JPH0680686A - Acidic functional group-bearing lipid derivative and fine carrier particle coated therewith - Google Patents

Abstract

PURPOSE:To provide fine carrier particles for drug delivery, to be hardly scavenged by the reticulo-endothelial tissue. CONSTITUTION:The objective lipid derivative with a compound having at least one acidic functional group added to one end of the polyethylene glycol chain >=3 in the polymerization degree of ethylene glycol and a compound having at least one >=5C alkyl and/or alkenyl group at the other end. The other objective fine carrier particles coated with this derivative.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a lipid derivative having a novel acidic functional group and a fine particle carrier using the derivative. More specifically, it relates to a lipid derivative having an acidic functional group used as a substance for producing a fine particle carrier coated with a substance having an acidic group, and a fine particle carrier obtained by using the derivative.

[0002]

2. Description of the Related Art Liposomes, lipid microspheres, etc. are used as one means of drug delivery system for delivering effective drug treatment by delivering a drug administered to a living body to a required tissue in a required amount at a required time. It is generally already known to utilize the fine particle carriers of

However, liposomes are easily trapped by reticuloendothelial tissues and do not stay in blood for a desired time. Therefore, how to make the liposome difficult to be captured by the reticuloendothelial system remains a problem to be solved in using the liposome.

[0004]

Means for Solving the Problems To solve the above problems, the present inventor has conducted various studies, and as a result, obtained by introducing a polyethylene glycol chain between the acidic group-containing portion and the lipid portion. The present invention has been completed by finding that the above problems can be solved by coating a liposome with a lipid derivative having an acidic functional group of a novel substance.

That is, according to the present invention, a compound having one or a plurality of acidic functional groups is added to one end of a polyethylene glycol chain having a degree of polymerization of ethylene glycol of 3 or more and one or a plurality of carbon atoms is added to the other end. The present invention relates to a lipid derivative having an acidic functional group to which a compound having an alkyl group and / or an alkenyl group having 5 or more atoms is added, and a fine particle carrier coated with the lipid derivative.

The present invention will be described in detail below.

First, the lipid derivative having an acidic functional group of the present invention will be described.

In the lipid derivative having an acidic functional group of the present invention, a compound having one or a plurality of acidic functional groups is added to one end of a polyethylene glycol chain having a degree of polymerization of ethylene glycol of 3 or more, and 1 is added to the other end. A compound having one or more alkyl groups and / or alkenyl groups having 5 or more carbon atoms is added,
The degree of ethylene glycol polymerization of this polyethylene glycol chain is such that an acidic functional group exists in a form separated from the surface of the fine particles of the fine particle carrier,
It is 3 or more, preferably 3 to 10, and more preferably 3 to 7. When the degree of polymerization of ethylene glycol is 2 or less, the solubility of the lipid derivative having an acidic functional group in an aqueous solvent is low as shown in Test Example 1 (Comparative Example with Polymerization Degree 1). I can not use it. The degree of polymerization of ethylene glycol is included as one even when the terminal hydroxyl group of polyethylene glycol is substituted or eliminated by another functional group.

Examples of the acidic functional group include a phosphoric acid residue,
Sulfate residue, carboxyl group, sulfonyl group, sulfenyl group, sulfinyl group, phosphono group, phosphonyl group, phosphinyl group, phosphenyl group, dihydrohydroxophosphorus group, hydrodihydroxophosphorus group, hydrohydroxophosphorus group and dihydro A xosophorus group can be mentioned.

Examples of compounds having one or more of these acidic functional groups include phosphoric acid; sulfuric acid; compounds having phosphoric acid residues such as phosphoric acid monomethyl ester; sulfuric acid N--
A compound having a sulfuric acid residue such as (3-hydroxypropyl) amide; a phosphonic acid derivative such as 2-hydroxyethanephosphonic acid; a phosphenic acid derivative such as 2-hydroxyethanephosphonic acid; a sulfone such as hydroxymethanesulfonic acid. Acid derivatives; Sulfenic acid derivatives such as p-hydroxymethylbenzenesulfenic acid; Sulfinic acid derivatives such as 3-hydroxy-2-butanesulfinic acid; Malic acid-1-methyl ester,
Mention may be made of carboxylic acids such as glutamic acid; and sugars having acidic functional groups.

And as the sugar having an acidic functional group,
Examples thereof include N-acetylneuraminic acid; uronic acids such as glucuronic acid and galacturonic acid; and those in which one or more of the above-mentioned acidic functional groups are bonded to the following sugars. Examples of the following sugars include, for example, monosaccharides such as arabinopyranose, xylopyranose, lyxopyranose, and ribofuranose; aldopentose; glucopyranose (glucose), galactopyranose (galactose), and mannopyranose ( Mannose), fucopyranose (fucose), and other aldohexoses; 2-amino-2-deoxyglucopyranose, 2-amino-2-deoxygalactopyranose, and other hexosamines; and 2-acetamino-2-deoxyglucopyranose, 2 -Hexosamine derivatives such as acetamino-2-deoxygalactopyranose; and oligosaccharides, lactose, xylopiose,
Disaccharides such as maltose, cellobiose, chitobiose, melibiose, epicellobiose, turanose, sucrose, lactulose and rutinose; trisaccharides such as raffinose, umbelliferose, sialyllactose and 6'-galactosyl lactose; and difucosyl lactose, lacto-N. And tetrasaccharides such as tetraose and lacto-N-neotetraose.

[0012] The bonding mode of an acidic functional group and a sugar, for _{example, -OPO 3 H 2, -OPO 3} Na 2, -OPO
(OPh) ₂ etc., phosphate ester, -OSO
₃ H, be via acid ester an ester bond, such as _{-OSO 3 Na; -O- (CH 2} ) n -COO
Mentioned and, for example, those acidic functional group is bonded directly to a carbon atom of the sugar as follows; H, -O- (CH ₂₎ shall through an ether bond, such as _n -OPO ₃ H ₂ be able to.

[0013]

[Chemical 1] Furthermore, an acidic functional group may be attached to the carbon atom of the sugar via a lower alkyl group such as a methylene group.

When a compound other than a sugar having an acidic functional group is added to one end of polyethylene glycol, the coupling mode is, for example, a phosphate ester such as -OPO ₃ H ₂ , -OPO ₃ Na ₂ or -OSO _3. H, sulfuric acid ester an ester bond, such as -OSO ₃ Na; -O- (CH
_{2) n -COOH, -O- (CH} 2) n -OPO
Ether linkages such as ₃ H ₂ , —O— (CH ₂ ) _n —CONH—, and, for example, those in which an acidic functional group is directly bonded to a carbon atom of polyethylene glycol as described below. it can.

[0015]

[Chemical 2] When a sugar having an acidic functional group is added to polyethylene glycol, for example, a glycosidic bond can be mentioned.
The sugar having an acidic functional group may be added to polyethylene glycol at any carbon atom of the sugar skeleton, and when added via a glycosidic bond, the coordination of the anomeric center may be α or β. Incidentally, addition of sugar having an acidic functional group to polyethylene glycol facilitates glycosidic bond.

The number of carbon atoms of the alkyl group and the alkenyl group in the compound having one or more alkyl groups and / or alkenyl groups having 5 or more carbon atoms attached to the other end of the polyethylene glycol chain is preferably It is 10 or more, but if it exceeds 50, the efficiency of the synthesis reaction of these compounds decreases. The alkyl group and alkenyl group may be linear or branched.

As an embodiment in which these compounds have one or a plurality of alkyl groups and / or alkenyl groups, there are firstly a branched alkyl group or alkenyl group and secondly a branched chain type. And / or a linear alkyl group or an alkenyl group may be bonded via a linker as exemplified below.

[0018]

[Chemical 3] The bonding mode of polyethylene glycol (PEG) and a compound having an alkyl group and / or an alkenyl group is
For example, an ester bond such as PEG-OCO-n-C ₁₆ H ₃₃ and the like; an ether bond such as PEG-O-n-C ₁₈ H ₃₇ and the like; to an amino group of polyethylene glycol in which a terminal hydroxyl group is converted to an amino group. On the other hand, PEG-NHCO-
_{n-C 15 H 31, PEG} -NHCO-CH- (n-C 16 H
₃₃ ) An amide bond such as ₂ ; a urethane bond; and a urea bond; and further those having an alkyl group or an alkenyl group directly bonded to the terminal carbon atom of polyethylene glycol.

Incidentally, the end of polyethylene glycol
In order to change the OH group to the —NH ₂ group, for example, the following may be performed.

[0020]

[Chemical 4] As described above, the lipid derivative having an acidic functional group of the substance of the present invention is a novel substance, but it can be generally produced, for example, as follows.

[0021] That is, after the introduction of the compound or an acidic functional group itself has an acidic functional group such as sugars, having an acidic functional group at one end of the PEG, the other end, changing the terminal -OH groups of the aforementioned -NH ₂ A protected compound of the target compound can be obtained by converting it to an amino group by a method and then acylating, urethanizing or urea-converting the amino group. This can be deprotected to induce the desired compound.

There is also a method in which a protected compound is obtained through etherification or esterification without conversion to an amino group and then deprotected to obtain the desired compound.

Further, after introducing an alkyl group or an alkenyl group into one end of PEG and then introducing a compound having an acidic functional group such as a sugar having an acidic functional group or the acidic functional group itself into the PEG, deprotection is carried out. Can be induced by compounds.

The compound having an acidic functional group can be synthesized based on a general method for introducing an acidic functional group including a sugar having an acidic functional group, or when only an acidic functional group is introduced. It can be performed based on a general method.

Next, the fine particle carrier of the present invention will be described.

The fine particle carrier of the present invention is a fine particle carrier obtained by blending the above-mentioned substance of the present invention, which is a lipid derivative having an acidic functional group, and is a product which makes full use of specific properties of the substance. .

Specific examples of the fine particle carrier of the present invention include liposomes, lipid microspheres, micelles and emulsions. Each of these carriers may be prepared by a conventionally known method, and basically, the substance of the present invention is dissolved or dispersed in a solvent and mixed with other membrane components which are amphipathic substances.

For example, in the case of liposomes, lipids such as phosphatidylcholine, sphingomyelin and phosphatidylethanolamine, and membrane component substances such as dialkyl-type synthetic surfactants and the substance of the present invention are mixed in advance, and the mixture is subjected to a known method. (Ann. Rev. Biophys. Bioeng., 9, 467 (198
An aqueous dispersion of liposomes is prepared according to 0)). Such liposomes may contain sterols such as cholesterol, charged substances such as dialkylphosphoric acid and stearylamine, and antioxidants such as tocopherol as a membrane stabilizer.

In the case of lipid microspheres,
Premixing the phosphatidylcholine with the substance of the invention,
The desired lipid microspheres can be obtained by adding soybean oil to this and treating it according to a known method for preparing lipid microspheres.

In the case of micelles, a surfactant such as polyoxysorbitan fatty acid ester, fatty acid sodium polyoxyethylene hydrogenated castor oil and the substance of the present invention are mixed in advance and treated according to a known method for preparing micelles. The desired micelle can be manufactured.

In the case of an emulsion, a surfactant such as polyoxysorbitan fatty acid ester, sodium fatty acid, polyoxyethylene hydrogenated castor oil, etc. and the substance of the present invention are mixed in advance, and oils such as soybean oil are added thereto. The target emulsion can be produced by treating according to a known emulsion preparation method.

The ratio of the substance of the present invention to the total lipid membrane components in the fine particle carrier produced as described above is preferably about 1/40 molar ratio or more, and more preferably 1/20 molar ratio or more. .

Thus, a fine particle carrier coated with the substance of the present invention is obtained. The substance of the present invention is, for example, a lipid derivative having an acidic group but no water-soluble spacer (PEG structure in the substance of the present invention). In comparison, the water solubility is remarkably improved (see Test Example 1 below), which makes it extremely easy to prepare the fine particle carrier.

There is no particular limitation on the drug which the fine particle carrier can hold, and it may be a water-soluble drug or a fat-soluble drug. For example, an anticancer drug represented by cytosine arabinoside, daunorubicin and methotrexate, and an antibiotic represented by penicillin G. Examples include substances, insulin, interferons, and physiologically active substances represented by tissue plasminogen activator.

[0035]

The present invention will be further described below with reference to examples and inspection examples.

Example 1 The reaction in this example is shown in FIG.

(A) Glycosylation Reaction of Compound 1-1 and Compound 1-2 Compound 1-1 (1.05 g) and alcohol (Compound 1-2)
Dissolve (3.38 g) in methylene chloride (100 ml) and add BF ₃ ·.
Et ₂ O (1.59 g) was added, and the mixture was stirred at room temperature for 7 days. Dilute the reaction mixture with chloroform and add water, 5% NaHCO 3.
₃ Washed successively with water and water, dried and the solvent was distilled off under reduced pressure. The residue was dissolved in pyridine (20 ml), acetic anhydride (15 ml) was added, and the mixture was stirred at room temperature for 2 hours.

The reaction solution was diluted with ethyl acetate, washed successively with water, citric acid water, water, 5% NaHCO ₃ water and water, dried and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane-ethyl acetate 2: 1) using silica gel (150 g). Again, silica gel (150 g)
Was purified by column chromatography (chloroform) to give α-glycoside (Compound 1-3) (0.56 g) and β-glycoside (Compound 1-4) (0.83 g).

(Α-Glycoside) ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J =
6.84Hz), 1.20-1.34 (30H, m), 1.57 (2H,
m), 2.02 (3H, s), 2.03 (3H, s), 2.06 (3
H, s), 3.44 (2H, m), 3.58 (2H, m), 3.63
-3.74 (9H, m), 3.75 (3H, s), 3.82-3.86
(1H, m), 4.45 (1H, d, J = 10.26Hz), 4.8
8 (1H, dd, J = 3.67Hz, 10.26Hz), 5.16
(1H, dd, J = 9.52Hz, 10.26Hz), 5.21 (1
H, d, J = 3.67 Hz), 5.55 (1 H, dd, J = 9.52)
Hz, 10.26 Hz). (Β-glycoside) [α] _D −16.4 ° (c 1.09, CHCl ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J =
6.84Hz), 1.20-1.34 (30H, m), 1.57 (2H,
m), 2.02 (3H, s), 2.02 (3H, s), 2.05 (3
H, s), 3.44 (2H, m), 3.58 (2H, m), 3.60
-3.69 (8H, m), 3.73-3.79 (1H, m), 3.75
(3H, s), 3.39-3.98 (1H, m), 4.04 (1H,
d, J = 8.08Hz), 4.66 (1H, d, J = 7.82H)
z), 5.01 (1H, dd, J = 7.82Hz, 8.79Hz),
5.22 (1H, dd, J = 8.80Hz, 9.28Hz), 5.26
(1H, dd, J = 8.79Hz, 9.28Hz). (b) Synthesis of Compound 1-5 Compound 1-3 (155 mg) was dissolved in methanol (5 ml), 28% NaOMe in MeOH (20 μl) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (5 ml), 0.1N NaOH aqueous solution (2 ml) was added, and the mixture was stirred at room temperature for 20 hr.

After heating the reaction solution, a cation exchange resin "Amberlite IRC-50" manufactured by Rohm and Haas was added, insoluble materials were filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was washed with ether. The target compound 1-5 (80 mg) was obtained as a colorless powder.

[Α] _D + 31.7 ° (c 0.99, MeO
H). ¹ H-NMR (CD ₃ OD) δ: 0.90 (3 H, t, J =
6.59Hz), 1.24-1.38 (30H, m), 1.57 (2H,
m), 3.40-3.45 (2H, m), 3.46-3.50 (2H,
m), 3.57-3.61 (2H, m), 3.62-3.73 (10H,
m), 3.86-3.90 (1H, m), 3.92 (1H, d, J =
10.26 Hz). Example 2 The reaction in this example is also shown in FIG.

(A) Synthesis of Compound 2-1 Compound 1-4 (138 mg) was dissolved in methanol (5 ml), added to 28% NaOMe in MeOH (20 μl), and stirred at room temperature for 5 hours. The reaction solution was compressed under reduced pressure, the residue was dissolved in methanol (5 ml), added to 0.1 N NaOH aqueous solution (3 ml), and stirred at room temperature for 20 hours.

After heating the reaction solution, "Amberlite IRC-
50 "was added, the insoluble matter was filtered off, the filtrate was concentrated to dryness under reduced pressure,
The residue was washed with ether to obtain the target compound 2-1 (87 mg) as a colorless powder.

[Α] _D −22.8 ° (c 0.68, MeO
H). ¹ H-NMR (CD ₃ OD) δ: 0.90 (3 H, t, J =
6.59Hz), 1.24-1.36 (30H, m), 1.57 (2H,
m), 3.22-3.28 (1H, m), 3.40-3.45 (2H,
m), 3.45-3.50 (2H, m), 3.55-3.61 (3H,
m), 3.62-3.75 (8H, m), 3.76-3.82 (1H,
m), 4.06-4.11 (1H, m), 4.32 (1H, d, J =
7.82Hz). Example 3 The reaction in this example is shown in FIG.

(A) Glycosylation Reaction of Compound 1-1 and Compound 3-1 Compound 1-1 (6.00 g) and an alcohol compound (Compound 3-
1) (8.04g) is dissolved in methylene chloride (180ml),
F ₃ · Et ₂ O (9.05 g) was added, and the mixture was stirred at room temperature for 5 days.

The reaction solution was diluted with chloroform and diluted with water, 5%.
It was washed successively with NaHCO ₃ water and water, dried and the solvent was evaporated under reduced pressure. The residue was purified twice by column chromatography (chloroform) using silica gel (200 g) and α-
Glycoside (Compound 3-2) (3.66 g) and β-glycoside (Compound 3-3) (1.60 g) were obtained.

(Α-Glycoside) [α] _D ; + 92.1 ° (c 0.91, CHCl ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 2.02 (3H, s), 2.0
3 (3H, s), 2.06 (3H, s), 3.63-3.73 (9
H, m), 3.75 (3H, s), 3.77 (2H, m), 3.82
-3.87 (1H, m), 4.45 (1H, d, J = 10.02 H
z), 4.88 (1H, dd, J = 3.67Hz, 10.26H
z), 5.17 (1H, dd, J = 9.77Hz, 10.02H
z), 5.21 (1H, d, J = 3.67Hz), 5.54 (1H,
dd, J = 9.77 Hz, 10.26 Hz). (b) Synthesis of compound 3-4 Compound 3-2 (3.70 g) was dissolved in DMF (40 ml), sodium azide (0.74 g) was added, and the mixture was stirred at a bath temperature of 60 ° C for 20 hours.

The reaction mixture was diluted with ethyl acetate, washed with water, dried and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform) using silica gel (200 g) to obtain the target compound 3-4 (2.10 g) as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ: 2.02 (3
H, s), 2.03 (3H, s), 2.06 (3H, s), 3.40
(2H, t, J = 5.13Hz), 3.63-3.73 (9H,
m), 3.75 (3H, s), 3.82-3.87 (1H, m), 4.
45 (1H, d, J = 10.26 Hz), 4.88 (1H, dd,
J = 3.66Hz, 10.26Hz), 5.17 (1H, dd, J =
9.77Hz, 10.26Hz), 5.21 (1H, d, J = 3.66H)
z), 5.54 (1H, dd, J = 9.77Hz, 10.26H
z). (c) Synthesis of compound 3-5 Compound 3-4 (1.70 g) and p-toluenesulfonic acid monohydrate (0.66 g) are dissolved in ethanol (100 ml), Lindlar catalyst (3.00 g) is added, and the mixture is allowed to stand at room temperature. Catalytic reduction was performed at 40 psi for 5 hours.

After filtering the catalyst, the filtrate was concentrated under reduced pressure to obtain the target compound 3-5 (2.05 g) as a colorless foamy substance.

(D) Synthesis of compound 3-7 Amine (compound 3-5) (198 mg) and active ester (compound 3-6) (110 mg) were dissolved in methylene chloride (10 ml), and triethylamine (63 mg) was added. The mixture was stirred at room temperature for 3 hours.

The reaction solution was diluted with ethyl acetate, washed successively with water, citric acid water and water, dried and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform-ethyl acetate 1: 1) using silica gel (20 g),
The target compound 3-7 (135 mg) was obtained as a colorless powder.

[Α] _D + 68.3 ° (c 0.98, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J =
3.84Hz), 1.22-1.34 (24H, m), 1.63 (2H,
m), 2.03 (6H, s), 2.06 (3H, s), 2.18 (2
H, t, J = 7.57Hz), 3.46 (2H, m), 3.55 (2
H, m), 3.58-3.65 (2H, m), 3.67 (2H,
m), 3.70-3.76 (1H, m), 3.75 (3H, s), 3.
82-3.87 (1H, m), 4.45 (1H, d, J = 10.02 H
z), 4.88 (1H, dd, J = 3.67Hz, 10.26H
z), 5.17 (1H, dd, J = 9.53Hz, 10.02H
z), 5.24 (1H, d, J = 3.67Hz), 5.55 (1H,
dd, J = 9.53 Hz, 10.26 Hz), 6.11 (1H, br
s). (e) Synthesis of Compound 3-8 Compound 3-7 (110 mg) was dissolved in methanol (3 ml), 28% NaOMe in MeOH (20 μl) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (3 ml), 0.1N NaOH aqueous solution (2 ml) was added, and the mixture was stirred at room temperature for 3 hr.

"Amberlite IRC-50" was added to the reaction solution, the insoluble matter was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was washed with ether to obtain the target compound 3-8 (80 mg) as a colorless powder. Obtained.

[Α] _D + 35.4 ° (c 1.01, MeO
H). ¹ H-NMR (CD ₃ OD) δ: 0.90 (3 H, t, J =
6.84Hz), 1.24-1.36 (24H, m), 1.60 (2H,
m), 2.20 (2H, t, J = 7.33Hz), 3.34-3.38
(2H, m), 3.41-3.46 (2H, m), 3.54-3.56
(2H, m), 3.60-3.64 (2H, m), 3.65-3.73
(6H, m), 3.90 (1H, m), 3.97 (1H, J = 1
0.26 Hz). Example 4 The reaction in this example is also shown in FIG.

(A) Synthesis of Compound 4-2 Carboxylic acid (Compound 4-1) (204 mg), N-hydroxysuccinimide (HOSu) (46 mg) and N, N '.
-Dicyclohexylcarbodiimide (DCC) (83 mg)
A methylene chloride (20 ml) solution of was stirred at room temperature for 20 hours.
The amine compound (compound 3-5) (364 mg) dissolved in methylene chloride (5 ml) was added to the reaction solution, triethylamine (115 mg) was added, and the mixture was stirred at room temperature for 3 hours.

The reaction solution was diluted with chloroform and diluted with water, 5%.
The organic layer was washed successively with NaHCO ₃ water, water, citric acid water and water, dried and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using silica gel (30 g) (hexane-ethyl acetate 1: 1) to obtain the target compound 4-2 (65 mg) as a colorless powder.

[Α] _D + 50.0 ° (c 0.83, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 0.88 (6H, t, J =
6.59Hz), 1.20-1.33 (56H, m), 1.34-1.43 (2
H, m), 1.53-1.63 (2H, m), 1.98-2.05 (1
H, m), 2.03 (6H, s), 2.06 (3H, s), 3.45
-3.50 (2H, m ₂ ), 3.25-3.57 (2H, m), 3.58
-3.64 (4H, m), 3.64-3.69 (2H, m), 3.70-
3.76 (1H, m), 3.75 (3H, s), 3.81-3.87 (1
H, m), 4.45 (1H, d, J = 10.26 Hz), 4.88
(1H, dd, J = 3.66Hz, 10.26Hz), 5.17 (1
H, dd, J = 9.28Hz, 10.26Hz), 5.24 (1H,
d, J = 3.66Hz), 5.55 (1H, dd, J = 9.28H
z, 10.26 Hz), 6.04 (1H, m). (b) Synthesis of Compound 4-3 Compound 4-2 (540 mg) was added to methanol (3 ml),
28% NaOMe in MeOH (20 μl) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, methanol (3 ml) and 0.1 N NaOH aqueous solution (2 ml) were added to the residue,
Stir at room temperature for 6 hours.

The reaction solution was ice-cooled and the mother liquor was removed by decantation to obtain the precipitated target compound 4-3 (35 mg) as a colorless powder.

[Α] _D + 23.1 ° (c 0.46, MeO
H). ¹ H-NMR (CD ₃ OD) δ: 0.90 (6 H, t, J =
6.84Hz), 1.12-1.34 (56H, m), 1.34-1.45 (2
H, m), 1.50-1.58 (2H, m), 2.19 (1H,
m), 3.34-3.46 (4H, m), 3.52-3.56 (2H,
m), 3.60-3.64 (2H, m), 3.64-3.74 (6H,
m), 3.88-3.92 (1H, m), 3.93 (1H, d, J =
10.26 Hz), 4.86 (1H, d, J = 3.91 Hz). Example 5 The reaction in this example is shown in FIG.

(A) Glycosylation Reaction of Compound 5-1 and Compound 1-2 Powder "Molecular Sieve 4A" (MS4A) (600 mg) and zinc bromide (177 mg) dried under reduced pressure at 150 ° C. for 3 hours.
The alcohol compound (Compound 1-2) (631 mg) was stirred in methylene chloride (20 ml) at room temperature for 2 hours. On the other hand, chloro form (Compound 5-1) (400 mg) and "MS4A" (1.00
g) was stirred in methylene chloride (15 ml) at room temperature for 2 hours and then added dropwise to the above reaction mixture. After stirring at room temperature for 20 hours, the insoluble material was filtered through Celite, the filtrate was washed successively with water, 5% NaHCO ₃ water and water, dried and the solvent was evaporated under reduced pressure.

The residue was subjected to column chromitography (chloroform-methanol 2) using silica gel (100 g).
00: 1) and β-glycoside (compound 5-3)
(157 mg) and. α-Glycoside (Compound 5-2)
(262 mg) was obtained as a colorless foam.

(Α-Glycoside) [α] _D -13.0 ° (c 0.92, CHCl ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J =
6.84Hz), 1.20-1.34 (30H, m), 1.57 (2H,
m), 1.88 (3H, s), 1.98 (1H, dd, J = 12.4
6 Hz, 12.70 Hz), 2.03 (3H, s), 2.04 (3
H, s), 2.14 (3H, s), 2.15 (3H, s), 2.61
(1H, dd, J = 4.64Hz, 12.70Hz), 3.42-3.
48 (3H, m), 3.56-3.67 (10H, m), 3.80 (3
H, s), 3.90 (1H, m), 4.06 (1H, ddd, J
= 9.53Hz, 9.77Hz, 10.50Hz), 4.08 (1H, d
d, J = 1.96 Hz, 10.50 Hz), 4.09 (1H, dd,
J = 5.62Hz, 12.46Hz), 4.29 (1H, dd, J =
2.69 Hz, J = 12.46 Hz), 4.86 (1H, ddd, J
= 4.64Hz, J = 9.77Hz, 12.46Hz), 5.10 (1
H, d, J = 9.53Hz), 5.32 (1H, dd, J = 1.96)
Hz, 8.55Hz), 5.39 (1H, ddd, J = 2.96H
z, 5.62 Hz, 8.55 Hz). (Β-Glycoside) [α] _D + 55.4 ° (c 0.89, CHCl ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J =
6.59Hz), 1.20-1.34 (30H, m), 1.52-1.59 (2
H, m), 1.86 (1H, dd, J = 11.72 Hz, 12.70
Hz), 1.87 (3H, s), 2.00 (3H, s) 2.03 (3
H, s), 2.05 (3H, s), 2.15 (3H, s), 2.44
(1H, dd, J = 5.13Hz, 12.70Hz), 3.43 (2
H, m), 3.49-3.53 (1H, m), 3.58 (2H,
m), 3.61-3.65 (2H, m), 3.65-3.76 (5H,
m), 3.79 (3H, s), 3.80-3.85 (1H, m), 3.
86-3.92 (1H, m), 4.12 (1H, dd, J = 8.55H
z, 12.46 Hz), 4.13 (1H, ddd, J = 10.26 H
z, 10.50 Hz, J = 10.75 Hz), 4.62 (1H, d
d, J = 2.20 Hz, 10.50 Hz), 4.89 (1H, dd,
J = 2.44Hz, 12.46Hz), 5.22 (1H, ddd, J
= 5.13Hz, 10.75Hz, 11.72Hz), 5.31 (1H,
ddd, J = 2.44Hz, J = 3.42Hz, J = 8.55H
z), 5.39 (1H, dd, J = 2.20Hz, 3.42Hz),
6.40 (1H, d, J = 10.26 Hz). (b) Synthesis of Compound 5-4 Compound 5-2 (190 mg) was dissolved in methanol (5 ml), 28% NaOMe in MeOH (20 μl) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (3 ml), 0.1 N NaOH aqueous solution (3 ml) was added, and the mixture was stirred at room temperature for 20 hr.

"Amberlite IRC-50" was added to the reaction solution, the insoluble matter was removed by filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was washed with ether to obtain the target compound 5-4 (113 mg) as a colorless powder. Obtained.

[Α] _D −0.3 ° (c 1.08, MeO
H). ¹ H-NMR (CD ₃ OD) δ: 0.90 (3 H, t, J =
6.84Hz), 1.26-1.38 (30H, m), 1.58 (2H,
m), 1.60 (1H, dd), 2.01 (3H, s), 2.82
(1H, dd, J = 4.46Hz, 12.46Hz), 3.46-3.
51 (3H, m), 3.58-3.72 (15H, m), 3.81-3.88
(2H, m), 3.90-3.95 (1H, m). Example 6 The reaction in this example is shown in FIG.

(A) Glycosylation reaction of compound 6-1 and compound 1-2 Compound 6-1 (293 mg) and alcohol (compound 1-2)
(664 mg) was dissolved in methylene chloride (15 ml), and BF ₃ ·
Et ₂ O (312 mg) was added, and the mixture was stirred at room temperature for 20 hours.

The reaction solution was diluted with chloroform and diluted with water, 5%.
It was washed successively with NaHCO ₃ water and water, dried and the solvent was evaporated under reduced pressure. Column chromatography of the residue using silica gel (60 g) (chloroform-ethyl acetate 1: 1).
Purified in. Column chromatography again using silica gel (60 g) (chloroform-methanol 200:
1) and β-glycoside (compound 5-3) (303
mg) and α-glycoside (Compound 5-2) (26 mg) were obtained.

(B) Synthesis of Compound 6-2 Compound 5-3 (141 mg) was dissolved in methanol (5 ml), 28% NaOMe in MeOH (20 μl) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (3 ml), 0.1 N NaOH aqueous solution (4 ml) was added, and the mixture was stirred at room temperature for 2 days.

"Amberlite IRC-50" was added to the reaction solution, the insoluble material was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was washed with ether to obtain the target compound 6-2 (85 mg) as a colorless powder. Obtained.

[Α] _D -11.4 ° (c 0.76, MeO
H). ¹ H-NMR (CD ₃ OD) δ: 0.90 (3 H, t, J =
6.84Hz), 1.25-1.38 (30H, m), 1.58 (2H,
m), 1.66 (1 H, dd, J = 11.48 Hz, 12.95 H
z), 2.00 (3H, s), 2.39 (1H, dd, J = 4.64)
Hz, 12.95 Hz), 3.46-4.02 (21H, m). Example 7 The reaction in this example is shown in FIG.

(A) Glycosylation reaction of compound 6-1 and compound 3-1 Compound 6-1 (876 mg) and alcohol (compound 3-1)
(830 mg) was dissolved in methylene chloride (50 ml), and BF ₃ ·
Et ₂ O (932 mg) was added, and the mixture was stirred at room temperature for 21 hours.

The reaction solution was diluted with chloroform and diluted with water, 5%.
It was washed successively with NaHCO ₃ water and water, dried and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (150 g) (chloroform-methanol 200: 1).
→ Purify with chloroform-methanol 100: 1), β-
Glycoside (Compound 7-2) (566 mg), followed by β-glycoside (Compound 7-2) and α-glycoside (Compound 7)
A 3: 1 mixture of -1) (208 mg) was obtained.

(Β-Glycoside) [α] _D + 4.6 ° (c 1.75, CHCl ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 1.89 (1 H, dd, J
= 11.70 Hz, 12.95 Hz), 1.89 (3 H, s), 2.01
(3H, s), 2.03 (3H, s), 2.06 (3H, s),
2.15 (3H, s), 2.43 (1H, dd, J = 4.88Hz,
12.95 Hz), 3.51-3.56 (1H, m), 3.62-3.85
(9H, m), 3.80 (3H, s), 3.88-3.97 (2H,
m), 4.12 (1H, dd, J = 8.30Hz, 12.46H
z), 4.13 (1H, ddd, J = 10.26 Hz, 10.51 H
z, 10.99 Hz), 4.56 (1H, dd, J = 2.20 Hz,
10.51 Hz), 4.89 (1H, dd, J = 2.44Hz, 12.4
6 Hz), 5.25 (1H, ddd, J = 4.88Hz, 10.99
Hz, 11.70 Hz), 5.28 (1H, ddd, J = 2.44H
z, 3.42Hz, 8.30Hz), 5.40 (1H, dd, J = 2.
20Hz, 3.42Hz), 5.93 (1H, d, J = 10.26H
z). (b) Synthesis of compound 7-3 Compound 7-2 (675 mg) was dissolved in DMF (15 ml), sodium azide (137 mg) was added, and the mixture was stirred at a bath temperature of 60 ° C for 40 hours.

The reaction mixture was diluted with ethyl acetate, washed with water,
After drying, the solvent was distilled off under reduced pressure. The residue is treated with silica gel (50
The target compound 7-3 was purified by column chromatography (chloroform-methanol 150: 1) using g).
(510 mg) was obtained as a colorless oily substance.

[Α] _D + 2.6 ° (c 1.02, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 1.89 (1 H, dd, J
= 11.70 Hz, 12.94 Hz), 1.89 (3 H, s), 2.01
(3H, s), 2.03 (3H, s), 2.06 (3H, s),
2.15 (3H, s), 2.44 (1H, dd, J = 4.89Hz,
12.94 Hz), 3.43-3.50 (2H, m), 3.50-3.54
(1H, m), 3.61-3.73 (7H, m), 3.75-3.90
(2H, m), 3.80 (3H, s), 4.12 (1H, dd,
J = 8.55Hz, 12.46Hz), 4.14 (1H, ddd, J
= 10.02 Hz, 10.50 Hz, 10.75 Hz), 4.46 (1
H, dd, J = 2.20Hz, 10.50Hz), 4.90 (1H,
dd, J = 2.44 Hz, 12.46 Hz), 5.25 (1H, dd
d, J = 4.89Hz, 10.75Hz, 11.70Hz), 5.27
(1H, ddd, J = 2.44Hz, 3.42Hz, 8.55H
z), 5.40 (1H, dd, J = 2.20Hz, 3.42Hz),
5.94 (1H, d, J = 10.02 Hz). (c) Synthesis of compound 7-4 Compound 7-3 (510 mg) and p-toluenesulfonic acid monohydrate (150 mg) were dissolved in methanol (50 ml), Lindlar catalyst (1.50 g) was added, and the temperature was 50 psi. The catalytic reduction was performed for 7 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain the target compound (590 mg).

(D) Synthesis of Compound 7-5 The amine compound 7-4 and N-palmitoyloxysuccinimide (102 mg) were dissolved in methylene chloride (20 ml),
Triethylamine (58 mg) was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with methylene chloride, washed successively with water, citric acid water and water, dried and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using silica gel (50 g) (chloroform-methanol 150: 1 → chloroform-methanol 100: 1) to obtain the target compound (181 m
g) was obtained as a colorless oil.

[Α] _D + 9.5 ° (c 0.94, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J =
6.59Hz), 1.20-1.36 (24H, m), 1.62 (2H,
m), 1.86 (3H, s), 1.90 (1H, dd, J = 11.7)
3 Hz, 12.70 Hz), 2.02 (3H, s), 2.03 (3
H, s), 2.05 (3H, s), 2.15 (3H, s), 2.19
(2H, m), 2.42 (1H, dd, J = 4.89Hz, 12.7
0 Hz), 3.28-3.35 (1H, m), 3.48-3.74 (10
H, m), 3.80 (3H, s), 3.80-3.90 (1H,
m), 4.12 (1H, dd, J = 8.55Hz, 12.22H
z), 4.12 (1H, ddd, J = 10.50 Hz, 10.75 H
z), 4.52 (1H, dd, J = 2.20Hz, 10.50H
z), 4.90 (1H, dd, J = 2.44Hz, 12.2Hz),
5.25 (1H, ddd, J = 2.44Hz, 3.17Hz, 8.55H
z), 5.27 (1H, ddd, J = 4.89Hz, 10.75H
z, 11.73 Hz), 5.41 (1H, dd, J = 2.20 Hz,
3.17Hz), 6.37-6.40 (2H, m). (e) Synthesis of Compound 7-6 Compound 7-5 (170 mg) was dissolved in methanol (4 ml) and 28% sodium methoxide methanol solution (20 μm) was added.
1) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol (4 ml), and 0.1 N N
aOH water (2 ml) was added and the mixture was stirred at room temperature for 5 hours. "Amberlite IRC-50" was added to the reaction solution, the insoluble matter was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was washed with ether,
The target compound (113 mg) was obtained as a colorless powder.

[Α] _D -17.3 ° (c 0.97, MeO
H). ¹ H-NMR (CD ₃ OD) δ: 0.90 (3 H, t, J =
6.84Hz), 1.24-1.36 (24H, m), 1.56-1.36 (3
H, s), 1.99 (3H, s), 2.20 (2H, t, J = 7.
33Hz), 2.41 (1H, dd, J = 4.89Hz, 12.95H
z), 3.35-3.38 (2H, m), 3.44-3.48 (1H,
m), 3.53-3.72 (11H, m), 3.76-4.02 (5H,
m). Example 8 The reaction in this example is also shown in FIG.

(A) Synthesis of Compound 8-1 Carboxylic acid (Compound 4-1) (153 mg), N-hydroxysuccinimide (35 mg) and N, N'-dicyclohexylcarbodiimide (62 mg) in methylene chloride (40 ml) A mixed solution of hexane and hexane (20 ml) was stirred at room temperature for 15 hours.
Amine compound 7-4 (200 mg) dissolved in acetonitrile (20 ml) was added to the reaction solution, triethylamine (53 mg) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, diluted with chloroform, water, 5% NaHCO ₃
The extract was washed successively with water, water, citric acid water and water, dried and the solvent was distilled off under reduced pressure. Column chromatography of the residue using silica gel (50 g) (chloroform-methanol)
Purification with 150: 1) gave the target compound 8-1 (162 mg) as a colorless wax.

[Α] _D + 5.9 ° (c 1.03, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 0.88 (6H, t, J =
6.84Hz), 1.20-1.33 (56H, m), 1.33-1.44 (2
H, m), 1.53-1.64 (2H, m), 1.86 (3H,
s), 1.90 (1 H, dd, J = 11.48 Hz, 12.94 H
z), 1.99-2.05 (1H, m), 2.01 (3H, s), 2.
03 (3H, s), 2.05 (3H, s), 2.15 (3H,
s), 2.43 (1H, dd, J = 4.89Hz, 12.94H
z), 3.30-3.38 (1H, m), 3.40-3.70 (9H,
m), 3.80 (3H, s), 3.79-3.89 (1H, m), 4.
12 (1H, dd, J = 8.55Hz, 12.46Hz), 4.12
(1H, ddd, J = 10.02 Hz, 10.75 Hz, 10.75
Hz), 4.51 (1H, dd, J = 2.44Hz, 10.75H
z), 4.91 (1H, dd, J = 2.44Hz, 12.46H
z), 5.25 (1H, ddd, J = 2.44Hz, 3.42Hz,
8.55Hz), 5.28 (1H, ddd, J = 4.89Hz, 10.7
5 Hz, 11.48 Hz), 5.41 (1H, dd, J = 2.44H
z, 3.42Hz), 6.28 (1H, m), 6.36 (1H, d,
J = 10.02 Hz). (b) Synthesis of Compound 8-2 Compound 8-1 (155 mg) was dissolved in methanol (4 ml), 28% NaOMe in MeOH (20 μl) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (12 ml), 0.1 N NaOH aqueous solution (3 ml) was added, and the mixture was stirred at room temperature for 16 hr. After heating the reaction solution, "Amberlite IRC-50" was added, the insoluble matter was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was washed with ether,
The target compound 8-2 (99 mg) was obtained as a colorless powder.

¹ H-NMR (CD ₃ OD) δ: 0.90 (6
H, t, J = 6.59Hz), 1.20-1.44 (58H, m), 1.
50-1.58 (2H, m), 1.63 (1H, dd, J = 11.72)
Hz, 12.95 Hz), 1.99 (3H, s), 2.18 (1H,
m), 2.42 (1H, dd, J = 4.89Hz, 12.95H
z), 3.36-3.40 (2H, m), 3.43-3.47 (1H,
m), 3.51-3.59 (3H, m), 3.60-3.74 (8H,
m), 3.76-3.83 (2H, m), 3.84-3.94 (2H,
m), 3.96-4.02 (1H, m). Example 9 The reaction in this example is shown in FIG.

(A) Synthesis of Compound 9-1 Triethylene glycol monooctadecyl ether 1.02
20 ml of pyridine was added to g to dissolve, and the mixture was stirred under ice cooling. 788 μl of diphenylphosphonium chloride was added thereto, and the mixture was stirred at room temperature for 17.5 hours.

The reaction solution was diluted with methylene chloride and washed with 1N hydrochloric acid until the washing solution became neutral. Then, it was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent; n-hexane-ethyl acetate).
1: 1), 1.48 g of the desired product was obtained.

¹ H-NMR (δ, CDCl ₃ ): 0.88
(T, 3H, J = 7.0 Hz), 1.25 (s, 30H), 1.54
-1.58 (m, 2H), 3.43 (t, 2H, J = 6.8H
z), 3.55-3.57 (m, 2H), 3.61-3.63 (m, 6
H), 3.72-3.74 (m, 2H), 4.36-4.40 (m, 2)
H), 7.17-7.20 (m, 2H), 7.23-7.25 (m, 4
H), 7.32-7.35 (m, 4H). (b) Synthesis of compound 9-2 20 ml of ethyl acetate was added to 1.46 g of compound 9-1 to dissolve it, and 0.065 g of platinum oxide was added thereto and catalytically reduced at normal pressure for 23 hours.

The catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue is a Sephadex L gel filtration resin manufactured by Pharmacia.
It was purified by gel filtration on "H-20" (elution solvent; methanol). The solvent was distilled off under reduced pressure to obtain 1.02 g of the desired product.

¹ H-NMR (δ, CDCl ₃ ): 0.88
(T, 3H, J = 7.0 Hz), 1.21-1.31 (m, 30
H), 1.58 (m, 2H), 3.47 (t, 2H, J = 7.0 H
z), 3.60-3.63 (m, 2H), 3.65-3.72 (m, 8)
H), 4.09 (bs, 2H), 4.19-4.22 (m, 2H). FAB-MS: [M + H] ⁺ ; m / z = 483. Example 10 The reaction in this example is shown in FIG. 6 (b).

(A) Synthesis of Compound 10-1 Triethylene glycol monooctadecyl ether 1.09
To g, 5 ml of tetrahydrofuran and 5 ml of N, N-dimethylformamide were added and dissolved. To this, 1.07 g of triphenylphosphine and 219 μl of pyridine were added, and the mixture was stirred under ice cooling. 210 μl of bromine was added thereto, and the mixture was stirred at room temperature for 17 hours.

The solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent: n-
Hexane-ethyl acetate 8: 1), 1.21 g of the desired product was obtained.

¹ H-NMR (δ, CDCl ₃ ): 0.88
(T, 3H, J = 7.0 Hz), 1.18-1.34 (m, 30
H), 1.55-1.60 (m, 2H), 3.45 (t, 2H, J =
6.5 Hz), 3.47 (t, 2H, J = 6.4 Hz) 3.58-3.
89 (m, 2H), 3.64-3.70 (m, 6H), 3.82 (t,
2H, J = 6.4 Hz). (b) Synthesis of compound 10-2 Compound 1.-1, 1.91 g of triethylphosphite 2.2 m
l was added and the mixture was stirred at 150 ° C. for 17 hours under an argon atmosphere.

Triethylphosphite was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methylene chloride-methanol 50:
1), 1.35 g of the desired product was obtained.

¹ H-NMR (δ, CDCl ₃ ): 0.88
(T, 3H, J = 6.8 Hz), 1.23-1.31 (m, 30
H), 1.54-1.60 (m, 2H), 2.13 (dt, 2H, J
= 9.5 Hz, 7.5 Hz), 3.44 (t, 2H, J = 6.8 H
z), 3.56-3.66 (m, 8H), 3.72 (dt, 2H, J
= 11.0 Hz, 7.5 Hz), 4.06-4.14 (m, 4H). (c) Synthesis of Compound 10-3 To 0.60 g of Compound 10-2, 10 ml of methylene chloride was added and dissolved. Trimethylsilyl bromide under argon atmosphere 3.
05 ml was added, and the mixture was stirred at room temperature for 7 days. The solvent was distilled off under reduced pressure, the residue was dissolved in 2 ml of methylene chloride, 1 ml of acetone and 0.5 ml of water were added, and the mixture was stirred for 30 minutes.

The solvent was distilled off under reduced pressure and reprecipitated from methyl chloride-n-hexane to give 0.26 g of the desired product as a colorless powder.
Obtained.

¹ H-NMR (δ, CDCl ₃ ): 0.88
(T, 3H, J = 6.8 Hz), 1.18-1.34 (m, 30
H), 1.58 (m, 2H), 2.16-2.21 (bs, 2H),
3.46 (t, 2H, J = 7.0 Hz), 3.58-3.70 (m, 8
H), 3.81-3.84 (m, 2H), 6.95 (bs, 2H). FAB-MS: [M + H] ⁺ ; m / z = 466. Example 11 The reaction in this example is shown in FIG.

(A) Synthesis of compound 11-1 Sodium hydride (60%, 2.955 g) was washed with hexane three times, and 50 ml of DMF was added. Dibenzyl malonate (20 g) was added dropwise to the suspension under ice cooling, and the mixture was stirred at room temperature for 30 minutes.
The resulting solution was ice-cooled and cetyl bromide (51.56g) was added dropwise. After stirring at room temperature for 1 hour, the mixture was heated with stirring at 50 ° C. for 15 hours.

The solution was extracted twice with 500 ml of a 2: 1 hexane-ethyl acetate mixed solvent. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solution was filtered, the solvent was evaporated under reduced pressure, and then the residue was separated by 1,000 ml of silica gel column chromatography (hexane: toluene = 2: 1-1: 1.5) to obtain the desired product. 43.423 g.

M. p. 43-43.5 ° C. ¹ H-NMR (δ, CDCl ₃ ): 0.880 (t, 6H,
J = 6.9 Hz), 1.02-1.07 (m, 2H), 1.16-1.32
(M, 52H), 1.86-1.89 ( m, 2H 2), 5.098
(S, 2H), 7.24-7.31 (m, 10H). (b) Synthesis of compound 11-3 via compound 11-2 Compound 11-1 (35.605 g) was dissolved in 200 ml of ethyl acetate, 10% palladium-carbon (700 mg) was added, and hydrogenation was performed at 50 psi. went. The crystals and catalyst formed are filtered off,
600 ml of chloroform was added and heated at 50 ° C. to filter the catalyst. The filtrate was collected and the solvent was evaporated under reduced pressure to give a crude product of compound 11-2. m. p. = 88.5-89.5
° C, 26.36 g.

The crude product of compound 11-2 was heated at 170 ° C. without solvent.
Heated for 4 hours. The residue was recrystallized from chloroform / methanol to obtain compound 11-3. 21.545g.

M. p. 77.0-79.0 ° C. ¹ H-NMR (δ, CDCl ₃ ): 0.880 (t, 6H,
J = 6.9 Hz), 1.02-1.33 (m, 52H), 1.43-1.50
(M, 52H), 1.58-1.66 (m, 2H), 2.32-2.37
(M, 1H). (c) Synthesis of compound 11-4 10 ml of thionyl chloride was added to 2.98 g of compound 11-3 and refluxed under heating for 2 hours. Thionyl chloride was distilled off under reduced pressure, benzene was added and dissolved therein, and benzene was distilled off again under reduced pressure to obtain compound 11-4. This was used in the next reaction without purification.

(D) Synthesis of compound 11-5 To 30.6 g of 2- [2- (2-chloroethoxy) ethoxy] ethanol, 150 ml of N, N-dimethylformamide was added and dissolved. 17.7 g of sodium azide was added thereto, and the mixture was stirred at 80 ° C. for 13 hours under an argon atmosphere.

After the precipitate was filtered off, the solvent was distilled off under reduced pressure. Ethyl acetate was added thereto, the resulting precipitate was filtered off, and the solvent was distilled off again under reduced pressure. The residue was dissolved in 300 ml of water, and the cross-linked polyethylene resin “CHP-2” manufactured by Mitsubishi Kasei Co., Ltd.
It is adsorbed on a column packed with "0" and poured into water to desalt,
Then, the solvent was changed to methanol to elute the desired product.
The solvent was distilled off under reduced pressure, and the remaining water was removed azeotropically with benzene and ethanol to obtain 30.1 g of the desired product as a colorless oil.

¹ H-NMR (δ, CDCl ₃ ): 2.27
(T, 1H, J = 6.0 Hz), 3.40 (t, 2H, J = 5.
0 Hz), 3.62-3.63 (m, 2H), 3.67-3.71 (6
H, m), 3.73-3.76 (m, 2H). (e) Synthesis of compound 11-6 5.0 g of compound 11-5 was dissolved in 150 ml of methanol, 2 g of Lindlar catalyst was added, and catalytic reduction was performed for 21 hours under a pressure of about 40 psi.

After the catalyst was filtered off, the solvent was distilled off under reduced pressure,
4.3 g of the desired product was obtained as a colorless oil.

¹ H-NMR (δ, CDCl ₃ ): 1.94
(Bs, 3H), 2.88 (t, 2H, J = 5.3 Hz), 3.
56 (t, 2H, J = 5.3 Hz), 3.61-3.63 (m, 2
H), 3.64-3.66 (m, 2H), 3.68-3.70 (m, 2)
H), 3.73-3.74 (m, 2H). (f) Synthesis of compound 11-7 2.62 g of compound 11-6 was dissolved in 20 ml of methylene chloride and stirred under ice cooling. Here, the compound 11-4 obtained by the above method
The whole amount was dissolved in 10 ml of methylene chloride and added, and the mixture was stirred at room temperature for 17.5 hours.

The precipitate formed by the reaction was dissolved by adding methylene chloride and washed with water and then saturated saline. After drying over magnesium sulfate, the catalyst was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (elution solvent; methylene chloride-methanol 70: 1),
As a colorless powder, 2.90 g of the desired product was obtained.

¹ H-NMR (δ, CDCl ₃ ): 0.88
(T, 3H, J = 7.0 Hz), 1.20-1.31 (m, 56
H), 1.36-1.42 (m, 2H), 1.54-1.60 (m, 2)
H), 2.00 (m, 1H), 2.45 (t, 1H, J = 6.0 H
z), 3.48 (dt, 2H, J = 5.3 Hz), 3.57 (t,
2H, J = 5.3 Hz), 3.62-3.64 (m, 4H), 3.67
-3.69 (m, 2H), 3.73-3.77 (m, 2H), 6.02
(T, 1H, J = 5.3 Hz). (g) Synthesis of compound 11-8 To 0.100 g of compound 11-7, 2 ml of pyridine and 1 ml of methylene chloride were added and dissolved, and the mixture was stirred under ice cooling. Diphenyl phosphonyl chloride 48.4μl was added here, at room temperature
It was stirred for 22 hours.

The reaction solution was diluted with methylene chloride and washed with 1N hydrochloric acid until the washing solution became neutral. Then, it was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; n-hexane-ethyl acetate 2: 1) to obtain 0.110 g of the desired product.

¹ H-NMR (δ, CDCl ₃ ): 0.88
(T, 6H, J = 6.8 Hz), 1.18-1.30 (m, 58
H), 1.52-1.60 (m, 2H), 1.98 (m, 1H), 3.
42-3.45 (m, 2H), 3.51 (t, 2H, J = 5.0 H
z), 3.56-3.58 (m, 2H), 3.61-3.63 (m, 2
H), 3.74-3.76 (m, 2H), 4.38-4.42 (m, 2)
H), 6.06 (t, 1H, J = 5.5 Hz), 7.18-7.25
(M, 6H), 7.34 (t, 4H, J = 8.0 Hz). (h) Synthesis of compound 11-9 To 0.099 g of compound 11-8, 2 ml of ethyl acetate and 2 ml of tetrahydrofuran were added and dissolved, and platinum oxide 0.0
08 g was added, and catalytic reduction was carried out at normal pressure for 14 hours.

The catalyst was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by gel filtration with "Sephadex LH-20" (elution solvent; methylene chloride-methanol).
2: 1). The solvent was distilled off under reduced pressure to obtain 0.075 g of the desired product.

¹ H-NMR (δ, CDCl ₃ ): 0.88
(T, 6H, J = 7.0 Hz), 1.16-1.31 (m, 56
H), 1.35-1.42 (m, 2H), 1.54-1.62 (m, 2)
H), 2.04-2.10 (m, 1H), 2.67 (bs, 2H),
3.49 (bs, 2H), 3.64-3.70 (m, 8H), 4.19-
4.23 (m, 2H). FAB-MS: [M + H] ⁺ ; m / z = 720. Example 12 The reaction in this example is shown in FIG.

(A) Synthesis of compound 12-3 1,6-anhydrolactose peracetate (compound
12-1) (50 g, 86.7 mmol), 28% sodium methylate (2 ml) and methanol (600 ml) were stirred at room temperature for 4 hours and treated by a conventional method to prepare 1,6-anhydrolactose (compound 12-2) ( 28.5 g) was obtained.

[Α] _D −46.5 ° (c 1.0, H ₂ O). Compound 12-2 (16.2 g) was dissolved in pyridine (150 ml), trityl chloride (20.9 g) was added, and the mixture was reacted at 50 ° C for 2 hr. Then, at room temperature, a solution of benzoyl chloride in pyridine (5
0.6 g) was added and the mixture was stirred overnight.

The reaction solution was poured into ice water, extracted with chloroform and purified by silica gel column chromatography (ethyl acetate-hexane, 1: 1) to give compound 12-3.
(35 g) was obtained.

The elemental analysis values as C ₆₆ H ₅₄ O ₁₅ are calculated values: C, 72.93; H, 5.01 but actually measured values, C, 72.63;
It was H, 5.30.

[Α] _D + 54.2 ° (c 1.0, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ): 3.16 (1 H, dd, J =
9.5 Hz, 8.8 Hz), 3.35 (1H, dd, J = 9.5H
z, 5.6 Hz), 3.74 (1H, s), 3.76 (1H, d
d, J = 7.6 Hz, 6.0 Hz), 4.01 (1H, d, J =
7.6 Hz), 4.08 (1H, dd, J = 8.8 Hz, 5.6 H
z), 4.53 (1H, d, J = 5.4 Hz), 4.94 (1H,
s), 5.24 (1H, d, J = 8.1 Hz), 5.63 (1H,
dd, J = 10.3Hz, 3.4Hz), 5.64-5.65 (2H,
m), 5.78 (1H, dd, J = 10.3Hz, 8.1Hz),
7.0-8.1 (40H, m). (b) Synthesis of Compound 12-4 Compound 12-3 (34.5 g) was added to chloroform-methanol-
It was dissolved in 400 ml of a mixed solvent of water (100: 100: 1), paratoluenesulfonic acid (1.2 g) was added, and the mixture was reacted at 50 ° C. for 6 hours.

The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, the solvent was evaporated, the mixture was extracted with chloroform and purified by silica gel column chromatography (ethyl acetate-hexane, 1: 1) to give compound 12-4 (18.6 g). ) Got.

Elemental analysis values as C ₄₇ H ₄₀ O ₁₅ were calculated values: C, 66.86; H, 4.77 actually measured value: C, 66.43;
H, 4.95.

[Α] _D + 104.3 ° (c 1.02, CHCl
₃ ). (c) Synthesis of Compound 12-5 Compound 12-4 (18.5 g) was dissolved in 90 ml of pyridine and ice-cooled, diphenylphosphorochloridate (8.27 g) was added, and the mixture was returned to room temperature and stirred for 1 hour.

The reaction solution was poured into ice water, extracted with chloroform, and purified by silica gel column chromatography (ethyl acetate-hexane, 1: 1) to give compound 12-
5 (18.6 g) was obtained.

The elemental analysis values for C ₅₉ H ₄₉ O ₁₈ P were the calculated values: C, 65.79; H, 4.59; P, 2.88, whereas the measured values were C, 65.66; H, 4.83; P, 3.24.

[Α] _D + 53.8 ° (c 0.976, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ): 3.78 (2H, m), 4.02
(1H, d, J = 7.6Hz), 4.04 (1H, ddd, J
= 10.5Hz, 7.5Hz, 7.0Hz), 4.22 (1H, dd
d, J = 10.5Hz, 8.0Hz, 7.0Hz), 4.34 (1
H, t, J = 6.0Hz), 4.56 (1H, d, J = 5.4H)
z), 4.96 (1H, s), 5.31 (1H, d, J = 8.1 H
z), 5.58 (1H, dd, J = 10.4Hz, 3.4Hz),
5.67 (2H, m), 5.86 (1H, dd, J = 10.4Hz,
8.1 Hz), 7.0-8.1 (35 H, m). (d) Synthesis of compound 12-6 A mixture of compound 12-5 (18.2 g), trifluoroacetic acid 29 ml and acetic anhydride 356 ml was stirred at room temperature for 20 hours.

The reaction solution was concentrated under reduced pressure, and the residual solid was subjected to silica gel column chromatography (ethyl acetate-hexane,
Compound 12-6 (α / β = 71/2) after purification by 1: 1)
9, 17 g) was obtained.

Elemental analysis values as C ₆₃ H ₅₅ O ₂₁ P were calculated values: C, 64.18; H, 4.70; P, 2.63, but actually measured values:
C, 64.10; H, 4.79; P, 2.88.

[Α] _D + 50.5 ° (c 1.02, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ): (α-anomer); 2.0
3, 2.14 (each s), 3.43 (dt, J = 10.5Hz, 7.0
Hz, 7.0 Hz), 3.63 (dt, J = 10.5Hz, 10.5H
z, 7.0 Hz), 3.90 (t, J = 7.0 Hz), 4.03
(M), 4.06 (t, J = 10.3Hz), 4.22 (dd, J =
11.4Hz, 3.4Hz), 4.27 (dd, J = 11.4Hz, 1.
7 Hz), 4.77 (d, J = 8 Hz), 5.37 (dd, J =
8.5 Hz, 3.5 Hz), 5.67 (dd, J = 10.2 Hz, 7.8
Hz), 5.69 (s), 5.97 (dd, J = 10.3 Hz, 8.5
Hz), 6.47 (d, J = 3.5 Hz), 7.1-8.0
(M). (Β-anomer); 2.02, 2.10 (each s, 2 × OA
c), 3.40 (dt, J = 10.5Hz, 7.0Hz), 3.56
(Dt, J = 10.5Hz, 10.5Hz, 7.0Hz), 3.77
(M), 4.71 (d, J = 7.8 Hz), 5.50 (dd, J =
10.0Hz, 8.3Hz), 5.64 (dd, J = 10.5Hz, 7.
8 Hz), 5.74 (t, J = 9.5 Hz), 5.86 (d, J =
8.3 Hz), 7.1-8.0 (m). (e) Synthesis of compound 12-7 A mixture of compound 12-6 (10 g), triethylene glycol n-octadecyl ether (3.4 g), methylene chloride 150 ml and "Molecular Sieve 4A" (MS4A) was ice-cooled and trimethylsilyl triflate. The rate (2.82 g) was added dropwise, and the mixture was reacted at room temperature for 3 hours.

The reaction solution was poured into 10% aqueous sodium hydrogen carbonate, and the organic layer was purified by silica gel column chromatography (benzene-ethyl acetate-hexane, 1: 1: 1) to give compound 12
-7 (2.7 g) was obtained.

Mp: 39-40 ° C. The elemental analysis value as C ₈₅ H ₁₀₁ O ₂₃ P was calculated value: C,
67.08 ； H, 6.69 Actual value: C, 66.65 ； H, 6.72
Met.

[Α] _D + 18.4 ° (c 0.964, CHCl
₃ ). ¹ H-NMR (CDCl ₃ ): 0.89 (3H, t, J = 7.0
Hz), 1.27 (30H, s), 1.57 (2H, m), 2.00
(3H, s), 3.3-3.7 (14H, m), 3.65 (1H,
ddd, J = 9.4 Hz, 5.0 Hz, 1.7 Hz), 3.98
(1H, t, J = 9.4 Hz), 4.15 (1H, dd, J =
12.0Hz, 5.0Hz), 4.32 (1H, dd, J = 12.0H)
z, 1.7 Hz), 4.72 (1H, d, J = 7.9 Hz), 4.
74 (1H, d, J = 7.9 Hz), 5.34 (1H, dd, J
= 10.0Hz, 3.0Hz), 5.37 (1H, dd, J = 10.0
Hz, 7.9 Hz), 5.64 (1H, dd, J = 10.0Hz,
7.9Hz), 5.67 (1H, m), 5.69 (1H, t, J = 1
0.0Hz), 7.1-8.0 (35H). (f) Synthesis of compound 12-8 Compound 12-7 (0.9 g) was dissolved in 18 ml of ethyl acetate and catalytically reduced at room temperature and atmospheric pressure for 20 hours using platinum oxide as a catalyst.
After removing the catalyst by filtration and neutralizing with 28% sodium methylate (p
H6) The solvent was distilled off. The remaining solid was dissolved in benzene-methanol (1: 1, 24 ml) and 28% sodium methylate was added.
0.6 ml was added and stirred at room temperature for 20 hours.

To the reaction solution was added 3.1 ml of 1N HCl, the solvent was distilled off, and column chromatography (“CHP-
20 ", 22 mm x 40 cm, 0-50% acetonitrile) to give a powder of compound 12-8 (0.402 g, 80%).
A portion of this was recrystallized from 0.5N NaOH-ethanol to give a disodium salt of compound 12-8 as an analytical sample.

Mp: 195-199 ° C. (dec). The elemental analysis values as C ₃₆ H ₆₉ O ₁₇ PNa ₂ .4H ₂ O are calculated values: C, 46.85; H, 8.40; P, 3.36; Na,
Measured values for 4.98 C, 47.06; H, 8.32; P, 3.31; N
It was a, 4.83.

[Α] _D −4.5 ° (c 0.8, H ₂ O). ¹ H-NMR (D ₂ O): 0.91 (3 H, bs), 1.33 (3
0H, bs), 1.60 (2H, bs), 3.3-4.5 (28
H, bm). Example 13 The reaction in this example is shown in FIG.

(A) Synthesis of compound 13-1 Mannose peracetate (7.457 g) and triethylene glycol monostearyl ether (10 g) in methylene chloride (200 ml) were dissolved in boron trifluoride ether complex (9.40 ml) in methylene chloride. (30 ml) was added under ice cooling, and the mixture was stirred overnight at room temperature. The obtained solution was added to ice water, and 150 ml of chloroform was added for extraction. The organic layer was washed twice with water and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was separated by 100 ml of silica gel column chromatography (chloroform: acetonitrile = 100: 1-100: 1.5) to obtain a mixture of the desired product and the starting alcohol. 4.9162g.

This mixture was dissolved in 100 ml of methanol,
Sodium methylate methanol solution (5 mol / l)
20 drops were added, and the mixture was stirred at room temperature for 5 hours. D in the resulting solution
owex acidic ion exchange resin "Dowex 50W x
8 "was added for neutralization, the resin was filtered off, and the solvent was distilled off under reduced pressure. Toluene 100 ml was added to the residue, and toluene was distilled off under reduced pressure to remove alcohol and water. The residue was dissolved in 150 ml of pyridine, trityl chloride (3.511 g) was added, and the mixture was heated with stirring at 50 ° C. for 5 hours.

The obtained solution was added to ice water and extracted with 300 ml of chloroform. The organic layer was washed once with 2N hydrochloric acid and three times with water, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (500 ml) (chloroform: methanol = 100: 1-100: 2) to obtain the desired product. 3.2270g.

[Α] _D ²⁷ = + 10.3 ° (c 1.25, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.879 (3H, t,
J = 6.9 Hz), 1.17-1.32 (30H), 1.52-1.59 (2
H, m), 2.742 (1H, d), 2.57-2.58 (2H,
m), 3.429 (3H, t, J = 6.9 Hz), 3.56-3.78
(15H), 3.80-3.85 (1H, m), 3.96 (1H, br
dt), 4.905 (1H, d, J = 1.5 Hz), 7.23-7.
46 (15H). (b) Synthesis of compound 13-2 To a solution of compound 13-1 (3.2070 g) in pyridine (50 ml) was added benzoyl chloride (2.01 g), and the mixture was stirred overnight at room temperature.

The solution was added to ice water, and chloroform (100 m
l). The organic layer was washed once with 2N hydrochloric acid and twice with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by 350 ml silica gel column chromatography (hexane: ethyl acetate = 5: 1−).
4: 1), the desired product was obtained. 3.9575g.

[Α] _D ²⁹ = -67.1 ° (c 1.12, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.877 (t, 3H,
J = 6.9 Hz), 1.22-1.30 (m, 30H), 1.52-1.58
(M, 2H), 3.413 (t, 3H, J = 6.8 Hz), 3.
39-3.83 (m, 12H), 3.247 (dd, 1H, J = 4.4
Hz, 10.5Hz), 3.94-3.99 (m, 1H), 4.240
(M, 1H), 5.187 (d, 1H, J = 1.5 Hz), 5.
717 (dd, 1H, J = 3.4 Hz), 5.795 (dd, 1
H), 6.080 (t, 1H, J = 10.0Hz), 7.07-7.50
(M), 7.72-8.17 (m, 6H). (C) Synthesis of compound 13-3 Compound 13-2 (3.5800 g) and paratoluenesulfonic acid (200 mg) were mixed with chloroform: methanol: water = 65:
Dissolve in a 15: 1 mixed solvent (40 ml) and mix the solution at 50 ° C for 7
The mixture was heated and stirred for an hour.

The obtained solution was cooled to room temperature and then neutralized with triethylamine. The solvent was evaporated under reduced pressure, and the residue was extracted with a mixed solvent of water and chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated by 200 ml silica gel column chromatography (hexane: ethyl acetate = 2:
1-2: 1.5), the target product was obtained. 2.795 g.

[Α] _D ²³ = -84.2 ° (c 1.04, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.878 (t, 3H,
J = 6.9 Hz), 1.18-1.31 (m, 30H), 1.50-1.57
(M, 2H), 3.369 (t, 2H, J = 6.8 Hz), 3.
53-3.55 (m, 2H), 3.63-3.65 (m, 2H), 3.68
-3.84 (m, 9H), 3.93-3.97 (m, 1H), 4.196
(Brd, 1H), 5.157 (d, 1H, J = 1.5 H
z), 5.692 (dd, 1H, J = 3.4 Hz), 5.811
(T, 1H, J = 10.0Hz), 5,980 (dd, 1H),
7.23-7.62 (m, 9H), 7.80-8.11 (m, 6H). (d) Synthesis of compound 13-4 To a solution of compound 13-3 (2.2457 g) in pyridine (5 ml) was added dropwise a solution of diphenylphosphoric acid chloride (1.050 g) in pyridine (6 ml) under ice cooling, and the mixture was stirred at room temperature overnight. .

The reaction solution was added to ice water, and chloroform 10
It was extracted with 0 ml. The organic layer was washed once with 2N hydrochloric acid and three times with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was separated by 250 ml silica gel column chromatography (hexane: ethyl acetate = 2: 1−).
4: 3), and the target product was obtained. 2.7398 g.

[Α] _D ²⁶ = -55.9 ° (c 1.34, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.887 (t, 3H,
J = 6.8 Hz), 1.24-1.31 (m, 30H), 3.411
(T, 1H, J = 6.8 Hz), 3,58-3.73 (m, 11
H), 3.83-3.88 (m, 1H), 4.39-4.43 (m, 1)
H), 4.44-4.48 (m, 2H), 5.084 (d, 1H, J
= 1.7 Hz), 5.679 (dd, 1H, J = 2.7 Hz),
5.86-5.91 (m, 2H), 7.09-7.59 (m, 19H), 7.
80-8.09 (m, 6H). (e) Synthesis of compound 13-5 To compound 13-4 (700 mg) and platinum oxide (50 mg) were added ethyl acetate (8 ml) and methanol (4 ml), and the mixture was stirred overnight under a hydrogen atmosphere at normal pressure. The catalyst was filtered and the solvent was distilled off under reduced pressure. To the residue was added 8 ml of methanol and 2 ml of benzene to dissolve, and a sodium methylate methanol solution (5 mol / mol) was added.
The pH was adjusted to 11 by adding 20 drops of 1) and the mixture was stirred overnight at room temperature.

After the solution was neutralized with 1N hydrochloric acid, the solvent was distilled off under reduced pressure. The residue was dissolved in water and "CHP-20" column chromatography (22 mmφ x 400 mm, 10% acetonitrile-90% acetonitrile gradient elution, total amount
It was separated with 1000 ml, 125 fractions). Fractions 61-82 were concentrated. The residue was dissolved in 50 ml of water, treated with an acidic ion exchange resin “Dowex 50W × 8”, and then the resin was filtered. The filtrate was freeze-dried to obtain the desired product. 282m
g.

[Α] _D ¹⁹ = + 21.2 ° (c 1.50, chloroform: methanol: water = 10: 10: 1). ¹ H-NMR (DMSO, δ): 0.860 (t, 3H, J
= 6.9 Hz), 1.19-1.31 (m, 30H), 1.45-1.51
(M, 2H), 3.364 (t, 2H, J = 6.6 Hz), 3.
43-3.57 (m, 14H), 3.626 (brs), 3.66-3.70
(M, 1H), 3.88-3.93 (m, 1H), 4.045 (br
dd, 1H, J = 10.3Hz, 6.2Hz), 4.646 (d,
1H, J = 1.5 Hz). ¹³ C-NMR (DMSO, δ): 13.87, 22.07, 25.6.
2, 28.6-29.2, 31.27, 65.01 (J = 4.7 Hz), 6
5.89, 66.44, 69.46, 69.51, 69.82, 70.18, 70.
37, 70.66, 72.10 (J = 7.6 Hz), 100.05. Example 14 The reaction in this Example is shown in FIG.

(A) Synthesis of compound 14-1 Mannose peracetate (20.0 g, 51.24 mmol) and 2- [2- (2-chloroethoxy) ethoxy] ethanol (11.232 g) in methylene chloride (300 ml) were dissolved in boron. A solution of trifluoride ether complex (25.21 ml) in methylene chloride (25 ml) was added under ice cooling, and the mixture was stirred overnight at room temperature.

The obtained solution was added to ice water and 200 ml of chloroform was added for extraction. The organic layer was washed 4 times with water and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was separated by 1700 ml silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 1) to obtain the desired product. 6.861 g.

[Α] _D ²³ = + 33.3 ° (c 1.35, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 1.987, 2.039, 2,10
0.2.153 (4s, 3H), 3.397 (t, 2H, J = 5.1
Hz), 3.61-3.85 (m, 10H), 4.064 (m, 1
H), 4.107 (dd, 1H, J = 2.4 Hz, 12.2H
z), 4.286 (dd, 1H, J = 5.1 Hz), 4.873
(D, 1H, J = 1.7 Hz), 5.270 (dd, 1H, J
= 3.4 Hz), 5.288 (t, 1H, J = 10.0 Hz), 5.
364 (dd, 1H). (b) Synthesis of compound 14-2 Compound 14-1 (5.861 g) and sodium azide (1.
DMF (50 ml) was added to 146 g) and the mixture was heated with stirring at 60 ° C. for 17 hours.

100 ml of water was added to the obtained solution and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated by 350 ml silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product. 4.468 g.

[Α] _D ²¹ = + 35.6 ° (c 1.04, CHC
l ₃ ) ¹ H-NMR (CDCl ₃ , δ): 1.988, 2.040, 2.100,
2.153 (4s, 3H), 3.640 (t, 2H, J = 5.9H
z), 3.64-3.84 (m, 10H), 4.068 (m, 1H),
4.117 (dd, 1H, J = 2.4 Hz, 12.2 Hz), 4.28
7 (dd, 1H, J = 5.1 Hz), 4.874 (d, 1H,
J = 1.5 Hz), 5.267 (dd, 1H, J = 3.7 H)
z), 5.289 (t, 1H, J = 10.0Hz), 5.362 (d
d, 1H). (c) Synthesis of Compound 14-3 A solution of Compound 14-2 (4.4676 g) in methanol (100 ml) was dissolved in sodium methylate in methanol (5 mol / l).
10 drops of was added and stirred at room temperature for 3 hours. To the resulting solution was added an acidic ion exchange resin "Dowex 50W x 8" for neutralization, the resin was filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in 100 ml of pyridine and trityl chloride (3.20
3 g) was added and the mixture was heated with stirring at 50 ° C. for 3 hours. Further, trityl chloride (1.231 g) was added, and the mixture was heated at 70 ° C for 14 hours. The resulting solution was cooled to room temperature, benzoyl chloride (3.692 ml) was added, and the mixture was stirred overnight at room temperature. The solution was added to ice water and extracted with 200 ml of chloroform. The organic layer was washed twice with 2N hydrochloric acid and three times with water, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, 200 mg of paratoluenesulfonic acid was added to the residue, and 50 ml of a mixed solvent of chloroform: methanol: water = 65: 15: 1 was added and dissolved.
The mixture was heated and stirred at 50 ° C for 5 hours.

The obtained solution was neutralized with triethylamine, and the solvent was evaporated under reduced pressure. 50 ml of water was added to the residue and extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was
Separation was performed by 500 ml of silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 1) to obtain the desired product. 2.4106g, 42.0%.

[Α] _D ²³ = −107.2 ° (c 1.75, CH
Cl ₃ ). ¹ H-NMR (CDCl ₃ , δ): 3.376 (t, 2H,
J = 5.1 Hz), 3.68-3.86 (m, 12H), 3.92-3.96
(M, 1H), 4.166 (brd, dd), 4.196 (br
d, 1H), 5.168 (d, 1H, J = 1.5 Hz), 5.70
2 (dd, 1H, J = 3.4 Hz), 5.823 (t, 1H,
J = 10.0Hz), 5.993 (dd, 1H), 7.23-7.63
(M, 9H), 7.80-8.12 (m, 6H). (d) Synthesis of compound 14-4 To a solution of compound 14-3 (2.4066 g) in pyridine (20 ml) was added dropwise a solution of diphenylphosphoric acid chloride (1.493 g) in pyridine (3 ml) under ice cooling, and the mixture was stirred at room temperature overnight. . The resulting solution was added to ice water and extracted with chloroform (100 ml). The organic layer was washed twice with 2N hydrochloric acid and three times with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated by 500 ml silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product. 2.848 g, 87.2%.

[Α] _D ²⁷ = -58.6 ° (c 1.04, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 3.384 (t, 2H,
J = 5.0 Hz), 3.68-3.75 (m, 9H), 3.83-3.89
(M, 1H), 4.39-4.43 (m, 1H), 4.45-4.48
(M, 2H), 5.092 (d, 1H, J = 1.7 Hz), 5.
683 (dd, 1H, J = 2.5 Hz), 5.86-5.92 (m,
2H), 7.10-7.59 (m, 19H), 7.80-8.08 (m, 6
H). (e) Synthesis of Compound 14-5 Compound 14-4 (2.8443 g) and paratoluenesulfonic acid monohydrate (613.5 mg) were dissolved in a mixed solvent of 20 ml of methanol and 20 ml of ethyl acetate, and the Lindlar catalyst (1.0
g) was added, and the mixture was stirred under a hydrogen atmosphere of 50 psi for 6 hours. A Lindlar catalyst (1.0 g) was further added, and the mixture was stirred under a hydrogen atmosphere of 50 psi for 3 hours.

The catalyst was filtered and the solvent was distilled off under reduced pressure to obtain the desired product. 3.075 g. This compound was used for the next step synthesis without any particular purification.

(F) Synthesis of Compound 14-6 To a solution of Compound 14-5 (0.972 g) in methylene chloride (20 ml) was added N-palmitoyloxysuccinimide (400 mg) and triethylamine (0.171 ml), and the mixture was stirred overnight. did.

The obtained solution was added to ice water to extract the desired product. After the solution was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was separated by 100 ml silica gel column chromatography (hexane: ethyl acetate =
1: 1.5) to obtain the desired product. 0.6493g.

[Α] _D ²³ = -55.2 ° (c 1.47, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.877 (t, 3H,
J = 6.9 Hz), 1.23-1.31 (m, 24H), 1.55-1.62
(M, 2H), 2.129 (t, 2H, J = 7.6 Hz), 3.
42-3.46 (m, 2H), 3.561 (t, 2H), 3.64-3.
76 (m, 7H), 3.87-3.91 (m, 1H), 4.43-4.50
(M, 3H), 5.112 (ds, 1H, J = 1.9 Hz),
5.685 (dd, 1H, J = 2.9 Hz), 5.87-5.93
(M, 2H), 7.11-7.61 (m, 19H), 7.81-8.08
(M, 6H). (g) Synthesis of compound 14-7 To compound 14-6 (0.630 g) and platinum oxide (50 mg) were added ethyl acetate (15 ml) and methanol (15 ml), and the mixture was stirred overnight under a hydrogen atmosphere at normal pressure. The catalyst was filtered and the solvent was distilled off under reduced pressure. To the residue was added 8 ml of methanol to dissolve it, and 25 drops of sodium methylate methanol solution (5 mol / l) was added to adjust the pH.
Was set to 11, and the mixture was stirred at room temperature for 5 hours.

After the solution was neutralized with 1N hydrochloric acid, the solvent was distilled off under reduced pressure. The residue was dissolved in water and "CHP-20" column chromatography (22 mmφ x 400 mm, gradient elution with 10% acetonitrile-90% acetonitrile, total 10
It was separated with 00 ml, 103 fractions). Fraction
40-49 was concentrated. The residue was dissolved in water, treated with an acidic ion exchange resin "Dowex 50W x 8", and then the resin was filtered. The target substance was obtained by freeze-drying the filtrate. 295.2 mg,
81.4%.

[Α] _D ²³ = + 22.1 ° (c 1.00, chloroform: methanol: water = 10: 10: 3). ¹ H-NMR (DMSO, δ): 0.857 (t, 3H, J
= 6.9 Hz), 1.18-1.29 (m, 24H), 1.43-1.49
(M, 2H), 2.047 (t, 3H, J = 7.6 Hz), 3.
186 (brq, 2H, J = 5.6-5.9 Hz), 3.396
(T, 2H, J = 5.9 Hz), 3.42-3.61 (m, 10
H), 3.610 (brs, 1H), 3.66-3.70 (m, 1
H), 3.85-3.90 (m, 1H), 4.043 (brdd, 1
H, J = 10.3Hz, 6.3Hz), 4.642 (d, 1H, J =
1.2 Hz), 7.816 (t, 1H, J = 5.6 Hz). ¹³ C-NMR (DMSO, δ): 13.86, 22.03, 25.2.
2, 31.24, 35.28 (CO- CH 2), 38,42, 65.03
(J = 4.7 Hz), 65.84, 66.45, 69.18, 69.48,
69.54, 69.71, 70.15, 70.62, 72.11 (J = 7.8 H
z), 100.02, 172.22. Example 15 The reaction in this example is also shown in FIG.

(A) Synthesis of Compound 15-1 Compound 14-5 (2.1047), 2-palmitylstearic acid (1.354 g), N-hydroxysuccinimide (306 mg)
And a mixture of triethylamine (0.683 ml) are dissolved in 40 ml of methylene chloride and 20 ml of hexane and D is added to this solution.
CC (549 mg) was added, and the mixture was stirred overnight at room temperature. The solution was added to ice water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by 200 ml silica gel column chromatography (hexane: ethyl acetate = 2: 1-1:
1), the desired product was obtained. 796 mg.

[Α] _D ²⁷ = -52.4 (c 1.11, CHCl
₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.876 (t, 6H,
J = 6.9 Hz), 1.18-1.39 (m, 56H), 1.52-1.60
(M, 4H), 1.95-2.01 (m, 1H), 3.43-3.47
(M, 2H), 3.538 (m, 2H), 3.62-3.77 (m, 11
H), 3.85-3.89 (m, 1H), 4.39-4.48 (m, 3
H), 5.103 (d, 1H, J = 1.8 Hz), 5.679 (d
d, 1H, J = 2.7 Hz), 5.86-5.93 (m, 2H),
6.062 (brt, 1H), 7.09-7.59 (m, 19H), 7.
80-8.08 (m, 6H). (b) Synthesis of compound 15-2 To compound 15-1 (780 mg) and platinum oxide (50 mg) were added ethyl acetate (20 ml) and methanol (10 ml), and the mixture was stirred overnight under a normal pressure hydrogen atmosphere. The catalyst was filtered and the solvent was distilled off under reduced pressure. To the residue, 2 ml of benzene and 6 ml of methanol were added and dissolved, and a sodium methylate methanol solution (5 mol /
The pH was adjusted to 11 by adding 30 drops of l), and the mixture was stirred overnight at room temperature.

After the solution was neutralized with 1N hydrochloric acid, the solvent was distilled off under reduced pressure. The residue was dissolved in 2 ml of a mixed solvent of chloroform: methanol: water = 65: 15: 1 and subjected to 150 ml of silica gel column chromatography (chloroform: methanol: water = gradient elution from 65: 25: 3 to 60: 35: 7, The total amount was 2000 ml and 100 fractions) were separated. Fractions 38-47 were concentrated. The residue was dissolved in a mixed solvent of chloroform: methanol: water = 65: 15: 1, treated with a strongly acidic ion exchange resin “Dowex 50W × 8”, and then the resin was filtered off. The solvent is concentrated under reduced pressure,
Dissolved in a mixed solvent of chloroform: methanol = 9: 1, "Sephadex LH-20" (22mmφ x 400mm
, Chloroform: methanol = 9: 1 elution). Fractions 5-10 were concentrated to obtain the desired product.
230 mg, 65.8%.

[Α] _D ²³ = + 15.3 ° (c 1.12, chloroform: methanol = 9: 1). Example 16 The reaction in this example is shown in FIG.

(A) Synthesis of Compound 16-1 Galactose peracetate (19.60 g) and triethylene glycol mono-n-octadecyl ether (2
A solution of boron trifluoride ether complex (27.8 ml) in methylene chloride (50 ml) was added to a solution of 4.70 g) in methylene chloride (500 ml) under ice cooling, and the mixture was stirred overnight at room temperature.

The obtained solution was added to ice water and chloroform (300 ml) was added for extraction. Wash the organic layer 4 times with water,
It was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by 1000 ml silica gel column chromatography (toluene: ethyl acetate = 2: 1-2: 1.
5), the desired product was obtained. 20.95 g.

[Α] _D ²⁶ = −4.4 ° (c 1.10, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.876 (t, 3H,
J = 6.9 Hz), 1.21-1.36 (m, 30H), 1.53-1.60
(M, 2H), 1.984 (s, 3H), 2.048 (s, 3)
H), 2.060 (s, 3H), 2.148 (s, 3H), 3.43
9 (t, 2H, J = 6.9 Hz), 3.56-3.69 (m, 10
H), 3.65-3.77 (m, 1H), 3.906 (brt, 1
H), 3.92-3.98 (m, 1H), 4.13 (dd, 1H, J
= 6.8 Hz, J = 11.1 Hz), 4.167 (dd, 1H, J
= 6.3 Hz), 4.563 (d, 1H, J = 7,8 Hz), 5.
012 (dd, 1H, J = 3.4 Hz), 5.203 (dd, 1
H, J = 10.4 Hz), 5.381 (brd, 1H). (b) Synthesis of Compound 16-2 To a solution of Compound 16-1 (5.12 g) in methanol (70 ml) was added 10% methanol solution of Nalium methylate (5 mol / l).
The mixture was added dropwise and stirred at room temperature for 3 hours. The solution was neutralized by adding an acidic ion exchange resin “Dowex 50W × 8”, and the solvent was distilled off under reduced pressure. The residue was dissolved in pyridine (100 ml), and diphenylphosphoric chloride (2.439
A solution of g) in pyridine (10 ml) was added dropwise, and the mixture was stirred at room temperature for 4 hours. Acetic anhydride (10.0 ml) was added to the resulting solution and stirred overnight.

The solution was added to ice water, and chloroform (200 m
l). The organic layer was washed twice with 2N hydrochloric acid and three times with saturated saline, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated by 500 ml silica gel column chromatography (hexane: ethyl acetate =
2: 1.5), and the target product was obtained. 3.317 g.

[Α] _D ²¹ = −9.9 ° (c 1.04, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.879 (t, 3H,
J = 6.9 Hz), 1.17-1.30 (m, 30H), 1.54-1.60
(M, 2H), 1.986, 2.051, 2.105 (4s, 3
H), 3.434 (t, 2H, J = 6.9 Hz), 3.56-3.69
(M, 11H), 3.87-3.92 (m, 2H), 4.215 (1
H, ddd, J = 6.1 Hz, 10.6 Hz, 8.3 Hz), 4.
341 (ddd, 1H, J = 6.8 Hz, 8.1 Hz), 4.51
7 (d, 1H, J = 8.1 Hz), 4.980 (dd, 1H,
J = 3.7 Hz), 5.195 (dd, 1H, J = 10.5H)
z), 5.415 (brd, 1H), 7.19-7.37 (m, 10
H). (c) Synthesis of compound 16-3 Ethyl acetate (10 ml) and methanol (10 ml) were added to compound 16-2 (622 mg) and platinum oxide (120 mg), and the mixture was stirred overnight under a hydrogen atmosphere at normal pressure. The catalyst was filtered and the solvent was distilled off under reduced pressure. Methanol (20 ml) and benzene (5 ml) were added to the residue to dissolve it, and 40 drops of sodium methylate methanol solution (5 mol / l) was added to adjust the pH to 11,
Stir overnight at room temperature.

After the solution was neutralized with 1N hydrochloric acid, the solvent was distilled off under reduced pressure. The residue was dissolved in water and "CHP-20" column chromatography (22 mmφ x 400 mm, 10% acetonitrile-90% acetonitrile gradient elution, total amount
It was separated in 1000 ml, 100 fractions). Fractions 54-63 were concentrated. The residue was dissolved in water, treated with an acidic ion exchange resin “Dowex 50W × 8”, and then the resin was filtered. The filtrate was freeze-dried to obtain the desired product. 350mg, 7
9.2%.

[Α] _D ²⁸ = −2.0 ° (c 0.98, chloroform: methanol: water = 10: 10: 3) Mass M / Z: 645 (M + H), 667 (M + N)
a), 683 (M + K). ¹ H-NMR (DMSO, δ): 0.857 (t, 3H, J
= 6.9 Hz), 1.20-1.30 (m, 30H), 1.45-1.49
(M, 2H), 3.28-3.32 (m, 2H), 3.358 (t,
2H, J = 5.9 Hz), 3.45-3.65 (m, 12H), 3.64
3 (brd, 1H, J = 1.0 Hz), 3.81-3.88 (m,
2H), 3.918 (ddd, 1H, J = 5.9Hz, 10.5H
z, 7.8 Hz), 4.130 (d, 1H, J = 7.6 Hz). ¹³ C-NMR (DMSO, δ): 13.85, 22.02, 25.5.
8, 31.22, 64.15 (J = 4.4 Hz), 67.75, 67.92
, 69.41, 69.67, 69.74, 70.26, 70.30, 73.05
, 73.17 (J = 7.5 Hz), 103.44. Example 17 The reaction in this example is shown in FIG.

(A) Synthesis of compound 17-1 Galactose peracetate (10.0 g) and 2- [2
-(Chloroethoxy) ethoxy] -ethanol (5.616
g) in methylene chloride (150 ml) solution of boron trifluoride ether complex (12.6 ml) in methylene chloride (30 ml)
The solution was added under ice cooling and stirred overnight at room temperature.

The obtained solution was added to ice water, and chloroform (150 ml) was added for extraction. Wash the organic layer twice with water,
It was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by 1000 ml silica gel column chromatography (hexane: ethyl acetate = 2: 1-1:
1), the desired product was obtained. 6.51 g.

[Α] _D ²⁰ = −0.4 ° (c 1.098, chloroform). ¹ H-NMR (CDCl ₃ , δ): 1.986, 2.051, 2.0
63, 2.152 (4s, 3H), 3.63-3.78 (m, 11
H), 3.95-3.98 (m, 1H), 3.917 (brt, 1
H), 4.131 (dd, 1H, J = 6.8 Hz, 11.2H
z), 4.178 (dd, 1H, J = 6.6 Hz), 4.576
(D, 1H, J = 8.1 Hz), 5.023 (dd, 1H, J
= 3.4 Hz), 5.212 (dd, 1H, J = 10.5Hz),
5.390 (brd, 1H). (b) Synthesis of Compound 17-2 Compound 17-1 (6.445 g) and sodium azide (1.
DMF (50 ml) was added to 26 g) and the mixture was heated with stirring at 60 ° C. for 17 hours.

Water (100 ml) was added to the obtained solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated by 500 ml silica gel column chromatography (hexane: ethyl acetate = 2: 1.5-1: 1) to obtain the desired product. 5.30g.

[Α] _D ¹⁷ = −3.2 ° (c 1.04, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 1.984, 2.048, 2.0
60, 2.148 (4s, 3H), 3.398 (t, 2H, J =
5.0 Hz), 3.63-3.69 (m, 8H), 3.73-3.78
(M, 1H), 3.95-3.98 (m, 1H), 3.910 (br
t, 1H), 4.131 (dd, 1H, J = 6.8 Hz, 1
1.2Hz), 4.176 (dd, 1H, J = 6.3Hz), 4,5
71 (d, 1H, J = 7.8 Hz), 5.023 (dd, 1
H, J = 3.4 Hz), 5.210 (dd, 1H, J = 10.5H
z), 5.387 (dd, 1H, J = 1.0 Hz). (c) Synthesis of compound 17-3 To a solution of compound 17-2 (4.957 g) in methanol (70 ml) was added sodium methylate methanol solution (5 mol / l).
10 drops were added, and the mixture was stirred at room temperature for 3 hours. The solution was neutralized by adding an acidic ion exchange resin “Dowex 50W × 8”, and the solvent was evaporated under reduced pressure. The residue was dissolved in pyridine (30 ml), and diphenylphosphoric chloride (3.
A pyridine solution of 688 g) was added dropwise, and the mixture was stirred at room temperature for 8 hours. Benzoyl chloride (4.55 ml) was added to the resulting solution, and the mixture was stirred overnight.

The solution was added to ice water, and chloroform (200 m
l). The organic layer was washed twice with 2N hydrochloric acid and three times with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated by 500 ml silica gel column chromatography (hexane: ethyl acetate =
2: 1-1: 1), the target product was obtained. 3.468 g.

[Α] _D ²¹ = + 91.8 ° (c 1.02, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 3.305 (t, 2H,
J = 5.0 Hz), 3.35-3.63 (m, 8H), 3.753
(M, 1H), 3.978 (m, 1H), 4.196 (brt,
1H), 4.364 (ddd, 1H, J = 5.6 Hz, 10.7H
z, 8.3 Hz), 4.467 (ddd, 1H, J = 7.1 H
z, 9.0 Hz), 4.859 (d, 1H, J = 8.1 Hz),
5.524 (dd, 1H, J = 3.4 Hz), 5.746 (dd,
1H, J = 10.5Hz), 5.881 (brd, 1H), 7.14
-7.62 (m, 19H), 7.78-8.05 (m, 6H). (d) Synthesis of Compound 17-4 Compound 17-3 (3.424 g) and paratoluenesulfonic acid monohydrate (739 mg) were dissolved in a mixed solvent of methanol (20 ml) and ethyl acetate (120 ml) to give a Lindlar catalyst ( 1.2 g) was added, and the mixture was stirred under a hydrogen atmosphere of 50 psi for 7 hours.

The catalyst was filtered and the solvent was distilled off under reduced pressure to obtain the desired product (4.00 g). This compound was used for the next step synthesis without any particular purification.

(E) Synthesis of Compound 17-5 To a solution of Compound 17-4 (2.001 g) in methylene chloride (50 ml) was added N-palmitoyloxysuccinimide (825 mg), and the mixture was stirred overnight.

The obtained solution was added to ice water to extract the desired product. After the solution was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was separated by 200 ml silica gel column chromatography (hexane: ethyl acetate =
1: 1-1: 1.5) to obtain the desired product. 1.942 g.

[Α] _D ²¹ = + 70.7 ° (c 1.00, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.877 (t, 3H,
J = 6.9 Hz), 1.23-1.31 (m, 24H), 1.55-1.62
(M, 2H), 2.127 (t, 2H, J = 7.5 Hz), 3.
31-3.63 (m, 10H), 3.73-3.78 (m, 1H), 3.97
-4.01 (m, 1H), 4.207 (brt, 1H), 4.35
9 (ddd, 1H, J = 5.6 Hz, 10.7 Hz, 8.5 H
z), 4.473 (ddd, 1H, J = 7.1 Hz, 8.8 H
z), 4.857 (d, 1H, J = 8.1 Hz), 5.529 (d
d, 1H, J = 3.5 Hz), 5.750 (dd, 1H, J =
10.4Hz), 5.883 (brd, 1H), 6.014 (br
t, 1H), 7.13-7.63 (m, 19H), 7.77-8.05
(M, 6H). (f) Synthesis of compound 17-6 Ethyl acetate (15 ml) and methanol (15 ml) were added to compound 17-5 (1.0215 g) and platinum oxide (100 mg),
The mixture was stirred overnight under a normal pressure hydrogen atmosphere. The catalyst was filtered and the solvent was distilled off under reduced pressure. Methanol (15 ml) was added to the residue to dissolve it, and sodium methylate methanol solution (5 mol / mol)
The pH was adjusted to 11 by adding 60 drops of 1) and the mixture was stirred at room temperature for 5 hours.

After the solution was neutralized with 1N hydrochloric acid, the solvent was distilled off under reduced pressure. The residue was dissolved in a mixed solvent of methanol-water 95: 5 and separated by "CHP-20" column chromatography (22 mmφ x 400 mm, gradient elution with 10% acetonitrile-90% acetonitrile, total volume 1000 ml, 97 fractions). Fractions 46-61 were concentrated. The residue is dissolved in water and the acidic ion exchange resin “Dowex 50
After treating with "W × 8", the resin was filtered off. The filtrate was freeze-dried to obtain the desired product. 365 mg.

[Α] _D ²⁸ = −1.8 ° (c 1.13, water). Mass M / Z: 630 (M + H), 652 (M + N)
a). ¹ H-NMR (DMSO, δ): 0.858 (t, 3H, J
= 6.9 Hz), 1.19-1.29 (m, 24H), 1.43-1.50
(M, 2H), 2.048 (t, 2H, J = 7.4 Hz), 3.
185 (q, 2H, J = 5.9 Hz), 3.28-3.32 (m, 2
H), 3.395 (t, 2H, J = 5.9 Hz), 3.48-3.61
(M, 8H), 3.650 (brd, 1H, J = 1.0H
z), 3.82-3.87 (m, 2H), 3.915 (ddd, 1
H, J = 6.1 Hz, 10.5 Hz, 8.1 Hz), 4.133
(D, 1H, J = 7.7 Hz), 7.819 (t, 1H, J =
5.9 Hz). ¹³ C-NMR (DMSO-d ₆ , δ): 13.86, 22.03.
, 25.21, 28.6-29.0, 31.23, 35.28, 38.41, 64.
04 (J = 4.9 Hz, 67.77, 67.90, 69.17, 69.54, 6
9.69, 70.29, 73.06, 73.19 (J = 7.3 Hz), 10
3.45, 172.20. Example 18 The reaction in this example is also shown in FIG.

(A) Synthesis of Compound 18-1 Compound 17-4 (2.00 g), 2-palmitylstearic acid (1.188 g), N-hydroxysuccinimide (269 mg)
And 4-dimethylaminopyridine (523 mg) in DMF
N, N'-Dicyclohexylcarbodiimide (482 mg) was added to the (100 ml) solution, and the mixture was stirred overnight at room temperature. N, N '
-Dicyclohexylcarbodiimide (200 mg) was further added, and the mixture was further stirred overnight.

The N, N'-dicyclohexylurea that had separated out was filtered off, and the solvent was distilled off at 40 ° C. Ethyl acetate (40 ml) was added to the residue, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the residue was separated by 200 ml silica gel column chromatography (hexane: ethyl acetate = 2: 1-1:
1), the desired product was obtained. 773 mg.

[Α] _D ²¹ = + 58.9 ° (c 1.13, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.877 (t, 6H,
J = 6.9 Hz), 1.16-1.34 (m, 56H), 1.52-1.61
(M, 4H), 1.91-1.99 (m, 1H), 3.30-3.33
(M, 2H), 3.35-3.63 (m, 8H), 3.73-3.77
(M, 1H), 3.97-4.01 (m, 1H), 4.196 (br
t, 1H), 4.357 (ddd, 1H, J = 5.6 Hz,
10.7Hz, 8.5Hz), 4.468 (ddd, 1H, J = 7.
1 Hz, 9.0 Hz), 4.848 (d, 1H, J = 8.1 H
z), 5.523 (dd, 1H, J = 3.5 Hz), 5.747
(Dd, 1H, J = 10.4Hz), 5.878 (brd, 1
H), 7.13-7.62 (m, 19H), 7.77-8.05 (m, 6
H). (b) Synthesis of Compound 18-2 Tetrahydrofuran (20 ml) and methanol (10 ml) were added to Compound 18-1 (506 mg) and platinum oxide (50 mg), and the mixture was stirred overnight under a hydrogen atmosphere at normal pressure. Filter the catalyst,
The solvent was distilled off under reduced pressure. Methanol (15 ml) was added to the residue to dissolve it, and 20 drops of sodium methylate methanol solution (5 mol / l) was added to adjust the pH to 11, and the mixture was stirred at room temperature for 5 hours.

After neutralizing the solution with 1N hydrochloric acid, the solvent was distilled off under reduced pressure. The residue is chloroform: methanol =
It was dissolved in a 1: 1 mixed solvent, 2.5 g of silica gel was added, and the solvent was evaporated under reduced pressure. The dried silica gel obtained
150 ml of chloroform: methanol: water = 65: 25: 4
The mixture was packed in a silica gel column packed with the solvent mixture described above, and the fraction containing the desired product was collected (22 mmφ × 400 mm, chloroform: methanol: water = 65: 25: 4 to 2 :).
2: Gradient elution up to 0.5, total volume 1000 ml, 100 fractions). Fractions 13-41 were concentrated. The residue was dissolved in a mixed solvent of chloroform: methanol = 9: 1 and filled with the same solvent "Sephadex LH-20".
(22mmφ × 400mm, chloroform: methanol = 9:
(1 elution). Fractions 5-8 were concentrated to give the desired product. 201 mg.

[Α] _D ²⁸ = −3.8 ° (c 1.09, chloroform: methanol = 9: 1). Mass M / Z: 882 (M + H). ¹ H-NMR (CDCl ₃ -CD ₃ OD = 5/1,
δ): 0.884 (t, 6H), 1.20-1.33 (m, 56H),
1.36-1.44 (m, 2H), 1.51-1.59 (m, 2H), 2.
05-2.11 (m, 1H), 3.416 (brt, 2H, J =
5.0 Hz), 3.51-3.77 (m, 12H), 3.931 (br
d, 1H, J = 1.0 Hz), 4.01-4.20 (m, 3H),
4.267 (d, 1H, J = 7.6 Hz). ¹³ C-NMR (CDCl ₃ -CD ₃ OD = 5/1,
δ): 14.16, 22.87, 27.83, 32.13, 33.18, 39.1
8, 47.88, 64.55 (J = 4.9 Hz), 67.97, 68.53
, 70.17, 70.31, 70.51, 70.60, 71.51, 73.33
, 73.54 (J = 8.1 Hz), 103.77, 177.71. Example 19 The reaction in this example is shown in FIG.

(A) Synthesis of Compound 19-1 Compound 16-1 (38.939 g) in anhydrous methanol (500 ml)
0.3 ml of a methanol solution of sodium methoxide (5 mol / l) was added to the solution, and the mixture was stirred at room temperature for one day. The resulting solution is an acidic ion exchange resin "Dowex 50W x 8"
After neutralizing with, the resin was filtered, and the solvent was distilled off under reduced pressure. Trityl chloride (19.255g, 1.3eq) was added to the residue, and 20
It was dissolved in 0 ml of pyridine and heated at 50 ° C for 6 hours.

The obtained solution was added to ice water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The desiccant was filtered, the solvent was distilled off under reduced pressure, and the residue was separated on a 1000 ml silica gel column. Trityl chloride was eluted only with chloroform, 0.5 -3%
The target substance could be eluted with methanol-chloroform.
33.093g.

[Α] _D ²⁶ = -16.1 ° (c 1.06, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.879 (3H, t,
J = 6.9 Hz), 1.21-1.32 (m, 30H), 1.56-1.59
(2H, m), 2.325 (d, 1H), 2.776 (d, 1)
H), 3.440 (t, 2H, J = 6.9 Hz), 3.39-3.42
(M, 1H), 3.55-3.67 (m, 14H), 3.69-3.76
(M, 1H), 4.01-4.07 (m, 1H), 4.061 (br
t, 1H), 4.268 (d, 1H, J = 7.6 Hz), 4.
563 (brs, 1H), 7.22-7.46 (m, 15H). (b) Synthesis of compound 19-2 To a solution of compound 19-1 (6.023 g) in pyridine (150 ml) was added dropwise benzoyl chloride (2.622 g) under ice cooling, and the mixture was stirred at room temperature for 2 days.

The obtained solution was added to ice water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The desiccant was filtered, the solvent was distilled off under reduced pressure, and the residue was separated with a 500 ml silica gel column. Target compound 19-2 (2.4649) in toluene: ethyl acetate = 10: 1
g) was eluted.

[Α] _D ²⁶ = -29.5 ° (c 1.07, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.878 (t, 3H,
J = 6.9 Hz), 1.20-1.32 (m, 30H), 1.51-1.56
(M, 2H), 3.38-3.65 (m, 14H), 3.76-3.83
(M, 2H), 3.98-4.03 (m, 1H), 4.359 (br
s, 1H), 4.767 (d, 1H, J = 8.1 Hz), 5.28
1 (dd, 1H, J = 2.9 Hz), 5.747 (dd, 1
H, J = 10.3Hz), 7.23-7.52 (m, 21H), 7.96-
8.00 (m, 4H). (c) Synthesis of Compound 19-3 A solution of compound 19-2 (2.450 g) in pyridine (10 ml) was added dropwise with a solution of diphenylphosphoric chloride (2.6 g) in pyridine (10 ml), and the mixture was stirred at room temperature for 2 days.

The obtained solution was added to ice water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The desiccant was filtered, the solvent was distilled off under reduced pressure, and the residue was separated with a 500 ml silica gel column. The target substance (2.3174 g) was eluted with toluene: ethyl acetate = 12: 1.

[Α] _D ²⁵ = + 13.5 ° (c 1.26, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.878 (t, 3H,
J = 6.9 Hz), 1.21-1.32 (m, 30H), 1.52-1.58
(M, 2H), 3.35-3.69 (m, 15H), 3.81-3.85
(M, 1H), 4.03-4.07 (m, 1H), 4.761 (d,
1H, J = 7.9 Hz), 5.219 (dd, 1H, J = 9.3
Hz, 2.9 Hz), 5.317 (brd, 1H), 5.775
(Dd, 1H, J = 10.5Hz), 6.96-7.52 (m, 31
H), 7.73-7.98 (m, 4H). (d) Synthesis of Compound 19-4 Compound 19-3 (2.3012 g) and paratoluenesulfonic acid dihydrate (230 mg) were combined with chloroform: methanol:
Dissolve in 10 ml of a mixed solvent of water = 65: 15: 1,
The mixture was heated and stirred for an hour.

The obtained solution was cooled to room temperature, neutralized with triethylamine, and the solvent was evaporated under reduced pressure.
Water was added to the residue and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The desiccant was filtered, the solvent was distilled off under reduced pressure, and the residue was separated with a 200 ml silica gel column. Hexane: ethyl acetate = 1: 1.5
The target product (879.4 mg) was eluted with the mixed solvent of.

[Α] _D ²⁴ = + 65.5 ° (c 1.14, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.878 (t, 3H,
J = 6.9 Hz), 1.21-1.31 (m, 30H), 1.52-1.58
(M, 2H), 3.41-3.84 (m, 12H), 3.90-3.95
(M, 2H), 3.96-4.01 (m, 1H), 4.868 (d,
1H, J = 8.1 Hz), 5.37-5.43 (m, 2H), 5.78
8 (dd, 1H, J = 10.2Hz), 6.76-7.54 (m, 16
H), 7.75-8.02 (m, 4H). (e) Synthesis of Compound 19-5 Benzoyl chloride (151 μl, 1.5 eq) was added dropwise to a solution of compound 19-4 (874 mg) in pyridine (5 ml), and the mixture was stirred at room temperature overnight.

The obtained solution was added to ice water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The desiccant was filtered, the solvent was distilled off under reduced pressure, and the residue was separated on an 80 ml silica gel column. toluene:
The target product (858 mg) was eluted with a mixed solvent of ethyl acetate = 4: 1-4: 1.5. The target substance could be obtained as crystals. Melting point 51.7-52.8 ° C.

[Α] _D ¹⁹ = + 17.2 ° (c 1.04, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.878 (t, 3H,
J = 6.9 Hz), 1.22-1.32 (m, 30H), 1.51-1.57
(M, 2H), 3.38-3.67 (m, 12H), 3.79-3.85
(M, 1H), 3.98-4.04 (m, 1H), 4.20 (br
t, 1H), 4.337 (dd, 1H, J = 7.3 Hz, 11.2
Hz), 4.674 (dd, 1H, J = 6.3 Hz), 4.905
(D, 1H, J = 7.8 Hz), 5.419 (dd, 1H, J
= 9.0 Hz), 5.470 (dd, 1H, J = 2.8 Hz),
5.839 (dd, 1H, J = 10.5Hz-2), 7.06-7.57
(M, 19H), 7.78-7.99 (m, 6H). (f) Synthesis of Compound 19-6 Compound 19-5 (500 mg) was dissolved by adding methanol (5 ml) and ethyl acetate (5 ml) thereto, and then adding platinum oxide (50 mg).
mg) was added and hydrogen reduction was performed overnight at room temperature and atmospheric pressure. After filtering the catalyst, the solution was neutralized with 1N sodium methylate methanol solution. The solution was concentrated under reduced pressure, the residue was dissolved in methanol (7 ml) and sodium methylate (5 mol / mol) was added.
1 methanol solution, 20 drops) was added, and the mixture was stirred at room temperature overnight. Furthermore, sodium methylate (5 mol / l methanol solution, 10 drops) was added, and the mixture was stirred at room temperature for 7 hours.

The solution was neutralized with 1N hydrochloric acid and concentrated under reduced pressure. The residue was dissolved in water (50 ml) and purified with a “CHP-20” column (22 mmφ × 400 mm). That is, 500 ml
Elution was performed with a linear gradient of water and then 10-90% acetonitrile-water (total volume 1000 ml, 99 fractions). Fractions 44-53 were concentrated. Water (40 ml) and H type of H type acidic ion exchange resin “Dowex 50W × 8” were added to the residue and stirred. The resin was filtered and the filtrate was lyophilized to obtain the desired product. 66.6 mg.

[Α] _D ²¹ = −6.9 ° (c 1.01, pyridine: water = 1: 1). ¹³ C-NMR (DMSO-d ₆ , δ): 13.85, 22.01.
, 25.58, 28.6-29.1, 31.22, 59.43, 67.76, 69.
40, 69.65, 9.73, 70.28, 70.83, 72.18 (d, J
= 4.6 Hz), 72.41, 73.72 (J = 4.2 Hz), 103.
31. ¹ H-NMR (DMSO, δ): 0.856 (t, 3H, J
= 6.9 Hz), 1.18-1.30 (m, 30H), 1.45-1.51
(M, 2H), 3.247 (dd, 1H, J = 7.8 Hz, 9,
5 Hz), 3.358 (t, 2H, J = 6.6 Hz), 3.38-
3.60 (m, 15H), 3.80-3.83 (m, 1H), 4.140
(D, 1H, J = 7.8 Hz), 4.332 (dd, 1H, J
= 10.3 Hz, 3.0 Hz). Example 20 The reaction in this example is also shown in FIG.

(A) Synthesis of Compound 20-1 Compound 19-1 (3.50 g) and carbonyldiimidazole (1.758 g) were dissolved in benzene (30 ml) and the mixture was heated at 80 ° C.
The mixture was heated and stirred for 11 hours.

The obtained solution was cooled to room temperature, added to ice water, and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The desiccant was filtered, the solvent was distilled off under reduced pressure, and the residue was separated by 350 ml of silica gel column chromatography. Hexane: Ethyl acetate =
The desired product (2.6288 g) was eluted with a 1: 1 mixed solvent.

[Α] _D ¹⁷ = −25.5 ° (c 1.02, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.879 (t, 3H,
J = 6.9 Hz), 1.21-1.31 (M, 30H), 1.56-1.61
(M, 2H), 3.378 (dd, 1H, J = 6.7Hz, 9.8
Hz), 3.450 (t, 2H, J = 6.9 Hz), 3.551
(Dd, 1H, J = 6.4 Hz), 3.56-3.75 (m, 11
H), 3.782 (dt, 1H), 3.97-4.01 (m, 1
H), 4.397 (d, 1H, J = 7.1 Hz), 4.644 (d
d, 1H, J = 7.2 Hz), 4.762 (dd, 1H, J =
2.0 Hz), 4.901 (d, 1H, J = 2.9 Hz), 7.23
-7.45 (m, 15H). (b) Synthesis of Compound 20-2 A solution of Compound 20-1 (2.5016 g) in pyridine (10 ml) was added with diphenylphosphoric chloride (1.60 g, 6 eq) pyridine (6 m
l) The solution was added dropwise and stirred at room temperature for 2 days and nights.

The obtained solution was added to ice water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was evaporated under reduced pressure, and the residue was separated by 300 ml silica gel column chromatography. The target product (2.7845 g) was eluted with a mixed solvent of hexane: ethyl acetate = 3: 1-2: 1.

[Α] _D ²¹ = -17.3 ° (c 1.01, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.879 (t, 3H,
J = 7.0 Hz), 1.21-1.31 (m, 30H), 1.52-1.58
(M, 2H), 3.306 (dd, 1H, J = 6.8Hz, J
9.5 Hz), 3.414 (t, 2H, J = 6.8 Hz), 3.48
3 (dd, 1H, J = 6.3 Hz), 3.53-3.63 (m, 11
H), 3.906 (dt, 1H), 4.711 (dt, 1H, J
= 3.2 Hz, 10.5 Hz), 4.795 (dd, 1H, J = 8.
3 Hz, 1.0 Hz), 4.856 (dd, 1H, J = 1.8 H
z), 4.951 (d, 1H, J = 3.7 Hz), 7.21-7.44
(M, 25H). (c) Synthesis of Compound 20-3 Compound 20-2 (2.750 g) and paratoluenesulfonic acid dihydrate (210 mg) were combined with chloroform: methanol:
It was dissolved in a mixed solvent (50 ml) of water = 65: 15: 1 and heated and stirred at 50 ° C. for 5 hours.

The obtained solution was cooled to room temperature, neutralized with triethylamine, and the solvent was evaporated under reduced pressure.
Water was added to the residue and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was separated on a 250 ml silica gel column. Chloroform: Methanol = 10
Target compound (1.074 g) in a mixed solvent of 0: 1-100: 1.5
Was eluted.

[Α] _D ²⁰ −2.9 ° (c 1.24, CHCl
₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.879 (t, 3H,
J = 6.9 Hz), 1.20-1.34 (m, 30H), 1.54-1.60
(M, 2H), 2.663 (dd, 1H, J = 4.4, 7.8H
z), 3.433 (t, 2H, J = 6.8 Hz), 3.52-3.66
(M, 10H), 3.68-4.00 (m, 5H), 4.696 (d
t, 1H, J = 3.9 Hz, 9.5 Hz), 4.785 (dd,
1H, J = 2.0 Hz), 4.836 (dd, 1H, J = 8.3
Hz), 4.957 (d, 1H, J = 4.6 Hz), 7.20-7.
39 (m, 10H). (d) Synthesis of Compound 20-4 Benzoyl chloride (218 mg, 1.2 eq) was added dropwise to a solution of compound 20-3 (1.0628 g) in pyridine (6 ml), and the mixture was stirred at room temperature overnight.

The obtained solution was added to ice water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was separated by 150 ml of silica gel column chromatography. The target product (888 mg) was eluted with a mixed solvent of toluene: ethyl acetate = 3: 1. The target substance could be obtained as crystals. Melting point 46.8-47.3 [deg.] C.

[Α] _D ²² = + 9.5 ° (c 1.02, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.879 (t, 3H,
J = 6.9 Hz), 1.20-1.32 (m, 30H), 1.51-1.55
(M, 2H), 3.421 (t, 2H, J = 6.8 Hz), 3.
54-3.70 (m, 11H), 3.87-3.91 (m, 1H), 4.22
7 (br t, 1H), 4.491 (dd, 1H, J = 6.3
Hz, 11.5Hz), 4.605 (dd, 1H, J = 6.6H
z), 4.771 (dt, 1H, J = 10.3Hz, 3.2H
z), 4.849 (brs, 2H), 5.059 (d, 1H, J
= 3.4 Hz), 7.18-7.62 (m, 13H), 8.04-8.06
(M, 2H). (e) Synthesis of compound 20-5 Compound 20-4 (500 mg) was dissolved by adding methanol (6 ml) and ethyl acetate (4 ml) thereto,
mg) was added and hydrogen reduction was performed overnight at room temperature and atmospheric pressure. After filtering the catalyst, the solution was neutralized with 1N sodium methylate methanol solution. The solution was concentrated under reduced pressure, the residue was dissolved in methanol (2 ml) and benzene (2 ml), sodium methylate (5 mol / l methanol solution, 20 drops) was added, and the mixture was stirred overnight at room temperature.

The solution was neutralized with 1N hydrochloric acid and concentrated under reduced pressure. The residue was dissolved in water (50 ml) and purified with a “CHP-20” column (22 mmφ × 400 mm). Elution was carried out with a linear gradient of water (500 ml) and then 10-90% acetonitrile-water (total gradient solvent 1000 ml, 98 fractions). Fractions 45-51 were concentrated. Water (40m) on the residue
l), H-type acidic ion exchange resin “Dowex 50W ×
8 ”was added and stirred. The resin was filtered off, and the filtrate was freeze-dried to obtain the desired product.

[Α] _D ²⁵ = −6.9 ° (c 1.10, chloroform: methanol: water = 10: 10: 3). ¹³ C-NMR (DMSO-d ₆ , δ): 13.85, 22.03.
, 25.58, 28.6-29.2, 31.23, 60.26, 67.50, 67.
65, 69.41, 69.59, 69.74-69.79, 70.32, 73.15
, 75.04, 75.71 (d, J = 5.8 Hz), 101.19
(D, J = 8.1 Hz). Example 21 The reaction in this example is shown in FIG.

(A) Synthesis of Compound 21-1 A solution of Compound 16-1 (5.200 g) in methanol (20 ml) was added to a solution of sodium methoxide in methanol (5 M / l, 10
(Droplet) was added and the mixture was stirred at room temperature for 5 hours. The resulting solution was neutralized by adding H-type of a strongly acidic ion exchange resin "Dowex 50W × 8". The resin was filtered off, the solvent was evaporated under reduced pressure, dibutyltin oxide (1.766 g) and anhydrous methanol (40 ml) were added to the residue, and the mixture was heated under reflux for 3 hours. After distilling off methanol under atmospheric pressure, benzene (50 ml) was added to the residue.
Was added and residual methanol was distilled off together with benzene. Benzene was further added to the residue and the residue was distilled off twice. Tetrabutylammonium iodide (2.621
g), benzene (30 ml) and allyl bromide (30 ml) were added and the mixture was heated under reflux for 3 hours. The solvent and allyl bromide were distilled off under reduced pressure, and the residue was dissolved with pyridine (20 ml). Benzoyl chloride (5.982 g, 6 times mol) was added dropwise to the resulting solution, and the mixture was stirred overnight.

The obtained solution was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and silica gel column chromatography (hexane: ethyl acetate = 4: 1-3: 1).
And separated to obtain the desired product. 2.050 g, 31.5%.

[Α] _D ²² = + 22.8 ° (c 1.01, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.879 (t, 3H,
J = 6.9 Hz), 1.18-1.33 (m, 30H), 1.52-1.58
(M, 2H), 3.35-3.65 (m, 12H), 3.75-3.80
(M, 1H), 3.834 (dd, 1H, J = 10.0Hz, 3.
4 Hz), 3.95-4.03 (m, 2H), 4.11-4.17 (m,
2H), 4.418 (dd, 1H, J = 6.1 Hz, 11.3H
z), 4.607 (dd, 1H, J = 6.8 Hz), 4.775
(D, 1H, J = 8.1 Hz), 5.045 (brdd, 1
H, J = 17.3Hz), 5.159 (brdd, 1H, J = 1
0.4Hz), 5.504 (dd, 1H, J = 10.4Hz), 5.6
66 (m, 1H, J = 4.9 Hz, 6.3 Hz, 10.5H
z), 5.838 (dd, 1H, J = 0.9 Hz), 7.43-7.
61 (m, 9H), 8.03-8.16 (m, 6H). (b) Synthesis of Compound 21-2 Compound 21-1 (1.6433 g) was mixed with paratoluenesulfonic acid (300 mg), 10% palladium carbon (300 mg) and a mixed solvent of chloroform: methanol: water = 65: 15: 1 (30 ml). ) Was added and the mixture was heated with stirring at 60 ° C. for 10 hours.

The obtained solution was cooled to room temperature and neutralized with triethylamine. The solvent was evaporated under reduced pressure, and the residue was separated by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product. 1.176 g.

[Α] _D ²¹ = 3.2 ° (c 0.94, CHCl
₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.878 (t, 3H,
J = 6.9 Hz), 1.17-1.32 (m, 30H), 1.52-1.58
(M, 2H), 2.742 (d, 1H, J = 5.9 Hz), 3.
408 (t, 2H, J = 6.8 Hz), 3.43-3.68 (m, 10
H), 3.80-3.85 (m, 1H), 4.00-4.05 (m, 1
H), 4.13-4.19 (m, 1H), 4.424 (1H, dd,
J = 6.3 Hz, 11.5 Hz), 4.599 (dd, 1H, J =
6.8 Hz), 4.839 (d, 1H, J = 7.9 Hz), 5.36
0 (dd, 1H, J = 10.0Hz), 5.779 (dd, 1
H, J = 3.5 Hz, 0.9 Hz), 7.41-7.63 (m, 9
H), 8.02-8.17 (m, 6H). (c) Synthesis of Compound 21-3 A solution of Compound 21-2 (811 mg) in pyridine (3 ml) was charged with diphenylphosphoric chloride (745 mg, 3 eq) of pyridine (3 m).
l) The solution was added dropwise and stirred at room temperature for one day.

The obtained solution was added to ice water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was separated by 100 ml of silica gel column chromatography. The target product (0.969 g) was eluted with a mixed solvent of hexane: ethyl acetate = 2: 1.

[Α] _D ²⁵ = + 33.5 ° (c 1.01, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.879 (t, 3H,
J = 6.8 Hz), 1.21-1.32 (m, 30H), 1.51-1.57
(M, 2H), 3.33-3.62 (m, 10H), 3.74-3.79
(M, 1H), 3.95-4.00 (m, 1H), 4.159 (br
t, 1H), 4.407 (dd, 1H, J = 6.1 Hz, 1
1.4Hz), 4.534 (dd, 1H, J = 6.6Hz), 4.81
6 (d, 1H, J = 8.1 Hz), 5.140 (dt, 1H,
J = 9.8 Hz), 5.753 (dd, 1H, J = 10.0H
z), 5.951 (dd, 1H, J = 1.0 Hz), 6.77-7.
64 (m, 19H), 7.99-8.11 (m, 6H). (d) Synthesis of Compound 21-4 Compound 21-3 (514 mg) was dissolved by adding methanol (8 ml) and ethyl acetate (8 ml) to the platinum oxide (55 mg).
mg) was added and hydrogen reduction was carried out at room temperature and atmospheric pressure for 2 days. After filtering the catalyst, the solution was neutralized with 1N sodium methylate methanol solution. The solution was concentrated under reduced pressure, the residue was dissolved in methanol (8 ml), sodium methylate (5 mol / l methanol solution, 15 drops) was added, and the mixture was stirred at room temperature overnight. Further, sodium methylate (5 mol / l methanol solution, 10 drops) was added, and the mixture was stirred at room temperature overnight.

The solution was neutralized with 1N hydrochloric acid and concentrated under reduced pressure. The residue was dissolved in water (50 ml) and purified with a “CHP-20” column (22 mmφ × 400 mm). Elution was carried out with a linear gradient of water (500 ml) and then 10-90% acetonitrile-water (total volume 1000 ml, 113 fractions). Fractions 52-68 were concentrated. Water (40 ml) and H-type acidic ion exchange resin (H-type of “Dowex 50W × 8”) were added to the residue, and the mixture was stirred. The resin was filtered off, and the filtrate was freeze-dried to obtain the desired product.

[Α] _D ¹⁷ = −3.6 ° (c 1.00, CHC
l ₃ ). ¹ H-NMR (DMSO, δ): 0.856 (t, 1H, J
= 6.9 Hz), 1.16-1.31 (m, 30H), 1.44-1.50
(M, 2H), 3.359 (t, 2H, J = 6.6 Hz), 3.
44-3.61 (m, 12H), 3.82-3.92 (m, 3H), 4.18
7 (d, 1H, J = 7.6 Hz). Example 22 The reaction in this example is shown in FIG.

(A) Synthesis of compound 22-1 To 9.45 g of monochloroacetic acid was added 100 ml of a 1.0 M solution of tetra-n-butylammonium hydroxide in methanol to dissolve it, and the solvent was distilled off under reduced pressure. Toluene was added to the residue,
Water was removed azeotropically by distillation under reduced pressure (twice). Thus, a tetra-n-butylammonium salt of monochloroacetic acid was obtained and used as it was in the following reaction.

Dimethylformamimod (200 ml) was added to sodium hydride (purity 60%, 3.20 g) washed with a small amount of hexane three times, and compound 11-5 (11.68 g) was added dropwise. After stirring at room temperature for 3 hours, the above monochloroacetic acid salt was added together with dimethylformamide (20 ml), and the mixture was stirred at room temperature overnight. Benzyl bromide (19.38 g, 1.
7eq) was added, and the mixture was stirred at room temperature for 3 days.

The solution was added with water (700 ml) and ethyl acetate (70
0 ml) was added for extraction. The organic layer was washed twice with water and dried over anhydrous sodium sulfate. The solution was filtered, the solvent was distilled off from the filtrate under reduced pressure, and the residue was separated by silica gel column chromatography (silica gel 2000 ml, hexane: ethyl acetate = 3: 1.25-2: 1) to give the desired product as an oily substance. Obtained. 13.03 g.

¹ H-NMR (CDCl ₃ , δ): 3.66-
3.76 (m, 10H), 3.373 (t, 2H), 4.205 (s,
2H), 5.192 (s, 2H), 7.33-7.37 (m, 5
H). (b) Synthesis of Compound 22-2 A Lindlar catalyst (7 g) was added to a solution of Compound 22-2 (14.00 g) in ethyl acetate (250 ml), and reduction was carried out under a hydrogen atmosphere of 50 psi for 4 hours. Furthermore, Lindlar catalyst (7
g) was added and reduction was carried out under a hydrogen atmosphere of 50 psi for 4 hours. The catalyst was filtered and the filtered catalyst was washed with chloroform. The filtrate and the catalyst washings were collected, the solvent was distilled off under reduced pressure, and the residue was dissolved in methylene chloride (300 ml). Compound 11-4 (synthesized from 11.02 g of compound 11-3) in methylene chloride (150 ml) and triethylamine (6.56)
g) was added, and the mixture was stirred at room temperature for 2 days.

Water was added to the solution for washing. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (silica gel 1000 ml, hexane: ethyl acetate = 2: 1−).
2: 1.5) and the target object was obtained as a white solid. 1
2.694 g.

¹ H-NMR (CDCl ₃ , δ): 0.880
(T, 6H, J = 7.1 Hz), 1.20-1.37 (m, 56
H), 1.54-1.57 (m, 4H), 1.96-2.20 (m, 1)
H), 3.458 (brq, 2H, J = 5.1-5.4 Hz),
3.536 (brt, 2H, J = 4.9-5.1 Hz), 3.59
-3.77 (m, 8H), 4.202 (s, 2H), 5.304
(S, 2H), 6.054 (t, 1H, J = 5.3 Hz), 7.
35-7.37 (m, 5H). (c) Synthesis of Compound 22-3 Compound 22-2 (10.73 g) in tetrahydrofuran (200
10% palladium on carbon (0.6g) was added to the
Reduction was performed for 6 hours under hydrogen atmosphere of i. The catalyst is filtered off,
The solvent was evaporated under reduced pressure, and the residue was separated by silica gel chromatography (silica gel 1000 ml, chloroform: methanol = 100: 3-100: 20) to obtain the desired product. 9.20
2 g.

¹ H-NMR (CDCl ₃ , δ): 0.880
(T, 6H, J = 6.9 Hz), 1.10-1.33 (m, 56
H), 1.33-1.43 (m, 2H), 1.53-1.63 (m, 2)
H), 2.07-2.14 (m, 1H), 3.482 (brq, 2)
H, J = 4.9-5.1 Hz), 3.552 (brt, 2H,
J = 4.9 Hz), 4.166 (2,2H), 6.263 (br
s, 1H). Example 23 The reaction in this example is shown in FIG. 15 (b).

(A) Synthesis of Compound 23-1 Compound 22-2 (720 mg) in tetrahydrofuran (50 ml)
10% Palladium on carbon (0.06 g) was added to the solution, and reduction was carried out under a hydrogen atmosphere of 50 psi for 6 hours. The catalyst was filtered off, and the solvent was distilled off from the filtrate under reduced pressure.
l), N-hydroxysuccinimide (126 mg), dibenzyl L-glutamic acid paratoluenesulfonate (548
mg), dicyclohexylcarbodiimide (207 mg) and triethylamine (120 mg) were added, and the mixture was stirred at room temperature overnight.

Ethyl acetate (10 ml) was added to the residue obtained by evaporating the solvent under reduced pressure, and the insoluble material was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel (silica gel).
The product was separated with 80 ml of hexane: ethyl acetate = 2: 1-1: 1) to obtain the desired product as a white solid. 543 mg.

[Α] _D ¹⁶ = −0.2 ° (c 1.01, CHC
l ₃ ). ¹ HNMR- (CDCl ₃ , δ): 0.879 (t, 6H,
J = 6.9 Hz), 1.16-1.40 (m, 56H), 1.52-1.54
(M, 4H), 1.97-2.20 (m, 1H), 2.09-2.20
(M, 1H), 2.24-2.31 (m, 1H), 2.36-2.50
(M, 2H), 3.39-3.72 (m, 12H), 4.020 (d,
1H, J = 15.9Hz), 4.062 (d, 1H, J = 15.9H)
z), 4.721 (dt, 1H, J = 5.1 Hz, 8.3 H
z), 5.078 (d, 1H, J = 12.2Hz), 5.113
(D, 1H, J = 12.2Hz), 5.161 (s, 2H), 6.
173 (t, 1H, J = 5.6 Hz), 7.398 (d, 1H,
J = 8.3 Hz), 7.29-7.41 (m, 5H). (b) Synthesis of compound 23-2 To compound 23-1 (488.3 mg) was added ethyl acetate (20 ml), methanol (20 ml) and 10% palladium carbon (0.04 g), and reduction was carried out under a hydrogen atmosphere of 50 psi for 5 hours. went. Further, 10% palladium carbon (0.04 g) was added, and reduction was performed for 3 hours under a hydrogen atmosphere of 50 psi.

The catalyst was filtered off, the solvent was evaporated under reduced pressure, and the residue was separated with "LH-20" (22 mm x 400 mm) to obtain the desired product. 301 mg.

¹ H-NMR (CDCl ₃ , δ): 0.880
(T, 6H, J = 6.9 Hz), 1.77-1.33 (m, 56
H), 1.35-1.44 (m, 2H), 1.52-1.62 (m, 2)
H), 1.99-2.05 (m, 1H), 2.15-2.23 (m, 1)
H), 2.27-2.34 (m, 1H), 2.40-2.57 (m, 2)
H), 3.464 (brq, 2H, J = 4.9-5.6 Hz),
3.581 (brt, 2H, J = 5.4 Hz), 3.39-3.72
(M, 8H), 4.051 (s, 2H), 4.61-4.66 (m,
1H), 6.179 (t, 1H, J = 5.7 Hz), 7.645
(D, 1H, J = 7.6 Hz). Example 24 The reaction in this example is shown in FIG.

(A) Synthesis of Compound 24-1 Heptaethylene glycol monocetyl ether (1.0
Diphenylphosphoric acid chloride (731 mg) was added to a solution of g) in pyridine (20 ml), and the mixture was stirred at room temperature overnight.

The solution was added to ice water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The resulting solution was filtered and the solvent was evaporated under reduced pressure. The residue was applied to tricagel column chromatography (silica gel).
The desired product was obtained by separation with 150 ml, 0.5-3.0% methanol-chloroform). 1.3674 g.

¹ H-NMR (CDCl ₃ , δ): 0.880
(T, 3H, J = 6.9 Hz), 1.21-1.33 (m, 26
H), 1.54-1.59 (m, 2H), 3.439 (t, 2H, J
= 6.8 Hz), 3.56-3.66 (m, 24H), 3.728 (dd
d, 2H, J = 1.2, 3.4, 4.6Hz), 4.379 (dd
dd, 2H, J = 3.4, 6.9, 6.1, 8.3 Hz). (b) Synthesis of Compound 24-2 Methanol (20 ml) and platinum oxide (0.08 g) were added to Compound 24-2 (1.401 g), and reduction was performed overnight under a hydrogen atmosphere at normal pressure.

The catalyst was filtered off, the solvent was filtered off under reduced pressure, and the residue was separated with "LH-20" (22 mm x 400 mm, methanol). The solvent was distilled off under reduced pressure, and the residue was treated with methanol (5 m
l), water (0.5 ml) and acidic ion exchange resin "Dowex 50W x 8" were added and stirred. The resin was filtered off, and the filtrate was concentrated to obtain the desired product. 1.0332g.

¹ H-NMR (CDCl ₃ , δ): 0.880
(T, 3H, J = 6.9 Hz), 1.18-1.34 (m, 26
H), 1.54-1.61 (m, 2H), 3.452 (t, 2H, J
= 6.9 Hz), 3.58-3.68 (m, 24H), 3.70-3.72
_{(M, 2H, CH 2)} , 4.177 -4.214 (m, 2H). Example 25 The reaction in this example is shown in FIG.

(A) Synthesis of compound 25-1 2.241 g of β-D-glucose pentaacetate and 3.00 of triethylene glycol mono-n-octadecyl ether
5 g was dissolved in 40 ml of methylene chloride, 1/16 of "Molecular Sieve 4A" was added with a spatula, and the mixture was stirred at room temperature for 30 minutes. This was ice-cooled, 2.8 ml of boron trifluoride diethyl ether complex was dissolved in 5 ml of methylene chloride, and the mixture was added dropwise over 5 minutes. After stirring at room temperature for 12 hours, the mixture was poured into ice water and the organic layer was separated.

After washing with water three times (the water layer became neutral),
The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Dissolve the residue in pyridine and add acetic anhydride.
2.71 ml was added, and the mixture was stirred at room temperature for 21.5 hours. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent: toluene-ethyl acetate 3: 2),
The desired product was obtained as a colorless oily substance (1.683 g).

¹ H-NMR (δ, CDCl ₃ ): 0.88
(T, 3H, J = 7.0 Hz), 1.18-1.33 (m, 30
H), 1.54-1.60 (m, 2H), 2.00 (s, 3H), 2.
02 (s, 3H), 2.05 (s, 3H), 2.09 (s, 3)
H), 3.44 (t, 2H, J = 6.8 Hz), 3.57-3.77
(M, 12H), 3.94 (dt, 1H, J = 4.2 Hz, 10.6
Hz), 4.14 (dd, 1H, J = 2.8 Hz, 12.0H
z), 4.26 (dd, 1H, J = 4.8 Hz, 12.0 Hz),
4.61 (d, 1H, J = 8.0 Hz), 4.99 (dd, 1H,
J = 8.0Hz, 9.8Hz), 5.08 (t, 1H, J = 9.8
Hz), 5.20 (t, 1H, J = 9.8 Hz). [Α] _D ²⁶ = −10.7 ° (c = 1.12, CHCl ₃ ). _Rf : 0.32 (toluene-AcOEt 3: 2). (b) Synthesis of Compound 25-2 50 ml of methanol was added to 1.683 g of Compound 25-1 to dissolve it, and the mixture was stirred under ice cooling. Seven drops of 28% sodium methoxide methanol solution was added thereto to adjust the pH to 10, and the mixture was stirred at room temperature for 12 hours. "Dowex 50WX-8" ion exchange resin (H type) was added thereto for neutralization, and the resin was filtered off. The solvent was evaporated under reduced pressure to give the desired product as a colorless amorphous substance, 1.295 g.
Obtained.

¹ H-NMR (δ, pyridine-d ₅ -D ₂
O): 0.88 (t, 3H, J = 6.8 Hz), 1.22-1.38
(M, 30H), 1.58-1.64 (m, 2H), 3.45 (t, 2)
H, J = 6.5 Hz), 3.59-3.76 (m, 10H), 3.90-
3.95 (m, 2H), 4.02 (t, 1H, J = 8.3 Hz),
4.18-4.28 (m, 3H), 4.34 (dd, 1H, J = 5.5
Hz, 12.0Hz), 4.53 (dd, 1H, J = 2.5Hz,
12.0 Hz), 4.85 (d, 1H, J = 8.0 Hz). [Α] _D ²⁶ = −10.5 ° (c = 1.04, MeOH). _{R f: 0.52 (CHCl 3 -MeOH} -H 2 O 65:15:
1). (c) Synthesis of Compound 25-3 20 ml of pyridine was added to 1.295 g of Compound 25-1 to dissolve it, and the mixture was stirred under ice cooling. 714 μl of diphenylphosphorochloridate was added thereto, and the mixture was stirred at room temperature for 22 hours. This was ice-cooled, benzoyl chloride (1.04 ml) was added, and the mixture was stirred for 1.5 hours. Ethyl acetate was added and the insoluble precipitate was filtered off,
The solvent was distilled off under reduced pressure. Chloroform and distilled water were added, and the mixture was stirred at room temperature for 30 hours.

The organic layer was separated, and the aqueous layer was extracted with chloroform. The combined organic layers were washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate 2: 1) to obtain 1.233 g of the desired product as a colorless viscous oily substance.

¹ H-NMR (δ, CDCl ₃ ): 0.88
(T, 3H, J = 7.1 Hz), 1.18-1.32 (m, 30
H), 1.52-1.63 (m, 2H), 3.38-3.61 (m, 12
H), 3.72 (ddd, 1H, J = 3.6 Hz, 11.1H
z), 3.91 (ddd, 1H, J = 3.6 Hz, 4.6 Hz,
11.1Hz), 4.05-4.08 (m, 1H), 4.40 (ddd,
1H, J = 6.0 Hz, 11.3 Hz, 8.5 Hz), 4.46 (d
dd, J = 2.5 Hz, 11.3 Hz, 7.0 Hz), 4.89
(D, 1H, J = 7.9 Hz), 4.44 (dd, 1H, J =
7.9 Hz, 9.8 Hz), 4.45 (t, 1H, J = 9.8 H)
z), 5.84 (t, 1H, J = 9.8 Hz), 7.13-7.54
(M, 19H), 7.81 (dd, J = 1.5 Hz, 8.5 H
z), 7.90 (dd, J = 1.5 Hz, 8.5 Hz), 7.95
(Dd, J = 1.2 Hz, 8.3 Hz). [Α] _D ²⁵ = + 3.3 ° (c = 1.04, CHCl ₃ -MeO
H 1: 1) _Rf : 0.47 (n-hexane-AcOEt 1: 1). (d) Synthesis of compound 25-4 To 0.498 g of compound 25-3, 4 ml of ethyl acetate and 4 ml of methanol were added and dissolved, and 0.05 g of platinum oxide was added and subjected to catalytic reduction overnight under normal pressure. Further, 0.05 g of platinum oxide was added and the mixture was reduced overnight. The mixture was neutralized with a 28% sodium methoxide methanol solution, and the catalyst was filtered off. The solvent was evaporated under reduced pressure, the residue was dissolved in 10 ml of methanol, 20 drops of 28% sodium methoxide methanol solution was added, and the mixture was stirred at room temperature for 2 days. further
10 drops of 28% sodium methoxide methanol solution was added, and the mixture was stirred at room temperature overnight.

It was neutralized with 1N hydrochloric acid, and the solvent was distilled off under reduced pressure. The residue is a "CHP-20" column (22
mmφ × 400 mm) (elution solvent: gradient from 10% acetonitrile to 90% acetonitrile). Acetonitrile was distilled off under reduced pressure, and the remaining aqueous solution containing the target compound was freeze-dried to give the target compound as colorless amorphous 0.099 g.
Obtained.

¹ H-NMR (δ, DMSO-d ₆ -D ₂
O): 0.86 (t, 3H, J = 6.8 Hz), 1.16-1.29
(M, 30H), 1.47 (quintet, 2H, J = 6.2H
z), 2.97 (br t, 1H), 3.10 (t, 1H, J =
9.0 Hz), 3.16 (t, 1H, J = 9.0 Hz), 3.23−
3.26 (m, 1H), 3.36 (t, 2H, J = 6.6 Hz),
3.49-3.61 (m, 11H), 3.83 (dt, 1H, J = 4.0
Hz, 11.6 Hz), 3.86-3.91 (m, 1H), 4.01-4.
04 (m, 1H), 4.18 (d, 1H, J = 7.8 Hz). ¹³ C-NMR (δ, DMSO-d ₆ ): 13.97, 22.11
, 25.67, 28.71, 28.90, 29.02, 29.23, 31.31
, 64.76 (J = 4.8 Hz), 67.95, 69.44, 69.49
, 69.70, 69.81, 70.37, 73.26, 75.07 (J = 7.5
Hz), 76.11, 103.01. [Α] _D ²⁵ = -12.8 ° (c = 1.03, CHCl ₃ -MeO
H-H2 O 10: 10: . 3) R f: 0.58 (CHCl 3 -MeOH-H 2 O 10:10:
3). FAB-MS [M + H] ⁺ M / Z = 645. Example 26 The reaction in this example is shown in FIG.

(A) Synthesis of Compound 26-1 A trifluoroboron ether complex (4.47 g) was added to a solution of galactose peracetate (2.733 g) and heptaethylene glycol monocetyl ether (5.012 g) in dichloromethane (200 ml) at room temperature. It was stirred overnight at.
The solution was added to ice water and extracted with chloroform. The organic layer was washed twice with saturated aqueous sodium hydrogen carbonate, washed three times with water, and dried over anhydrous sodium sulfate. The solution was filtered, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (silica gel 1000 ml, chloroform: methanol = 100: 1).
The mixture was separated by -100: 2) to obtain 3.13 g of a mixture of the target glycoside and the starting alcohol acetate (acetylheptaethylene glycol monocetyl ether). Incidentally, the molar ratio of the target substance to the by-product was 4: 1 in the NMR spectrum. This mixture is methanol (50 ml)
Was added to the solution, and a 5M / 1 sodium methoxide methanol solution (10 drops) was added, followed by stirring at room temperature overnight. H-type acidic ion exchange resin in solution (H-type of "Dowex 50W x 8")
Was added and stirred, the resin was filtered off, and the filtrate was concentrated. The residue was dissolved in pyridine (40 ml) and trityl chloride (2.48) was added.
7 g) was added and the mixture was stirred at 60 ° C. for 10 hours. The solution was cooled to room temperature, benzoyl chloride (2.0 g) was added, and the mixture was stirred at room temperature overnight. The solution was added to ice water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solution was filtered, the solvent was evaporated under reduced pressure, and the residue was separated by silica gel column chromatography (silica gel 500 ml, hexane: ethyl acetate = 1: 1-1: 2) to obtain the desired product. 2.9066g.

[Α] _D ²¹ = + 43.8 ° (c 1.07, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.878 (t, 3H,
J = 6.9 Hz), 1.17-1.35 (m, 26H), 1.53-1.59
(M, 2H), 3.270 (t, 2H, J = 8.5 Hz), 3.
34-3.69 (m, 28H), 3.76-3.81 (m, 1H), 3.96
-4.01 (m, 1H), 4.06-4.07 (brt, 1H),
4,837 (d, 1H, J = 7.6 Hz), 5.595 (dd, 1
H, J = 3.4 Hz), 5.646 (dd, 1H, J = 10.5H
z), 6.043 (dd, 1H, J = 1.0 Hz), 7.10-7.
60 (m, 24H), 7.78-7.95 (m, 6H). (b) Synthesis of Compound 26-2 Compound 26-1 (2.900 g) was dissolved in a mixed solvent (50 ml) of chloroform: methanol: water = 65: 15: 1, and paratoluenesulfonic acid monohydrate (200 mg) was added. In addition, the mixture was stirred at 50 ° C for 3 hours.

The solution was neutralized with triethylamine, the solvent was distilled off under reduced pressure, and the residue was separated by tricagel column chromatography to obtain the desired product. 1.8236g.

[Α] _D ²⁰ = + 100.9 ° (c 1.03, CH
Cl ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.879 (t, 3H,
J = 7.0 Hz), 1.21-1.31 (m, 26H), 1.54-1.59
(M, 2H), 2.90 (brs, 1H), 3.42-3.69
(M, 29H), 3.81-3.90 (m, 2H), 3.98-4.07
(M, 2H), 4.940 (d, 1H, J = 8.1 Hz), 5.5
79 (dd, 1H, J = 3.4 Hz, 10.5 Hz), 5.805
-5.841 (m, 2H), 7.23-7.64 (m, 9H), 7.80
-8.12 (m, 6H). (c) Synthesis of Compound 26-3 To a solution of Compound 26-2 (1.8200 g) in pyridine (20 ml) was added dropwise diphenylphosphoric acid cloid (715 mg, 1.5 eq), and the mixture was stirred at room temperature overnight.

The solution was added to ice water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solution was filtered, the solvent was evaporated under reduced pressure, and the residue was separated by silica gel column chromatography (silica gel 200 ml, chloroform: methanol = 100: 1) to obtain the desired product. 2.0818 g.

[Α] _D ²⁵ = + 60.7 ° (c 1.16, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ , δ): 0.878 (t, 3H,
J = 6.9 Hz), 1.21-1.31 (m, 26H), 1.53-1.59
(M, 2H), 3.35-3.67 (m, 28H), 3.73-3.77
(M, 1H), 3.95-3.99 (m, 1H), 4.192 (br
t, 1H), 4.357 (ddd, 1H, J = 5.7 Hz,
10.8Hz, 8.2Hz), 4.463 (ddd, 1H, J = 7.
1 Hz, 8.8 Hz), 4.875 (d, 1H, J = 8.1 H
z), 5.513 (dd, 1H, J = 3.4 Hz), 5.739
(Dd, J = 10.5 Hz), 5.878 (brd, 1H), 7.
13-7.62 (m, 19H), 7.77-8.05 (m, 6H). (d) Synthesis of Compound 26-4 Compound 26-3 (501 mg) was dissolved in methanol (8 ml), platinum oxide (50 mg) was added, and hydrogen reduction was carried out at room temperature and atmospheric pressure for 2 days. The catalyst was filtered off and the filtrate was neutralized with 1N sodium methylate methanol solution. The solution was concentrated under reduced pressure, the residue was dissolved in methanol (10 ml), sodium methylate (5 mol / 1 methanol solution, 20 drops) was added, and the mixture was stirred at room temperature for 2 days.

The solution was neutralized with 1N hydrochloric acid and concentrated under reduced pressure. The residue was dissolved in water (50 ml) and purified with a “CHP-20” column (22 mmφ × 400 mm). Elution was carried out with a linear gradient of water (500 ml) and then 20-90% acetonitrile-water (total volume 1000 ml, 102 fractions). Fractions 42-60 were concentrated. Water (40 ml) and H-type acidic ion exchange resin (H-type of “Dowex 50W × 8”) were added to the residue and stirred. The resin was filtered off, and the filtrate was freeze-dried to obtain the desired product.

[Α] _D ²¹ = −3.8 ° (c 1.09, pyridine). ¹³ C-NMR (DMSO-d ₆ ): 13.85, 22.01, 2
5.57, 28.62 −29.14, 31.22, 63.26 (J = 4.3 H
z), 67.60, 67.73, 69.43, 69.67 −69.85, 70.28
, 70.38, 73.03, 73.26 (J = 6.8 Hz), 103.4
6. ¹ H-NMR (DMSO-d ₆ ): 0.858 (t, 3H,
J = 3.7 Hz), 1.18-1.30 (m, 26H), 1.44-1.50
(M, 2H), 3.26-3.29 (m, 2H), 3.361 (t,
2H, J = 6.6 Hz), 3.43-3.61 (m, 28H), 3.67
8 (brs, 1H), 3.73-3.81 (m, 1H), 3.80-
3.85 (m, 1H), 3.86-3.93 (m, 1H), 4.120
(D, 1H, J = 7.1 Hz). Example 27 The reaction in this example is shown in FIG.

(A) Synthesis of compound 27-1 β-D-glucose pentaacetate 6.509 g and 2-
[2- (2-azidoethoxy) ethoxy] ethanol 3.
808 g was dissolved in 50 ml of methylene chloride and stirred under ice cooling.
9.23 ml of boron trifluoride diethyl ether complex was dissolved in 10 ml of methylene chloride and added dropwise over 5 minutes. After stirring at room temperature for 14 hours, the mixture was poured into ice water and the organic layer was separated.

The extract was washed 5 times with saturated saline and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate 1: 1) to obtain 4.462 g of the desired product as a colorless oil.

¹ H-NMR (δ, CDCl ₃ ): 2.01
(S, 3H), 2.03 (s, 3H), 2.05 (s, 3H),
2.09 (s, 3H), 3.41 (t, 2H, J = 5.0 Hz),
3.63-3.78 (m, 10H), 3.93-3.97 (ddd, 1H,
J = 3.9 Hz, 4.9 Hz, 11.2 Hz), 4.14 (dd, 1
H, J = 2.0 Hz, 12.5 Hz), 4.26 (dd, 1H, J
= 5.0 Hz, 12.5 Hz), 4.62 (d, 1H, J = 7.9 H
z), 5.00 (dd, 1H, J = 7.9 Hz, 9.8 Hz),
5.09 (t, J = 9.8 Hz), 5.21 (t, 1H, J = 9.8)
Hz). [Α] _D ²⁰ = -12.1 ° (c = 1.01, CHCl ₃ ). _Rf : 0.20 (n-hexane-AcOEt 1: 1). (b) Synthesis of compound 27-2 50 ml of methanol was added to and dissolved in 4.862 g of compound 27-1. Eight drops of 28% sodium methoxide methanol solution was added to adjust the pH to 10, and the mixture was stirred at room temperature for 12 hours.

[0254] "Dowex 50WX-8" ion exchange resin (H type) was added thereto for neutralization, and the resin was filtered off. The solvent was evaporated under reduced pressure to give the desired product as a pale brown viscous oil.
2.916 g was obtained. It was used in the following reaction without further purification.

R _f : 0.61 (CHCl ₃ -MeOH-H ₂
O 65: 25: 4). (e) Synthesis of compound 27-3 40 ml of pyridine was added to 2.916 g of compound 27-2 to dissolve, and the mixture was stirred under ice cooling. 2.33 ml of diphenylphosphorochloridate was added thereto, and the mixture was stirred at room temperature for 9.5 hours. It was ice-cooled again, 3.91 ml of benzoyl chloride was added, and the mixture was stirred at room temperature for 24 hours.

Ethyl acetate was added to remove insoluble precipitate by filtration,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate 3: 2), and the desired product was a colorless oily substance, 4.315 g.
Obtained.

¹ H-NMR (δ, CDCl ₃ ): 3.31
(T, 2H, J = 5.1 Hz), 3.38-3.40 (m, 2
H), 3.46-3.48 (m, 2H), 3.53 (t, 2H, J =
5.1 Hz) 3.54-3.62 (m, 1H), 3.73 (ddd, 1
H, J = 3.7 Hz, 7.4 Hz, 11.3 Hz), 3.92 (dd
d, 1 GmH = 3.5 Hz, 4.8 Hz, 11.3 Hz), 4.05
-4.09 (m, 1H), 4.41 (ddd, 1H, J = 6.3 H
z, 11.4Hz, 8.6Hz), 4.46 (ddd, 1H, J =
2.6 Hz, 11.4 Hz, 7.2 Hz), 4.90 (d, 1H, J
= 8.1 Hz), 5.45 (dd, 1H, J = 8.1 Hz, 9.8
Hz), 5.45 (t, J = 9.8 Hz), 5.85 (t, 1H,
J = 9.8 Hz), 7.14-7.54 (m, 19H), 7.81 (d
d, 2H, J = 1.0 Hz, 8.3 Hz), 7.89 (dd, 2
H, J = 1.1 Hz, 8.2 Hz), 7.95 (dd, 2H, J
= 1.2 Hz, 8.3 Hz). [Α] _D ²² = + 2.0 ° (c = 1.01, CHCl ₃ ). _Rf : 0.44 (n-hexane-AeOEt 1: 1). (d) Synthesis of Compound 27-4 Compound 27-3 (0.997 g) was dissolved by adding ethyl acetate (50 ml), p-toluenesulfonic acid monohydrate (0.215 g) and Lindlar catalyst (0.498 g) were added thereto, and the mixture was heated at 50 psi for 3.5 hours. Catalytically reduced. Furthermore, 0.498 g of Lindlar catalyst was added,
Catalytic reduction at psi for 4 hours.

The catalyst was filtered off to obtain 1.073 g of the desired product as a pale brown oily substance. It was used in the following reaction without further purification.

(E) Synthesis of compound 27-5 To 1.073 g of compound 27-4, 10 ml of methylene chloride was added and stirred under ice cooling. Triethylamine (146 μl) was added thereto, and the mixture was stirred under ice cooling. 0.480 g of N-palmitoyloxysuccinimide was added to this while heating to room temperature.
It was stirred for 17 hours.

The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluting solvent: n-hexane-
Ethyl acetate 1: 4), 0.78 as the target product as colorless amorphous
6 g were obtained.

¹ H-NMR (δ, CDCl ₃ ): 0.88
(T, 3H, J = 7.0 Hz), 1.19-1.31 (m, 24
H), 1.52-1.60 (m, 2H), 2.12 (t, 2H, J =
7.6 Hz), 3.34-3.43 (m, 6H), 3.46-3.48
(M, 2H), 3.56-3.59 (m, 2H), 3.73 (dd
d, 1H, J = 3.6 Hz, 7.2 Hz, 11.2 Hz), 3.92
(Ddd, 1H, J = 3.5 Hz, 4.8 Hz, 11.2H
z), 4.06-4.10 (m, 1H), 4.41 (ddd, 1H,
J = 6.2 Hz, 11.4 Hz, 8.7 Hz), 4.47 (ddd,
1H, J = 2.6 Hz, 11.4 Hz, 7.5 Hz), 4.90
(D, 1H, J = 7.8 Hz), 5.44 (dd, 1H, J =
7.8 Hz, 9.7 Hz), 5.45 (t, J = 9.7 Hz), 5.
85 (t, 1H, J = 9.7 Hz), 6.05 (brs, 1
H), 7.13-7.54 (m, 19H), 7.81 (dd, 1H, J
= 1.2 Hz, 8.3 Hz), 7.90 (dd, 2H, J = 1.2
Hz, 8.3 Hz), 7.95 (dd, 2H, J = 1.2 Hz,
8.3 Hz). [Α] _D ²⁵ = + 1.0 ° (c = 1.01, CHCl ₃ -MeO
H 1: 1). _Rf : 0.18 (n-hexane-AcOEt 1: 3). (f) Synthesis of Compound 27-6 Compound 27-5 (0.721 g) was dissolved by adding ethyl acetate (5 ml) and methanol (5 ml), and platinum oxide (0.071 g) was added, followed by catalytic reduction for 1 week under normal pressure. The catalyst was filtered off, and the solvent was distilled off under normal pressure. The residue was dissolved in 10 ml of methanol, 20 drops of 28% sodium methoxide methanol solution was added, and the mixture was stirred at room temperature for 3 days.

It was neutralized with 1N hydrochloric acid, and the solvent was distilled off under reduced pressure. It was purified with a “CHP-20” column (22 mmφ × 40 cm) (elution solvent: gradient from distilled water to acetonitrile). Fractions containing the desired product were collected, and the solvent was evaporated under reduced pressure. 50 ml of distilled water was added to the residue to dissolve it, "Dowex 50WX-8" ion exchange resin (H type) was added to neutralize, and the resin was filtered off. The filtrate was freeze-dried to obtain 0.067 g of the target compound as a colorless amorphous substance.

¹ H-NMR (δ, DMSO-d ₆ & D
₂ O): 0.86 (t, 3H, J = 7.0Hz), 1.16-1.29
(M, 24H), 1.44-1.50 (m, 2H), 2.05 (t, 2)
H, J = 7.4 Hz), 2.98 (brt, 1H), 3.05-
3.07 (m, 1H), 3.16 (t, 1H, J = 9.3 Hz),
3.18 (quintet, 2H, J = 5.9 Hz), 3.28 (t, 1
H, J = 9.3 Hz), 3.40 (t, 2H, J = 5.9 H)
z), 3.43 to 3.60 (m, 7H), 3.71 (br t, 1)
H), 3.82 (ddd, 1H, J = 3.1 Hz, 7.1 Hz,
13.9 Hz), 4.00 (dt, J = 3.1 Hz, 11.6 Hz),
4.15 (d, 1H, J = 7.8 Hz), 7.92 (br t, 1
H). ¹³ C-NMR (δ, DMSO-d ₆ ): 13.88, 22.02
, 25.21, 28.62 −31.22, 35.24, 38.39, 63.06
(J = 5.1 Hz), 67.78 −69.66, 68.74, 73.52,
75.61, 76.09 (J = 4.0 Hz), 103.26, 172.20. [Α] _D ²³ = -2.7 ° (c = 0.95, CHCl ₃ -MeO
_{H-H 2 O 10: 10} : 3). R _f : 0.54 (CHCl ₃ —MeOH—H ₂ O 10:10:
3) FAB-MS: [M + H] ⁺ ; M / Z = 630, [M + N
a] ⁺ ; M / Z = 652, [M + 2Na] ⁺ ; M / Z = 674
． Example 28 The reaction in this example is shown in FIG.

(A) Synthesis of Compound 11-4 To 0.745 g of Compound 11-3, 4 ml of thionyl chloride was added, and 5
The mixture was refluxed under heating for an hour. Thionyl chloride was distilled off under reduced pressure,
Benzene was added to the residue and evaporated under reduced pressure (twice). It was used in the following reaction without further purification.

(B) Synthesis of Compound 28-1 To 1.175 g of Compound 27-4, 10 ml of methylene chloride was added and dissolved, and the mixture was stirred under ice cooling. Triethylamine 350 μ
1 was added, and the whole amount of compound 11-4 obtained in (a) was dissolved in 5 ml of methylene chloride and added, and the temperature was raised to room temperature.
Stir for hours.

The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; n-hexane-
Ethyl acetate 1: 1), 1.23 as the desired product as colorless amorphous
2 g was obtained.

¹ H-NMR (δ, CDCl ₃ ): 0.88
(T, 6H, J = 7.0 Hz), 1.18-1.31 (m, 56
H), 1.33-1.41 (m, 2H), 1.52-1.60 (m, 2
H), 1.93-1.99 (m, 1H), 3.33-3.34 (m, 2)
H), 3.37-3.42 (m, 4H), 3.45-3.48 (m, 2)
H), 3.56-3.64 (m, 2H), 3.73 (ddd, 1H,
J = 3.6 Hz, 7.2 Hz, 10.9 Hz), 3.94 (ddd,
1H, J = 3.5 Hz, 4.7 Hz, 11.2 Hz), 4.06-4.
10 (m, 1H), 4.41 (ddd, 1H, J = 6.3 Hz,
11.5Hz, 8.7Hz), 4.47 (ddd, 1H, J = 2.5
Hz, 7.3 Hz, 11.5 Hz), 4.89 (d, 1H, J = 8.
0 Hz), 5.45 (dd, 1H, J = 8.0 Hz, 9.8 H
z), 5.45 (t, J = 9.8 Hz), 5.85 (t, 1H, J
= 9.8 Hz), 5.96 (brs, 1H), 7.13-7.54
(M, 19H), 7.81 (dd, 2H, J = 1.2 Hz, 8.3
Hz), 7.90 (dd, 2H, J = 1.2 Hz, 8.3 H
z), 7.95 (dd, 2H, J = 1.2 Hz, 8.3 Hz). [Α] _D ²⁵ = + 1.3 ° (c = 1.02, CHCl ₃ -MeO
H 1: 1) _Rf : 0.27 (n-hexane-AcOEt 2: 3). (c) Synthesis of Compound 28-2 To 1.216 g of Compound 28-1, 30 ml of tetrahydrofuran and 10 ml of methanol were added and dissolved. Platinum oxide 0.01
5 g was added, and catalytic reduction was carried out under normal pressure for 6 days. The catalyst was filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved by adding 8 ml of benzene and 8 ml of methanol, 22 drops of 28% sodium methoxide methanol solution (pH = 11) was added, and the mixture was stirred at room temperature for 11.5 hours.

It was ice-cooled and neutralized with 1N hydrochloric acid, and the solvent was evaporated under reduced pressure. The residue was purified by "Sepphadex LH-20" column (resin: about 150 ml, elution solvent: chloroform-methanol-water 10: 10: 3). 0.640 g of the target compound was obtained as a colorless powder.

¹ H-NMR (δ, CDCl ₃ -D ₂ O
5: 1): 0.88 (t, 6H, J = 7.0 Hz), 1.16-1.
34 (m, 56H), 1.34-1.44 (m, 2H), 1.46-1.59
(M, 2H), 2.04-2.11 (m, 1H), 3.26-6.36
(M, 19H). ¹³ C-NMR (δ, CDCl ₃ -CD ₃ OD-D ₂ O
10: 10: 3): 14.25, 23.04, 27.83, 29.71, 29.84
, 30.02, 32.30, 33.07, 39.23, 47.78, 63.09
(J = 2.4 Hz), 69.00-70.50, 69.28, 74.12,
75.70, 76.42 (J = 5.5 Hz), 103.55, 178.38. [Α] _D ²⁶ = -14.2 ° (c = 1.05, CHCl ₃ -MeO
H 1: 1). _{R f: 0.44 (CHCl 3 -MeOH} -H 2 O 60:35:
7). FAB-MS: [M + H] ⁺ ; M / Z = 882, [M + N
a] ⁺ ; M / Z = 904. Example 29 The reaction in this example is shown in FIG.

(A) Synthesis of compound 29-2 Compound 29-1, 0.422 g, was dissolved by adding 15 ml of pyridine. Add 0.307 g of sulfur trioxide pyridine complex and add 2 at room temperature.
Stir for half a day. 10 ml of saturated barium hydroxide aqueous solution was added (pH = 10), and then chloroform-methanol (1:
1) 90 ml was added and centrifuged at 3000 rpm for 10 minutes. The supernatant was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Toluene was added and the solvent was evaporated under reduced pressure. Add 20 ml of methanol to suspend (partially dissolve), add 7 drops of 28% sodium methoxide methanol solution (pH = 10), and at room temperature.
Stir for 4.5 hours. As the reaction proceeded, it became a one-phase solution.

100 ml of methanol was added, and "Dowex
50WX-8 "ion exchange resin (H type) is added to neutralize,
The resin was filtered off. Crystals of sodium bicarbonate were added to the filtrate, the mixture was vigorously stirred, and the remaining crystals were filtered off. The solvent was distilled off under reduced pressure. The residue was reprecipitated from methanol-chloroform to obtain 0.199 g of the objective compound as a pale yellow powder.

¹ H-NMR (δ, DMSO-d ₆ ): 0.8
6 (t, 3H, J = 7.0 Hz), 1.20-1.29 (m, 30
H), 1.45 to 1.50 (quintet, 2H, J = 7.0 Hz),
3.25-3.62 (m, 17H), 3.80 (dd, 1H, J = 6.3
Hz, 10.5 Hz), 3.81-3.85 (m, 1H), 3.86 (d
d, 1H, J = 6.0 Hz, 10.5 Hz), 4.11 (d, 1
H, J = 7.6 Hz). ¹³ C-NMR (δ, DMSO-d ₆ ): 14.00, 22.14
−31.33, 65.21, 67.89 −70.40, 68.28, 70.30,
72.90, 73.12, 103.51. [Α] _D ²⁵ = −3.3 ° (c = 1.00, CHCl ₃ —MeO
_{H-H 2 O 10: 10} : 3). R _f : 0.32 (CHCl ₃ —MeOH—H ₂ O 65:25:
4). FAB-MS: [M + H] ⁺ ; M / Z = 667. Example 30 The reaction in this example is shown in FIG.

(A) Synthesis of compound 30-1 Mannose pentaacetate (3.90 g) and 2- [2-
The (2-chloroethoxy) ethoxy] ethyl ether complex (5.68 g) was dissolved in methylene chloride (200 ml), boron trifluoride diethyl ether complex (5.68 g) was added, and the mixture was stirred at room temperature for 5 days.

The reaction solution was diluted with methylene chloride, water, 5%
It was washed successively with NaHCO ₃ water and water, dried and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (chloroform) using silica gel (200 g) to obtain the desired product (4.13 g) as a colorless oil.

[Α] _D + 38.7 ° (c 1.51, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 0.24 (3H, s), 2.1
0 (3H, s), 2.16 (3H, s), 3.63-3.70 (9
H, m), 3.75-3.85 (3H, m), 4.07 (1H, dd
d, J = 2.4 Hz, 5.1 Hz, 10.0 Hz), 4.11 (1
H, dd, J = 2.4H, 12.2Hz), 4.29 (1H, d
d, J = 5.1 Hz, 12.2 Hz), 4.88 (1H, d, J =
1.7 Hz), 5.27 (1 H, dd, J = 1.7 Hz, 3.4 H
z), 5.29 (1H, t, J = 10.0Hz), 5.36 (1H,
dd, J = 3.4 Hz, 10.0 Hz). (b) Synthesis of Compound 30-2 Compound 30-1 (3.68 g) was dissolved in DMF (50 ml), sodium azide (0.72 g) was added, and the mixture was stirred at 60 ° C. for 24 hours.

The reaction solution was diluted with ethyl acetate, washed with water, dried and the solvent was distilled off under reduced pressure. The residue is treated with silica gel (150
g) is used for purification by column chromatography (chloroform-acetone 10: 1) to give an azide compound 30-2.
(3.05 g) was obtained as a colorless oil.

[Α] _D + 35.6 ° (c 2.54, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 1.99 (3H, s), 2.0
4 (3H, s), 2.11 (3H, s), 2.16 (3H,
s), 3.40 (2H, t, J = 5.1 Hz), 3.62-3.86
(10H, m), 4.06 (1H, ddd, J = 2.4 Hz, 4.
9 Hz, 10.0 Hz), 4.10 (1 H, dd, J = 2.4 H)
z, 12.2Hz), 4.29 (1H, dd, J = 4.9Hz, 1
2.2Hz), 4.88 (1H, d, J = 1.5Hz), 5.27
(1H, dd, J = 1.5 Hz, 3.4 Hz), 5.29 (1
H, t, J = 10.0Hz), 5.36 (1H, dd, J = 3.4)
Hz, 10.0 Hz) (c) Synthesis of compound 30-3 Compound 30-2 (386 mg, 0.76 mmol) and p-toluenesulfonic acid (145 mg, 0.76 mmol) are dissolved in ethanol (20 ml), and Lindlar catalyst (770 mg) is dissolved. At room temperature 50 psi
The catalytic reduction was carried out for 7.5 hours. After filtering the catalyst, the filtrate was concentrated under reduced pressure to obtain the desired product.

(D) Synthesis of Compound 30-4 Compound 30-3 (820 mg) and Nt-butoxycarbonyl-γ-benzylglutamic acid-α-N-hydroxysuccinimide ester (547 mg) were added to methylene chloride (40 ml).
, Triethylamine (255 mg) was added, and the mixture was stirred at room temperature for 1 hour.

The reaction solution was diluted with methylene chloride, water, 10%
It was washed successively with citric acid water and water, dried and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using silica gel (60 g) (chloroform-methanol 150:
Purification in 1) yielded the desired product (834 mg).

[Α] _D + 20.9 ° (c 1.87, CHC
l ₃ ). 1 H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 1.8
8-1.96 (1H, m), 1.99 (3H, s), 2.04 (3
H, s), 2.10 (3H, s), 2.15 (3H, s), 2.10
-2.20 (1H, m), 2.40-2.56 (2H, m), 3.46
(H, m), 3.55 (2H, m), 3.58-3.71 (7H,
m), 3.78-3.84 (1H, m), 4.07 (1H, ddd,
J = 2.4 Hz, 4.9 Hz, 10.0 Hz), 4.12 (1H, d
d, J = 2.4 Hz, 12.2 Hz), 4.14-4.20 (1H,
m), 4.28 (1H, dd, J = 4.9Hz, 12.2Hz),
4.88 (1H, d, J = 1.7Hz), 5.12 (2H,
s), 5.27 (1H, dd, J = 1.7 Hz, 3.4 Hz),
5.30 (1H, t, J = 10.0Hz), 5.36 (1H, dd,
J = 3.4 Hz, 10.0 Hz), 6.58 (1 H, m), 7.32-
7.37 (5H, m). (e) Synthesis of Compound 30-5 Compound 30-4 (810 mg) was dissolved in ethanol (30 ml), 10% Pd-C (300 mg) was added, and catalytic reduction was carried out at room temperature of 40 psi for 4 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain the desired product.

(F) Synthesis of compound 30-6 Compound 30-5 (226 mg) was dissolved in methylene chloride (20 ml), and N-hydroxysuccinimide (37 mlg) and N, N 'were added.
-Dicyclohexylcarbodiimide (66 mg) was added, and the mixture was stirred at room temperature for 20 hours. Compound 7-4 (244m
g) and triethylamine (65 mg) were added, and the mixture was stirred at room temperature for 4 hours.

The insoluble matter was filtered off, the filtrate was diluted with chloroform, washed successively with water, 5% aqueous NaHCO ₃ solution, water, 10% aqueous citric acid solution and water. After drying, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (chloroform-methanol 25: 1) using silica gel (40 g) to obtain the target compound (308 mg).

[Α] _D + 6.8 ° (c 1.93, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 1.8
5 (3H, s), 1.99 (3H, s), 2.04 (3H,
s), 2.04 (3H, s), 2.04 (3H, s), 2.10 (3
H, s), 2.14 (3H, s), 2.16 (3H, s), 2.18
(3H, s), 2.24-2.39 (2H, m), 2.66 (1H,
dd, J = 4.6 Hz, 12.7 Hz), 3.37-3.70 (22H,
m), 3.80 (3H, s), 3.74-3.90 (2H, m), 4.
00-4.22 (6H, m), 4.28 (1H, dd, J = 4.9H
z, 12.2Hz), 4.36 (1H, dd, J = 2.7Hz, 1
2.5Hz), 4.87 (1H, d, J = 1.7Hz), 4.89-
4.96 (1H, m), 5.26 (1H, dd, J = 1.7 Hz,
3.4 Hz), 5.29 (1H, t, J = 10.0 Hz), 5.32-
5.37 (2H, m), 5.39 (1H, m), 5.55 (1H,
d). Example 31 The reaction in this example is shown in FIG.

(A) Synthesis of compound 31-2α Tetraacetate compound 31-1 (10.16 g) obtained by treating L-fucose with acetic anhydride and pyridine
[2- (2-Chloroethoxy) ethoxy] ethanol (10.31 g) was dissolved in methylene chloride (300 ml), boron trifluoride diethyl ether complex (17.36 g) was added, and the mixture was stirred at room temperature for 25 hours. Dilute the reaction solution with methylene chloride,
It was washed successively with water, 5% NaHCO ₃ water and water, dried and the solvent was distilled off under reduced pressure. The residue was dissolved in pyridine (26 ml), acetic anhydride (20 ml) was added, and the mixture was stirred at room temperature for 15 hr.

The reaction mixture was diluted with ethyl acetate, washed with water, 5
% NaHCO ₃ water, water, 10% citric acid water and water in this order, and after drying, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform) using silica gel (250 g) to obtain α-glycoside compound 31-2α.
(4.40 g) and β-glycoside compound 31-2β (1.79)
g) was obtained as a colorless oil.

Α-Glycoside compound 31-2α: [α] _D -112.3 ° (c 0.96, CHCl ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, d, J =
6.6 Hz), 1.99 (3H, s), 2.08 (3H, s), 2.
17 (3H, s), 3.62-3.84 (12H, m), 4.23 (1
H, q, J = 6.6 Hz, 5.11 (1 H, d, J = 3.7 H)
z), 5.12 (1H, dd, J = 3.7 Hz, 10.0 Hz),
5.30 (1H, d, J = 3.4 Hz), 5.37 (1H, dd,
J = 3.4 Hz, 10.0 Hz). (b) Synthesis of compound 31-3 Chloride compound 31-2α (3.56 g) was dissolved in DMF (50 ml), sodium azide (1.05 g) was added, and the mixture was stirred at 70 ° C for 2 hours.
It was stirred for a day.

The reaction solution was diluted with ethyl acetate, washed with water, dried and the solvent was distilled off under reduced pressure. The residue is treated with silica gel (100
The product was purified by column chromatography (chloroform) using g) to obtain the desired product (2.98 g) as a colorless oil.

[Α] _D −113.7 ° (c 0.96, CHCl
₃ ). ¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, d, J =
6.6 Hz), 1.99 (3H, s), 2.07 (3H, s), 2.
16 (3H, s), 3.40 (2H, t, J = 5.0 Hz), 3.
62-3.70 (9H, m), 3.78-3.84 (1H, m), 4.23
(1H, dq, J = 1.2 Hz, 6.6 Hz), 5.10 (1
H, d, J = 3.7 Hz), 5.12 (1H, dd, J = 3.7)
Hz), 5.30 (1 H, dd, J = 1.2 Hz, 3.4 H
z), 5.37 (1H, dd, J = 3.4 Hz, 10.3 Hz). (c) Synthesis of compound 31-4 Azide compound 31-3 (2.21 g) and p-toluenesulfonic acid (0.94 g) were dissolved in ethanol (100 ml), Lindlar catalyst (4.40 g) was added, and room temperature was 50 psi. The catalytic reduction was performed for 7 hours.

After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain the desired product (2.84 g) as a colorless oily substance.

(D) Synthesis of Compound 31-5 Amine compound 31-4 (637 mg) and Nt-butoxycarbonyl-γ-benzylglutamic acid-α-N-hydroxysuccinimide ester (466 mg) were added to methylene chloride (30 ml). , Ethyl acetate (217 mg) was added, and the mixture was stirred at room temperature for 3.5 hours.

The reaction solution was diluted with methylene chloride, and water, 10%
It was washed successively with citric acid water and water, dried and the solvent was distilled off under reduced pressure. Column chromatography of the residue using silica gel (50 g) (chloroform-methanol 100: 1)
And the target compound (689 mg) was obtained as a colorless oil.

[Α] _D −52.1 ° (c 1.80, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, d, J =
6.6 Hz), 1.43 (9H, s), 1.88-1.96 (1H,
m), 1.99 (3H, s), 2.07 (3H, s), 2.16 (3
H, s), 2.10-2.20 (1H, m), 2.40-2.56 (2
H, m), 3.42-3.48 (2H, m), 3.54 (2H,
m), 3.56-3.68 (7H, m), 3.76-3.83 (1H,
m), 4.14-4.22 (1H, m), 4.23 (1H, dq, J
= 1.0 Hz, 6.6 Hz), 5.09-5.14 (4H, m), 5.
29 (1H, dd, J = 1.0 Hz, 3.4 Hz), 5.37 (1
H, dd, J = 3.4 Hz, 10.3 Hz), 6.60 (1 H,
m). (e) Synthesis of compound 31-6 Benzyl ester compound 31-5 (546 mg) was dissolved in ethanol (20 ml), 10% Pd-C (200 mg) was added,
Catalytic reduction was carried out at room temperature of 40 psi for 4 hours. After filtering off the catalyst,
The filtrate was concentrated under reduced pressure to obtain the desired product (546 mg).

(F) Synthesis of compound 31-7 Carboxylic acid 31-6 (232 mg) was dissolved in methylene chloride (20 ml), and N-hydroxysuccinimide (41 mg) and N,
N'-Dicyclohexylcarbodiimide (74 mg) was added, and the mixture was stirred at room temperature for 4.5 hours. Amine compound 7-4 (273 mg) dissolved in methylene chloride (15 ml) in the reaction mixture
And triethylamine (72 mg) were added, and the mixture was stirred at room temperature for 4 hours.

The insoluble matter was filtered off, the filtrate was diluted with chloroform, washed successively with water, 5% NaHCO ₃ water, water, 10% citric acid water and water, dried and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform-methanol 25: 1) using silica gel (50 g) to obtain the target compound (295 mg).

[Α] _D −36.7 ° (c 1.00, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, d, J =
6.6 Hz), 1.43 (9H, s), 1.85 (3H, s), 1.
99 (3H, s), 2.03 (3H, s), 2.04 (3H,
s), 2.07 (3H, s), 2.13 (3H, s), 2.14 (3
H, s), 2.17 (3H, s), 2.24-2.39 (2H,
m), 2.67 (1H, dd, J = 4.6 Hz, 12.7H
z), 3.37-3.70 (22H, m), 3.80 (3H, s), 3.
76-3.89 (2H, m), 4.00-4.12 (3H, m), 4.14
-4.22 (1H, m), 4.22 (1H, dq, J = 1.0 H
z, 6.6 Hz), 4.37 (1H, dd, J = 2.7 Hz, 1
2.5Hz), 4.92 (1H, m), 5.11 (1H, d, J =
3.7 Hz, 5.11 (1H, dd, J = 3.7 Hz, 10.0H
z), 5.29 (1H, dd, J = 1.0 Hz, 3.4 Hz),
5.34 (1H, m), 5.36-5.42 (2H, m), 5.59 (1
H, d), 5.66 (1H, d). (g) Synthesis of compound 31-8 Compound 31-7 (146 mg) was dissolved in methanol (2 ml) and 28% sodium methoxide methanol solution (20 μm) was added.
1) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated to dryness under reduced pressure, 0.1 N NaOH aqueous solution (4 ml) was added to the residue, and the mixture was stirred at room temperature for 2 hours.

"Amberlite IRC-50" was added to the reaction solution, the insoluble matter was filtered off, and the filtrate was concentrated to dryness under reduced pressure. A mixed solvent of chloroform-methanol 1: 1 was added to the residue, the insoluble material was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was washed with ether to obtain the target compound (88 mg) as a colorless powder.

[Α] _D −34.7 ° (C 0.78, MeO
H). ¹ H-NMR (CD ₃ OD) δ: 1.21 (3 H, d, J =
6.6 Hz), 1.44 (9H, s), 1.85-1.94 (1H,
m), 2.01 (3H, s), 1.97-2.06 (1H, m), 2.
31 (2H, m), 2.85 (1H, dd, J = 4.2 Hz, 1
2.2 Hz). Example 32 The reaction in this example is shown in FIG.

(A) Synthesis of Compound 32-1 Compound 31-7 (150 mg) was added to trifluoroacetic acid (2
ml) was added and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain the target compound. This product was used in the next reaction without purification.

(B) Synthesis of Compound 32-2 Carboxylic acid 31-6 (78 mg) was dissolved in methylene chloride (10 ml) to prepare N-hydroxysuccinimide (14 mg) and N, N.
-Dicyclohexylcarbodiimide (25 mg) was added, and the mixture was stirred at room temperature for 5 hours. Methylene chloride (15 ml) in the reaction mixture
The amine compound 32-1 dissolved in and triethylamine were added, and the mixture was stirred at room temperature for 24 hours.

The insoluble matter was removed by filtration, the filtrate was diluted with chloroform, and water, 5% NaHCO ₃ water, water, 10% citric acid water,
And successively washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform-methanol 25: 1) using silica gel (30 g),
The target compound (130 mg) was obtained as a colorless oil.

[Α] _D −38.5 ° (c 0.88, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ) δ: 1.14 (6H, d, J =
6.5 Hz), 1.42 (9H, s), 1.85 (3H, s), 1.
99 (6H, s, CH ₃ CO × 2), 2.04 (3H, s, C
H ₃ CO), 2.04 (3H, s, CH ₃ CO), 2.07 (3
H, s, CH ₃ CO), 2.08 (3H, s), 2.14 (3
H, s), 2.14 (3H, s), 2.17 (3H, s), 2.17
(3H, s), 2.24-2.44 (4H, m), 2.66 (1H,
dd, J = 4.6 Hz, 12.7 Hz), 3.32-3.70 (33 H,
m), 3.81 (3H, s), 3.76-3.89 (3H, m), 4.
03-4.15 (4H, m), 4.18-4.25 (2H, m), 4.39
(1H, dd, J = 2.0 Hz, 11.5 Hz 9, 4.43-4.50
(1H, m), 4.92 (1H, m), 5.09-5.14 (4H,
m), 5.28-5.32 (2H, m), 5.33-5.40 (4H,
m). (c) Synthesis of Compound 32-3 Compound 32-2 (116 mg) was dissolved in methanol (2 ml), and 28% sodium methoxide methanol solution (20 μm was added.
1) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure, 0.1 N NaOH aqueous solution (4 ml) was added to the residue,
Stir at room temperature for 4 hours.

"Amberlite IRC-50" was added to the reaction solution, the insoluble material was filtered off, and the filtrate was concentrated to dryness under reduced pressure. A mixed solvent of chloroform-methanol 1: 1 was added to the residue, the insoluble material was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was washed with ether to obtain the target compound (80 mg) as a colorless powder.

[Α] _D −30.4 ° (C 1.05, MeO
H). ¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J =
6.5 Hz), 1.44 (9H, s), 2.02 (3H, s), 2.
85 (1H, dd, J = 4.4 Hz, 12.2 Hz). Example 33 The reaction in this example is shown in FIG.

(A) 2- (Trimethylsilyl) ethyl O −
(Methyl 5-Acetamido-4,7,8,9-tetra-
O −acetyl−3.5 −dideoxy −D −glycero −α−D −
galacto-2-nonulopyranosylonate) (2 → 3)-
2,4-di-O-acetyl-6-O-benzoyl-β-D-g
Synthesis of alactopyranoside (Compound 33-1) J. Carbohydrate Chemistry, 8 (2), 265-283 (198
It was synthesized as described in 9).

(B) Synthesis of Compound 33-2 Compound 33-1 (2.00 g) was dissolved in methylene chloride (30 ml), boron trifluoride diethyl ether complex (1.30 ml) was added, and the mixture was stirred at 0 ° C. for 5 hours. did. The reaction mixture was diluted with methylene chloride, washed with saturated aqueous sodium hydrogen carbonate solution, dried and the solvent was evaporated under reduced pressure. Then, the obtained residue was dissolved in methylene chloride (15 ml), trichloroacetonitrile (5 ml) and 1,8-diazabicyclo [5.4.0]-
Add 7-undensen (160 μl) sequentially and add 30 ° C at 0 ° C.
Stir for minutes.

The reaction solution was concentrated under reduced pressure and then purified by column chromatography using silica gel (90 g) (methylene chloride-methanol 50: 1) to obtain the desired compound (1.
83 g) was obtained as a mixture of α and β of 1: 1. In addition,
¹ H-NMR displays ¹ H for each of α and β as ¹ H.

¹ H-NMR (CDCl ₃ ) δ: 8.67, 8.6
2 (each s), 8.03-7.99 (4H, m), 7.57-7.52
(2H, m), 7.44-7.38 (4H, m), 6.56 (1H,
d, J = 3.9 Hz), 5.99 (1H, d, J = 8.3 H)
z), 5.57 (1H, ddd, J = 8.8, 6.1, 2.4H
z), 5.47 (1H, ddd, J = 9.5, 4.2, 3.2H
z), 5.38-5.29 (5H, m), 5.14 (1H, d, J =
3.4 Hz), 5.11 (1H, d, J = 10.0), 5.07 (1
H, dd, J = 10.3, 3.4 Hz), 5.06 (1H, d, J
= 10.5Hz), 4.93 (1H, ddd, J = 12.3, 10.5,
4.7 Hz), 4.89 (1H, ddd, 12.3, 10.5, 4.6 H
z), 4.79 (1H, dd, J = 10.3, 3.4 Hz), 4.58
(1H, dd, J = 6.8, 6.4 Hz), 4.45-4.36 (3
H, m), 4.28-4.17 (4H, m), 4.12 (1H, d
d, J = 12.5, 4.2 Hz), 4.05 (1H, m), 4.02-
3.94 (2H, m), 3.75 (1H, dd, J = 10.7,2.2
Hz), 3.65 (1H, dd, J = 10.7, 2.7 Hz), 2.
61 (1H, dd, J = 12.9, 4.6 Hz), 2.51 (1H,
dd, J = 12.7, 4.6 Hz), 1.73 (1H, dd, J =
12.7, 12.3Hz), 1.71 (1H, dd, J = 12.9, 12.3
Hz), 3.79, 3.78, 2.18, 2.15, 2.13, 2.13, 2.11,
2.04, 2.03, 2.01, 2.00, 1.87, 1.85, (each 3H,
s). (c) Synthesis of Compound 33-3 Compound 33-2 (300 mg) and 2- [2-] in methylene chloride (10 ml) containing "Molecular Sieves 4A" (4 g).
(2-azidoethoxy) ethoxy] ethanol (160mg
) Was dissolved and the mixture was stirred at room temperature for 2 hours, then boron trifluoride diethyl ether complex (112 μl) was added at 0 ° C., and the mixture was stirred at the same temperature for 1 hour.

The reaction solution was filtered through Celite, the filtrate was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using silica gel (20 g) (toluene-acetone 3: 1) to obtain the target compound (219 mg) as a colorless oil.

[Α] _D ²⁷ -17.0 ° (c 1.03, CHCl
₃ ). IR (CHCl ₃ ): 1744, 1690 cm ⁻¹ . ¹ H-NMR (CDCl ₃ ) δ: 8.03 (2H, d, J =
7.0 Hz), 7.57 (1H, m), 7.44 (1H, m), 5.
56 (1H, ddd, 9.3, 5.4, 2.7 Hz), 5.38 (1
H, dd, 9.3, 2.7), 5.09 (1H, br.d, J =
11.5Hz), 5.07 (1H, dd, J = 10.3, 8.1H
z), 5.06 (1H, br.d), 4.89 (1H, m), 4.
69 (1H, d, J = 8.1 Hz), 4.61 (1H, dd, J
= 10.3, 3.4Hz), 4.43 (1H, dd, J = 11.2, 6.6)
Hz), 4.35 (1H, dd, J = 12.7, 2.7 Hz),
4.22 (1H, dd, 11.2, 6.8 Hz), 4.08-3.98 (4
H, m), 3.77 (1H, m), 3.77 (3H, s), 3.71
-3.61 (9H, m), 3.39 (2H, t, J = 5.0H
z), 2.59 (1H, dd, J = 12.7, 4.6 Hz), 1.72
(1H, dd, J = 12.7, 12.3Hz), 2.22, 2.13, 2.
12, 2.09, 2.06, 2.01, 1.86 (each 3H, s). (d) Synthesis of Compound 33-4 Compound 33-3 (90 mg) and paratoluenesulfonic acid (17.5
Lindlar catalyst (70 mg) was added to a solution of methanol (5 ml) in which (mg) was dissolved, and the mixture was stirred at room temperature under a medium-pressure hydrogen stream (50 psi) for 2 hours. Subsequently, the same catalyst (70 mg) was further added, and the mixture was stirred under the same conditions for 1 hour.

After removing the catalyst from the reaction solution by filtration, the filtrate was concentrated under reduced pressure to obtain the desired compound (103 mg) as a crude product.

(E) Synthesis of compound 33-5 Compound 31-6 (71 mg) was dissolved in methylene chloride (1.5 ml), and N-hydroxysuccinimide (12.5 mg) and N, N 'were added.
-Dicyclohexylcarbodiimide (22.5 mg) was added,
Stirred at 0 ° C. for 3 hours. Compound 33-4 (10
A methylene chloride (1.5 ml) solution in which 3 mg) and triethylamine (13 μl) were dissolved was added, and the mixture was stirred at room temperature for 4 hours.

The insoluble material was filtered off, the filtrate was diluted with methylene chloride, washed with saturated brine, dried and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using silica gel (20 g) (methylene chloride-methanol 25: 1) to obtain the target compound (96 mg) as a colorless oil.

[Α] _D ²⁷ -38.6 ° (c 1.05, CHCl
₃ ). IR (CHCl ₃ ): 1744, 1690 cm ⁻¹ . ¹ H-NMR (CDCl ₃ ) δ: 8.03 (2H, d, J =
8.0 Hz), 7.57 (1H, m), 6.77 (1H, br.
s), 5.71 (1H, br.d, J = 7.3 Hz), 5.56
(1H, ddd, J = 9.3, 5.6, 2.7 Hz), 5.37
(1H, dd, J = 9.3, 2.7 Hz), 5.35 (1H, d
d, J = 10.5, 3.4 Hz), 5.29 (1H, dd, J = 3.
4, 1.2 Hz), 5.16 (1H, d, 10.3 Hz), 5.13-
5.10 (2H, m), 5.06 (1H, d, J = 3.2 Hz),
5.05 (1H, dd, J = 10.3, 8.0 Hz), 4.90 (1
H, ddd, J = 12.3, 10.5, 4.6 Hz), 4.67 (1
H, d, J = 8.1 Hz), 4.61 (1H, dd, J = 10.
3,3.4 Hz), 4.44 (1H, dd, J = 11.0,6.6H
z), 4.36 (1H, dd, J = 12.2, 2.7 Hz), 4.21
(1H, dd, J = 11.0, 6.9 Hz), 4.21 (1H,
m), 4.12 (1H, m), 4.07-3.97 (4H, m), 3.
80 (2H, m), 3.69-3.54 (18H, m), 3.51-3.40
(4H, m), 2.69 (1H, dd, J = 12.7, 4.6 H
z), 2.35 (1H, m), 2.27 (1H, m), 1.71 (1
H, dd, J = 12.7, 12.3 Hz), 1.13 (3H, d, J
= 6.6 Hz), 3.77, 2.22, 2.16, 2.13, 2.12, 2.09,
2.07, 2.05, 2.01, 1.99, 1.85 (each 3H, s), 1.
43 (9H, s). (f) Synthesis of compound 33-6 A solution of compound 33-5 (60 mg) in methanol (1 ml) dissolved in 3% sodium methoxide-methanol solution (20
0 μl) was added, and the mixture was stirred at room temperature for 2 hours. "Amberlite IRC-50" was added to the reaction solution, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Then, a 0.1 N sodium hydroxide aqueous solution (1 ml) was added to the obtained residue and the mixture was stirred at room temperature for 3 hours.

Then, neutralization with "Amberlite IRC-50", filtration of insoluble matter, concentration of the filtrate under reduced pressure, and purification by column chromatography (methanol) using "Sephadex LH-20" (45 g). Thus, the target compound (37 mg) was obtained as a white powder.

[Α] _D ²⁷ -18.2 ° (c 0.53, MeO
H). ¹ H-NMR (D ₂ O) δ: 4.87 (1 H, d, J = 3.7
Hz), 4.47 (1H, d, J = 7.8 Hz), 4.10-4.03
(2H, m), 3.98-3.52 (37H, m), 3.43-3.35
(3H, m), 2.73 (1H, dd, J = 12.3, 4.6 H
z), 2.34 (2H, m), 2.02 (1H, m), 2.01 (3
H, s), 1.88 (1H, m), 1.79 (1H, dd, J =
12.3, 12.0Hz), 1.41 (9H, s), 1.19 (3H,
d, J = 6.6 Hz). Test Example 1 (Water Solubility Test) The compound represented by the following structural formula A was not dissolved at all in a chloroform-methanol solvent, but the compound of the present invention represented by the following structural formula B was Despite being large, it easily dissolved in the same solvent at a concentration of 10 mg / ml. Thus, by introducing the polyethylene glycol part into the compound, the solubility could be improved.

[0316]

[Chemical 5] Example 34 (Preparation of fine particle carrier) L-α-dipalmitoylphosphatidylcholine 80 μmo
l, cholesterol 80 μmol, and compounds 3-8, 4-
3, 7-6 or 8-2, 16 µmol was dissolved in a mixed solution of chloroform and methanol (volume ratio 1: 1). Next, the organic solvent was removed in a nitrogen gas stream to form a lipid film on the glass wall of the centrifuge tube.

Here, ³ H-inulin preheated to 45 ° C.
Add 8 ml of 1 mM inulin phosphate-buffered saline (pH 7.4; sometimes abbreviated as PBS hereinafter) containing 5.29 MBq (160 μCi), shake at a temperature of about 50 ° C, and shake lightly. A liposome suspension was prepared by sonication. This is heated to 60 ℃, 0.2 μm, 0.1 μm and 0.
It was passed through a polycarbonate membrane filter having a pore size of 08 μm in order to prepare a liposome suspension having a particle size of about 0.08 μm.

Then, this was subjected to ultracentrifugation three times (10 times for the first time).
14 hours ⁵ × g, 2 h 2 and the third time 10 ⁵ × g), to remove the inulin was not retained in the liposomes by removing the supernatant, the total amount added to PBS 6 ml
4 types of liposome suspensions were obtained.

Further, a liposome suspension having a total amount of 6 ml was obtained in the same manner as described above without compounding. This was used as a control liposome.

Test Example 2 (Drug Delivery Ability of Microparticle Carrier) a. Test method The 5 samples prepared in Example 34 were each injected from the hindlimb vein of SD male rats (body weight: 200 to 250 g) in an amount of 5 μmol as a total of L-α-dipalmitoylphosphatidylcholine and cholesterol per 100 g of body weight. did.

Approximately 0.2 ml of blood was collected from the jugular vein at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours and 6 hours after administration, and 0.1 ml of plasma was collected on a filter paper after centrifugation and dried on a combustion device. Then, the radioactivity was determined by liquid scintillation method. Rats were sacrificed 6 hours after the administration, various tissues (about 200 mg each) were dried, burned in a burning device, and the radioactivity was determined by liquid scintillation method.
The inulin concentration per gram was determined.

B. Results and Discussion As shown in FIG. 26, the concentration in the spleen was decreased in all of the compounds 3-8, 4-3, 7-6 and 8-2 compared with the control, and therefore these compounds were It was clarified that all liposomes having circadian circumscription avoid the reticuloendothelial system tissue.

[0323]

EFFECTS OF THE INVENTION The conventional fine particle carrier has been trapped in the reticuloendothelial tissue and has a short residence time in blood. The fine particle carrier coated with the lipid derivative having an acidic functional group of the present invention is not easily trapped by the reticuloendothelial system tissue and is useful as a drug carrier.

[Brief description of drawings]

FIG. 1 shows the reactions in Examples 1 and 2.

FIG. 2 shows the reactions in Examples 3 and 4.

FIG. 3 shows the reaction in Example 5.

FIG. 4 shows the reaction in Example 6.

FIG. 5 shows the reactions in Examples 7 and 8.

FIG. 6 shows the reactions in Examples 9 and 10.

FIG. 7 shows the reaction in Example 11.

FIG. 8 shows the reaction in Example 12.

FIG. 9 shows the reaction in Example 13.

FIG. 10 shows the reaction in Examples 14 and 15.

FIG. 11 shows the reaction in Example 16.

FIG. 12 shows the reactions in Examples 17 and 18.

FIG. 13 shows the reactions in Examples 19 and 20.

FIG. 14 shows the reaction in Example 21.

FIG. 15 shows the reaction in Examples 22 and 23.

16 shows the reaction in Example 24. FIG.

FIG. 17 shows the reaction in Example 25.

FIG. 18 shows the reaction in Example 26.

FIG. 19 shows the reaction in Example 27.

FIG. 20 shows the reaction in Example 28.

FIG. 21 shows the reaction in Example 29.

22 shows the reaction in Example 30. FIG.

23 shows the reaction in Example 31. FIG.

FIG. 24 shows the reaction in Example 32.

FIG. 25 shows the reaction in Example 33.

FIG. 26 shows the results of inspection example 2.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Jun Sasaki 4-19-13 Kasuga, Tsukuba, Ibaraki Prefecture Eisai Shiyama Dormitory (72) Inventor Naoichi Murahashi 7-2-4 Matsumaedai, Moriya-cho, Kitasoma-gun, Ibaraki ( 72) Inventor Masahiro Sakagami 4-4-4 Meihara, Kashiwa City, Chiba Imperial Residence 102

Claims (10)

[Claims] 1. A polyethylene glycol chain having a degree of polymerization of ethylene glycol of 3 or more is added with one or more compounds having an acidic functional group at one end and one or more carbon atoms having 5 or more carbon atoms at the other end. A lipid derivative having an acidic functional group, which is formed by adding a compound having an alkyl group and / or an alkenyl group. 2. The lipid derivative having an acidic functional group according to claim 1, wherein the compound having an acidic functional group is a sugar having an acidic functional group. 3. The lipid derivative having an acidic functional group according to claim 2, wherein the sugar having an acidic functional group is one or more sugars selected from galactose, fucose, mannose, glucose and derivatives thereof. 4. The acidic functional group according to claim 1, wherein the compound having the acidic functional group is a compound having one or more of sialic acid and uronic acid in the molecule, or sialic acid or uronic acid. A lipid derivative having 5. The compound having an acidic functional group is phosphoric acid,
Compounds having a phosphoric acid residue, sulfuric acid, compounds having a sulfuric acid residue, phosphenic acid, phosphonic acid, sulfonic acid,
A lipid derivative having an acidic functional group according to any one of claims 1 to 3, which is sulfinic acid, sulfenic acid, or a carboxylic acid. 6. The acidic functional group is a phosphoric acid residue, a sulfuric acid residue,
The lipid derivative having an acidic functional group according to claim 1, which is a phosphonyl group, a phosphonyl group, a sulfonyl group, a sulfinyl group, a sulfenyl group or a carboxyl group. 7. The degree of polymerization of the polyethylene glycol is 3.
The lipid derivative having an acidic functional group according to any one of claims 1 to 6, which is -10. 8. An alkyl group added to the other end and /
Alternatively, the lipid derivative having an acidic functional group according to claim 1, which has two alkenyl groups. 9. A fine particle carrier coated with the lipid derivative having an acidic functional group according to claim 1. 10. The fine particle carrier according to claim 9, wherein the fine particle carrier is a liposome.