (VI)

The substituents of the compound according to the present invention will be described in detail below.

Examples of the benzyl group having a substituent include P-alkoxybenzyl such as P-methoxybenzyl, P-halogenobenzyl such as P-chlorobenzyl, and P-alkylbenzyl such as P-methylbenzyl.

Examples of the amino-protecting group include a lower acyl group, a trichloroethoxycarbonyl group and a trichlorotertiary-butoxycarbonyl group.

As the protecting group for the phosphono group, those which can be eliminated by catalytic reduction are preferable, and examples thereof include a phenyl group and a benzyl group which may have a substituent such as a halogen atom, a nitro group and a lower alkoxy group. it can. Examples of the hydroxyl-protecting group include trichloroethoxycarbonyl, trichlorotert-butoxycarbonyl, lower acyl, and benzyl which may have a substituent.
Protecting group of the hydroxyl group in the substituents A _1, A ₂ in the compound of the present invention, trichloroethoxycarbonyl, trichloroacetyl tert-butoxycarbonyl group is preferred for Y ₆ and Y _4, the Y _8, Y _9, Y ₁₀ is Lower acyl, such as acetyl, is preferred.

Examples of the carboxyl-protecting group include those which can be eliminated by catalytic reduction such as a benzyl group which may have a substituent such as a halogen atom, a nitro group and a lower alkoxy group, and a lower alkyl group. An alkylene group is
Methylene, polymethylene or methylene or polymethylene substituted with an alkyl group having 1 to 6 carbon atoms, examples of which include methylene, ethylene, propylene, trimethylene, ethylethylene, tetramethylene, 2-methyltetramethylene, 2, 3-dimethyltetramethylene, 2-
Ethyl-3-methylpentamethylene, octamethylene and the like can be mentioned. Examples of the alkyl group include methyl,
Ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, hexyl, nonyl, decyl, 3-ethylundecyl, 3-ethyl-4-methyltridecyl, tetradecyl, nonadecyl, tetraeicosyl, 2-ethyl −
6-propyltetraeicosyl and the like can be mentioned. Specific examples of the cyclic alkyl group include cyclopropyl, cycloheptyl, cyclohexyl, cyclononyl,
And cyclodecyl. Examples of the halogen atom include chlorine, bromine, fluorine and iodine.

 The method for producing the compound of the formula (I) will be described.

In (wherein, Q ₃ means benzylidene or isopropylidene, Y ₁ and Y ₂ are the same.) The presence of an acid such as hydrochloric acid a compound of formula (IX), Y ₁ OH type,
Y ₁ is the same as above. ) To produce a compound of formula (X). The compound of formula (XI) can be produced by reacting the obtained compound with benzaldehyde or dimethoxypropane in an organic solvent such as benzene or acetone in the presence of D-camphor-10-sulfonic acid. The compound of formula (XII) can be prepared by reacting the obtained compound with R ₁ OH (where R ₁ is the same as above) in a suitable organic solvent in the presence of dimethylaminopyridine and dicyclohexylcarbodiimide. . The resulting compound can be prepared a compound of formula (XIII) by removing the protecting group Q ₃ in the presence of an acid such as acetic acid or P- toluenesulfonic acid. The 6-hydroxyl group of the obtained compound is protected by a usual method, and then in a suitable organic solvent in the presence of chlorine. (Wherein, X ₃ represents a halogen atom, and Y ₃ is the same as described above)
The compound of formula (I) can be produced by reacting

Next, a method for producing the compound of the formula (II), which comprises reacting the compound of the formula (I) with a trialkylsilyl halide or hydrogen halide and a Lewis acid, will be described. Examples of the trialkylsilyl halide include trimethylsilyl bromide, trimethylsilyl fluoride, trimethylsilyl iodine, and the like. Examples of the Lewis acid include zinc bromide, zinc chloride, stannous bromide, stannous chloride and the like. The trialkylsilyl halide or hydrogen halide is generally used in an amount of 1 to 15 equivalents, preferably 10 equivalents, relative to the compound of the formula (I). The Lewis acid is used in an amount of usually 1 to 10 equivalents, preferably 1 equivalent, relative to the compound of the formula (I). As a solvent used in the reaction, methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, acetonitrile, benzene, toluene, etc.,
Preferably, methylene chloride can be used. The solvent is usually used in an amount of 20 times by weight the compound of the formula (I).
The reaction is carried out for several hours to several days at a temperature from ice cooling to the boiling point of the solvent. After completion of the reaction, the desired product can be isolated by appropriately combining ordinary post-treatment means.

Next, a method for producing the compound of the formula (III) will be described, which comprises reacting the compound of the formula (Ia) with a hard acid in the presence of a soft nucleophile.

Examples of the soft nucleic acid required include thioanisole, anisole, selenoanisole, dimethyl selenide, dimethyl sulfide, ethyl mercapto and the like. The reagent is usually used at 10 times the molar amount of the compound of the formula (Ia). Examples of the hard acid include Lewis acids such as aluminum chloride and ferric chloride, and organic sulfonic acids such as trifluoromethanesulfonic acid and methanesulfonic acid. The Lewis acid is generally 1 to the compound of the formula (Ia).
10 equivalents, preferably about 5 equivalents, and the organic sulfonic acid is 1 to 10 equivalents to the compound of the formula (Ia),
Preferably 2.5 equivalents are used. Solvents used in the reaction include methylene chloride, ethylene dichloride, chloroform, acetonitrile, diethyl ether, benzene,
Examples include toluene and trifluoroacetic acid, and preferably methylene chloride and trifluoroacetic acid. The solvent is usually used at 15 times the weight of the compound of the formula (Ia). The reaction is carried out at a temperature from ice-cooling to the boiling point of the solvent for 30 minutes to 1 hour.
It takes place for a week. After completion of the reaction, the target substance can be isolated by appropriately combining ordinary post-treatment means such as column chromatography, recrystallization and the like.

Next, a process for producing a compound of the formula (VI), which comprises reacting a compound of the formula (IV) with a compound of the formula (V) in the presence of a Lewis acid and optionally a trityl halide, will be described.

Examples of the Lewis acid include zinc chloride, zinc bromide, ferric chloride and the like, preferably zinc chloride and zinc bromide. The acid is usually used in an amount of 1 to 2 equivalents to the compound of the formula (IV). Trityl halides include trityl chloride and the like, and the reaction reagent is usually used in an equimolar amount to the compound of the formula (IV). Examples of the solvent used for the reaction include methylene chloride, ethylene dichloride, chloroform, acetonitrile, diethyl ether, benzene, toluene, tetrahydrofuran, and preferably methylene chloride.

The solvent is usually used at 20 times the weight of the compound of the formula (IV). The amount of the compound of the formula (V) to be used is usually equimolar to the compound of the formula (IV).

The reaction is usually carried out for 1 to 24 hours at a temperature between ice-cooling and about the boiling point of the solvent.

In this reaction, when the above-mentioned Lewis acid is used alone as a reaction reagent, the target compound of the formula (VI) becomes α
It can be an isomer. On the other hand, when a trityl halide is combined with the above-mentioned Lewis acid as a reaction reagent, the resulting compound of the formula (VI) can be a β-isomer. After completion of the reaction, the desired product can be isolated by appropriately combining commonly used post-treatment means such as column chromatography and recrystallization.

Next, the compound of formula (VII) is reacted with a compound of formula (V) in the presence of a trialkylsilyl halide or hydrogen halide and a Lewis acid.
The method for producing the compound of the formula (VI), which comprises reacting the compound with the compound of the formula (VI), will be described.

Examples of trialkylsilyl halides and Lewis acids include those described above. The amount of the trialkylsilyl halide to be used is generally 1 to 3 equivalents to the compound of the formula (VII). The amount of the Lewis acid used is determined by the formula (VI
It is usually 1 equivalent to the compound of I). Further, the amount of the compound of the formula (V) used is based on the compound of the formula (VII)
It is 1 to 1.3 times mol. Examples of the solvent used in the reaction include methylene chloride, dichloroethylene, chloroform, carbon tetrachloride, acetonitrile, diethyl ether, benzene, toluene, tetrahydrofuran and the like, preferably methylene chloride. The solvent is usually used at 20 times the weight of the compound of the formula (VII).

The compound of the formula (VII) is a novel compound and can be produced as follows.

(In the formula, Y ₁₂ and Y ₇ are the same as described above.) The compound of the formula (VII) can be produced by protecting the hydroxyl group of the compound of the formula (X) using a conventional method.

From the compound of formula (II) or (III) and formula (VI) obtained as described above, R in the desired formula (VIII) (Wherein Z ₁ and Z ₂ are the same as above) may be prepared as follows.

(Where Y ₂ , Y ₃ , Y ₄ , Y ₇ , Y ₈ , Y ₉ , Y ₁₀ , Y ₁₁ , Z ₁ ,
Z ₂ , R ₁ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ are the same as described above, and Y ₁₃
Is a carboxyl protecting group which can be removed by catalytic reduction,
R ₂ , R ₃ and R ₄ are -COA ₁ , -COZA ₂ , -CO (CH ₂ ) _n2 OCOA ₁ , -CO (CH ₂ ) _n2 OCOZA ₂ ,-(CH ₂ ) _n2 OCA ₁ , -CO (CH ₂ ) _n2 COZA ₂ , A ₁ , A ₂ , Z, n 1, n 2, n 3, Q ₁ and Q ₂ are the same as described above.) When Y ₇ is lower acyl than the compound of the formula (VI), a Meyerbain reagent is used. _{When 7} is trichloroethoxycarbonyl or trichlorotertiary-butoxycarbonyl, it is treated with zinc dust in the presence of an acid such as hydrochloric acid or acetic acid to release the 2-position amino group, and then R ₂ OH and acid chloride method, carbodiimide The compound of the formula (XV) can be produced by condensation using a method, an eintop method or an active ester method.

It can be prepared a compound of formula (XVI) by elimination of hydroxy-protecting groups (Y ₈ ~Y ₁₀₎ with sodium alkoxide of the compound.

The compound of the formula (XV) wherein Y ₁₁ is a lower alkyl group is reacted with lithium hydroxide in a mixture of water and an alcohol solvent such as methanol to form a hydroxyl-protecting group (Y _{8 to} Y ₁₀ ) Removal of the lower alkyl group followed by reaction with Y ₁₃ -X ₃ (where X ₃ represents a halogen atom) in the presence of chlorine such as sodium bicarbonate leads to formula (XVa).

By protecting the 4- and 6-positions of the thus obtained compound with isopropylidene according to a conventional method, the compound of the formula (XVI
The compound of I) can be produced. The resulting compound is condensed with R ₃ OH according to a conventional method to give a compound of formula (XVIII)
Can be produced.

The compound of formula (XVIII) is hydrolyzed in aqueous acetic acid such as 50-90% acetic acid aqueous solution, or methanol, ethanol,
The compound of formula (XIX) can be produced by treating with P-toluenesulfonic acid in water or a mixture thereof. On the other hand, by reacting the compound of the formula (III) with acetic anhydride in the presence of a base such as pyridine, the compound of the formula (XIV)
Can be produced. The compound of formula (II) can be produced by reacting the compound with hydrogen halide in the presence of an acid such as acetic acid.

Formula (II) obtained in this way or as described above
The compound of formula (XIX) can be used alone or in combination with mercuric cyanide, mercury bromide, silver carbonate, silver oxide, silver perchlorate or mercuric nitrate, or a mixture thereof to dehydrate anhydrous calcium sulfate or the like. By reacting in the presence of an agent, the formula (X
The compound of X) can be produced.

The compound of the formula (XXI) can be produced by reacting the compound of the formula (XX) in the presence of acetic acid and zinc powder to eliminate Y ₄ and Y ₂ .

The obtained compound of the formula (XXII) is condensed with R ₄ -OH using a condensation method commonly used in the field of peptide chemistry, for example, a carbodiimide method, an eintop method or an active ester method, to thereby obtain the compound of the formula (XXII). Compounds can be prepared.

The resulting compound of the formula (XXII) is catalytically reduced under a hydrogen gas atmosphere using a catalyst such as palladium black, palladium carbon, and platinum dioxide to remove the protecting group, thereby obtaining the compound of the formula (VI)
The compound of IIa) can be prepared.

In addition, in the formula (VIII), R is Can be produced according to the production method described in JP-A-63-183594.

<Effect of the Invention> The compound of the formula (I) and the compound of the formula (II) according to the present invention,
The process for producing the compounds of the formulas (III) and (VI) is an excellent intermediate for producing the compound of the formula (VIII), which has an excellent antitumor effect, and a process for producing the intermediate.

Hereinafter, the present invention will be further described with reference examples, examples, and test examples, but the present invention is not limited thereto.

Reference Example 1 Methyl 2-deoxy-3,4,6,0-triacetyl-2-
(2,2,2-trichloroethoxycarbonylamino) -D
-Glucopyranoside N- (2,2,2-trichloroethoxycarbonyl) -D
4.6 g of glucosamine was suspended in 100 ml of methanol, 25 ml of a 5% hydrochloric acid-dioxane solution was added dropwise under reflux with heating, and the mixture was refluxed for 2 hours. The solvent was distilled off and the residue was pyridine 30m
l, 20 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, the residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, 1N hydrochloric acid, and saturated saline, dried over magnesium sulfate, and then the solvent was distilled off. The residue was subjected to silica gel chromatography (eluent; first chloroform, then a mixture of chloroform and acetone (50/1)) to give the title compound in the order of 4.8 g of the α-isomer and 1.5 g of the β-isomer.

α isomer Melting point 119-124 ° C ▲ [α] _{25 D} ▼ + 64.7 ° (c 1.5, chloroform) Elemental analysis C ₁₆ H ₂₂ Cl ₃ NO ₁₀ Calculated C, 38.85; H, 4.48; N, 2.83. H, 4.59; N, 2.97. Β isomer Melting point 85-93 ° C ▲ [α] _{25 D} ▼ + 15.8 ° (c 1.0, chloroform) Elemental analysis C ₁₆ H ₂₂ Cl ₃ NO ₁₀ , Found C, 38.85; H, 4.48; N, 2.83. Analytical value C, 38.55; .H, 4.34; N, 2.85. Reference Example 2 Benzyl 2-deoxy-3,4,6,0-triacetyl-2
-(2,2,2-trichloroethoxycarbonylamino)-
D-Glucopyranoside Reaction was carried out in the same manner as in Reference Example 1 to obtain α- and β-isomers of the title compound.

alpha isomer colorless oil _{▲ [α] 25 D ▼ +} 82.4 ° (c 0.5, chloroform) beta isomer mp _{122~123 ℃ ▲ [α] 25 D} ▼ -22.7 ° (c 0.7, chloroform) Elemental analysis C ₂₂ H ₂₆ Cl ₃ NO ₁₀ , Calculated C, 46.36; H, 4.88; N, 2.58. Found C, 46.29; H, 4.59; N, 2.45. Reference Example 3 Isopropyl 2-deoxy-3,4,6, 0-Triacetyl-2- (2,2,2-trichloroethoxycarbonylamino) -D-glucopyranoside The reaction was carried out in the same manner as in Reference Example 1 to obtain the α- and β-isomers of the title compound.

α isomer Melting point 122-125 ° C ▲ [α] _{25 D} ▼ + 95.7 ° (c 0.7, chloroform) Elemental analysis C ₁₈ H ₂₆ Cl ₃ NO ₁₀ , Calculated C, 41.36; H, 5.01; N, 2.68. Found, C, 41.20; H, 5.26; N, 2.72. Β-isomer Melting point 149-151 ° C ▲ [α] _{25 D} ▼ + 3.8 ° (c 0.6, chloroform) Elemental analysis C ₁₈ H ₂₆ Cl ₃ NO ₁₀ , Calculated value C, 41.36; H, 5.01; N, 2.68. Found value C, 41.20; H, 5.26; N, 2.72. Example 1 1) Methyl 2-deoxy-3-0- (N-dodecanoylglycyl) 2.4 g of 2- (2,2,2-trichloroethoxycarbonylamino) -α-D-glucopyranoside 2-deoxy-2- (2,2,2-trichloroethoxycarbonylamino) -D-glucopyranose in 50 ml of methanol Suspended and reduced by heating, 5% hydrochloric acid-dioxane 15
ml was added and stirred for 2 hours. The solvent was distilled off, and to the residue were added 20 ml of acetone and 10 ml of dimethoxypropane, 200 mg of D-camphor-10-sulfonic acid and 3 g of magnesium sulfate, and the mixture was stirred at room temperature for 6 hours. The mixture was neutralized with toluethylamine, the insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was partitioned between chloroform and water, the organic layer was washed with water and saturated saline, dried, and the solvent was distilled off. The residue was dissolved in 10 ml of methylene chloride, and N-dodecanoylglycine 2.
0 g, dimethylaminopyridine 100 mg and dicyclohexylcarbodiimide 1.9 g were added, and the mixture was stirred at room temperature for 40 minutes. The insolubles were filtered, and the filtrate was concentrated under reduced pressure to give methanol 10
0 ml and 200 mg of p-toluenesulfonic acid were added and stirred at room temperature for 1 hour. The solvent was distilled off, diluted with ethyl acetate, water,
After washing with saturated aqueous sodium hydrogen carbonate and drying, the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (eluent; first, chloroform, and then a mixture of chloroform and acetone (10/1)) to give 1.86 g of the α-isomer of the title compound as the first eluate, and as the second eluate 610 mg of the beta isomer of the title compound were obtained.

▲ [α] _{25 D} ▼ + 39.2 ° (c 1.8, chloroform) 2) Methyl 2-deoxy-4-0-diphenylphosphono-3-0- (N-dodecanoylglycyl) -6-0-
(2,2,2-trichloroethoxycarbonyl) -2-
(2,2,2-trichloroethoxycarbonylamino) -α
-D-Glucopyranoside 1.8 g of the obtained compound was dissolved in 20 ml of pyridine, and 0.5 ml of 2,2,2-trichloroethyl chloroformate was added thereto under ice cooling, followed by stirring at the same temperature for 30 minutes. The mixture was diluted with ethyl acetate, washed with 1N-hydrochloric acid and saturated saline, and dried. The solvent was distilled off, the residue was dissolved in methylene chloride (30 ml), pyridine (0.5 ml) and dimethylaminopyridine (500 mg) were added, and then diphenylphosphoric acid chloride (0.74 ml) was added under ice cooling. After stirring at room temperature for 20 minutes, the solvent was distilled off, diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated saline, and dried. The solvent was distilled off and the resulting residue was chromatographed on silica gel (eluent; first chloroform,
Then, the residue was purified by a mixed solution of chloroform and acetone (20/1) to give 2.13 g of the title compound as a colorless oil.

▲ [α] _{25 D} ▼ + 38.7 ° (c 0.8, chloroform) H-NMR (δ) CDCl ₃ : 0.88 (3H, t), 1,25 (16H, br), 1.55 (2H, m), 2.09 (2H, m), 3.46 (3H, s), 3.77 (1H, dd, J = 18.5Hz), 3.93 (1H, dd, J = 18.5Hz), 4.07 (3H, m), 4.33 (1H, dd, J = 12.4Hz), 4.47 (1H, d, J = 12Hz), 4.58,4.71 (2H, ABq), 4.80 (3H, m), 5.26 (1H, t, J = 9H)
z), 5.43 (1H, d, J = 9 Hz), 6.21 (1H, br, NH), 7.1 to 7.4 (10H, m). Example 2 1) Benzyl 4.6.0-benzylidene-2-deoxy-2
-(2,2,2-trichloroethoxycarbonylamino)-
α-D-glucopyranoside 10 g of 2-deoxy-2- (2,2,2-trichloroethoxycarbonylamino) -D-crocopyranose is added to 2 (W /
V) Anhydrous benzyl alcohol 4% containing hydrogen chloride gas
The suspension was stirred in a 150 ° C. oil bath for 30 minutes. After allowing to cool to room temperature, the solvent was distilled off under reduced pressure. Benzene was added to the residue for crystallization. After the crystals were collected by filtration, the crystals were dissolved in ethanol, 500 mg of activated carbon was added, and the mixture was stirred with heating for 30 minutes and filtered. After ethanol was distilled off, the residue was recrystallized from ethyl acetate-hexane to remove benzyl 2-deoxy-2- (2,2,2-trichloroethoxycarbonylamino) -β-D-glucopyranose.

Next, the mother liquor was concentrated, the residue was suspended in 200 ml of benzene, 2.2 ml of benzaldehyde and 160 mg of D-camphor-10-sulfonic acid were added, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the reaction solution was neutralized with triethylamine, washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was recrystallized from ethyl acetate to obtain 6.3 g of the title compound as white crystals.

Mp _{155~157 ℃ ▲ [α] 24 D} ▼ + 67.8 ° (c 1.4, chloroform) Elemental analysis _{C 23 H 24 Cl 3 NO 7} · 1 / 2H 2 O Calculated C, 50.99; H, 4.75; N, 2.59 found C, 50.99; H, 5.01; N, 2.56 2) Benzyl 2-deoxy-3-0-tetradecanoyl-2- (2,2,2-trichloroethoxycarbonylamino) -α-D-glucopyranoside 2.90 g of the obtained compound and 1.37 g of myristic acid were dissolved in 50 ml of methylene chloride. 4-dimethylaminopyridine 0.73
g and dicyclohexylcarbodiimide (1.23 g) were added, and the mixture was stirred at room temperature for 20 hours. The insoluble material is removed by filtration, and the filtrate is water, 10%
The extract was washed sequentially with aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate and water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, 40 ml of 80% aqueous acetic acid was added to the residue, and the mixture was heated and stirred at 100 ° C. for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with 5% aqueous sodium hydrogen carbonate and water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue (eluent; mixed solution of chloroform and acetone (20/1))
And the title compound was obtained as a viscous oil. The product crystallized on standing at room temperature.

Yield 2.03g Melting point 65-68 ° C ▲ [α] _{25 D} ▼ + 69.8 ° (c 0.8, chloroform) Elemental analysis C ₃₀ H ₄₆ Cl ₃ NO ₈ Calculated C, 55.00; H, 7.08; N, 2.14 Actual value C, 55.46; H, 7.15; N, 2.18 3) Benzyl 2-deoxy-4-0-diphenylphosphono-3-0-tetradecanoyl-6-0- (2,2,2-
Trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -α-D-glucopyranoside 2.03 g of the obtained compound is dissolved in 15 ml of pyridine, and chloroformic acid 2,2,2 0.85 g of trichloroethyl was added, and the mixture was stirred at the same temperature for 1 hour. Methanol was added to the reaction solution, and the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the organic layer was washed with 10% aqueous citric acid and water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml of methylene chloride, and 0.32 g of pyridine and 4-dimethylaminopyridine were dissolved.
0.49 g and 1.08 g of diphenylphosphoric chloride were sequentially added. The reaction solution was stirred at room temperature for 15 hours, diluted with methylene chloride, washed sequentially with water, 10% aqueous citric acid and water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent, a mixture of hexane and ethyl acetate (4/1)) to give the title compound as a colorless oil.

Yield: 1.23 g ▲ [α] _{25 D} ▼ + 49.3 ° (c 0.8, chloroform) ¹ H-NMR (CDCl ₃ ) δ; 0.88 (3H, t, J = 7.0 Hz), 1.05 to 1.50 (22H, m) , 2.11 (2H, m), 4.04 to 4.08 (2H, m), 4.33 (2H, d, J = 3.3Hz), 4.57 (1H, d, J = 11.7Hz), 4.64 (1H, d, J = 12.1) Hz), 4.64, 4.67 (2H, ABq, J = 12.1Hz), 4.73 (1H, d, J = 11.7Hz), 4.74 (1H, d, J = 11.7Hz), 4.76 (1H, dd, J = 9.5) , 17.6Hz), 5.28 (1H, d, J = 3.7Hz), 5.29 (1H, d, J = 9.9Hz), 5.47 (1H, t, J = 9.5Hz), 7.14 to 7.20 (6H, m), 7.30~7.40 (9H, m), elemental analysis _{C 45 H 56 Cl 6 NO 13} P: calculated C, 50.86; H, 5.31; N, 1.32 Found C, 51.34; H, 5.83; N, 1.76 example 3 1) Benzyl 2-deoxy-3-0- (N-dodecanoylglycyl) -2- (2,2,2-trichloroethoxycarbonylamino) -α-D-glucopyranoside benzyl 4,6,0-benzylidene-2 -Deoxy-2
-(2,2,2-trichloroethoxycarbonylamino)-
3.67 g of α-D-glucopyranoside was added with 50 m of anhydrous methylene chloride.
Then, 2.12 g of N-dodecanoylglycine and 1.00 g of 4-dimethylaminopyridine were added, and the mixture was stirred under ice cooling. Then add 1.70 g of dicyclohexylcarboxyimide and add
The mixture was stirred for 0 minutes, and further stirred at room temperature for 3 hours. The precipitated insolubles were removed by filtration and the solvent was distilled off. The residue was dissolved in 5 ml of an 80% aqueous acetic acid solution, and heated and stirred at 100 ° C. for 1.5 hours.

The solvent was distilled off and azeotroped twice with toluene. The residue was dissolved in ethyl acetate, washed with 10% hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue was separated and purified by silica gel column chromatography (eluent; first, chloroform, then a mixture of chloroform and methanol (30/1)) to give 2.45 g of the title compound as a colorless oil.

120-124 ° C ▲ [α] _{25 D} ▼ + 65.0 ° (c 1.0, chloroform) 2) Benzyl 2-deoxy-4-0-diphenylphosphono-3-0- (N-dodecanoylglycyl)- 6-0
-(2,2,2-trichloroethoxycarbonyl) -2-
(2,2,2-trichloroethoxycarbonylamino) -α
-D-Glucopyranoside 2.45 g of the obtained compound was dissolved in 25 ml of pyridine and stirred under ice cooling. Next, 550 μl of 2,2,2-trichloroethyl chloroformate was added dropwise, and the mixture was stirred under ice-cooling for 20 minutes. 5 ml of water in the reaction solution
Was added and stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with 10% hydrochloric acid and saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.

Dissolve the residue in anhydrous methylene chloride and add pyridine 42 at room temperature.
4 mg, 1.44 g of diphenylphosphoric acid chloride and 655 mg of 4-dimethylaminopyridine were sequentially added, followed by stirring at room temperature overnight.

The solvent was distilled off, and the residue was dissolved in ethyl acetate, washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography (eluent; a mixture of chloroform and acetone (20/1)) to give 2.49 g of the title compound as a white solid.

▲ [α] _{23 D} ▼ + 53.1 ° (c 1.0, chloroform) Melting point 107-109 ° C Elemental analysis C ₄₅ H ₅₅ Cl ₆ N ₂ O ₁₄ P Calculated C, 49.51; H, 5.08; N, 2.57 Actual value C, 49.30; H, 5.21; N, 2.58 ¹ H-NMRδ (CDCl ₃ ) 0.88 (t, 3H, J = 7.2 Hz), 1.25 (brs) 1.46 (brs, 2H), 1.55 (brs, 2H) 2.07- 2.10 (m, 2H) 3.85 (dd, 2H, J = 18,4.8 Hz) 5.01 (d, 1H, J = 3.2 Hz) 5.26 (d, 1H, J = 10.3 Hz) 5.46 (t, 1H, J = 9.5) Hz) 6.23 (m, 1H), 7.10-7.41 (m, 15H) Example 4 2-deoxy-4-0-diphenylphosphono-3-0-
(N-dodecanoylglycyl) -6-0- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -α-D-glucopyranosyl bromide methyl 2-deoxy -4-0-Diphenylphosphono-3-0- (N-dodecanoylglycyl) -6-0-
(2,2,2-trichloroethoxycarbonyl) -2- (2,
2,2-trichloroethoxycarbonylamino) -α-D
-Dissolve 98 mg of glucopyranosides in 2 ml of methylene chloride,
Twenty mg of zinc bromide and 120 μl of trimethylsilyl bromide were added, sealed, and stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform) to obtain 87.3 mg of the title compound.

▲ [α] _{25 D} ▼ + 66.6 ° (c 1.0, chloroform) ¹ H-NMR δ (CDCl ₃ ): 0.88 (t, 3H, J = 7.2 Hz), 1.26 (16H, br,), 2.09 (1H , t, J = 7.2Hz), 2.10 (1H, t, J = 7.2Hz), 3.76 (1H, dd, J = 18.3,5.2Hz), 4.00 (1H, dd, J = 18.3,5.2Hz), 4.18 (1H, dd, J = 9.5,4.0Hz), 4.34 (2H, m), 4.50 (1H, m), 4.54 (1H, d, J = 11.9Hz), 4.70 (1H, d, J = 11.9Hz) , 4.71 (1H, d, J = 11.9 Hz), 4.79 (1H, d, J = 11.9 Hz), 4.92 (1H, q, J = 9.5 Hz), 5.51 (1H, d, J = 9.5 Hz), 5.54 (1H, t, J = 9.5Hz), 6.32 (1H, t, J = 5.2Hz), 6.53 (1H, d, J = 4.0Hz), 7.10 to 7.40 (10H, m). Example 5 2-deoxy-4-0-diphenylphosphono-3-0-
Tetradecanoyl-6-0- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -D-glucopyranose benzyl 2-deoxy-4-0-diphenylphospho 237 mg of no-3-0-tetradecanoyl-6-0- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -α-D-glucopyranoside and thioanisole 277mg methylene chloride 4ml
, And 149 mg of aluminum chloride was added, and the mixture was reacted at room temperature for 2.5 hours. Dilute the reaction solution with methylene chloride and add
% Aqueous sodium bicarbonate was added. The mixture was neutralized by adding citric acid, the organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; a mixture of chloroform and acetone (30/1)) to give the title compound as a viscous oil.

Yield 181 mg ▲ [α] _{25 D} ▼ + 21.6 ° (c 1.2, chloroform) ¹ H-NMR (CDCl ₃ ) δ 0.88 (3H, t, J = 7.0 Hz), 1.10-1.48 (22H, m), 2.12 (2H, m), 4.03 (1H, dt, J = 3.3,9.5Hz), 4.30-4.34 (2H, m), 4.43 (1H, brd, J = 12.1Hz), 4.70 (1H, d, J = 12.1) Hz), 4.72 (1H, d, J = 12.1 Hz), 4.76 (1H, dd, J = 9.2, 17.6 Hz), 5.31 (1H, d, J = 3.3 Hz), 5.44 (1H, d, J = 9.5) Hz), 5.52 (1H, t, J = 9.5Hz), 7.15-7.21 (6H, m), 7.31-7.34 (4H, m). Example 6 2-deoxy-4-0-diphenylphosphono-3-0-
Tetradecanoyl-6-0- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -D-glucopyranose benzyl 2-deoxy-4-0-diphenylphospho No-3-0-tetradecanoyl-6-0- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -α-D-glucopyranoside 150 mg and thioanisole 175 mg trifluoroacetic acid
The solution was dissolved in 0.5 ml, and 53 mg of trifluoromethanesulfonic acid was added under ice-cooling and stirring. Thereafter, the reaction was performed at room temperature for 0.5 hour, and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 5% aqueous sodium hydrogen carbonate, the organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; a mixture of chloroform and acetone (30/1)) to give the title compound.

Yield 110 mg Example 7 2-deoxy-4-0-diphenylphosphono-3-0-
(N-dodecanoylglycyl) -6-0- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -D-glucopyranose benzyl 2-deoxy-4 -0-diphenylphosphono-3-0- (N-dodecanoylglycyl) -6-0-
(2,2,2-trichloroethoxycarbonyl) -2- (2,
2,2-trichloroethoxycarbonylamino) -α-D
-1.50 g of glucopyranosides were dissolved in 20 ml of anhydrous methylene chloride. 1.61 ml of thioanisole was added, and 1.09 g of aluminum chloride was added under ice cooling, and the mixture was gradually returned to room temperature and stirred for 5 hours. The reaction was neutralized with sodium bicarbonate and diluted with methylene chloride. The precipitated aluminum hydroxide was dissolved with citric acid, separated, and the organic layer was washed with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; first, chloroform, and then a mixture of chloroform and acetone (40/1)) to give the desired compound. The fractions were concentrated to give 1.21 g of the title compound.

Colorless caramel Rf = 0.40 (chloroform: acetone = 10: 1) Example 8 2-deoxy-4-0-diphenylphosphono-3-0-
(N-dodecanoylglycyl) -6-0- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -D-glucopyranose benzyl 2-deoxy-4 -0-diphenylphosphono-3-0- (N-dodecanoylglycyl) -6-0-
(2,2,2-trichloroethoxycarbonyl) -2- (2,
2,2-trichloroethoxycarbonylamino) -α-D
-1.51 g of glucopyranoside and 1.61 ml of thioanisole are dissolved in 3 ml of trifluoroacetic acid, 0.3 ml of trifluoromethanesulfonic acid is added under ice cooling, and the temperature is gradually returned to room temperature.
Stirred for hours. The reaction solution was concentrated to dryness under reduced pressure, and the obtained residue was dissolved in ethyl acetate and neutralized with an aqueous sodium hydrogen carbonate solution. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent; first chloroform, then a mixture of chloroform and acetone (40/1)).
The target compound fraction was concentrated to give the title compound (960 mg).

Colorless caramel Rf = 0.40 (chloroform: acetone = 10: 1) Example 9 (1,3-dimethoxycarbonyl) isopropyl-2-deoxy-3,4,6,0-triacetyl-2- (2,2, 2-trichloroethoxycarbonylamino) -α-D-glucopyranoside (compound A) 2-deoxy-3,4,6,0-triacetyl-2- (2,2,2
-Trichloroethoxycarbonylamino) -α-D-glucopyranosyl bromide (Compound B) (210 mg) and dimethyl 3-hydroxyglutarate (70 mg) in anhydrous methylene chloride
The solution was dissolved in 4 ml, zinc chloride (50 mg) was added, and the mixture was stirred at room temperature for 12 hours. Saturated aqueous sodium hydrogen carbonate was added, extracted with ethyl acetate, washed with saturated saline, and dried over sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (eluent; first, chloroform, and then a mixture of chloroform and acetone (20/1)).
g was obtained.

Example 10 380 mg of compound B and 110 mg of dimethyl 3-hydroxyglutarate were dissolved in 10 ml of anhydrous methylene chloride, and zinc bromide 1
50 mg was added, and the mixture was stirred at room temperature for 12 hours. Saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate, washed with saturated saline, and treated in the same manner as in Example 9 to obtain 347 mg of compound A.

Example 11 (1,3-Dimethoxycarbonyl) isopropyl-2-deoxy-3,4,6,0-triacetyl-2- (2,2,2-trichloroethoxycarbonylamino) -β-D-glucopyranoside (compound C) Compound B (340 mg) and dimethyl 3-hydroxyglutarate (110 mg) were dissolved in anhydrous methylene chloride (4 ml), and trityl chloride (167 mg) and stannous chloride (110 mg) were added.
Stirred for hours. Saturated aqueous sodium hydrogen carbonate was added, extracted with ethyl acetate, washed with saturated saline, and dried over sodium sulfate.
The solvent was distilled off, and the residue was subjected to silica gel column chromatography (eluent; first, chloroform, then a mixture of chloroform and acetone (20/1)) to obtain 260 mg of Compound C from the desired fraction.

Example 12 130 mg of Compound B and 45 mg of dimethyl 3-hydroxyglutarate were dissolved in 4 ml of anhydrous methylene chloride, 65 mg of trityl chloride and 32 mg of zinc chloride were added, and the mixture was heated under reflux for 10 hours.
Thereafter, the same treatment as in Example 11 was carried out, and Compound A (5 mg) and Compound C were treated.
132 mg were obtained.

Example 13 Compound B (175 mg) and dimethyl 3-hydroxyglutarate (60 mg) were dissolved in anhydrous methylene chloride (4 ml), and trityl bromide (110 mg) and zinc bromide (70 mg) were added, followed by heating under reflux for 4 hours. Thereafter, the same treatment as in Example 11 was performed to obtain 135 mg of compound A and 60 mg of compound C.

Example 14 100 mg of Compound B and 35 mg of dimethyl 3-hydroxyglutarate were dissolved in 4 ml of anhydrous methylene chloride, 90 mg of trityl bromide and 25 mg of zinc chloride were added, and the mixture was heated under reflux for 12 hours. Thereafter, the same treatment as in Example 11 was carried out to obtain 18 mg of compound A and 73 mg of compound C.

Example 15 Benzyl 2-deoxy-3,4,6,0-triacetyl-
2- (2,2,2-trichloroethoxycarbonylamino)
-D-glucopyranoside (100 mg) and dimethyl 3-hydroxyglutarate (40 mg) were dissolved in methylene chloride (2 ml), and zinc bromide (40 mg) and bromotrimethylsilane (70 μl) were added.
Heated to reflux for an hour. Dilute with ethyl acetate, add saturated aqueous sodium bicarbonate,
The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; first, chloroform, then a mixture of chloroform and acetone (50/1)) to obtain 95 mg of Compound A as a colorless oil from the target fraction. Was.

Example 16 100 mg of isopropyl 2-deoxy-3,4,6,0-triacetyl-2- (2,2,2-trichloroethoxycarbonylamino) -D-glucopyranoside and 40 mg of dimethyl 3-hydroxyglutarate were mixed with 2 ml of methylene chloride. , And 45 mg of zinc bromide and 75 μl of bromotrimethylsilane were added, and the mixture was refluxed for 12 hours. Thereafter, the same treatment as in Example 15 was carried out to obtain 90 mg of Compound A as a colorless oil.

Example 17 Methyl 2-deoxy-3,4,6,0-triacetyl-2
-(2,2,2-trichloroethoxycarbonylamino)-
100 mg of D-glucopyranoside and 40 mg of dimethyl 3-hydroxyglutarate were dissolved in 2 ml of methylene chloride, 45 mg of zinc bromide and 80 μl of bromotrimethylsilane were added, and the mixture was heated under reflux for 12 hours. Thereafter, the same treatment as in Example 15 was carried out to obtain 115 mg of compound A as a colorless oil.

Reference Example 4 1) 1-0-acetyl-2-deoxy-4-0-diphenylphosphono-3-0- (N-dodecanoylglycyl)
-6-0- (2,2,2-trichloroethoxycarbonyl)
-2- (2,2,2-trichloroethoxycarbonylamino) -D-glucopyranose 2-deoxy-4-0-diphenylphosphono-3-0
-(N-dodecanoylglycyl) -6-0- (2,2,2-
2.31 g of (trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -D-glucopyranose was dissolved in 40 ml of anhydrous methylene chloride, and 0.93 ml of pyridine and 1.18 g of acetic anhydride were added at room temperature. Stirred for 19 hours. Water was added to the reaction solution, and the mixture was stirred, extracted with chloroform, and washed with 1N hydrochloric acid, water, and 5% aqueous sodium hydrogen carbonate. After drying over sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; a mixture of chloroform and acetone (10/1)) to obtain 2.25 g of the title compound as a caramelized pale yellow oil.

▲ [α] _{25 D} ▼ + 43.8 ° (c 1.2, chloroform) 2) 2-Deoxy-4-0-diphenylphosphono-3-
0- (N-dodecanoylglycyl) -6-0- (2,2,2
-Trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -α-D-glucopyranosyl bromide 705 mg of the obtained compound is dissolved in 2.5 ml of anhydrous methylene chloride and 8 ml of 25% hydrogen bromide- Acetic acid was added, the mixture was sealed, and the mixture was stirred for 1.5 hours. Chloroform was added, and the mixture was washed with ice water, a 5% aqueous sodium hydrogen carbonate solution and saturated saline, and dried over sodium sulfate. The solvent was distilled off to give the title compound 72 as an oil.
4 mg were obtained.

Reference Example 5 1) 1,3- (Dimethyloxycarbonyl) isopropyl 2-deoxy-3,4,6,0-triacetyl-2-tetradecanoylamino-D-glucopyranoside Compound A 23.2 g was dissolved in acetic acid 100 ml. And 20 g of zinc dust, and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the solvent was distilled off. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The solvent was distilled off, the residue was dissolved in 200 ml of methylene chloride, 8.2 g of myristic acid and 7.5 g of cycyclohexylcarbodiimide were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After removing the insoluble material by filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; first, chloroform and then a mixed solution of chloroform and acetone (20/1)) to obtain the title compound from the target fraction. 15.6 g was obtained as a colorless oil.

▲ [α] _{25 D} ▼ + 49.3 ° (c 1.4, chloroform) 2) 1,3- (dibenzyloxy) isopropyl 2-deoxy-2-tetradecanoylamino-α-D-glucopyranoside 500 mg of the obtained compound Of methanol-water (3/1)
Dissolved in 20 ml, added lithium hydroxide and stirred at room temperature overnight. The pH was adjusted to 1 with 10% hydrochloric acid, neutralized again with a saturated aqueous solution of sodium hydrogen carbonate, and the solvent was distilled off under reduced pressure. Next, the residue was dissolved in 14 ml of dimethylformamide,
4 mg and 2.2 ml of benzyl bromide were added, and the mixture was stirred at room temperature for 24 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: first, a mixed solution of chloroform and acetone (10/1), then, a mixed solution of chloroform and methanol (20/1)) to obtain a white waxy solid. 337 mg of the title compound were obtained.

3) 1,3- (Dibenzyloxycarbonyl) isopropyl 2-deoxy-3-0- (N-dodecanoylglycyl) -2-tetradecanoylamino-α-D-glucopyranoside 1.23 g of the obtained compound was dried. Dissolve in 30 ml of benzene,
15 ml of 2,2-dimethoxypropane and D-camphor-10
-80 mg of sulfonic acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in anhydrous methylene chloride (20 ml), N-dodecanoylglycine (679 mg) and dimethylaminopyridine (323 mg) were added, and under ice cooling, dicyclohexylcarbodiimide (545 mg) was added, followed by stirring at room temperature overnight. The precipitate was filtered off, washed with saturated aqueous sodium hydrogen carbonate, 10% hydrochloric acid and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. 90% aqueous acetic acid 40
The mixture was dissolved in ml and stirred at 90 ° C. for 20 minutes. After evaporating the solvent under reduced pressure, the residue was azeotroped with toluene and the residue was subjected to silica gel column chromatography (eluent; first, a mixed solution of chloroform and acetone (10/1)), and then, a mixed solution of chloroform and methanol (20/1) To give 1.38 g of the title compound as a waxy solid.

▲ [α] _{25 D} ▼ + 36.9 ° (c 1.3, chloroform) 4) 1,3- (dibenzyloxycarbonyl) isopropyl 2-deoxy-6-0- [2-deoxy-4-0-
Diphenylphosphono-3-O- (N-dodecanoylglycyl) -6-0- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -β- D-glucopyranosyl] -3-0- (N
-Dodecanoylglycyl) -2-tetradecanoylamino-α-D-glucopyranoside 15.1 g of the obtained compound and 2-deoxy-4-0-diphenylphosphono-3-0- (N-dodecanoylglycyl) Dissolve 17.1 g of -6-0- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -α-D-glucopyranosyl bromide in 100 ml of anhydrous methylene chloride and activate Calcium sulfate 1
0 g and mercuric cyanide (8.13 g) were added, and the mixture was stirred at 50-60 ° C. for 4 hours. The insolubles were filtered through celite, washed with 5% aqueous potassium iodide and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; first, a mixed solution of chloroform and acetone (10/1) and then a mixed solution of chloroform and methanol (20/1)) to give the title compound. 2 as a colorless oil
6.0 g were obtained.

5) 1,3- (dibenzyloxycarbonyl) isopropyl 2-deoxy-4-0-diphenylphosphono-6
0- [2-Deoxy-3-0- (N-dodecanoylglycyl) -2-tetradecanoylamino-β-D-glucopyranosyl] -3-0- (N-dodecanoylglycyl)
-2-Tetradecanoylamino-α-D-glucopyranoside The obtained compound (2.58 g) was dissolved in acetic acid (40 ml), 2.0 g of zinc dust was added, and the mixture was vigorously stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the filtrate was distilled off under reduced pressure. Further, toluene was added and the mixture was azeotroped, and the residue was diluted with ethyl acetate, washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an oil.

On the other hand, 459 mg of tetradecanoic acid and 272 mg of 1-hydroxybenzotriazole were dissolved in 10 ml of anhydrous tetrahydrofuran, 415 mg of dicyclohexylcarbodiimide was added under cooling with water, and the mixture was stirred at room temperature for 2 hours.

Dissolve the previous oil in 5 ml of anhydrous methylene chloride and cool with ice.
The solution was added to the precipitate while filtering off the precipitate, and the mixture was stirred at room temperature for 22 hours. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (eluent: first chloroform, then a mixture of chloroform and acetone (10/1), and further a mixture of chloroform and methanol (20/1)). This gave 1.79 g of the title compound as a white powder.

▲ [α] _{25 D} ▼ + 18.8 ° (c 0.5, chloroform) Melting point 116-122 ° C. 6) 1,3- (Dicarboxy) isopropyl 2-deoxy-6-0- [2-deoxy-4-0- Phosphono-3-
0- (N-dodecanoylglycyl) -2-tetradecanoylamino-β-D-glucopyranosyl] -3-0-
(N-dodecanoylglycyl) -2-tetradecanoylamino-α-D-glucopyranoside 350 mg of the obtained compound was added to 10% aqueous tetrahydrofuran 4
The solution was dissolved in 4 ml, and 400 mg of 10% palladium-carbon was added thereto and subjected to catalytic reduction for 2 hours. Then add 200 mg of platinum oxide and add 2.5 mg
An hourly catalytic reduction was performed. After filtering off the catalyst, the solvent was distilled off under reduced pressure. The residue was developed by thin-layer chromatography (solvent; mixed solution of chloroform, methanol and water (6/4 / 0.7), and the desired fraction was scraped and eluted with a mixed solution of chloroform, methanol and water (6/4/1). The solvent was distilled off under reduced pressure, and the residue was dissolved in the lower layer of a mixed solution of chloroform, methanol and water (8/3/1), and Dowex5OW ion exchange resin (strongly acidic H ⁺ type)
The solution was passed through a column, and the solvent was distilled off under reduced pressure. Suspend the residue in dioxane and freeze-dry to give the title compound as a white powder.
187 mg were obtained.

▲ [α] _{25 D} ▼ + 10.3 ° (c 0.6, mixed solution of chloroform and methanol (3/1)) Melting point 140-145 ° C (colors and becomes candy) IRν (KBr) 3330, 2925, 2855, ^{1755,1645,1550cm -1 1 H-NMR [CDCl} 3 -CD 3 OD] δ 0.90 (12H, t), 1.30 (s) 2.1~2.3 (8H, m) 2.6~3.0 (4H, m) 4.89 (1H , d) 4.99 (1H, d) 5.09 (1H, t) 5.45 (1H, t) Reference Example 6 1) 2-acetoxyethyl 3,4,6-tri-0-acetyl-2-deoxy-2- (2 , 2,2-Trichloroethoxycarbonylamino) -α-D-glucopyranoside 5.0 m in 5.00 g of 2-deoxy-2- (2,2,2-trichloroethoxycarbonylamino) -D-glucopyranose
l of ethylene glycol and 0.5 ml of dioxane containing 5 N hydrogen chloride gas were added, and the mixture was heated to 90 ° C. and stirred for 4 hours. The reaction solution was ice-cooled, 75 ml of pyridine was added, 30.6 g of acetic anhydride was added, and the mixture was stirred. After 20 minutes, the temperature was returned to room temperature, and the mixture was further stirred for 16 hours. The reaction solution was poured into 350 ml of ice water and stirred, and the precipitated solid was collected by filtration and washed with water.

The obtained solid was dissolved in chloroform, 1N hydrochloric acid,
The extract was washed successively with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol to obtain 4.96 g of the title compound as colorless prism-like crystals.

Melting point 138-140 ° C ▲ [α] _{25 D} ▼ + 74.0 ° (c 1.2, chloroform) 2) 2-acetoxyethyl 3,4,6-tri-0-acetyl-2-deoxy-2-tetradecanoylamino -Α-
D-Glucopyranoside 4.96 g of the obtained compound was dissolved in 60 ml of acetic acid, and 7 g of zinc powder was added little by little while stirring at room temperature, followed by stirring for 1 hour. The insoluble material was removed by filtration, the solvent was distilled off under reduced pressure, toluene was added to the obtained residue, and the solvent was distilled off again under reduced pressure. The obtained residue was dissolved in dioxane, dioxane containing hydrogen chloride gas was added, and the solvent was distilled off under reduced pressure, followed by drying.

Dissolve the obtained oil in 70 ml of anhydrous methylene chloride,
Under ice cooling, 2.88 ml of N-methylmorpholine and 3.24 g of tetradecanoic acid chloride were added, and the mixture was stirred for 1 hour. After adding 10 ml of methanol and stirring at room temperature for 10 minutes, the mixture was diluted with chloroform and washed with 1N hydrochloric acid and saturated saline in this order. After drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the obtained residue is applied to a silica gel column (elution solvent: a mixture of benzene and ethyl acetate (first changed to 9/1 and then changed to 1/1)). Purification gave 4.77 g of the title compound as a colorless oil.

3) 2-Hydroxyethyl 2-deoxy-2-tetradecanoylamino-α-D-glucopyranoside 4.77 g of the obtained compound was dissolved in 80 ml of anhydrous methanol, and a methanol solution of 9 mmol of sodium methylate was added under ice cooling. The mixture was stirred at room temperature for 30 minutes. Tetrahydrofuran was added to dissolve the precipitated insoluble matter, and then neutralized with a strongly acidic ion exchange resin Dowex-50 (H ⁺ type), and the resin was removed by filtration. The solvent of the filtrate was distilled off under reduced pressure, and the residue obtained was washed with ether and collected by filtration to obtain 3.02 g of the title compound.
Was obtained as a white solid. Recrystallization from ethanol-water Melting point 158-160 ° C ▲ [α] _{25 D} ▼ + 82.1 ° (c 0.8, tetrahydrofuran:
Water = 4/1) 4) 2-hydroxyethyl 2-deoxy-4,6-0-
Isopropylidene-2-tetradecanoylamino-α-
D-glucopyranoside 0.87 g of the obtained compound was dissolved in 20 ml of dimethylformamide, and 0.62 g of 2,2-dimethoxypropane was added at room temperature.
38 mg of p-toluenesulfonic acid-hydrate was added and stirred for 1.5 hours. Neutralize with 5% aqueous sodium bicarbonate,
The solvent was distilled off under reduced pressure. Dissolve the residue in ethyl acetate,
The extract was washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by a silica gel column (elution solvent; first, a mixed solution of chloroform and acetone (19/1), and then changed to a mixed solution of chloroform and methanol (19/1)). 0.78 g of the title compound was obtained as a colorless viscous oil.

5) 2- (Diphenylphosphonoxy) ethyl 2-deoxy-4,6-0-isopropylidene-2-tetradecanoylamino-α-D-glucopyranoside 0.77 g of the obtained compound was dissolved in 15 ml of anhydrous methylene chloride. Under ice-cooling, 0.48 g of diphenyl phosphorochloridate, 0.19 ml of pyridine and 0.30 g of dimethylaminopyridine were added, and the mixture was stirred for 1 hour. After returning to room temperature and stirring for 1 hour
Add 0.17 g diphenyl phosphorochloridate and add 30
Stirred for minutes. After adding 3 ml of methanol to the reaction solution and stirring for a while, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: mixed solution of chloroform and acetone (19/1)) to give 0.81 g of the title compound.
Was obtained as a colorless viscous oil.

6) 2- (Diphenylphosphonoxy) ethyl 2-deoxy-3-0- (N-dodecanoylglycyl) -2-tetradecanoylamino-α-D-glucopyranoside 0.51 g of the obtained compound was dissolved in 5 ml of anhydrous After dissolving in methylene chloride, 0.22 g of N-dodecanoylglycine, 44 mg of dimethylaminopyridine and 0.18 g of dicyclohexylcarbodiimide were added under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling, and then returned to room temperature and stirred for 2 hours. The insoluble material was removed by filtration, and the filtrate was washed successively with 1N hydrochloric acid, water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure.
A 90% acetic acid aqueous solution was added, and the mixture was stirred for 30 minutes while heating to 90 ° C. The solvent was distilled off under reduced pressure, and the procedure of adding toluene to the residue and distilling off the solvent under reduced pressure was repeated twice, and the obtained residue was subjected to silica gel column chromatography (elution solvent; initially, a mixed solution of chloroform and acetone (19/1 ), And then purified with a mixed solution of chloroform and methanol (19/1)) to obtain 0.51 g of the title compound as a colorless viscous oil.

▲ [α] _{25 D} ▼ + 46.2 ° (c 1.1, chloroform) NMR (CDCl ₃ ), δ (ppm): 0.88 (6H, t), 1.26 (S), 2.07 (2H, t), 2.27 (2H , t), 4.84 (1H, d), 5.18 (1H, m), 7.2 to 7.4 (10H, m) 7) 2-phosphonoxyethyl 2-deoxy-6-0-
[2-Deoxy-3-0- (N-dodecanoylglycyl) -4-0-phosphono-2-tetradecanoylamino-β-D-glucopyranosyl] -3-0- (N-dodecanoylglycyl) -2-tetradecanoylamino-α-
D-Glucopyranoside The obtained compound was reacted in the same manner as in the steps 4) to 6) of Reference Example 5 to obtain the title compound.

Melting point 140-150 ° C (colors to become candy) ▲ [α] _{25 D} ▼ + 13.3 ° (c 0.6, chloroform: methanol = 3: 1) IRν: 3400,2930,2855,1750,1660,1560cm ^-1 NMR (CDCl ₃ -CD ₃ OD), δ: 0.90 (12H, t), 1.32 (s) 2.1 to 2.3 (8H, m), 5.10 (1H, t), 5.38 (1H, t) Test Example 1 Methylcholanthrene-induced BALB / C mice with 2 × 10 ⁵ fibrosarcoma cells (Meth A) were used for syngeneic BALB / C mice (7
Per animal). Seven days after transplantation, a solution prepared by dissolving or suspending the triethylamine salt of the compound of Reference Examples 5 and 6 in a 0.1% aqueous solution of triethylamine (v / v%) and adjusting the concentration to 500 μg / ml was adjusted to 100 μg / mouse. , 1
After administration into the tail vein on the 2nd and 17th days, the antitumor activity after 21 days was examined.

As a control compound, 2-deoxy-6-0- {2-
Deoxy-2-[(R) -3-dodecanoyloxytetradecanoylamino] -4-0-phosphono-3-0-
[(R) -3-tetradecanoyloxytetradecanoyl] -β-D-glucopyranosyl} -3-0-[(R)
-3-Hydroxytetradecanoyl] -2-[(R)-
The antitumor activity was examined using 3-hydroxytetradecanoylamino-1-0-phosphono-α-D-glucopyranose (hereinafter, compound E) in the same manner as in the compounds of Reference Examples 5 and 6. The results are shown in Table 1.

As is clear from the above table, it was confirmed that the compounds of Reference Examples 5 and 6 had an antitumor activity equal to or higher than that of Compound E as a control.

Test Example 2 A solution prepared by dissolving or suspending the triethylamine salt of the compound of Reference Examples 5 and 6 in 5% glucose solution containing 0.1% triethylamine to 100 μg / ml in three NZW male rabbits per group was prepared at 50 μg / kg. (Body weight) was administered to the ear vein for three consecutive days. The safety of the sample was determined by the number of dead rabbits / the number of rabbits used 24 hours after the last administration. Compound E
Administered 5 μg / kg. The results are shown in Table 2.

As is clear from the above table, it was confirmed that the compounds of Reference Examples 5 and 6 were far less toxic than the compound E as a control, and were excellent in safety.

Continuation of front page (56) References Can. J. Biochem. , 52 [9] (1974) pp. 723-725 Izv, Akad. Nauk SSS R, Ser. Khim. , [9] (1987) pp. 2106-2109 (58) Fields investigated (Int. Cl. ⁶ , DB name) C07H 15/04 C07H 11/04 C07H 1/00 C07H 13/04 REGISTRY (STN) CA (STN)

Claims (3)

(57) [Claims] (1) Formula (I) (Wherein, Y ₁ represents an optionally substituted benzyl group or an alkyl group, Y ₂ represents a protecting group for an amino group, Y ₃ represents a protecting group for a phosphono group, Y ₄ represents a protecting group for a hydroxyl group, ₁ is -COA ₁ , A ₁ is an alkyl group having 1 to 30 carbon atoms which may be substituted with one or more hydroxyl groups protected by a hydroxyl protecting group,
Z represents an alkylene group having 1 to 9 carbon atoms, A ₂ represents a cyclic alkyl group having 3 to 12 carbon atoms which may be substituted with one or more hydroxyl groups protected by a protecting group for a hydroxyl group, and Q ₁ represents hydrogen. Or an alkyl group having 1 to 20 carbon atoms, Q ₂ is hydrogen, an alkyl group having 1 to 6 carbon atoms, -CONH ₂ , -COOY ₅ or -CH ₂ OY ₆ , Y ₅ is a protecting group of a carboxyl group, Y ₆ is a hydroxyl-protecting group, and n1 is 0 to
10 integer of, the compound represented by n2 and n3 represents an integer of 1 to 20, respectively) (where, Y ₁ is a methyl group, Y ₂ is an acetyl group, Y ₃ is a phenyl group, Y ₄ is an acetyl group Excluding certain compounds.) 2. Formula (I) (Wherein, Y ₁ represents an optionally substituted benzyl group or an alkyl group, Y ₂ represents a protecting group for an amino group, Y ₃ represents a protecting group for a phosphono group, Y ₄ represents a protecting group for a hydroxyl group, ₁ is -COA ₁ , A ₁ is an alkyl group having 1 to 30 carbon atoms which may be substituted with one or more hydroxyl groups protected by a hydroxyl protecting group,
Z represents an alkylene group having 1 to 9 carbon atoms, A ₂ represents a cyclic alkyl group having 3 to 12 carbon atoms which may be substituted with one or more hydroxyl groups protected by a protecting group for a hydroxyl group, and Q ₁ represents hydrogen. Or an alkyl group having 1 to 20 carbon atoms, Q ₂ is hydrogen, an alkyl group having 1 to 6 carbon atoms, -CONH ₂ , -COOY ₅ or -CH ₂ OY ₆ , Y ₅ is a protecting group of a carboxyl group, Y ₆ is a hydroxyl-protecting group, and n1 is 0 to
A compound represented by the formula (II), wherein a compound represented by the formula (II) is reacted with a trialkylsilyl halide or hydrogen halide and a Lewis acid. (Wherein, Y ₂ , R ₁ , Y ₃ and Y ₄ are the same as above, and X ₁ represents a halogen atom.) 3. The formula (Ia) (Wherein, the Y _a is an optionally substituted benzyl group, a Y ₂ is an amino-protecting group, Y ₃ is a protecting group of phosphono group, Y ₄ is a hydroxyl-protecting group, R ₁ is - COA ₁ , -COZA ₂ , A ₁ is an alkyl group having 1 to 30 carbon atoms which may be substituted with one or more hydroxyl groups protected by a hydroxyl protecting group,
Z represents an alkylene group having 1 to 9 carbon atoms, A ₂ represents a cyclic alkyl group having 3 to 12 carbon atoms which may be substituted with one or more hydroxyl groups protected by a protecting group for a hydroxyl group, and Q ₁ represents hydrogen. Or an alkyl group having 1 to 20 carbon atoms, Q ₂ is hydrogen, an alkyl group having 1 to 6 carbon atoms, -CONH ₂ , -COOY ₅ or -CH ₂ OY ₆ , Y ₅ is a protecting group of a carboxyl group, Y ₆ is a hydroxyl-protecting group, and n1 is 0 to
A compound represented by the formula (III), wherein a compound represented by the formula (III) is reacted with a hard acid in the presence of a soft nucleophile. (Wherein Y ₂ , Y ₃ , Y ₄ and R ₁ are the same as described above)